AER 7.2

Arrhythmia & Electrophysiology Review Volume 7 • Issue 2 • Summer 2018

Volume 7 • Issue 2 • Summer 2018

www.AERjournal.com

Risk Factor Management in Atrial Fibrillation Axel Brandes, Marcelle D Smit, Bao Oanh Nguyen, Michiel Rienstra and Isabelle C Van Gelder

Treatment of Atrial Fibrillation in Patients with Co-existing Heart Failure and Reduced Ejection Fraction: Time to Revisit the Management Guidelines?

Alex Baher and Nassir Marrouche

Sudden Cardiac Death and Arrhythmias Neil T Srinivasan and Richard J Schilling

Pharmacological Therapy in Brugada Syndrome

A Illustration of normal conduction

Oholi Tovia Brodie, Yoav Michowitz and Bernard Belhassen

AV node Fibres predestined for left bundle branch

His bundle

Myocardium Bundle branches

CENTRAL TRIGGERS

Fibres predestined for right bundle branch

Visceral afferents Sympathetic efferents

Vagus efferents

SOMATIC AND VISCERAL TRIGGERS

Vagus afferents

Response to hypotension

Pace maker

A

CPP Syncope

Blood Pressure

Proximal left bundle branch block bypassed by pacing lead positioned distal to site of block

A SUDDEN BRADYCARDIA/ ASYSTOLE Example of RDR functioning as a simple rate hysteresis device

B

RATE DROP RESPONSE

CLOSED LOOP STIMULATION • RV impedence measurement reflective of RV contractility

• ↓ in HR detected Pacing for Vasovagal Physiology, Technology AV • Abruptly ↑ HR by pacing (AV sequential) at a Syncope and Potentialnode of His higher rate • CLS algorithm ↑pacing rate Bundle Pacing Distal site of

HR ↓ Vasodepression (VD)

Syncope

C

Proximal site of left bundle branch block VASODILATATION

BRADYCARDIA/ ASYSTOLE

Vasodepression (VD)

Blood Pressure

CPP

Blood vessels

Mechanoreceptors

BRADYCARDIA/ ASYSTOLE RESPONSE TO VVS TRIGGER

Blood Pressure

AV node

Lower extremity

SPLANCHNIC VASODILATATION

B

AV Node node

Vasodepression (VD)

SLOWER ONSET BRADYCARDIA + PROMINENT VD Example of RDR introducing pacing late and possibly inefficiently

C EARLY ONSET OF VD Detected by CLS algorithm

CPP Syncope

Stratifying Risk AV in Patients nodeSyndrome with Brugada Distal left bundle branch block overcome by electrical remote activation.

Consider: higher outputs, source-sink or virtual electrode theories

left bundle Abort syncope branch block

HR ↓

ISSN – 2050-3369

D Reversal due to close proximity to high septal branch

Radcliffe Cardiology

AV node

AV node

bundle branch block Lifelong Learning for CardiovascularLeft Professionals

Left bundle branch block AER 7.2 FC + Spine.indd All Pages

Septal branch of bundle

overcome by pacing lead in close proximity to high septal branch, with initial retrograde activation back up branch before 11/06/2018 23:28 facilitating antegrade conduction beyond block

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Further Insight, Further Efficiency in mapping all your complex arrhythmias *In a single center study, after the first ablation set **Compared to the focal ablation catheter §Ischemic ventricular tachycardia in a single center study 1. Luther. V. et al. A Prospective Study of Ripple Mapping in Atrial Tachycardias. CIRCEP. 2016 2. Body Surface Morphology Matching Pre-Clinical Evidence Report. Test report: REP9819. June 2017 3. Imanli, H. et al, A Novel CARTO® Segmentation Software for Contrast enhanced Computed Tomography guided radiofrequency ablation in patients with atrial fibrillation. HRS poster. 2016 4. Jaïs, P. et al. Impact of New Technologies and Approaches for Post–Myocardial Infarction Ventricular Tachycardia Ablation During Long-Term Follow-Up. Circep. 2016 These products can only be used by healthcare professionals in EMEA. Important information: Prior to use, refer to the instructions for use supplied with this device for indications, contra-indications, side effects, warnings and precautions.

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Volume 7 • Issue 2 • Summer 2018

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

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, UK

John Hopkins Medical Institution, Baltimore, USA

Fondazione Cardiocentro Ticino, Lugano, Switzerland

Charles Antzelevitch

Warren Jackman

Mark O’Neill

Lankenau Institute for Medical Research, Wynnewood, USA

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

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

Uppsala University, Uppsala, Sweden

Pierre Jaïs

IRCCS Policlinico San Donato, Milan, Italy

Johannes Brachmann

University of Bordeaux, CHU Bordeaux, France

Carina Blomström-Lundqvist

Carlo Pappone Sunny Po

Klinikum Coburg, II Med Klinik, Germany

Prapa Kanagaratnam

Pedro Brugada

Imperial College Healthcare NHS Trust, London, UK

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

University of Brussels, UZ-Brussel-VUB, Belgium

Josef Kautzner

Antonio Raviele

Josep Brugada,

Institute for Clinical and Experimental Medicine, Prague, Czech Republic

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

Karl-Heinz Kuck

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

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

Asklepios Klinik St Georg, Hamburg, Germany

Alfred Buxton

Pier Lambiase

Beth Israel Deaconess Medical Center, Boston, USA

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

David J Callans University of Pennsylvania, Philadelphia, USA

Samuel Lévy

A John Camm

Aix-Marseille University, France

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

Richard Schilling Barts Health NHS Trust, London, UK

St George’s University of London, UK

Cecilia Linde

Riccardo Cappato

Karolinska University, Stockholm, Sweden

William Stevenson Vanderbilt School of Medicine, USA

Richard Sutton

IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy

Gregory YH Lip

Ken Ellenbogen

University of Birmingham, UK

National Heart and Lung Institute, Imperial College London, UK

Virginia Commonwealth University, Richmond, VA, USA

Francis Marchlinski

Panos Vardas

Sabine Ernst

University of Pennsylvania Health System, Philadelphia, USA

Heraklion University Hospital, Greece

Royal Brompton and Harefield NHS Foundation Trust, London, UK

John Miller

Marc A Vos

Indiana University School of Medicine, USA

University Medical Center Utrecht, The Netherlands

Hein Heidbuchel

Fred Morady

Hein Wellens

Antwerp University and University Hospital, Antwerp, Belgium

Cardiovascular Center, University of Michigan, USA

University of Maastricht, The Netherlands

Gerhard Hindricks

Sanjiv M Narayan

Katja Zeppenfeld

Stanford University Medical Center, USA

Leiden University Medical Center, The Netherlands

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, USA

University of Leipzig, Germany

Carsten W Israel JW Goethe University, Germany

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

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

Cover images www.stock.adobe.com | Cover design Tatiana Losinska

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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 that of the author(s) and do not necessarily reflect or represent the views and opinions of Radcliffe Cardiology.

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Established: October 2012

Aims and Scope • Arrhythmia & Electrophysiology Review aims to assist time-pressured physicians to keep abreast of key advances and opinion in the arrhythmia and electrophysiology sphere.

• Arrhythmia & Electrophysiology Review comprises balanced and comprehensive articles written by leading authorities, addressing the most pertinent developments in the field.

• Arrhythmia & Electrophysiology Review provides comprehensive updates on a range of salient issues to support physicians in continuously developing their knowledge and effectiveness in day-to-day clinical practice.

• The journal endeavours, through its timely teaching reviews, to support the continuous medical education of both specialist and general cardiologists, and disseminate knowledge of the field to the wider cardiovascular community.

Structure and Format • Arrhythmia & Electrophysiology Review is a quarterly journal comprising review articles and editorials.

• The structure and degree of coverage assigned to each category of the journal is the decision of the Editor-in-Chief, with the support of the Section Editors and Editorial Board.

• Articles are fully referenced, providing a comprehensive review of existing knowledge and opinion.

• Each edition of Arrhythmia & Electrophysiology Review is replicated in full online at www.AERjournal.com

Frequency: Quarterly

Current Issue: Summer 2018

• Once the authors have amended a manuscript in accordance with the reviewers’ comments, the manuscript is returned to the reviewers to ensure the revised version meets their quality expectations.

Once approved, the manuscript is sent to the Editor-in-Chief for final approval prior to publication.

Submissions and Instructions to Authors • Contributors are identified by the Editor-in-Chief with the support of the Section Editors and Managing Editor, and guidance from the Editorial Board.

• Following acceptance of an invitation, the author(s) and Managing Editor, in conjunction with the Editor-in-Chief, formalise the working title and scope of the article.

• Subsequently, the Managing Editor provides an ‘Instructions to Authors’ document and additional submission details.

• The journal is always keen to hear from leading authorities wishing to discuss potential submissions, and will give due consideration to any proposals. Please contact the Rita Som for further details at rita.som@radcliffe-group.com. The ‘Instructions to Authors’ information is available for download 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 and www.radcliffecardiology.com.

Also available at www.radcliffecardiology.com are other journals within Radcliffe Cardiology’s portfolio: Interventional Cardiology Review, Cardiac Failure Review, European Cardiology Review and US Cardiology Review. n

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

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

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Radcliffe Cardiology Arrhythmia & Electrophysiology Review is part of the Radcliffe Cardiology family.

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Contents

Foreword

74

Evolution of the Editorial Board Underpins the Integrity of Arrhythmia and Electrophysiology Review Demosthenes Katritsis, Editor-in-Chief

Editorial

76

Pacing in Vasovagal Syncope Richard Sutton

Expert Opinions

77

Second-Degree Atrioventricular Block: Conceptions and Misconceptions

79

Risk Stratification in Brugada Syndrome: Current Status and Emerging Approaches

Demosthenes G Katritsis Shohreh Honarbakhsh, Rui Providencia and Pier D Lambiase

Electrophysiology and Ablation

84

Atrial Fibrillation Ablation in Patients with Heart Failure: One Size Does Not Fit All

91

Treatment of Atrial Fibrillation in Patients with Coexisting Heart Failure and Reduced Ejection Fraction: Time to Revisit the Management Guidelines?

Rahul K Mukherjee, Steven E Williams, Steven A Niederer and Mark D O’Neill

Alex Baher and Nassir Marrouche

Cardiac Pacing

95 103

Pacing for Vasovagal Syncope Rakesh Gopinathannair, Benjamin C Salgado and Brian Olshansky

His Bundle Pacing: A New Frontier in the Treatment of Heart Failure Nadine Ali, Daniel Keene, Ahran Arnold, Matthew Shun-Shin, Zachary I Whinnett and SM Afzal Sohaib

Arrhythmias

111

Sudden Cardiac Death and Arrhythmias

118

Risk Factor Management in Atrial Fibrillation

128

Premature Ventricular Complex-induced Cardiomyopathy

Neil T Srinivasan and Richard J Schilling Axel Brandes, Marcelle D Smit, Bao Oanh Nguyen, Michiel Rienstra and Isabelle C Van Gelder Jorge G Panizo, Sergio Barra, Greg Mellor, Patrick Heck and Sharad Agarwal

Drugs and Devices

135

Pharmacological Therapy in Brugada Syndrome Oholi Tovia Brodie, Yoav Michowitz and Bernard Belhassen

Letters

143

The Cost of Hybrid Treatment for Atrial Fibrillation

143

Authors’ Reply: The Cost of Hybrid Treatment for Atrial Fibrillation

144

Origins of Ablation of Bradyarrhythmias

144

Authors’ Reply: Origins of Ablation of Bradyarrhythmias

145

New Information on Asymptomatic Pre-excitation

145

Authors’ Reply: New Information on Asymptomatic Pre-excitation

72

AER_7.2 CONT.indd 72

George Paxinos Vincent Umbrain, Mark La Meir and Carlo De Asmundis JC Pachon Stavros Stavrakis and Sunny Po Eleftherios Giazitzoglou Josep Brugada and Roberto Keegan

© RADCLIFFE CARDIOLOGY 2018

12/06/2018 08:04

Cardiology

Lifelong Learning for Cardiovascular Professionals

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

www.ECRjournal.com

Resistant Hypertension: A Real Entity Requiring Special Treatment?

Stefano Taddei and Rosa Maria Bruno

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

Rocio Hinojar, Eike Nagel and Valentina O Puntmann

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

Volume 13 • Issue 1 • Spring 2018

Atrial Fibrillation, Cognitive Decline and Dementia

Volume 12 • Issue 1 • Spring 2018

Interventional Cardiology Review Volume 13 • Issue 1 • Spring 2018

European Cardiology Review Volume 11 • Issue 1 • Summer 2016

Volume 11 • Issue 1 • Summer 2016

Alvaro Alonso and Antonio P Arenas de Larriva

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

Transcatheter Treatment of Functional Tricuspid Regurgitation Using the Trialign Device

Artery

Christian Besler, Christopher U Meduri and Philipp Lurz

Vein Arterioles

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

Understanding Neurologic Complications Following TAVR Mohammed Imran Ghare and Alexandra Lansky

J

K

ISSN: 1758-3756

I

L

T1 mapping using the modified look-locker sequence

Meshal Soni, MD and Edo Y Birati, MD

Fulminant Myocarditis: A Review of the Current Literature

Adventitial progenitor

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

Smooth muscle cell

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

Pericyte

Endothelial cell

Catheter Ablation for Ventricular Tachycardia in Patients with Structural Heart Disease

Pericyte-derived MSC

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

Collagen

Carlo De Innocentiis, Marco Zimarino and Raffaele De Caterina

www.USCjournal.com

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

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

Venules Capillaries

E

Volume 12 • Issue 1 • Spring 2018

Adventitia-derived MSC

Sagittal fused PET/ CT showing increased FDG uptake

A

Origin of potential stem cells

B

Radcliffe Cardiology

ISSN: 1756-1477

A

Transthoracic crossclamping using a transthoracic (Chitwood) clamp

29/07/2016 00:08

B

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

ISSN: 1758-3896 • eISSN: 1758-390X

Lifelong Learning for Cardiovascular Professionals

ECR11.1_FC+Spine.indd All Pages

C

D

Transcatheter Treatment of Severe Tricuspid Regurgitation With the Trialign Device

Heart valve surgery for removing expandable transcatheter aortic valve implantation

Anatomic location and sensing vectors of the subcutaneous implantable cardioverterdefibrillator system

Radcliffe Cardiology

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Lifelong Learning for Cardiovascular Professionals

ICR 13.1_FC + Spine.indd All Pages

18/01/2018 23:22

USC 12.1 FC MOCK.indd All Pages

www.ECRjournal.com www.AERjournal.com

A4 RC PRODUCTS AD 2018.indd 143

X-ray showing the correct placement of catheter ablation for atrial fibrillation

02/03/2018 15:03

www.ICRjournal.com

www.CFRjournal.com

www.USCjournal.com

07/03/2018 02:11

Foreword

Evolution of the Editorial Board Underpins the Integrity of Arrhythmia and Electrophysiology Review

S

ince the inauguration of the journal in 2012, the Editorial Board has been one of its strengths. Highly esteemed colleagues in the field of electrophysiology and arrhythmia, in general, have honoured us by participating in the Editorial

Board and actively contributing to the scientific status of Arrhythmia and Electrophysiology Review (AER) by submitting their work, reviewing papers, encouraging colleagues and reflecting upon our continually evolving faculty.

In a previous editorial, I have reflected upon our institutional policy to renew the

Editorial Board at predetermined time intervals.1 This should allow us to include new motivated colleagues, and deliver long-standing members from the time-consuming tasks emanating from their commitment. In this context, I am more than happy â&#x20AC;&#x201C; honoured â&#x20AC;&#x201C; to announce two important additions: Hugh Calkins has agreed to serve as Section Editor for Clinical Electrophysiology and Ablation, replacing KarlHeinz Kuck who will, of course, remain a member of the Editorial Board, and Prapa Kanagaratnam has joined the new Editorial Board. Neither of them needs any introduction, both being world-class experts at the frontiers of clinical cardiac electrophysiology.

AER is indebted to Karl-Heinz for his invaluable support and encouragement all these years, and I remain

confident he will continue his valued work as a member of the Editorial Board. n Demosthenes G Katritsis Editor-in-Chief, Arrhythmia and Electrophysiology Review Hygeia Hospital, Athens, Greece

1.

Katritsis DG. A Renovated Editorial Board. Arrhythmia & Electrophysiology Review 2017;6(4):151. https://doi.org/10.15420/aer.2017.6.4.151.

https://doi.org/10.15420/aer.2018.7.2.FO1

74

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Editorials

Pacing in Vasovagal Syncope Richard Sutton

Citation: Arrhythmia & Electrophysiology Review 2018;7(2):76. https://doi.org/10.15420/aer.2018.7.2.ED1 Correspondence: Richard Sutton, Emeritus Professor of Clinical Cardiology, National Heart & Lung Institute, Imperial College London, London, UK. E: r.sutton@imperial.ac.uk

T

he critical issues for pacing in vasovagal syncope (VVS) are timing of onset, mode of pacing, stimulation rate, duration of stimulation and identifying patients that will receive sufficient benefit to justify such invasive permanent therapy. Research to date has answered none of these questions.

Timing of Onset VVS manifests vasodepression (probably better stated as low venous return and, thus, low cardiac output), which usually precedes cardioinhibition – vagally mediated. In this knowledge, waiting for bradycardia will trigger pacing too late in the evolution of VVS. Earlier delivery of pacing might be better and can be triggered by rising right ventricular impedance reflecting falling venous return, this function is available as the Closed Loop System (Biotronik). A welldesigned randomised controlled trial is now ongoing. If successful, this trial will beg the question of how does pacing work in VVS – just by avoiding bradycardia?

Mode of Pacing Consensus favours dual-chamber pacing and there is evidence suggesting that both right atrial and right ventricular pacing alone are inadequate.

Stimulation Rate The rate drop response (RDR) algorithm (Medtronic) introduced higher-rate (~100 BPM) hysteresis-type pacing for a programmable period (~60 sec) as used in the ISSUE-3 study (Pacemaker Therapy in Patients with Neurally-Mediated Syncope and Documented Asystole.

Third International Study on Syncope of Uncertain Etiology (ISSUE-3): A Randomized Trial study). As this algorithm has had some success

76

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AER 7.2_Sutton_FINAL.indd 76

(ISSUE-3) despite its handicap of waiting for bradycardia, perhaps this aspect has some value?

Duration of Stimulation In RDR, the duration of stimulation is programmable, typically ~60 seconds, and is terminated by rate step-down to ~70 BPM to meet the recovering sinus rhythm. This aspect of the algorithm has received little study.

Which Patients May Benefit Sufficiently to Balance the Aggression of the Therapy?

Emphasis to date has been on older patients, which is reasonable considering that their tolerance for trauma (induced by falls) is not good, epidemiologically their attacks increase in frequency and their therapy time is reduced, which limit long-term complications. We know that some young patients, even those who are highly symptomatic, have recovered fully to present no clinical need for pacing. Older patients (usually >60 years) must be symptomatic to be considered for pacing, involving more than two attacks in the previous 2 years and severe attacks, often without warning, prompting traumatic falls and frequently associated with incontinence of urine and abnormal movements during attacks. These latter features tend to reflect asystole in the attack. It would be useful to know how helpful these criteria are for selection of pacing in older patients and affecting outcomes when applied to younger patients. These decisions are currently clinical with little evidence base, especially in younger patients.

This brief commentary accompanies a very detailed review of VVS by Gopinathannair and Olshansky (page 95). The points raised here are referenced in that review. n

© RADCLIFFE CARDIOLOGY 2018

09/06/2018 14:19

Expert Opinion

Second-degree Atrioventricular Block: Conceptions and Misconceptions Demosthenes G Katritsis Hygeia Hospital, Athens, Greece

Keywords Atrioventricular block, type I block, type II block, QRS complex, His-Purkinje Disclosure: The author has no conflicts of interest to declare.

Received: 11 April 2018 Accepted: 11 April 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(2):77–8. https://doi.org/10.15420/aer.2018.7.2.EO1 Correspondence: Demosthenes G Katritsis, Hygeia Hospital, Erithrou Stavrous 4, Athens 15123, Greece. E: dkatrits@dgkatritsis.gr

Since its first description by Hays in England in 1906, second-degree atrioventricular (AV) block has been a fascinating clinical entity, mainly due to obscure points regarding its diagnosis that emanate from misconceptions and errors regarding its proper definition.1–3 The practicing clinician should be aware of the following points that may assist a proper diagnosis and, consequently, accurate identification of patients in need of a pacemaker.

1. Not all blocks are due to conduction system disease. Non-conducted atrial premature beats may mimic AV block. Concealed His bundle or ventricular extrasystoles confined to the specialised conduction system without myocardial depolarisation can also produce electrocardiographic patterns that mimic a type I and/or type II

block (pseudo-AV block). Occasionally, retrograde P waves may be present. Thus, AV block due to concealed junctional beats that might represent activity of a pathway inserting into the AV junction may require catheter ablation rather than a pacemaker for therapy.4 2. The diagnosis of a type II block cannot be established if the first post-block P wave is followed by a shortened PR interval or is not discernible.

3. An apparent narrow QRS type II block may be a type I block with miniscule increments of the PR interval.

4. A 2:1 AV block is not necessarily a type II block; it can be nodal or infranodal.2,3 It can be high grade if the sinus rate is low or even a normal response of the AV node to an atrial tachycardia or flutter.

Figure 1: Phase 3 Conduction Block and Mechanism for Phase 4 Block A

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source

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+ –

3 sink

+ + +30mV 2

+

– – –90mV

2 sink

1

D

+

– – –90mV

2

1 source

2

+

+ –

sink

+

+

–

– 3

Left: Phase 3 conduction block. Impulse conduction is shown from the His bundle (region 1), to more distal regions in the bundle branches (regions 2 and 3), indicated by the arrows. The cycle length is abruptly decreased at the large downward arrow causing 2:1 block of conduction. Block occurs because impulses from region 1 reach region 2 before it has sufficiently repolarised and is still in early phase 3, generating only a small non-conducted depolarisation (dashed arrows). Source: Reproduced with permission from Cardiotext Publishing from Wit AL, Wellins HJ, Josephson ME, Electrophysiological Foundations of Cardiac Arrhythmias, Minneapolis, MN: Cardiotext; 2017.6 Right: Mechanism for phase 4 block. Action potentials are shown in four contiguous regions in the His-Purkinje system (A–D), with A representing the proximal His bundle. Propagation from one region to the next is indicated by the arrows. Source: Shenasa et al., 2017.5 Reproduced with permission from Wiley. © 2017 Wiley Periodicals, Inc.

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Expert Opinion 5. If the PR is >300 ms, the block is in the AV node. If the PR is <160 ms, the block is in the bundle of His or bundle branches.1 6. A pattern resembling a narrow QRS type II block in association with an obvious type I structure in the same recording effectively rules out a type II block, because the coexistence of both types of narrow QRS block is exceedingly rare.

7. If the QRS complex demonstrates bundle branch block, the site of conduction can be anywhere in the AV conduction system. If the QRS complex is normal, the block is in the AV node or bundle of His, whereas a type I block with bundle branch block barring acute myocardial infarction is infranodal in 60–70 % of cases.2,3 8. If the conduction improves with atropine or exercise, or worsens with carotid sinus massage, the block is in the AV node. If the conduction worsens with atropine or exercise, or improves with carotid sinus massage, the block is in the bundle of His or branches.1

1.

2.

3.

Josephson ME, Wellens HJJ. Episodic dizziness in a 74-yearold woman. Heart Rhythm. 2014;11:2329–30. https://doi. org/10.1016/j.hrthm.2014.08.018; PMID: 25454060.

Barold SS, Hays DL. Second-degree atrioventricular block: a reappraisal. Mayo Clin Proc. 2001;76:44–57. https://doi. org/10.4065/76.1.44; PMID: 11155413.

Katritsis DG, Gersh BJ, Camm AJ. Atrioventricular and Intraventricular Block. Clinical Cardiology. Oxford

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4.

5.

9.

Although the diagnosis of a type II block is possible with an increasing sinus rate, the absence of sinus slowing is an important criterion of a type II block, because a vagal surge can cause simultaneous sinus slowing and AV nodal block, which can superficially resemble a type II block. Significant PR prolongation before and after a block, and prolonged PP intervals during ventricular asystole are indicative of vagal block that is a benign condition rather than paroxysmal AV block; that is, pause- or bradycardia-dependent phase 4 AV block, which is potentially dangerous for syncope.5 Phase 4 AV block occurs mostly in the diseased His-Purkinje system, when an impulse enters the system during phase 4 diastolic depolarisation (Figure 1).

10.

Phase 3 AV block, which involves conduction block of early premature impulses in myocardium that is refractory because of phase 3 repolarisation, is a physiological phenomenon that is often due to a high atrial rate (Figure 1). 5,6 n

University Press, 2016; 724–35. https://doi.org/10.1093/ med/9780199685288.001.0001.

Tuohy S, Saliba W, Pai M, Tchou P. Catheter ablation as a treatment of atrioventricular block. Heart Rhythm. 2018;15: 90–6. https://doi.org/10.1016/j.hrthm.2017.08.015; PMID: 28823599.

Shenasa M, Josephson ME, Wott AL. Paroxysmal atrioventricular block: Electrophysiological mechanism

6.

of phase 4 conduction block in the His-Purkinje system: A comparison with phase 3 block. Pacing Clin Electrophysiol.

2017;40:1234–41. https://doi.org/10.1111/pace.13187; PMID: 28846146.

Wit AL, Wellens HJ, Josephson ME. Electrophysiological Foundations of Cardiac Arrhythmias: A Bridge Between Basic Mechanisms and Clinical Electrophysiology. Minneapolis, MN: Cardiotext, 2017.

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Expert Opinion

Risk Stratification in Brugada Syndrome: Current Status and Emerging Approaches Shohreh Honarbakhsh, Rui Providencia and Pier D Lambiase Barts Heart Centre, St Bartholomew’s Hospital, London, UK

Abstract Brugada syndrome (BrS) is one of the most common inherited channelopathies associated with an increased risk of sudden cardiac death.

Appropriate use of an ICD in high-risk patients is life-saving. However, there remains a lack of consensus on risk stratification, and even on the diagnosis of BrS itself. Some argue that people with a type 1 Brugada ECG pattern but no symptoms should not be diagnosed with BrS, and guidelines recommend observation without therapy in these patients. Others argue that the presence of a spontaneous (rather than drug-induced) type 1 ECG pattern alone is enough to label them as high-risk for arrhythmic events, particularly if syncope is also present. Syncope and a spontaneous type 1 ECG pattern are the only factors that have consistently been shown to predict ventricular arrhythmic events and sudden cardiac death. Other markers have yielded conflicting data. However, in combination they may have roles in risk scoring models. Epicardial catheter ablation in the right ventricular outflow tract has shown promise in studies as an alternative management option to an ICD, but longer follow-up is required to ensure that the ablation effect is permanent.

Keywords Brugada syndrome, sudden cardiac death, arrhythmia, risk stratification, implantable cardioverter-defibrillator Disclosure: Pier Lambiase receives educational and research grants from Boston Scientific. Shohreh Honarbakhsh receives a British Heart Foundation project grant (grant number PG/16/10/32016).

Received: 18 January 2018 Accepted: 22 March 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(2):79–83. https://doi.org/10.15420/aer.2018.2.2 Correspondence: Professor Pier D Lambiase, Institute of Cardiovascular Science, University College London, The Barts Heart Centre, St Bartholomew’s Hospital, West Smithfield, London EC1A 7BE, UK. E: p.lambiase@ucl.ac.uk

Brugada syndrome (BrS) remains one of the most common inherited channelopathies associated with an increased risk of sudden cardiac death (SCD), with a worldwide prevalence of approximately 0.05 %.1–3 It is accepted that appropriate utilisation of the ICD in high-risk patients with aborted SCD and haemodynamically compromising arrhythmias is life-saving. However, there remains a lack of consensus on the management of patients with BrS and no history of ventricular arrhythmias or aborted SCD, especially in the context of a resting type 1 coved ECG pattern. The current guidelines and consensus statement recommend ICD implantation in patients with BrS with spontaneous type 1 ECG pattern and probable arrhythmia-related syncope, the latter being heavily dependent on the quality of the syncope history.4,5 This recommendation is based on several studies that demonstrated a higher risk of arrhythmic events in such patients compared to those without these factors present.2,3,6,7 However, whether other clinical factors are better predictors or facilitate more refined risk stratification before any arrhythmic event is still up for debate. This is especially important as the first clinical event may be cardiac arrest. Indeed, the recent Survey on Arrhythmic Events in BrS (SABRUS) study, which specifically evaluated patients presenting with a lethal arrhythmic event, found that 25 % of patients did not reach the current ICD implantation criteria.8

Brugada ECG Pattern or BrS Before refining risk stratification strategies, it is important to clarify what establishes a diagnosis of BrS. The guideline defines it as the presence of a type 1 Brugada ECG pattern, whether drug-induced or spontaneous.4,5 However, others argue that, without the presence of

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symptoms, the ECG features only indicate the presence of a Brugada pattern ECG and not the syndrome itself. This argument stems from the fact that the yearly cardiac event rate is only 0.5 % in these patients, compared with 1.9 % in patients with a history of syncope.3 With the annual risk of death from any cause being around 0.4 % in the middleaged male population most commonly affected,9 the additional risk of BrS-induced cardiac arrest appears minimal in the asymptomatic population.10 Therefore, it can be argued that labelling patients with only a type 1 Brugada ECG pattern and no symptoms as having a syndrome, and proposing that they are at a significantly enhanced risk of SCD, might be inappropriate. Offering advice on the aggressive treatment of a fever, avoidance of type 1 ECG pattern-provoking drugs and offering review in the presence of symptoms may be sufficient for this cohort of patients. This is supported by the up-to-date guideline, which provides a class I recommendation for observation without therapy in these patients.4 However, there is a spectrum of risk. Sacher et al. showed that 12 % of BrS patients who were asymptomatic at ICD implantation had appropriate ICD therapy during a 10-year follow-up period.10 Furthermore, the presence of a spontaneous type 1 ECG pattern alone has been shown to be associated with a lower cumulative survival,2 a doubled risk of arrhythmic events3,11,12 and shorter time to first arrhythmic event3 compared with a drug-induced type 1 ECG pattern. Therefore, the diagnosis of an isolated Brugada ECG pattern should potentially be restricted to those patients with a drug-induced type 1 ECG pattern and exclude those with a spontaneous type 1 ECG pattern. Furthermore, as the presence of both a spontaneous type 1

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Expert Opinion ECG pattern and syncope is associated with a significantly higher risk of cardiac arrest compared with a spontaneous type 1 ECG pattern alone, those with the former should potentially be labelled as a highrisk group and those with the latter as an intermediate-risk group.3

programmed electrical stimulation and genetic mutation testing in the risk stratification of these patients would not be strongly recommended on a population level unless there is a particularly malignant family history or specific highly arrhythmogenic mutations.

Ajmaline Testing

ECG Markers with Promising Predictive Value

Another area that requires clarification is the use of ajmaline testing.

Ajmaline is used to provoke a type 1 Brugada ECG pattern. Along the same lines as already discussed, the presence of a provoked type 1 ECG pattern in the absence of symptoms is not associated with a significant risk of SCD: 0.3 % over 3 years.3 This raises the question whether performing this investigation is appropriate if it will not result in a change in patient management yet might lead not only to enhanced patient anxiety but also to unnecessary risk associated with ajmaline testing. This is of particular importance as studies have reported high rates of concealed type 1 Brugada ECG pattern in asymptomatic patients;13 should all of these patients be labelled with a syndrome that has life-long implications?

The presence of a type 1 Brugada pattern in peripheral leads,18 early repolarisation (ER),19–22 aVR sign23 and S-wave in lead 1,17 and fragmented QRS24 (Figure 1) have been associated with an increased risk of ventricular arrhythmia occurrence during follow-up. However, as these factors have not been consistently assessed in a range of studies, it is unclear whether their predictive value applies across a general BrS population. The presence of ER has already been associated with a higher risk of ventricular arrhythmic events in patients with idiopathic ventricular fibrillation,25,26 and it is therefore possible that its presence indicates an arrhythmogenic predisposition. It is plausible that the presence of type 1 Brugada pattern in peripheral leads is indicative of a higher Brugada substrate burden and, as a result, may be associated with a greater risk of ventricular arrhythmia. Evaluating all these factors together in a large BrS population is required to effectively establish their importance.

However, if patients are symptomatic, ajmaline testing is warranted because of the increased risk of SCD seen in these patients with BrS.10 Further to this, in those with a family history of SCD in first-degree relatives, ajmaline testing can not only help to explain the cause of death in the proband but also, if positive, to identify family members with potential high-risk features.5

Risk Stratification in BrS Identifying factors that are associated with an increased risk of ventricular arrhythmias and SCD in BrS is a significant challenge. With ICDs being associated with a life-long complication risk of up to 45 %,14 the decision to implant these devices should not be taken lightly.

Indeed, although the advent of subcutaneous ICDs could reduce the risk of transvenous lead problems in the long term, there remains the morbidity associated with inappropriate device therapies and the risk of infection with multiple generator changes over time.

Several risk factors have been proposed over the years. The France, Italy, Netherlands, Germany (FINGER) registry, the largest international cohort to date, assessed the role of six proposed risk factors in predicting ventricular arrhythmic events: syncope, spontaneous type 1 ECG, gender, family history of SCD, inducibility of ventricular tachyarrhythmias during electrophysiological study and presence of an SCN5A mutation.3 Syncope and spontaneous type 1 ECG pattern were the only significant predictors. These factors are the only ones that have remained consistent in their predictive role in other studies.3,6,15,16 Other markers, however, either yield conflicting data or have only been assessed in a small proportion of studies, making it difficult to evaluate their true role in the risk stratification of Brugada patients (Table 1).

Factors with Conflicting Evidence A positive programmed electrical stimulation test is a good example of the factors in this pool of conflicting evidence, in that it has been shown to be a strong predictor of ventricular arrhythmias in BrS in some studies15,16 while in others it has played no role in BrS risk stratification.3,6,17,18 Recent data from the FINGER registry suggest that a positive study with up to two extra stimuli could have prognostic significance, and a negative study has a high negative predictive value.15 The presence of an SCN5A mutation3,6,15,17 and family history of SCD3,15,17 are further factors whose role in risk stratification of Brugada patients remains uncertain. Based on these findings, utilising

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Risk Scoring Model in BrS A number of studies have combined risk factors to predict the risk of SCD.11,16,27 The initial study by Delise et al. showed that no single risk factor was able to identify BrS patients at high risk of arrhythmic events and that a multi-parametric approach was a more robust strategy.11 The authors showed that the subjects at highest risk were those with a spontaneous type 1 ECG pattern and at least two further risk factors (including syncope, family history of SCD and positive programmed electrical stimulation).

More recently, Sieira et al. evaluated several factors and proposed a score that included the presence of: spontaneous type 1 ECG pattern; early familial SCD (<35 years old); positive programmed electrical stimulation; presentation as syncope or as aborted SCD; and sinus node dysfunction.16 The authors demonstrated a predictive performance of 0.82 for this score. They showed that a score greater than two conferred a 5-year event probability of 9.2 %. However, it is important to consider several points prior to implementing the use of this score. The factors utilised in this risk score were derived only from univariate analysis. Since no multivariate analysis was conducted, it is unclear whether all these factors have an independent predictive role for ventricular events. Furthermore, the validation of the risk score that established its predictive performance was undertaken in a cohort from the same centre. Since the risk score has not yet been evaluated externally and the baseline characteristics of the cohort showed several differences to those of other, larger studies, it is unclear whether this predictive performance is applicable to the general BrS population. Therefore, even though this approach of integrating risk factors is promising, further validation in other BrS cohorts is warranted prior to its use in clinical practise. However, there is clearly a role for combined risk factor scoring in BrS.

The Future in BrS Several studies have demonstrated prolonged right ventricular outflow tract (RVOT) activation with marked regional conduction delay and fractionated late potentials in patients with BrS.17,24,28 As well as utilising clinically derived risk factors in risk stratification, there may be a role for more refined evaluation of the arrhythmogenic substrate. Electrocardiographic imaging (ECG-I) has demonstrated

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Risk Stratification in Brugada Syndrome Table 1: Studies Evaluating Predictive Factors for Ventricular Arrhythmia Occurrence and/or SCD during Follow-up in Patients with Brugada Syndrome Study

Factors Assessed

HR [95 % CI]

Follow-up (Median [Range] or Mean ± SD)

p-value Probst et al.3

Priori et al.

6

Syncope

3.4 [1.6–7.4] p=0.002

Spontaneous type 1 ECG

1.8 [1.03–3.33] p=0.04

Male gender

N/S

SCN5A mutation positive

N/S

Family history of SCD

N/S

PES positive

N/S

Spontaneous type 1 ECG + syncope

4.20 [1.38–12.79] p=0.012

QRS fragmentation

4.94 [1.54–15.8] p=0.007

VRP <200 ms

3.91 [1.03–12.79] p=0.045

31.9 months (14.0–54.4)

36 ± 8 months

PES positive

N/S

Sroubek et al.15

PES positive

2.66 [1.44–4.92] p<0.001

38 months (20.9–60.3)

Sieira et al.16

Syncope

3.7 [1.6–8.6] p<0.01

80.7 ± 57.2 months

Spontaneous type 1 ECG

2.7 [1.3–5.4] p<0.01

Male gender

2.7 [1.2–6.2] p=0.02

Sinus node dysfunction

5.0 [1.5–16.3] p<0.01

PES positive

4.7 [2.2–10.2] p<0.01

Proband status

2.1 [1.0–4.2] p=0.04

QRS duration >120 ms

1.03 [1.01–1.04] p<0.01

Family history of SCD

N/S

S-wave pattern in lead 1

39.1 [5.34–287.10] p<0.0001

Presence of AF

3.70 [1.59–8.73] p=0.0024

Male gender

N/S

Family history of SCD

N/S

First-degree heart block

N/S

QTc prolongation

N/S

Early repolarisation

N/S

Epsilon wave present

N/S

QRS fragmentation

N/S

QRS duration >120 ms

N/S

SCN5A mutation positive

N/S

PES positive

N/S

Family history of SCD

3.28 [1.42–7.60] p=0.005

Early repolarisation

2.66 [1.06–6.71] p=0.03

Spontaneous type 1 ECG

N/S

PES positive

N/S

Calo et al.17

Kamakura et al.

19

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48 ± 38.6 months

48.7 ± 14.9 months

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Expert Opinion Table 1: Cont.

Study

Factors Assessed

HR [95 % CI]

Follow-up (Median [Range] or Mean ± SD)

p-value Tokioka et al.22

Syncope

28.57 [6.14–142.86] p<0.001

QRS fragmentation

5.21 [1.69–16.13] p=0.004

Early repolarisation

2.87 [1.16–7.14] p=0.023

45.1 ± 44.3 months

* Multivariate analysis except Sieira et al.16, which was univariate analysis. CI = confidence interval; SCD = sudden cardiac death; PES = programmed electrical stimulation; VRP = ventricular refractory period.

Figure 1: Proposed ECG Markers with Evidence of a Role in Predicting Ventricular Arrhythmias in Brugada Syndrome

(A) Type 1 Brugada pattern in peripheral leads. (B) aVR sign (dominant R wave in aVR) in a Brugada syndrome patient with a non-spontaneous type 1 electrocardiogram pattern.

(C) Early repolarisation in a non-Brugada syndrome patient (ST elevation in the inferolateral leads). (D) S-wave in lead I. (E) QRS fragmentation in V1 (fragmentation within the QRS complex, with ≥4 spikes in a single lead or ≥8 spikes in leads V1, V2 and V3).

Figure 2: Conduction Delays in the RVOT on Ripple Mapping

Figure 3: Normalisation of Brugada ECG After Epicardial Catheter Ablation in the RVOT

(1A and 1B) Precordial leads (V1 to V3) show presence of spontaneous type 1 Brugada pattern at the start of the procedure, and its disappearance 9 months later. (2) Epicardial voltage map of the RV using the Rhythmia™ mapping system (Boston Scientific, Marlborough, MA, USA), anteroposterior view with 0.5–1.5 mV as voltage cut-off points, showing large areas of fibrosis in the RVOT and anterior wall of the RV. (3) Endocardial voltage map of the RV, posteroanterior view, showing an area of fibrosis in the posteroseptal aspects of the RVOT. A long (>120 ms), complex, small-amplitude and fractionated potential is highlighted. (4) Potential duration map of the epicardial aspects of the RV, anteroposterior view, showing area of potentials lasting more than 291 ms (purple), corresponding to the ablated zone. Areas of potentials lasting less than 200 ms are in red. Highlighted is a very long and complex potential, measuring approximately 371 ms. PA = pulmonary artery; RV = right ventricle; RVOT = right ventricular outflow tract; TV = tricuspid valve.

Source: Providencia et al, with permission from the Revista Portuguesa de Cardiologia.34

marked conduction delays in the RVOT (Figure 2), and this area of delay is expanded in the presence of ajmaline.29 The degree and/or area of delay may be another useful biomarker to predict risk; indeed, an ECG-I approach to risk has been proposed in a preliminary study utilising exercise stress.30 Although genetic factors are important, their role to date has been limited to individual mutations; the burden of specific variants may also be utilised in the future to refine risk scoring.

Epicardial map showing ripples in the anterior part of the RVOT that occurs after the QRS complex (right part of image), which suggests delayed conduction. The electrograms obtained in this region (right part of image) also show typical long fractionated potentials, supporting delayed conduction in the RVOT. RVOT = right ventricular outflow tract.

Source: Providencia R et al.33

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The current American College of Cardiology, American Heart Association and Heart Rhythm Society guideline for management of ventricular arrhythmias recommends catheter ablation or quinidine for patients: experiencing recurring shocks for ventricular arrhythmias; and with spontaneous type 1 pattern and symptomatic ventricular arrhythmias who either are not candidates for an ICD or decline an ICD (class I recommendation, level of evidence B [non-randomised for both]).4 Two studies have shown that epicardial catheter ablation

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Risk Stratification in Brugada Syndrome performed in the RVOT, with a view of eliminating this arrhythmogenic electrophysiological substrate, resulted in the normalisation of the Brugada ECG in majority of patients, even after ajmaline (Figure 3).31,32 In the study with the larger cohort of patients,31 the current follow-up is less than 1 year; therefore, a longer follow-up period is required

Mizusawa Y, Wilde AA. Brugada syndrome. Circ Arrhythm Electrophysiol 2012;5:606–16. https://doi.org/10.1161/ CIRCEP.111.964577; PMID: 22175240.

2. Priori SG, Napolitano C, Gasparini M, et al. Natural history of Brugada syndrome: insights for risk stratification and management. Circulation 2002;105:1342–7. https://doi. org/10.1161/hc1102.105288; PMID: 11901046.

3. Probst V, Veltmann C, Eckardt L, et al. Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome registry. Circulation 2010;121:635– 43. https://doi.org/10.1161/CIRCULATIONAHA.109.887026; PMID: 20100972.

4. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation 2017; https://doi.org/10.1161/ CIR.0000000000000548; PMID: 29084733; epub ahead of press.

5. Priori SG, Wilde AA, Horie M, et al. Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Europace 2013;15:1389–406. https://doi.org/10.1093/europace/eut272; PMID: 2399479.

6. 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.

7. Eckardt L, Probst V, Smits JP, et al. Long-term prognosis of individuals with right precordial ST-segmentelevation Brugada syndrome. Circulation 2005;111:257–63. https://doi.org/10.1161/01.CIR.0000153267.21278.8D; PMID: 14642768.

8. Milman A, Andorin A, Gourraud JB, et al. Profile of patients with Brugada syndrome presenting with their first documented arrhythmic event: Data from the Survey on Arrhythmic Events in BRUgada Syndrome (SABRUS). Heart Rhythm 2018; https://doi.org/10.1016/jhrthm.2018.01.014; PMID: 29325976; epub ahead of print.

9. Office for National Statistics. Mortality statistics. UK Gov National Statistics Series DH2 no.32. London: ONS, 2006.

10. Sacher F, Probst V, Maury P, et al. Outcome after implantation of a cardioverter-defibrillator in patients with Brugada syndrome: a multicenter study-part 2.

Circulation 2013;128:1739–47. https://doi.org/10.1161/ CIRCULATIONAHA.113.001941; PMID: 23995538.

11. Delise P, Allocca G, Marras E, et al. Risk stratification in individuals with the Brugada type 1 ECG pattern without previous cardiac arrest: usefulness of a combined clinical and electrophysiologic approach. Eur Heart J 2011;32:169–76. https://doi.org/10.1093/eurheartj/ehq381; PMID: 20978016.

12. Adler A, Rosso R, Chorin E, et al. sk stratification in Brugada syndrome: clinical characteristics, electrocardiographic 1.

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13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

to ensure that the ablation effect is permanent. Indeed, a clinical trial is now in progress to evaluate the role of prophylactic ablation in BrS (ClinicalTrials.gov identifier: NCT02641431). However, given that the condition may be a progressive disease, issues relating to risk stratification even after ablation will remain for the foreseeable future. n

parameters, and auxiliary testing. Heart Rhythm 2016;13:299– 310. https://doi.org/10.1016/j.hrthm.2015.08.038; PMID: 26341603.

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.

Hamilton RM. Implantable devices in young patients: Hitting the reset button on risk versus benefit. Heart Rhythm 2016;13:455–6. https://doi.org/10.1016/jhrthm.2015.10.002; PMID: 26440551.

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.

Sieira J, Conte G, Ciconte G, et al. A score model to predict risk of events in patients with Brugada syndrome. Eur Heart J 2017;38:1756–63. https://doi.org/10.1093/eurheartj/ehx119; PMID: 28379344.

Calò L, Giustetto C, Martino A, et al. A new electrocardiographic marker of sudden death in Brugada syndrome: the S-wave in lead I. J Am Coll Cardiol 2016;67: 1427–40. https://doi.org/10.1016/j.jacc.2016.01.024; PMID: 27012403.

Rollin A, Sacher F, Gourraud JB, et al. Prevalence, characteristics, and prognosis role of type 1 ST elevation in the peripheral ECG leads in patients with Brugada syndrome.

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Kamakura S, Ohe T, Nakazawa K, et al.; Brugada Syndrome Investigators in Japan. Long-term prognosis of probands with Brugada-pattern ST-elevation in leads V1–V3. Circ Arrhythm Electrophysiol 2009;2:495–503. https://doi.org/10.1161/ CIRCEP.108.816892; PMID: 19843917.

Takagi M, Aonuma K, Sekiguchi Y, et al.; Japan Idiopathic Ventricular Fibrillation Study (J-IVFS) Investigators. The prognostic value of early repolarization (J wave) and ST-segment morphology after J wave in Brugada syndrome: multicenter study in Japan. Heart Rhythm 2013;10:533–9. https://doi.org/10.1016/j.hrthm.2012.12.023; PMID: 23274366.

Kawata H, Morita H, Yamada Y, et al. Prognostic significance of early repolarization in inferolateral leads in Brugada patients with documented ventricular fibrillation: a novel risk factor for Brugada syndrome with ventricular fibrillation.

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Tokioka K, Kusano KF, Morita H, et al. Electrocardiographic parameters and fatal arrhythmic events in patients with Brugada syndrome: combination of depolarization and repolarization abnormalities. J Am Coll Cardiol 2014;63:2131–8. https://doi.org/10.1016/j.jacc.2014.01.072; PMID: 24703917.

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24.

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34.

https://doi.org/10.1016/j.hrthm.2007.04.017; PMID: 17675073.

Morita H, Kusano KF, Miura D, et al. Fragmented QRS as a marker of conduction abnormality and a predictor of prognosis of Brugada syndrome. Circulation 2008;118: 1697–704. https://doi.org/10.1161/ CIRCULATIONAHA.108.770917; PMID: 18838563.

Haïssaguerre M, Derval N, Sacher F, et al. Sudden cardiac arrest associated with early repolarization. N Engl J Med 2008;358:2016–23. https://doi.org/10.1056/NEJMoa071968; PMID: 18463377.

Honarbakhsh S, Srinivasan N, Kirkby C, et al. Medium-term outcomes of idiopathic ventricular fibrillation survivors and family screening: a multicentre experience. Europace 2017;19:1874–80. https://doi.org/10.1093/europace/euw251; PMID: 27738067.

Conte G, de Asmundis C, Sieira J, et al. Prevalence and clinical impact of early repolarization pattern and QRSfragmentation in high-risk patients with Brugada syndrome.

Circ J 2016;80:2109–16. https://doi.org/10.1253/circCJ-16-0370; PMID: 27558008.

Lambiase PD, Ahmed AK, Ciaccio EJ, et al. High-density substrate mapping in Brugada syndrome: combined role of conduction and repolarization heterogeneities in arrhythmogenesis. Circulation 2009;120:106–17, 1–4. https://doi.org/10.1161/CIRCULATIONAHA.108.771401; PMID: 19564561.

Zhang J, Sacher F, Hoffmayer K, et al. Cardiac electrophysiological substrate underlying the ECG phenotype and electrogram abnormalities in Brugada syndrome patients. Circulation 2015;131:1950–9. https://doi.org/10.1161/ CIRCULATIONAHA.114.013698; PMID: 25810336.

Leong KMW, Ng FS, Yao C, et al. ST-elevation magnitude correlates with right ventricular outflow tract conduction delay in type I Brugada ECG. Circ Arrhythm Electrophysiol 2017;10:e005107. https://doi.org/10.1161/CIRCEP.117.005107; PMID: 29038102.

Nademanee K, Veerakul G, Chandanamattha P, et al. Prevention of ventricular fibrillation episodes in Brugada syndrome by catheter ablation over the anterior right ventricular outflow tract epicardium.

Circulation 2011;123:1270–9. https://doi.org/10.1161/ CIRCULATIONAHA.110.972612; PMID: 21403098.

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.

Providencia R, Cavaco D, Carmo P, et al. Ripple-mapping for the detection of long duration action potential areas in patients with Brugada syndrome. BioRxiv 2018; https://doi. org/10.1101/263145; article in press.

Providencia R, Carmo P, Moscoso Costa F, et al. Brugada syndrome is associated with scar and endocardial involvement: Insights from high-density mapping with the Rhythmia™ mapping system. Rev Port Cardiol 2017;36: 773.e1–e4. https://doi.org/10.1016/j.repc.2017.08.004; PMID: 29050870.

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Clinical Review: Electrophysiology and Ablation

Atrial Fibrillation Ablation in Patients with Heart Failure: One Size Does Not Fit All Rahul K Mukherjee, 1 Steven E Williams, 1,2 Steven A Niederer 1 and Mark D O’Neill 1,2 1. King’s College London, London, UK; 2. Guy’s and St Thomas’ NHS Foundation Trust, London, UK

Abstract Atrial fibrillation (AF) is common in patients with heart failure and is associated with poorer clinical outcomes compared with patients with heart failure alone. Recent evidence has challenged previous treatment paradigms in which rate control was considered equivalent to rhythm control in this population. Catheter ablation has emerged as a safe and effective treatment strategy in selected patients and overcomes the issues of limited efficacy and drug toxicities associated with pharmacological rhythm control. Numerous studies have explored the benefits of catheter ablation in patients with heart failure, but these have included heterogeneous patient cohorts and variable ablation strategies. This state-of-the-art review explores the evidence from these trials and examines the need for tailored, patient-specific strategies for AF ablation in patients with heart failure.

Keywords Atrial fibrillation, catheter ablation, heart failure, pulmonary vein isolation, cardiomyopathy Disclosure: The authors have no conflicts of interest to declare.

Acknowledgement: This work was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. The views expressed in this manuscript are those of the authors and not those of the NIHR or NHS. Received: 2 March 2018 Accepted: 18 April 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(2):84–90. https://doi.org/10.15420/aer.2018.11.3 Correspondence: Rahul K Mukherjee, School of Biomedical Engineering and Imaging Sciences, King’s College London, St Thomas’ Hospital, Westminster Bridge Road, London, SE1 7EH, UK. E: Rahul.r.mukherjee@kcl.ac.uk

AF is the most common cardiac arrhythmia of clinical significance with an estimated prevalence of >33 million individuals globally.1 AF can be associated with significant symptoms and impaired quality of life of affected patients while also increasing the risk of stroke, heart failure and death.2 AF frequently co-exists with heart failure (HF). Up to half of patients with HF in the Framingham Heart Study developed AF, while HF occurred in more than one-third of individuals with AF.3 Initial studies of rhythm control versus rate control to treat AF demonstrated equivalent outcomes, but rhythm control was pursued with electrical cardioversion or anti-arrhythmic medications associated with limited efficacy and adverse effects.4,5 Safety concerns have also been raised with anti-arrhythmic drugs with some medications independently associated with higher mortality rates.6,7 Catheter ablation has emerged as an effective treatment strategy in patients with AF and HF with observational studies, randomised controlled trials (RCTs) and meta-analyses all demonstrating clinical improvements compared with rate-control strategies.8–12 However, there remain unanswered questions as to which group of patients with HF might benefit the most from catheter ablation, the optimal ablation strategy in this population and when to pursue ablation. In this stateof-the-art review, we assess the evidence from RCTs published within the last 10 years as well as additional observational and mechanistic studies to clarify what remains unknown and what could be a priority for future investigation.

Current Guidelines for Management In patients who have co-existing AF and HF, the main aims of treatment are to prevent adverse outcomes, improve symptoms and maintain a

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good quality of life. The 2016 European Society of Cardiology guidelines on the management of AF state that the ‘indications for catheter ablation in HF patients with reduced ejection fraction (HFrEF) should be carefully balanced and procedures performed in experienced centres.’13 The guidelines also recognise that AF ablation can be more demanding in this patient cohort compared with patients without HF. In patients presenting acutely with AF and HF, the guidelines recommend focusing on normalising fluid balance, aiming for an initial heart rate target of <110 bpm, use of anticoagulation, inhibition of the renin–angiotensin–aldosterone system and early consideration of rhythm control.13 However, there is no clear consensus on which patients with HF should be offered catheter ablation or the optimal ablation strategy in this setting. A growing number of studies have now been published to assess the effectiveness of catheter ablation on improving clinical outcomes in patients with AF and HF (Table 1). These studies have challenged previous treatment paradigms in which rate control was considered equivalent to rhythm control in this patient population.

Clinical Trials of Catheter Ablation in Patients with AF and Heart Failure Early trials of catheter ablation versus rate control therapy for patients with AF and HF included small numbers of patients and were not adequately powered to assess hard endpoints such as mortality. In the Pulmonary Vein Antrum Isolation versus AV node Ablation with Bi-Ventricular Pacing for Treatment of Atrial Fibrillation in patients with Congestive Heart Failure (PABA-CHF) study, 81 patients with drug-resistant AF and an EF <40 % were randomised to undergo

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AF Ablation in Patients with Heart Failure

Patient Group

Aetiology

Ablation

Medical/Rate-control of AF

Duration

Pharmacological rate control

Pharmacological rate control

Pharmacological rate control

Amiodarone therapy

Pharmacological rate control

Type of AF

Exclusion Criteria

Procedural

Ablation

Overall

Assessment

AF recurrence

Method for

Results

Improved LVEF, 6MWT and QoL score in PVI group (6-month f/u)

Success (%) 88

Loop recorder worn in PVI group between months 2–6 post procedure

No difference in LVEF between groups; no difference in BNP, 6MWT or QoL (12-month f/u)

49 % PAF in PVI group; 54 % PAF in rate-control group

50

24-hour ambulatory ECG monitoring at baseline, 3 months and 6 months

Improvement in exercise performance and BNP in ablation arm (12-month f/u)

Reversible AF or HF; previous LA ablation; life expectancy ≤2 years; MI or PCI in the last 3 months; severe pulmonary disease

100 % persistent AF Paroxysmal AF; QRS >150 ms or QRS 120–150 with evidence of mechanical dysynchrony; primary valvular disease

48h ambulatory ECG at 6 and 12 months; 12-lead ECGs at 3, 6 and 12 months post procedure

51 ± 76 months

100 % persistent AF Cardiac device insertion within 88 last 6 months; PCI or AVN ablation within last 3 months; reversible causes of AF; primary valvular disease 100 % persistent AF Reversible cause of HF, previous LA ablation, Paroxysmal AF, cardiac device implantation, cardiac surgery or MI in last 6 months

75

70

ICDs or CRT-Ds interrogated at 3,6,12,24,36,48 and 60 months

Loop recorder or Reveal Linq used to monitor recurrence

Improved primary composite end-point of mortality + HF hospitalisation in ablation arm

Improved LVEF in ablation arm; those who were LGE negative had greater improvements in LVEF

Implanted devices Improved AF interrogated at recurrence3-,6-,12- and free survival, 24-month f/u lower mortality and unplanned hospitalisations in ablation arm

73

24 months

100 % persistent AF Reversible cause of AF; valvular or IHD requiring surgical intervention; early post-operative AF (<3 months); patients on regular amiodarone ≥200 mg/day

48h ambulatory ECG at 1, 3, 6 and 12 months

8.6 ± 3.2 months

Paroxysmal AF; any contraindication to AF ablation or MRI; significant coronary artery disease on angiography or CT

Improved LVEF, better exercise performance and QoL score in ablation arm (12-month f/u)

23 ± 18 months

28 % persistent AF; 72 % long-standing persistent AF

Previous LA ablation for 63.1 % (at AF; LA diameter >6 cm on 60-month f/u echocardiography; MI or stroke visit) in last 2 months; no implanted device

28 % in ablation arm had persistent AF >1 year duration

33 % paroxysmal AF; 67 % persistent AF (of which 29 % long-standing persistent AF)

44 ± 36.5 months (ablation arm); 64 ± 47.6 months (medical arm)

4.0 ± 2.4 years

Strategy

PVI ± additional linear lesions

PVI ± additional linear lesions

AV node ablation + Biventricular pacing

Strategy

PVI ± additional linear lesions

33 % ICM

Step wise: PVI, linear ablation at roof and mitral isthmus, CFE ablation

PVI ± additional linear lesions

26 % ICM

62 % ICM

0 % ICM; 100 % idiopathic cardiomyopathy

46 % ICM

PVI ± linear lesions ± CFE ablation

PVI ± linear lesions ± CFE ablation

50 % ICM

73 % ICM

of HF

Table 1: Randomised Controlled Trials of Catheter Ablation for the Treatment of Atrial Fibrillation in Patients with Heart Failure Published Within the Past 10 Years Study

PABACHF14 81 patients with EF ≤40 %; NYHA II or III HF

363 patients with LVEF ≤35 %; NYHA II–IV HF

68 patients with idiopathic cardiomyopathy; LVEF ≤45 %

203 patients with LVEF <40 %; implanted device

50 patients with LVEF <50 %

52 patients with LVEF ≤35 %

MacDonald 41 patients with LVEF ≤35 %, NYHA et al.15 II–IV HF

ARC-HF16

CAMTAF17

AATAC10

CAMERAMRI22

CASTLEAF21

Pharmacological rate control (efforts to maintain sinus rhythm encouraged)

6MWT = 6-minute walk test; ARC-HF = Catheter Ablation Versus Medical Rate Control for Atrial Fibrillation in Patients with Heart Failure; BNP = B-type natriuretic peptide; CFE = complex fractionated electrograms; CRT = cardiac resynchronisation therapy; f/u = follow-up; ICD = implantable cardioverter-defibrillator; ICM = ischaemic cardiomyopathy; LA = left atrium; LGE = late gadolinium enhancement; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association; PVI = pulmonary vein isolation; QoL = quality of life.

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Clinical Review: Electrophysiology and Ablation either AF ablation with pulmonary vein isolation (PVI) or AV node ablation with biventricular pacing.14 Additional linear lesions as well as targeting of complex fractionated electrograms (CFE) were allowed according to the preference of the centre and operator. Patients who underwent PVI showed improvements in the composite primary endpoint including EF measurement with echocardiography, 6-minute walk test and a quality of life score compared with AV node ablation with biventricular pacing. The majority of patients in both arms of the study had ischaemic cardiomyopathy (73 % and 68 %, respectively) and a mean duration of AF of 4 years. In the ablation group, 51 % had persistent or long-standing persistent AF where clinical outcomes are known to be inferior to paroxysmal AF. Intriguingly, those patients who underwent AV node ablation and biventricular pacing did not demonstrate more significant improvements in their LVF (EF 28 %), although this group of patients appeared to have narrow QRS intervals at baseline (90 ± 10 ms).14 In a smaller study (41 patients), MacDonald et al. found no difference in EF measured using cardiac MRI in patients undergoing catheter ablation versus medical rate control at 6-month follow-up.15 In this study, only patients with persistent AF were included, while mean LVEF measured at baseline was only 16.1 % in the ablation group and 19.6 % in the medical group, suggesting more advanced disease. Around 90 % of patients were in New York Heart Association (NYHA) class III or above. Furthermore, only 50 % of patients in the ablation group maintained sinus rhythm at the end of the study. Although the study was likely underpowered to detect a difference in the primary endpoint, it does raise the importance of careful consideration of the likelihood of success in specific groups of patients with AF and HF.15 In a subsequent study (ARC-HF), with an improvement in maintenance of sinus rhythm and higher singleprocedure success rate, catheter ablation led to an increase in peak oxygen consumption compared with rate control.16 The Catheter Ablation Versus Medical Treatment of Atrial Fibrillation (CAMTAF) trial included a higher proportion of patients with non-ischaemic cardiomyopathy (74 %) compared to previous trials, while 92 % of all patients in the study had long-standing persistent AF.17 In addition, those patients who were thought to be clearly symptomatic from AF were excluded, as the aim of the study was to use ablation to treat HF rather than symptomatic refractory AF. An improvement in LVEF, peak oxygen consumption and quality of life score was seen in the ablation arm versus medical rate control. Interestingly, the duration of continuous AF was significantly lower in the CAMTAF study compared with that in the study by MacDonald et al.13 (24 months versus 53 months).17 In these early RCTs, the duration of follow-up ranged 6–10 months.

Meanwhile, the single-procedure success rates of catheter ablation ranged 38–71 %, with overall success rates ranging 50–88 %. Whether catheter ablation maintained sinus rhythm in the long term is unclear based on these early results. The ablation strategy was also heterogeneous with all patients undergoing at least PVI, but a large proportion had additional linear lesions dependant on the operator and centre. A meta-analysis of these trials revealed that an improvement in LVEF was the most consistent benefit in functional outcome with a mean difference of 8.53 % (95 % CI [6.40–10.67]).11 This raises the issue of whether catheter ablation would improve functional outcome in patients with HF and preserved EF (HFpEF) with limited data that suggest that these patients may be older, have more co-morbidities, be more commonly female and may have higher procedural complications.18,19 However, a recent study of 230 patients found no differences in arrhythmia-free recurrence, NYHA

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functional class and procedural characteristics between HFpEF and HFrEF patients undergoing AF ablation.20 This was a single-centre, retrospective study and further research is needed to assess the role of catheter ablation in HFpEF. The early RCTs included small numbers of patients and were therefore adequately powered only to assess surrogate end-points such as ejection fraction, exercise capacity and quality of life. More recently a number of highly anticipated trials have now been published assessing hard end-points such as mortality. In the Ablation vs. Amiodarone for Treatment of Atrial Fibrillation in Patients with Congestive Heart Failure and an Implanted ICD/CRTD (AATAC) study, patients with persistent AF, LVEF <40 % and NYHA Class II–III heart failure were randomised to either receive catheter ablation or amiodarone.10 Unlike previous RCTs, the aim in both arms was rhythm control with a primary endpoint of AF recurrence and secondary endpoints including all-cause mortality and unplanned hospitalisation. Interestingly, catheter ablation was superior to amiodarone in achieving freedom from AF recurrence as well reducing all-cause mortality and unplanned hospitalisation rates. During a longer 24-month follow-up period, 70 % of patients in the ablation arm (95 % CI [60–78]) and 34 % in the control arm (95 % CI [25–44]) remained arrhythmia-free. The duration of AF at randomisation was significantly shorter than in previous studies (8.6 months in the ablation arm and 8.4 months in the amiodarone arm), while all patients had an implanted device, which strengthened the quality of the outcome data. A lower all-cause mortality rate (secondary endpoint) was also reported in the catheter ablation arm (8 % versus 18 %; p=0.037).

Although promising, it should be noted that the AATAC study compared ablation with a drug known to have significant toxicities; 10.4 % of treatment failures in the amiodarone group had the drug withdrawn due to adverse effects. The study does, however, raise the importance of early treatment before long-standing persistent AF develops.10 In this context, the Catheter Ablation versus Standard Conventional Therapy in Patients with Left Ventricular Dysfunction and Atrial Fibrillation (CASTLE-AF) trial assessed the impact of ablation on mortality and HF progression rates.21 In this study, 363 patients with symptomatic paroxysmal or persistent AF, NYHA II–IV heart failure, LVEF <35 % and an implanted device were randomised to receive either catheter ablation or medical therapy (with rhythm control encouraged).

Over a median follow-up of 37.8 months, the primary composite endpoint of death from any cause or hospitalisation due to HF was significantly less frequent in the ablation group than the medical therapy group (HR 0.62; 95 % CI [0.43–0.87]). Similar to the AATAC trial, all patients had AF recurrence monitored with an implanted device.

A mortality benefit (13.4 % versus 25 %; HR 0.53; 95 % CI [0.32–0.86]; p=0.01) was also demonstrated in the ablation arm, which was driven by a lower rate of cardiovascular death.21 CASTLE-AF builds on the accumulating evidence that catheter ablation may have benefits in patients with HF but does not necessarily add clarity as to which patients with HF should be targeted for ablation.

The patients appeared to be highly selected with >3000 screened for eligibility, but only 13.2 % ultimately enrolled. Patients whose implanted device was from a different vendor (study sponsored by Biotronik) were excluded (32.4 %). Among the ablation arm, 69 % had NYHA class I or II HF, 40 % had ischaemic cardiomyopathy and 30 % had paroxysmal AF. Long-standing persistent AF was observed in 28 % of patients in the ablation arm and 30 % in the medical therapy arm. This

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AF Ablation in Patients with Heart Failure clearly reveals a highly heterogeneous cohort of patients with HF. There was also significant heterogeneity in terms of the catheter ablation procedure itself with the aim of the procedure to isolate all pulmonary veins and achieve sinus rhythm. Additional lesions involving the cavotricuspid isthmus, roof, superior vena cava and inferior vena cava were permitted at the discretion of the operator.

Although promising, the results of CASTLE-AF may not apply to asymptomatic patients with HF, older patients (with a median age of 64 years in the study) as well as patients with advanced HF. Indeed, there is some evidence to suggest that some groups of patients with HF respond much better to catheter ablation. In the Catheter Ablation Versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction (CAMERA-MRI) study, patients with idiopathic cardiomyopathy and persistent AF were randomised to undergo either catheter ablation or medical rate control.22 All patients had a cardiac MRI scan at baseline after optimisation of rate control to assess LVEF and presence of late gadolinium enhancement (LGE) – a surrogate of ventricular fibrosis. These patients were younger (mean age 59 ± 11 years in ablation arm and 62 ± 9.4 years in the medical therapy arm) and had a mean LVEF of 35 %, but a large majority (72–76 %) had long-standing persistent AF. The primary outcome was a change in LVEF during a repeat MRI at 6 months. The ablation group had a better improvement in LVEF compared with medical rate control, but, more interestingly, among patients undergoing catheter ablation, those who were LGE negative at baseline had an even better response compared with those who had evidence of LGE on MRI. These findings indicate that restoration of sinus rhythm in a cohort of patients with no other apparent cause of their cardiomyopathy may result in improved LV function, but a pure effect of improved heart rate cannot be excluded for the effect seen.

The true value of CAMERA-MRI may be that risk stratification tools such as cardiac MRI with LGE could identify a cohort of patients who may be super-responders to catheter ablation.22 These findings are consistent with a previous report by the same authors in which 15/16 LGE-negative patients with long-standing persistent AF who underwent catheter ablation maintained sinus rhythm at 6 months with a significant improvement in LV function.23 However, it remains unclear if ablation improves outcomes beyond LV function in the CAMERA-MRI study as there were no data on HF-related hospitalisations or mortality in this cohort.

Complication rates related to the catheter ablation procedure may also be higher in patients with HF compared with general cohorts of patients undergoing an AF ablation, which bears consideration during patient selection. In the CASTLE-AF study, procedure-related complications or serious adverse events occurred in 7.8 %, while in a contemporary cohort of general patients undergoing AF ablation the complication rate was 2.3 %.24

Differences in Electrophysiological Substrate Within Patients with Heart Failure and Between Patients With and Without Heart Failure: Implications for Ablation Strategy Persistent AF appears to be more prevalent than paroxysmal AF in patients with HFrEF.25 There is building momentum towards increasing the single-procedure success rates for paroxysmal AF with more reproducible, standardised PVI workflows, incorporating composite ablation indices such as ‘ablation index’ or tracking inter-lesion

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distance to minimise gaps between adjacent lesions.26,27 However, standardised approaches for catheter ablation of persistent AF remain a long way off, with the results of the Substrate and Trigger Ablation for Reduction of Atrial Fibrillation Trial Part II (STAR AF II) demonstrating no benefit of additional linear ablation or ablation of complex fractionated activity (CFE) to PVI alone in this population.28 This is particularly relevant in patients with HF as the results from an international multicentre registry have suggested that long-term success rates for persistent AF ablation are significantly lower in patients with HF compared with those without HF (57.3 % versus 75.8 %; p<0.001), while there was no significant difference in success rates for paroxysmal AF ablation (78.7 % versus 85.7 %; p=0.186).29 Most of the clinical trials of AF ablation in HF described above have had significant heterogeneity between studies in terms of the ablation protocol used, while data comparing different ablation strategies in HF populations are sparse. In a meta-regression analysis of clinical trials and observational studies of AF ablation in HF patients, there was no difference in sinus rhythm maintenance between a PVI approach versus extensive left atrial ablation (linear lesions or CFE ablation).30 However, there are some cardiomyopathies with extensive left atrial structural remodelling such as hypertrophic cardiomyopathy or cardiomyopathies secondary to valvular heart disease.12 A higher prevalence of CFE has also been reported in some groups of patients with HF.12 Only a minority of these patients with significant structural and electrical remodelling have undergone PVI alone in observational studies.12 Whether PVI alone is adequate or sufficient or whether more aggressive substrate modification strategies are required in these groups of patients remains unclear.

Even in patients with paroxysmal AF, those patients with HFrEF appear to have more non-PV triggers than patients with normal LVEF. Furthermore, in a cohort with HFrEF, when ablation of non-PV triggers was performed in addition to PVI, a significantly improved long-term ablation success was achieved compared with PVI alone (75.0 % versus 32.2 %; p<0.001).31 There are important structural and anatomical abnormalities in the atria of patients with HF compared with patients without HF that may impact on their electrophysiological properties. Using a cohort of patients with symptomatic HF and age-matched controls, Sanders et al. demonstrated that patients with HF had an increase in atrial effective refractory period, no change in the heterogeneity of refractoriness and an increase in atrial conduction time along the low lateral right atrium and coronary sinus.32 They also found evidence of functional delay at the crista terminalis and indirect evidence of conduction slowing across the left atrium and Bachmann’s bundle.32 Taken together, these electrophysiological differences may have led to the observation of increased inducibility and duration of AF in patients with HF.32 Specific causes of cardiomyopathy such as valvular heart disease, which may cause advanced structural remodelling in the left atrium, also demonstrate different conduction patterns. Patients with persistent AF associated with mitral regurgitation (MR) had greater conduction delay and anisotropy in the posterior left atrium associated with fractionated electrograms in these regions compared with patients with MR but without AF.33 The ideal AF ablation protocol in patients with HF remains unclear.

Although PVI alone may be appropriate in certain groups of patients, further investigation and innovation in ablation tools are required to

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Clinical Review: Electrophysiology and Ablation Figure 1: Atrial Late-gadolinium Enhancement on Cardiac MRI and Corresponding 3D Shells Demonstrating Regions of Scar

associated with clinical outcome following AF ablation including type of AF, age, gender, LVEF, left atrial size/volume, and presence of hypertension, obstructive sleep apnoea or diabetes.35 The use of cardiac MRI to assess left atrial (LA) structure and function has also led to the identification of additional parameters such as LA reservoir function,35 LA sphericity36 and LA fibrosis37 that may be related to ablation outcome. The extent of baseline atrial LGE (as a surrogate of fibrosis) (Figure 1), in particular, has received significant attention, with some centres reporting limited value in risk stratification,38 but a growing volume of literature supporting the belief that patients with a higher burden of atrial LGE have worse outcomes following AF ablation.39,40

A and B: 3D late-gadolinium-enhanced MRI scan of the left atrium in a patient with persistent AF. Images obtained in an axial orientation and show regions of hyper-enhancement (white arrows) in two different slices. C and D: 3D shells of the left atrium in the same patient generated using the image intensity ratio technique. Scar is shown in red and normal myocardium in blue; C: postero-anterior view; D: antero-posterior view.

clarify the role of additional linear lesions and develop reproducible strategies in patients with HF and persistent AF. In cohorts of high-risk patients with advanced structural remodelling, extensive left atrial ablation may be needed first-line, but an individualised strategy with a greater understanding of the underlying electrophysiological substrate will likely be required.

Interestingly, in a recent study, Halder et al. used CFEs as a surrogate marker of substrate complexity.34 In patients without HF who had persistent AF, a higher baseline burden of CFEs was seen in both the left and right atrium compared with patients with AF and HF. This finding challenges the belief that the presence of structural heart disease leads to additional complexity in atrial substrate. However, the importance of distinguishing between which is the initiating disease may be relevant to explain these findings â&#x20AC;&#x201C; whether AF occurred first leading to subsequent development of HF or whether HF occurred first.

Halder et al. suggest that those patients without HF with persistent AF may have a more complex primary bi-atrial substrate as a result of the primary electrical disturbance.34 In their study, a left atrial step-wise ablation strategy with more extensive substrate modification resulted in a higher single-procedure arrhythmia-free survival rate at 12 months in the HF group compared with the non-HF group.34 Taken one step further, whether identification of patients who develop AF first prior to HF development may be a means of stratifying which patients may respond to rhythm control with ablation remains unclear and warrants further investigation. In reality, this is difficult to perform in clinical practice due to the large numbers of patients presenting with both AF and HF with no clear indication of which was the primary disturbance.

Improved risk stratification tools to identify subsets of patients with HF who might respond better to catheter ablation are warranted and may also help to tailor ablation strategies. Based on the results of the CAMERA-MRI study, cardiac imaging, in particular, bears consideration in selecting the right patients for catheter ablation. The ongoing Delayed Enhancement MRI-guided Ablation Versus Conventional Catheter Ablation of Atrial Fibrillation (DECAAF-II) trial (NCT20529319) will examine the impact of targeting LGE-MRI detected atrial fibrosis during AF ablation to improve procedural outcomes. Although this study will include a general cohort of patients, it is likely that it will also include a subset with co-existing HF. Non-invasive electrocardiographic imaging, whereby a subject undergoes a multi-detector CT scan while wearing a 252-electrode vest on the thorax to record epicardial unipolar electrograms to reconstruct epicardial electrical potentials on patient-specific geometry, also offers potential as a tool to guide ablation strategy.41 In patients with persistent AF, electrocardiographic imaging has been used to demonstrate the increasing complexity of AF drivers with prolonged AF duration.42 Prior knowledge of the principle locations of AF drivers may help guide ablation strategy in specific groups of patients.43 Based on results of completed clinical trials of AF ablation in HF (Table 1), patients who tend to have the least benefit from catheter ablation appear to have a higher NYHA functional class, longer duration of AF and extensive structural remodelling. Those who appear to respond best to catheter ablation have no other structural abnormalities related to their cardiomyopathy.22 There may be a third group of patients that have both AF and an underlying occult cardiomyopathy that persists despite improvements in AF burden after ablation.44 What is clear from all the trials to date is that HF populations with AF are highly heterogeneous; this can have a significant impact on clinical outcomes. However, the presence of significant structural heart disease does not universally imply more complex electrophysiological substrate and tailored strategies will likely be required to obtain the best clinical outcome.34

Future Perspectives Risk Stratification Tools for Atrial Fibrillation Ablation Improved risk stratification tools to identify patients with AF and HF who might respond best to catheter ablation will be of great value to electrophysiologists to reduce unnecessary procedures in patients unlikely to benefit or to offer more procedures to patients most likely to see clinical benefit. A number of clinical parameters have been

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Despite significant progress in catheter ablation in patients with HF, a number of unanswered questions remain including the optimal means of risk stratification of patients with HF to AF ablation, optimal ablation technique and timing of catheter ablation. Whether intervention will be cost effective if patients require multiple re-do ablations, particularly as HF progresses, is also unclear. A number of clinical trials are currently underway that may provide some clarification. The

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AF Ablation in Patients with Heart Failure Ablation of Atrial Fibrillation in Heart Failure Patients (CONTRA-HF) trial will investigate the impact of cryoablation in patients with HF and implanted cardiac devices/cardiac resynchronisation therapies (NCT03062241). An improved reproducibility of the ablation procedure itself is expected in the cryoablation arm and its impact on hard endpoints such as mortality will be welcome. The Catheter Ablation Versus Anti-arrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial will also assess the impact of ablation on the hard endpoints of mortality, stroke and hospitalisations in a large cohort (>2,000) of patients (NCT00911508). Patients with both HFrEF and HFpEF will be included in the study, which will likely give further insights into the optimal management of patients with AF and HF. The Catheter Ablation Versus Medical Therapy in Congested Hearts with AF (CATCH-AF) trial will assess the impact of catheter ablation in patients with newly diagnosed symptomatic AF with the aim of assisting electrophysiologists in understanding the benefits of early AF ablation (NCT02686749). The Atrial Fibrillation Management in Congestive Heart Failure With Ablation (AMICA) trial will investigate whether PVI alone in patients with persistent AF or longstanding persistent AF improves outcomes compared with best medical therapy (NCT00652522). This will allow the impact of a standardised procedure to be investigated in a less heterogeneous group of patients.

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13.

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.

Piccini JP, Fauchier L. Rhythm control in atrial fibrillation.

Lancet 2016;388:829–40. https://doi.org/10.1016/S01406736(16)31277-6; PMID: 27560278.

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Roy D, Talajic M, Nattel S, et al. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med 2008;358:2667–77. https://doi.org/10.1056/NEJMoa0708789; PMID: 18565859.

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.

Kober L, Torp-Pedersen C, McMurray JJ, et al. Increased mortality after dronedarone therapy for severe heart failure.

N Engl J Med 2008;358:2678–87. https://doi.org/10.1056/ NEJMoa0800456; PMID: 18565860.

Lopes RD, Rordorf R, De Ferrari GM, et al. Digoxin and mortality in patients with atrial fibrillation. J Am Coll Cardiol 2018;71:1063–74. https://doi.org/10.1016/j.jacc.2017.12.060; PMID: 29519345.

Hunter RJ, Berriman TJ, Diab I, et al. A randomised 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.

Dagres N, Varounis C, Gaspar T, et al. Catheter ablation for atrial fibrillation in patients with left ventricular systolic dysfunction. A systematic review and meta-analysis. J Card Fail 2011;17:964–70. https://doi.org/10.1016/j.cardfail.2011.07.009; PMID: 22041335.

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.

Al Halabi S, Qintar M, Hussein A, et al. Catheter ablation for atrial fibrillation in heart failure patients: a meta-analysis of randomized controlled trials. JACC Clin Electrophysiol 2015;1:200–9. https://doi.org/10.1016/j.jacep.2015.02.018; PMID: 26258174.

Anselmino M, Matta M, Castagno D, et al. Catheter ablation of atrial fibrillation in chronic heart failure: state-of-the-art and future perspectives. Europace 2016;18:638–47. https://doi. org/10.1093/europace/euv368; PMID: 26857188.

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.

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The Randomised Ablation-based Atrial Fibrillation Rhythm Control Trial in Patients with Heart Failure and High Burden Atrial Fibrillation (RAFT-AF) will assess the cost-effectiveness of an ablation strategy in patients with HF as well as assess hard endpoints including all-cause mortality; patients with HF will be stratified according to those with HFrEF and HFpEF (NCT01420393).

The advent of permanent His bundle pacing to preserve physiological conduction of the ventricles and enable a means of achieving cardiac resynchronisation therapy could also offer an alternative management strategy in selected groups of patients with AF and HF, if combined with AV node ablation.45 Further studies to assess clinical outcomes using this strategy are anticipated.

Conclusions AF ablation in certain patients with HF may be safe and effective, but most data in this setting are derived from experienced centres. Ablation may not be appropriate in patients with advanced HF, poor functional status or in those with extensive structural remodelling. Improved risk stratification tools and standardisation of ablation strategies in different groups of patients should lead to the development of patient-orientated approaches that seek to identify the patients most likely to benefit from catheter ablation and improve procedural success rates in those patients. n

14. Khan MN, Jais P, Cummings J, et al. Pulmonary-vein isolation for atrial https://doi.org/10.1056/NEJMoa0708234; PMID: 18946063.

15. 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.

16. 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.

17. 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.

18. Zylla MM, Brachmann J, Lewalter T, et al. Sex-related outcome of atrial fibrillation ablation: insights from the German Ablation registry. Heart Rhythm 2016;13:1837–44. https://doi. org/10.1016/j.hrthm.2016.06.005; PMID: 27289011.

19. Verma A, Kalman JM, Callans DJ. Treatment of patients with atrial fibrillation and heart failure with reduced ejection fraction. Circulation 2017;135:1547–63. https://doi.org/10.1161/ CIRCULATIONAHA.116.026054; PMID: 28416525.

20. Black-Maier E, Ren X, Steinberg RA, et al. Catheter ablation of atrial fibrillation in patients with heart failure and preserved ejection fraction. Heart Rhythm 2017;pii: S1547-5271(17)31422-4. https://doi.org/10.1016/j.hrthm.2017.12.001; PMID: 29222043.

21. 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.

22. 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.

23. Ling LH, Taylor AJ, Ellims AH, et al. Sinus rhythm restores ventricular function in patients with cardiomyopathy and no late gadolinium enhancement on cardiac magnetic resonance imaging who undergo catheter ablation for atrial fibrillation.

Heart Rhythm 2013;10:1334–9. https://doi.org/10.1016/ j.hrthm.2013.06.019; PMID: 23811081.

24. Muthalay RG, John RM, Schaeffer B, et al. Temporal trends in safety and complication rates of catheter ablation for atrial fibrillation. J Cardiovasc Electrophysiol 2018; https://doi. org/10.1111/jce.13484; PMID: 29570900; epub ahead of press.

25. Mogensen UM, Jhund PS, Abraham WT, et al. Type of atrial fibrillation and outcomes in patients with heart failure and reduced ejection fraction. J Am Coll Cardiol 2017;70:2490–500. https://doi.org/10.1016/j.jacc.2017.09.027; PMID: 29145948.

26. Duytschaever M, O’Neill M, Martinek M. Increasing the singleprocedure success rate of pulmonary vein isolation. Arrhythm Electrophysiol Rev 2017;6:217–21. https://doi.org/10.15420/

aer.2017.38/1; PMID: 29326838.

27. El Haddad M, Taghji P, Phlips T, et al. Determinants of acute and late pulmonary vein reconnection in contact-force guided pulmonary vein isolation: identifying the weakest link in the ablation chain. Circ Arrhythm Electrophysiol 2017;10:pii:e004867. https://doi.org/10.1161/CIRCEP.116.004867; PMID: 28381417.

28. 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/NEJMoa 1408288; PMID: 25946280.

29. 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.

30. 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.

31. Zhao Y, Di Biase L, Trivedi C, et al. Importance of nonpulmonary vein triggers ablation to achieve long-term freedom from paroxysmal atrial fibrillation in patients with low ejection fraction. Heart Rhythm 2016;13:141–9. https://doi. org/10.1016/j.hrthm.2015.08.029; PMID: 26304713.

32. Sanders P, Morton JB, Davidson NC, et al. Electrical remodelling 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.

33. Roberts-Thomson KC, Stevenson I, Kistler PM, et al. The role of chronic atrial stretch and atrial fibrillation on posterior left atrial wall conduction. Heart Rhythm 2009;6: 1109–17. https://doi.org/10.1016/j.hrthm.2009.04.008; PMID: 19574109.

34. Haldar SK, Jones DG, Khan H, et al. Characterising the difference in electrophysiological substrate and outcomes between heart failure and non-heart failure patients with persistent atrial fibrillation. Europace 2017;20:451–8. https:// doi.org/10.1093/europace/euw380; PMID: 28108547.

35. Habibi M, Lima JA, Gucuk Ipek E, et al. The association of baseline left atrial structure and function measured with cardiac magnetic resonance and pulmonary vein isolation outcome in patients with drug-refractory atrial fibrillation.

Heart Rhythm 2016;13:1037–44. https://doi.org/10.1016/ j.hrthm.2016.01.016; PMID: 26775143.

36. Bisbal F, Guiu E, Calvo N, et al. Left atrial sphericity: a new method to assess atrial remodelling. Impact on the outcome of atrial fibrillation ablation. J Cardiovasc Electrophysiol 2013;24:752–9. https://doi.org/10.1111/jce.12116; PMID: 23489827.

37. McGann C, Akoum N, Patel N, et al. Atrial fibrillation ablation outcome is predicted by left atrial remodelling on MRI. Circ Arrhythm Electrophysiol 2014;7:23–30. h ttps://doi.org/10.1161/ CIRCEP.113.000689; PMID: 24363354.

38. Sramko M, Peichl P, Wichterle D, et al. Clinical value of

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39. Marrouche NF, Wilber D, Hindricks G, et al. Association of atrial tissue fibrosis identified by delayed enhancement MRI and atrial fibrillation catheter ablation: the DECAAF study.

JAMA 2014;311:498–506. https://doi.org/10.1001/jama.2014.3; PMID: 24496537.

40. Khurram IM, Habibi M, Gucuk Ipek E, et al. Left atrial LGE and arrhythmia recurrence following pulmonary vein isolation for paroxysmal and persistent AF. JACC Cardiovasc Imaging

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41. Yamashita S, Shah AJ, Mahida S, et al. Body surface mapping to guide atrial fibrillation ablation. Arrhythm Electrophysiol Rev 2015;4:172–6. https://doi.org/10.15420/aer.2015.4.3.172; PMID: 26835121.

42. Lim HS, Hocini M, Dubois R, et al. Complexity and distribution of drivers in relation to duration of persistent atrial fibrillation.

J Am Coll Cardiol 2017;69:1257–69. https://doi.org/10.1016/ j.jacc.2017.01.014; PMID: 28279292.

43. Haissaguerre M, Hocini M, Denis A, et al. Driver domains in persistent atrial fibrillation. Circulation 2014;130:530–8. https://doi.

org/10.1161/CIRCULATIONAHA.113.005421; PMID: 25028391.

44. Wijesurendra RS, Liu A, Eichhorn C, et al. Lone atrial fibrillation is associated with impaired left ventricular energetics that persists despite successful catheter ablation.

Circulation 2016;134:1068–81. https://doi.org/10.1161/ CIRCULATIONAHA.116.022931; PMID: 27630135.

45. Sharma PS, Dandamudi G, Herweg B, et al. Permanent His-bundle pacing as an alternative to biventricular pacing for cardiac resynchronization therapy: a multicenter experience. Heart Rhythm 2018;15:413–20. https://doi.org/10.1016/j.hrthm.2017.10.014; PMID: 29031929.

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Clinical Review: Electrophysiology and Ablation

Treatment of Atrial Fibrillation in Patients with Co-existing Heart Failure and Reduced Ejection Fraction: Time to Revisit the Management Guidelines?

Alex Baher 1,2 and Nassir F Marrouche 1,2 1. Division of Cardiovascular Medicine, University of Utah; 2. Comprehensive Arrhythmia Research & Management (CARMA) Center, University of Utah, Salt Lake City, USA

Abstract AF in patients with heart failure and reduced ejection fraction (HFrEF) is common and is associated with an increased risk of stroke, heart failure hospitalisation and all-cause mortality. Rhythm control of AF in this population has been traditionally limited to the use of antiarrhythmic drugs. Clinical trials assessing superiority of pharmacological rhythm control over rate control have been largely disappointing. Catheter ablation has emerged as a viable alternative to pharmacological rhythm control in symptomatic AF and has enjoyed significant technological advancements over the past decade. Recent clinical trials have suggested that catheter ablation is superior to pharmacological interventions in patients with co-existing AF and HFrEF. In this article, we will review the therapeutic options for AF in patients with HFrEF in the context of the latest clinical trials beyond the current established guidelines.

Keywords Catheter ablation, atrial fibrillation, heart failure, reduced ejection fraction, rhythm control Disclosure: The authors have no conflicts of interest to declare.

Received: 17 March 2018 Accepted: 24 April 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(2):91–4. https://doi.org/10.15420/aer.2018.17.2 Correspondence: Nassir F Marrouche, CARMA Center, Division of Cardiology, University of Utah Health Sciences Center, 30 North 1900 East, Room 4A100, Salt Lake City, UT 84132-2400, USA. E: nassir.marrouche@carma.utah.edu

AF is the most common rhythm disorder. It is estimated AF will affect 6–12 million Americans by 2050 and 17.9 million Europeans by 2060.1–4 AF is responsible for significant morbidity, mortality and healthcare costs.5–7 Heart failure with reduced ejection fraction (HFrEF) is also a rising epidemic that will afflict over 8 million Americans by 2030.8 AF is common in patients with HFrEF9,10 and leads to increased risk of stroke, heart failure hospitalisation and death.11–13

Current Recommendations for Management of AF in Patients with HFrEF The current American and European guidelines for AF management do not make specific recommendations for patients with co-existing AF and HFrEF (Figure 1). Rather, they suggest a strategy similar to that in AF patients with structurally normal hearts, combined with heart failure specific therapies.14–16 Rate control and rhythm control are considered to be equally effective and aggressive rhythm control is recommended only in highly symptomatic patients despite rate control. For sinus rhythm maintenance, pharmacologic rhythm control is preferred over catheter ablation. Amiodarone is recommended as the only pharmacologic rhythm-control agent in the European Society of Cardiology/European Association for Cardio-Thoracic Surgery guidelines, while either amiodarone or dofetilide are recommended in the American Heart Association/American College of Cardiology/Heart Rhythm Society (HRS) guidelines.14,15 Catheter ablation is recommended as a second line therapy unless it is the patient’s initial preference. In the 2017 HRS/European Heart Rhythm Association/European Cardiac Arrhythmia Society/Asia Pacific Heart Rhythm Society/Latin American Society of Electrophysiology and Cardiac Stimulation AF ablation

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guidelines, use of ablation for treatment of AF ablation in patients with HFrEF was again given the same recommendation as in patients with structurally normal hearts.16 In this updated guideline, ablation has been given class I indication in symptomatic paroxysmal AF when used as second-line therapy (failed medical management) and class IIa recommendation as first-line therapy.

Current Evidence for Rhythm Control in Patients with Co-existing AF and HFrEF Pharmacological Rhythm Control Two landmark studies have assessed the efficacy of pharmacological rhythm control in patients with concomitant AF and HFrEF (Table 1). In the Danish Investigators of Arrhythmia and Mortality on Dofetilide in Congestive Heart Failure (DIAMOND-CHF) trial,17 1,518 patients were randomised to receive either dofetilide (n=762) or placebo (n=758). At the conclusion of the trial, 65 % of patients in the dofetilide arm were in sinus rhythm versus 30 % of patients in the placebo arm. There was no difference in overall mortality between the dofetilide and placebo groups. Among the patients who were in AF at baseline, those in the dofetilide arm had lower rates of heart failure hospitalisation compared with those in placebo.

In the Atrial Fibrillation and Congestive Heart Failure (AF-CHF) trial,18 1,376 patients with HFrEF (mean left ventricular ejection fraction 27 %) were assigned to either aggressive rhythm control (n=682) or rate control (n=694). The rhythm-control strategy mainly involved cardioversions and antiarrhythmics (if needed) for sinus rhythm maintenance. Overall, 82 % of patients in the rhythm control arm were placed on amiodarone

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Clinical Review: Electrophysiology and Ablation Figure 1: Current Guideline Recommendation for Management of AF in Patients with HFrEF 14,15 Long-term rhythm-control therapy for symptomatic AF

Figure 2: Kaplan–Meier Curves Comparing Survival Free of the Primary Endpoint (Death From Any Cause) or Admission for Worsening Heart Failure) and its Two Components in the Catheter Ablation and Medical Treatment Groups in CASTLE-AF A. Composite of all-cause death and WHF admission

Heart failure

Heart failure

Amiodarone dofetilide

2016 ESC/EACTS AF guidelines

Catheter ablation

1.0 Survival probability

2014 AHA/ACC/HRS AF guidelines

Patient’s choice

0.8 Ablation

0.6

HR 0.62 (95 % CI, 0.43-0.87) Cox regression, P=0.007

0.4

Pharmacological

Log-rank, P=0.006

0.2 0.0 0

12

24

36

48

60

58 48

22 12

Follow-up time (months)

Amiodarone (I)

Catheter ablation (IIa)

ACC = American College of Cardiology; AHA = American Heart Association; EACTS = European Association for Cardio-Thoracic Surgery; ESC = European Society of Cardiology; HRS = Heart Rhythm Society.

Patients at risk Ablation 179 Pharmacological 184

141 145

114 111

76 70

B. All-cause death 1.0

Pharmacological rhythm control for patients with co-existing HFrEF and AF is currently limited to amiodarone and dofetilide, with dofetilide mostly unavailable outside of the US. Class I antiarrhythmics, along with sotalol and dronedarone, are contraindicated in patients with reduced ejection fraction. 19–23 Although amiodarone and dofetilide are safe to be used in HFrEF, dofetilide initiation requires initial hospitalisation. Amiodarone use is associated with a high discontinuation rate and is suggested to be associated with increased non-cardiovascular death.24

Ablation

Survival probability

versus 7 % in the rate control arm. After a median of 47 months, 73 % of patients in the rhythm control arm were in sinus rhythm compared to 35 % in the rate control arm. There was no difference in cardiovascular mortality between the two groups.

0.6

Pharmacological

HR 0.53 (95 % CI, 0.32-0.86) Cox regression, P=0.011

0.4

Log-rank, P=0.009

0.2 0.0 0

12

24

36

48

60

71 63

27 19

Follow-up time (months) Patients at risk 179 Ablation Pharmacological 184

154 168

130 130

94 97

C. WHF admission 1.0 Survival probability

Catheter Ablation The DIAMOND-CHF and AF-CHF trials raised valid scepticism on the benefit of sinus rhythm maintenance over rate control in patients with co-existing AF and HFrEF. The reason for such a lack of clinical benefit of pharmacologic rhythm control may be in part due to the significant toxicity that is associated with antiarrhythmic drugs. Catheter ablation is an alternative means for sinus rhythm maintenance while sparing the patient from potential side effects of antiarrhythmic drugs.

0.8

0.8

Ablation

0.6

HR 0.56 (95 % CI, 0.37-0.83) Cox regression, P=0.004

0.4

Pharmacological

Log-rank, P=0.004

0.2 0.0 0

12

24

36

48

60

58 48

22 12

Follow-up time (months)

Several randomised controlled trials have assessed the efficacy of catheter ablation for rhythm control in patients with concomitant AF and HFrEF (Table 2).25-31 The Pulmonary Vein Antrum Isolation Versus Atrioventricular Node Ablation with Biventricular Pacing for Treatment of Atrial Fibrillation in Patients with Congestive Heart Failure (PABACHF) trial compared pulmonary vein isolation (n=41) to atrioventricular (AV) node ablation plus biventricular pacing (n=40) for the composite of ejection fraction, 6-minute walk distance and Minnesota Living with Heart Failure (MLWHF) questionnaire.25 The study showed pulmonary vein isolation to be superior to AV node ablation and biventricular pacing with respect to the primary endpoint.

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Patients at risk Ablation 179 Pharmacological 184

141 145

114 111

76 70

WHF = worsening heart failure. Source: From N Engl J Med, Marrouche NF, Brachmann J, Andresen D, et al., Catheter ablation for atrial fibrillation with heart failure, 378, 417-27, © 2018, Massachusetts Medical Society. Reprinted with permission.30

The Randomised Trial to Assess Catheter Ablation Versus Rate Control in the Management of Persistent Atrial Fibrillation in Chronic Heart Failure (ARC-HF) trial compared catheter ablation (n=26) with rate control (n=26) in patients with HFrEF (ejection fraction <35 %) and persistent AF. Patients who underwent catheter ablation had a

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Treatment of Atrial Fibrillation Table 1: Landmark Trials for Pharmacological Rhythm Control of Atrial Fibrillation in Patients with Heart Failure and Reduced Ejection Fraction Study

Publication

Sample

Treatment

Comparator

Follow-up

Year

Size

Arm (n)

Arm (n)

(months)

Primary Endpoint

Results

DIAMOND-CHF17

1999

1,518

Dofetilide (762)

Placebo (756)

AF-CHF18

2008

1,376

Rhythm control with mainly amiodarone (682)

Rate control (694)

36

Death from any cause

No difference in mortality

60

Death from cardiovascular causes

No difference for cardiovascular death

Table 2: Landmark Trials for Catheter Ablation of Atrial Fibrillation in Patients with Heart Failure and Reduced Ejection Fraction Publication

Sample

Catheter

Comparator

Follow-up

Year

Size

Ablation

Arm (n)

(months)

Primary Endpoint

Results

PABA-CHF25

2008

81

PVI (41)

AV node ablation with biventricular pacing (40)

6

Composite of ejection fraction, 6-minute walk distance and MLWHF score

Catheter ablation was superior to AV nodal ablation and biventricular pacing

MacDonald et al., 200131

2011

41

PVI ± linear ablations ± CFAE ablation (22)

Rate control (19)

6

Cardiac MRI ejection fraction

No significant difference between groups

ARC-HF26

2013

52

PVI ± linear ablations ± CFAE ablation (26)

Rate control (26)

12

Peak VO2

Improvement in peak VO2 in the catheter ablation group compared with rate control

CAMTAF27

2014

50

PVI ± linear ablations ± CFAE ablation (26)

Rate control (24)

12

Left ventricular ejection fraction at 6 months

Improvement in left ventricular ejection fraction at 6 months in catheter ablation group

AATAC28

2016

203

PVI ± posterior wall isolation ± CFAE ablation (102)

Amiodarone (101)

36

Freedom from AF

Significant improvement in freedom from AF in the catheter ablation group

CAMERAMRI29

2017

68

PVI + posterior wall isolation (34)

Rate control (34)

6

Left ventricular ejection fraction

Significant improvement in ejection fraction in catheter ablation group

CASTLE-AF30

2018

363

PVI ± linear ablations ± CFAE ablation (179)

Medical rate or rhythm control (184)

60

Death or heart failure hospitalisation

Significant improvement in composite endpoint of death and heart failure hospitalisation in catheter ablation group

Study

Arm (n)

AV = atrioventricular; CFAE = complex fractionated atrial electrograms; MLWHF = Minnesota Living with Heart Failure; PVI = pulmonary vein isolation; VO2 = maximum rate of oxygen consumption.

significant improvement in the primary endpoint of peak oxygen consumption at 12 months.26 The patients who underwent catheter ablation also had significant improvements in their B-type natriuretic peptide and MLWHF scores, as well as a trend towards improving their ejection fraction. Eighty-eight per cent of patients who underwent catheter ablation were able to maintain sinus rhythm at 1 year with a single procedure success rate of 68 %.

In the Catheter Ablation Versus Medical Treatment of Atrial Fibrillation (CAMTAF) trial, patients with persistent AF and symptomatic heart failure (ejection fraction <50 %) were randomised to either catheter ablation (n=26) or rate control (n=24).27 The primary endpoint was improvement in ejection fraction at 6 months. Patients who underwent catheter ablation had a significant improvement in their ejection fraction as well as improvement in their peak oxygen consumption and MLWHF scores compared with patients who underwent rate control.

In the Ablation Versus Amiodarone for Treatment of Atrial Fibrillation in Patients with Congestive Heart Failure and an Implanted ICD/CRT

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Defibrillator (AATAC) trial, 203 patients with persistent AF and HFrEF (ejection fraction <40 %) and an ICD or CRT defibrillator were randomised to either catheter ablation (n=102) or amiodarone (n=101) for rhythm control.28 The primary endpoint of the study was freedom from AF or atrial flutter during the follow-up period of 2 years. The patients in the catheter ablation group had significantly higher rates of freedom from AF (70 %) compared with the amiodarone (34 %) group. The secondary endpoints of the AATAC trial were unplanned hospitalisation and death; the catheter ablation group showed significant improvement in both. The number needed to treat (NNT) to avoid one unplanned hospitalisation was 3.8 patients and NNT to avoid one death was 10 patients for catheter ablation versus amiodarone. Patients who underwent catheter ablation also had significantly higher improvements in their ejection fraction, 6-minute walk distance and MLWHF scores.

Catheter Ablation Versus Medical Rate Control in Atrial Fibrillation and Heart Failure: An MRI Guided Multicentre Randomised Controlled Trial (CAMERA-MRI) randomised 68 patients with persistent AF and idiopathic cardiomyopathy (ejection fraction <45 %) to receive either catheter

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Clinical Review: Electrophysiology and Ablation ablation (n=34) or medical rate control (n=34).29 All patients received a cardiac MRI prior to randomisation. Patients in the catheter ablation arm had a significantly higher improvement in their left ventricular ejection fraction at 6 months. In patients who underwent catheter ablation, absence of left ventricular late gadolinium enhancement at baseline was a predictor for greater improvement in the ejection fraction at 6 months.

CASTLE-AF is distinct from previous randomised controlled trials as it is the first trial to include hard primary endpoints of death and worsening heart failure hospitalisation. It is also the largest study for catheter ablation in AF and HFrEF population and has the longest follow-up period (60 months), which included patients with both paroxysmal and persistent AF. Moreover, the comparison arm included both rate and rhythm control as the target strategy.

Most recently, the efficacy of catheter ablation in patients with AF and HFrEF was studied in the Catheter Ablation Versus Standard Conventional Treatment in Patients with Left Ventricular Dysfunction and Atrial Fibrillation (CASTLE-AF) trial.30 In this study, 363 patients with either paroxysmal or persistent AF, HFrEF (ejection fraction <35 %), New York Heart Association class >II and an ICD or CRT defibrillator were randomised to undergo catheter ablation (n=179) or medical therapy with either rate or rhythm control (n=184). This was the first ablation study to report hard primary endpoint of the composite of all-cause mortality or hospitalisation for worsening heart failure. The trial showed a significantly improved primary endpoint in the catheter ablation arm compared with the medical therapy arm (Figure 2). Catheter ablation resulted in an 18 % absolute risk reduction and the NNT to prevent one primary endpoint event was six patients. The catheter ablation group also showed significant improvements in endpoints of death, heart failure hospitalisation, cardiovascular death and cardiovascular hospitalisation compared with the medical therapy group. At 60 months, left ventricular ejection fraction in the catheter ablation group had increased by 9 % compared with none in the medical therapy arm.

Some limitations of CASTLE-AF are prolonged enrolment period, lack of blinding with respect to randomisation and treatment. In addition, all patients in the study had an ICD or a CRT defibrillator, which may have affected the overall mortality.

1.

iyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends M 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.org/10.1161/CIRCULATIONAHA.105.595140; PMID: 16818816.

2. 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.

3. 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.

4. Colilla S, Crow A, Petkun W, et al. Estimates of current and future incidence and prevalence of atrial fibrillation in the U.S. adult population. Am J Cardiol 2013;112:1142–7. https://doi.org/10.1016/j.amjcard.2013.05.063; PMID: 23831166.

5. Andersson T, Magnuson A, Bryngelsson IL, et al. All-cause mortality in 272,186 patients hospitalized with incident atrial fibrillation 1995-2008: a Swedish nationwide longterm case-control study. Eur Heart J 2013;34:1061–7. https://doi.org/10.1093/eurheartj/ehs469; PMID: 23321349.

6. Wattigney WA, Mensah GA, Croft JB. Increased atrial fibrillation mortality: United States, 1980–1998. Am J Epidemiol 2002;155:819–26. https://doi.org/10.1093/aje/155.9.819; PMID: 11978585.

7. Kim MH, Johnston SS, Chu BC, et al. Estimation of total incremental health care costs in patients with atrial fibrillation in the United States. Circ Cardiovasc Qual Outcomes 2011;4:313–20. https://doi.org/10.1161/CIRCOUTCOMES.110.958165; PMID: 21540439.

8. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics 2015 update: a report from the American Heart Association. Circulation 2015;131:e29–322. https://doi.org/10.1161/CIR.0000000000000152; PMID: 25520374.

9. Santhanakrishnan R, Wang N, Larson MG, et al. Atrial fibrillation begets heart failure and vice versa: temporal associations and differences in preserved versus reduced ejection fraction. Circulation 2016;133:484–92. https://doi.org/10.1161/CIRCULATIONAHA.116.022835; PMID: 26746177.

10. Anter E, Jessup M, Callans DJ. Atrial fibrillation and heart failure: treatment considerations for a dual epidemic. Circulation 2009;119:2516–25. https://doi.org/10.1161/CIRCULATIONAHA.108.821306; PMID: 19433768.

11. Dries DL, Exner DV, Gersh BJ, et al. Atrial fibrillation is associated with an increased risk for mortality and heart failure progression in patients with asymptomatic

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12.

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Should Catheter Ablation be the First Line of Therapy?

The current American and European guidelines for management of patients with AF and HFrEF relied heavily on the DIAMOND-CHF and AF-CHF trials, which found no mortality benefit in pharmacological rhythm control over rate control. At the time of these publications, randomised controlled trials to assess the efficacy of catheter ablation were small and none had assessed mortality as a primary endpoint.

The CASTLE-AF trial, on the other hand, evaluated the hard endpoints of death and heart failure hospitalisations and showed catheter ablation to be superior to conventional medical treatment of either rate or rhythm control. Given this information, the CASTLE-AF trial argues the current guidelines endorse catheter ablation as first-line therapy for the treatment of AF in patients with HFrEF regardless of AF type. n

and symptomatic left ventricular systolic dysfunction: a retrospective analysis of the SOLVD trials. Studies of left ventricular dysfunction. J Am Coll Cardiol 1998;32:695–703. https://doi.org/10.1016/S0735-1097(98)00297-6; PMID: 9741514.

Wang TJ, Larson MG, Levy D, et al. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study. Circulation 2003;107:2920–5. https://doi.org/10.1161/01.CIR.0000072767.89944.6E; PMID: 12771006.

Mamas MA, Caldwell JC, Chacko S, et al. A meta-analysis of the prognostic significance of atrial fibrillation in chronic heart failure. Eur J Heart Fail 2009;11:676–83. https://doi.org/10.1093/eurjhf/hfp085; PMID: 19553398.

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.

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/10.1093/europace/euw295; PMID: 27567465.

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. Europace 2018;20:157–208. https://doi.org/10.1093/europace/eux275; PMID: 29016841.

Torp-Pedersen C, Møller M, Bloch-Thomsen PE, et al. Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish investigations of arrhythmia and mortality on dofetilide study group. N Engl J Med 1999;341:857– 65. https://doi.org/10.1056/NEJM199909163411201; PMID: 10486417.

Roy D, Talajic M, Nattel S, et al. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med 2008;358:2667–77. https://doi.org/10.1056/NEJMoa0708789; PMID: 18565859.

Lafuente-Lafuente C, Valembois L, Bergmann JF, Belmin J. Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation.

Cochrane Database Syst Rev 2015;3:CD005049. https://doi.org/10.1002/14651858.CD005049.pub4; PMID: 25820938.

Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The cardiac arrhythmia suppression trial. N Engl J Med 1991;324:781–8. https://doi.org/10.1056/NEJM199103213241201; PMID: 1900101.

Flaker GC, Blackshear JL, McBride R, et al.

Antiarrhythmic drug therapy and cardiac mortality in atrial fibrillation. The stroke prevention in atrial fibrillation investigators. J Am Coll Cardiol 1992;20:527–32.

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Waldo AL, Camm AJ, deRuyter H, et al. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD investigators survival with oral d-sotalol. Lancet 1996;348:7–12. https://doi.org/10.1016/S0140-6736(96)02149-6; PMID: 8691967.

Køber L, Torp-Pedersen C, McMurray JJ, et al.

Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med 2008;358:2678–87. https://doi.org/10.1056/NEJMoa0800456; PMID: 18565860.

Steinberg JS, Sadaniantz A, Kron J, et al. Analysis of cause-specific mortality in the atrial fibrillation follow-up investigation of rhythm management (AFFIRM) study. Circulation 2004;109:1973–80. https://doi.org/10.1161/01.CIR.0000118472.77237.FA; PMID: 15051639.

Khan MN, Jaïs P, Cummings J, et al. Pulmonary-vein isolation for atrial fibrillation in patients with heart failure. N Engl J Med 2008;359:1778–85. https://doi.org/10.1056/NEJMoa0708234; PMID: 18946063.

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.

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.

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.

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.

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.

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Clinical Reviews: Cardiac pacing

Pacing for Vasovagal Syncope Rakesh Gopinathannair, 1 Benjamin C Salgado 1 and Brian Olshansky 2 1. Division of Cardiovascular Medicine, University of Louisville, Louisville, USA; 2. Mercy Heart and Vascular Institute, Mason City; and the University of Iowa Hospitals, Iowa City, USA

Abstract Vasovagal syncope (VVS) is due to a common autonomic reflex involving the cardiovascular system. It is associated with bradycardia (cardioinhibitory response) and/or hypotension (vasodepressor response), likely mediated by parasympathetic activation and sympathetic inhibition. While generally a situational, isolated and/or self-limited event, for some, VVS is recurrent, unpredictable and debilitating.

Conservative, non-pharmacological management may help, but no specific medical therapy has been proven widely effective. Permanent pacing may have specific benefit, but its value has been debated. The temporal causative association of bradycardia with syncope in those with VVS may help identify which patient could benefit from pacing but the timing and type of pacing in lieu of blood pressure changes may be critical. The mode, rate, pacing algorithm and time to initiate dual-chamber pacing preferentially with respect to the vasovagal reflex may be important to prevent or ameliorate the faint but completely convincing data are not yet available. Based on available data, DDD pacing with the closed loop stimulation algorithm appears a viable, if not the best, alternative presently to prevent recurrent VVS episodes. While several knowledge gaps remain, permanent pacing appears to have a role in managing select patients with VVS.

Keywords Syncope, vasovagal syncope, pacing, closed loop stimulation, asystole, rate drop response Disclosure: Rakesh Gopinathannair has received consultant/speaker fees from Abbott, the American Heart Association, Pfizer, Bristol Myers Squibb and Zoll, and is on the advisory board of HealthTrust PG. Brian Olshansky has received consultant/speaker fees from Amarin Corporation, Boehringer Ingelheim, Cryolife and Lundbeck.

Benjamin Salgado has no conflicts of interest to declare.

Received: 5 April 2018 Accepted: 3 May 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(2):95–102. https://doi.org/10.15420/aer.2018.22.2 Correspondence: Brian Olshansky, Division of Cardiology, University of Iowa Hospitals, 4426a JCP, 200 Hawkins Drive, Iowa City, IA 52242, USA. E: brian-olshansky@uiowa.edu

Heart rate and blood pressure are tightly regulated by autonomic control to effect adequate blood flow as needed. This regulatory process breaks down when the vasovagal reflex is activated.

Profound, but brief, circulatory collapse manifests as bradycardia (cardioinhibitory response) and/or hypotension (vasodepressor response) and/or altered cerebral autoregulation, resulting in transient loss of consciousness, often with prodromal signs and symptoms (pallor, sweating and nausea) and profound fatigue and nausea during recovery.1,2 This complex neurocardiogenic reflex presents with a wide range of clinical scenarios, from isolated, sporadic, easily explained episodes, to frequent, recurrent and baffling events that, while not usually life-threatening, can be devastating.3,4 Vasovagal syncope (VVS) in otherwise healthy individuals is the most common cause for syncope.5,6 The vasovagal reflex is often responsible for syncope in other conditions as well, such as pulmonary emboli, aortic stenosis, hypertrophic cardiomyopathy, inferior myocardial infarction, gastrointestinal bleeding and dehydration.

The exact mechanism underlying and triggering the vasovagal reflex continues to be studied and debated, but inputs causing the reflex are manifold.7 Afferent signals from the peripheral vagus (and perhaps from central locations), processed in the nucleus tractus solitarius, elicit an efferent, phasic, abrupt and rapidly reversible parasympathetic response, causing transient relative sinus bradycardia, sinus arrest or paroxysmal atrioventricular (AV) block.8. Frequently, there is sudden disappearance of muscle sympathetic nerve activity at a time of

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diminishing cardiac output, causing vasodilation and hypotension,9-11 and it has been argued the bradycardia and asystole are due to sympathetic withdrawal.12 There can be impairment of ventricular contractility, with consequent reduction in cardiac output,13,14 and changes in cerebrovascular autoregulation.15 There are influences of circulating mediators, such as epinephrine, renin, endothelin, vasopressin, cortisol, prolactin, beta-endorphins, substance P, nitric oxide synthase and even adenosine, in some individuals.16–19 One postulated initiating factor is transient, excess, time-dependent, sympathetic activation, causing increased ventricular contractility, subsequent mechanoreceptor activation, initiating vagal (atrial and/or ventricular C fibre) afferent activation that is epinephrine dependent and the subsequent reflex.20 However, for those who are susceptible, triggers include prolonged standing, pain, psychological or emotional stressors, noxious stimuli or, simply, nothing at all.21–23 The reflex may be manifest in many ways and no individual necessarily has a unique footprint of their physiological perturbations.

Two processes, parasympathetic activation and sympathetic inhibition, are linked but are not necessarily concomitant or the same for recurrent events.24 Tachycardia may precede bradycardia and collapse (Figure 1).25 Whatever the mechanism, it is complex, different in younger versus older individuals, occurs in phases (often with contradictory physiology) and resolves rapidly and mysteriously likely in concert with enhanced venous return.7

Access at: www.AERjournal.com

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Clinical Review: Cardiac Pacing Figure 1: Example of a Typical Vasovagal Reflex

Table 1: Caveats Concerning Vasovagal Syncope • Triggers of vasovagal syncope (VVS) may or may not be reproducible.

• Exact mechanisms of VVS are unknown, with no pharmacological target to address.

• Mechanisms leading to recovery from the vasovagal reflex are unknown.

• It remains unclear if VVS can be aborted once the reflex is underway.

• Heart rate and blood pressure manifestations can vary from episode to episode.

• Heart rate and blood pressure perturbations may not be simultaneous.

• Syncope can occur before asystole and even if asystole is prevented.

• Heart rate and blood pressure manifestations of VVS can vary by age.

• There is no gold standard test to emulate what happens during VVS.

5 seconds

An example of a transient vasovagal response during a tilt table testing that begins with tachycardia followed subsequently by bradycardia and hypotension that develop nearly simultaneously and resolve upon laying the patient flat. The upper panel shows heart rate and the lower panel shows systolic blood pressure measured through an arterial line.

Figure 2: Hypotension and Bradycardia in Vasovagal Syncope

Preventing Recurrence of Vasovagal Syncope While most episodes of VVS are self-limiting, for some, the problem can be recurrent and devastating. Multiple non-pharmacological approaches may modulate the vasovagal response. Adequate hydration, avoidance of triggering events (e.g. donating blood) and physical counter-pressure manoeuvres during an event have been advocated,26,27 yet, no robust data point to any benefit of these recommendations or any effective pharmacological approach. This is not surprising, since the reflex is abrupt and transient and so any tonic intervention would not necessarily prevent an occasional autonomic destabilisation and may in fact worsen episodes if the autonomic nervous system otherwise becomes unbalanced.28 Pacing has been postulated to be effective as it can prevent severe bradycardia and asystole. Here, we explore the data on the use of pacing to prevent recurrent VVS.

Caveats Concerning Vasovagal Syncope A prodrome, often present in VVS, may occur before bradycardia or hypotension.29 It is likely that this involves early changes in the autonomic activation and cardiac contractility before the faint.12 The relationship of bradycardia to hypotension can vary from person to person, and between episodes in the same individual (Table 1).24 Furthermore, there is no physiological gold standard to assess VVS; tilt-testing (with or without adjunct nitroglycerin or isoproterenol) does not emulate what happens in real life and thus may not reproduce heart rate and blood pressure responses that occur spontaneously.30 Recently, Saal et al. used video recordings, electroencephalography, and blood pressure and heart rate measurements to assess the relationship of bradycardia and hypotension to loss of consciousness during a vasovagal faint. Asystole occurred after the faint began in one-third of cases, making it unlikely to be the primary cause of syncope, and suggesting that bradycardia monitoring alone may overestimate which patients with VVS actually passed out from asystole31 (Figure 2). The incidence and extent of bradycardia, presumably related to a vasovagal reflex, but as a cause for syncope, may be age-dependent and confusing.

While the incidence of bradycardia and asystole due to the vasovagal reflex may not vary by age as determined by tilt table testing,32,33 bradycardia in older patients may present due to concomitant underlying sinus node dysfunction. Older patients have different mechanisms at play that lead to hypotension and reduced cardiac output compared with younger ones.6,7 Reliance on rhythm monitoring to decide upon the utility of pacing in VVS may thus be misguided in some patients.24.

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Relationship between the onset of hypotension and bradycardia in a patient with vasovagal syncope. Note the blood pressure drop occurring prior to the decline in heart rate. Afferent signals from the peripheral vagus and, perhaps, central locations, processed in the nucleus tractus solitarius, elicit an efferent, abrupt and rapidly reversible parasympathetic response causing transient relative sinus bradycardia, sinus arrest or paroxysmal AV block. Also, there is sudden disappearance of muscle sympathetic nerve activity at a time of diminishing cardiac output causing vasodilation and hypotension. These two processes, parasympathetic activation and sympathetic inhibition, are linked but are not necessarily concomitant.

However, given no clearly effective drug or drug combination,34,35 the association of episodes with bradycardia or asystole naturally makes one consider permanent pacing for selected individuals including those who are young (Figure 3). In this manuscript, we provide a critical review of the role of permanent cardiac pacing for VVS.

Pacing for Vasovagal Syncope Even if bradycardia or asystole occur around the time of syncope, pacing may not prevent syncope if hypotension is profound and the cause for syncope (Table 2).36–38 However, pacing may be able to modulate the VVS episode if performed early in the onset of hypotension, perhaps at rates greater than the lower rate limit of the pacemaker. If pacing were to work, it would be unlikely to be effective if it were single chamber ventricular pacing or pacing at the lower rate limit. Because hypotension is likely to be a concomitant factor, AV sequential pacing at approximately 100 BPM would be desirable.39.

However, it is uncertain what rate is best to pace and if this could offset the effect of vasodilatation enough to prevent loss of consciousness.

Pacing too fast may also drop the blood pressure. Moreover, the type, timing and rate of pacing likely makes a difference; physiological (AV sequential) pacing would be more likely to provide haemodynamic support in a patient who has peripheral vasodilatation (Figure 4).

The relationship of the timing of pacing to events that occur during the vasovagal reflex may determine success.24

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Pacing for Syncope Figure 3: Asystole in Recurrent Syncope

Table 2: Pacing for Vasovagal Syncope • Single chamber atrial or ventricular pacing is not likely to have any benefit.

• Pacing at the lower rate limit will likely be ineffective.

• An algorithm to increase rate abruptly with AV synchrony at episode onset is desirable.

• Mechanisms to increase rate have utilised algorithms such as the rate-drop response, during which the rate increases abruptly if a gradual slowing is seen; or the algorithm associated with closed loop stimulation, during which pacing rate increases if there is evidence of changes in local impedance that may reflect changes in right ventricular contractility by a proprietary algorithm.

Asystole in a 21-year-old woman with recurrent syncope. She had a negative tilt-table test.

She received a pacemaker after having multiple syncope episodes and, since then, has never fainted in over 10 years of follow-up. Source: Reprinted from J Am Coll Cardiol, 70, Olshansky, Vasovagal syncope: to pace or not to pace, 1729-1731, 2017. Reprinted with permission from Elsevier.24

Figure 4: Pathophysiological Mechanisms in VVS Leading to Bradycardia and Hypotension, Role of Pacing and C ­ urrently Used Pacing Algorithms

CENTRAL TRIGGERS

Visceral afferents Sympathetic efferents

SOMATIC AND VISCERAL TRIGGERS

Vagus efferents

Vagus afferents

Response to hypotension

Pace maker

VASODILATATION Lower extremity

SPLANCHNIC VASODILATATION

Mechanoreceptors BRADYCARDIA/ ASYSTOLE

RESPONSE TO VVS TRIGGER A

Vasodepression

Blood pressure CPP

A SUDDEN BRADYCARDIA/ ASYSTOLE Example of RDR functioning as a simple rate hysteresis device

Syncope

B

PACING Blood pressure

B

HR ↓ Vasodepression

CPP Syncope

C

Blood pressure

Blood vessels

Vasodepression

SLOWER ONSET BRADYCARDIA + PROMINENT VD Example of RDR introducing pacing late and possibly inefficiently

C

CLOSED LOOP STIMULATION

RATE DROP RESPONSE

• RV impedence measurement reflective of RV contractility

• ↓ in HR detected • Abruptly ↑ HR by pacing (AV sequential) at a higher rate

• CLS algorithm ↑pacing rate

Abort syncope

EARLY ONSET OF VD Detected by CLS algorithm

CPP Syncope

HR ↓

There is generally considered to be a close relationship between systolic blood pressure and CPP with a critical level of 60-70 mmHg. CPP = cerebral perfusion pressure; CLS = closed loop stimulation; HR = heart rate; VD = vasodepression; RV = right ventricle; RDR = rate drop response.

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Clinical Review: Cardiac Pacing Figure 5: Asystolic Spell During a Vasovagal Episode

one episode lasting 63 seconds.41 Despite no pacemaker implant and with generally conservative management, after a median of 42 months of follow-up, four had syncope and only one had syncope-related injury, suggesting that pacing is not required for all individuals even if they have asystole on the tilt-table test41 (Figure 5).

Nevertheless, there are those who continue to collapse without warning and with asystole, for whom a pacemaker may prevent or reduce the frequency or severity of episodes (Figure 3).

Studies Evaluating Pacing

Long asystolic spell during a vasovagal episode. This patient, however, did well with conservative management and did not need a pacemaker.

Figure 6: Ventricular Pacing During Head-up Tilt Testing

Early data supported use of pacing for VVS. Fitzpatrick et al. compared symptoms and haemodynamics in patients with VVS who had a positive tilt-table test response with evident bradycardia. Temporary AV sequential pacing during tilt-table testing with simulated rate hysteresis aborted five out of six syncopal episodes.42 Similarly, DDI pacing with rate hysteresis appeared effective in patients with cardioinhibitory VVS.43 However, Sra et al. evaluated patients who had bradycardia and/or asystole with hypotension during tilt table testing.

For most patients, blood pressure declined much earlier (42 ± 29 seconds) than heart rate. With temporary AV sequential pacing, most patients continued to have a blood pressure drop with symptoms but to a lesser degree than without it (Figure 6).25 This finding likely has mechanistic implications with regard to patients employing counterpressure manoeuvres or adopting a safer position such as sitting or lying down, thereby avoiding injury. It appears that rapid pacing faster than the lower rate may be necessary to provide adequate improvement in cardiac output and this reduce risk of syncope. Initial attempts at pacing were rather disappointing,44 but with a rate-drop response algorithm triggered by abrupt slowing in rate at the onset of VVS could lead to rapid AV sequential pacing for a selected time interval. Initial data looked promising.45,46

The heart rate and blood pressure measured with the patient supine and at the start of the head-up tilt test are shown in A and B, respectively. At 5 minutes (C), cardiac asystole ensued, lasting 10.5 seconds. After the patient was placed in the supine position again and heart rate and blood pressure were stabilised (D), the test was repeated during ventricular pacing (E). At 6.5 minutes (F), there was a significant decrease in arterial pressure and syncope occurred despite ventricular pacing at a rate of 80 BPM. A negative response to the tilt test was seen after 3 days of oral metoprolol therapy, as exemplified by the tracing at 15 minutes (G).

Source: Sra et al., 1993.25 Reprinted with permission from Massachusetts Medical Society.

Is Pacing Necessary?

Although it may seem straightforward that pacing can help patients with syncope and bradycardia, cardiac pacing has a limited role in managing VVS. It is more than just the fact that data conflict regarding benefit of pacing to prevent syncope recurrence.40 Pacing may not effectively counteract vasodilatation, but may modulate hypotension if fast enough. It is important to know the frequency of recurrent VVS and also the need for future intervention. Those with VVS and documented asystole during tilt-table testing do not necessarily require any intervention.

Carvalho et al. performed 2,263 consecutive tilt-table tests (utilising isosorbide dinitrate) in 2,247 patients with syncope finding that 149 had asystole (mean 10 seconds); 11 had asystole for ≥30 seconds with

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The North American Vasovagal Pacemaker Study (VPS I) randomised patients with three or more episodes of syncope and a positive tilttable test (hypotension and relative bradycardia) to dual chamber pacing (lower rate of 60 BPM with rate-drop response) versus no pacemaker. Subsequent syncope occurred in 70 % with no pacemaker but only 22 % in the pacemaker group, a stunning 85 % reduction (CI [59.7–94.7 %]; p=0.00002). The mean time from randomisation to syncope was 54 days in the no-pacemaker group and 112 days in the pacemaker group.37 Since this study was not blinded, a placebo response to pacing could not be ruled out.

VASIS (Vasovagal Syncope International Study), a multicentre randomised study, compared DDI pacing with rate hysteresis to standard therapy in patients with three or more syncope episodes over 2 years and positive cardioinhibitory response at tilt-table testing. Only one patient (5 %) in the pacemaker group had syncope versus 61 % given standard therapy (p=0.0006).47 Similarly, Ammirati et al. performed a multicentre, randomised study of dual-chamber pacing with rate-drop response versus atenolol in patients ≥35 years who had three or more syncopal episodes in the preceding 2 years and positive tilt-table test showing relative bradycardia [Syncope Diagnosis and Treatment (SYDIT) study].48 There was a 4.3 % recurrence of syncope after a median of 390 days in the pacemaker group versus 25.5 % after median of 135 days in the atenolol group (OR 0.133; 95 % CI [0.028–0.632], p=0.004). Again, a placebo response to pacing could not be excluded.

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Pacing for Syncope To determine the impact of a placebo response, the VPS II (North American Vasovagal Pacemaker Study II) was performed. This multicentre, double-blinded trial compared VVS patients randomised to DDD pacing with rate-drop response or to pacemaker turned off (placebo). There was no significant reduction in syncope recurrence with active pacing indicating a potential contributory placebo effect of pacing but the study may have been underpowered to show a small difference as there was a 30 % reduction in syncope recurrence between groups (95 % CI [−33–63 %]; 1-sided p=0.14).36 Moreover, the follow-up was only 6 months and intense bradycardia documentation was not an entry criterion. These data were further supported by SYNPACE (The vasovagal Syncope and Pacing Trial), a multicentre randomised, double-blinded, placebo-controlled study of syncope positive tilt-table test patients who underwent pacemaker placement. There was no difference in syncope recurrence between those who had active DDD pacing with rate-drop response versus no effective pacing.49 SYNPACE also did not require a thorough effort to document intense bradycardia as an inclusion criteria. These issues prompted development of the ISSUE-2 registry.50 The ISSUE-3 (Third International Study on Syncope of Uncertain Etiology) trial, a double-blinded, randomised, placebo-controlled, multicentre study, included patients ≥40 years, with three or more syncopal episodes in the previous 2 years who had documentation of syncope with an implantable loop recorder (ILR) showing ≥3 seconds of asystole in a symptomatic episode or ≥6 seconds of asystole in an asymptomatic episode. Patients were randomly assigned to DDD pacing with rate-drop response or sensing only. With pacing, the risk of syncope recurrence was reduced 57 % (95 % CI [4–81]) from 57 % to 25 %; p=0.039).51 ISSUE-3, however, was not without issues. Patients who had asystole during tilt-table testing had less benefit from pacing. As the average age of enrollees was 63 years and only 44 % had a typical vasovagal/ situational presentation, one must wonder if the benefit of pacing to prevent bradycardia was due to VVS or to sinus node dysfunction in this older population. While this point is worth considering, much thought and discussion went into distinguishing sinus node dysfunction from a vasovagal response as part of the publication; ultimately sinus node dysfunction was considered unlikely since there was no clinical difference between the patients who might have had sinus node dysfunction and those who did not. This issue was thoroughly argued before ISSUE-3’s publication. In another report of an older population with VVS, the Syncope Unit Project (SUP-2) pacing reduced syncope burden from 200 episodes per year to 11 episodes per year, a 95 % relative reduction in 2 years of follow-up.52

Impact of Closed Loop Stimulation Until recently, rate-drop response was the most commonly studied algorithm for VVS,36,37,48,49,51 but pacing support, even at faster rates, may be too little and too late to counteract reflex vasodilation. 37 Recent evidence points to the use of closed loop simulation (CLS) to initiate pacing at an earlier stage. 24,53–59 CLS is a proprietary Biotronik algorithm, purported to measure intracardiac impedance during systole for each beat, but it actually measures local impedance in the right ventricle, which may relate to contractility.

Influencing impedance is right ventricular volume. Based on this, the algorithm adjusts pacing rate dependent upon changes in measured impedance, such as may be noted early in the onset of a vasovagal event.55,60 How best to program the CLS algorithm to allow

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intervention early on in a vasovagal reflex, and thereby prevent the faint, is detailed in Table 3.

Reports using CLS to adjust pacing are not new and date from 2004.

In an observational study, Kanjwal et al. followed patients with two or more syncopal episodes in the preceding 6 months, refractory to other treatments and evident asystole (>10 seconds) or severe bradycardia (<30 BPM) observed by implantable loop recorder or tilttable testing. Compared to those who had pacing with rate hysteresis or rate-drop response, the CLS group had less recurrent syncope (83 % versus 59 %) and greater reduction in syncope burden (84 % versus 25 %, p=0.002).53 The INVASY (Inotropy Controlled Pacing in Vasovagal Syncope) study, a randomised study, compared DDD rate-adaptive CLS to DDI pacing in patients with recurrent VVS and a positive tilt-table test with cardioinhibitory response. Seven of nine patients randomised to DDI mode had recurrent syncope during the first year, whereas none randomised to DDD-CLS did.55 The long-term utility of CLS pacing was investigated in a prospective study that followed patients for 3 years comparing events before and after implant. During follow-up, 83 % of patients were asymptomatic; only five had syncope with CLS pacing.54 In a prospective randomised single-blinded multicentre study of patients with cardioinhibitory VVS (age 62 ± 14 years), DDD-CLS (versus DDD) pacing reduced syncope occurrence induced by tilt-table testing (30 % versus 77 %; p<0.001), reduced blood pressure drop during tilt-table testing and significantly delayed onset of syncope.57 In another report of patients (age 53 ± 5.1 years) with tilt-table induced cardioinhibitory response who were randomised to CLS “off” versus “on” for 18 months in a crossover design showed that CLS pacing was associated with fewer syncopal and presyncopal events (syncope: 2 versus 15; p=0.007; presyncope: 5 versus 30; p=0.004).58 The SPAIN (Closed Loop Stimulation for Neuromediated Syncope) trial, a recent, randomised, double-blinded, crossover study, enrolled patients ≥ 40 years old with high burden of syncope (five or more episodes or two or more episodes in the past year) and a cardioinhibitory response to tilt-table testing (bradycardia <40 BPM for 10 seconds or asystole >3 seconds). Patients were randomised to DDD-CLS versus sham DDI pacing (30 pulse/minute subthreshold) and crossed over at 12 months or when a maximum of three syncopal episodes occurred within 1 month. The proportion with ≥50 % reduction in syncopal episodes was 72 % (95 % CI [47–90 %]) with DDD-CLS versus 28 % (95 % CI [9.7–53.5 %]) with sham DDI mode (p=0.017). Overall, four patients in the CLS group passed out versus 21 in the DDI group. There was substantial improvement in time to first syncope in the CLS group (29 months versus 9 months; OR 11; p<0.0001). Following crossover, marked reductions in events were seen with DDD-CLS pacing in both groups. CLS resulted in a 37 % absolute risk reduction in time to first syncope (number needed to treat to prevent one syncopal episode was 2.7).59 Detecting changes in cardiac impedance measurements early using the CLS algorithm might provide prompt and aggressive heart rate support to prevent relative bradycardia or asystole and may modulate hypotension enough to prevent syncope. Thus, DDD-CLS pacing has been shown to be effective in a double-blinded trial.

To keep this in perspective, ISSUE-3, also double-blinded, showed statistically significant benefit for pacing versus sensing only modes.

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Clinical Review: Cardiac Pacing Table 3: Optimal Programming of the Closed Loop Stimulation Algorithm for Vasovagal Syncope Patients

Figure 7: Syncopal Episode During Head-up Tilt-table Testing

• T urn Resting Rate Control to “off”. This allows the closed loop stimulation (CLS) algorithm to vary rate response from base rate to the maximum programmed CLS rate based on cardiac impedance measurement variations, enabling intervention much earlier • Set the mode to “DDD-CLS Program”, with base/lower rate of 60-65 BPM, upper tracking rate of 160 BPM, and maximum CLS rate (akin to maximum sensor rate) to between 130 and 140 BPM. • Set the CLS response (aggressiveness of the CLS algorithm) to “high” or “very high”.

• Atrioventricular (AV) delay is programmed to minimise ventricular pacing using the AV hysteresis function of the pacemaker.

Source: Adapted from Kanjwal and Grubb, 2008.63

Additionally, the prospective, multicentre, observational Syncope Unit Project 2 (SUP-2) study validated a standardised guideline-based algorithm to select those for pacing.52,61 In this study, patients age >40 years with severe unpredictable recurrent reflex syncope having evidence for an asystolic response underwent dual-chamber pacing (often with a rate drop feature). Of 281 patients meeting inclusion, 137 received a pacemaker. At 3 years, the actuarial syncope recurrence rate was 20 % (95 % CI [12–30]), lower than those monitored by an implantable loop recorder (43 %, 95 % CI [29–57]; p=0.01). In our clinical experience, DDD pacing with rate-drop response, with or without additional medical therapy, can be effective as well.

The ongoing Benefit of Dual Chamber Pacing with Closed Loop Stimulation (CLS) in Tilt-induced Cardioinhibitory Reflex Syncope (BIOSync CLS) study (NCT02324920) a multicentre randomised, double-blinded, parallel trial, evaluating patients 40 years old and older with frequent VVS, will compare dual-chamber DDD-CLS pacing with placebo (pacemaker mode ODO). The study has a prespecified 2-year follow-up, with estimated completion in October 2019.62

Who Needs a Pacemaker?

The fact that pacing can be effective in some patients with syncope does not mean that it is required for all patients. Moreover, even in patients with episodic asystole that is directly temporally related to the event itself and even if it is not associated with hypotension, pacing might still not be indicated (Figure 7). Since vasovagal episodes are common, pacing needs to be directed at the subset of patients who have recurrent episodes for whom pacing will abort the episode(s).

This may include older (>40 years) individuals as well as those who experience frequent recurrences, debilitating consequence, repeated injury, limited prodrome and documented asystole.34 There is no specific reason a pacemaker would not be effective in an individual younger than 40 years, but careful consideration for an implant in a young patient is required.

An example of a syncopal episode during head-up tilt-table testing. Note asystole occurring after the patient lost consciousness. Source: Reprinted from J Am Coll Cardiol, 70, Olshansky, Vasovagal syncope: to pace or not to pace, 1729-1731, 2017. Reprinted with permission from Elsevier.24

pacing as reasonable for patients over the age of 40 years with recurrent vasovagal syncope and spontaneous pauses (class IIb, LOE B-R).33 The 2018 ESC Guidelines for the Diagnosis and Management of Syncope consider pacing is reasonable for patients over 40 years old with spontaneous documented symptomatic asystolic pauses >3 seconds or asymptomatic pauses >6 seconds due to sinus arrest, AV block or a combination (Class IIa, LOE B).26 These guidelines also recommend that pacing may be considered to reduce syncope recurrences in patients with tilt-induced asystolic response who are >40 years with recurrent frequent unpredictable syncope (Class IIb, LOE B), but advises against pacing in the absence of a cardioinhibitory response.

Similarly, the 2015 HRS Expert Consensus Statement gives a Class IIa (LOE B-R) indication for pacing in patients >40 years with recurrent, unpredictable syncope and a documented pause >3 seconds during clinical syncope or an asymptomatic pause >6 seconds.65 Pacing has a Class IIb, LOE B-R recommendation for paediatric patients with recurrent syncope with documented symptomatic asystole refractory to medical therapy.

The 2017 Systematic Review for ACC/AHA/HRS Guidelines concluded that the current evidence does not support pacing for patients with recurrent VVS and asystole.40 However, establishing a relationship between symptoms and severe bradycardia is essential before considering permanent pacing. This is easier said than done, as the role of hypotension in the reflex sequence complicates the picture.

Prolonged ECG monitoring, usually by an ILR, may be useful,34 but still the mechanism of syncope could be due to hypotension.

Confounding Issues Guidelines Guideline and consensus recommendations agree in part, but are not fully aligned.34,40,63–66 The 2008 American College of Cardiology/ American Heart Association (ACC/AHA) Pacemaker Guidelines gives a class IIb indication for pacing for symptomatic neurocardiogenic syncope associated with bradycardia documented spontaneously or by tilt-table test (level of evidence [LOE] B).63 Similarly, the 2017 ACC/ AHA/Heart Rhythm Society (HRS) Guideline for the Evaluation and Management of Patients with Syncope recommends dual-chamber.

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Older patients have a higher likelihood of sick sinus syndrome and consequent bradycardia rather than VVS and the two can be difficult to distinguish. Bradycardia recorded from a loop recorder could be problematic, as no information is available on temporal relationship of blood pressure changes relative to heart rate (Figure 8). Asystole on a tilt-table test, however, may not be a sensitive or specific indication of spontaneous asystole or the need for pacing but recurrent, frequent and severe VVS episodes could justify implanting a pacemaker.

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Pacing for Syncope Further complicating matters, a small subgroup of patients may have idiopathic AV block during syncope detected by ECG monitoring. These patients usually have a structurally normal heart, a normal ECG, no sign of conduction system disease on ECG or electrophysiology study, a normal tilt-table test and low levels of adenosine. This form of syncope generally occurs with no prodrome and is mediated by adenosine.

These patients will likely need cardiac pacing.67,68 Young patients with VVS and asystole may have a specific trigger, may have rare episodes of syncope and may not benefit from pacing therapy. Thus, caution is advised with use of long-term pacing in individuals younger than 40 years, especially since living with a pacemaker at a young age can be difficult and can lead to long-term complications. However, younger patients with frequent, debilitating, recurrent asystolic vasovagal syncope unresponsive to any other therapy or unable to be treated in any other way may indeed be candidates for pacing.

Radiofrequency ablation of ganglionic plexi in the right atrium, near the superior vena cava and sinus node, inferior vena cava, near the coronary sinus and AV node, and in the left atrium near the floor and near all four pulmonary veins with the aim of abolishing vagal efferent activation during VVS (cardioneuroablation) has shown promise in early observational studies,69-71 but larger, controlled studies with long-term follow-up are needed to confirm the safety and efficacy of this procedure.

Knowledge Gaps Despite the trials outlined above, several knowledge gaps remain: • What is the mechanism responsible for VVS and how can it be best counteracted?

• Is there a way to abort an episode of VVS before it goes to completion?

• Is pacing useful for those under the age of 40 years with recurrent VVS associated with severe bradycardia and/or asystole?

• Is there a role for concomitant medical therapy with pacing for VVS patients?

• Why does the reflex reset itself after a few seconds, and how?

• Which patients with VVS over 40 years of age require and benefit from pacing?

• Does tilt-table testing combined with ILR monitoring provide better insights into identifying the best candidates for pacing in VVS?

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Moya A. Tilt testing and neurally mediated syncope: too many protocols for one condition or specific protocols for different situations? Eur Heart J 2009;30:2174-6. https://doi.org/10.1093/ eurheartj/ehp290; PMID:19622515.

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Figure 8: Severe Bradycardia and Asystole

An example of severe bradycardia and asystole associated with syncope that was recorded by an implantable loop recorder. Since no information is available on the temporal relationship of blood pressure changes relative to heart rate, a determination as to whether this is bradycardia from organic sinus node disease or vasovagal syncope cannot be made.

• I s tilt-table testing required to evaluate the need for pacing in VVS? • Can pacing algorithms other than CLS benefit select patient subsets?

• How is it best to programme the pacemaker?

Conclusion VVS is a common problem due to a ubiquitous, counterintuitive reflex.

Initiating factors may affect sympathetic activation. While most patients can be managed conservatively without the need for specific medical interventions, emerging evidence indicates that pacing may reduce recurrent syncope for select patients, especially if episodes are frequent, recurrent and otherwise difficult to manage.

The pacing algorithm, rate, type and timing of pacing, with respect to onset of the reflex, may be critical to prevent fainting. Pacing should be considered especially if syncope occurs concomitant with a cardioinhibitory response. Tilt-table testing may help quantify the heart rate and blood pressure responses temporally associated with vasovagal syncope. By detecting local impedance in the right ventricle which may relate to contractility, CLS may assess autonomic function and improve the timing for onset of pacing. DDD pacing with rate response gauged by the CLS algorithm appears to be the current best alternative to detect the need for pacing and prevent recurrent episodes in VVS. However, compelling data also support the use of pacing with rate-drop response for patients selected by the presence of asystolic episodes. n

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45. Benditt DG, Sutton R, Gammage M, et al. “Rate-drop response” cardiac pacing for vasovagal syncope.

J Interv Card Electrophysiol 1999;3:27-33. https://doi. org/10.1023/A:1009815304770; PMID: 10354973.

46. Benditt DG, Sutton R, Gammage MD, et al. Clinical experience with Thera DR rate-drop response pacing algorithm in carotid sinus syndrome and vasovagal syncope. Pacing Clin Electrophysiol 1997;20:832-9. https://doi.org/10.1111/j.1540-8159.1997. tb03916.x; PMID: 9080522.

47. Sutton R, Brignole M, Menozzi C, et al. Dual-chamber pacing in the treatment of neurally mediated tilt-positive cardioinhibitory syncope : pacemaker versus no therapy.

Circulation 2000;102:294-9. https://doi.org/10.1161/01.

CIR.102.3.294; PMID: 10899092.

48. Ammirati F, Colivicchi F, Santini M, et al. Permanent cardiac pacing versus medical treatment for the prevention of recurrent vasovagal syncope:. Circulation 2001;104:52-7. https://doi.org/10.1161/hc2601.091708; PMID: 11435337.

49. Raviele A, Giada F, Menozzi C, et al. A randomized, doubleblind, placebo-controlled study of permanent cardiac pacing for the treatment of recurrent tilt-induced vasovagal syncope. Eur Heart J 2004;25:1741-8. https://doi.org/10.1016/j. ehj.2004.06.031; PMID: 15451153.

50. Brignole M, Sutton R, Wieling W, et al. Analysis of rhythm variation during spontaneous cardioinhibitory neurallymediated syncope. Europace 2007;9:305-11. https://doi. org/10.1093/europace/eum017; PMID: 17400603.

51. Brignole M, Menozzi C, Moya A, et al. Pacemaker therapy in patients with neurally mediated syncope and documented asystole. Circulation 2012;125:2566-71. https://doi.org/10.1161/ CIRCULATIONAHA.111.082313; PMID: 22565936.

52. Brignole M, Ammirati F, Arabia F, et al. Assessment of a standardized algorithm for cardiac pacing in older patients affected by severe unpredictable reflex syncopes. Eur Heart J 2015;36:1529-35. https://doi.org/10.1093/eurheartj/ehv069; PMID: 25825044.

53. Kanjwal K, Karabin B, Kanjwal Y, Grubb BP. Preliminary observations on the use of closed-loop cardiac pacing in patients with refractory neurocardiogenic syncope. J Interv Card Electrophysiol 2010;27:69-73. https://doi.org/10.1007/s10840009-9452-1; PMID:19937372.

54. Bortnik M, Occhetta E, Dell’Era G, et al. Long-term follow-up of DDDR closed-loop cardiac pacing for the prevention of recurrent vasovagal syncope. J Cardiovasc Med (Hagerstown) 2012;13:242-5. https://doi.org/10.2459/ JCM.0b013e328351daf5; PMID: 22367575.

55. Occhetta E, Bortnik M, Audoglio R, et al. Closed loop stimulation in prevention of vasovagal syncope. Europace

2004;6:538-47. https://doi.org/10.1016/j.eupc.2004.08.009; PMID: 15519257.

56. P almisano P, Zaccaria M, Luzzi G, et al. Closed-loop cardiac pacing vs. conventional dual-chamber pacing with specialized sensing and pacing algorithms for syncope prevention in patients with refractory vasovagal syncope. Europace 2012;14:1038-43. https://doi.org/10.1093/europace/eur419; PMID: 22247273.

57. Palmisano P, Dell’Era G, Russo V, et al. Effects of closed-loop stimulation vs. DDD pacing on haemodynamic variations and occurrence of syncope induced by head-up tilt test in older patients with refractory cardioinhibitory vasovagal syncope.

Europace 2017. https://doi.org/10.1093/europace/eux015 PMID: 28407148; epub ahead of press.

58. Russo V, Rago A, Papa AA, et al. The effect of dual-chamber closed-loop stimulation on syncope recurrence in healthy patients with tilt-induced vasovagal cardioinhibitory syncope. Heart 2013;99:1609-13. https://doi.org/10.1136/ heartjnl-2013-303878; PMID: 23723446.

59. Barón-Esquivias G, Morillo CA, Moya-Mitjans A, et al. Dualchamber pacing with closed loop stimulation in recurrent reflex vasovagal syncope. J Am Coll Cardiol 2017;70:1720–8. https://doi.org/10.1016/j.jacc.2017.08.026; PMID: 28958328.

60. Kanjwal K, Grubb BP. Observations on optimal programming of closed loop cardiac pacemakers in patients with refractory neurocardiogenic syncope. Journal of Innovations in Cardiac Rhythm Management 2011;2:395-9.

61. Brignole M, Arabia F, Ammirati F, et al. Standardized algorithm for cardiac pacing in older patients affected by severe unpredictable reflex syncope. Europace 2016;18:1427-33. https://doi.org/10.1093/europace/euv343; PMID: 26612880.

62. Brignole M, Tomaino M, Aerts A, et al. Benefit of dualchamber pacing with closed loop stimulation in tilt-induced cardio-inhibitory reflex syncope (BIOSync trial): study protocol for a randomized controlled trial. Trials 2017;18:208. https:// doi.org/10.1186/s13063-017-1941-4; PMID:28472974.

63. Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities. Circulation 2008;117:e350-408. https://doi. org/10.1161/CIRCUALTIONAHA.108.189742; PMID: 18483207.

64. Romme JJ, Reitsma JB, Black CN, et al. Drugs and pacemakers for vasovagal, carotid sinus and situational syncope.

Cochrane Database Syst Rev 2011: CD004194. https://doi. org/10.1002/14651858.CD004194.pub3; PMID: 21975744.

65. Sheldon RS, Grubb BP 2nd, Olshansky B, et al. 2015 Heart Rhythm Society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope.

Heart Rhythm 2015;12:e41–63. https://doi.org/10.1016/j. hrthm.2015.03.029; PMID: 25980576.

66. Moya A, Sutton R, Ammirati F, et al. Guidelines for the diagnosis and management of syncope (version 2009). Eur Heart J 2009;30:2631-71. https://doi.org/10.1093/eurheartj/ ehp298; PMID: 19713422.

67. Brignole M, Deharo JC, De Roy L, et al. Syncope due to idiopathic paroxysmal atrioventricular block. J Am Coll Cardiol 2011;58:167-73. https://doi.org/10.1016/j.jacc.2010.12.045; PMID: 21570228.

68. Aste M, Brignole M. Syncope and paroxysmal atrioventricular block. J Arrhythm 2017;33:562-567. https://doi.org/10.1016/j. joa.2017.03.008; PMID: 29255501.

69. Pachon JC, Pachon EI, Cunha Pachon MZ, et al. Catheter ablation of severe neurally meditated reflex (neurocardiogenic or vasovagal) syncope. Europace 2011;13:1231–42. https://doi. org/10.1093/europace/eur163; PMID: 21712276.

70. Aksu T, Guler TE, Bozyel S, et al. Cardioneuroablation in the treatment of neurally mediated reflex syncope: a review of the current literature. Turk Kardiyol Dern Ars 2017;45:33-41. https://doi.org/10.5543/tkda.2016.55250; PMID: 28106018.

71. Yao Y, Shi R, Wong T, et al. Endocardial autonomic denervation of the left atrium to treat vasovagal syncope: an early experience in humans. Circ Arrhythm Electrophysiol 2012;5:279-86. https://doi.org/10.1161/CIRCEP.111.966465; PMID: 22275485.

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Clinical Review: Cardiac Pacing

His Bundle Pacing: A New Frontier in the Treatment of Heart Failure Nadine Ali, Daniel Keene, Ahran Arnold, Matthew Shun-Shin, Zachary I Whinnett and SM Afzal Sohaib National Heart and Lung Institute, Imperial College London, UK

Abstract Biventricular pacing has revolutionised the treatment of heart failure in patients with sinus rhythm and left bundle branch block; however, left ventricular-lead placement is not always technically possible. Furthermore, biventricular pacing does not fully normalise ventricular activation and, therefore, the ventricular resynchronisation is imperfect. Right ventricular pacing for bradycardia may cause or worsen heart failure in some patients by causing dyssynchronous ventricular activation. His bundle pacing activates the ventricles via the native His-Purkinje system, resulting in true physiological pacing, and, therefore, is a promising alternate site for pacing in bradycardia and traditional CRT indications in cases where it can overcome left bundle branch block. Furthermore, it may open up new indications for pacing therapy in heart failure, such as targeting patients with PR prolongation, but a narrow QRS duration. In this article we explore the physiology, technology and potential roles of His bundle pacing in the prevention and treatment of heart failure.

Keywords His bundle, pacing therapy, heart failure, left bundle branch block reversal, bradycardia pacing, atrial fibrillation Disclosure: The authors have no conflicts of interest to declare.

Received: 27 February 2018 Accepted: 24 April 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(2):103–10. https://doi.org/10.15420/aer.2018.6.2 Correspondence: Zachary I Whinnett, Imperial College London, 2nd Floor B Block South, Hammersmith Campus, Ducane Road, London, W12 0HS, UK. E: z.whinnett@imperial.ac.uk

His bundle pacing in humans was first described in 1970 by Narula et al.1 They demonstrated that it was possible to stimulate the His bundle to produce normal physiological ventricular activation via the His-Purkinje system. However, the first report of permanent His bundle pacing, by Deshmukh et al., did not occur until 2000.2 In that study, His pacing was performed in a series of patients with impaired left ventricular systolic function and AF prior to atrioventricular (AV) node ablation.

The lack of dedicated tools for implantation initially hampered enthusiasm; however, the development of specially designed sheaths and leads for delivering permanent His bundle pacing has led to a renewed interest. The potential role of His pacing in heart failure is large: it may prevent the development of pacing-induced cardiomyopathy; it may be used as an alternative to biventricular pacing in patients with heart failure and left bundle branch block (LBBB); and it may extend pacing therapy in heart failure to patients with narrow QRS and PR prolongation by providing AV synchrony without inducing ventricular dyssynchrony.

Anatomy of the His Bundle and Implant Technique The bundle of His extends from the compact AV node to the membranous interventricular septum, and measures approximately 20 mm in length. The bundle is a cord-like structure made up of multiple strands, which, even before the branching, are predestined to become the right or left bundle branches. His bundle pacing can be achieved by placing the lead at the atrial portion against the septum.

fixation lead. Importantly, the screw forms part of the tip electrode allowing penetration of the capsule of the bundle of His and, therefore, direct stimulation of the His bundle fibres. The lead can be delivered to the His bundle region using either the speciallydesigned non-deflectable His delivery sheath (C315 43 cm; Medtronic) or a deflectable sheath (C304 69 cm; Medtronic). Unlike traditional lead placement that primarily uses fluoroscopic guidance, His lead placement primarily uses electrical mapping. An electrogram from the lead tip is displayed using placement via either a lab electrophysiology system or a standard pacing system analyser.

A His signal is targeted, aiming for the local ventricular electrogram to be approximately twice the amplitude of the atrial signal (Figure 1). To confirm successful His capture, a 12-lead ECG is used to assess the QRS morphology with pacing. Criteria used to establish whether His capture has occurred are well described.3 Recently-published data suggests thresholds of <2.5 at 1 ms should be achieved.3 An increase in pacing threshold is observed in ~10 % of patients, leading to shorter battery duration. There is also a higher rate of lead revisions (6.7 %) due to loss of capture or increased threshold.4 His bundle capture may be either selective or non-selective. With selective capture, only the His bundle fibres are stimulated and, therefore, activation occurs entirely via the His-Purkinje system. With non-selective capture both the His bundle fibres and local myocardium are captured. During non-selective capture a pseudo delta wave on the surface ECG is formed from local myocardial capture.

Indications The most commonly used lead for His bundle pacing is the 69 cm Select Secure™ 3830 (Medtronic). This is a non-stylet-driven active

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His pacing has the potential to provide better pacing solutions in several clinical situations compared with existing techniques. It may

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Clinical Review: Cardiac Pacing Figure 1: Electrical and Fluoroscopic Guidance for His Bundle Pacing

pacing failed to demonstrated superiority to right ventricular pacing in patients with normal LVF.15 This was defined as left ventricular ejection fraction >45 %, but did not exclude patients with symptoms of heart failure. Therefore, right ventricular pacing should be avoided in patients with impaired LVF but biventricular pacing may not be the optimal way to prevent the adverse consequences since it does not produce true physiological pacing.16 Furthermore, some patients with normal baseline ventricular function who received high percentages of right ventricular pacing develop pacing-induced cardiomyopathy.17 His pacing offers an elegant solution to potentially avoid pacinginduced deterioration in cardiac function. Since activation occurs via the normal conduction system, it does not result in ventricular dyssynchrony.18 Compared with right ventricular pacing, His pacing results in improved LVF both acutely19 and with chronic pacing.20 Pacing-avoidance algorithms may be unnecessary, which has the advantage of allowing physiological AV delays to be programmed.

There have been no large randomised controlled-outcome studies comparing His pacing with right ventricular pacing; however, the available data are encouraging (Table 1). Data from observational studies show chronic His pacing, in patients with a bradycardia pacing indication, appears to be feasible and safe.4 His pacing success rates have improved with the development of dedicated tools, and, in this population, successful His lead implantation occurs in 90 % of patients.

Top: With electrical mapping a distinct, sharp His signal is found with a small atrial signal and large ventricular signal. Bottom: Fluoroscopic image of defibrillator with an atrial lead in the right atrial appendage, the defibrillator lead in the right ventricular apex and the His lead pacing the His bundle. A = atrium; H = his; V = right ventricle.

be useful in preventing pacing-induced cardiomyopathy, and pacing therapy may be an option for patients with existing heart failure in a range of settings (Figure 2).

His Pacing to Prevent Right Ventricular Pacing-induced Cardiomyopathy Right ventricular apical pacing results in non-physiological dyssynchronous ventricular activation. This may lead to reverse ventricular remodelling and impaired cardiac function.5–10 In the Dual Chamber and VVI Implantable Defibrillator (DAVID) trial, programming that promotes right ventricular pacing was associated with increased mortality and hospitalisations for heart failure in patients with a standard ICD indication, no pacing indication and impaired LVF.5 Therefore, pacing algorithms have been developed to avoid right ventricular pacing.11–13

A recent non-randomised case control study found that patients who received His pacing for a bradycardia indication had a lower incidence of death and hospitalisation for heart failure compared with a group of patients treated with right ventricular pacing.21 A randomised controlled trial is now required to establish whether these encouraging results translate into clinical benefits in adequatelypowered randomised control trials.

Heart Failure Patients with Atrial Fibrillation and Atrioventricular Node Ablation His bundle pacing may deliver substantial benefits in patients with heart failure after AV node ablation for AF. In patients with AF and LBBB, the evidence for biventricular pacing is minimal, often limited to subgroup data from randomised controlled trials.33 Observational data have suggested some benefit of AV node ablation and left ventricular lead implantation in this group to ensure 100 % biventricular pacing.34,35 Permanent His bundle pacing may yet allow a more elegant solution if His bundle pacing allows reversal of LBBB. Theoretically, His pacing is a better method for delivering pacing since the lead can be positioned distal to the ablation site, and can maintain normal conduction via the His-Purkinje system. This is also an option in patients with a narrow QRS where inadequate rate-controlled AF contributes to poor LVF.

Biventricular pacing has been investigated as a way for mitigating the detrimental effects of ventricular pacing in patients who require high percentages of right ventricular pacing. In the Biventricular Versus Right Ventricular Pacing in Heart Failure Patients With Atrioventricular Block (BLOCK HF) study, biventricular pacing was associated with a lower incidence of death or urgent care visits for heart failure and significantly improved left ventricular end-diastolic volumes compared with right ventricular pacing.14 This study included patients with heart failure, left ventricular ejection fraction <50 % and evidence of AV block.

Heart failure patients were the first group in which permanent His pacing was applied. Despite lacking dedicated tools for His pacing, Deshmukh et al. achieved successful His pacing in 60 % of patients and were able to successfully perform AV node ablation with the His lead in situ.2 Improvements in left ventricular systolic function and left ventricular dimensions were observed.

However, in the Biventricular Pacing for Atrioventricular Block to Prevent Cardiac Desynchronisation (BIOPACE) trial, biventricular

Observational studies performed with dedicated tools for His pacing have found a higher rate of implant success (Table 1). A recent study

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His Bundle Pacing to Treat Heart Failure Figure 2: Potential of His Bundle Pacing Initial cardiac activation (Narrow or broad QRS)

A

Current pacing solutions (Never narrow QRS)

B

C

His bundle pacing solutions

RVP BVP Narrow QRS

LBBB

Narrow QRS long PR interval

Activation prolonged

Activation moderately improved

Activation prolonged

Ventricular activation preserved

BVP

BVP

Ventricular activation restored

Ventricular activation preserved and AVD optimised

His bundle pacing across three classes of indications: (A) narrow QRS, (B) left bundle branch block (LBBB), and (C) long PR interval and narrow QRS. Right ventricular apical pacing (RVP) and biventricular pacing (BVP) do not completely restore narrow QRS. His bundle pacing fully maintains or restores narrow QRS and ventricular synchrony with atrioventricular delay optimisation.

successfully achieved permanent His pacing in 80 % of patients with both heart failure with a preserved ejection fraction and heart failure with reduced ejection fraction. These patients had AF and a narrow QRS, and despite rate-controlled AF they observed a reduction in hospital admissions, diuretic use, symptoms and improved cardiac function.28 However, despite the benefits seen in observational data, no randomised controlled studies are available.

His Pacing to Deliver Ventricular Resynchronisation in Patients with Left Bundle Branch Block

the left or right bundle branches. Conduction delays within the His bundle are a common cause of bundle branch block and pacing distal to this can reverse it.39,40 • Source-sink relationships: overcoming the block with sufficient stimulus to activate distal dormant tissue relying on either sourcesink relationships during pacing versus intrinsic impulse propagation or the virtual electrode polarisation effects.

• Retrograde activation: retrograde activation of the His-Purkinje system via capture of an upper septal branch allowing onward antegrade activation beyond a site of block.

Biventricular pacing, when delivered to patients with heart failure and LBBB, improves both morbidity and mortality.36 However, even with biventricular pacing, symptom burden and mortality remain high.36 Biventricular pacing delivers imperfect ventricular resynchronisation, with only modest reductions in QRS duration, and does not return left ventricular activation times to those seen in individuals with intrinsically narrow QRS.16 Furthermore, when biventricular pacing is delivered to patients with a narrow QRS duration, or moderate QRS prolongation, it may actually prolong ventricular activation time and worsen dyssynchronous activation.16,37

His pacing has been shown to be feasible in this population of patients. Reductions in QRS duration have been observed in 70–92 % of patients with LBBB (Table 1). The reductions in QRS duration appear to be maintained even with chronic pacing, and mean thresholds are similar to those seen for left ventricular leads; for example, in one study thresholds to achieve this are 2.0 V at 1 ms (mean threshold 1.4 V at 1 ms). There has been no demonstrated correlation with QRS morphology and axis, and QRS normalisation patterns (i.e. even broad LBBB with left axis deviation where the lead is unlikely to be screwed in distally to the block).

There is significant potential to deliver additional improvements in cardiac function if more effective ventricular resynchronisation can be delivered.38

No large randomised trial has been conducted comparing His pacing with biventricular pacing. Studies that have been carried out are summarised in Table 1. In these studies, the mean QRS reduction with His pacing is 46 ms. This compares with typical values of 20 ms seen with biventricular pacing.41 Improvements in left ventricular ejection fraction and symptoms have been observed with His pacing.31,42,43

His bundle pacing is an alternative technique for delivering cardiac resynchronisation therapy. It can dramatically shorten QRS duration (Figure 3) and restore normal intrinsic activation patterns in some patients with ventricular conduction delays.

A number of mechanisms have been proposed for His bundle pacing narrowing or reversing a bundle branch block (Figure 4): • P ositioning the pacing lead distal to the site of bundle branch block: fibres within the His bundle are arranged in strands predestined for

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His pacing was initially assessed as a rescue strategy in cases where biventricular pacing failed,29,32 and some authors have shown that His pacing is feasible as a primary strategy for cardiac resynchronisation.30 In a crossover study, His pacing was more effective than biventricular pacing at reducing QRS duration in 72 % of patients (21/29). Two patients achieved QRS narrowing with His pacing but with high outputs, and six patients did not show any QRS narrowing with His

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Clinical Review: Cardiac Pacing Table 1: Summary of Studies Investigating His Pacing for Heart Failure Study

Total Patients

Study Design

His Pacing Success

Outcomes

Summary

Rate

and Inclusion Criteria Bradycardia Pacing Zanon et al.

200822

12

Non-randomised crossover study (3 months His pacing and 3 months RVP)

Only patients with confirmed His bundle pacing

Intra-patient myocardial perfusion (myocardial perfusion score) during His pacing compared to RVP

Myocardial perfusion score during His pacing was better than RVP

Catanzariti et al. 201318

26

Non-randomised crossover study

Patients selected after successful His pacing established

Measurements of echocardiographic dyssynchrony parameters made during His pacing and RVP (intra-patient comparison)

Reduction of pacing-induced ventricular dyssynchrony with His pacing

Kronborg et al. 201420

38 (12 months His pacing and 12 months RVP)

Randomised double-blind crossover study

84 % (32/38) Six patients had leads in high septal position and were still included in study

Left ventricular ejection fraction

Left ventricular ejection fraction was significantly higher during His pacing (55 % +/- 10 % versus 50 % +/- 11 %)

Vijayaraman et al. 20174

192 (94 His and 98 RVP)

Case control study

80 % (75 from 94 attempted)

Death and heart failure hospitalisation

Death or heart failure was significantly lower in the His pacing group (32 % versus 53 %; HR 1.9)

Sharma et al.

201723

30 (post-prosthetic valve surgery)

Prospective observational

93 % (28/30)

Feasibility of His pacing in this subgroup of patients

His bundle pacing was feasible and achieved pacing in 93 % of patients post-valve surgery

Shan et al.

201724

18 (upgrade from Prospective RVP to His pacing in observational RVP patients)

90 % (16/18)

Left ventricular ejection fraction, left ventricular end-diastolic dimensions, NYHA class and BNP

Reduced left ventricular end-diastolic dimensions and BNP. Improved ejection fraction and NYHA class

Abdelrahman et al. 201821

756 (332 His and 433 RVP)

92 % (302/332)

Death, heart failure hospitalisation and upgrade to BVP

Combined primary endpoint of death, heart failure hospitalisation and upgrade to BVP was significantly less in His pacing (HR 0.71)

Case control study

Atrial Fibrillation (AV Node Ablation and His Pacing) Deshmukh et al. 20002

18 (dilated cardiomyopathy)

Prospective observational

66 % (12/18)

Left ventricular dimensions and systolic function (ejection fraction and fractional shortening)

Reduced left ventricular dimensions and improved systolic function

Deshmukh et al. 200425

54 (cardiomyopathy and narrow QRS)

Prospective observational

72 % (39/54)

Ejection fraction and functional class. In subset of 12 who also received an RV lead, comparison of cardiopulmonary exercise parameters between RVP and His pacing

Ejection fraction and NYHA class improved after His pacing. Improved exercise time and higher O2 uptake with His pacing compared to RV pacing

Occhetta et al. 200626

18 (AF and AV node ablation; 6 months RVP and 6 months His pacing)

Randomised blinded crossover

89 % (16/18)

QOL score, NYHA, 6-minute walk QOL score, NYHA, 6-minute walk test test, left ventricular ejection fraction and left ventricular synchrony all and ventricular synchrony improved with His pacing compared with both baseline and RVP

Vijayaraman et al. 201727

42

Retrospective observational

95 % (40/42)

Left ventricular ejection fraction and Left ventricular ejection fraction NYHA class improved with His pacing and NYHA reduced

Huang et al.

201728

52 (all heart failure HFrEF and HFpEF)

Prospective observational

80 % (42/52)

Left ventricular ejection fraction, left ventricular end-diastolic dimensions, NYHA class and use of diuretics at follow up

Increased left ventricular ejection fraction, reduced left ventricular enddiastolic dimensions, improved NYHA and reduced use of diuretics

56 % (13/16 achieved His pacing acutely, in 9/16 permanent His pacing was achieved)

Cardiac resynchronisation as defined by disappearance of LBBB, QRS duration shortening, improved NYHA class and echocardiographic parameters (left ventricular ejection fraction, left atrial and left ventricular dimensions)

Disappearance of LBBB, QRS shortening, improved NYHA class, improved echocardiographic parameters (reduced left atrial and left ventricular dimensions and increased left ventricular ejection fraction) with His pacing

Left Bundle Branch Block Reversal BarbaPichardo et al. 201329

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16 (failed coronary sinus cannulation)

Prospective observational

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His Bundle Pacing to Treat Heart Failure Table 1: Cont.

Study

Total Patients

Study Design

His Pacing Success

Outcomes

Summary

Rate

and Inclusion Criteria Lustgarten et al. 201530

29

Prospective crossover study (His and biventricular pacing)

29 patients started, 21 QRS narrow acutely with His pacing, 17 randomised (high output, left ventricular lead failure), 12 completed follow up (complications: lead dislodged [His/left ventricular], failure to narrow, device dehiscence)

QOL assessment, left ventricular ejection fraction, NYHA and 6-minute walk test

Improved QOL, left ventricular ejection fraction, NYHA class and 6-minute walk test compared with baseline during both BVP and His pacing. No significant difference between the two modalities shown

Ajijola et al.

201731

21

Retrospective observational

76 % (16/21)

QRS duration, left ventricular ejection fraction, left ventricular dimensions and NYHA class

Reduced QRS duration and improved left ventricular ejection fraction, reduced left ventricular dimensions and reduced NYHA class with His pacing

Sharma et al.

201732

106

Retrospective observational

90 % (95/106)

Left ventricular ejection fraction, NYHA and QRS duration

Improved left ventricular ejection fraction and NYHA. QRS duration shortening with His pacing

AV = atrioventricular; BVP = biventricular pacing; HFpEF = heart failure with a preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; LBBB = left bundle branch block; NYHA = New York Heart Association; QOL = quality of life; RVP = right ventricular apical pacing.

pacing despite multiple sites tried. With improved technology and experience, permanent His pacing achieved QRS narrowing in 90 % of patients.32 The reasons for failure in achieving QRS narrowing is not fully understood. It is possible this subgroup of patients have abnormal left ventricular conduction due to disease outside of the His bundle and, therefore, cannot be treated with His pacing, or the block is too severe to overcome. The proportion of patients with conduction delays caused by disease distal to the His bundle is not known.

His pacing has the advantage that it does not require the use of contrast and can often be performed more quickly than left ventricular lead placement. However, adequately powered randomised studies are required to compare this strategy for resynchronisation therapy with biventricular pacing. In 2016 recruitment started for the His Bundle Pacing Versus Coronary Sinus Pacing for Cardiac Resynchronisation Therapy (His-SYNC; NCT02700425) study, which is aiming to randomise 40 patients to either His pacing or biventricular pacing and will look at time to first cardiovascular hospitalisation or death.

Heart Failure in Patients with Narrow QRS and PR Prolongation PR prolongation results in impaired left ventricular filling, and in patients with heart failure it is associated with a higher risk of death than those whose AV delay was within normal limits.12 When biventricular pacing is delivered to patients with LBBB, those with PR prolongation appear to obtain greater benefit than those with a normal PR interval. In the Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure (COMPANION) trial, patients with a long PR interval had a 17 % greater relative risk reduction in heart failure admissions and death compared with those with a normal PR interval.44 Biventricular pacing requires a compulsory shortening of the AV delay to ensure biventricular capture.

This shortening of the AV delay appears to be one of the mechanisms by which biventricular pacing delivers its beneficial effect.38

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Figure 3: Left Bundle Branch Block Reversal with His Bundle Pacing A

B

Intrinsic rhythm LBBB

Selective His pacing with LBBB reversal

A: Left bundle branch block (LBBB) pattern at baseline. B: A narrow QRS is restored with His bundle pacing. A short isoelectric period is visible immediately after the pacing spike consistent with activation through the His bundle.

Adjusting AV delay is known to change acute haemodynamic function.45 There PR prolongation may represent a treatment target in patients with heart failure and normal QRS duration or right bundle branch block (RBBB). Delivering biventricular pacing to this group of patients may induce ventricular dyssynchrony relative to normal intrinsic activation, which may offset some of the beneficial effects of AV delay shortening.16 In the context of a normal QRS, biventricular pacing can increase mortality.16,37,46 His pacing has the advantage that it may allow AV delay to be optimised while normal intrinsic ventricular activation is maintained. We have previously demonstrated that acute haemodynamic function is improved with AV-optimised His bundle pacing in patients with heart failure and PR prolongation with either a normal QRS or RBBB.47 The magnitude of acute haemodynamic corresponded to approximately 60 % of the benefit seen in patients with LBBB receiving biventricular pacing (Figure 5).

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Clinical Review: Cardiac Pacing Figure 4: Mechanisms for Left Bundle Branch Block Reversal with His Bundle Pacing

Figure 5: Acute Haemodynamic Improvements Seen with His Pacing in Narrow QRS and Long PR Interval 8

A Illustration of normal conduction Increase in systolic blood pressure (mmHg)

AV node Fibres predestined for left bundle branch

His bundle

Myocardium Bundle branches

Fibres predestined for right bundle branch

B Reversal due to distal pacing lead AV Node node

AV node

Proximal site of left bundle branch block

Proximal left bundle branch block bypassed by pacing lead positioned distal to site of block

AV node Distal left bundle branch block overcome by electrical remote activation.

Consider: higher outputs, source-sink or virtual electrode theories

Distal site of left bundle branch block

D Reversal due to close proximity to high septal branch AV node Left bundle branch block Septal branch of bundle

AV node

Left bundle branch block overcome by pacing lead in close proximity to high septal branch, with initial retrograde activation back up branch before facilitating antegrade conduction beyond block

A: Normal ventricular activation, with activation from the atrioventricular (AV) node down the bundle of His and then into the left and right bundle branches. Fibres within the bundle of His are already predestined for their respective bundle branches. B: Proximal site of left bundle branch block (LBBB; left); pacing lead has been positioned in a site distal to this block allowing an electrical bypass of the LBBB, reversing the electrical abnormality (right).

C: Distal site of LBBB where positioning the His pacing lead would not be possible (left); remote electrical activation with a more proximally-placed lead could reverse this electrical abnormality. This could occur because of increased pacing outputs, as a consequence of the source-sink-theory and a high likelihood of their being some diseased fibres already in the proximal location or the virtual electrode polarisation theory (right). D: Each bundle branch has multiple branches (left); high septal branch may fortuitously be activated with a conventionally placed His lead, resulting in retrograde activation down the branch back to a place in the bundle branch, which is distal to the site of block allowing antegrade activation from this site forward (right).

The His Optimised Pacing Evaluated for Heart Failure Trial (HOPE-HF; NCT02671903) trial is a multicentre, double-blind, randomised, crossover study that aims to randomise 160 patients with PR prolongation (≥200 ms), left ventricular impairment (ejection fraction ≤40 %), and either narrow QRS (≤140 ms) or RBBB. Participants are first randomised to either 6 months with the His lead programmed on or off before crossing over to the alternate arm. The primary endpoint is

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4

~60 % of the increase in BP seen with biventricular pacing in LBBB

2

0 AV optimised biventricular pacing in LBBB

AV optimised His pacing in narrow QRS

When compared to the acute haemodynamic studies that investigated atrioventricular (AV)optimised biventricular pacing in left bundle branch block (LBBB), the acute blood pressure (BP) increase in a study of AV-optimised His pacing in patients with PR prolongation >200 ms showed approximately 60 % of the increase.47

C Reversal due to remote electrical activation AV node

6

exercise capacity measured using cardiopulmonary exercise testing.

When randomised to the His pacing arm, the patients are set to an AV delay determined by our high resolution haemodynamic optimisation protocol.45 If the results are positive then this would offer the potential of a new therapeutic option to a cohort of patients with heart failure who are not currently eligible for pacing therapy for heart failure.

Current Limitations There is currently limited published data available for His pacing in any clinical setting. While pacing thresholds for His pacing in bradycardia appear to be stable, there is limited long-term follow-up data available.

When His pacing is used to deliver ventricular resynchronisation in patients with bundle branch block, the pacing thresholds can be relatively high, though comparable to left ventricular pacing thresholds.

This has the potential implications on battery longevity, though pacing is only required via a single lead (compared to biventricular pacing).

Success rates for His lead implantation have been as low as 60 % without dedicated tools and experience. Success rates have improved with the development of dedicated tools; however, the range of tools currently available are still limited, and these could be further improved.

Adequately powered randomised control trials are required to investigate whether the theoretical advantages of physiological ventricular activation are achieved with His pacing and if the encouraging results in observational studies translate into clinical benefit.

Finally, current device-based algorithms do not dovetail with His bundle pacing and this pacing sphere could benefit from industry investment in His pacing customised algorithms.

Conclusion His pacing is a novel pacing therapy that allows ventricular stimulation to occur via the normal conduction system. Therefore, it maintains normal ventricular activation in patients with a narrow QRS duration and may even reverse bundle branch block.

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His Bundle Pacing to Treat Heart Failure Technical limitations have restricted the use of this therapy despite its existence for over four decades. In recent years tools dedicated to His pacing have been developed, which have improved the ease with which His pacing can be delivered. His pacing is now technically feasible in most patients and has shown promising results in small, mainly non-randomised studies in various clinical situations.

His pacing may be beneficial in the prevention of pacing-induced cardiomyopathy, as an alternative to biventricular pacing in patients with heart failure and LBBB, and as a method for extending pacing therapy for heart failure to patients with narrow QRS and PR prolongation. Large randomised studies are now required to provide confirmation these promising results translate into proven clinical benefits.

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arula OS, Scherlag BJ, Samet P. Pervenous pacing of N the specialized conducting system in man: His bundle and A-V nodal stimulation. Circulation 1970;41:77–87. https://doi.org/10.1161/01.CIR.41.1.77; PMID: 5420636.

Deshmukh P, Casavant DA, Romanyshyn M, Anderson K. Permanent, direct His-bundle pacing: a novel approach to cardiac pacing in patients with normal His-Purkinje activation. Circulation 2000;101:869–77. https://doi.org/10.1161/01.CIR.101.8.869; PMID: 10694526.

Vijayaraman P, Dandamudi G, Zanon F, et al. Permanent His bundle pacing: recommendations from a multi-center HBP collaborative working group for standardization of definitions, implant measurements, and follow-up. Heart Rhythm 2018;15:460–8. https://doi.org/10.1016/j.hrthm.2017.10.039; PMID: 29107697.

Vijayaraman P, Naperkowski A, Subzposh FA, et al.

Permanent His bundle pacing: long-term lead performance and clinical outcomes. Heart Rhythm 2017; https://doi.org/10.1016/j.hrthm.2017.12.022; PMID: 29274474; epub ahead of press.

Wilkoff BL, Cook JR, Epstein AE, et al. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the dual chamber and VVI implantable defibrillator (DAVID) trial. JAMA 2002;288:3115–23. https://doi.org/10.1001/jama.288.24.3115; PMID: 12495391.

Sweeney MO, Hellkamp AS, Ellenbogen KA, et al. Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction. Circulation 2003;107:2932–37. https://doi.org/10.1161/01.CIR.0000072769.17295.B1; PMID: 12782566.

Thambo JB, Bordachar P, Garrigue S, et al. Detrimental ventricular remodeling in patients with congenital complete heart block and chronic right ventricular apical pacing. Circulation 2004;110:3766–72. https://doi.org/10.1161/01.CIR.0000150336.86033.8D; PMID: 15583083.

O’Keefe JH Jr, Abuissa H, Jones PG, et al. Effect of chronic right ventricular apical pacing on left ventricular function. Am J Cardiol 2005;95:771–3. https://doi.org/10.1016/j.amjcard.2004.11.034; PMID: 15757609.

Thackray SD, Witte KK, Nikitin NP, et al. The prevalence of heart failure and asymptomatic left ventricular systolic dysfunction in a typical regional pacemaker population. Eur Heart J 2003;24:1143–52. https://doi.org/10.1016/S0195-668X(03)00199-4; PMID: 12804929.

Frias PA, Corvera JS, Schmarkey L, et al. Evaluation of myocardial performance with conventional single-site ventricular pacing and biventricular pacing in a canine model of atrioventricular block. J Cardiovasc Electrophysiol 2003;14:996–1000. https://doi.org/10.1046/j.1540-8167.2003.02483.x; PMID: 12950546.

Gillis AM, Pürerfellner H, Israel CW, et al. Reducing unnecessary right ventricular pacing with the managed ventricular pacing mode in patients with sinus node disease and AV block. Pacing Clin Electrophysiol 2006;29:697–705. https://doi.org/10.1111/j.1540-8159.2006.00422.x; PMID: 16884504.

Milasinovic G, Tscheliessnigg K, Boehmer A, et al. Percent ventricular pacing with managed ventricular pacing mode in standard pacemaker population. Europace 2008;10:151–5. https://doi.org/10.1093/europace/eum288; PMID: 18203737.

Yadav R, Jaswal A, Chennapragada S, et al. Effectiveness of ventricular intrinsic preference (VIP) and ventricular autocapture (VAC) algorithms in pacemaker patients: results of the validate study. J Arrhythm 2016;32:29–35. https://doi.org/10.1016/j.joa.2015.07.004; PMID: 26949428.

Curtis AB, Worley SJ, Adamson PB, et al. Biventricular pacing

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Clinical perspective • H is-bundle pacing is a feasible method for delivering permanent pacing. It produces physiological ventricular activation via the HisPurkinje system.

• His pacing offers an alternative bradycardia pacing modality to right ventricular pacing and has the advantage that it does not cause intraventricular dyssynchrony.

• His pacing can achieve cardiac resynchronisation in patients with heart failure and bundle branch block.

• Data regarding safety, chronic sensing and pacing thresholds are encouraging, but data from larger registries is awaited.

• Randomised controlled trial data to assess the benefits of His bundle pacing for bradycardia and heart failure indications are not yet available. n

for atrioventricular block and systolic dysfunction. N Engl J Med 2013;368:1585–93. https://doi.org/10.1056/NEJMoa1210356; PMID: 23614585.

15. Yu CM, Chan JY, Zhang Q, et al. Biventricular pacing in patients with bradycardia and normal ejection fraction. N Engl J Med 2009;361:2123–34. https://doi.org/10.1056/NEJMoa0907555; PMID: 19915220.

16. Ploux, S, Eschalier R, Whinnett ZI, et al. Electrical dyssynchrony induced by biventricular pacing: implications for patient selection and therapy improvement. Heart Rhythm 2015;12:782–91. https://doi.org/10.1016/j.hrthm.2014.12.031; PMID: 25546811.

17. Dreger H, Maethner K, Bondke H, et al. Pacing-induced cardiomyopathy in patients with right ventricular stimulation for >15 years. Europace 2012;14:238–42. https://doi.org/10.1093/europace/eur258; PMID: 21846642.

18. Catanzariti D, Maines M, Manica A, et al. Permanent His-bundle pacing maintains long-term ventricular synchrony and left ventricular performance, unlike conventional right ventricular apical pacing. Europace 2013;15:546–53. https://doi.org/10.1093/europace/eus313; PMID: 22997222.

19. Kronborg MB, Poulsen SH, Mortensen PT, Nielsen JC. Left ventricular performance during para-His pacing in patients with high-grade atrioventricular block: an acute study. Europace 2012;14:841–46. https://doi.org/10.1093/europace/eur368; PMID: 22170898.

20. Kronborg MB, Mortensen PT, Poulsen SH, et al. His or para-His pacing preserves left ventricular function in atrioventricular block: a double-blind, randomized, crossover study. Europace 2014;16:1189–96. https://doi.org/10.1093/europace/euu011; PMID: 24509688.

21. Abdelrahman M, Subzposh FA, Beer D, et al.

Clinical outcomes of His bundle pacing compared to right ventricular pacing. J Am Coll Cardiol 2018; https://doi.org/10.1016/j.jacc.2018.02.048; PMID: 29535066; epub ahead of press.

22. Zanon F, Bacchiega E, Rampin L, et al. Direct His bundle pacing preserves coronary perfusion compared with right ventricular apical pacing: a prospective, cross-over mid-term study. Europace 2008;10:580–7. https://doi.org/10.1093/europace/eun089; PMID: 18407969.

23. Sharma PS, Subzposh FA, Ellenbogen KA, Vijayaraman P. Permanent His-bundle pacing in patients with prosthetic cardiac valves. Heart Rhythm 2017;14:59–64. https://doi.org/10.1016/j.hrthm.2016.09.016; PMID: 27663607.

24. Shan P, Su L, Zhou X, et al. Beneficial effects of upgrading to His bundle pacing in chronically paced patients with left ventricular ejection fraction <50%. Heart Rhythm 2018;15:405–12. https://doi.org/10.1016/j.hrthm.2017.10.031; PMID: 29081396.

25. Deshmukh PM, Romanyshyn M. Direct His-Bundle Pacing: present and future. Pacing Clin Electrophysiol 2004;27:862–70. https://doi.org/10.1111/j.1540-8159.2004.00548.x; PMID: 15189517.

26. Occhetta E, Bortnik M, Magnani A, et al. Prevention of ventricular desynchronization by permanent para-Hisian pacing after atrioventricular node ablation in chronic atrial fibrillation: a crossover, blinded, randomized study versus apical right ventricular pacing. J Am Coll Cardiol 2006;47:1938–45. https://doi.org/10.1016/j.jacc.2006.01.056; PMID: 16697308.

27. Vijayaraman P, Subzposh FA, Naperkowski A. Atrioventricular node ablation and His bundle pacing. Europace 2017;19:iv10–6. https://doi.org/10.1093/europace/eux263; PMID: 29220422.

28. Huang W, Su L, Wu S, et al. Benefits of permanent His bundle pacing combined with atrioventricular node ablation in atrial fibrillation patients with heart failure with both preserved and reduced left ventricular ejection fraction. J Am Heart Assoc 2017;6:e005309. https://doi.org/10.1161/JAHA.116.005309; PMID: 28365568.

29. Barba-Pichardo R, Manovel Sánchez A, FernándezGómez JM, et al. Ventricular resynchronization

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therapy by direct His-bundle pacing using an internal cardioverter defibrillator. Europace 2013;15:83–8. https://doi.org/10.1093/europace/eus228; PMID: 22933662.

Lustgarten DL, Crespo EM, Arkhipova-Jenkins I, et al. His-bundle pacing versus biventricular pacing in cardiac resynchronization therapy patients: a crossover design comparison. Heart Rhythm 2015;12:1548–57. https://doi.org/10.1016/j.hrthm.2015.03.048; PMID: 25828601.

Ajijola OA, Romero J, Vorobiof G, et al. Hyper-response to cardiac resynchronization with permanent His bundle pacing: is parahisian pacing sufficient? HeartRhythm Case Rep 2015;1:429–33. https://doi.org/10.1016/j.hrcr.2015.05.006; PMID: 27722091.

Sharma PS, Dandamudi G, Herweg B, et al. Permanent His-bundle pacing as an alternative to biventricular pacing for cardiac resynchronization therapy: a multicenter experience. Heart Rhythm 2018;15:413–20. https://doi.org/10.1016/j.hrthm.2017.10.014; PMID: 29031929.

Tang AS, Wells GA, Talajic M, et al. Cardiac-resynchronization therapy for mild-to-moderate heart failure. N Engl J Med 2010;363:2385–95. https://doi.org/10.1056/NEJMoa1009540; PMID: 21073365.

Gasparini M, Regoli F, Galimberti P, et al. Cardiac resynchronization therapy in heart failure patients with atrial fibrillation. Europace 2009;11:v82–6. https://doi.org/10.1093/europace/eup273; PMID: 19861396.

Gasparini M, Auricchio A, Regoli F, et al. Four-year efficacy of cardiac resynchronization therapy on exercise tolerance and disease progression: the importance of performing atrioventricular junction ablation in patients with atrial fibrillation. J Am Coll Cardiol 2006;48:734–43. https://doi.org/10.1016/j.jacc.2006.03.056; PMID: 16904542.

Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539–49. https://doi.org/10.1056/NEJMoa050496; PMID: 15753115.

Ruschitzka F, Abraham WT, Singh JP, et al. Cardiacresynchronization therapy in heart failure with a narrow QRS complex. N Engl J Med 2013;369:1395–405. https://doi.org/10.1056/NEJMoa1306687; PMID: 23998714.

Jones S, Lumens J, Sohaib SM, et al. Cardiac resynchronization therapy: mechanisms of action and scope for further improvement in cardiac function. Europace 2017;19:1178–86. https://doi.org/10.1093/europace/euw136; PMID: 27411361.

Narula OS. Longitudinal dissociation in the His bundle.

Bundle branch block due to asynchronous conduction within the His bundle in man. Circulation 1977;56:996–1006. https://doi.org/10.1161/01.CIR.56.6.996; PMID: 923070.

El-Sherif N, Amay-Y-Leon F, Schonfield C, et al. Normalization of bundle branch block patterns by distal His bundle pacing. Clinical and experimental evidence of longitudinal dissociation in the pathologic His bundle. Circulation 1978;57:473–83. https://doi.org/10.1161/01.CIR.57.3.473; PMID: 624157.

Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845–53. https://doi.org/10.1056/NEJMoa013168; PMID: 12063368.

Wu G, Cai Y, Huang W, Su L. Hisian pacing restores cardiac function. J Electrocardiol 2013;46:676–8. https://doi.org/10.1016/j.jelectrocard.2013.05.003; PMID: 23773655.

Dabrowski P, Kleinrok A, Kozluk E, Opolski G. Physiologic resynchronization therapy: a case of His bundle pacing reversing physiologic conduction in a patient with CHF and LBBB during 2 years of observation. J Cardiovasc Electrophysiol 2011;22:813–7. https://doi.org/10.1111/j.1540-8167.2010.01949.x; PMID: 21087328.

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Clinical Review: Cardiac Pacing 44. B ristow MR, Saxon LA, Boehmer J, et al. Cardiacresynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350:2140–50. https://doi.org/10.1056/NEJMoa032423; PMID: 15152059.

45. Whinnett ZI, Davies JE, Willson K, et al. Haemodynamic effects of changes in atrioventricular and interventricular delay in cardiac resynchronisation therapy show a

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consistent pattern: analysis of shape, magnitude and relative importance of atrioventricular and interventricular delay. Heart 2006;92:1628–34. https://doi.org/10.1136/hrt.2005.080721; PMID: 16709698.

46. Sohaib SM, Chen Z, Whinnett ZI, et al. Meta-analysis of symptomatic response attributable to the pacing component of cardiac resynchronization therapy. Euro J Heart Fail 2013;15:1419–28. https://doi.org/10.1093/eurjhf/hft139;

PMID: 24259043.

47. S ohaib SM, Wright I, Lim E, et al. Atrioventricular optimized direct His bundle pacing improves acute hemodynamic function in patients with heart failure and PR interval prolongation without left bundle branch block. JACC Clin Electrophysiol 2015;1:582–91. https://doi.org/10.1016/j.jacep.2015.08.008; PMID: 29759412.

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Clinical Review: Arrhythmias

Sudden Cardiac Death and Arrhythmias Neil T Srinivasan and Richard J Schilling Barts Heart Centre, St Bartholomew’s Hospital, London, UK

Abstract Sudden cardiac death (SCD) and arrhythmia represent a major worldwide public health problem, accounting for 15–20 % of all deaths.

Early resuscitation and defibrillation remains the key to survival, yet its implementation and the access to public defibrillators remains poor, resulting in overall poor survival to patients discharged from hospital. Novel approaches employing smart technology may provide the solution to this dilemma. Though the majority of cases are attributable to coronary artery disease, a thorough search for an underlying cause in cases where the diagnosis is unclear is necessary. This enables better management of arrhythmia recurrence and screening of family members. The majority of cases of SCD occur in patients who do not have traditional risk factors for arrhythmia. New and improved large scale screening tools are required to better predict risk in the wider population who represent the majority of cases of SCD.

Keywords Arrhythmia, sudden cardiac death, coronary artery disease, screening, risk factors Disclosure: The authors have no conflicts of interest to declare.

Received: 7 March 2018 Accepted: 30 April 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(2):111–7. https://doi.org/10.15420/aer.2018.15.2 Correspondence: Neil T Srinivasan, Department of Cardiac Electrophysiology, Barts Heart Centre, St Bartholomew’s Hospital, London, EC1A 7BE, UK. E: neil.srinivasan@nhs.net

An estimated 180,000–300,000 sudden cardiac deaths (SCD) occur in the US annually.1,2 Worldwide, sudden and unexpected cardiac death is the most common cause of death,2 accounting for 17 million deaths every year with SCD accounting for 25 % of these. The accepted definition of SCD is death that occurs within one hour of onset of symptoms in witnessed cases, and within 24 hours of last being seen alive when it is unwitnessed.2 The majority of deaths are unwitnessed, with VF being the final underlying mechanism.2–5 The majority of patients are found in asystole or pulseless electrical activity (PEA) and heart block is increasingly noted as an aetiology.

Despite the decline in cardiovascular deaths over the past several decades,6 due to improved preventative strategies, the incidence of SCD as a proportion of overall cardiovascular deaths has increased.2 This has occurred because in-hospital mortality has declined more rapidly,2 highlighting the need for better risk stratification methods and preventative strategies.

Medical therapy with class Ic agents or amiodarone to prevent SCD has been shown to be to be ineffective.7,8 The major advance in the prevention of SCD has been the development of the ICD.9 Secondary prevention trials, Antiarrhythmic Versus Implantable Defibrillator (AVID),10 Canadian Implantable Defibrillator Study (CIDS)11 and Cardiac Arrest Study of Hamburg (CASH),12 have demonstrated statistically significant improvement in survival rates with ICD implantation compared with drug therapy in this patient population.

The Multicenter Automatic Defibrillator Implantation Trial (MADIT)13 and the Multicenter Unsustained Tachycardia Trial (MUSTT)14 studies enrolled patients post MI, comparing primary prevention with an ICD against standard medical therapy in patients with a reduced ejection

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fraction (EF) (<35 % and <40 %, respectively), plus either documented or induced ventricular tachycardia (VT) and demonstrated a 58–59 % relative risk reduction in death. Subsequently MADIT II15 showed a 28 % relative risk reduction in 2-year mortality in post-MI patients with an EF of <30 % without the requirement for documented or induced VT. The Defibrillators in Non-Ischemic Cardio-myopathy Treatment Evaluation (DEFINITE)16 study compared the benefit of ICD against standard therapy in patients with heart failure, EF ≤35 % and premature ventricular contractions or non-sustained ventricular tachycardia (NSVT), demonstrating a strong trend towards reduced mortality with ICD. While the Sudden Cardiac Death in Heart Failure Trial (SCD-HEFT),17 which enrolled patients with both ischaemic and non-ischaemic cardiomyopathy with New York Heart Association class II or III and EF of ≤35 %, showed a benefit of ICD when comparing ICD with standard medical therapy. What is interesting within these primary prevention trials is that apart from a low EF, no other significant major risk predictors identify who will benefit from an ICD. The major studies have used an EF cut-off between ≤30–40 %; however, the median populations within these studies tend to have far lower EF, and subgroup analysis of patients closer to the cutoff often shows no clear benefit.3,13,15,17,18 Additionally, in the ‘high risk’ population studies, such as MADIT II15 and SCD-HeFT,17 <40 % of patients received appropriate ICD shock therapy during the first 4 years of follow up. Finally, the recent Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality (DANISH) showed prophylactic ICD implantation in patients with non-ischaemic cardiomyopathy in patients >68 years was not associated with a reduced long-term mortality.19 Using these studies to guide prescription of ICDs means that we have only targeted a subgroup of patients where the incidence of events is high and, therefore, they have been labelled as high risk

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Clinical Review: Arrhythmias Figure 1: Incidence and Occurrence of Sudden Cardiac Death Over 1 Year

General population

High risk subgroups

Any prior coronary event

MADIT II & SCD-HeFT

EF <30 %

AVID, CIDS, CASH

Cardiac arrest survivor

MADIT I, MUSST

Arrhythmia risk markers post MI 0

5

10

15

20

25

30

0

75,000

150,000

225,000

300,000

Events (n)

Incidence (%)

The majority of events occur in patients without traditional risk factors for sudden cardiac death. EF = ejection fraction; MI = myocardial infarction. Reprinted from J Am Coll Cardiol, 54, Myerburg RJ, Reddy V, Castellanos A., Indications for implantable cardioverter-defibrillators based on evidence and judgment, 747–63, 2009. With permission from Elsevier.3

(Figure 1). The challenge for clinicians lies in the fact most episodes of SCD occur in individuals who, prior to the event, have no known cardiac disease and are not perceived high risk by traditional measures, or occurs as a first presentation of an undiagnosed underlying cardiac condition (Figure 2B).3 Thus, the vast majority of SCD events occur in patients who are considered at ‘low risk’ of events.3 Although the incidence within this group of patients is low, they cumulatively account for the greatest number of events (Figure 1). Finally, the indications for primary prevention in less common conditions, such as hypertrophic cardiomyopathy (HCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), long QT syndrome (LQT), Brugada syndrome and early repolarisation, remain less clear, with few if any definite risk markers beyond patient symptoms.3,20

Sudden Cardiac Arrest: Chain of Survival The majority of cardiac arrests occur outside of hospital, with poor outcomes. In the UK survival to admission may be as low as 8.1 % and survival to discharge as low as 3.2 % for out-of-hospital cardiac arrest.21 The first step to improving outcomes involves the chain of survival: 1. immediate recognition of cardiac arrest and activation of the emergency response system; 2. early CPR with an emphasis on chest compressions; 3. rapid defibrillation; 4. effective advanced life support; and 5. integrated post-cardiac arrest care.

The importance of early recognition and CPR is emphasised by the finding that prompt and immediate bystander response, CPR and early automated defibrillation to an out-of-hospital cardiac arrest by lay members in the community is an important public health initiative that can drive improvements in outcome. Every minute without CPR reduces the chance of survival by 7–10 %. A study of 30,381 cardiac arrests in Sweden found that CPR performed before the arrival of emergency medical services (EMS) more than doubled survival at 30 days.22 Additionally, standardised EMS care, as well as standardised and integrated post-resuscitation care, play a major role in improving outcomes. A study in Oslo where improvements

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were made to EMS care with an emphasis on uninterrupted and good CPR, followed by goal-directed post-resuscitation care, including therapeutic hypothermia and percutaneous coronary intervention (PCI), doubled survival, with survival as high as 35 % in cases of bystander-witnessed VT/VF arrests.23 In cases of refractory VT/VF, early coronary intervention with extracorporeal membrane oxygenation and uninterrupted mechanical defibrillation during PCI has been shown to produce good outcomes.24 These findings emphasise the importance of a cohesive public health strategy, with public education and engagement in CPR, early access to EMS and focused post-resuscitation care.25 The importance of early bystander defibrillation is emphasised by the fact the early use of public automated defibrillator devices (AEDs) in cases of out-of-hospital cardiac arrest significantly improves outcome.26,27 However, this requires significant political and strategic will to implement, with a need for both widespread and organised access to such devices, as well as public education with regard to their availability. At present, despite campaigns to raise public awareness and make AEDs more publicly available, many public spaces have no available AED. Where they are available, their use may be as low as 1.7 % in out-of-hospital cardiac arrests,28 highlighting the need to re-engage with the public and for better regional planning to close this weak link in the chain of survival, which is the biggest contributor to poor survival rates. New and novel approaches implementing smart technology to detect cardiac arrest and drone networks with automated defibrillators may be the future to improving outcomes.29

Establishing a Diagnosis Initial Assessment and Management of Patients Who Survive a Cardiac Arrest Assessment of patients who survive an out-of-hospital cardiac arrest involves a thorough history of the nature of events, including collateral history. The causes of SCD are shown in Figure 2, with ischaemic heart disease being the most common cause. Symptoms prior to the event, such as chest pain, palpitations and breathlessness syncope or presyncope, should be assessed. Risk factors, such as hypertension,

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Sudden Cardiac Death and Arrhythmias diabetes, hyperlipidaemia and smoking, should be sought. A drug history should be attained, along with specific questions relating to recreational drug use and use of psychiatric drugs that may prolong the QT interval. Additionally precipitating factors, such as exercise and emotional stress, should be looked for, as well as family history.

Figure 2: Causes of Sudden Cardiac Death

3%

The 12-lead ECG remains the hallmark of initial non-invasive evaluation.

Where there is evidence of ischaemia, prompt coronary intervention should be performed. However, even in the absence of ischaemic changes on the ECG, up to 29 % of patients with out-of-hospital cardiac arrest will have a culprit lesion, and PCI in this setting is associated with a two-fold outcome in cerebral performance category.30 Thus, all patients should have ischaemia assessed both through the 12-lead ECG and through invasive coronary angiography. The ECG should also be closely analysed for evidence of inherited cardiac conditions and structural cardiac abnormalities. Common inherited cardiac conditions to look for on an ECG include Brugada syndrome, long and short QT and early repolarisation. Additionally, structural cardiac abnormalities, such as HCM, ARVC and dilated cardiomyopathy (DCM), may also present with characteristic ECG changes.

Imaging in the form of echocardiography and MRI play an important role in the assessment of structural causes of out-of-hospital cardiac arrest. Echocardiography is the mainstay of initial assessment, allowing assessment of regional wall motion abnormalities, overall ventricular function, valvular heart disease and heart muscle disorders, such as HCM, ARVC and DCM. Increasingly cardiac MRI (cMRI) is also used to provide additional information to echocardiography, through the ability to provide greater information about tissue wall characterisation, and may contribute to the diagnosis in 50 % of cases and provide a decisive diagnosis in 30 % of cases.31

5% 2%

75%

15%

Coronary heart disease Cardiomyopathies (DCM, HCM, ARVC) Inherited arrhythmia syndromes (LQT, BrS, CPVT, ERS) Valvular heart disease Others ARVC = arrhythmogenic right ventricular cardiomyopathy; BrS = Brugada syndrome; CPVT = catecholaminergic polymorphic ventricular tachycardia; DCM = dilated cardiomyopathy; ERS = early repolarisation syndrome; HCM = hypertrophic cardiomyopathy; LQTS = long QT syndrome.

Figure 3: The Barts Protocol for Assessment of Unexplained Cardiac Arrest in the Context of Unobstructed Coronary Vessels

Standard 12 lead ECG lying and standing

LQT, BrS ECG changes, bidirectional leads in CPVT, ERS, T-wave inversion and non-specific T-wave changes in cardiomyopathy/myocarditis

High lead ECG

Type 1 BrS ECG change

Imaging Echocardiography + cMRI ± cardiac CT/CT-PET

Structural heart disease/ cardiomyopathy/myocarditis

Patients Where the Cardiac Arrest is Apparently Unexplained: The Barts Protocol Where cases of ischaemic heart disease are excluded, EF is preserved and repolarisation disorders are not apparent on the resting ECG, further assessment is required. This may increase the diagnostic yield and provide a diagnosis in nearly half of patients where an initial diagnosis is unclear.32 Figure 3 describes the Barts Protocol for Assessment of such patients, and Table 1 details the diagnostic criteria.

Provocation Testing Initial assessment involves a lying and standing ECG to look for evidence of QT prolongation during brief tachycardia induced by standing, which may expose concealed LQT1 and LQT2 phenotypes.33,34 This is followed by exercise testing to look for QT prolongation on exercise or a failure to shorten the QT interval on exercise, which is a prominent feature of the exercise ECG in LQT1 patients.34 Figure 4 shows an example of QT prolongation on exercise along with the tangent method for measuring the QT interval. During treadmill testing particular attention should also be paid to the recovery ECG during the first 1–4 minutes, as LQT2 patients may only exhibit QT prolongation in the recovery phase of exercise where sympathetic withdrawal may provoke late QT lengthening.34,35 A QTc >445 ms at 4 minutes of recovery has been shown to have a sensitivity of 92 % and specificity of 88 % in identifying LQT1 and LQT2 individuals.35 Exercise testing may also expose polymorphic or bidirectional VT, which may hint at a diagnosis of catecholaminergic polymorphic ventricular tachycardia (CPVT) as demonstrated in Figure 5A, though this test is neither sensitive nor specific for the condition.

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Provocation testing • Exercise testing • Ajmaline test

LQT/BrS/CPVT

Others • Electrophysiological study* • Genetic testing • Cardiac biopsy** BrS = Brugada syndrome; CPVT = catecholaminergic polymorphic ventricular tachycardia; ERS = early repolarisation syndrome; LQT = long QT syndrome. *Only in cases of suspected pre-excitation. **Only in cases of suspected sarcoidosis.

Additionally, we routinely record the ECG in the standard and highright precordial positions36 to look for characteristic evidence of type 1 Brugada ECG change.37 We also perform provocative testing using ajmaline at a dose of 1 mg/kg over 5 minutes, with the ECG right precordial leads in the high and standard positions, though the sensitivity and specificity of this is debated.36 Figure 6 shows an example of a positive ajmaline challenge test.

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Clinical Review: Arrhythmias Table 1: Diagnostic Criteria of Inherited Arrhythmia Syndromes Condition

ECG Diagnostic Criteria

Provocation Test Indications

Diagnostic Provocation Test

Long QT syndrome

Bazett’s formula (QTc) ≥500 ms in repeated 12-lead ECG or QTc between 480–499 ms (470–449 ms in men) in repeated 12-lead ECGs in a patient with unexplained syncope

QTc (man: 440–470 ms; woman: 450–480 ms) or QTc (man: <440 ms; woman: <450 ms), consider provocation test if high clinical suspicion

Failure to shorten QT or QTc lengthening or QTc > 445 ms at 4 min recovery

Brugada syndrome

ST-segment elevation with type 1 morphology ≥2 mm in ≥1 lead among the right precordial leads V1, V2, positioned in the 2nd, 3rd or 4th intercostal space occurring either spontaneously or after provocative drug testing

Ajmaline testing if clinical suspicion

≥2 mm ST elevation in ≥1 lead among the right precordial leads

Catecholaminergic polymorphic ventricular tachycardia

Bidirectional VT or polymorphic ventricular premature beats or exercise-induced PVCs or bidirectional/polymorphic VT

Exercise testing if clinical indication

Polymorphic or bidirectional VT on exercise

Early repolarisation

J-point elevation ≥1 mm in ≥2 contiguous inferior and/or lateral leads

NA

NA

Findings

NA = Not applicable; PVC = premature ventricular contractions; VT = ventricular tachycardia.

Figure 4: Exercise Stress Test ECG in Long-QT Syndrome A

Imaging Echocardiography and cMRI form the mainstay of assessment to look for evidence of structural cardiac causes. cMRI is increasingly proving to be useful through the ability to detect morphological abnormalities and characterise tissue fibrosis, which provides vital clues to the pathogenesis of sudden cardiac arrest.31 Increasingly, where patients do not have a history or ECG changes that warrant immediate coronary intervention, cardiac CT is being used to look at the coronary anatomy and anomalous coronary artery courses, thus negating the need to conventional angiography.

Other Tests/Investigations

B

C

Electrophysiological testing has not been shown to influence management or predict outcome in cardiac arrest survivors,38 and its role in management and risk prediction in inherited conditions, such as Brugada syndrome, is debated.39 We only perform this in cases where pre-excitation is suspected. Genetic testing is useful where a clear diagnosis is established or the pre-test probability is high, such that a positive test will influence the management not only of the patient but of their family. Cardiac biopsy may have a role in diagnosing inflammatory or infiltrative diseases, such as myocarditis or sarcoidosis, but is increasingly less used with the advent of advanced imaging modalities, such as cMRI and PET-CT, which we only perform when the imaging findings are in doubt in cases of suspected sarcoidosis.

Management of Patients after Stabilisation from Cardiac Arrest While implantation of an ICD remains the mainstay of management in most patients who survive an out-of-hospital cardiac arrest, in patients who cannot have an ICD due to clinical reasons or where patients are undecided about having an ICD, the ZOLL® LifeVest may be considered as a bridge to ICD implantation or until the arrhythmic risk subsides.40 In patients who have an ICD implanted, further appropriate ICD therapy is seen in >23 % of cases.32 Identifying the cause of the cardiac arrest is important as this may allow directed therapy that reduces the risk of future cardiac arrest, and may also allow for the identification and prevention of the same, potentially inherited, condition in first-degree relatives.

A: The baseline ECG showed a normal QTc interval. QT interval on V5 was 340 ms and RR = 0.7 s. Using Bazzet’s formula the following QTc was obtained: 340/√0.70 = 406 ms.

B: Peak exercise revealed a pronounced increase in QTc (280/√0.36 = 529 ms), suggesting almost an attachment of the QT interval to the start of the P wave (“QT stretching”).

C: Illustration of the tangent method for measuring the QT interval.

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Ischaemic Cardiomyopathy Ischaemia is the underlying aetiology in the majority of cases, and arrhythmia management is based on adequate secondary prevention

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Sudden Cardiac Death and Arrhythmias Figure 5: Catecholaminergic Polymorphic Ventricular Tachycardia and Early Repolarisation Syndrome A

Figure 6: Ajmaline Challenge Testing A

B B

C

High V1

C High V2

A: Baseline 12-lead ECG showing resting type 2 ECG change, with 1–2 mm J-point elevation in V1–V2, saddleback ST elevation and positive/biphasic T-wave. B: Baseline 12 lead now with additional high leads in V1–V2 position. Note the presence of ≥2 mm J-point elevation, with >1 mm trough/saddleback ST elevation and the inverted T-wave. Still a type 2 ECG but significantly different in the high leads. C: Positive test. After administration of 90 mg Ajmaline, there is ≥2 mm J-point elevation and ≥2 mm coved ST elevation with a negative T-wave in high V1–V2 (conventional V5–V6 on this 12-lead ECG).

and ensuring adequate revascularisation has occurred. Beta-blockers remain the mainstay of management to prevent further shocks, with additional use of amiodarone or class IB agents, if necessary, to avoid shocks and treat VT storms. Increasingly the use of VT ablation is being performed with success rates >75 % in some cohorts.41

effective.42,43 In patients with LQT3, the addition of oral mexiletine to block late sodium currents may be helpful in patients with a QT interval >500 ms and syncope/pre-syncope or ICD therapy.44 In patients with ongoing ICD therapy despite medical therapy, or with markedly prolonged QT intervals >550 ms where risk becomes higher,20 left cardiac sympathectomy may be effective.45 Additionally, the avoidance of drugs that prolong the QT interval should be emphasised. This list is frequently changing and should be checked by patients and physicians: crediblemeds.org.46

Long QT Syndrome

Brugada Syndrome and Early Repolarisation Syndrome

In patients with LQT, beta-blockers remain the mainstay of treatment, with propranolol, bisoprolol and nadolol being the most effective in shortening the QT interval. Evidence suggestes metoprolol is not as

Avoidance of fever, including the use of anti-pyretics and avoidance of drugs that precipitate arrhythmia and type 1 ECG change, is the mainstay of treatment in Brugada syndrome (brugadadrugs.org).47

A: Exercise test C showing bidirectional and polymorphic VT in a patient with CPVT. B: 1-mm early repolarisation in the lateral and inferior leads. C: Ectopic triggered polymorphic VT in the same patient.

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Clinical Review: Arrhythmias Acute VT storms respond well to isoproterenol infusion and hydroquinidine can be used as an oral alternative in patients with recurrent ICD therapy. 20 Increasingly, epicardial substrate ablation is showing promise48 and may become a major component in patient management.

Early repolarisation syndrome responds in a similar manner to Brugada syndrome, with isoproterenol infusion and hydroquinidine being useful treatments. In some patients with early repolarisation syndrome, VT/ VF is triggered by closely coupled ectopic beats (Figure 5B and C), and suppression of these using either beta-blockade, calcium channel blockers or ablation may be useful.

Catecholaminergic Polymorphic Ventricular Tachycardia Beta-blockers are the first-line drug of choice in preventing ectopy and arrhythmia in this patient cohort. The addition of flecainide is thought to prevent cellular calcium overload in CPVT and may be useful in patients with recurrent syncope, VT or ICD therapy. Verapamil has also been shown to be effective.20 Implantation of an ICD should be avoided in these patients, if possible, because the sympathetic drive associated with a shock can precipitate arrhythmia whether or not the original shock is appropriate or inappropriate. Additionally, there are case reports of ventricular ectopic ablation in CPVT, which may prevent the Purkinje triggers in these patients.49 Finally, left cardiac sympathectomy may be effective in preventing arrhythmia and ICD shocks in cases resistant to medical therapy.45

Idiopathic Ventricular Fibrillation Management of recurrent arrhythmia in this subset of patients is largely empirical. Recurrence of arrhythmia and appropriate shocks may occur in up to 29 % of patients, and therapy with hydroquinidine50 may be helpful in reducing ICD therapy.51 As with patients with early repolarisation, short coupled ventricular premature beats may be a common arrhythmia trigger in this cohort of patients, often via Purkinje firing, and ablation of these may prove successful in abolishing further arrhythmia.52

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Structural Heart Disease Management of cardiomyopathies is best performed in specialist clinics, where the multitude of symptoms, as well as family screening and follow up, can be performed by physicians with an expertise in the field. Beta-blockers and amiodarone remain the mainstay of treatment for recurrent ventricular arrhythmia in HCM and DCM. Sotolol is the initial drug of choice during the active arrhythmia phase of ARVC, followed by amiodarone or beta-blockers. Catheter ablation may prove useful in reducing arrhythmia burden in ARVC53 and DCM.

Family Screening Family screening in cases where the diagnosis is clear, or where a clear pathogenic genetic mutation is identified, is necessary to exclude a diagnosis in first-degree relatives, and to manage their risk accordingly. Additionally, screening the family members of victims from unexplained sudden death may identify a disease phenotype that is latent in the proband,54 and may aid in diagnosing and managing the risk to relatives.55 Our screening of family members follows the Barts Protocol.

Conclusion SCD and arrhythmia continues to represent a major international public health problem and is still the biggest killer worldwide, despite huge improvements in cardiovascular care in the past 30 years. The majority of patients do not survive to hospital discharge, highlighting the need for larger and better public health initiatives to improve the chain of survival. Importantly, the majority of events occur in patients without traditional risk factors for cardiac events, highlighting the need for new and better markers of arrhythmic risk. In patients who survive to arrival at hospital, a thorough assessment of the underlying aetiology is required, and where the diagnosis is unclear, further testing including provocation testing and cMRI is warranted.

Management of further arrhythmic events is dependent on the underlying aetiology and screening of family members may aid not only in establishing a diagnosis but also in managing arrhythmic risk of first-degree relatives. n

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Philips B, Madhavan S, James C, et al. Outcomes of catheter ablation of ventricular tachycardia in arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ Arrhythm Electrophysiol 2012;5:499–505. https://doi.org/10.1161/CIRCEP.111.968677; PMID: 22492430.

Honarbakhsh S, Srinivasan N, Kirkby C, et al. Medium-term outcomes of idiopathic ventricular fibrillation survivors and family screening: a multicentre experience. Europace 2017;19:1874–80. https://doi.org/10.1093/europace/euw251; PMID: 27738067.

Quenin P, Kyndt F, Mabo P, et al. Clinical yield of familial screening after sudden death in young subjects: the French experience. Circ Arrhythm Electrophysiol 2017;10:e005236. https://doi.org/10.1161/CIRCEP.117.005236; PMID: 28912206.

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Clinical Review: Arrhythmias

Risk Factor Management in Atrial Fibrillation Axel Brandes, 1 Marcelle D Smit, 2 Bao Oanh Nguyen, 2 Michiel Rienstra 2 and Isabelle C Van Gelder 1,2 1. Department of Cardiology, Cardiology Research Unit, Odense University Hospital, University of Southern Denmark, Odense, Denmark; 2. Thoraxcentre, University of Groningen, University Medical Centre, Groningen, The Netherlands

Abstract Atrial fibrillation (AF) is the most common clinical arrhythmia and is associated with increased morbidity and mortality. There is growing evidence that numerous cardiovascular diseases and risk factors are associated with incident AF and that lone AF is rare. Beyond oral anticoagulant therapy, rate and rhythm control, therapy targeting risk factors and underlying conditions is an emerging AF management strategy that warrants better implementation in clinical practice. This review describes current evidence regarding the association between known modifiable risk factors and underlying conditions and the development and progression of AF. It discusses evidence for the early management of underlying conditions to improve AF outcomes. It also provides perspective on the implementation of tailored AF management in daily clinical practice.

Keywords Atrial fibrillation, risk factors, lifestyle modification, prevention, integrated management Disclosure: The authors have no conflicts of interest to declare.

Acknowledgement: Netherlands Cardiovascular Research Initiative: an initiative with support of the Dutch Heart Foundation, CVON 2014-9: Reappraisal of Atrial fibrillation: interaction between hyperCoagulability, Electrical remodeling, and Vascular destabilisation in the progression of AF (RACE V).

Received: 16 March 2018 Accepted: 12 April 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(2):118–27. https://doi.org/10.15420/aer.2018.18.2 Correspondence: Isabelle C Van Gelder, Department of Cardiology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands. E: i.c.van.gelder@umcg.nl

Atrial fibrillation (AF) is the most common clinical arrhythmia worldwide and is expected to increase in the coming decades.1,2 It currently affects up to 3 % of Western populations aged 20 years or older, and the number of affected individuals in the EU will increase from about 7 million to almost 13 million by 2030.3–5 This growing epidemic is not only caused by the natural ageing of the population, but also by the accumulation of chronic cardiovascular diseases and risk factors, and thus at least in part is caused by inadequate lifestyle.5–7 AF is a chronic condition and is independently associated with increased morbidity and mortality, including ischaemic stroke, dementia, cognitive dysfunction, heart failure (HF), MI and all-cause mortality.8–14 Stroke and HF can even be the first manifestation of AF. Although AF can be completely asymptomatic, about two-thirds of patients experience at least intermittent symptoms, which can be disabling and markedly impair health-related quality of life.15,16 AF-related symptoms and complications, as well as underlying cardiovascular diseases, lead to unplanned hospital admissions in a substantial number of patients every year.17,18 Therefore, it is not surprising that inpatient AF care accounts for more than two-thirds of the annual direct costs of AF and is the major cost driver.19–21

Contemporary AF Management AF treatment has largely focused on the prevention of stroke and HF as well as symptom control, as reflected in previous European and current American guidelines for the management of AF.22–24 However, these guidelines make only narrow recommendations on upstream therapy in selected patient groups, e.g. treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II-receptor blockers (ARBs) in patients with HF or hypertension, or statin treatment in patients

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with postoperative AF. In contrast, contemporary AF management as outlined in the current European guidelines pursues an integrated approach with five domains that have to be individually addressed according to the needs of each patient.25 These five domains include: acute rhythm management in patients presenting with hemodynamic instability; detection and treatment of underlying predisposing conditions; stroke risk assessment and oral anticoagulation for stroke prevention; rate control; and rhythm control. The second domain now puts upstream therapy into a much broader perspective. The present review focuses on the detection and treatment of associated diseases and risk factors, i.e. the targeting of underlying conditions.26

Early Detection and Treatment of Underlying Conditions AF is commonly considered a progressive disease – developing from a paroxysmal, self-terminating form through persistent to permanent AF – and is perpetuated by on-going electrical and structural remodelling of the atria.27–29 Some patients already have persistent AF at the time of first diagnosis.30 Registry data showed that patients with progression from paroxysmal to more sustained AF were more frequently admitted to hospital due to cardiovascular causes and had more strokes, but were also older and had a larger number of underlying comorbidities such as hypertension, HF, coronary artery disease (CAD) and previous stroke or transient ischaemic attack (TIA).31,32 A pooled analysis of the non-anticoagulated populations from the Atrial Fibrillation Clopidogrel Trial with Ibersartan for Prevention of Vascular Events (ACTIVE-A) and Apixaban Versus Acetylsalicyclic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trials found that patients with persistent or permanent AF at baseline had significantly higher

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Risk Factor Management in Atrial Fibrillation Table 1: Modifiable Risk Factors Associated with Atrial Fibrillation that can be Targeted Through Optimal Treatment and Lifestyle Intervention Conventional Risk Factors

Less Established Risk Factors

Emerging Risk Factors

Coronary heart disease

Chronic obstructive pulmonary disease

Subclinical atherosclerosis

Hypertension (>140/90 mmHg)

Left atrial dilatation

Borderline hypertension (between 120/80 mmHg and 140/90 mmHg)

Heart failure (with reserved and preserved ejection fraction)

Atrial conduction delay/PR interval

Chronic kidney disease

Left ventricular diastolic dysfunction Diabetes

Subclinical hyperthyroidism Left ventricular hypertrophy

Inflammation

Hyperthyroidism Obesity

Elevated natriuretic peptides Obstructive sleep apnoea syndrome

Valvular heart disease

Widened pulse pressure Excessive endurance exercise, physical inactivity, excessive alcohol intake, smoking, caffeine intake

Source: Adapted from J Am Coll Cardiol, 63, Wyse DG, Van Gelder IC, Ellinor PT, et al, Lone atrial fibrillation: does it exist?, 1715–23, 2014, with permission from Elsevier.45

stroke rates than those with paroxysmal AF. Findings from recent population-based studies and registries also demonstrated that at least 25–30 % of all patients with an ischaemic stroke and >80 % of those with cardioembolic ischaemic stroke also had AF, suggesting a strong association between these two entities.3,33–40 Another important finding in this context was that stroke was the first manifestation of previously unknown AF in >25 % of AF-related strokes.3,33–35,41 This

left ventricular function, but increasingly rely on a broader individual and complete approach with timely detection and optimal treatment of risk factors and underlying conditions to improve outcomes and reduce AF burden by targeting the substrate for AF in a more fundamental way.25,53 As patients with AF have different unfavourable risk factor profiles and many have more than one subclinical or clearly elevated modifiable risk factor,45,54 interventions aiming at risk factor

association was even higher if prolonged noninvasive or invasive monitoring was performed following a stroke.42,43 Taken together, these findings call for earlier diagnosis and comprehensive treatment of AF to reduce stroke risk and improve outcomes.30

management – including lifestyle modification and treatment and targeting underlying conditions – need to be patient-centred and tailored to individual needs. Thus, targeted therapy of risk factors and underlying conditions has becomes the fourth pillar of integrated AF.25,55 This was recently investigated in the Routine Versus Aggressive Upstream Rhythm Control for Prevention of Early Atrial Fibrillation in Heart Failure (RACE 3) trial.26

In recent years, a number of risk factors and conditions have been identified that are associated with the development and progression of AF.7,44–46 A few of these risk factors and predisposing conditions cannot be modified, such as advancing age, gender, ethnicity and genetic predisposition; however, most are modifiable or can at least be optimally treated (Table 1; Figure 1). Many risk factors and underlying conditions predisposing to AF are also risk factors for other cardiovascular conditions such as CAD, vascular disease and HF. Targeting these risk factors and underlying conditions as early as possible – ideally before AF becomes clinically manifest – would not only prevent or reverse atrial remodelling and thus prevent or limit AF progression but also improve the underlying conditions themselves and in turn reduce strokes and other cardiovascular adverse events.47–49 This becomes even more important in patients with HF, in whom new-onset AF has a marked effect on mortality compared to patients without HF.50 Moreover, patients with HF who later develop AF have a worse prognosis than those with AF who then develop HF.51

Targeting Risk Factors and Underlying Conditions Due to our increasing knowledge about AF aetiologies and mechanisms, there are questions as to whether lone AF exists, as a substantial number of patients who would previously have been classified as having lone AF actually have risk factors (Table 1).45,52 Thoroughly searching for modifiable risk factors and cardiovascular diseases associated with incident AF and initiating treatment as early as possible to prevent or at least delay the development of AF seems prudent (Figure 2).45 For this reason, AF management should also no longer solely address single domains such as stroke prevention, symptom relief or preservation of

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Hypertension Hypertension is one of the major risk factors for AF. The reported prevalence rates of hypertension in AF studies range from 49 to 90 %.56 In the Framingham Heart Study, not only stage II–IV hypertension (systolic blood pressure (BP) >160 mmHg and diastolic BP >95 mmHg) was significantly associated with the risk of AF with an odds ratio (OR) of 1.5 for men and 1.4 for women,57 but also borderline systolic BP was associated with a slightly increased risk of incident AF.7 Data from the Atherosclerotic Risk in Communities (ARIC) study showed that hypertension (systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg and/or treatment for hypertension) accounted for about 22 % of incident AF. The proportion was even higher (24.5 %) if borderline BP values (systolic BP of 120–139 mmHg or diastolic BP of 80–90 mmHg) were included, meaning that even slightly elevated BP is a clear risk factor for AF.54 Similar results were reported from the Women’s Health Initiative (WHI) observational study in postmenopausal women, where an elevated systolic (≥140 mmHg) or diastolic (≥90 mmHg) BP accounted for almost one-third of the population-attributable risk of incident AF.58 In the recently published community-based Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study, use of antihypertensive drugs as a proxy for hypertension more than doubled the risk of incident AF. Likewise, every 10-mmHg increase in systolic BP increased risk for incident AF (HR 1.11).46 The first evidence that optimal treatment of hypertension may prevent AF and improve outcomes came from intervention trials

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Clinical Review: Arrhythmias Figure 1: Risk Factors and Underlying Comorbidities to be Addressed in Chronic Comprehensive Atrial Fibrillation Management

Figure 2: Time-dependent Atrial Remodelling and Development of Atrial Fibrillation “Lone” AF Remodelling

Smoking

Inflammatory diseases

Development of AF risk factors

Alcohol consumption

Valve disease

ECV

ECV

SR

(Borderline) hypertension

AF

Paroxysmal Persistent

Permanent

Progression of AF risk factors

Chronic obstructive pulmonary disease

Lipid profile Multidisciplinary AF team

Clinical detection level of AF risk factors

AF Patient

Obstructive sleep apnoea

(Pre-) diabetes

Providing all treatments

Chronic kidney disease

Vascular disease

Coronary artery disease

Physical inactivity Obesity

Heart failure

in hypertensive patients. In the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study, which compared the use of ARB losartan with the beta-blocker atenolol, losartan prevented more cardiovascular morbidity and death than atenolol for a similar reduction in BP.59 A post-hoc analysis from this trial showed that the greatest reduction (40 %) in risk of incident AF occurred in patients who achieved optimal systolic BP levels of <130 mmHg, compared to those with systolic BP ≥142 mmHg. Moreover, incident AF occurred less frequently in patients treated with losartan than in those treated with atenolol, although there was no significant difference in BP reduction.60 A Danish nationwide nested case-control study also found less new-onset AF in patients with hypertension treated with ARBs or ACE inhibitors compared to beta-blockers or diuretics.61 These findings suggest that inhibition of the renin–angiotensin system itself might have a beneficial effect on the reduction of incident AF besides BP control. In a small, randomised study in patients with AF and drugresistant hypertension undergoing pulmonary vein isolation (PVI) for AF, optimisation of BP treatment by renal denervation on top of PVI significantly reduced AF recurrence at 12 months compared with PVI alone in addition to markedly improved BP.62 A more comprehensive treatment approach was investigated in the RACE 3 trial, where patients with early persistent AF and mild to moderate HF were randomised to causal treatment of AF and HF alone or targeted treatment with mineralocorticoid receptor antagonists (MRAs), statins, ACE inhibitors or ARBs with a BP target of <120/80 mmHg and cardiac rehabilitation on top of causal treatment. Targeted treatment led not only to significantly improved sinus rhythm maintenance but also better BP control at 1 year.26

Heart failure Beyond age, HF is the most important risk factor for incident AF, increasing the risk by two- to threefold.9,31,57,63–67 Despite this, HF only accounts for a modest proportion of the population-attributable risk of

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Years

+5

+10

+15

+20

A hypothetic construct over time indicating the interrelationship between time, risk factors for atrial fibrillation (AF), atrial remodelling, detection of risk factors for atrial remodelling and progression from sinus rhythm (SR) through paroxysmal and persistent to permanent AF. ECV = electrical cardioversion. Source: J Am Coll Cardiol, 63, Wyse DG, Van Gelder IC, Ellinor PT, et al, Lone atrial fibrillation: does it exist?, 1715–23, 2014, with permission from Elsevier.45

incident AF and has decreased over recent decades, as demonstrated by data from the Framingham Heart Study.7,54,58 These reductions could be ascribed to improvements in HF therapy.

Compared to other risk factors and underlying conditions, HF and AF frequently coexist and have a complex interrelationship. They share many fundamental predisposing factors and pathophysiological pathways, promoting each other and mutually leading to a worse prognosis.50,51,68–70 Data from the PREVEND study have demonstrated that HF is associated with incident AF and that adverse outcomes including HF are associated with AF.46 In daily practice it is often difficult to determine whether AF is a major contributor to shortness of breath, impaired quality of life, clinical signs and worse prognosis or just a coexisting condition. This is because HF – particularly HF with preserved ejection fraction (HFpEF) – and AF share many common clinical signs and symptoms.69,70 Optimisation of HF treatment may prevent AF or at least improve sinus rhythm maintenance. Adding MRA treatment to otherwise optimal HF therapy in patients with mild systolic HF leads to a significant reduction of new-onset AF, as shown in an analysis from the Eplerenone in Mild Patients Hospitalization And Survival Study in Heart Failure (EMPHASIS-HF) trial.71 In addition to improved maintenance of sinus rhythm, comprehensive targeted treatment in the RACE 3 study resulted in improvement of HF, as reflected by a significantly greater decrease in brain natriuretic peptide levels at 1 year compared to baseline.26

Coronary and Vascular Disease CAD is an established risk factor for incident AF. Data from the Framingham Heart Study demonstrated that a history of MI was significantly associated with incident AF in men (OR 1.4), but not women.57 A later analysis from this study found a significant association when adjusting for age and gender.65 Krahn et al. found a 3.6-fold increase in the relative risk of AF after MI.9 Previous MI was also a predictor of incident AF in elderly patients (mean age 75 years; HR 2.2),63 which was confirmed by the ARIC study66 and in a combined analysis from the ARIC and Cardiovascular Health Studies.64 The PREVEND study also found a significant association between previous MI and stroke and incident AF, with incidence rates of AF comparable to those described in several of the studies mentioned

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Risk Factor Management in Atrial Fibrillation above, although these studies recruited patients much earlier than PREVEND and the treatment of patients with MI and stroke has markedly improved over time. However, incident AF was associated with an increased risk of all forms of vascular disease, HF and death.46 According to data from the Framingham Heart Study, the populationattributable risk of MI remained unchanged over 5 decades despite substantial improvements in the treatment of MI during this time.7 Weijs et al. found a surprisingly high proportion of patients with subclinical CAD in a relatively young (mean age 55 years) cohort of patients with an original diagnosis of lone AF compared to matched controls with sinus rhythm.72 Some of these patients had already developed advanced CAD. Taking into account that patients with AF and vascular disease are at increased risk of fatal and non-fatal cardiovascular events, it seems prudent to screen patients with AF for vascular diseases because treatment in an early stage could reduce AF and improve their prognosis.73 Hypercoagulability may also lead to fibroblast activation, cellular hypertrophy and fibrosis; in this way it may be involved in the creation of a substrate for AF.29,52,74 The contribution of hypercoagulability to the progression of AF is currently being investigated in the RACE V study (ClinicalTrials.gov, NCT03124576).

Obesity The evidence that obesity is an independent risk factor for incident AF has grown in recent years. Data from the ARIC study showed that overweight and obesity (BMI ≥25 kg/m2) accounted for about 18 % of incident AF, making obesity the second strongest risk factor for AF.54 Comparable results were found in the WHI observational study, where these conditions accounted for 12 % of the population-attributable risk.58 Interestingly, obesity is not only a risk factor for incident AF in postmenopausal women but also in young and essentially healthy women.75 Data from the Framingham Heart Study demonstrated a 4 % increase in AF risk for each unit increase in BMI. Obesity (BMI ≥30 kg/m2) was significantly associated with incident AF in men and women.76 There has been an increase in the population-attributable risk of obesity for incident AF in the past 50 years7 and numerous cohort and case-control studies have confirmed the strong and consistent association between obesity and AF.46,58,77–82 A recent meta-analysis found not only a 29 % and 19 % increase in incident AF risk for every 5 additional BMI units, respectively, but also a 10 % increase in postoperative AF and a 13 % increase in post-ablation AF.83 The PREVEND study found similar results, with an increased rate of incident AF for every 5 additional BMI units.46 Taking these results into account and the fact that overweight is associated with increased risk of fatal and non-fatal coronary heart disease outcomes, it seems prudent to implement fitness and weight reduction in AF therapy.84,85 Cardiac rehabilitation, including regular physical activity, dietary restrictions and scheduled counselling, should be part of a comprehensive targeted treatment approach. In the RACE 3 trial, this approach led to a slight reduction in BMI and weight at 1 year as well as improved sinus rhythm maintenance.26 These figures also demonstrate that a substantial improvement requires long-term patient involvement and persistent adherence to treatment.

Diabetes Diabetes and elevated blood glucose (BG) levels are also significant risk factors for incident AF, as demonstrated in several studies.

However, the results are conflicting and difficult to compare due to differences in methodology, e.g. adjustment for confounding variables which was not performed in all studies. Data from the ARIC

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study showed that diabetes and poor glycaemic control, reflected by elevated HbA1c levels, were independently associated with an increased risk of incident AF.86 However, another analysis from the same study demonstrated that only 3 % of incident AF was attributable to diabetes.54 The same population-attributable risk was seen in the in WHI observational study.58 The population-attributable risk of diabetes increased over time despite improvements in treatment.7 In a recent Danish nationwide cohort study, the risk for incident AF was most pronounced in diabetes patients aged 18–39 years.87 Poor glycaemic control and longer duration of diabetes were also associated with incident AF in a population-based case-control study that identified a 3 % higher risk of incident AF for each year of diabetes duration.88 In a meta-analysis, individuals with diabetes had 39 % greater risk of incident AF than unaffected individuals.89 Interestingly, AF in patients with diabetes is associated with 61 % greater risk of all-cause mortality and a comparable higher risk of cardiovascular death, stroke and HF.90 The pathophysiological mechanisms implicated in promoting AF in individuals with diabetes are complex and include autonomic, electrical, electromechanical and structural remodelling, oxidative stress, connexin remodelling and glycaemic fluctuations.91 In general, patients with metabolic disorders including diabetes already have an increased risk of fatal and non-fatal coronary heart disease outcomes.84 Taking all these findings together, the vicious combination of AF and diabetes warrants timely evaluation and treatment. In a populationbased study, metformin use was associated with a significant reduction in new-onset AF in patients with type 2 diabetes who were not taking other antidiabetic medications.92

Physical Inactivity and Cardiorespiratory Fitness It is generally accepted that physical activity considerably lowers cardiovascular mortality and morbidity, which is why it is also recommended in current cardiovascular disease prevention guidelines.93 Greater cardiorespiratory fitness (CRF) reduces allcause mortality and cardiovascular events.94 Results from a large cohort study also showed a graded inverse relationship between CRF and the development of AF, especially in obese patients: every additional metabolic equivalent achieved during exercise testing was associated with a 7 % lower risk of incident AF.95 Similar results were found in a large Swedish cohort study in middle-aged and elderly women that compared self-reported levels of leisure activity. The risk of developing AF decreased with increasing levels of leisuretime exercise at study entry.96 However, the relationship between the amount of exercise and incident AF does not seem to be linear but U-shaped – at least in older adults. This was demonstrated by data from the Cardiovascular Health Study, where individuals doing moderate-intensity exercise developed less AF than those doing high-intensity exercise or no exercise.97 A similar U-shaped relationship has also been found between CRF and incident AF.98 Currently, no exact dose–response relationship has been established between physical activity and reduction of incident AF, but evidence suggests that >220 minutes of moderate-intensity exercise per week or a CRF >8 metabolic equivalents carries a lower risk of AF; whereas high-intensity exercise and endurance training might be harmful and increase this risk.99,100 In practice, routine exercise testing to determine CRF and identify patients at higher risk of AF as well as recommending 150–200 minutes of moderate-intensity exercise per week could be an appropriate solution and should be implemented in the management of AF.85,93,101 This strategy has been investigated as part of a comprehensive targeted treatment approach in the RACE 3 trial, which improved sinus rhythm maintenance.26

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Clinical Review: Arrhythmias Renal Dysfunction Beyond the established risk factors and conditions associated with AF such as age, hypertension, DM, HF and obesity, renal dysfunction has also been related to incident AF. In the ARIC study, reduced renal function and the presence of albuminuria were strongly associated with incident AF independent of other risk factors.102 Similar results were found in the PREVEND study, where microalbuminuria – as a measure of renal vascular dysfunction – was related to incident AF independent of cardiovascular risk factors.103 Likewise, in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, renal dysfunction – regardless of severity – was associated with increased prevalence of AF.104 On the other hand, patients with AF have a higher risk of chronic kidney disease, as demonstrated by a large population-based study from the UK and a meta-analysis including approximately 10 million patients from 104 studies.105,106 Reduced renal function is associated with increased risk of adverse cardiovascular outcomes, such as stroke and HF.107,108 It has also been associated with increased risk of stroke and systemic embolism in patients with non-valvular AF.109 The coexistence of both conditions results in a marked increase in both thromboembolic and haemorrhagic risk.110 AF and chronic kidney disease not only share risk factors such as DM, hypertension and HF;111 there is growing evidence that both diseases share underlying pathophysiological mechanisms, such as left ventricular hypertrophy, inflammation, hypercoagulability and activation of the renin–angiotensin–aldosterone system.112–116 Timely treatment of risk factors and underlying conditions could lead to improvement of both conditions and reduce adverse outcomes.

Obstructive Sleep Apnoea In recent years, obstructive sleep apnoea (OSA) has emerged as one of the novel risk factors for AF.45 Sleep-disordered breathing is a common condition: at least mild OSA affects one in five adults; whereas one in 15 has moderate or severe OSA.117 Moreover, there is a higher prevalence of OSA in men and obese adults, while advancing age and increasing BMI also are risk factors for incident OSA.118 Among patients with AF, the prevalence of OSA is estimated at about 50 % or even higher.119,120 Patients with OSA have a significantly higher risk of developing AF, especially those with severe disease.121,122 A study in patients with OSA and symptomatic AF undergoing AF ablation showed that arrhythmia-free survival was better in those receiving continuous positive air pressure treatment than in those not on this treatment.123 It is important to note that OSA and AF share several characteristics – hypertension, diabetes, obesity and advancing age are common in both conditions. Screening for OSA is regarded as important when evaluating patients with AF, particularly in those with obesity and hypertension. This can be achieved by using simple scoring systems, e.g. the NoSAS score.124

Alcohol Consumption Acute heavy alcohol consumption has long been known as a cause of AF and is commonly called “holiday heart” syndrome.125 Binge drinking was associated with increased risk of incident AF in an analysis of pooled data from two antihypertensive drug treatment trials.126 Several prospective cohort studies have also looked at the association between chronic alcohol consumption and incident AF. However, the issue with such studies is that, in contrast to other risk factors for AF that can be objectively measured, the quantities of alcohol intake are usually self-reported by the enrolled individuals. Data from the Framingham Heart Study suggested that heavy alcohol consumption of

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>36 g/day (>3 drinks/day) was associated with a significantly increased risk of incident AF, but also showed that heavy alcohol consumption has decreased over time.7,127 Similar results were reported from the Copenhagen City Heart Study.128 Women who consumed ≥2 drinks/ day also had an increased risk of AF, as shown in an analysis from the Women’s Health Study.129 More recently, data form a prospective Swedish cohort study demonstrated that consumption of even small quantities of alcohol was associated with increased risk of AF.130 Furthermore, two meta-analyses showed a linear dose–response relationship between alcohol intake and risk of AF, with a significant 8 % increase in the relative risk of incident AF for each standard drink per day compared to no drinks a day.130,131 These results suggest that there is no safe level of chronic alcohol intake with regard to the development of AF.

Smoking Numerous cohort studies have investigated the association between smoking and incident AF. Some of them found an increase in risk – ranging from 32 % to more than a doubling in current smokers and 32–49 % in former smokers9,54,132–135 – while other studies did not.77,136–139 An analysis from the ARIC study showed that current smoking accounted for about 10 % of incident AF.54 Moreover, there might also be a dose–response relationship, in that current smokers with the longest duration of smoking and those with the highest number of cigarettes per day had the highest risk of AF.132,133 Generally, smoking cessation is recommended, but data on AF prevention are lacking.

Dyslipidaemia Current data on the association between dyslipidaemia and incident AF are inconsistent. Unlike ischaemic heart disease, which is clearly associated with elevated LDL cholesterol, it seems that there is an inverse correlation between LDL levels and the development of AF, as shown in several epidemiological studies.138,140–142 Analysis of a pooled dataset from the Multi-ethnic Study of Atherosclerosis (MESA) and the Framingham Heart Study did not find any association between LDL levels and AF, but higher levels of HDL cholesterol and lower levels of triglycerides were associated with lower AF risk.143 The association between higher HDL levels and lower AF risk was also found in two other studies,142,144 whereas no such association was found in an analysis of data from the Women’s Health Study.141 A recent posthoc analysis from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial showed that patients with AF and higher levels of apolipoprotein A1 had a lower risk of adverse outcomes, i.e. ischaemic stroke, systemic embolism, MI and cardiovascular death, suggesting that interventions increasing HDL levels could have a beneficial effect.145 Data on the effect of lipid-lowering therapy on AF predominantly come from retrospective and small randomised studies investigating statins in patients with post-operative AF (POAF) and their results are mixed.146 A large randomised, controlled trial of rosuvastatin in patients with POAF did not show any beneficial effect of statin treatment in AF prevention.147 Nevertheless, a comprehensive treatment strategy targeting vascular diseases including lipid-lowering therapy with statins could prevent AF progression and improve sinus rhythm maintenance, as shown in the RACE 3 trial.26

Comprehensive Management of Risk Factors and Underlying Conditions While substantial improvements have been achieved in the field of anticoagulation to reduce stroke and its associated disease

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Risk Factor Management in Atrial Fibrillation Table 2: Studies Investigating Risk Factor Management for Secondary Atrial Fibrillation Prevention Study

Design

Subjects n

AF

(% women)

Follow-up

Intervention

Outcomes

(months)

Effect of weight reduction and cardiometabolic risk factor management on symptom burden and severity in patients with atrial fibrillation162

Prospective, randomised controlled study

150 (33 %)

Paroxysmal or persistent AF, BMI >27 kg/m2

15

Structured weight management versus general lifestyle advice

Significantly greater reduction in weight (14.3 versus 3.6 kg); AF symptom burden scores (11.8 versus 2.6 points); symptom severity scores (8.4 versus 1.7 points); AF episodes (2.5 versus no change); cumulative AF duration (692 min decline versus 419 min increase)

LEGACY164

Prospective observational cohort study

355 (34 %)

Paroxysmal or persistent AF, BMI ≥27 kg/m2

60

Structured weight management; tailored risk-factor management

Significantly greater decrease in AF burden and symptom severity in WL ≥10 %; WL ≥10 % with sixfold greater probability of freedom from AF; weight fluctuation >5 % with twofold increased AF recurrence

BMI Reduction Decreases AF Recurrence Rate in a Mediterranean Cohort166

Retrospective cohort study

258 (n/r)

Paroxysmal or permanent AF; BMI >25 kg/m2

602 patientyears (overall)

Diet and/or moderate exercise

AF recurrence most frequent in patients with BMI >25 kg/m2 and weight gain ≥2 units

ARREST-AF165

Prospective cohort study with control group

149 (36 %)

Symptomatic AF 42 (mean) scheduled for ablation; BMI ≥27 kg/m2 plus ≥1 other risk factor(s)

Structured weight management; aggressive risk-factor management versus information and risk-factor management by treating physician

Significant decrease in AF frequency, duration, symptoms and symptom severity versus controls; single-procedure AF-free survival off drugs markedly better than in controls

CARDIO-FIT167

Prospective cohort study

308 (51 %)

Symptomatic paroxysmal or persistent AF; BMI ≥27 kg/m2

49 (mean)

Risk-factor management and tailored exercise programme

AF-free survival greatest in patients with highest cardiorespiratory fitness; AF burden and symptom severity decreased significantly in patients with cardiorespiratory fitness gain ≥2 METs; AF-free survival greatest in patients with cardiorespiratory fitness gain ≥2 METs

RACE 326

Prospective, randomised controlled trial

245 (21 %)

Early persistent AF and mild-tomoderate HF

12

Conventional therapy (causal treatment of AF and HF and rhythm control therapy) versus conventional therapy plus medical therapy with MRAs, statins, ACE-Is and/or ARBs, and cardiac rehabilitation including physical activity, dietary restriction, and counselling

Significantly more patients in sinus rhythm at 1 year follow-up with targeted therapy of underlying conditions compared to conventional therapy; significantly more successful modification of blood pressure, NT-proBNP, weight, BMI and lipid profile with targeted therapy of underlying conditions compared to conventional therapy; AF symptoms decreased more with targeted therapy

ACE-I = angiotensin-converting enzyme inhibitor; ARB = angiotensin II-receptor blocker; ARREST AF = Aggressive risk factor reduction study for atrial fibrillation and implications for the outcome of ablation; CARDIO-FIT = CARDIOrespiratory FITness on Arrhythmia Recurrence in Obese Individuals With Atrial Fibrillation; HF = heart failure; LEGACY = Long-Term Effect of Goal-Directed Weight Management in an Atrial Fibrillation Cohort: A Long-Term Follow-Up Study; METs = metabolic equivalents; MRA = mineralocorticoid receptor antagonist; NT-proBNP = N-terminal pro-brain natriuretic peptide; n/r = not reported; RACE 3 = Routine Versus Aggressive Upstream Rhythm Control for Prevention of Early Atrial Fibrillation in Heart Failure; WL = weight loss.

burden in patients with AF, important unmet therapeutic needs remain, particularly regarding the prevention of cardiovascular death, HF, unplanned cardiovascular hospitalisations and rhythm control.25,52,148–155 This has led to the concept that “upstream therapy” or “prevention of atrial remodelling” could improve the outcome of rhythm control therapy and possibly also prognosis in patients with AF.30,53,156 Several early retrospective and observational studies on upstream therapy with ACE inhibitors, ARBs and statins have produced encouraging results in terms of reduction in AF recurrences, but larger prospective randomised placebo-controlled trials have failed to show any significant reduction in AF recurrences and

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adverse cardiovascular outcomes, possibly because these studies only addressed a single risk factor.147,157–161 More recently, evidence has become available that comprehensive interventions that aim to reduce risk factors and underlying conditions of AF are able to reduce AF recurrence and burden in addition to improving the underlying conditions (Table 2). In a small randomised study in overweight or obese patients with symptomatic paroxysmal or persistent AF structured weight management and regular exercise in addition to intensive cardiometabolic risk-factor management led to greater weight reduction, greater reduction of the severity and burden of

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Clinical Review: Arrhythmias Table 3: Risk Factor Management Strategies and Treatment Goals Risk Factor

Treatment Goal

Comments

Hypertension

Blood pressure <140/90 mmHg93 Blood pressure <130/80 mmHg173

For atrial fibrillation prevention consider angiotensinconverting enzyme inhibitor, angiotensin II-receptor blocker,174 beta-blocker or mineralocorticoid receptor antagonist

Obesity

BMI 20–25 kg/m2;93 BMI 18.5–24.9 kg/m2, weight loss 5–10 % baseline weight if BMI ≥25 kg/m2 174

Avoid weight fluctuations

Diabetes

HbA1c ≤7.0 %93,176

Metformin as first-line therapy93,174

Physical inactivity

Physical activity of moderate intensity 150–200 min/week93 Aerobic exercise 90–150 min/week173

Obstructive sleep apnoea

Appropriate screening, particularly in high-risk patients (hypertension, obesity), manage with continuous positive airway pressure

Alcohol consumption

Maximum of two glasses per day (20 g/day of alcohol) for men and one glass per day (10 g/day of alcohol) for women93,173

Smoking

Complete cessation

Dyslipidaemia

LDL cholesterol <2.6 mmol/l or at least 50 % if baseline LDL cholesterol 2.6–5.1 mmol/l in patients at high cardiovascular risk93 No specific LDL cholesterol targets175

AF symptoms, and fewer and shorter AF episodes on Holter monitoring compared with general lifestyle advice and cardiometabolic risk-factor management.162 Structured weight management also led to a significant decline in left atrial volumes and pericardial adipose tissue compared with controls.163 Two other non-randomised studies from the same group also showed that aggressive risk-factor management including a structured weight management programme had beneficial effects in terms of AF recurrence, severity and burden of AF symptoms and global well-being in patients with symptomatic AF who were medically managed and underwent catheter ablation for AF.164,165 Importantly, greater weight fluctuations also led to a significantly increased risk of AF recurrence.164 Similar results were reported from a retrospective Italian study in patients with AF – those with higher and increasing BMI had a greater risk of AF recurrence during long-term follow-up.166 In the CARDIOrespiratory FITness on Arrhythmia Recurrence in Obese Individuals With Atrial Fibrillation (CARDIO-FIT) study, risk factor management and a comprehensive exercise programme led to the greatest reduction in AF recurrence in individuals who had the highest CRF at baseline, and those with the greatest CRF gain and weight loss, suggesting an additional benefit of CRF on top of weight loss.167 Overall, the findings of CARDIO-FIT suggest that fitness might be even more important than weight loss. It is important to recognise that all Australian studies used an aggressive risk-factor management approach in very motivated patients, which might be difficult to apply in daily clinical practice (Table 2).

There is a lack of prospective randomised trials investigating the effect of comprehensive risk-factor management in patients with AF. The RACE 3 trial investigated whether targeted therapy of underlying conditions on top of causal treatment of AF and HF and rhythm control therapy was superior for the prevention of AF in patients with HF compared to causal treatment of AF and HF and rhythm control alone.26 The primary endpoint was sinus rhythm on 7-day Holter monitoring at 12 months. Inclusion criteria were a history of HF <12 months and early symptomatic persistent AF of <6 months duration, not more than one direct current cardioversion, and history of AF <5 years. Targeted therapy included treatment with MRA,

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Use statins

statins and ACE inhibitors or ARBs as well as cardiac rehabilitation including supervised physical training two to three times a week, dietary restrictions and counselling.53 At 12 months, significantly more patients in the targeted therapy group had sinus rhythm compared to conventional therapy alone. Moreover, targeted therapy of the underlying conditions led to significantly more successful modification of BP, N-terminal pro-brain natriuretic peptide, weight, BMI and lipid profile. Additionally, AF symptoms assessed by European Heart Rhythm Association symptom score decreased more in the targeted therapy group.

Contemporary Integrated AF Management Patients with AF commonly have multiple risk factors and underlying conditions to deal with. This is why AF care becomes increasingly complex and is ideally delivered through an integrated multidisciplinary approach,25,52,151 where medical or invasive treatments and management of risk factors and underlying conditions are tailored and adjusted over time according to the individual needs of patients. As lifestyle interventions and treatment adherence are recognised as being increasingly important, patient involvement in the care process is central in AF management. Key elements of this process are the provision of tailored information about the disease, advice and education on lifestyle modification and risk-factor management, empowerment for self-management, and patient involvement in all treatment decisions, e.g. through shared medical decision-making.

Given encouraging data on integrated AF care interventions, a dedicated multidisciplinary AF team or clinic systematically coordinating the patient care and determining individual treatment goals according to current recommendations is key (Table 3).168–171 In the future, early and comprehensive management of risk factors and underlying conditions targeting the substrate of AF together with optimal oral anticoagulation and early targeted and direct treatment of electrical drivers of AF provided by a multidisciplinary AF team could slow progression and improve the outcomes of AF.154,172

Conclusion Common cardiovascular risk factors – such as hypertension, DM, obesity, OSA, physical inactivity and alcohol consumption – as well as

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Risk Factor Management in Atrial Fibrillation underlying conditions like HF and CAD significantly contribute to the development of AF. Optimal and timely management targeting these conditions is feasible, reduces AF and improves quality of life. However, 1.

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169. Hendriks JM, de Wit R, Crijns HJ, et al. Nurse-led care vs. usual care for patients with atrial fibrillation: results of a randomized trial of integrated chronic care vs. routine clinical care in ambulatory patients with atrial fibrillation. Eur Heart J. 2012;33:2692–9. https://doi.org/10.1093/eurheartj/ehs071; PMID: 22453654.

170. Stewart S, Ball J, Horowitz JD, et al. Standard versus atrial fibrillation-specific management strategy (SAFETY) to reduce recurrent admission and prolong survival: pragmatic, multicentre, randomised controlled trial. Lancet. 2015; 385:775–84. https://doi.org/10.1016/S0140-6736(14)61992-9; PMID: 25467562.

171. Carter L, Gardner M, Magee K, et al. An integrated management approach to atrial fibrillation. J Am Heart Assoc. 2016;5: pii: e002950. https://doi.org/10.1161/JAHA.115.002950; PMID: 26811169.

172. Kirchhof P, Breithardt G, Camm AJ, et al. Improving outcomes in patients with atrial fibrillation: rationale and design of the Early treatment of Atrial fibrillation for Stroke prevention Trial. Am Heart J. 2013;166:442–8. https://doi.org/10.1016/j.ahj.2013.05.015; PMID: 24016492.

173. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/ AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2017: pii: S0735-1097(17)41518-X. https://doi. org/10.1016/j.jacc.2017.11.006; PMID: 29146535.

174. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines and The Obesity Society. J Am Coll Cardiol. 2014;63:2985–3023. https://doi.org/10.1016/j.jacc.2013.11.004; PMID: 24239920.

175. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/ AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol.

2014;6:2889–934. https://doi.org/10.1016/j.jacc.2013.11.002; PMID: 24239923.

176. Smith SC, Jr., Benjamin EJ, Bonow RO, et al. AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation endorsed by the World Heart Federation and the Preventive Cardiovascular Nurses Association. J Am Coll Cardiol.

2011;58:2432–46. https://doi.org/10.1016/j.jacc.2011.10.824; PMID: 22055990.

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Clinical Review: Arrhythmias

Premature Ventricular Complex-induced Cardiomyopathy Jorge G Panizo, Sergio Barra, Greg Mellor, Patrick Heck and Sharad Agarwal Royal Papworth Hospital NHS Foundation Trust, Cambridge University Health Partners, Cambridge, UK

Abstract Premature ventricular complex-induced cardiomyopathy is a potentially reversible condition in which left ventricular dysfunction is induced by the occurrence of frequent premature ventricular complexes (PVCs). Various cellular and extracellular mechanisms and risk factors for developing cardiomyopathy in this context have been suggested but the exact pathophysiological mechanism remains unclear.

The suppression of PVCs is usually indicated in symptomatic patients with frequent PVCs and also those with left ventricular dysfunction.

Antiarrhythmic drugs are a useful non-invasive treatment to eliminate PVCs, but the side effect profile, including the risk of pro-arrhythmia, along with suboptimal clinical effectiveness, should be weighed against the usually more effective but not risk-free treatment with catheter ablation. The latter has progressively become first line therapy in many patients with PVC-induced cardiomyopathy and should be particularly considered in specific scenarios.

Keywords Premature ventricular complex, cardiomyopathy, ventricular dysfunction, heart failure; palpitations; arrhythmia; radiofrequency catheter ablation; antiarrhythmic drug; outflow tract; non-sustained ventricular tachycardia Disclosure: The authors have no conflicts of interest to declare.

Received: 4 April 2018 Accepted: 5 May 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(2):128–34. https://doi.org/10.15420/aer.2018.23.2 Correspondence: Sharad Agarwal, Division of Cardiac Electrophysiology, Cardiology Department, Royal Papworth Hospital NHS Foundation Trust, Papworth Everard, Cambridge CB23 3RE, UK. E: sharad.agarwal@nhs.net

Premature ventricular complexes (PVCs) are the most common ventricular arrhythmia. Their prognostic significance cannot be interpreted without considering the presence or absence of any associated underlying cardiac condition. In the absence of structural heart disease, PVCs were generally considered to be benign.1,2 In the 1970s and 1980s, it was postulated that frequent PVCs could be a trigger for ventricular tachycardia (VT), ventricular fibrillation (VF) and sudden cardiac death in post-MI patients, and therefore PVC suppression was thought to be warranted in this context.

In the Cardiac Arrhythmia Suppression Trial (CAST), treatment of PVCs with antiarrhythmic drugs increased mortality in patients with previous MI, despite effectively suppressing asymptomatic PVCs;3 findings attributed to the proarrhythmic effects of the drugs used. Despite the CAST trial showing a decrease in PVC burden and no mortality benefit, more recent work has revealed that PVCs can contribute to cardiomyopathy and heart failure and treating PVCs could lead to improved cardiac function.4,5 PVC-induced cardiomyopathy is a potentially reversible condition in which left ventricular dysfunction is induced by frequent PVCs and function improves on suppressing PVCs. Our aim is to review the underlying mechanisms and risk factors associated with the development of PVC-induced cardiomyopathy, and compare the indications and effectiveness of the interventional and medical treatment options.

Epidemiology, Prevalence and Prognosis In a normal healthy population, PVCs have been observed in up to 75 % of subjects on 48-hour Holter monitoring,6 with >60 PVCs/hour

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detected in up to 4 % of individuals.2 This latter prevalence increases progressively with age, comorbidity burden and duration of monitoring, ranging from 1–69 %.7,8 The adverse impact of frequent PVCs on prognosis in patients with underlying or structural cardiac disease, such as previous MI, is well established.9 In the late 1990s, Duffee et al. demonstrated that pharmacological suppression of PVCs in patients with presumed idiopathic dilated cardiomyopathy subsequently improved left ventricular ejection fraction (LVEF).10 Recent studies have demonstrated the potential detrimental effects of frequent PVCs in patients with structurally normal hearts and the development and reversibility of PVC-induced cardiomyopathy.4,5 Frequent PVCs can also worsen a preexisting cardiomyopathy, in which case PVC suppression may only lead to partial recovery of the LV dysfunction.11 A PVC burden >24 % has been suggested as having the highest sensitivity and specificity (79 % and 78 %, respectively) to predict the occurrence of PVC-induced cardiomyopathy.5 However, a recent study has shown that heart failure may be caused by a much lower PVC burden than that traditionally associated with PVC-induced cardiomyopathy.12 Further studies are necessary to clarify why cardiomyopathy can develop with such a low PVC burden.

Mechanisms and Pathophysiology Tachycardia-induced cardiomyopathy was originally considered to be the underlying mechanism of PVC-induced cardiomyopathy.4,13 However, the exact underlying mechanism is not entirely clear, as many patients with frequent PVCs and cardiomyopathy have similar

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Premature Ventricular Complex-induced Cardiomyopathy average heart rates when compared with individuals without PVCs and/or cardiomyopathy.13,14 From a cellular perspective, the mechanisms of PVC-induced cardiomyopathy are speculative and based on animal models, from which extrapolation for humans is sometimes limited. In their assessment of a canine model, Wang et al. postulated that the prolongation and marked beat-to-beat variation in action potential duration, as well as decreased outward and inward (L-type calcium) currents, could result in increased repolarisation heterogeneity.15 This may be associated with an increased risk of sudden cardiac death due to triggered activity and malignant ventricular arrhythmias. They also postulated that the contractile dysfunction observed in PVCinduced cardiomyopathy could be explained by an altered calciuminduced calcium release from the sarcoplasmic reticulum. In another canine model,16,17 it was reported that LVEF impairment could occur within 3 months of induced ventricular ectopy. This suggests that the underlying mechanism is functional rather than structural, given the absence of myocardial fibrosis and changes in apoptosis.

From a clinical perspective, the mechanical ventricular dyssynchrony resulting from the abnormal electrical ventricular activation may be a more straightforward explanation.18,19 Ventricular dyssynchrony may contribute to LV impairment in the same way as it has been described in the context of left bundle branch block, either physiological or induced by chronic right ventricular pacing, asymmetrically increased wall thickness in the late-activated regions and altered myocardial blood flow.20–22

Risk Factors for the Development of Cardiomyopathy Not all patients with PVCs will go on to develop a cardiomyopathy.

Indeed, some patients with high burdens of PVCs remain free from symptoms and never seem to develop any LV dysfunction. Factors that have been suggested to influence the development of PVC-induced cardiomyopathy are discussed below.

Premature Ventricular Complex: QRS Features, Interpolation and Coupling Intervals A PVC QRS duration ≥140 ms has been reported as an independent predictor of LVEF impairment,23–25 which is more commonly observed in PVCs originating from the free wall and outflow tracts. Those with a narrower QRS typically originate from the septum or fascicles. The presence of interpolated PVCs has also been reported as predictive of PVC induced cardiomyopathy. In a single-centre, small study, both the occurrence of interpolated PVCs and the burden of PVCs associated with a higher risk of PVC-induced cardiomyopathy.26 PVC coupling intervals ≤600 ms are associated with a lower mean LVEF, possibly due to an abnormal filling of the LV and decreased stroke volume.27,28 A coupling interval variability of 60 ms was found to be more frequent in PVCs originating from the sinus of Valsalva or the great cardiac vein and may be associated with increased frequency of cardiac events.29 However, this is yet to be confirmed in larger studies.

Premature Ventricular Complex Burden A high PVC burden is one of the factors thought to predispose a person to the development of cardiomyopathy. However, not every patient with frequent PVCs develops cardiomyopathy. An increased long-term risk of incident chronic heart failure (CHF) and death has

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been reported in patients with high density of PVCs, suggesting that PVCs may represent a modifiable risk factor for CHF.12 Some studies have shown a correlation between the burden of PVCs and the severity of the LV impairment.14,18 A cut-off point of 24 % has been proposed as having the best sensitivity and specificity for the prediction of cardiomyopathy with a sensitivity of 79 % and specificity of 78 %.5 However, we cannot currently consider a clear cut-off value, as PVCinduced cardiomyopathy can be observed even in patients with lower PVC burden (>10 %)4,5,12 and people with high PVC burden could be completely asymptomatic with no LV dysfunction. We also need to take into account that 24-hour Holter monitoring may be insufficient to accurately characterise the real PVC burden in some patients and may influence studies when assessing cut-off values for PVC percentage.30

Origin PVCs originating from the ventricular outflow tract musculature, and especially those from the right ventricular outflow tract (RVOT), represent two-thirds of idiopathic PVCs.23 These include those arising from myocardial extensions to the aortic and pulmonary cusps. The remaining third originate from different locations (septum, papillary muscles, free walls or left ventricular fascicles). The typical outflow tract arrhythmia pattern on the surface 12-lead ECG includes an inferior axis, characterised by a positive QRS in leads II, III and aVF. A left bundle branch block-like morphology often suggests an RVOT origin, although an aortic cusp origin may also present like this, albeit with earlier QRS transition. On the other hand, a right bundle branch block-like morphology typically suggests a left-sided focus. However, the anatomy of the outflow tracts has complex 3D anatomical relationships, with the RVOT located leftward and anterior to the LVOT and the pulmonary valve superior to the aortic valve. As such, there are different and subtle ECG differences that may suggest alternative anatomical locations of the PVCs: • A QRS transition in the precordial leads later than that in sinus rhythm suggests an RVOT exit (and vice versa), as the more anterior structure, the later precordial transition.31,32 If the QRS transition in both PVC and sinus beats is at V3, the “R wave transition ratio” can provide further guidance. When comparing the PVC R-wave amplitude in V2 with that in sinus rhythm, a ratio ≥0.6 predicts a leftsided origin with a sensitivity of 95 % and a specificity of 100 %.33 • The maximum deflection index, defined as the ratio between the time to maximum deflection and the QRS duration, can help determine whether the PVC focus is epicardial. A value above 0.55 has been suggested as predictive of an epicardial origin.34 These apparently subtle ECG differences become key when evaluating a patient for the first time in the clinic and planning an ablation procedure.

Different PVC locations may require different vascular access and are associated with different rates of success and complications.

Del Carpio et al. found that right ventricular (RV) PVCs could cause LVEF impairment at a lower daily burden than those originating in the LV (10 % versus 20 % burden, respectively).23 This may be due to the increased LV dyssynchrony potentially associated with RV PVCs compared with those originating from the LV. This was a small study so this finding should be interpreted with caution. A more recent study has postulated that an epicardial origin may associate with the highest risk for developing cardiomyopathy. As before, a possible explanation is the greater degree of mechanical ventricular dyssynchrony seen with epicardial PVCs.19

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Clinical Review: Arrhythmias Circadian Variability The consistency in PVC burden throughout the day has been reported as an independent predictor of PVC-induced cardiomyopathy.35 A recent study in patients with frequent monomorphic PVCs referred for radiofrequency ablation (RFA) hypothesised that PVC circadian variation may help predict PVC inducibility in the electrophysiology lab, facilitating the success of the ablation procedure.36 In fact, those patients with fast heart rate dependent PVCs had the highest successful outcomes from RFA as they responded to isoproterenol during the procedure, while patients with no correlation between PVCs and mean heart rate had the least successful outcomes.

Gender A large study by Latchamsetty et al. suggested that male sex may be an independent risk factor for the development of cardiomyopathy.37,38 Surksha et al. found that the incidence of symptomatic PVCs was greater in women, while that of idiopathic ventricular tachycardia was similar among sexes.39 Considering that asymptomatic status could delay the diagnosis and hence facilitate the development of a cardiomyopathy, women may be less prone to develop cardiomyopathy as they will be treated at an earlier stage. This sex-related variation may, in part, be secondary to hormonal differences, but may also be related to differences in symptom perception â&#x20AC;&#x201C; women may be more sensitive to PVCs and seek medical attention sooner than men.40

Clinical Presentation and Initial Approach Identifying the primary disorder is essential due to the potential reversibility of PVC-induced cardiomyopathy. However, it can be difficult to determine whether the PVCs preceded the cardiomyopathy or were a result of it. Therefore, PVC-induced cardiomyopathy is often a diagnosis of exclusion after ruling out other potential causes of cardiomyopathy.

Symptoms and Initial Evaluation In the acute setting, the most frequent symptoms related with PVCs are palpitations, either secondary to the PVCs themselves or due to the increased stroke volume of the post-PVC beat. The latter hypothesis has been challenged recently.41 Patients may also present with shortness of breath, pre-syncope/syncope and chest pain/discomfort.

The cumulative haemodynamic effect of frequent PVCs means that in the chronic setting, symptoms can range from different degrees of functional deterioration to manifest decompensated heart failure as a result of decreased effective cardiac output. This scenario includes patients receiving cardiac resynchronisation therapy (CRT) with sub-optimal CRT response or lack thereof, in whom the role of PVCs as the trigger for the progressive cardiomyopathy might have been underestimated.41

beats. An ECG is essential to assess PVC morphology and estimate the location of the PVC foci, particularly in patients who are referred for catheter ablation. The PVC burden is best assessed by continuous Holter monitoring, ideally for 48â&#x20AC;&#x201C;72 hours to avoid the misleading effect on the true PVC density that the day-to-day variability can produce in monitoring limited to 24 hours.30,41 A 12-lead Holter would be very useful, particularly in patients under consideration for ablation, in order to accurately identify the number of PVC morphologies.

Complementary Tests Transthoracic echocardiography is mandatory to exclude other causes of PVCs such as valvular or ischaemic heart disease, and for the assessment of LV impairment. The most common echocardiographic findings in PVC-induced cardiomyopathy include increased systolic and diastolic LV size, with global rather than regional LV systolic impairment (2D speckle tracking strain might show altered LV contractility despite normal LVEF43), and functional mitral regurgitation. However, it should be considered that LVEF may be difficult to assess in people having incessant PVCs or bigeminy and attempts should be made to assess the LVEF during cardiac cycles where no PVCs are observed.

Cardiac MRI with gadolinium is a useful technique to evaluate the presence of scar and rule out infiltrative diseases, as well as for the detection of arrhythmogenic right ventricular cardiomyopathy, with or without LV involvement.37 A pre-procedural cardiac MRI is helpful in planning an ablation procedure and might help select appropriate candidates for catheter ablation, whether they have ischaemic or non-ischaemic cardiomyopathy, or even if there is no evidence of structural heart disease.44,45 One study of 162 patients presenting with palpitations and documented exercise-induced PVCs, but no evidence of structural heart disease, found that cardiac MRI showed evidence of myocardial disease consistent with acute or previous myocarditis or myopericarditis in the majority of those patients.46 In general, it is likely that imaging modalities may be more helpful in the future by defining more suitable candidates for intervention.

Coronary angiography or a CT angiogram, depending on the cardiovascular risk profile, should be performed in every patient with impaired LV systolic function to exclude significant coronary artery disease.

As a diagnosis of exclusion, PVC-induced cardiomyopathy requires the exclusion of other causes of cardiomyopathy, such as infective, drug-induced and metabolic, if imaging tests are inconclusive. Other possible triggers for PVCs, such as excess alcohol/caffeine intake or emotional stress, must also be excluded (Figure 1).

Treatment Options and Management Nevertheless, some patients are asymptomatic and diagnosed incidentally during a routine check. Asymptomatic presentation may be a risk factor for PVC-induced cardiomyopathy as the diagnosis of the arrhythmia could be delayed and subsequently lead to cardiomyopathy.19,42 It is important to emphasise that many patients with PVCs are asymptomatic and have preserved LV function. In these patients, there could be a considerable duration between the incidental diagnosis of PVC and development of LV dysfunction and some may never develop any symptoms or cardiomyopathy.

The physical examination is often unremarkable in patients without heart failure, except for the irregular pulse caused by the ectopic

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Treatment is usually indicated in patients with debilitating symptoms, LV systolic dysfunction, malignant ventricular arrhythmias triggered

by PVCs and suboptimal biventricular pacing in those with CRT. In general, treatment includes management of secondary causes, pharmacotherapy to suppress PVCs, or catheter ablation to reduce or eliminate PVCs. The reduction of caffeine and alcohol intake and a better control of emotional stress have modest effectiveness in reducing PVC frequency.47 At present, there is no evidence to support that asymptomatic patients with frequent PVCs and preserved LVEF should be considered for any specific treatment, though beta-blockers or calcium channel blockers (CCB), as tolerated, could be discussed.

Such patients should have their LVEF assessed at regular intervals

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Premature Ventricular Complex-induced Cardiomyopathy and they should be advised to report if they develop symptoms of heart failure. Despite the fact a high PVC burden is a key factor for developing cardiomyopathy, it is noteworthy that the majority of patients presenting with frequent PVCs have a preserved LVEF and will not develop cardiomyopathy, suggesting a differential susceptibility among individuals despite similar PVC burden.4,14

Pharmacotherapy In the presence of symptoms, the first line of pharmacological treatment is usually a beta-blocker. In a randomised, double-blinded, placebocontrolled study, atenolol significantly decreased symptom frequency, PVC count and average heart rate compared with placebo.48 In patients with slow baseline heart rate, or in those with increased PVC burden due to bradycardia, beta-blockers with intrinsic sympathomimetic activity may be particularly helpful.49 Alternatively, in patients intolerant to beta-blockers and with no heart failure, a non-dihydropyridine CCB may be considered, given the relatively low adverse effect profile.

Reported efficacy of beta-blockers or CCB is in the range of 20 %, but they are reasonable first-line options due to their relative safety and additional symptomatic benefit provided by the dampening of hypercontractile compensatory beats following a PVC.19 The second line of treatment to consider is the use of antiarrhythmic drugs (AADs), such as flecainide, propafenone, sotalol or mexiletine.50,51 Class I and III AADs have been reported to achieve higher rates of PVC reduction (≥70 % in more than 90 % of patients taking flecainide, and in 55 % of patients on mexiletine) than beta-blockers or CCB.51,52 Class I AADs were usually contraindicated in patients with LV dysfunction or significant structural heart disease.3 However, in a small cohort of patients with suspected PVC-induced cardiomyopathy and at least one previous unsuccessful ablation procedure and then treated with Class IC AADs, PVCs were effectively suppressed with no adverse events in the follow-up period.53 In this cohort, the mean PVC burden decreased significantly and LVEF improved (including LVEF improvement in seven patients with myocardial delayed enhancement on cardiac MRI, all with less than 5 % of the total myocardium). There were no sustained ventricular arrhythmias or sudden cardiac deaths reported during an average treatment near to 4 years.

Class IC drugs have been contraindicated in people with cardiomyopathy because of the increased mortality seen in the CAST trial.3 Hyman et al. suggest that this increased mortality could be related to the interaction of Class IC AADs with residual ischaemia.53 In a substudy of the CAST trial, increased mortality was seen in people with non Q wave MI and people with both non Q wave MI and angina were more likely to die, suggesting an association between ongoing ischaemia and electrical instability.54 Thus it is possible that ongoing ischaemia rather than structural heart disease increases the risk of mortality with the use of class IC drugs. Hence in people with no ongoing ischaemia, a class IC AAD may be used, though further studies are required.

Amiodarone has shown to effectively suppress PVCs and improve LVEF.55 However, its long-term use is limited by its adverse effect profile. Dronedarone is a reasonable alternative to amiodarone, but is contraindicated in patients with recently decompensated heart failure or chronic AF.

Catheter Ablation As with any invasive intervention, the potential benefit of catheter ablation must be weighed against the risk of major complications,

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Figure 1: Management of Patients Presenting With Frequent Premature Ventricular Complexes Diagnosis • Symptoms: palpitations, presyncope, shortness of breath.

• Physical exam: irregular pulse (ectopics), crackles/swelling, often unremarkable.

• PVC morphology on ECG: suggestion of anatomical location.

• Holter monitor: quantification of real PVC burden.

Ideally ≥48 hours.

Transthoracic echocardiography • Evaluation of biventricular size and systolic function.

• Exclusion of major structural abnormalities.

Complementary tests • MRI: more refined assessment of structural abnormalities/ presence of scar.

• Coronary angiogram/stress imaging: if LVEF impairment or RWMA. • Exclude infective, drug-induced and metabolic cardiomyopathy.

Interventions Drugs • Beta-blocker/calcium channel blocker. and/or • Flecainide/propafenone if normal LVEF. • Amiodarone if LVEF impairment.

Catheter ablation • PVC burden > 10% + LVEF impairment • RVOT/LVOT locations or • Aortic root/epicardial/ papillary muscles if no response to drugs.

Follow-up Holter monitoring + echocardiography • As conservative strategy in asymptomatics with preserved LVEF despite high PVC burden • 3–12 months after intervention Flow chart showing the complete diagnosis, treatment options and follow-up of patients presenting with frequent premature ventricular complexes (PVCs).

LVEF = left ventricular ejection fraction; LVOT = left ventricular outflow tract; RVOT = right ventricular outflow tract; RWMA = regional wall motion abnormalities.

estimated to occur in up to 3 % of patients.56 These include vascular complications, such as femoral pseudoaneurysm, arteriovenous fistula or groin haematoma, cardiac perforation with tamponade, intraprocedural stroke or death.57 Pharmacological alternatives, patients’ comorbidities, the anatomical location of the PVC and operator experience are factors that should be taken into account. Nevertheless, the constant improvements and innovation in ablation technology, sources of energy and advanced 3D mapping software have allowed catheter ablation to emerge as a relatively safe and effective option to eliminate or drastically reduce PVC burden and restore ventricular function. This may prevent unnecessary defibrillator insertion in patients who previously met the criteria.58 A higher prevalence of repeating forms of PVCs and shorter coupling intervals have been reported as potential risk markers for imminent ventricular tachyarrhythmia and probably justify more aggressive management.59 Catheter ablation has become a reasonable first-line option in patients presenting with RV outflow tract PVCs given the high success rate of such ablation and the low risk of complications.4,41 Other locations formerly considered as riskier, such as the aortic root or the papillary muscles, may be also safely ablated with the support of intracardiac echocardiography and electroanatomical mapping systems. At present, successful ablation of PVCs normally involve a combination of

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Clinical Review: Arrhythmias Figure 2: Comparison Between Radiofrequency Catheter Ablation Versus Antiarrhythmic Drugs Treatment A

∆ PVC frequency (PVCs/24h)

0

OT n=189

RVOT n=104

LVOT n=85

RV non-OT LV non-OT n=61 n=155

-5,000 -10,000 p=0.8

-15,000 p=0.007

-20,000

p=0.03 p=0.001

p=0.7 p=0.01

-25,000

RFA

B

Non-OT n=216

AADs

6 p=0.03

5

∆ EF (%)

4

p=0.1

In patients with ischaemic cardiomyopathy and frequent PVCs, Sarrazin et al. reported that successful ablation of PVCs could increase LVEF in a significant percentage of patients. This study interestingly reported that patients with frequent PVCs had a significantly smaller scar burden by delayed enhancement MRI when compared to control patients (ventricular tachycardia patients). The presence of limited scar tissue despite severe LV impairment may suggest a superimposed cardiomyopathy because of the PVC.45

p=0.5

3

p=0.04

p=0.04

2

p=0.5

1 0 -1

In patients with a pre-existing diagnosis of cardiomyopathy and subsequent development of frequent PVCs and deterioration of LV function, successful PVC ablation may improve ejection fraction, but it is unlikely to completely normalise.44 The same study found that the arrhythmogenic substrate was located in scar tissue in most patients who underwent an effective ablation. However, reverse remodelling has been also reported in approximately half of the patients with longterm failure of the ablation procedure. This “reverse paradox” was probably due to underlying reversible cardiomyopathy.64

OT n=189

RVOT n=104

LVOT n=85

Non-OT n=216

RV non-OT LV non-OT n=61 n=155

A: Decrease in premature ventricular complex PVC burden. The reduction in PVC frequency was greater with radiofrequency ablation (RFA) than with antiarrhythmic drugs (AADs) (-21,799/24 h versus -8,376/24 h; p<0.001). B: Improvement in Left Ventricular Ejection Fraction (LVEF). The LVEF was increased significantly after RFA (53 %–56 %; p<0.001) but not after AAD (52 %–52 %; p=0.6) therapy. Of 121 (24%) patients with reduced LVEF, 39 (32 %) had LVEF normalisation to 50 % or greater. LVEF was restored in 25/53 (47 %) patients in the RFA group compared with 14/68 (21 %) patients in the AAD group (p=0.003).

LVOT = left ventricular outflow tract; OT = outflow tract; RVOT = right ventricular outflow tract.

Source: Reprinted from Heart Rhythm, 11, Zhong L, Lee YH, Huang XM, et al, Relative efficacy of catheter ablation vs antiarrhythmic drugs in treating premature ventricular contractions: A single-center retrospective study, 187–93, 2014, with permission from Elsevier.52

In a study by Penela et al., patients with frequent PVCs, LV dysfunction and an indication for primary prevention implantable cardioverter–defibrillator (ICD) underwent catheter ablation. They reported significant improvement of LV function over 12 months.

More importantly, LV function improved enough in the majority of the patients that they did not need an ICD, without increasing the risk of ventricular arrhythmias while waiting for LV function to improve.65 To achieve adequate resynchronisation, catheter ablation would also be relevant in patients with cardiac resynchronisation device and high PVC burden.

Pharmacotherapy Versus Catheter Ablation

Recovery Post-ablation

Catheter ablation is currently being evaluated as a potential first line therapy in patients with PVC-induced cardiomyopathy.

Recent publications have shown that RFA is more effective than pharmacotherapy in, at least, the RVOT location, with a safe profile and a more favourable LVEF normalisation compared with AAD (Figure 2).52,66 The 2015 European Society of Cardiology guidelines state that, in patients with RVOT PVCs needing treatment, catheter ablation should be recommended as first-line treatment, whereas in patients with LVOT PVCs catheter ablation should only be considered after failed AAD.67 The 2017 American Heart Association/American College of Cardiology/Heart Rhythm Society guidelines consider catheter ablation useful for patients who require arrhythmia suppression for symptoms or declining ventricular function suspected to be due to frequent PVCs (generally >15 % of beats and with one predominant morphology) and for whom antiarrhythmic medications are ineffective, not tolerated or refused by the patient.68

In a study to assess predictors of LV recovery and reverse remodelling in patients with frequent PVCs referred for ablation, there was a relationship between the PVC QRS duration and the probability of recovery.62 Following a successful ablation, the only predictor of lack of recovery was a broader PVC QRS duration. It was suggested that increases in PVC QRS duration may be represent more extensive underlying fibrosis, possibly contributing to the persistence of LVEF impairment. Mountantonakis et al. found that the degree of LV function recovery post-ablation in patients with true PVC-related cardiomyopathy is more pronounced than in patients with a preexisting diagnosis of cardiomyopathy.63

In patients with decreased LVEF, a follow-up period of 3–12 months after initiation of antiarrhythmic therapy or catheter ablation is suggested to allow for recovery of LV function and to avoid unnecessary ICD insertions in a potentially reversible condition,18,22 provided the patient does not fulfil other criteria for implantation (such as previous cardiac arrest or the occurrence of haemodynamically unstable ventricular arrhythmia). If a decision is made to implant an ICD, consideration could be given to the implantation of subcutaneous ICD, as there is usually no need for pacing in these patients and recovery of LV function is frequent following a successful ablation.

activation and pace-mapping guided by fluoroscopy, electroanatomical mapping and intracardiac echocardiography.

In patients with failed RVOT ablations, although the most frequent site of origin may still be the RVOT, consideration should be given to mapping the pulmonary artery, the coronary venous system and, importantly, the aortic cusps – especially if the earliest site of activation in the RVOT is in the posteroseptal location.60 Cryoablation may become a promising alternative to radiofrequency when ablating in certain locations, such as the left aortic root near the left main ostium, or the papillary muscle given the difficulties with catheter stability and papillary muscle mobility.61

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Premature Ventricular Complex-induced Cardiomyopathy Since the LVEF is difficult to assess in patients with frequent PVCs, the question remains whether, in some cases, the LV dysfunction and subsequent improvement in LVEF post-ablation may be actually the result of inadequate assessment of LVEF. Therefore, it has been recommended that an echocardiogram should be performed immediately postablation to evaluate LVEF in sinus rhythm. An immediate improvement suggests a PVC related measurement issue. In contrast, the LV dysfunction should persist immediately after successful ablation but improve gradually over time in true PVC-induced cardiomyopathy.69

effectively, catheter ablation, is indicated in symptomatic patients with frequent PVCs and also those with LV dysfunction or decreased percentage of biventricular pacing. Catheter ablation has progressively become a potential first-line therapy in patients with PVC-induced cardiomyopathy and should be strongly considered, particularly in patients with right-sided outflow tract PVCs.

Conclusion

There is little evidence at present to recommend treating asymptomatic patients with normal LVEF. The benefit of performing PVC ablation in these patients guided only by a high PVC burden has not yet been demonstrated and can be potentially hazardous.70

Premature ventricular complexes are commonly seen in the general population and may produce LV dysfunction and cardiomyopathy independently of any pre-existing underlying cardiac disease. The suppression of PVCs, either through medical therapy or, more

Further research is still needed to clarify the molecular, cellular and haemodynamic mechanisms of LV dysfunction in PVC-induced cardiomyopathy, as well as the risk factors for its development. n

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Clinical Review: Drugs and Devices

Pharmacological Therapy in Brugada Syndrome Oholi Tovia Brodie, 1,2 Yoav Michowitz 2 and Bernard Belhassen 2 1. University of Miami Miller School of Medicine, Miami, USA; 2. Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel

Abstract Brugada syndrome (BrS) is a cardiac disease caused by an inherited ion channelopathy associated with a propensity to develop ventricular fibrillation. Implantable cardioverter defibrillator implantation is recommended in BrS, based on the clinical presentation in the presence of diagnostic ECG criteria. Implantable cardioverter defibrillator implantation is not always indicated or sufficient in BrS, and is associated with a high device complication rate. Pharmacological therapy aimed at rebalancing the membrane action potential can prevent arrhythmogenesis in BrS. Quinidine, a class 1A antiarrhythmic drug with significant Ito blocking properties, is the most extensively used drug for the prevention of arrhythmias in BrS. The present review provides contemporary data gathered on all drugs effective in the therapy of BrS, and on ineffective or contraindicated antiarrhythmic drugs.

Keywords Brugada syndrome, arrhythmia, pharmacology, quinidine, disopyramide, isoproterenol, denopamine, orciprenaline, cilostazol, bepridil, quinine Disclosure: The authors have no conflicts of interest to declare.

Received: 3 April 2018 Accepted: 1 May 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(2):135–42. https://doi.org/10.15420/aer.2018.21.2 Correspondence: Dr Bernard Belhassen, Department of Cardiology, Tel-Aviv Sourasky Medical Center, Weizman St 6, Tel-Aviv, 64239, Israel. E: bblhass@gmail.com

Brugada syndrome (BrS) is a cardiac disease caused by an inherited ion channelopathy. It was first described by the Brugada brothers in 19921 and is associated with a propensity to develop ventricular fibrillation (VF). Brugada syndrome is characterised by prominent J waves appearing as an ST segment elevation in the right precordial leads. In the latest guidelines, diagnosis of BrS constitutes ST elevation with type 1 morphology (coved) ≥2 mm in one or more leads among the right precordial leads V1 and V2, occurring either spontaneously or after intravenous administration of class I antiarrhythmic drugs. 2–4 A recent expert consensus differs in the definition and recommends that when a type 1 ST segment elevation is unmasked using a sodium channel blocker, diagnosis of BrS should require that the patient also presents with one of the following: documented VF or polymorphic ventricular tachycardia (VT), syncope of probable arrhythmic cause, a family history of sudden cardiac death (SCD) at <45 years of age with negative autopsy, coved-type ECGs in family members, or nocturnal agonal respiration.5 Historically, BrS was considered to be inherited in an autosomal dominant inheritance with incomplete penetrance. There is growing evidence that presenting with BrS and the susceptibility to VF and SCD may not be due to a single mutation (classic Mendelian view) but rather to inheritance of multiple BrS susceptibility variants (oligogenic) acting in concert through one or more mechanistic pathways. 5 Multiple mutations have been associated with the Brugada phenotype. These mutations cause either a decrease in the inward sodium or calcium current or an increase in the transient outward potassium channel current (Ito). Both result in an outward shift in the net transmembrane current active at the end of phase one of the right ventricular epicardial action potential (where Ito is most prominent).6–8

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The guidelines recommend ICD implantation in patients with BrS who have survived a cardiac arrest, or have documented spontaneous sustained VT (class I).3,4 ICD implantation should also be considered in patients with BrS who have had a syncopal episode suspected to be caused by VT or VF (class IIa). In asymptomatic BrS individuals who have inducible sustained VF during programmed ventricular stimulation with two or three extrastimuli at two sites, ICD implantation is controversial and is a class IIb indication. ICDs are not recommended (class III) in reflex-mediated syncope or in asymptomatic patients.3,4 This recommendation is based on the low yearly event rate of 0.5 % found in asymptomatic Brugada patients,9,10 coupled with the high complication rate reported for ICDs in BrS.11–13 Aggregate rates of inappropriate shocks and lead failure have been reported to be as high as 37 and 29 %, respectively, at 10 years, including one death as a result of inappropriate ICD discharge resulting from lead failure.14,15 A near-fatal VF in BrS despite an implanted ICD has been reported, suggesting that lone therapy of ICD in cardiac arrest survivors with BrS is not without risks.16 The death of a BrS patient diagnosed after syncope (with an ajmaline provocation test), due to incessant VT and VF that developed during lead extraction procedure, has also been reported.17 In children and adolescents with BrS, high rates of inappropriate shocks and device-related complications were reported at 20 and 14 %, respectively.18 The option of subcutaneous ICD (S-ICD) for young patients with inherited arrhythmic syndromes who do not need pacing therapy is being increasingly used. A recent study found high rates of sensing screening failure in patients with BrS, due to high T wave voltages.19 Long-term clinical data are lacking at present on the utility of S-ICD in BrS. A pharmacological therapy approach aimed at rebalancing the epicardial action potential in the right ventricle and normalising the action potential dome can prevent arrhythmogenesis in BrS, unlike a

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Clinical Review: Drugs and Devices Figure 1: Twelve-lead ECG of a Man Aged 38 Years Presenting with Syncope A

B

A

I

V1

II

V2

III

V3

aVR

V4

aVL

V5

aVF

V6

B

Syncope occurred when the patient had stopped at a red light while driving.

Echocardiogram was normal. A: Baseline ECG was unremarkable except for the presence of 1 mm saddle ST-elevation in V2; B: During a flecainide challenge test, type 1 Brugada-ECG was unmasked.

device therapy approach, which addresses only the symptoms of BrS without preventing the arrhythmias from occurring. Drug therapy in BrS has several utilities: first, in the acute management of arrhythmic storm; second, in prevention of arrhythmic events in patients with implanted ICD who require many shocks; and third, as an alternative to ICD implantation when the latter is contraindicated, not feasible (infants and young children), unaffordable, or refused by the patient.

This review provides contemporary data gathered on all drugs effective in the therapy of BrS as well as ineffective or contraindicated antiarrhythmic drugs that should be avoided.

Class IA Antiarrhythmic Drugs Quinidine Quinidine’s beneficial effect in preventing arrhythmic events in BrS is mainly attributed to its significant Ito blocking property. It was shown that quinidine is effective in normalising the epicardial action potential dome and the ST segment and preventing phase-two re-entry and polymorphic VT in experimental models of BrS.6,20,21 The anticholinergic effect of quinidine may also contribute to its antiarrhythmic effect.8

Electrophysiologically Guided Quinidine Therapy The first case showing the efficacy of oral quinidine in preventing inducible VF during electrophysiological study (EPS) and recurrent arrhythmias was reported in 1981 by Belhassen et al.22 in a young male with recurrent storms of idiopathic VF (IVF). This patient is still arrhythmia-free on quinidine treatment and with no implanted ICD after a follow-up of 39 years. Two of the five patients with IVF successfully

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treated with EP-guided class 1A antiarrhythmic drugs (AD) were later diagnosed as suffering from BrS.23 The first prospective series of 25 BrS patients treated with EP-guided therapy were also reported by Belhassen et al.24 Quinidine prevented VF inducibility in 22 (88 %) patients and no arrhythmic events were observed during follow-up in EP-quinidine responders treated by the medication. The latest study reporting the 33-year experience of the same group involved 96 patients with BrS (10 cardiac arrest survivors, 27 who presented with syncope and 59 who were asymptomatic). VF was induced in 66 (68.8 %) patients using an aggressive protocol of programmed ventricular stimulation (inducibility rates of 100 %, 74 % and 61 % in patients with cardiac arrest, syncope and no symptoms, respectively). All but six of the 66 patients with inducible VF underwent EPS on quinidine (n=54), disopyramide (n=2) or both (n=4). Two different formulations of quinidine were used during EP-guided therapy: quinidine bisulphate (QBS) (750–2000 mg daily) and hydroquinidine chlorhydrate (HQ) (600–900 mg daily). Fifty-four (90 %) patients were EP responders to more than one AD with similar efficacy rates (≈90 %) in all patient groups. After a mean follow-up of 113.3 ± 71.5 months, 92 patients were alive, whereas four had died from non-cardiac causes. No arrhythmic event occurred during class 1A AD therapy in any of the EP drug responders and in patients with no baseline inducible VF. Arrhythmic events occurred in only two cardiac arrest survivors treated with ICD alone but did not recur on quinidine. All cases of recurrent syncope (n=12) were attributed to a vasovagal (n=10) or nonarrhythmic mechanism (n=2). Class 1A AD resulted in a 38 % incidence of side-effects (mainly diarrhoea) that resolved after drug discontinuation. Sixty per cent of patients were compliant with the medication by the end of follow up.25 An illustrative example of the efficacy of quinidine in preventing VF induction is shown in Figures 1 and 2.

Based on these results, Belhassen et al.25 suggested that EP-guided therapy may be an excellent alternative to ICD therapy in selected patients who are committed to a life-long drug therapy and exhibit good tolerance to the medication.

Hermida et al.26 reported data of 31 asymptomatic BrS patients with inducible VF at baseline. They used HQ 600 mg daily in all their patients but two in whom they used 900 mg and found prevention of VT/VF inducibility in 76 % of their inducible patients. Syncope occurred in two of the 21 patients who received long-term (17 ± 13 months) HQ therapy. One syncope associated with QT interval prolongation and one unexplained syncope associated with probable noncompliance.26 Bouzeman et al.27 reported the results from two French centres, on 44 asymptomatic BrS patients. In 34 (77 %) of these patients, 600 mg HQ daily effectively prevented VF induction during a follow-up period of 3–6.2 years. VF occurred only in one patient in whom HQ was discontinued due to intolerance. Among the 10 other patients (22 %) who remained inducible and received ICD, none received appropriate therapy during a mean follow-up of 2–7.7 years. The overall annual rate of arrhythmic events was 1.04 %. One-third of patients experienced device-related complications.27 The higher rates of prevention of VF inducibility reported by Belhassen might be explained by the higher doses of HQ were used in their studies24,25,28 (900 mg daily versus 600 mg daily).26,27 It is noteworthy that in the current guidelines “quinidine should be considered (class IIa) in patients who qualify for an ICD but present a contraindication or refuse it, and in patients requiring treatment for supraventricular arrhythmias”.4

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Pharmacological Therapy in Brugada Syndrome Empiric Quinidine Therapy for Arrhythmic Storm Electric storms of VF represent the more malignant form of ventricular arrhythmias in patients with BrS, accounting for up to 10 % of the untreated patient population29 and up to 38 % of arrhythmic events in ICD patients.30 Isoproterenol infusion has been shown to be very effective in the acute management of arrhythmic storms in the setting of BrS.31 However, it can be administered only intravenously during a short period of time, and the arrhythmia frequently recurs upon drug discontinuation. Quinidine has been shown in multiple studies to successfully control arrhythmic storms as a single agent or in combination with isoproterenol.29,32–42 Anguera43 reported the effectiveness of quinidine in 29 BrS patients treated for secondary prevention due to arrhythmic storm (31 %) or frequent ICD shocks (69 %). Ten patients received QBS (mean dose 591 ± 239 mg/day), and 19 patients HQ (mean dose 697 ± 318 mg/day). After a mean period of 60 ± 41 months under quinidine treatment, 19 patients (66 %) remained free of appropriate ICD discharges. A significant reduction in total number of shocks and median number of shocks per patient was observed, from 203 to 41 shocks and from six shocks per patient IQR (4 to 9) to no shocks per patient IQR (0 to 2.5), p<0.0001, respectively.

A total of 10 patients (34 %) experienced at least one recurrent shock (in four patients, shocks were related to a reduction in the dose of quinidine due to side-effects [n=2] or to temporary discontinuation of treatment by the patient [n=2]). During quinidine therapy, QT intervals corrected for heart rate increased by a mean of <10 % (413 ± 18 to 442 ± 35; p=0.001) without episodes of torsade de pointes. Side-effects appeared in five patients (17 %). The effectiveness of quinidine in controlling VF storm has also been described in children44,45 and pregnant women.46 The use of low-dose quinidine (<600 mg) in four patients with arrhythmic storms was reported by Márquez et al.47; quinidine prevented the recurrence of arrhythmic events in all patients.47 In the current guidelines, quinidine should be considered (class IIa indication) in BrS patients presenting with electrical storms and in patients implanted with an ICD who are experiencing repeated appropriate shocks.4

Empiric Quinidine Therapy for Asymptomatic Patients The prophylactic use of empirical quinidine for asymptomatic patients with type 1 Brugada-ECG was first suggested by Viskin et al.48 Preliminary results in 19 patients who received empiric quinidine therapy were reported.49 No arrhythmic events occurred, and five patients (26 %) discontinued therapy due to side-effects. The administration of quinidine without further risk stratification to all asymptomatic patients with a type 1 Brugada-ECG is controversial.

We routinely give quinidine to asymptomatic patients only in those who have inducible ventricular arrhythmias at EP testing.25 The recently published QUIDAM study: Hydroquinidine Therapy for the Management of Brugada Syndrome Patients at High Arrhythmic Risk50 is a prospective multicentre randomised (HQ versus placebo) double-blinded study with two 18-month crossover phases in highrisk patients with BrS and implanted with an ICD. Of the 50 patients enrolled, only 26 (52 %) fully completed both phases. Thirty-four (68 %) patients presented HQ-related side-effects, mainly gastrointestinal, which led to discontinuation of the therapy in 13 (26 %). During the 36-month follow-up period, two arrhythmic events occurred under placebo therapy (one appropriate ICD shock [0.97 % event per year] and one self-terminating VF). In addition, one inappropriate ICD shock occurred under placebo therapy. No arrhythmic events were reported under HQ therapy. The authors concluded that although HQ seems

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Figure 2: Twelve-lead ECG of a Man Aged 38 Years Undergoing Programmed Ventricular Stimulation

A: Baseline programmed ventricular stimulation (PVS). Induction of sustained polymorphic VT using double extrastimuli from the right ventricular outflow tract (RVOT); B: Repeated PVS on quinidine bisulfate (1,500 mg/day, 2.78 mg/l) demonstrated no inducible arrhythmias using triple extrastimuli delivered from the RV apex and the RVOT, with repetition (n=5) of triple extrastimulation at the shortest coupling intervals. The patient has remained asymptomatic on quinidine therapy during follow-up without implantation of an ICD.

to be effective in preventing life-threatening arrhythmic events, it could not be an alternative for ICD implantation due to its frequent side-effects limiting compliance to the drug. This study, although well structured, was underpowered to prove the efficacy of HQ due to the small number of patients enrolled and even smaller number of patients who completed both phases. In addition, the very high incidence of side-effects reported was inconsistent with previous reports.25,27 In his editorial comment on the paper by Andorin et al., Belhassen51 pointed to the study’s patient population being mainly at intermediate and low arrhythmic risk, which explains the difficulty of assessing the efficacy of quinidine therapy, even more so with a small cohort population. In addition, he postulated that the high rate of side effects (mainly diarrhoea) requiring drug discontinuation could have been related to patients’ reluctance to continue the trial while they felt fully protected by the implanted ICDs. Due to the low incidence of arrhythmic events in asymptomatic BrS patients, a large-scale double-blinded trial is needed for further validation of the efficacy of HQ in asymptomatic BrS patients. A prospective registry of empiric quinidine for asymptomatic Brugada syndrome has been established.48

Low-dose Quinidine To decrease the frequency of side-effects associated with quinidine, administration of lower doses of the drug have been attempted.

Márquez et al.47 reported a small series of six BrS patients, in whom doses of quinidine or hydroquinidine (<600 mg) prevented the recurrence of arrhythmic events in all patients without side-effects during a median follow-up of four years. In the literature review, 14 additional patients treated with <600 mg of quinidine were found.

Quinidine was well tolerated and associated with acute and long-term arrhythmia control in 85 % of cases. In four patients who stopped taking the medication, recurrent arrhythmias occurred, which were successfully controlled after treatment was reinitiated.47 Hasegawa reported the normalisation of J waves and coved-type ST-segment

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Clinical Review: Drugs and Devices elevation with VF suppression in a patient who presented with a VF storm after daily administration of 300 mg quinidine and a follow-up of 20 months.52 These data suggest that low doses of quinidine, which are generally well tolerated, may be useful in controlling arrhythmias.

Further studies of larger scale are needed to validate the efficacy and safety of low-dose HQ.

Limited Worldwide Commercial Availability of the Drug A major limitation for the wide use of quinidine in the world is its lack of accessibility.53,54 Viskin et al.54 asked a total of 273 physicians from 131 countries regarding the availability of quinidine in their countries. Quinidine was readily available in 19 countries (14 %), not accessible in 99 countries (76 %), and available only through specific regulatory processes that require 4 to 90 days for completion in 13 countries (10 %). Viskin et al.54 were able to gather information concerning 22 patients who had serious arrhythmias probably related (10 cases) or possibly related (12 cases) to the absence of quinidine, including two fatalities possibly attributable to the unavailability of quinidine.

preventing electrical storm and recurrent ICD shocks. This medication also resulted in normalisation of ST-segment elevation.32 The use of intravenous quinine was reported for the acute management of an arrhythmic storm in a 10-year-old child.62

Beta Adrenergic Agonists A diminished inward current of Ica combined with the prominent Ito current in the epicardium results in an intensified repolarisation of the RV subepicardium, where Ito activity is most pronounced. When phase one is repolarised beyond the voltage range at which L-type Ca2+ channels activate, the Ca2+ channels fail to activate, resulting in loss of the action potential dome.7 Beta adrenergic agents, such as isoproterenol, denopamine or orciprenaline, augment L-type calcium channels, and this is the basis for their usefulness in controlling VF storms in BrS.29,33,63 Isoproterenol has been shown to be effective in controlling VF storm either as a lone agent or in combination with quinidine.29,37,38,40,46,57,64–70 The effectiveness of isoproterenol in controlling VF storm was also described in children45,62,71 and pregnant women.46,66 Current guidelines recommend the administration of isoproterenol for BrS patients in VF storm (class IIA).3–5

Disopyramide Disopyramide, a class IA antiarrhythmic drug, exhibits a moderate use-dependent block of INa and moderate block of Ito. In addition, disopyramide has been reported to decrease the inhomogeneity between infarcted area and normal myocardium refractory period, while lengthening the ventricular refractory period, hence decreasing the chance for phase two re-entry.55 These effects can explain its efficacy

Phosphodiesterase Inhibitors

in BrS. Even though the effect of disopyramide in slightly augmenting ST elevation in BrS has been described in small studies, it has not been associated with development of premature ventricular complexes or VT/VF.56,57

electrical inhomogeneity of action potentials. The reduced electrical inhomogeneity of action potentials would prevent phase two re-entry and subsequent VF, thereby leading to the diminution or disappearance of coved-type ST-segment elevation or J waves. The successful use of cilostazol 200 mg daily in preventing VF storm in BrS, resulting in abolition of J waves and transformation of coved-type ST-segment elevation to saddleback-type has been reported in several cases.52,72–77 However, the failure of cilostazol 200 mg daily in preventing a VF storm has also been reported.32, 80 Worthy of mention, cilostazol can cause symptomatic palpitations,77 and its long-term effects have not been reported. The combined use of cilostazol and bepridil has been reported to attenuate cilostazol induced palpitations (see below).77

Miyazaki et al.57 reported the use of disopyramide in three BrS patients, and found that 50 mg of IV disopyramide resulted in augmentation of ST elevation. However, in one patient, the combined use of intravenous and oral disopyramide resulted in VF non-inducibility.

Belhassen et al.25 reported that the use of disopyramide at a mean dose of 500 ± 71 mg (300–600) prevented VF induction during EPS in three (50 %) of the six patients tested; two of the three disopyramide non-responders responded to BSQ. The efficacy of disopyramide in VF suppression was described in case reports of BrS patients with VF storm.58,59 VF suppression occurred despite exacerbation of ST segment elevation, suggesting the efficacy of disopyramide in suppressing VF might not correlate with ECG normalisation.59

Cilostazol is a phosphodiesterase III inhibitor with therapeutic focus on cyclic adenosine monophosphate (cAMP). It inhibits platelet aggregation and is a direct arterial vasodilator. It increases cellular cAMP levels and L-type calcium currents, and, like isoproterenol, counteracts Ito, resulting in attenuation or abolishment of the

Milrinone is another phosphodiesterase III inhibitor recently identified as a more potent alternative to cilostazol in suppressing ST elevation and arrhythmogenesis in an experimental model of BrS.76,79 So far, no clinical data have been reported in humans.

Bepridil Current data suggests that disopyramide may be useful in controlling ventricular arrhythmias in BrS; however, larger studies are needed to fully characterise the effect of oral and intravenous disopyramide in BrS.

Quinine Sulphate Quinine is the diastereomer of quinidine that has been used to treat malaria. In dogs, it has similar effects to quinidine on conduction time but does not prolong epicardial repolarisation time or ventricular refractoriness. In experimental models, studies have demonstrated the antiarrhythmic effect of quinine in suppressing VF thresholds.60 In humans, quinine is effective in suppressing both spontaneous and inducible ventricular arrhythmias without the proarrhythmic potential of QT prolongation, torsade de pointes, or heart block.61 In one case report,32 monotherapy with quinine sulphate was effective in

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Bepridil is a long-acting, non-selective, amine calcium channel blocker previously used for its significant anti-anginal activity. Its antiarrhythmic effects have not been fully characterised. Bepridil has demonstrated multiple effects on cardiac ion channel currents. Effects that appear to be relevant are block of Ito, augmentation of INa via up-regulation of the channels80 and prolongation of QT at slow rates, thus increasing the slope of QT-RR.81,82 The effectiveness of bepridil in preventing VF, usually in combination with other drugs, has been described in several small studies and case reports.29,70,77,81–83 In a study of seven patients with repetitive VF episodes, Murakami et al.84 reported that the use of bepridil 100–200 mg daily prevented recurrence of VF along with improvement of ST elevation and of low-amplitude signals in four patients with BrS with the SCN5A

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Pharmacological Therapy in Brugada Syndrome Table 1: List of Medications for the Therapy of Brugada Syndrome and their Utility, Based on Level of Evidence Dosing

Storm

VF prophylaxis

Asymptomatic BrS

Quinidine

HQ 600–900 mg/day; BSQ 1,000–2,250 mg/day

*** ***

*** ***

**

Disopyramide

300–600 mg/day

Isoproterenol

0.003 ± 0.003 μg/kg/min

Denopamine

30 mg/day

Orciprenaline

IV bolus 0.5 mg, followed by IV drip 3.3 μg/min

Cilostazol

200 mg/day

*

Bepridil

100–200 mg/day

*

* *** * *

* = evidence from case reports,; ** = evidence from small cohort studies; *** = evidence from several large cohort studies, BSQ = bisulfate quinidine; HQ = hydroquinidine chlorhydrate; IV = intravenous; VF = ventricular fibrillation.

mutation but not in those without this mutation. Bepridil was effective in the long-term prevention of VF in the highest-risk patients with electrical storms who demonstrated early repolarisation in addition to BrS.85 Addition of bepridil attenuated cilostazol-induced palpitations by eliminating sinus tachycardia, and maintained the suppressive effect of cilostazol against VF in a study of seven patients with J wave-syndrome-associated recurrent ICD shocks (five BrS patients).77 This effect of bepridil may be due to its effect to block If86 as well as its ICa-blocking effect.7 Currently, bepridil is available only in Japan.

Traditional Chinese Medicine Wenxin Keli Wenxin Keli (WK) is a Chinese herb extract, reported to be effective in the treatment of atrial and ventricular cardiac arrhythmias.87–93 WK has been reported to block Ito, sodium current (INa) and L-type calcium current (ICa) in rat and rabbit ventricular cardiomyocytes.94 A recent study found that WK, particularly in combination with low-dose quinidine (5 μM), effectively suppresses arrhythmogenesis in an experimental model of BrS via inhibition of Ito and indirect adrenergic sympathomimetic effects.95

Dimethyl Lithospermate B Dimethyl lithospermate B, an extract of danshen, a traditional Chinese herbal remedy, has been reported to slow inactivation of INa, thus increasing INa during the early phases of the action potential and suppressing arrhythmogenesis in experimental models of BrS.96 No clinical data are available yet.

phases) to receive an ICD or propranolol. During the 3-year followup period of the main trial, there were four deaths; all occurred in the beta-blocker group (p=0.02). Seven subjects in the ICD arm had recurrent VF, and all were effectively treated by the ICD. In total (both from the pilot study and the main trial), there were seven deaths (18 %) in the beta-blocker group and no death in the ICD group.106 Beta-blockers and calcium channel blockers are known to increase ST-segment elevation57,107 and to cause initiation of VF.108,109 Experimental data suggest that beta blockers and calcium channel blockers decrease inward calcium current and cause an outward shift in current at the end of phase one of the action potential. This creates a transmural voltage gradient, leading to ST-segment elevation and ventricular arrhythmias.109 Some clinical studies supporting these experimental data have been reported with small samples. In two case reports, severe propranolol toxicity was reported to result in the Brugada ECG pattern in an otherwise healthy individual or to unmask BrS.109,110 This can be explained by the fact that at high doses, propranolol binds to the cardiac sodium channels and inhibits sodium uptake. Kasanuki et al.112 reported that VF induction was exacerbated by intravenous injection of propranolol in BrS patients.

However, in a recent study of 29 patients receiving a beta-blocker (22 patients) or calcium channel blocker (eight patients) for more than one year for the treatment of comorbidities, Kamakura et al.113 found that the long-term oral intake of these medications at normal dosage range was not associated with the aggravation of ECG parameters and clinical outcome in patients with BrS; thus they concluded that the use of these medications is acceptable under careful observation.113

Ineffective Drugs Amiodarone

Contraindicated Drugs

Amiodarone has not been shown to be effective in controlling arrhythmias in BrS.1,97,98 Moreover, there are a few case reports in which acute amiodarone infusion unmasked a Brugada phenotype ECG pattern and aggravated a VF storm.99–103 Amiodarone is predominantly a potassium ion channel–blocking agent, but has been shown in vitro to have sodium ion channel-blocking properties,104,105 especially in the acute phase of its administration. This effect provides a plausible scientific basis for unmasking BrS ECG pattern.

Class IA (ajmaline, procainamide) and class IC (flecainide, propafenone and pilsicainide) sodium channel blockers drugs are known to unmask type I ST-segment elevation in the ECG and induce cardiac arrhythmias in BrS.56,85,97,109,114–123 The occurrence of cardiac arrhythmias during sodium channel blockers challenge ranges from 0–17.8 %.121 Hence, these drugs are contraindicated in the therapy of BrS.

Beta Blockers and Calcium Channel Blockers In the Defibrillator Versus beta-Blockers for Unexplained Death in Thailand (DEBUT) trial,106 Nademanee et al. compared the use of defibrillators versus beta-blockers in sudden unexplained death syndrome survivors. Approximately 55–60 % of patients had ECG features of BrS. Eighty-six patients were randomised (in two study

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Conclusion This review provides contemporary data on each of the drugs effective in the therapy of BrS. A pharmacological approach to therapy is aimed at rebalancing the epicardial action potential in the right ventricle, normalising the ECG abnormalities and preventing cardiac arrhythmias.

Regardless of whether or not an ICD is implanted, prevention of recurrent arrhythmic events, especially in the high-risk population of cardiac arrest survivors, should be considered. Quinidine is the most

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Clinical Review: Drugs and Devices extensively studied medication with proven efficacy in successfully controlling and preventing arrhythmic events in BrS. It is the authors’ opinion that this medication is an alternative to ICD therapy in all

types of BrS patients who have fulfilled the strict conditions detailed elsewhere.124 Table 1 provides a summary of the drugs effective in BrS, their recommended dosing and their utility. n

Clinical Perspectives • Q uinidine is the most extensively studied medication with proven efficacy in successfully controlling and preventing arrhythmic events in BrS. • Quinidine should be considered as an adjacent therapy to an ICD in high-risk patients and as an alternative to ICD under strict conditions.

• Available medications effective in the therapy of BrS are isoproterenol, cilostazol, bepridil, denopamine, orciprenaline disopyramide and quinine sulphate.

• Antiarrhythmic medications to be avoided in BrS are amiodarone, beta-blockers, calcium channel blockers, ajmaline, procainamide, flecainide, propafenone and pilsicainide.

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Letters

The Cost of Hybrid Treatment for Atrial Fibrillation

Citation: Arrhythmia & Electrophysiology Review 2018;7(2):143. https://doi.org/10.15420/aer.2018.7.2.L1

Dear Sir, I read with great interest the elegant article of Umbrain et al.1 on hybrid AF treatment in issue 6.4 of AER. It delineates in a comprehensive but succinct manner the technical problems and peculiarities of this promising approach. However, in my capacity as a general cardiologist and director of a primary care centre, I am very much concerned about the costs of such procedures. In the current era of fiscal constraints and continuous budget cuts regarding healthcare internationally, we must prove the cost-effectiveness of medical innovations and complicated approaches before advocating their clinical use. This is true, particularly when considering “integrated approaches involving different teams”. Have the authors taken into account the financial burden of the proposed method, particularly when the anticipated success rates, judging from RCTs on conventional ablation, range between 57 and 77 % following single and multiple procedures, respectively?2 George Paxinos, Ithaca Health Center, Ithaca, Greece

1.

2.

Umbrain V, Verbogh C, Chierchia G-B, et al. One-stage approach for hybrid atrial dibrillation treatment. Arrh Electrophysiol Rev 2017;6(4):210–6. https://doi.org/10.15420/2017.36.2; PMID:29326837.

Katritsis D, Gersh BJ, Camm AJ. Atrial fibrillation. In: Clinical Cardiology. Current Practice Guidelines. Oxford University Press, 2017;561–612.

Authors’ Reply: The Cost of Hybrid Treatment for Atrial Fibrillation

Citation: Arrhythmia & Electrophysiology Review 2018;7(2):143. https://doi.org/10.15420/aer.2018.7.2.L1.R1

Dear Sir, The question referring to the financial costs of one-stage hybrid surgery for atrial fibrillation in countries where reimbursement is limited is relevant in our modern cost–benefit driven society. But your question is out of the context of our manuscript as we never alluded to the financial aspects of the technique.

Costs for one-stage hybrid atrial fibrillation surgery are important as several highly specialised teams are simultaneously involved and specific, quickly changing electrophysiological material is requested.

A financial contribution from the Belgian patient is currently requested for the epicardial ablation part of the procedure in Belgium. This is in contrast with the endocardial ablation part, which is in most cases covered by the patient’s own medical health Insurance.

The evaluation of costs for patients living abroad in Europe is a more complex, more individually and state-regulated matter and is calculated in agreement with our financial department.

Vincent Umbrain, Department of Anaesthesiology and Perioperative Medicine, University Hospital Brussels, Free University of Brussels, Belgium Mark La Meir, Department of Cardiac Surgery, University Hospital Brussels, Free University of Brussels, Belgium Carlo De Asmundis, Heart Rhythmn Management Centre, University Hospital Brussels, Free University of Brussels, Belgium

© RADCLIFFE CARDIOLOGY 2018

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Letters

Origins of Ablation of Bradyarrhythmias

Citation: Arrhythmia & Electrophysiology Review 2018;7(2):144. https://doi.org/10.15420/aer.2018.7.2.L2

Dear Sir, In December, Dr Stavrakis and Dr Po published the excellent article “Ganglionated Plexi Ablation: Physiology and Clinical Applications” in AER.1 Despite the outstanding quality, unfortunately the article presents a very small fault.

The authors state that autonomic ablation for the treatment of bradyarrhythmias was proposed by Yao. GP ablation for vasovagal syncope was first introduced by Yao et al., who reported their initial experience on 10 patients with highly symptomatic vasovagal syncope.

In fact, the ablation of bradyarrhythmias was created, proposed and patented by us, 7 years before, having been developed in the 1990s. The first series of 21 patients was published in 2005 in PACE and was patented in the US in 2005 as well (US 2011 0098.699A1 Patent Application Publication Pub. No.: US 2011/0098.699 A1, JC Pachon Mateos, EI Pachon Mateos).

We also developed and patented a system for strict control of vagal denervation for the treatment of bradyarrhythmias.

Considering the high quality and notability of the authors, the article is highly attractive so it is very important to correct this flaw.

Relevant publications by our group will provide further information.2,3 JC Pachon, São Paulo Heart Hospital Arrhythmias Service, São Paulo University and São Paulo Heart Hospital, São Paulo, Brazil

1.

2.

3.

Stavrakis S, Po S. Ganglionated Plexi Ablation: Physiology and clinical applications. Arrhythm Electrophysiol Rev 2017;6(4):186–90. https://doi.org/10.15420/aer2017.26.1; PMID:29326833.

Pachon JC, Pachon EI, Pachon JC, et al. ‘Cardioneuroablation’ – new treatment for neurocardiogenic syncope, functional AV block and sinus dysfunction using catheter RF-ablation.

Europace 2005;7:1–13. https://doi.org/10.1016/j.eupc.2004.10.003; PMID:15670960.

Pachon JC, Pachon EI, Cunha Pachon MZ, et al. Catheter ablation of severe neurally meditated reflex (neurocardiogenic or vasovagal) syncope: cardioneuroablation long-term results. Europace 2011;13:1231–42. https://doi.org/10.1093/europace/eur163; PMID:21712276.

Authors’ Reply: Origins of Ablation of Bradyarrhythmias Citation: Arrhythmia & Electrophysiology Review 2018;7(2):144. https://doi.org/10.15420/aer.2018.7.2.L2.R2

We thank Dr Pachon for his interest in our manuscript.1 While we acknowledge that the concept of autonomic ablation for treatment of bradyarrhythmias was first proposed by Dr Pachon’s group,2,3 we would like to draw the reader’s attention to the methods of identifying the ganglionated plexi (GP). The original description by Dr Pachon’s group was based on Fast-Fourier Transform (FFT) analysis of the endocardial atrial electrograms, with GP sites showing fractionated signals and shift of the FFT spectrum to the right. In contrast, the study by Yao et al.4 used high-frequency stimulation to identify the GP sites. The actual sites and extent of ablation also differed between the two studies. As the two techniques have not been compared with each other, it remains unclear which is the preferred technique. These differences highlight the need for more research to understand the intricacies of the cardiac autonomic nervous system and how its manipulation can be used to treat vexing cardiovascular diseases, such as neurocardiogenic syncope.

Stavros Stavrakis and Sunny Po, University of Oklahoma Health Sciences Center, Oklahoma, US 1.

2.

3.

4.

Stavrakis S, Po S. Ganglionated plexi ablation: physiology and clinical applications. Arrhythm Electrophysiol Rev 2017;6:186–90. https://doi.org/10.15420/aer2017.26.1; PMID:29326833.

Pachon JC, Pachon EI, Pachon JC, et al. ‘Cardioneuroablation’ – new treatment for neurocardiogenic syncope, functional AV block and sinus dysfunction using catheter RF-ablation.

Europace 2005;7:1–13. https://doi.org/10.1016/j.eupc.2004.10.003; PMID:15670960.

Pachon JC, Pachon EI, Cunha Pachon MZ. Catheter ablation of severe neurally meditated reflex (neurocardiogenic or vasovagal) syncope: cardioneuroablation long-term results.

Europace 2011;13:1231–42. https://doi.org/10.1093/europace/eur163; PMID:21712276.

Yao Y, Shi R, Wong T, et al. Endocardial autonomic denervation of the left atrium to treat vasovagal syncope: an early experience in humans. Circ Arrhythm Electrophysiol 2012;5: 279–86. https://doi.org/10.1161/CIRCEP.111.966465; PMID:22275485.

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Letters

New Information on Asymptomatic Pre-excitation

Citation: Arrhythmia & Electrophysiology Review 2018;7(2):145. https://doi.org/10.15420/aer.2018.7.2.L3

Dear Sir, I read with great interest the comprehensive review of Dr Brugada and Dr Keegan on asymptomatic pre-excitation, and the issues of risk stratification and need for catheter ablation.1 Perhaps the authors would like to comment on two additional studies that have just appeared, but contain vital information for the appropriate management of these patients. The first study emanates from a Danish registry of 310 individuals with pre-excitation (age range 8–85 years). A higher hazard of atrial fibrillation and heart failure, driven by a right anteroseptal accessory pathway, was detected in this population, and in patients >65 years of age there was also a statistically significant higher risk of death.2 In the second retrospective study in 912 young patients ≤21 years old with Wolff-Parkinson-White (WPW) syndrome, patients experienced rapidly conducted pre-excited AF (49 %), aborted sudden death (45 %) and sudden death (6 %). In those subjected to EPS risk stratification, 22 of 60 (37 %) did not have EPS-determined highrisk characteristics, and 15 of 60 (25 %) had neither concerning pathway characteristics nor inducible atrioventricular re-entrant tachycardia. Do the authors interpret these results as clearly suggesting a more substantial role of ablation for patients who present with an active, anterogradely conduction accessory pathway?

Eleftherios Giazitzoglou, Clinical Electrophysiology, Hygeia Hospital, Athens, Greece

1.

2.

3.

Brugada J, Keegan, R. Asymptomatic ventricular pre-excitation: between sudden cardiac death and catheter ablation. Arrhythm Electrophysiol Rev 2018;7:32–8. https://doi. org/10.105420/aer.2017.51.2; PMID:29636970.

Skov MW, Rasmussen PV, Ghouse J, et al. Electrocardiographic preexcitation and risk of cardiovascular morbidity and mortality: results from the Copenhagen ECG study. Circ Arrhythm Electrophysiol 2017;10:pii,e004778. https://doi.org/10.1161/CIRCEP.116.004778; PMID: 28576781.

Etheridge SP, Escudero CA, Blaufox AD, et al. Life-threatening event risk in children with Wolff–Parkinson–White syndrome. A multicenter international study. J Am Coll Cardiol 2018;4:433–44. https://doi.org/10.1016/j.jacep.2017.10.009.

Authors’ Reply: New Information on Asymptomatic Pre-excitation Citation: Arrhythmia & Electrophysiology Review 2018;7(2):145. https://doi.org/10.15420/aer.2018.7.2.L3.R3

Dear Sir, We appreciate the interest of Dr Eleftherios Giozitzoglou in our work.1 In the first retrospective registry,2 in which more than 300,000 individuals had an ECG over a period of 11 years (29 % of total population), a separate analysis of asymptomatic subjects and sudden cardiac death was not addressed in the group of 310 subjects with ventricular pre-excitation. However, and interestingly, ventricular pre-excitation was associated with an increased morbidity related to increased risk of AF (HR 3.12, 95 % CI [2.07–4.70]) and heart failure (HF) (HR 2.11, 95 % CI [1.27–3.50]). The risk of AF persisted even after performing catheter ablation.

The higher risk of HF was associated in particular with the anteroseptal localisation, with tachycardiomyopathy or dyssynchrony as the potential mechanism. Although there was no significant difference between subjects with and without pre-excitation in the entire population, total mortality was significantly higher in those ≥65 years of age (HR 1.85, 95 % CI [1.07–3.18]). The poorly tolerated supraventricular tachycardias among individuals with pre-excitation ≥60 years and the increased burden of AF could explain this finding. The anteroseptal localisation was associated with a borderline statistically significant higher risk of total mortality (HR 2.4, 95 % CI [0.96–4.77]) and the higher risk of HF with this localisation could be the reason for that.

The second multicentre retrospective observational study in a paediatric population (≤21 years of age),3 published subsequent to our review, showed a high incidence of life-threatening events (49 % of rapidly conducted pre-excited AF, 45 % of aborted sudden death and 6 % of sudden death) and in 40 % of these cases as a first manifestation of the disease. But, more importantly, 36 % of evaluated cases had a shortest pre-excited RR interval (SPERRI) >250, 37 % did not have concerning pathway characteristics and 25 % had neither concerning pathway characteristics nor inducible atrioventricular reciprocant tachycardia.

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

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Letters Consequently, and according to these data, catheter ablation could be considered as a better strategy than follow-up in all asymptomatic subjects to reduce the known risk of sudden cardiac death regardless of the anterograde conduction properties.

Despite ventricular pre-excitation being a risk factor for HF, total mortality needs to be confirmed in future studies. Available data so far reinforce the role of catheter ablation in decreasing morbidity and mortality in this group of patients.

Josep Brugada, Cardiovascular Institute, Hospital Clínic and Pediatric Arrhythmia Unit, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain Roberto Keegan, Electrophysiology Service, Private Hospital of the South, Bahia Blanca, Argentina

1.

2.

3.

Brugada J, Keegan R. Asymptomatic ventricular pre-excitation: between sudden cardiac death and catheter ablation. Arrhyth & Electrophysiol Rev 2018;7:32–8. https://doi.org/10.15420/aer.2017.51.2; PMID:29636970.

Skov MW, Rasmussen PV, Ghouse J, et al. Electrocardiographic preexcitation and risk of cardiovascular morbidity and mortality: results from the Copenhagen ECG study.

Circ Arrhythm Electrophysiol 2017;10:pii,e004778. https://doi.org/10.1161/CIRCEP.116.004778; PMID: 28576781.

Etheridge SP, Escudero CA, Blaufox AD, et al. Life-threatening event risk in children with Wolff–Parkinson–White syndrome. JACC: Clin Electrophysiol 2018;4:433–44. https://doi.org/10.1016/j.jacep.2017.10.009.

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

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