AER 6.2 by Radcliffe Cardiology

Arrhythmia & Electrophysiology Review Volume 6 • Issue 2 • Summer 2017

Volume 6 • Issue 2 • Summer 2017

www.AERjournal.com

Supraventricular Arrhythmias in Patients with Adult Congenital Heart Disease Carina Blomström Lundqvist, Tatjana Potpara and Helena Malmborg

A Review of Image-guided Approaches for Cardiac Resynchronisation Therapy Haipeng Tang, Shaojie Tang and Weihua Zhou

Practical Implementation of Anticoagulation Strategy for Patients Undergoing Cardioversion of Atrial Fibrillation Andreas Goette and Hein Heidbuchel

Percutaneous Catheter Ablation of Epicardial Accessory Pathways Eduardo Back Sternick, Mariana Faustino, Frederico Soares Correa, Cristiano Pisani and Maurício Ibrahim Scanavacca

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Tachycardia mechanism more evident with optimal points density of 1.0–1.5 points/cm2.4 * Compared with the focal ablation catheter. 1. Liang, J. et al. Comparison of Left Atrial Bipolar Voltage and Scar Using Multielectrode Fast Automated Mapping versus Point-by-Point Contact Electroanatomic Mapping in PatientsWith Atrial Fibrillation Undergoing Repeat Ablation. JCE. 2016. 2. Anter, E. et al, High-Resolution Mapping of Scar-Related Atrial Arrhythmias Using Smaller Electrodes With Closer Interelectrode Spacing. Circulation Arrhythmia Electrophysioly. 2015; 3. Berte, B. et al, Impact of Electrode Type on Mapping of Scar-Related VT. Journal of Cardiovascular Electrophysiology. 2015 4. Williams, S. et al, Local activation time sampling density for atrial tachycardia contact mapping: how much is enough? Europace. 2017. This product can only be used by healthcare professionals.Important information: Prior to use, refer to the instructions for use supplied with this device for indications, contraindications, side effects, warnings and precautions. Always verify catheter tip location using fluoroscopy or IC signals and consult the CARTO® System User Guide regarding recommendations for fluoroscopy use. Sporton S, Earley M, Nathan A, and Schilling R, Electroanatomic versus fluoroscopic mapping for catheter ablation procedures: A prospective randomized study. Journal of Cardiovascular Electrophysiology 2004;15,3:310-315 The CARTO VISITAG™ Module provides access to data collected during the application of RF energy. The data does not indicate the effectiveness of RF energy application. CARTO VISITAG™ Module settings are user defined based on the user’s clinical experience and medical judgment. Biosense Webster does not recommend any settings for the CARTO VISITAG™ Module.

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Volume 6 • Issue 2 • Summer 2017

Editor-in-Chief Demosthenes Katritsis Athens Euroclinic, Athens, Greece

Section Editor – Arrhythmia Mechanisms / Basic Science

Section Editor – Clinical Electrophysiology and Ablation

Section Editor – Implantable Devices

Andrew Grace

Karl-Heinz Kuck

Angelo Auricchio

University of Cambridge, UK

Asklepios Klinik St Georg, Hamburg, Germany

Fondazione Cardiocentro Ticino, Lugano, Switzerland

Charles Antzelevitch

Carsten W Israel

Carlo Pappone

JW Goethe University, Germany

IRCCS Policlinico San Donato, Milan, Italy

Warren Jackman

Sunny Po

Uppsala University, Uppsala, Sweden

University of Oklahoma Health Sciences Center, Oklahoma City, USA

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

Johannes Brachmann

Pierre Jaïs

Antonio Raviele

Lankenau Institute for Medical Research, Wynnewood, USA

Carina Blomström-Lundqvist

Klinikum Coburg, II Med Klinik, Germany

Pedro Brugada

University of Brussels, UZ-Brussel-VUB, Belgium

Alfred Buxton

Beth Israel Deaconess Medical Center, Boston, USA

Hugh Calkins

John Hopkins Medical Institution, Baltimore, USA

A John Camm

St George’s University of London, UK

Bordeaux University Hospital, Electrophysiology and Heart Modelling Institute (LIRYC), France

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

Josef Kautzner

Frédéric Sacher

Pier Lambiase

Richard Schilling

Samuel Lévy

William Stevenson

Cecilia Linde

Richard Sutton

Institute for Clinical and Experimental Medicine, Prague, Czech Republic Institute of Cardiovascular Science, University College London, and Barts Heart Centre, London, UK Aix-Marseille University, France

Riccardo Cappato

IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy

Ken Ellenbogen

Karolinska University, Stockholm, Sweden

Gregory YH Lip

University of Birmingham, UK

Virginia Commonwealth University School of Medicine, USA

Francis Marchlinski

Sabine Ernst

Royal Brompton and Harefield NHS Foundation Trust, London, UK

Juan Tamargo

University Complutense, Madrid, Spain

Marc A Vos

Hein Heidbuchel

Sanjiv M Narayan

Cardiovascular Center, University of Michigan, USA Stanford University Medical Center, USA

Mark O’Neill

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

University of Leipzig, Germany

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

Jose Merino

Fred Morady

Gerhard Hindricks

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

Panos Vardas

St Vincenz-Hospital Paderborn and University Hospital Magdeburg, Germany Antwerp University and University Hospital, Antwerp, Belgium

Barts Health NHS Trust, London Bridge Hospital, London, UK

University of Pennsylvania Health System, Philadelphia, USA Hospital Universitario La Paz, Madrid, Spain

Andreas Götte

Bordeaux University Hospital, Electrophysiology and Heart Modelling Institute (LIRYC), France

Heraklion University Hospital, Greece University Medical Center Utrecht, The Netherlands

Hein Wellens

University of Maastricht, The Netherlands

Katja Zeppenfeld

Leiden University Medical Center, The Netherlands

Douglas P Zipes

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

Managing Editor Becki Davies • Production Jennifer Lucy Digital Commercial Manager Ben Sullivan • New Business & Partnership Director Rob Barclay Publishing Director Liam O’Neill • Managing Director David Ramsey • Commercial Director David Bradbury •

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Published by Radcliffe Cardiology. All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use there of. Where opinion is expressed, it is that of the authors and does not necessarily coincide with the editorial views of Radcliffe Cardiology. Statistical and financial data in this publication have been compiled on the basis of factual information and do not constitute any investment advertisement or investment advice. Radcliffe Cardiology, Unit F, First Floor, Bourne End Business Park, Cores End Road, Bourne End, Buckinghamshire SL8 5AS © 2017 All rights reserved ISSN: 2050-3369 • eISSN: 2050–3377 © RADCLIFFE CARDIOLOGY 2017

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

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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

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Arrhythmia & Electrophysiology Review is distributed quarterly through controlled circulation to general and specialist senior cardiovascular professionals in Europe. All manuscripts published in the journal are free-to-access online at www.AERjournal.com and www.radcliffecardiology.com

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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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Contents

Foreword

Clinical Electrophysiology: A Glimpse Into The Future Demosthenes Katritsis, Editor-in-Chief Athens Euroclinic, Athens, Greece

Clinical Arrhythmias

Supraventricular Arrhythmias in Patients with Adult Congenital Heart Disease Carina Blomström Lundqvist,1 Tatjana S Potpara2 and Helena Malmborg1 1. Institution of Medical Science, Uppsala University, Uppsala, Sweden; 2. School of Medicine, University of Belgrade, Serbia; Cardiology Clinic, Clinical Center of Serbia.

Practical Implementation of Anticoagulation Strategy for Patients Undergoing Cardioversion of Atrial Fibrillation Andreas Goette1 and Hein Heidbuchel2 1. St Vincenz Hospital Paderborn, Paderborn, Germany; 2. Antwerp University Hospital, University of Antwerp, Antwerp, Belgium

Atrial Flutter, Typical and Atypical: A Review Francisco G Cosío Getafe University Hospital, European University of Madrid, Madrid, Spain

Atrial Fibrillation and Anticoagulation in Hypertrophic Cardiomyopathy C Fielder Camm1 and A John Camm2,3 1. University of Oxford, Oxford; 2. St George’s, University of London; 3. Imperial College, London, UK

Device Therapy

A Review of Image-guided Approaches for Cardiac Resynchronisation Therapy Haipeng Tang,1 Shaojie Tang2 and Weihua Zhou1 1. School of Computing, University of Southern Mississippi, Long Beach, MS, USA; 2. School of Automation, Xi’an University of Posts and Telecommunications, Xi’an, Shaanxi, China

Diagnostic Electrophysiology & Ablation

Evolution of Force Sensing Technologies Dipen Shah Division of Cardiology, Hospital Cantonal de Genève, Switzerland

Percutaneous Catheter Ablation of Epicardial Accessory Pathways Eduardo Back Sternick,1,2 Mariana Faustino,3 Frederico Soares Correa,1 Cristiano Pisani4 and Maurício Ibrahim Scanavacca4 1. Arrhythmia Unit, Biocor Instituto, Nova Lima, Brazil; 2. Medical Sciences Faculty of Minas Gerais, Belo Horizonte, Brazil; 3. Cardiology Department, Hospital Fernando Fonseca, Amadora, Portugal; 4. Arrhythmia Clinical Unit, Heart Institute, University of São Paulo Medical School, São Paulo, Brazil

Cardiac Electrophysiology Under MRI Guidance: an Emerging Technology Henry Chubb,1 Steven E Williams,1,2 John Whitaker,1 James L Harrison,1,2 Reza Razavi1 and Mark O’Neill1,2 1. King’s College London, London, UK; 2. Guy’s and St Thomas’ NHS Foundation Trust, London, UK

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Management of Tricuspid Regurgitation: The Role of Transcatheter Therapies Maurizio Taramasso, Christelle Calen, Andrea Guidotti, Shingo Kuwata, Hector Rodriguez Cetina Biefer, Fabian Nietlispach, Michel Zuber and Francesco Maisano

Managing Stroke During Transcatheter Aortic Valve Replacement Florian Hecker, Mani Arsalan and Thomas Walther

Aortic Dissection: Novel Surgical Hybrid Procedures Alessandro Cannavale, Mariangela Santoni, Fabrizio Fanelli and Gerard O’Sullivan

Use of Intravascular Ultrasound Imaging in Percutaneous Coronary Intervention to Treat Left Main Coronary Artery Disease Giovanni Luigi De Maria and Adrian P Banning

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Foreword

Clinical Electrophysiology: A Glimpse Into The Future

ardiology has traditionally been a high-tech subspecialty, and in no field is this more true than interventional cardiac electrophysiology. Following the advent of computer-assisted recording systems and electroanatomic mapping, impressive technological innovations are emerging. Fusion of intracardiac ultrasound, or cardiac CT,

and cardiovascular magnetic resonance (CMR)-derived imaging to electroanatomic mapping is used to improve intraprocedural guidance for ablation. Myocardial scar border zones can be visualised using late gadolinium enhancement (LGE) techniques, and, more importantly, smaller and more tightly-spaced electrodes. New materials for electrodes and other equipment have allowed the concept of the radiation-free electrophysiology laboratory with the use of CMR, and the vision of a fully radiation-free, magnetic laboratory is no longer science fiction. Mathematical modelling using fast Fourier and Gaussian models has been employed in the investigation of arrhythmia circuits. Histochemistry techniques such as connexin genotyping as well as the revolution in genetics have expanded our understanding of both the mechanism and clinical significance of specific tachycardias. Last, but not least, the emerging field of nanotechnology is being applied to electrophysiology both for characterisation and therapy of arrhythmia substrates. On 20 July 1969, mission commander Neil Armstrong and pilot Buzz Aldrin landed the lunar module Eagle on the moon. The total computer memory on board Apollo 11 was 32 kilobytes. It was the year Damato published his seminal study on His bundle recordings. Now I am writing this editorial on my personal computer with a storage memory of 512 gigabytes, and giants in the field, such as Mark Josephson, have bestowed upon us a totally new world of cardiac arrhythmias. We live in an era of revolutionary technological innovations and the future of arrhythmia treatment is more promising than ever. In Arrhythmia & Electrophysiology Review we are more than excited to see an increasing number of papers reviewing innovative applications in cardiac electrophysiology. We shall do our best to keep pace by disseminating this knowledge in as succinct, focused and reader-friendly a manner as possible. Demosthenes Katritsis, Editor-in-Chief, Arrhythmia & Electrophysiology Review Athens Euroclinic, Athens, Greece

DOI: 10.15420/AER.2017.6.2.ED1

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

barcelona spain

THE ANNUAL CONGRESS OF THE EUROPEAN HEART RHYTHM ASSOCIATION

18 / 20 MARCH

2018

www.escardio.org/EHRA d8227 - EHRA 2018 Pub A4-v1.indd 1

30/05/2017 16:45

Clinical Arrhythmias

Supraventricular Arrhythmias in Patients with Adult Congenital Heart Disease Carina Blomström Lundqvist, 1 Tatjana S Potpara 2 and Helena Malmborg 1 1. Institution of Medical Science, Uppsala University, Uppsala, Sweden; 2. School of Medicine, University of Belgrade, Serbia; Cardiology Clinic, Clinical Center of Serbia.

Abstract An increasing number of patients with congenital heart disease survive to adulthood; such prolonged survival is related to a rapid evolution of successful surgical repairs and modern diagnostic techniques. Despite these improvements, corrective atrial incisions performed at surgery still lead to subsequent myocardial scarring harbouring a potential substrate for macro-reentrant atrial tachycardia. Macroreentrant atrial tachycardias are the most common (75 %) type of supraventricular tachycardia (SVT) in patients with adult congenital heart disease (ACHD). Patients with ACHD, atrial tachycardias and impaired ventricular function – important risk factors for sudden cardiac death (SCD) – have a 2–9 % SCD risk per decade. Moreover, ACHD imposes certain considerations when choosing antiarrhythmic drugs from a safety aspect and also when considering catheter ablation procedures related to the inherent cardiac anatomical barriers and required expertise. Expert recommendations for physicians managing these patients are therefore mandatory. This review summarises current evidence-based developments in the field, focusing on advances in and general recommendations for the management of ACHD, including the recently published recommendations on management of SVT by the European Heart Rhythm Association.

Keywords Congenital heart disease, supraventricular tachycardia, atrial flutter, accessory pathway, atrial tachycardia, catheter ablation, sudden cardiac death Disclosure: The authors have no conflicts of interest to declare. Received: 9 September 2016 Accepted: 20 October 2016 Citation: Arrhythmia & Electrophysiology Review 2017;6(2):42–9. DOI: 10.15420/aer.2016:29:3 Correspondence: Carina Blomström Lundqvist, professor, Department of Cardiology and Medical Science, Uppsala University, 75185 Uppsala, Sweden. E: carina.blomstrom.lundqvist@akademiska.se

With the advent of successful surgical repairs and modern diagnostic techniques, an increasing number of patients with congenital heart disease survive to adulthood. Despite these improvements, the surgical corrective atrial incisions performed during childhood lead to subsequent myocardial scarring that have the inherent risk of harbouring substrates for macro-reentrant atrial tachycardias (MRATs). Apart from surgical conduction barriers such as patches, conduits and surgical scars, there are also natural barriers including valve annuli and venous orifices that potentially may become critical substrates for tachyarrhythmias.1 The 20-year risk of developing atrial arrhythmias among patients with adult congenital heart disease (ACHD) was 7 % in a patient aged 20 years and 38 % in a patient aged 50 years in a population-based study.2 MRATs are the most common type of supraventricular tachycardia (SVT) in patients with ACHD, occurring in 75 % of ACHD-associated SVT cases, most commonly in patients with Ebstein’s anomaly, Tetralogy of Fallot, single-ventricle Fontan procedures, transposition of the great arteries (TGA) or atrial septal defects (ASDs).3,4 Over 60 % of these MRATs involve the cavo-tricuspid isthmus (CTI) and are referred to as CTI-dependent atrial flutters, while the other MRATs are defined as non-CTI-dependent atrial flutters.3 In addition, some forms of ACHD are associated with tachyarrhythmias occurring prior to any surgical intervention, such as Ebstein’s anomaly with up to 44 % prevalence of atrioventricular (AV) or atriofascicular accessory pathways and congenitally corrected TGA with AV accessory connections in 2–5 % of patients.5 Apart from these tachyarrhythmias, patients with ACHD also have an increased risk of pump failure, stroke and sudden cardiac death

Access at: www.AERjournal.com

(SCD).6 Although the incidence of SCD is low (0.09 % per year) in the CHD population, it is higher compared with age-matched controls7 and related to arrhythmias in 14 % of all deaths after initial repair.8,9 Atrial tachycardias (ATs) and impaired ventricular function are thus important and consistent risk factors for SCD in patients with ACHD, of which those with corrected Tetralogy of Fallot, post-atrial switch operation (Mustard or Senning), left heart obstructive lesions and univentricular hearts have the highest risk of SCD (2–9 % per decade).8–10 In the German National Register for Congenital Heart Defects for adult patients, the mortality rate during a median follow-up of 3.7 years was 9.2 % among 2596 patients, with heart failure (27.6 %) and SCD (23.0 %) as the leading causes of death.11 Deceased patients had a more complex CHD and extracardiac comorbidities. The treatment of CHD imposes certain safety considerations when choosing antiarrhythmic drugs while various cardiac anatomical barriers and required operator expertise should be taken into account when referring patients for catheter ablation. The complex cardiac anatomy and haemodynamic changes require special precautions related to the increased risk of pro-arrhythmia when using antiarrhythmic drugs and the need for specialised expertise and sophisticated mapping systems when complex catheter ablation procedures are performed. Pre-procedural cardiac imaging with a variety of methodologies can assist with venous access to the heart, determining details of native cardiovascular anatomy and the nature of corrective surgery and evaluation of ventricular function. Reviewing all tachycardias from prior ECGs is also important before the procedure. The success rates after catheter ablation in patients with ACHD is somewhat lower compared with the general population, with acute and long-term success rates

Supraventricular Arrhythmias in Adult Congenital Heart Disease of 80 % and 68 %, respectively, for accessory pathway ablations, and 66–76 % and 50–53 %, respectively, for MRATs.12–15 As recommended for patients with AF, antithrombotic therapy is indicated in patients with ACHD who have AT or MRAT.16–18 Expert recommendations for physicians managing patients with ACHD is mandatory due to the small number of patients and the potentially life-threatening arrhythmias. This review summarises current evidence-based developments in the field, focusing on new advances and general recommendations for the management of patients with ACHD, including published recommendations on management of SVT19 that has adopted a new user-friendly system of ranking a recommendation using heart symbols in three different colours.

Diagnosis and Differential Diagnosis of Supraventricular Tachycardia Traditionally SVT (defined as an atrial and/or ventricular rate >100 beats per minute [bpm] at rest involving tissue from the His bundle or above) includes AV reentry tachycardia (AVRT) due to accessory connections, AV nodal reentry tachycardia (AVNRT) and various forms of ATs including focal atrial tachycardias and MRATs. 19,20 Most SVTs are regular and may manifest as narrow-QRS tachycardias (QRS duration <120 ms) or wide-QRS tachycardias (QRS duration ≥120 ms). Regular and paroxysmal palpitations with a sudden onset and termination are most likely related to AVRT or AVNRT. Termination by vagal manoeuvres further suggests a reentrant tachycardia involving AV nodal tissue. Preexcitation on the surface ECG in a patient with regular paroxysmal palpitations strongly suggests AVRT, whereas irregular palpitations suggest AF or non-sustained atrial tachycardia.

Narrow QRS Tachycardias An ECG recorded during tachycardia is of key importance for an adequate diagnosis of SVT.21 Focal atrial tachycardia is an organised atrial rhythm usually ranging between 100 and 250 (rarely, up to a maximum of 300) bpm and the diagnosis is clear when the ventricular rate is lower than the atrial rate. An automatic AT is characterised by gradual acceleration of the atrial rate at tachycardia onset (warmup phenomenon) and deceleration (cool down) before termination. Irregular R-R intervals during a tachycardia are consistent with AF if discernible P waves are absent, whereas although atrial flutter with varying degrees of conduction may also be irregular, it is often marked by a recurring pattern of ‘grouped beating’. During AT the conduction to the ventricles can be fast (1:1) or slow (3:1 or 4:1), but a 2:1 conducting atrial flutter should be strongly suspected for patients with ACHD with palpitations and seemingly inappropriately high heart rate, especially when there is a strong history of sinus node dysfunction. Although a discrete P wave with an intervening isoelectric interval suggests a focal AT, an MRAT cannot be excluded in a patient with significant ACHD.22 Vagal manoeuvres or adenosine injection may aid in clinical diagnosis (see Table 1). AV dissociation during narrow-QRS tachycardia excludes AVRT, as both atria and ventricles are parts of the circuit.

Wide-QRS Tachycardias Wide-QRS tachycardias are most commonly (80 %) ventricular tachycardias (VTs), but can be SVT with bundle-branch block (BBB)

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

aberration (15 %) or conduction over an accessory pathway (5 %).23 Diverse BBB morphology during wide-QRS tachycardia compared with sinus rhythm strongly favours VT. Functional BBB is more frequently right sided because of its longer refractoriness. An accessory pathway may participate in the reentry circuit (antidromic AVRT) or act as a bystander during SVT (AT, atrial flutter, AF and AVNRT). Differential diagnosis should always be considered in the context of the underlying disease, with conditions such as Tetralogy of Fallot favouring VT. A 12-lead ECG during wide-QRS tachycardia showing ventriculo-atrial (VA) dissociation (atrial activity slower and independent of ventricular activity), is a major ECG criterion for VT. A 1:1 VA conduction is found in up to 50 % of patients with VT and gives no diagnostic clue. The QRS morphology during wide-QRS tachycardia may be useful for diagnosis in the absence of VA dissociation, although conventional criteria may not apply as VT morphology has not been systematically evaluated in this population.1,23 The differentiation between VT and antidromic AVRT is difficult unless the surface ECG during sinus rhythm shows the same preexcitation pattern. SVTs conducted with aberrancy or antidromic AVRT respond to vagal manoeuvres and adenosine, as described for narrow-QRS tachycardia (see Table 1).

Clinical Presentation The clinical presentation of SVT depends on heart rate, blood pressure during the tachycardia, type of cardiac malformation and corrective surgery, and the individual patient symptom threshold. The symptoms may vary from an asymptomatic patient to a state mimicking panic disorders with breathlessness or to a serious symptom such as syncope.24 A clinical history including description of symptoms and precipitating factors with number of episodes, duration, frequency, mode of onset and an evaluation of cardiac function is mandatory. Patients with ACHD are more likely to present with breathlessness or chest discomfort/pain, particularly at fast heart rates of >150 bpm, as compared with patients without structural heart disease. Prolonged asymptomatic SVT episodes may lead to a tachycardiomyopathy if left untreated for weeks to months, with a fast ventricular rate. 25

Common Types of Supraventricular Tachycardia in Adult Congenital Heart Disease Macro-reentrant Atrial Tachycardias CTI-dependent atrial flutter is an MRAT in the right atrium that propagates in counter-clockwise direction with regular negative atrial deflections in inferior leads as a ‘saw-tooth pattern’, at rates of 240–350 bpm (see Figure 1).26 It propagates in the clockwise direction less often, resulting in positive atrial deflections in inferior leads and bimodal negative waves in V1. CTI-dependent right atrial flutter is a common tachycardia mechanism in patients with postsurgical ACHD. Although a typical, saw-tooth ECG pattern is seen in inferior leads, other MRATs should be considered.27–29 The relatively narrow passage, the CTI, is the preferred ablation target. Non-CTI-dependent atrial flutters can occur with cycle lengths as long as 400 ms, and with more than one ECG pattern, suggesting several tachycardia mechanisms.30 Right-sided MRATs include a ‘lower-loop’ circuit, considered to be a variant of CTI-dependent atrial flutter at a lower level than usual with its ECG pattern, described after the Fontan operation31 and Mustard/Senning repair,32 and ‘upper-loop’ circuits around the superior vena cava and upper portions of the crista terminalis or, more commonly, atriotomy circuits at the lateral right

Clinical Arrhythmias Figure 1: 12-Lead ECGs During Different Types of Supraventricular Tachycardia. Paper Speed 50 mm/s A

Left-sided MRATs (see Figure 1) are generally related to gaps along surgical lines and anatomical barriers, such as the mitral valve or the pulmonary veins29 and can be interrupted by localised ablation at those sites, but with a lower success rate and a higher recurrence rate than CTI ablation.34–39 Catheter ablation requires complete lines of block, preferably at the narrowest isthmus, which can be challenging, particularly at the mitral isthmus. Prevention of macro-reentry at cardiac surgery may be achieved by connecting large atriotomies to electrical obstacles whenever possible, to avoid creating new reentry circuits. The superior septal approach to the left atrium should therefore be avoided.

Focal Atrial Tachycardias Focal ATs usually have frequent interruptions and re-initiations as opposed to MRATs, which are stable. The ablation strategy for focal AT, irrespective of the mechanism, targets the site of earliest activation from which it spreads centrifugally to the rest of the atria, whereas the strategy for MRATs follow a large circuit around a central obstacle, usually a scar or an anatomical barrier.40 Atrial rates above or below 240 bpm and the presence or absence of an isoelectric baseline between atrial deflections are traditionally useful diagnostic features, but do not discriminate focal from macro-reentry mechanisms as activation in slow conduction tracts may not be recorded in the ECG.26,41 Thus, focal and reentrant ATs can thus only be distinguished by activation and entrainment mapping during an electrophysiological study.22 Although a negative P wave in lead aVL usually implies a left atrial origin while a negative in V1 supports a source in the lateral right atrium, the value of the P-wave morphology during tachycardia for assessing the origin of an AT is also limited in patients with ACHD (see Figure 1).

Atrioventricular Reentrant Tachycardias

Wolff–Parkinson–White (WPW) syndrome refers to the presence of preexcited ECG during sinus rhythm in association with recurrent tachyarrhythmias. AF with fast ventricular response is a potentially life-threatening arrhythmia in patients with WPW syndrome due to degeneration in ventricular fibrillation. Predictors of SCD in patients with WPW syndrome include: • • • •

Short R-R interval (<250 ms) during spontaneous or induced AF; History of symptomatic tachycardia; Multiple accessory pathways; Ebstein’s anomaly.42,43

Acute Therapy of Supraventricular Tachycardia in Adult Congenital Heart Disease A. Counterclockwise cavo-tricuspid isthmus-dependant atrial flutter proven by mapping and entrainment. Note the ‘saw-tooth’ pattern in inferior leads. Heart rate 150 beats per minute. A-A interval 200 ms; B. Left-sided macro-reentrant atrial tachycardia 2:1 atrioventricular blocked with a circuit propagating around the mitral valve. Note the negative P waves in aVL. A-A interval 210 ms; C. Left-sided macro-reentrant atrial tachycardia with a circuit consistent with a perimitral flutter. Note the sharp positive P waves in V1. A-A interval 200 ms; D. Atrial flutter with 1:1 atrioventricular conduction and wide QRS complexes with right bundle-branch block morphology and undetermined frontal plane axis. Heart rate 248 beats per minute. A-A interval 240 ms.

atrial surgical scars or a septal patch.29 In patients with complex ACHD undergoing the Mustard, Senning or Fontan procedures, complex suture lines and large areas of scar tissue result in substrates for MRAT, but the CTI is, in many cases, the critical isthmus for the reentry circuit, but with difficult access for ablation.32,33

Acute treatment of SVT in patients with ACHD should be preceded by an immediate clinical evaluation for efficient and safe treatment, including: • Evaluation of haemodynamic status and the cardiovascular disease; • Effect of previous acute treatments; • Current medical therapy; • Duration of the ongoing tachycardia. Acute treatment alternatives for SVT, shown in Table 2, have been reported in European guidelines.19 A tachycardia should be documented with a 12-lead-ECG before acute management unless the patient is severely haemodynamically unstable, when at least a rhythm strip should be recorded. Direct current (DC) synchronised

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Supraventricular Arrhythmias in Adult Congenital Heart Disease Table 1: Responses to Vagal Manoeuvres

Table 2: Acute Therapy of SVT in Patients with ACHD

1. Slowing of AV node conduction and AV block

Atrial electrical activity can be unmasked, revealing P waves or underlying atrial flutter or AF waves

Recommendation for haemodynamically unstable SVT

2. Temporary decrease in the atrial rate

Focal automatic atrial tachycardias or sinus tachycardia

3. Tachycardia termination Interruption of reentry circuit in AVNRT and AVRT by acting on the AV node that is part of the circuit. Rarely, focal ATs due to triggered activity can terminate 4. No effect in some cases AV = atrioventricular; AVRT = AV reentry tachycardia; AVNRT = AV nodal reentry tachycardia.

Electrical cardioversion is recommended (caution for sinus node dysfunction and impaired ventricular function with need for chronotropic or inotropic support)* IV adenosine for conversion may be considered (caution for sinus node dysfunction and impaired ventricular function with need for chronotropic or inotropic support) Recommendation for haemodynamically stable AVNRT/AVRT IV adenosine may be considered Atrial overdrive pacing (via oesophagus or endocardial) for pace termination may be considered Recommendation for haemodynamically stable MRAT/AT

cardioversion is the most effective method and first choice to terminate any haemodynamically unstable narrow or wide QRScomplex tachycardia.44–47 Vagal manoeuvres (i.e. Valsalva) should be used in the first attempt to terminate a tachycardia,48–50 during which an ECG should be recorded as the response may aid the diagnosis even if the arrhythmia does not terminate (see Table 1). Intravenous (IV) administration of adenosine (5–15 mg in a bolus) is the drug of first choice in haemodynamically stable patients if vagal manoeuvres fail.51,52 The advantages of adenosine include a rapid onset, short half-life, and avoidance of hypotension, which makes it the drug of choice except for in patients with severe asthma or angina pectoris.51 Adenosine may induce AF (1–15 %), which may be of concern for those with ventricular preexcitation, although the AF is usually transient. A short-acting beta-blocker (esmolol) is the second choice for acute tachycardia termination in haemodynamically stable patients (see Table 2).51,53,54 Longer-acting agents (e.g. IV metoprolol) may be preferred in patients with frequent premature beats, which may trigger early recurrence of paroxysmal supraventricular tachycardia. IV ibutilide given for conversion of atrial flutter is usually highly effective and may be considered, although caution is advised for proarrhythmia in patients with impaired ventricular function. IV calcium-channel blockers are not recommended as they may cause hypotension and/or bradycardia. A wide QRS-complex tachycardia of unknown mechanism should be treated as VT until otherwise proven. Adenosine may aid the diagnosis or interrupt an adenosinesensitive VT, but caution is advised in case of AF with ventricular preexcitation.55 DC cardioversion is recommended for termination of any irregular wide QRS-complex tachycardia.

Chronic Pharmacological Therapy of Supraventricular Tachycardia in Adult Congenital Heart Disease There are no randomised clinical trials evaluating the efficacy and safety of antiarrhythmic drugs (AADs) in patients with ACHD. Medication with beta-blocking agents may protect from rapid 1:1 AV conduction and tachycardia-mediated hypotension, but their preventive efficacy in SVT is uncertain (see Table 3). Non-use of betablockers was an independent predictor of appropriate implantable cardioverter defibrillator shocks in a multicentre cohort study of patients with TGA and intra-atrial baffle repair (hazard ratio 16.7; P=0.030).56 All AADs have an increased risk for proarrhythmia and many also aggravate sinus node dysfunction as well as heart failure and require in-hospital observation. Sinus node dysfunction may require pacemaker implantation prior to initiation of AADs.

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IV ibutilide for conversion of atrial flutter may be considered (caution for pro-arrhythmia in patients with impaired ventricular function) IV metoprolol (caution for hypotension) may be considered for conversion and rate control Atrial overdrive pacing for pace termination of atrial flutter (via oesophagus or endocardial) may be considered Scientific evidence that a treatment or procedure is beneficial and effective. Requires at least one randomised trial, or is supported by strong observational evidence and authors’ consensus. General agreement and/or scientific evidence favour the usefulness/efficacy of a treatment or procedure. May be supported by randomised trials that are based on too small number of patients to allow a green heart recommendation. *Supported by strong observational evidence and authors’ consensus but no specific RCT. ACHD = adult congenital heart disease; AT = atrial tachycardia; AVRT = AV reentry tachycardia; AVNRT = AV nodal reentry tachycardia; IV = intravenous; MRAT = macro-reentrant atrial tachycardia; RCT = randomised clinical trial; SVT = supraventricular tachycardia.

In the retrospective studies comparing AAD for prevention of SVT in patients with ACHD, only 45 % of the patients were free from SVT after 2.5 years of follow-up.57 Class III AADs sotalol and amiodarone were the most effective, but adverse effects were common (22 %). Class Ic drugs (encainide and flecainide) should not be used in patients with ACHD due to their proarrhythmic effects (see Table 3).58 The recent Cochrane Database System Review of randomised trials regarding the safety of AAD compared with controls in adult patients with AF showed that all AADs except amiodarone, dronedarone and propafenone were associated with an increased risk of proarrhythmia.59 Quinidine, disopyramide and sotalol were additionally associated with increased all-cause mortality rates.59 There is no reason to expect these drugs to be safer in a population with structural heart disease, such as ACHD, and therefore they cannot be recommended otherwise than as a last-choice therapy. Amiodarone is less often associated with proarrhythmia, but has severe side-effects (thyroid and pulmonary toxicity) that limit long-term use in these patients.59 Atrial-based pacing does not seem to prevent subsequent atrial arrhythmias according to multivariate analysis.60

Catheter and Surgical Ablation Catheter ablation of SVT is more complicated in patients with ACHD due not only to the nature of the MRAT per se, but also to the challenge with limited venous access to the heart, fibrotic atrial tissue, multiple atrial reentrant circuits, and atrial baffles separating the coronary sinus and CTI to the systemic venous atrium. Patients should preferably be referred to experienced centres with respect to complex MRATs and with access to advanced mapping systems as special expertise and knowledge of complex tachyarrhythmias and scar-related ablation procedures is required for a successful outcome (see Table 3). Catheter ablation is further challenged by the difficult access to the pulmonary venous atrium in patients who have undergone Fontan

Clinical Arrhythmias Table 3: Chronic Therapy of SVTs in Patients with ACHD Recommendations for recurrent symptomatic SVT Haemodynamic evaluation of structural defect for potential repair may be considered as initial evaluation of SVT Catheter ablation may be considered Oral beta-blockers may be considered for recurrent AT or atrial flutter Amiodarone may be considered for prevention, if other medications and catheter ablation are ineffective or contraindicated Antithrombotic therapy for AT or atrial flutter is the same as for patients with AF, as patients with ACHD with ATs and atrial flutter probably have similar risks for thromboembolism as patients with AF Oral sotalol should not be used related to increased risk for proarrhythmias and mortality

the recurrence rate after 45±15 months’ follow-up is as high as 18 %.68 The main factors related to higher success rates of catheter ablation in these patients are: • • •

Severity of ACHD (patients with single ventricle or dextro-TGA [d-TGA] with poorer outcomes); Age (worse outcomes with older age at repair); and Anatomical mapping systems and irrigated tip ablation catheters (higher success rates if used).

Arrhythmia surgery can be integrated into a corrective surgical procedure with high efficacy and with no obvious signs of increased surgical morbidity (see Table 4).69 A 5 % mortality rate was, however, reported with Fontan conversion when surgery was performed purely for refractory supraventricular arrhythmia.70

Flecainide should not be used in patients with ventricular dysfunction related to increased risk for proarrhythmia and mortality

Specific Disease Conditions

Implantation of a pacemaker for atrial-based pacing to decrease recurrence of AT/flutter is not recommended

Most MRATs occurring in patients without prior closure of the ASD are CTI dependent and susceptible to catheter ablation.3 The ASD closure unlikely eliminates the atrial flutter and catheter ablation of the CTI is therefore the recommended approach.71 If the ASD mandates a closure, MRAT ablation prior to closure should be considered. Significant ASDs in adults can even be closed later in life and result in improved morbidity and survival rates,72 although new or recurrent ATs are frequent.73 It is therefore preferable to perform both catheter ablation of the AT and closure of the ASD in patients with significant ASD and tachyarrhythmia. Both CTI-dependent atrial flutters and MRATs can occur and coexist in the same patient with repaired ASD, and catheter ablation has favourable outcomes.3,65 Both transcatheter closure and surgical closure of secundum ASDs have been reported to yield favourable long-term outcomes without significant differences with regard to atrial arrhythmias (9.3 %), survival or thromboembolism.3,74,75 Patients with unoperated significant ASD and arrhythmias should therefore undergo both ablation of the AT and closure of the ASD. The anatomical features of the ASD determine the most suitable choice between catheter and surgical treatment approach. No randomised trials have compared catheter-based versus surgical closure of ASD combined with arrhythmia intervention.

Scientific evidence or general agreement not to use or recommend a treatment or procedure. General agreement and/or scientific evidence favour the usefulness/efficacy of a treatment or procedure. May be supported by randomised trials that are based on too small number of patients to allow a green heart recommendation. ACHD = adult congenital heart disease; AT = atrial tachycardia; SVT = supraventricular tachycardia.

Table 4: Planned Surgical Repair and Symptomatic SVT Recommendations if planned surgical repair Surgical ablation of AT, atrial flutter or accessory pathway may be considered If surgical repair of Ebstein’s anomaly, preoperative electrophysiological study may be considered as a routine test In patients with SVT planned for surgical repair of Ebstein’s anomaly, preoperative catheter ablation or intraoperative surgical ablation of accessory pathways, flutter or AT may be considered General agreement and/or scientific evidence favour the usefulness/efficacy of a treatment or procedure. May be supported by randomised trials that are based on too small number of patients to allow a green heart recommendation. AT = atrial tachycardia; SVT = supraventricular tachycardia.

or atrial switch procedures. Trans-baffle access was reported to be successful in 96 % of 74 attempted cases without indications of higher incidence of adverse events.61 Trans-conduit puncture for patients who have undergone extra-cardiac Fontan procedures has more recently been reported without complication related to the puncture procedure.62 Remote magnetic navigation may be especially useful for complex venous anomalies such as intra-atrial baffle or interrupted inferior venous access for access to the pulmonary venous atrium.63 Post-ablation monitoring and prospective registries and studies are, however, warranted.39,61 The acute success rates of catheter ablation of SVT in patients with ACHD ranges from 65 to 100 %, with a higher recurrence rate (20–60 %) within 2 years than seen in other cohorts of routine SVT ablation.13, 64–66 Lower success rates (65–82 %) have been reported for AT or MRAT ablations as compared with those observed in the absence of ACHD,13,64,67 although better outcomes have been achieved with the advent of advanced mapping and ablation techniques.63 Although ablation of CTI-dependent atrial flutter has a high acute success rate of 96 %, depending on the type of anomaly,

Atrial Septal Defect

Ebstein’s Anomaly Accessory pathways are frequent (15–30 %), more often right sided and multiple in patients with ACHD than in other patients,76 and other SVTs that can occur include AF, atrial flutter and focal AT. The haemodynamic consequences of SVTs depend on the degree of malformation, varying from mild variants without any symptoms to severe haemodynamic compromise and cyanosis in cases of tricuspid regurgitation and large ASD. Preexcited AF or rapidly conducting MRATs may result in SCD. Catheter ablation of accessory pathways is challenging and associated with lower success rates (80 %) and higher recurrences (40 %) than in other patients, also depending on accessory pathway location.77 When surgical corrections are warranted and SVTs are present ablation is still recommended prior to surgery.77 Surgical ablation of accessory pathways is successful in 92–100 %.5,78 Preoperative electrophysiological evaluation has a high diagnostic and therapeutic yield and is recommended as a routine preoperative test for this population.79 Patients who underwent corrective surgery for Ebstein’s anomaly with preoperative electrophysiological study and intraoperative arrhythmia ablation had a lower risk of SCD than patients without arrhythmia intervention, in

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Supraventricular Arrhythmias in Adult Congenital Heart Disease a small series.80 Catheter ablation procedures should be performed by experienced physicians related to the complex anatomy and the more complex arrhythmias.81,82

Transposition of the Great Arteries with Post-atrial Switch Operation (Mustard or Senning) There is a high prevalence of both MRAT (14–24 %) and sinus node dysfunction in patients with TGA with post-atrial switch operation (Mustard or Senning), related to the extensive atrial surgery. Maintenance of sinus rhythm is desirable as SVTs have been associated with increased risk of sudden death, and recurrences are common and often associated with haemodynamic compromise. The number of suitable AADs is limited related to ventricular dysfunction and risk of proarrhythmia, as well as sinus node dysfunction. Catheter ablation of AT and AVNRT in patients post-Mustard or Senning operation for d-TGA has a high primary success rate, but high recurrence rates (30 %) of MRAT, although with favourable longterm results after a second ablation.66 Catheter ablation procedures are complex and should be performed in experienced centres using sophisticated mapping systems. The CTI is a critical area that is bisected by the atrial baffle, thus the portion of the isthmus connected to the tricuspid valve must often be reached either by a retrograde transaortic or an antegrade trans-baffle approach to achieve isthmus block.

Tetralogy of Fallot In patients with Tetralogy of Fallot, MRAT is common (20 %) as is sustained VT (11 %), with an 8 % risk of SCD.4,83,84 The MRATs are drug-refractory and/or severely symptomatic in most patients and approximately half of the sustained and symptomatic cases are CTI dependent.84 The occurrence of SVTs was recently reported to be associated with higher mortality rates (15.6 % versus 8.6 %; p=0.001).85 In the majority of patients, a right BBB is present during sinus rhythm, which may cause differential diagnostic difficulties requiring electrophysiology testing.86 MRAT can be a sign of worsening ventricular function and a haemodynamic evaluation of the repair is therefore warranted. Complete or partial control of the arrhythmia can be achieved by surgery or catheter-based haemodynamic revision of the repair in cases who are clinically and haemodynamically ill.87 Catheter ablation of AT is associated with a high procedural success rate during long-term follow-up in the vast majority of patients.88

1. Love BA, Collins KK, Walsh EP, Triedman JK. Electroanatomic characterization of conduction barriers in sinus/atrially paced rhythm and association with intra-atrial reentrant tachycardia circuits following congenital heart disease surgery. J Cardiovasc Electrophysiol 2001;12:17–25. PMID: 11204078. 2. Bouchardy J, Therrien J, Pilote L, et al. Atrial arrhythmias in adults with congenital heart disease. Circulation 2009;120:1679– 86. DOI: 10.1161/CIRCULATIONAHA.109.866319; PMID: 19822808. 3. Wasmer K, Kobe J, Dechering DG, et al. Isthmus-dependent right atrial flutter as the leading cause of atrial tachycardias after surgical atrial septal defect repair. Int J Cardiol 2013;168:2447–52. DOI: 10.1016/j.ijcard.2013.03.012; PMID: 23540398. 4. Khairy P, Aboulhosn J, Gurvitz MZ, et al. Arrhythmia burden in adults with surgically repaired tetralogy of Fallot: a multiinstitutional study. Circulation 2010;122:868–75. DOI: 10.1161/ CIRCULATIONAHA.109.928481; PMID: 20713900. 5. Khositseth A, Danielson GK, Dearani JA, et al. Supraventricular tachyarrhythmias in Ebstein anomaly: management and outcome. J Thorac Cardiovasc Surg 2004;128:826–33. DOI: 10.1016/j.jtcvs.2004.02.012; PMID: 15573066. 6. Engelfriet P, Boersma E, Oechslin E, et al. The spectrum of adult congenital heart disease in Europe: morbidity and mortality in a 5 year follow-up period. The Euro Heart Survey on adult congenital heart disease. Eur Heart J 2005;26:2325–33. DOI: 10.1093/eurheartj/ehi396; PMID: 15996978. 7. Silka MJ, Hardy BG, Menashe VD, Morris CD. A population-

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Fontan Repairs Despite more modern surgical approaches, the incidence of atrial arrhythmia remains high. The most common AT in patients who have undergone a Fontan procedure is an MRAT (66 %), and CTI-dependent atrial flutter or AF can develop in up to 42 % of patients.89 ATs can rapidly cause haemodynamic deterioration resulting in heart failure. Catheter ablation is often difficult due to multiple circuits and should be attempted only at experienced centres. When compared with other ACHD anomalies, both Fontan and Mustard repairs have been associated with less successful ablation results related not only to the low success rate of catheter ablation (54 % versus 83% for other CHDs), but also to a high recurrence rate (50 % versus 32 %) after an initial successful ablation procedure.64,67 Lower recurrence rates were achieved with modified right atrial maze procedures as compared with CTI ablation,90 but selection of suitable patients is important.91

Summary The prolonged survival of patients with ACHD has imposed further challenges for the adult electrophysiologists who are expected to manage even more complex MRATs. A rapid evolution of electroanatomical mapping systems with developments in computer technology and sophisticated ablation equipment have not only improved the mapping, but enhanced the understanding of specific arrhythmia mechanisms, appreciation of scar tissue and transmurality of ablation lesions, which should improve our efficiency and result in more controllable and safer procedures while treating these patients. Despite these novel evolving techniques, further development of prophylactic intraoperative ablation techniques at the time of congenital heart surgery is urgently needed to prevent subsequent MRATs. ■

Clinical Perspective • ACHD is a structural heart disease that imposes restrictions for safety reasons when choosing antiarrhythmic drugs related to the increased risk of proarrhythmias. • ACHD is further characterised by a large variety of cardiac anomalies and anatomical barriers resulting in complex macro-reentrant atrial tachycardias that require advanced knowledge and expertise for effective and safe catheter ablation procedures.

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and characteristics of atrial tachyarrhythmia recurrences. Circ Arrhythm Electrophysiol 2010;3:148–54. DOI: 10.1161/ CIRCEP.109.909838; PMID: 20194797. 14. Yap S-C, Harris L, Downar E, et al. Evolving electroanatomic substrate and intra-atrial reentrant tachycardia late after fontan surgery. J Cardiovasc Electrophysiol 2012;23:339–45. DOI: 10.1111/j.1540-8167.2011.02202.x; PMID: 22035149. 15. Correa R, Sherwin ED, Kovach J, et al. Mechanism and ablation of arrhythmia following total cavopulmonary connection. Circ Arrhythm Electrophysiol 2015;8:318–25. DOI: 10.1161/CIRCEP.114.001758; PMID: 25583982. 16. Ghali WA, Wasil BI, Brant R, et al. Atrial flutter and the risk of thromboembolism: a systematic review and meta-analysis. Am J Med 2005;118:101–7. DOI: 10.1016/j.amjmed.2004.06.048; PMID: 15694889. 17. 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. DOI: 10.1093/europace/euw295; PMID: 27567465. 18. Khairy P, Van Hare GF, Balaji S, et al. PACES/HRS expert consensus statement on the recognition and management of arrhythmias in adult congenital heart disease: developed in partnership between the Pediatric and Congenital Electrophysiology Society (PACES) and the Heart Rhythm Society (HRS). Endorsed by the governing bodies of PACES, HRS, the American College of Cardiology (ACC), the American Heart Association (AHA), the European Heart Rhythm Association (EHRA), the Canadian Heart Rhythm Society (CHRS), and the International Society for Adult Congenital

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Heart Rhythm 2015;12:1667–76. DOI: 10.1016/j.hrthm.2015.03.046; PMID: 25828600. 22. Akca F, Bauernfeind T, De Groot NMS, et al. The presence of extensive atrial scars hinders the differential diagnosis of focal or macroreentrant atrial tachycardias in patients with complex congenital heart disease. Europace 2014;16:893–8. DOI: 10.1093/europace/eut338; PMID: 24280196. 23. Alzand BS, Crijns HJ. Diagnostic criteria of broad QRS complex tachycardia: decades of evolution. Europace 2011;13:465–72. DOI: 10.1093/europace/euq430; PMID: 21131372. 24. Lessmeier TJ, Gamperling D, Johnson-Liddon V, et al. Unrecognized paroxysmal supraventricular tachycardia. Potential for misdiagnosis as panic disorder. Arch Intern Med 1997;157:537–43. PMID: 9066458. 25. Ellis ER, Josephson ME. What about tachycardia-induced cardiomyopathy? Arrhythm Electrophysiol Rev 2013;2:82–90. DOI: 10.15420/aer.2013.2.2.82; PMID: 26835045. 26. Saoudi N, Cosio F, Waldo A, et al. Working Group of Arrhythmias of the European of Cardiology and the North American Society of Pacing and Electrophysiology. A classification of atrial flutter and regular atrial tachycardia according to electrophysiological mechanisms and anatomical bases; a Statement from a Joint Expert Group from The Working Group of Arrhythmias of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Eur Heart J 2001;22:1162–82. DOI: 10.1053/euhj.2001.2658; PMID: 11440490. 27. Coffey JO, d’Avila A, Dukkipati S, et al. Catheter ablation of scar-related atypical atrial flutter. Europace 2013;15:414–9. DOI: 10.1093/europace/eus312; PMID: 23385050. 28. Granada J, Uribe W, Chyou PH, et al. Incidence and predictors of atrial flutter in the general population. J Am Coll Cardiol 2000;36:2242–6. PMID: 11127467. 29. Lukac P, Pedersen AK, Mortensen PT, et al. Ablation of atrial tachycardia after surgery for congenital and acquired heart disease using an electroanatomic mapping system: Which circuits to expect in which substrate? Heart Rhythm 2005;2:64– 72. DOI: 10.1016/j.hrthm.2004.10.034; PMID: 15851267. 30. Chugh A, Oral H, Lemola K, et al. Prevalence, mechanisms, and clinical significance of macroreentrant atrial tachycardia during and following left atrial ablation for atrial fibrillation. Heart Rhythm 2005;2:464–71. DOI: 10.1016/j.hrthm.2005.01.027; PMID: 15840468. 31. Mandapati R, Walsh EP, Triedman JK. Pericaval and periannular intra-atrial reentrant tachycardias in patients with congenital heart disease. J Cardiovasc Electrophysiol 2003;14:119–25. PMID: 12693488. 32. Zrenner B, Dong JUN, Schreieck J, et al. Delineation of intra-atrial reentrant tachycardia circuits after mustard operation for transposition of the great arteries using biatrial electroanatomic mapping and entrainment mapping. J Cardiovasc Electrophysiol 2003;14:1302–10. PMID: 14678105. 33. Collins KK, Love BA, Walsh EP, et al. Location of acutely successful radiofrequency catheter ablation of intraatrial reentrant tachycardia in patients with congenital heart disease. Am J Cardiol 2000;86:969–74. PMID: 11053709. 34. Miyazaki S, Shah AJ, Hocini M, et al. Recurrent spontaneous clinical perimitral atrial tachycardia in the context of atrial fibrillation ablation. Heart Rhythm 2015;12:104–10. DOI: 10.1016/j.hrthm.2014.09.055; PMID: 25277987. 35. Aktas MK, Khan MN, Di Biase L, et al. Higher rate of recurrent atrial flutter and atrial fibrillation following atrial flutter ablation after cardiac surgery. J Cardiovasc Electrophysiol 2010;21:760–5. DOI: 10.1111/j.1540-8167.2009.01709.x; PMID: 20132385. 36. Bai R, Di Biase L, Mohanty P, et al. Ablation of perimitral flutter following catheter ablation of atrial fibrillation: impact on outcomes from a randomized study (PROPOSE). J Cardiovasc Electrophysiol 2012;23:137–44. DOI: 10.1111/j.15408167.2011.02182.x; PMID: 21955215. 37. Bai R, Fahmy TS, Patel D, et al. Radiofrequency ablation of atypical atrial flutter after cardiac surgery or atrial fibrillation ablation: a randomized comparison of open-irrigation-tip and 8-mm-tip catheters. Heart Rhythm 2007;4:1489–96. DOI: 10.1016/j.hrthm.2007.07.027; PMID: 17997363. 38. Matsuo S, Wright M, Knecht S, et al. Peri-mitral atrial flutter in patients with atrial fibrillation ablation. Heart Rhythm 2010;7:2– 8. DOI: 10.1016/j.hrthm.2009.09.067; PMID: 19962945. 39. Moore JP, Russell M, Mandapati R, et al. Catheter ablation of tachycardia arising from the pulmonary venous atrium after surgical repair of congenital heart disease. Heart Rhythm

2015;12:297–304. DOI: 10.1016/j.hrthm.2014.11.038; PMID: 25451886. 40. Jais P, Matsuo S, Knecht S, et al. A deductive mapping strategy for atrial tachycardia following atrial fibrillation ablation: importance of localized reentry. J Cardiovasc Electrophysiol 2009;20:480–91. DOI: 10.1111/j.1540-8167.2008.01373.x; PMID: 19207747. 41. Cosio FG, Arribas F, Lopez-Gil M, Palacios J. Atrial flutter mapping and ablation. I. Studying atrial flutter mechanisms by mapping and entrainment. Pacing Clin Electrophysiol 1996;19:841–53. PMID: 8734753. 42. Beckman KJ, Gallastegui JL, Bauman JL, Hariman RJ. The predictive value of electrophysiologic studies in untreated patients with Wolff-Parkinson-White syndrome. J Am Coll Cardiol 1990;15:640–7. PMID: 2303633. 43. Montoya PT, Brugada P, Smeets J, et al. Ventricular fibrillation in the Wolff-Parkinson-White syndrome. Eur Heart J 1991;12:144–50. PMID: 2044547. 44. Ammash NM, Phillips SD, Hodge DO, et al. Outcome of direct current cardioversion for atrial arrhythmias in adults with congenital heart disease. Int J Cardiol 2012;154:270–4. DOI: 10.1016/j.ijcard.2010.09.028; PMID: 20934227. 45. Wittwer MR, Rajendran S, Kealley J, Arstall MA. A South Australian registry of biphasic cardioversions of atrial arrhythmias: efficacy and predictors of success. Heart Lung Circ 2015;24:342–7. DOI: 10.1016/j.hlc.2014.10.004; PMID: 25465515. 46. Lin J-HI, Kean AC, Cordes TM. The risk of thromboembolic complications in Fontan patients with atrial flutter/ fibrillation treated with electrical cardioversion. Pediatr Cardiol 2016;37:1351–60. DOI: 10.1007/s00246-016-1441-4; PMID: 27421846. 47. Priori SG, Blomstrom-Lundqvist C, Mazzanti A, et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J 2015;36:2793–867. DOI: 10.1093/eurheartj/ehv316; PMID: 26320108. 48. Lim SH, Anantharaman V, Teo WS, et al. Comparison of treatment of supraventricular tachycardia by Valsalva maneuver and carotid sinus massage. Ann Emerg Med 1998;31:30–5. PMID: 9437338. 49. Smith GD, Fry MM, Taylor D, et al. Effectiveness of the Valsalva Manoeuvre for reversion of supraventricular tachycardia. Cochrane Database Syst Rev 2015;2:CD009502. DOI: 10.1002/14651858.CD009502.pub3; PMID: 25922864. 50. Wen ZC, Chen SA, Tai CT, et al. Electrophysiological mechanisms and determinants of vagal maneuvers for termination of paroxysmal supraventricular tachycardia. Circulation 1998;98:2716–23. PMID: 9851958. 51. Delaney B, Loy J, Kelly AM. The relative efficacy of adenosine versus verapamil for the treatment of stable paroxysmal supraventricular tachycardia in adults: a metaanalysis. Eur J Emerg Med 2011;18:148–52. DOI: 10.1097/ MEJ.0b013e3283400ba2; PMID: 20926952. 52. DiMarco JP, Miles W, Akhtar M, et al. Adenosine for paroxysmal supraventricular tachycardia: dose ranging and comparison with verapamil. Assessment in placebocontrolled, multicenter trials. The Adenosine for PSVT Study Group. Ann Intern Med 1990;113:104–10. PMID: 2193560. 53. Amsterdam EA, Kulcyski J, Ridgeway MG. Efficacy of cardioselective beta-adrenergic blockade with intravenously administered metoprolol in the treatment of supraventricular tachyarrhythmias. J Clin Pharmacol 1991;31:714–8. PMID: 1880230. 54. Das G, Tschida V, Gray R, et al. Efficacy of esmolol in the treatment and transfer of patients with supraventricular tachyarrhythmias to alternate oral antiarrhythmic agents. J Clin Pharmacol 1988;28:746–50. PMID: 2905710. 55. Crijns HJ, Lie KI. Haemodynamic deterioration after treatment with adenosine. Br Heart J 1995;73:103. PMID: 7888252. 56. Khairy P, Harris L, Landzberg MJ, et al. Sudden death and defibrillators in transposition of the great arteries with intraatrial baffles: a multicenter study. Circ Arrhythm Electrophysiol 2008;1:250–7. DOI: 10.1161/CIRCEP.108.776120; PMID: 19808416. 57. Koyak Z, Kroon B, de Groot JR, et al. Efficacy of antiarrhythmic drugs in adults with congenital heart disease and supraventricular tachycardias. Am J Cardiol 2013;112:1461–7. DOI: 10.1016/j.amjcard.2013.07.029; PMID: 23993125. 58. Fish FA, Gillette PC, Benson DW, Jr. Proarrhythmia, cardiac arrest and death in young patients receiving encainide and flecainide. The Pediatric Electrophysiology Group. J Am Coll Cardiol 1991;18:356–65. PMID: 1906902. 59. 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. DOI: 10.1002/14651858.CD005049.pub4; PMID: 25820938. 60. Opic P, Yap SC, Van Kranenburg M, et al. Atrial-based pacing has no benefit over ventricular pacing in preventing atrial arrhythmias in adults with congenital heart disease. Europace 2013;15:1757–62. DOI: 10.1093/europace/eut213; PMID: 23851513. 61. Correa R, Walsh EP, Alexander ME, et al. Transbaffle mapping and ablation for atrial tachycardias after mustard, senning, or Fontan operations. J Am Heart Assoc

2013;2:e000325. DOI: 10.1161/JAHA.113.000325; PMID: 24052498. 62. Moore JP, Shannon KM, Fish FA, et al. Catheter ablation of supraventricular tachyarrhythmia after extracardiac Fontan surgery. Heart Rhythm 2016;13:1891–7. DOI: 10.1016/ j.hrthm.2016.05.019; PMID: 27236028. 63. Ueda A, Suman-Horduna I, Mantziari L, et al. Contemporary outcomes of supraventricular tachycardia ablation in congenital heart disease: a single-center experience in 116 patients. Circ Arrhythm Electrophysiol 2013;6:606–13. DOI: 10.1161/CIRCEP.113.000415; PMID: 23685536. 64. Yap SC, Harris L, Silversides CK, et al. Outcome of intraatrial re-entrant tachycardia catheter ablation in adults with congenital heart disease: negative impact of age and complex atrial surgery. J Am Coll Cardiol 2010;56:1589–96. DOI: 10.1016/j.jacc.2010.04.061; PMID: 21029876. 65. Scaglione M, Caponi D, Ebrille E, et al. Very long-term results of electroanatomic-guided radiofrequency ablation of atrial arrhythmias in patients with surgically corrected atrial septal defect. Europace 2014;16:1800–7. DOI: 10.1093/europace/ euu076. PMID: 24843050. 66. Wu J, Deisenhofer I, Ammar S, et al. Acute and long-term outcome after catheter ablation of supraventricular tachycardia in patients after the Mustard or Senning operation for D-transposition of the great arteries. Europace 2013;15:886–91. DOI: 10.1093/europace/eus402; PMID: 23355133. 67. Yap SC, Harris L, Downar E, et al. Evolving electroanatomic substrate and intra-atrial reentrant tachycardia late after Fontan surgery. J Cardiovasc Electrophysiol 2012;23:339–45. DOI: 10.1111/j.1540-8167.2011.02202.x; PMID: 22035149. 68. Dallaglio PD, Anguera I, Jimenez-Candil J, et al. Impact of previous cardiac surgery on long-term outcome of cavotricuspid isthmus-dependent atrial flutter ablation. Europace 2016;18:873–80. DOI: 10.1093/europace/euv237; PMID: 26506836. 69. Mavroudis C, Deal BJ, Backer CL, Tsao S. Arrhythmia surgery in patients with and without congenital heart disease. Ann Thorac Surg 2008;86:857–68; discussion 857–68. DOI: 10.1016/j. athoracsur.2008.04.087; PMID: 18721574. 70. Mavroudis C, Deal BJ, Backer CL, et al. J. Maxwell Chamberlain Memorial Paper for congenital heart surgery. 111 Fontan conversions with arrhythmia surgery: surgical lessons and outcomes. Ann Thorac Surg 2007;84:1457–65; discussion 1465–6. DOI: 10.1016/j.athoracsur.2007.06.079; PMID: 17954046. 71. Attie F, Rosas M, Granados N, et al. Surgical treatment for secundum atrial septal defects in patients >40 years old. A randomized clinical trial. J Am Coll Cardiol 2001;38:2035–42. PMID: 11738312. 72. Konstantinides S, Geibel A, Olschewski M, et al. A comparison of surgical and medical therapy for atrial septal defect in adults. N Engl J Med 1995;333:469–73. DOI: 10.1056/ NEJM199508243330801; PMID: 7623878. 73. Murphy JG, Gersh BJ, McGoon MD, et al. Long-term outcome after surgical repair of isolated atrial septal defect. Follow-up at 27 to 32 years. N Engl J Med 1990;323:1645–50. DOI: 10.1056/ NEJM199012133232401; PMID: 2233961. 74. Kutty S, Hazeem AA, Brown K, et al. Long-term (5- to 20-year) outcomes after transcatheter or surgical treatment of hemodynamically significant isolated secundum atrial septal defect. Am J Cardiol 2012;109:1348–52. DOI: 10.1016/j. amjcard.2011.12.031; PMID: 22335856. 75. Vecht JA, Saso S, Rao C, Dimopoulos K, et al. Atrial septal defect closure is associated with a reduced prevalence of atrial tachyarrhythmia in the short to medium term: a systematic review and meta-analysis. Heart 2010;96:1789–97. DOI: 10.1136/hrt.2010.204933; PMID: 20965992. 76. Wei W, Zhan X, Xue Y, et al. Features of accessory pathways in adult Ebstein’s anomaly. Europace 2014;16:1619–25. DOI: 10.1093/europace/euu028; PMID: 24614573. 77. Roten L, Lukac P, De Groot N, et al. Catheter ablation of arrhythmias in Ebstein’s anomaly: a multicenter study. J Cardiovasc Electrophysiol 2011;22:1391–6. DOI: 10.1111/j .1540-8167.2011.02161.x; PMID: 21914017. 78. Bockeria L, Golukhova E, Dadasheva M, et al. Advantages and disadvantages of one-stage and two-stage surgery for arrhythmias and Ebstein’s anomaly. Eur J Cardiothorac Surg 2005;28:536–40. DOI: 10.1016/j.ejcts.2005.04.047; PMID: 16179193. 79. Shivapour JK, Sherwin ED, Alexander ME, et al. Utility of preoperative electrophysiologic studies in patients with Ebstein’s anomaly undergoing the Cone procedure. Heart Rhythm 2014;11:182–6. DOI: 10.1016/j.hrthm.2013.10.045; PMID: 24513916. 80. Huang CJ, Chiu IS, Lin FY, et al. Role of electrophysiological studies and arrhythmia intervention in repairing Ebstein’s anomaly. Thorac Cardiovasc Surg 2000;48:347–50. DOI: 10.1055/s2000-8348; PMID: 11145402. 81. Cappato R, Schluter M, Weiss C, et al. Radiofrequency current catheter ablation of accessory atrioventricular pathways in Ebstein’s anomaly. Circulation 1996;94:376–83. PMID: 8759079. 82. Reich JD, Auld D, Hulse E, et al. The Pediatric Radiofrequency Ablation Registry’s experience with Ebstein’s anomaly. Pediatric Electrophysiology Society. J Cardiovasc Electrophysiol 1998;9:1370–7. PMID: 9869537. 83. Gatzoulis MA, Balaji S, Webber SA, et al. Risk factors for arrhythmia and sudden cardiac death late after repair of tetralogy of Fallot: a multicentre study. Lancet 2000;356:975–81. DOI: 10.1016/S0140-6736(00)02714-8; PMID: 11041398.

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Supraventricular Arrhythmias in Adult Congenital Heart Disease

84. Biviano A, Garan H, Hickey K, et al. Atrial flutter catheter ablation in adult patients with repaired tetralogy of Fallot: mechanisms and outcomes of percutaneous catheter ablation in a consecutive series. J Interv Card Electrophysiol 2010;28:125–35. DOI: 10.1007/s10840-010-9477-5; PMID: 20390332. 85. Wu MH, Lu CW, Chen HC, et al. Arrhythmic burdens in patients with tetralogy of Fallot: a national database study. Heart Rhythm 2015;12:604–9. DOI: 10.1016/j.hrthm.2014.11.026; PMID: 25461497. 86. Harrison DA, Harris L, Siu SC, et al. Sustained ventricular tachycardia in adult patients late after repair of tetralogy of

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Fallot. J Am Coll Cardiol 1997;30:1368–73. PMID: 9350941. 87. Miyazaki A, Sakaguchi H, Ohuchi H, et al. Efficacy of hemodynamic-based management of tachyarrhythmia after repair of tetralogy of Fallot. Circ J 2012;76:2855–62. PMID: 22893279. 88. de Groot NM, Lukac P, Schalij MJ, et al. Long-term outcome of ablative therapy of post-operative atrial tachyarrhythmias in patients with tetralogy of Fallot: a European multi-centre study. Europace 2012;14:522–7. DOI: 10.1093/europace/eur313; PMID: 21971346. 89. Quinton E, Nightingale P, Hudsmith L, et al. Prevalence of

atrial tachyarrhythmia in adults after Fontan operation. Heart 2015;101:1672–7. DOI: 10.1136/heartjnl-2015-307514; PMID: 26289423. 90. Deal BJ, Mavroudis C, Backer CL, et al. Comparison of anatomic isthmus block with the modified right atrial maze procedure for late atrial tachycardia in Fontan patients. Circulation 2002;106:575–9. PMID: 12147539. 91. Said SM, Burkhart HM, Schaff HV, et al. Fontan conversion: identifying the high-risk patient. Ann Thorac Surg 2014;97:2115–21; discussion 2121–2. DOI: 10.1016/j. athoracsur.2014.01.083; PMID: 24786860.

Clinical Arrhythmias

Practical Implementation of Anticoagulation Strategy for Patients Undergoing Cardioversion of Atrial Fibrillation Andreas Goette 1 and Hein Heidbuchel 2 1. St Vincenz Hospital Paderborn, Paderborn, Germany; 2. Antwerp University Hospital, University of Antwerp, Antwerp, Belgium

Abstract Anticoagulation is routinely prescribed to patients with persistent AF before cardioversion to reduce the risk of thromboembolic events. As direct oral anticoagulants (DOACs) have a rapid onset of action, a consistent anticoagulant effect, if taken correctly, and do not need monitoring or dose adjustments, there is considerable interest in their use for patients with AF undergoing cardioversion. Post-hoc analyses show that DOACs are safe to use prior to and following cardioversion. In addition, two randomised controlled trials, X-VeRT and ENSURE-AF, have demonstrated the efficacy and safety of the DOACs rivaroxaban and edoxaban, respectively, in this setting. The use of DOACs allows cardioversions to be performed promptly and reduces the number of cancelled procedures compared with the use of warfarin.

Keywords Atrial fibrillation, cardioversion, anticoagulation, direct oral anticoagulants Acknowledgement: Medical Media Communications (Scientific) Ltd provided medical writing and editing support to the authors, funded by Daiichi Sankyo. Disclosure: Professor Goette has received speaker fees from Astra Zeneca, Berlin Chemie, Boehringer Ingelheim, Bayer Healthcare, BMS / Pfizer and Daiichi-Sankyo. Professor Heidbuchel is coordinating clinical investigator for the Biotronik-sponsored EuroEco study on health-economics of remote device monitoring, has been a member of the scientific advisory boards and/or lecturer for Boehringer-Ingelheim, Bayer, Bristol-Myers Squibb, Pfizer, Daiichi-Sankyo and Cardiome, received travel support from St. Jude Medical, and received unconditional research grants through the University of Hasselt from Bayer and through the University of Antwerp from Medtronic, Boston Scientific and Bracco Imaging Europe. Submitted: 6 February 2017 Accepted: 12 May 2017 Citation: Arrhythmia & Electrophysiology Review 2017;6(2):50–4. DOI: 10.15420/aer.2017:3:2 Correspondence: Professor H Heidbuchel, University Hospital and University of Antwerp, Antwerp, Belgium. E: heinheid@gmail.com

AF is the most common sustained cardiac arrhythmia and poses a significant public health challenge.1 In cases of AF, if sinus rhythm does not spontaneously return, cardioversion may be needed to alleviate symptoms and to improve cardiac performance.2 This may be performed by pharmacological methods, i.e. the administration of antiarrhythmic drugs, which is the preferred strategy in recent-onset AF, or by direct current electrical cardioversion, which is preferred in prolonged AF.2 The latter is more effective than pharmacological cardioversion, especially in persistent AF, although it requires anaesthesia and well-trained staff.2 A recent European survey found that the use of cardioversion in patients with AF is increasing.3 However, cardioversion itself carries an inherent risk of thromboembolic complications in AF, 4 due to the possible embolisation of pre-existing thrombus from the atrial appendage. 5 In this setting, the process of thrombogenic endocardial remodelling appears to be of importance. In addition, the process of cardioversion may promote new thrombus formation due to transient atrial dysfunction (‘stunning’), which is related to the duration of AF rather than the mode of cardioversion. 6,7 In particular, comorbidities such as heart failure, hypertension or ageing induce a thrombogenic endocardial remodelling that persists even after restoration of sinus rhythm (see Figure 1).8 This increased risk has led to recommendations for the use of anticoagulation before and after cardioversion. Without adequate anticoagulation, the risk of thromboembolism associated with cardioversion is 5–7 %.9 The use of prophylactic anticoagulation can reduce this risk to <1 %.10–12 Historically, the standard therapy for AF has been warfarin, but in recent years,

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the direct oral anticoagulants (DOACs) apixaban, dabigatran, edoxaban and rivaroxaban have been approved for the prevention of stroke in patients with AF, after demonstrating non-inferiority to warfarin in clinical trials.13–16 Furthermore, clinical data indicate that patients receiving DOAC therapy as an alternative to warfarin can be safely cardioverted.17–19 In this article we aim to discuss the guidelines for the use of anticoagulation in cardioversion and review the clinical evidence in favour of the use of DOACs in this indication.

Guidelines and Recommendations on the Use of Anticoagulants in Cardioversion For patients undergoing cardioversion it is important to consider duration of AF and prior anticoagulation.20 The 2016 European Society of Cardiology (ESC) guidelines on cardioversion state that patients who have been in AF for longer than 48 hours should start OAC therapy at least 3 weeks before cardioversion and continue for 4 weeks afterwards (in those without a need for long-term anticoagulation). If transoesophageal echocardiography (TOE) is available and acceptable to the patient, it may be used to exclude the majority of left atrial thrombi (which would preclude the procedure), allowing immediate cardioversion shortly after the start of anticoagulation, but without precluding the need for ≥4 weeks treatment afterwards. OAC therapy should be continued indefinitely in patients at increased risk of stroke. When cardioverting AF of ≤48 hours in an anticoagulation-näive patient, the guidelines do not formally advise pre-treatment with OAC and/or TOE, but advise clinicians to follow institutional practice of administering heparin or low molecular weight heparin (LMWH) with/ without TOE before cardioversion.

Anticoagulation Strategy in Atrial Fibrillation Cardioversion However, a large observational study has suggested that even for patients with an AF lasting ≤48 hours, there may be a durationdependent risk for thromboembolism.21 Current guidelines recommend deferral of cardioversion and vitamin K antagonist (VKA) therapy for 3 weeks following detection of a left atrial or left atrial appendage thrombus in patients with AF despite long-term anticoagulant treatment. The use of TOE before cardioversion is controversial: while some data exist to support its use,22,23 it has been argued that current evidence is insufficient to justify its cost. In addition, TOE may fail to detect small thrombi, TOE examination is labour intensive, and small medical centres may lack the necessary expertise to detect thrombi.24,25 The European Heart Rhythm Association Practical Guide makes the following recommendations about the use of DOACs in cardioversion (see Figure 2). First, when cardioverting a patient with AF being treated for ≥3 weeks with DOACs, it is important to ask about adherence. If in doubt, TOE should be performed prior to cardioversion. When cardioverting AF of >48 hours in a patient not on DOACs, a strategy with at least a single DOAC dose ≥4 hours before cardioversion is safe and effective, provided that a TOE is performed prior to cardioversion. The alternative is at least 3 weeks of well-adherent DOAC therapy before scheduled cardioversion. The same scenario applies when the exact duration of AF cannot be established with certainty, which is often the case. When cardioverting AF that definitely lasts ≤48 hours in an anticoagulation-näive patient, adherence to institutional practice with heparin/LMWH with/without TOE is advised. Most institutions will opt to administer any anticoagulation with LMWH or unfractionated heparin before cardioversion in most of these patients. Given the increasing evidence from prospective trials such as X-VERT (Explore the Efficacy and Safety of Once-daily Oral Rivaroxaban for the Prevention of Cardiovascular Events in Subjects With Nonvalvular Atrial Fibrillation Scheduled for Cardioversion; NCT01674647) and ENSURE-AF (Edoxaban vs Warfarin in Subjects Undergoing Cardioversion of Atrial Fibrillation; NCT02072434), substitution of the pre-cardioversion administration of LMWH by DOAC seems defendable. 26

Patients with documented left atrial appendage thrombus should not undergo cardioversion. Rigorously followed-up international normalised ratio (INR) monitoring under VKA therapy until resolution of the thrombus is recommended (with heparin bridging if necessary), as long as trial data have not confirmed an equally effective and safe course with DOACs in this scenario. In addition, patients must be educated about the importance of treatment adherence and persistence, as missing DOAC doses leads to suboptimal anticoagulation and an increased risk of thromboembolic events. In February 2017, the American Heart Association released a scientific statement regarding the management of patients taking DOACs in the acute care and periprocedural setting.27 The recommendations for patients undergoing cardioversion were similar to the European guidelines. Patients should be anticoagulated for ≥3 weeks before elective cardioversion. If not, then a TOE should be performed to exclude the presence of left atrial appendage or left atrial thrombus. If a patient’s adherence to therapy is suboptimal (at least two missed doses) or in question, then a TOE should be considered. If a patient is found to have left atrial appendage or left atrial thrombus, then an alternate anticoagulant should be considered, with special attention to consistent anticoagulant use during the transition.27

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Figure 1: The Concept of ‘Endocardial Remodelling’ in Fibrillating Atria

Selectin

PAI-1

vWF

ICAM

VCAM

MCP-1

Atrial endothelium Atrial myocardium

Oxidases NF-kB CHA2DS2VASc parameters

Natriuretic peptides Oxidases NF-kB ROS ROS

Nitric oxide Angiotensin II Troponin

Proteases Phosphatases

Endothelin-1

In accordance to Virchow’s triad hypercoagulability, flow abnormalities, and endothelial changes must co-exist to induce thrombogenesis at the atrial endocardium. Molecular studies have revealed substantial endocardial changes in left atrial tissue samples. Prothrombogenic factors (vWF, adhesion molecules like VCAM-1, P-selectin, etc.; green) are expressed at the surface of endothelial cells causing an increased adhesiveness of platelets and leucocytes to the atrial endocardium. This initiates atrial thrombogenesis at the atrial endocardium. Several clinical factors like diabetes mellitus, heart failure ageing etc. (CHA2DS2VASc parameters) increase molecular alterations (oxidative stress pathways etc.) within myocytes and endothelial cells, and thereby increase the expression of prothrombogenic factors. These alterations are not directly related to the presence or absence of atrial fibrillation in the surface ECG, and therefore, help to explain why thrombogenesis is increased even during episodes of sinus rhythm. ICAM = intercellular adhesion molecule; MCP-1= monocyte chemoattractant protein-1; NF-κB = nuclear factor κB; PAI-1 = plasminogen activator inhibitor-1; ROS, reactive oxygen species; VCAM = vascular cell adhesion molecule; vWF = Von Willebrand factor. Source: Goette, et al., 2016.36

Practical Problems Associated with Warfarin Anticoagulation Limitations associated with the use of warfarin are well documented and include inter- and intra-individual variations in INR values, drug–drug interactions and the requirement for frequent INR testing. The use of warfarin can also delay cardioversion due to the timeconsuming nature of warfarin initiation and difficulties in achieving a target INR between 2 and 3 before cardioversion, and maintaining it stably within that range.25 A retrospective study of 288 consecutive patients with AF scheduled for elective cardioversion found that the median treatment duration prior to cardioversion with warfarin was 12 weeks, exceeding by far the recommended 3 weeks.28 Because warfarin takes several days to have a therapeutic effect, patients presenting with acute AF are typically treated with intravenous heparin or subcutaneous LMWH while they are awaiting stable INR values and cardioversion. In a recent study of 346 patients taking VKA prior to elective cardioversion, 55.2 % had a subtherapeutic INR prior to cardioversion.29 These data highlight the need for better anticoagulation options in patients requiring cardioversion.

Use of Direct Oral Anticoagulants in Patients Undergoing Cardioversion The pharmacological characteristics of the DOACs make them well suited to use in the setting of cardioversion. Their rapid onset of action (2–4 hours), short half-life and predictable pharmacokinetics and pharmacodynamics offer the potential benefit of their initiation in the outpatient setting and can potentially reduce the rate of hospitalisation and associated costs. Post-hoc analyses of data from the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY; 1,983 cardioversions in 1,270 patients),17 Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation (ARISTOTLE; 743 cardioversions in 540 patients),18 Rivaroxaban Once Daily

Clinical Arrhythmias Figure 2: Cardioversion Flowchart in Patients with AF Treated with Direct Oral Anticoagulants Need for cardioversion (electrical or medical)

Patient not anticoagulated

Patient on DOAC for 3 w

- Inquire patient about adherence to DOAC intake. - Make note about patient answer in the chart. AF 48 h

Deemed well-adherent

Doubt about adherence or deemed high-risk for left atrial thrombus:

Insufficient data on safe substitution of LMWH/UFH by DOAC

- Perform TOE Stick to existing institutional practice, i.e. - LMWH and/or UFH - With/without TOE

AF 48 h

Goal = early CV

Goal = late CV

- Start DOAC 4 h before CV - Perform TOE before CV (until more data from ongoing trials)

- Treat with DOAC for 3 w and ensure adherence

See “Patient on DOAC for 3 w”

If TOE detects atrial thrombus: postpone CV after longer period of anticoagulation, with repeat TOE (No data on best strategy: converting to (heparin +) VKA OR continuation of DOAC (trials ongoing))

Cardiovert

Continue DOAC for at least 4 weeks (longer based on CHA2DS2-VASc) DOAC = direct oral anticoagulant; LMWH = low molecular weight heparin; TOE = transoesophageal echocardiography; UFH = unfractionated heparins Adapted from Heidbuchel et al., 2015.26

Oral Direct Factor Xa Inhibitor Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKETAF; 460 cardioversions in 321 patients)30 and Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48; 632 cardioversions in 365 patients)31 trials have shown that thromboembolic and major bleeding events following cardioversion were infrequent and their incidence was not statistically different to those seen with VKAs when the precardioversion anticoagulation time period is long (i.e. patients on a chronic maintenance dose of anticoagulation). However, these were post-hoc, nonrandomised observations. The safety of dabigatran in patients undergoing electrical cardioversion has also been demonstrated in two other retrospective studies. The first (n=525) showed that the average time for treatment before cardioversion was significantly lower for dabigatran (25 days) versus warfarin (35 days; p<0.01).32 The second study comprised 631 patients, including 570 who were näive to OAC therapy when dabigatran was initiated and a warfarin control group (n=166). The median time from initiation of dabigatran to first cardioversion was 32 days versus 74 days with warfarin. In addition, treatment for 1 month with dabigatran before cardioversion was associated with a low incidence of thromboembolism (0.53 % over 30-day follow-up), even in anticoagulant-näive patients.33 The use of DOACs for cardioversion appears to be cost effective and increases the efficiency of cardioversion services. A retrospective

study examined the impact of dabigatran, as an alternative to warfarin, on the efficiency of an outpatient electrical cardioversion service.34 A total of 242 procedures performed on 193 patients over a 36-month period were analysed. Patients who received dabigatran had significantly lower rates of rescheduling compared with those who received warfarin (9.7 % versus 34.4 %; p<0.001). The length of time between initial assessment and cardioversion was 22 days shorter for those who took dabigatran than warfarin (p=0.0015).34 A recent meta-analysis of the RE-LY, ROCKET-AF, ARISTOTLE, ENGAGE AF-TIMI 48, and X-VeRT trials concluded that the short-term incidences of thromboembolic and major haemorrhagic events after cardioversion were low with DOACs and similar to those observed on dose-adjusted VKA therapy.35

Prospective Trials Investigating Direct Oral Coagulants in Patients Undergoing Cardioversion In the X-VeRT study, a prospective, randomised controlled trial in patients with AF undergoing elective cardioversion, rivaroxaban was compared with VKAs.19 Patients were randomised to a once-daily dose of rivaroxaban 20 mg orally (15 mg once daily in patients with creatinine clearance of 30–49 mL/min) or warfarin/another VKA at the investigator’s discretion. The target INR was 2.5 (range 2.0–3.0). Investigators had the option to use a parenteral anticoagulant drug in addition to VKA therapy, especially prior to cardioversion, until the target INR was obtained. In the early cardioversion strategy group, rivaroxaban or a VKA was given 1–5 days before intended

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Anticoagulation Strategy in Atrial Fibrillation Cardioversion cardioversion and continued for 6 weeks following cardioversion. In the delayed cardioversion strategy group, patients were given either a VKA or rivaroxaban for ≥3 weeks and ≤8 weeks before cardioversion. The primary efficacy outcome was a composite of stroke, transient ischaemic attack, peripheral embolism, MI and cardiovascular death. The primary safety outcome was major bleeding. Note that the trial was not powered to show significance on ischaemic or bleeding endpoints as this would have required the enrolment of around 30,000 patients. The incidence of both endpoints was comparable between rivaroxaban and VKA groups, with a numerical trend for lower ischaemic and bleeding outcomes in the rivaroxaban-treated patients. In addition, rivaroxaban was associated with a significantly shorter time to cardioversion compared with VKAs. Of the entire cohort, 77.6 % underwent cardioversion after anticoagulation within the target time range, primarily due to failure to achieve adequate anticoagulation (rivaroxaban: 1 patient, VKA: 95 patients). Among patients assigned to delayed cardioversion, 77 % of those in the rivaroxaban group and 36 % of those who received VKA underwent cardioversion within the target time range (p<0.001).19 It should be noted, however, that in this study almost 60 % of the patients with rivaroxaban treatment underwent TOE and patients with left atrial thrombus were excluded.

enoxaparin–warfarin over 2 months of follow-up (0.3 % versus 0.5 %, respectively; OR: 0.61; 95 % CI [0.09–0.13]). No intracranial bleedings were reported in the study in either of the treatment groups. No fatal bleeding was reported in the edoxaban group versus one patient in the enoxaparin–warfarin group. The results were independent of whether cardioversion was guided by TOE, which occurred in about half of patients in each of the edoxaban and enoxaparin groups.36 Unlike the X-VeRT trial, the enoxaparin lead-in resulted in better VKA treatment, allowing more patients in the VKA arm to achieve the required INR and undergo cardioversion. However, due to the low incidence of ischaemic events during cardioversion, ENSURE AF and X-VeRT trials were not statistically powered to demonstrate significance. A third prospective cardioversion trial, EMANATE (apixaban, NCT02100228) will soon report on the use of DOACs in AF patients.

The largest prospective clinical trial on cardioversion of persistent AF so far, the ENSURE-AF trial compared the use of edoxaban with enoxaparin–warfarin in patients undergoing electrical cardioversion.36

Other prospective randomised clinical trials are underway in patients scheduled for cardioversion, but in whom the TOE finding of left atrial appendage thrombus precludes cardioversion: RE-LATED-AF (dabigatran, NCT02256683) and X-TRA (rivaroxaban, NCT01839357). In the X-TRA study, resolved or reduced thrombus (as assessed centrally by blinded, independent adjudicators) was evident in 60.4 % of the modified intention-to-treat patient population, including two patients with two thrombi resolved in each case, demonstrating the potential of rivaroxaban in this setting.37

Patients (n=2,199) were stratified according to cardioversion approach (TOE or non-TOE) and randomly assigned to receive edoxaban (n=1,095) or enoxaparin-warfarin (n=1,104).

Practical Advantages Offered by Direct Oral Anticoagulants in Cardioversion

By contrast to the X-VeRT trial, the optimised strategy of enoxaparin bridging was selected for the comparator arm to reduce time to achieve the INR and to cover transient suboptimal anticoagulation periods with warfarin alone.36 In the TOE stratum, the cardioversion procedure had to be performed within a maximum of 3 days from randomisation. Patients in the enoxaparin–warfarin group with INR <2.0 received a minimum of one dose each of enoxaparin and warfarin before cardioversion, and these drugs were continued until INR >2.0 was obtained. Measurements were made once every 2–3 days until the therapeutic range was achieved. After achieving therapeutic range, patients discontinued enoxaparin and continue warfarin until end of treatment (day 28 after the procedure). Patients in the enoxaparin–warfarin group with INR >2 at the time of randomisation were treated with warfarin alone. The dose was adjusted to achieve and maintain the therapeutic INR of 2–3. Subsequently, patients attended planned study visits, but were given ad-hoc INR checks if considered necessary by the investigator. Patients in the edoxaban group had to start treatment at least 2 hours before cardioversion. The next dose of edoxaban was taken the day after cardioversion and then continued daily until day 28 post-cardioversion. The primary efficacy endpoint in ENSURE-AF was the composite of stroke, systemic embolic event, MI and cardiovascular mortality, and showed a similar incidence for edoxaban and enoxaparin–warfarin (0.5 % versus 1.0 %, respectively; odds ratio [OR], 0.46; 95 % CI [0.12–1.43]). The main difference between the treatment groups was in cardiovascular mortality, with one event in the edoxaban group and five events in the enoxaparin–warfarin group (0.1 % versus 0.5 %, respectively). Rates of major bleeding were low for patients receiving edoxaban and comparable with those randomised to

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

The rapid onset of action of DOACs offers the potential benefit of their initiation in the outpatient setting and can potentially reduce the rate of hospitalisation and associated costs. Based on the results of the ENSURE-AF study, a newly diagnosed and non-anticoagulated patient with AF could be started on edoxaban and the cardioversion procedure scheduled as early as 2 hours after the start of treatment with a TOE-guided approach, or elective cardioversion could be performed 3 weeks later without TOE, eliminating the risk to reschedule the cardioversion due to inadequate INR.36 The use of DOACs assures that cardioversions can occur at the planned time, which is advantageous as it prevents rescheduling. An important element to stress to the patient, however, is the need for perfect adherence to medication intake (once daily in the case of edoxaban).

Conclusion With the increased use of DOACs in routine clinical practice, several practical issues have emerged, including considerations for cardioversion. Cardioversion restores sinus rhythm in AF and can improve cardiac symptoms, but is associated with increased thromboembolic risks. While warfarin can decrease these risks, its use is associated with delayed procedures due to its slow onset of action. By contrast, DOACs act rapidly, have a short half-life and predictable pharmacokinetics. Two randomised clinical studies, X-VERT and ENSURE-AF, have demonstrated the efficacy and safety of rivaroxaban and edoxaban, respectively, in this setting. Compared with warfarin or other VKAs, both have been found to reduce the time between administration and cardioversion and may facilitate more predictability in planning cardioversions. Results from ongoing and future studies will add further data to inform optimal use of these agents. n

Clinical Arrhythmias 1.

amm AJ, Lip GY, De Caterina R, et al. 2012 focused update of C the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012;33:2719–47. DOI: 10.1093/eurheartj/ehs253; PMID: 22922413. 2. Sulke N, Sayers F, Lip GY, et al. Rhythm control and cardioversion. Heart 2007;93:29–34. DOI: 10.1136/ hrt.2006.099879; PMID: 16963490. 3. Hernandez-Madrid A, Svendsen JH, Lip GY, et al. Cardioversion for atrial fibrillation in current European practice: results of the European Heart Rhythm Association survey. Europace 2013;15:915–8. DOI: 10.1093/europace/eut143; PMID: 23709570. 4. Airaksinen KE, Gronberg T, Nuotio I, et al. Thromboembolic complications after cardioversion of acute atrial fibrillation: the FinCV (Finnish CardioVersion) study. J Am Coll Cardiol 2013;62:1187–92. DOI: 10.1016/j.jacc.2013.04.089; PMID: 23850908. 5. Lip GY. Cardioversion of atrial fibrillation. Postgrad Med J 1995;71:457–65. PMID: 7567751. 6. Fatkin D, Kuchar DL, Thorburn CW, et al. Transesophageal echocardiography before and during direct current cardioversion of atrial fibrillation: evidence for “atrial stunning” as a mechanism of thromboembolic complications. J Am Coll Cardiol 1994;23:307–16. PMID: 8294679. 7. Schotten U, Verheule S, Kirchhof P, et al. Pathophysiological mechanisms of atrial fibrillation: a translational appraisal. Physiol Rev 2011;91:265–325. DOI: 10.1152/physrev.00031. 2009; PMID: 21248168. 8. Goette A, Kalman JM, Aguinaga L, et al. EHRA/HRS/APHRS/ SOLAECE expert consensus on atrial cardiomyopathies: definition, characterization, and clinical implication. Europace 2016;18:1455–90. DOI: 10.1093/europace/euw161; PMID: 27402624. 9. Stellbrink C, Nixdorff U, Hofmann T, et al. Safety and efficacy of enoxaparin compared with unfractionated heparin and oral anticoagulants for prevention of thromboembolic complications in cardioversion of nonvalvular atrial fibrillation: the Anticoagulation in Cardioversion using Enoxaparin (ACE) trial. Circulation 2004;109:997–1003. DOI: 10.1161/01.CIR.0000120509.64740.DC; PMID: 14967716. 10. Arnold AZ, Mick MJ, Mazurek RP, et al. Role of prophylactic anticoagulation for direct current cardioversion in patients with atrial fibrillation or atrial flutter. J Am Coll Cardiol 1992; 19:851–5. PMID: 1545081. 11. Saeed M, Rahman A, Afzal A, et al. Role of transesophageal echocardiography guided cardioversion in patients with atrial fibrillation, previous left atrial thrombus and effective anticoagulation. Int J Cardiol 2006;113:401–5. DOI: 10.1016/ j.ijcard.2006.03.036; PMID: 16822564. 12. Apostolakis S, Haeusler KG, Oeff M, et al. Low stroke risk after elective cardioversion of atrial fibrillation: an analysis

of the Flec-SL trial. Int J Cardiol 2013;168:3977–81. DOI: 10.1016/j.ijcard.2013.06.090; PMID: 23871349. 13. C onnolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51. DOI: 10.1056/NEJMoa0905561; PMID: 19717844. 14. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–92. DOI: 10.1056/NEJMoa1107039; PMID: 21870978. 15. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365:883–91. DOI: 10.1056/NEJMoa1009638; PMID: 21830957. 16. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093–104. DOI: 10.1056/NEJMoa1310907; PMID: 24251359. 17. Nagarakanti R, Ezekowitz MD, Oldgren J, et al. Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients undergoing cardioversion. Circulation 2011;123:131–6. DOI: 10.1161/CIRCULATIONAHA.110.977546; PMID: 21200007. 18. Flaker G, Lopes RD, Al-Khatib SM, et al. Efficacy and safety of apixaban in patients after cardioversion for atrial fibrillation: insights from the ARISTOTLE Trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation). J Am Coll Cardiol 2014;63:1082–7. DOI: 10.1016/ j.jacc.2013.09.062; PMID: 24211508. 19. Cappato R, Ezekowitz MD, Klein AL, et al. Rivaroxaban vs. vitamin K antagonists for cardioversion in atrial fibrillation. Eur Heart J 2014;35:3346–55. DOI: 10.1093/eurheartj/ehu367; PMID: 25182247. 20. 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. DOI: 10.1093/eurheartj/ehw210; PMID: 27567408. 21. Nuotio I, Hartikainen JE, Gronberg T, et al. Time to cardioversion for acute atrial fibrillation and thromboembolic complications. JAMA 2014;312:647–9. DOI: 10.1001/jama. 2014.3824; PMID: 25117135. 22. Maltagliati A, Galli CA, Tamborini G, et al. Usefulness of transoesophageal echocardiography before cardioversion in patients with atrial fibrillation and different anticoagulant regimens. Heart 2006;92:933–8. DOI: 10.1136/hrt.2005.071860; PMID: 16284221. 23. Klein AL, Grimm RA, Murray RD, et al. Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation. N Engl J Med 2001;344:1411–20. DOI: 10.1056/ NEJM200105103441901; PMID: 11346805. 24. Klein AL, Murray RD, Grimm RA. Transesophageal echocardiography-guided cardioversion: going for broke? Ann Intern Med 1997;127:652–3. PMID: 9341067. 25. Silverman DI, Manning WJ. Role of echocardiography in patients undergoing elective cardioversion of atrial fibrillation. Circulation 1998;98:479–86. PMID: 9714099.

26. H eidbuchel H, Verhamme P, Alings M, et al. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace 2015;17:1467–507. DOI: 10.1093/europace/euv309; PMID: 26324838. 27. Raval AN, Cigarroa JE, Chung MK, et al. Management of patients on non-vitamin k antagonist oral anticoagulants in the acute care and periprocedural setting: a scientific statement from the American Heart Association. Circulation 2017;135:e604–e33. DOI: 10.1161/CIR.0000000000000477; PMID: 28167634. 28. Ryman J, Frick M, Frykman V, et al. Duration of warfarin sodium therapy prior to electrical cardioversion of atrial fibrillation. J Intern Med 2003;253:76–80. PMID: 12588539. 29. Erkuner O, Claessen R, Pisters R, et al. Poor anticoagulation relates to extended access times for cardioversion and is associated with long-term major cardiac and cerebrovascular events. Int J Cardiol 2016;225:337–41. DOI: 10.1016/j.ijcard. 2016.10.018; PMID: 27756038. 30. Piccini JP, Stevens SR, Lokhnygina Y, et al. Outcomes after cardioversion and atrial fibrillation ablation in patients treated with rivaroxaban and warfarin in the ROCKET AF trial. J Am Coll Cardiol 2013;61:1998–2006. DOI: 10.1016/j.jacc.2013.02.025; PMID: 23500298. 31. Plitt A, Ezekowitz MD, De Caterina R, et al. Cardioversion of atrial fibrillation in ENGAGE AF-TIMI 48. Clin Cardiol 2016;39:345–6. DOI: 10.1002/clc.22537; PMID: 27028520. 32. Kalejs O, Sakne S, Litunenko O, et al. Safety and efficacy of dabigatran versus warfarin in patients with persistent and long-acting atrial fibrillation undergoing electrical cardioversion. J Am Coll Cardiol 2014;63(12S). DOI: 10.1016/ S0735-1097(14)60328-4. 33. Johansson AK, Juhlin T, Engdahl J, et al. Is one month treatment with dabigatran before cardioversion of atrial fibrillation sufficient to prevent thromboembolism? Europace 2015;17:1514–7. DOI: 10.1093/europace/euv123; PMID: 26017466. 34. Choo MK, Fraser S, Padfiend G, et al. Dabigatran improves the efficiency of an elective direct current cardioversion service. Br J Cardiol 2014;21:29–32. DOI: 10.5837/bjc.2014.002. 35. Renda G, Zimarino M, Ricci F, et al. Efficacy and safety of nonvitamin K antagonist oral anticoagulants after cardioversion for nonvalvular atrial fibrillation. Am J Med 2016;129:1117–1123. e2. DOI: 10.1016/j.amjmed.2016.05.007; PMID: 27262782. 36. Goette A, Merino JL, Ezekowitz MD, et al. Edoxaban versus enoxaparin-warfarin in patients undergoing cardioversion of atrial fibrillation (ENSURE-AF): a randomised, open-label, phase 3b trial. Lancet 2016;388:1995–2003. DOI: 10.1016/ S0140-6736(16)31474-X; PMID: 27590218. 37. Lip GY, Hammerstingl C, Marin F, et al. Left atrial thrombus resolution in atrial fibrillation or flutter: Results of a prospective study with rivaroxaban (X-TRA) and a retrospective observational registry providing baseline data (CLOT-AF). Am Heart J 2016;178:126–34. DOI: 10.1016/ j.ahj.2016.05.007; PMID: 27502860.

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Clinical Arrhythmias

Atrial Flutter, Typical and Atypical: A Review Francisco G Cosío Getafe University Hospital, European University of Madrid, Madrid, Spain

Abstract Clinical electrophysiology has made the traditional classification of rapid atrial rhythms into flutter and tachycardia of little clinical use. Electrophysiological studies have defined multiple mechanisms of tachycardia, both re-entrant and focal, with varying ECG morphologies and rates, authenticated by the results of catheter ablation of the focal triggers or critical isthmuses of re-entry circuits. In patients without a history of heart disease, cardiac surgery or catheter ablation, typical flutter ECG remains predictive of a right atrial re-entry circuit dependent on the inferior vena cava–tricuspid isthmus that can be very effectively treated by ablation, although late incidence of atrial fibrillation remains a problem. Secondary prevention, based on the treatment of associated atrial fibrillation risk factors, is emerging as a therapeutic option. In patients subjected to cardiac surgery or catheter ablation for the treatment of atrial fibrillation or showing atypical ECG patterns, macro-re-entrant and focal tachycardia mechanisms can be very complex and electrophysiological studies are necessary to guide ablation treatment in poorly tolerated cases.

Keywords Typical atrial flutter, atypical atrial flutter, macro-re-entrant atrial tachycardia, flutter ablation, classification of atrial tachycardias Disclosure: The author has no conflicts of interest to declare. Received: 23 December 2016 Accepted: 22 May 2017 Citation: Arrhythmia & Electrophysiology Review 2017;6(2):55–62. DOI: 10.15420/aer.2017:5:2 Correspondence: Prof FG Cosío, Cardiology Department, Hospital Universitario de Getafe, Universidad Europea,28905 Getafe, Madrid, Spain. E: francisco.garciacosio@salud.madrid.org

The term ‘flutter’ was coined to designate the visual and tactile rapid, regular atrial contraction induced by faradic stimulation in animal hearts, in contrast with irregular, vermiform contraction in atrial fibrillation (AF).1,2 On the ECG, flutter was a regular continuous undulation between QRS complexes at a cycle length (CL) of ≤250 ms (≥240 bpm). Slower tachycardias displaying discrete P waves, separated by isoelectric baselines, were called ‘atrial tachycardia’. Early studies suggested that flutter had a re-entrant mechanism3–5 but others attributed flutter to focal discharge.6,7 Later human studies left the door open for a focal mechanism.8 This was not a significant consideration when digitalis and very few antiarrhythmic drugs (AADs) were the only therapeutic armamentarium, but determining the mechanism involved in flutter has become crucial for the design and application of catheter and surgical ablation techniques. Modern electrophysiology (EP) has confirmed the re-entrant mechanism of typical flutter, and has opened wide the spectrum of mechanisms of macro-re-entrant tachycardias (MRTs), prompting a new, more open view of clinical ECG-based classification (see Figure 1A and 1B).9

Typical Atrial Flutter The Re-entrant Mechanism Typical flutter is the type of MRT most frequently found in the clinical setting. The mechanism is a large re-entrant circuit contained in the right atrium (RA) with passive activation of the left atrium (LA).10 Activation courses superoinferiorly in the anterior and lateral RA and inferosuperiorly in the septal RA, with a critical inferior turning point between the tricuspid ring and inferior vena cava (IVC) known as the cavotricuspid isthmus (CTI) (see Figure 2). An area of transverse conduction block in the posterior RA related to anisotropic conduction

at the terminal crest11–14 and other structures15 forces activation toward the high RA so that the upper turning point can be at the RA roof or high in the posterior RA, depending of the size of the area of block.16–18 In either case, the CTI remains an obligatory passage for activation in the inferior RA. Either spontaneously or after programmed stimulation, re-entry may occur in the opposite (clockwise) direction – i.e. superoinferior in the septal wall and inferosuperior in the anterolateral wall – with the same zones of block in the posterior RA and obligatory passage through the CTI (see Figure 3).19 This reverse typical flutter is much less common clinically than the counter clockwise form, but the clinical manifestations are indistinguishable.

The ECG Patterns Typical (counter clockwise) flutter is associated with the ‘common’ flutter pattern20,21 (see Figure 2): a regular continuous undulation with dominant negative deflections in inferior leads II, III and aVF, often described also as a ‘saw tooth pattern’, and flat atrial deflections in leads I and aVL. Atrial deflections in V1 can be positive, biphasic or negative. The CL is usually 250–170 ms (rates 240–350/min). Reverse typical flutter (see Figure 3) usually shows rounded or bimodal positive deflections in inferior leads II, III and aVF, and a very characteristic bimodal negative wave in the shape of a W is seen in lead V1.21,22 One frequent presentation of flutter is in patients treated with class IC AADs for AF. Flutter rate may be slowed by the AAD to ≤200/min, facilitating 1:1 atrioventricular (AV) conduction that due to the effect of the ADD results in aberrant intraventricular conduction and a wide QRS complex tachycardia (see Figure 4).

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Clinical Arrhythmias Figure 1: The ECG Pattern May Not Reflect the Mechanism

It should be emphasised that ECG diagnosis is based on atrial deflections and not on ventricular (QRS) rate and rhythm. An irregular ventricular rhythm may be caused by changing degrees of AV nodal block (see Figures 1A and 3), including Wenckebach cycles. In doubtful cases it is essential to document atrial activity dissociated from ventricular activity by increasing AV block by vagal manoeuvres or intravenous adenosine. However adenosine can produce a rebound increase in AV conduction to 1:128,29 and in some cases it can precipitate AF,30 therefore it should only be used if necessary for diagnosis and resuscitation equipment should be readily available.

Pathogenesis of Typical Flutter About 80 % of flutter patients are male,31,32 otherwise flutter occurs in clinical contexts very much like those observed in AF (in old age, hypertension, diabetes, chronic obstructive lung disease, excessive alcohol consumption33 or during endurance sports practice).34 In many cases flutter episodes alternate with fibrillation episodes.32,35 Of those initially presenting with flutter as the only arrhythmia, 50 % develop fibrillation during long-term follow-up.36 This figure is not far from the proportion of patients developing fibrillation in the long term after CTI ablation for the treatment of typical flutter.37,38 The thickness of the terminal crest39,40 and its capacity to block transverse conduction41–44 are increased in cases of flutter compared to AF. EP studies have shown areas of low-voltage electrograms45 and slow conduction in the RA – particularly at the CTI46–48 – to be a sign of arrhythmogenic myocardial remodelling. LA dilatation and abnormalities in its reservoir function have been described as predictors of the incidence of atrial flutter or fibrillation.49 (A) ECG fulfilling classical flutter criteria (rate and lack of isoelectric baseline) in a case of focal tachycardia originating in the right superior pulmonary vein. Note the irregular ventricular rate in the face of regular atrial rate. (B) ECG of a case of scar macro-reentrant tachycardia of the right atrium fulfilling the classical ‘atrial tachycardia’ criteria. Discrete P waves separated by stable baselines are recorded between QRS complexes with 2:1 atrioventricular conduction.

Figure 2: ECG of a Typical Atrial Flutter

Atrial activity in leads II and III is a continuous undulation with a sharp negative deflection (‘saw-tooth pattern’). There is a biphasic deflection in V1. The schema on the right displays the atria in a left anterior oblique view. Mitral and tricuspid rings are enlarged in order to show the posterior walls. The terminal crest (TC) is shown as a vertically-dashed area reaching from the superior vena cava (SVC) to the inferior vena cava (IVC). The circular arrow shows typical counter clockwise re-entrant activation. CS = coronary sinus ostium; CTI = cavotricuspid isthmus; PV = left pulmonary veins ostia. For further explanation see text.

CTI-dependent MRT is also frequent in patients with previous surgical atriotomies or atrial baffle procedures, or after LA ablation for the treatment of AF.23,24 In these cases ECG patterns are often atypical. Conversely, a typical flutter ECG may be generated by atypical re-entry circuits, independent of the CTI, including LA circuits.25 Flutter wave morphology can be determined by activation outside the re-entry circuit, which would explain the often-difficult correlation between mechanism and ECG pattern.26,27

Clinical Presentation Flutter can be paroxysmal or persistent. Clinical presentation will depend in large part on the ventricular rate, which is most often around 120–150 due to 2:1 AV conduction, but in some cases 1:1 AV conduction leads to extremely high rates with poor clinical tolerance often requiring immediate intervention (see Figure 5). As in AF, loss of effective atrial contraction synchronised to ventricular contraction and rapid ventricular rates may result in hypotension, angina, heart failure, syncope or a feeling of palpitation making the patient seek medical attention.50 Occasionally flutter can be asymptomatic for weeks or months and the sustained tachycardia can lead to systolic ventricular dysfunction and heart failure (tachycardiomyopathy).51,52 Ventricular function and atrial dilatation may recover after return to sinus rhythm,53 but arrhythmia recurrence can again precipitate dysfunction with a risk of sudden death.54 LA appendage thrombi, spontaneous echo contrast and low appendage emptying velocities have been detected in cases of flutter submitted to cardioversion,55 although to a lesser extent than in AF,56 and normalisation can occur days after return to sinus rhythm.57 The frequency of systemic embolism in flutter is about one-third that in AF,36,58,59 but this difference disappears when both flutter and fibrillation occur in the same patient.

Management of Atrial Flutter Rate control should be the first treatment step in symptomatic patients with a rapid ventricular rate. This is often a difficult goal in flutter, and even associations of the AV node blocking drugs (digoxin, beta-blockers and calcium antagonists) may fail, making cardioversion to sinus rhythm necessary. Dofetilide and ibutilide, pure class III AADs, are effective for

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Atrial Flutter, Typical and Atypical interrupting flutter with a small risk of QT prolongation and torsade de pointes. Class IA and IC AADs are relatively ineffective or have no effect60–65 and can be problematic if they cause a slow atrial flutter rate ≤200/min with 1:1 AV conduction and QRS widening that mimics ventricular tachycardia (see Figure 4).66,67 Amiodarone may not be very effective at re-establishing sinus rhythm in the acute setting but it does help control ventricular rate.68,69

Figure 3: Reverse (Clockwise) Typical Flutter

Rhythm Control: Cardioversion The poor results of rhythm control strategies in AF may not apply in flutter because of a lower recurrence rate after cardioversion in flutter, making a strategy of repeated cardioversions supported with AADs a clinically applicable option.70,71 Transthoracic direct-current cardioversion, under short-lasting sedation, is the quickest and most effective method to recover sinus rhythm in patients with flutter, with a lower energy delivery and higher success rate than in AF.72,73 In 50–80 % of cases flutter interruption can be achieved by atrial pacing above the flutter rate through a transvenous catheter, through epicardial electrodes placed during cardiac surgery8 or by programming fast atrial rates in patients with atrial or dual-chamber pacemakers.74 Pacing runs of 20–30 s are started at a rate 10 bpm higher than flutter, increasing in 10 bpm steps up to 400 bpm or until flutter is interrupted and sinus (or paced) atrial rhythm is established (see Figure 6). Pacing may induce AF or a faster flutter (type II flutter),75 probably as an expression of functional re-entry76 that tends to return to baseline flutter or change to AF. AF induced by pacing usually results in a lower ventricular rate and, not infrequently, terminates spontaneously into sinus rhythm. Flutter cardioversion by pacing is painless and can be done without sedation or anaesthesia.77 It may be more effective in postoperative flutter78 and in younger patients without structural heart disease or heart failure79 and it may be facilitated by class I AADs.80,81 Atrial pacing can be applied from the oesophagus82 but the higher output stimulation necessary may be painful83 and can occasionally induce ventricular arrhythmias.84

Note the dominant positive deflections in the flutter waves and the W-shaped deflection in lead V1. For further explanation and abbreviations, see text and Figure 2.

Figure 4: One to One AV Conduction in Flutter Slowed by Flecainide

(A) Slow flutter (170 BPM) with 1:1 atrioventricular conduction and wide QRS complex (right bundle branch block and superior axis) in a patient treated with flecainide for paroxysmal atrial fibrillation. (B) A 2:1 atrioventricular block with slower ventricular rate and narrow QRS allows recognition of slow but typical flutter waves.

Figure 5: Spontaneous 1:1 AV Conduction in Typical Flutter

The patient should be anticoagulated if cardioversion is planned, be it by direct current shock or pacing, whenever the duration of flutter is >48 h. Patients with flutter of longer duration should be anticoagulated for 3–4 weeks before cardioversion or LA thrombi should be ruled out by transoesophageal echocardiography. Following cardioversion, anticoagulation should be maintained for a minimum of 3–4 weeks in patients with low embolic risk. If high embolic risk is present, anticoagulation should be continued indefinitely, unless prolonged follow-up monitoring demonstrates an absence of recurrence.85

Catheter Ablation Radiofrequency catheter ablation of the CTI has become a standard treatment for typical flutter.86 The full thickness of the CTI must be ablated along a line reaching from the tricuspid ring (TR) to the IVC. Radiofrequency can be applied point-by-point, keeping the catheter tip stable for 45–60 s at each site or by dragging the catheter tip slowly from the TR to IVC during continuous radiofrequency delivery.87 The endpoint of the procedure is complete, bidirectional CTI conduction block that has to be checked by recordings along the ablation line88,89 and differential pacing manoeuvres.90 CTI block can be transient, so an observation period of 20–30 min is necessary to confirm success.91,92 Only when this endpoint is reached is flutter recurrence post ablation

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

(A) Typical flutter with 1:1 atrioventricular conduction at 240 BPM spontaneously evolving to 2:1 atrioventricular conduction. (B) Typical flutter waves can be easily identified.

reduced to ≤10 %. At mid-term (months) conduction may still resume in 15 % of cases, even in the absence of flutter recurrence.93 For radiofrequency ablation large tipped (8 mm electrode length)94 or irrigated tip catheters95 are more effective than standard tip (4 mm electrode length) catheters. Supporting sheaths may be used to obtain good contact force on the CTI. Radiofrequency application to the CTI can be quite painful and moderate sedation is often needed during the procedure. Cryoablation can also be effective for CTI ablation and has the advantage of being painless.96 Resumption of CTI

Clinical Arrhythmias Figure 6: Flutter Cardioversion by Rapid Stimulation

ECG leads I, II and III in a patient with an implanted AAI pacemaker. Typical flutter is present at the onset. Rapid atrial asynchronous (A00) pacing abolishes negative deflections in II and III and a positive P wave appears in I. When pacing stops flutter is no longer present and atrial demand pacing resumes.

Figure 7: Atypical Right Atrial Macro-reentrant Circuits B

C SCA R

PATCH

A) Upper loop reentry (left anterior oblique view). Activation rotates around the superior vena cava (SVC) and the terminal crest (TC) but the cavotricuspid isthmus (CTI) is not part of the circuit. B) Right lateral view of the right atrium showing reentry around a surgical scar. C) Reentry around an atrial septal defect repair patch. Modified from Cosio et al., 2003.117

Figure 8: Two Flutter Mechanisms, Typical and Atypical, in the Same Patient

procedure in recurrent cases. The main problem is the incidence of AF after ablation, which can be 30–50 % in the long term (>3 years).38,104–106 More recent reports have reported even higher incidences of AF.107 AF is more likely in patients who have had AF episodes before flutter ablation and in those with dilated LA. The efficacies of CTI ablation and AADs have been compared for the treatment of typical flutter in two randomised studies.71,108 CTI ablation proved to be advantageous in terms of better quality of life, less hospitalisation and lower flutter recurrence, but the incidence of AF did not improve in both studies. In patients with flutter appearing during AAD treatment of AF, CTI ablation may help stabilise sinus rhythm109 at the same time allowing the use of class IC AADs without the risk of slow flutter with 1:1 AV conduction. Direct AF ablation has been proposed by some groups as a complement to CTI ablation in patients with both arrhythmias,110 and even in those with only flutter,111 to reduce the later incidence of AF. CTI ablation of typical flutter is associated with a favourable prognosis; however, given the higher incidence of severe complications in AF ablation, patients should be carefully selected for this strategy.112 There have been no randomised studies published on the risk–benefit ratio of anticoagulation after successful ablation of typical flutter with no associated AF. Prolonged monitoring of atrial rhythm under anticoagulation would appear to be indicated in patients with a high embolic risk score before anticoagulation is discontinued.

Summary: Long-term Strategy

(A) ECG of typical flutter and (B) right atrium macro-re-entrant tachycardia in the same patient. The scar macro-re-entrant tachycardia was induced after cavotricuspid isthmus ablation. Note the cycle length prolongation and atrial wave morphology resembling clockwise flutter in (B).

conduction at mid-term is more common after cryoablation than after radiofrequency ablation.93 Complications are infrequent (around 1 %)97 and are usually limited to vascular access; however, extension of ablation to the septal RA can result in AV block when using radiofrequency98,99 and cryoablation.96 Damage to the right coronary artery is rare but can result in myocardial infarction in some cases with pre-existing coronary atherosclerotic lesions.100,101 Cardiac perforation secondary to tissue disruption by boiling with audible ‘pops’ can occur when high energy is delivered with large-tip catheter-electrodes.102,103 A one in 1,000 incidence of cerebrovascular accidents is reported.97 The recurrence rate of typical flutter is ≤10 % after successful CTI ablation and definitive flutter suppression can be attained by a second

A first and well-tolerated episode of flutter terminated spontaneously or by electrical cardioversion or AAD can be followed clinically with or without AAD coverage. A recurrence rate of around 50 % can be expected in these patients. Amiodarone, dronedarone or sotalol are indicated to prevent recurrences after cardioversion, while class IC AADs should be used cautiously or avoided. Catheter ablation is more effective for the prevention of recurrence and is a better alternative than maintenance AAD, especially in patients with depressed systolic ventricular function. A rate control strategy could be adequate for asymptomatic elderly patients with no deterioration of systolic ventricular function; however, cardioversion in active patients without apparent functional limitation will often improve a patient’s well-being and functional capacity. Chronic anticoagulation should be considered on the bases of embolic and haemorrhagic risk scores, along the same lines as for AF.85 Progression to AF after successful CTI ablation for typical flutter underlines the presence of an atrial arrhythmogenic substrate that can evolve in many cases, even in the absence of flutter recurrence. The diagnosis of flutter should thus be complemented with a clinical profile of AF risk factors that could guide ‘upstream therapy’. Recent reports have shown that physical fitness programmes and vigorous treatment of obesity, metabolic syndrome and sleep apnoea can result in a significant reduction in AF recurrence in patients whether or not they undergo AF ablation,113–116 and this may be applicable to flutter given the very similar risk factor profiles. Atrial or AV pacing may be necessary in patients in whom conversion to sinus rhythm reveals sick sinus syndrome. In these cases, a device capable of overdrive atrial pacing should be implanted. In the absence of direct evidence of the risk–benefit ratio of chronic anticoagulation in flutter, present recommendations for

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Atrial Flutter, Typical and Atypical anticoagulation are the same as for AF, carefully balanced against bleeding risk scores.85

Figure 9: Schematic Representation of Macro-re-entrant Tachycardia Mechanisms in the Left Atrium

Atypical Flutter/Macro-re-entrant Tachycardia The term atypical has been applied to rapid atrial tachycardias with ECG patterns differing from the typical and reverse typical flutter described above, and also to re-entrant tachycardias with circuit configuration different from the typical RA flutter circuit, even if they have an ECG pattern similar to typical flutter. ECG waveform can be determined by activation of the atrial myocardium outside the re-entry circuit26,27 and the precise mechanism generating atypical ECG flutter patterns can only be determined by mapping and pacing EP studies.117 Atypical flutter is often associated with structural heart disease, especially in patients that have undergone cardiac surgery or extensive catheter ablation for the treatment of AF. In these cases focal (centrifugal) mechanisms can coexist with MRT with indistinguishable ECG patterns, making EP study the only way to unveil the mechanisms causing the arrhythmia and plan ablation when clinically indicated.118,119

LA anterior view

LA posterior view

Stippled, grey areas represent low-voltage, unexcitable ‘scars’. Yellow curved arrows indicate multiple possible re-entry pathways. The pulmonary veins are represented in blue. MV = mitral valve.

Figure 10: Left Atrial Macro-reentrant Tachycardia in a Patient with Interatrial Block

Right Atrial Macro-re-entrant Tachycardias MRT circuits turning around the superior vena cava and part of the terminal crest, not involving the CTI, can occasionally be found in patients without surgical atriotomy (see Figure 7). In patients with RA surgical atriotomy, the scar can become the centre of the MRT, but the small incisions used to cannulate the superior vena cava and IVC are rarely arrhythmogenic by themselves. Lateral wall, superoinferior atriotomy is a frequent cause of atypical (nonCTI-dependent) MRT. ECG pattern may or may not be atypical (see Figures 1B and 8) and it is not unusual for two or more ECG patterns to alternate, as CTI-dependent typical flutter often coexists with the scar MRT (see Figure 8).23 A patch closing an interatrial septal defect can also become the centre of a MRT circuit (see Figure 7). Atypical flutter or MRT related to surgery often occurs years after the procedure, suggesting that an atrial remodelling process is necessary to make re-entry stable around the surgical obstacles in many cases. In patients not subjected to cardiac surgery or AF ablation, unexcitable areas of low voltage, most often located in the lateral RA,120,121 can become the central obstacle sustaining atypical MRT. These areas are probably related to chronic atrial overload or cardiomyopathy and they are often considered to be fibrotic myocardium but there is no direct evidence of their histology. Low-voltage areas are most prevalent in the RA after a Fontan procedure,119 leading to the difficult management of recurrent MRTs in these cases.

Left Atrial Macro-re-entrant Tachycardias Surgical atriotomy scars are a well-known cause of MRT of the LA122–124 often combined with re-entry around low-voltage, inexcitable areas not related to atriotomy. In recent years the incidence of atypical flutter/MRT has become epidemic, with a wide variety of re-entry circuits following extensive LA ‘substrate ablation’ for the treatment of persistent AF (see Figure 9). A ‘maturation’ process appears to be necessary to make a MRT circuit stable, as tachycardia inducibility at the end of an AF ablation procedure does not predict later clinical occurrence.125,126 Recovery of slow conduction across ablation lines in the mid-term appears to be the arrhythmogenic mechanism in most cases.127,128 An ECG pattern of interatrial (Bachmann) block is often associated with atypical flutter/MRT based in the LA.129,130 This ECG

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

ECGs of a 63-year-old woman with mild mitral stenosis post-commissurotomy. (A) In the sinus rhythm note a very wide P wave with terminal negative deflection in II and III, diagnostic of interatrial (Bachmann) block. (B) ECG during macro-re-entrant tachycardia with very-low-voltage P waves in limb leads and late positive deflection in V1. Activation is rotated around the left pulmonary veins, supported by a wide area of low voltage in the posterior and superior left atrium.

pattern may be associated too with inexcitable, low-voltage areas in the LA (see Figure 10).131 EP studies with RA and LA activation mapping and the response to pacing are necessary to reveal the mechanism in order to guide catheter or surgical ablation. MRT involving the interatrial septum is particularly difficult to treat and success rates are lower than in MRT based on the free atrial walls.24,132 Ablation of all inducible tachycardias is the accepted objective; however, the significance of non-clinicallyinducible tachycardias is not well known. Long-term recurrences can occur despite repeat ablation.133,134 Some authors describe better results by targeting areas of focal activity as possible triggers than with ablation of re-entry circuits.135 MRT can occur after surgical ‘maze’ procedures for the treatment of AF on the basis of re-established slow conduction across suture lines.136,137 Heart transplantation with atrial-to-atrial suture is practically an experimental model of flutter.5,138 Knowledge acquired by mapping and ablation-scar-related MRT should help the surgeons and electrophysiologists function as a team to devise non-arrhythmogenic incisions, avoiding surgical approaches that have proved arrhythmogenic, such as the superior transeptal approach to the LA.139

Management of Atypical Flutter/Macro-re-entrant Tachycardia Management of atypical flutter does not differ from that of typical flutter, but the more frequent association with structural heart disease and the multiple possible mechanisms causing an atypical ECG

Clinical Arrhythmias pattern are important factors to consider before making therapeutic decisions. There is very little specific evidence regarding indications for anticoagulation in patients with atypical flutter/MRT and the same indications as in AF are generally recommended.85 When atypical flutter/MRT is poorly tolerated and is not controlled with AADs, catheter ablation should be considered. There is no set rule for catheter ablation of atypical MRT tachycardia circuits. Mapping and entrainment studies are necessary to define the focal (centrifugal spread) or MRT mechanism and localise the focal sources or the target isthmus or isthmuses. These procedures may be complicated by the induction of multiple MRT circuits that are not clinically documented. Ablation success is lower than in typical flutter and the recurrence rate is higher, especially in circuits located in the paraseptal areas.24,132–134 On the other hand, CTI-dependent flutter is a frequent finding in patients with atrial tachycardia and surgical or ablation scars.24 In cases with multiple MRT circuits, CTI ablation may make ablation success easier by stabilising the atypical MRT circuit and thus making mapping and ablation possible. In cases of atypical MRT of the RA, CTI ablation could be considered even if typical flutter is not documented in order to prevent the later appearance of typical flutter.

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Prognosis in these complex cases is difficult to predict24,128,132–135 but long remissions of tachycardias can be attained in many cases of free wall RA and LA scar. Indications for ablation should be established, taking into account the underlying pathology, quality of life and limitations in functional capacity.

Postoperative Atrial Flutter The incidence of atrial arrhythmias in the early postoperative period (days) after cardiac surgery is 20–30 %.140 This high incidence is related to inflammatory changes in the atrial myocardium,141 not unlike the experimental pericarditis animal models,142 and it may be prevented by anti-inflammatory corticosteroid treatment.143,144 AF is the most commonly reported arrhythmia but flutter can also occur in this setting,8,35,78 although its frequency in relation to AF is not clear. There are very few data on the long-term follow-up of this postoperative flutter, but the incidence of AF in such cases is reported to be around 30 %.145 If this incidence is extrapolated to flutter, it would appear reasonable to consider that in the early postoperative period after cardiac surgery flutter is an acute, one-time event in the majority of patients and ablation treatment should not be contemplated unless recurrences are documented. n

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95. J aïs P, Shah DC, Haïssaguerre M, et al. Prospective randomized comparison of irrigated-tip versus conventionaltip catheters for ablation of common flutter. Circulation 2000;101:772–6. DOI: 10.1016/j.ehj.2004.03.017; PMID: 15172468 96. Feld GK, Daubert JP, Weiss R, et al. Cryoablation Atrial Flutter Efficacy Trial Investigators. Acute and long-term efficacy and safety of catheter cryoablation of the cavotricuspid isthmus for treatment of type 1 atrial flutter. Heart Rhythm 2008;5: 1009–14.DOI: 10.1016/j.hrthm.2008.03.019; PMID: 1859895 97. Gil-Ortega I, Pedrote-Martínez A, Fontenla-Cerezuela A. Spanish Catheter Ablation Registry Collaborators. Spanish Catheter Ablation Registry. 14th Official Report of the Spanish Society of Cardiology Working Group on Electrophysiology and Arrhythmias (2014). Rev Esp Cardiol (Engl Ed) 2015;68: 1127–37. DOI: 10.1016/j.rec.2015.08.006; PMID: 2650796 98. Anselme F, Klug D, Scanu P, et al. Randomized comparison of two targets in typical atrial flutter ablation. Am J Cardiol 2000;85:1302–7. PMID: 1083194 99. Passman RS, Kadish AH, Dibs SR, et al. Radiofrequency ablation of atrial flutter: a randomized controlled study of two anatomic approaches. Pacing Clin Electrophysiol 2004;27: 83–8. DOI: 10.1111/j.1540-8159.2004.00390. 100. Weiss C, Becker J, Hoffmann M, et al. Can radiofrequency current isthmus ablation damage the right coronary artery? Histopathological findings following the use of a long (8 mm) tip electrode. Pacing Clin Electrophysiol 2002;25:860–2. PMID: 12049382 101. Sassone B, Leone O, Martinelli GN, et al. Acute myocardial infarction after radiofrequency catheter ablation of typical atrial flutter: histopathological findings and etiopathogenetic hypothesis. Ital Heart J 2004;5:403–7. DOI: 10.3346/ jkms.2014.29.2.292 102. Hillock RJ, Melton IC, Crozier IG. Radiofrequency ablation for common atrial flutter using an 8-mm tip catheter and up to 150 W. 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PMID: 1271402 107. Ellis K, Wazni O, Marrouche N, et al. Incidence of atrial fibrillation post-cavotricuspid isthmus ablation in patients with typical atrial flutter: left-atrial size as an independent predictor of atrial fibrillation recurrence. J Cardiovasc Electrophysiol 2007;18:799–802.DOI: 10.1111/ j.1540-8167.2007.00885.x; PMID: 1759323 108. Natale A, Newby KH, Pisanó E, et al. Prospective randomized comparison of antiarrhythmic therapy versus first-line radiofrequency ablation in patients with atrial flutter. J Am Coll Cardiol 2000;35:1898–904. PMID: 1084124 109. Bottoni N, Donateo P, Quartieri F, et al. Outcome after cavotricuspid isthmus ablation in patients with recurrent atrial fibrillation and drug-related typical atrial flutter. Am J Cardiol 2004;94:504–7.DOI: 10.1016/j.amjcard.2004.04.069; PMID: 1532594 110. Mohanty S, Mohanty P, Di Biase L, et al. Results from a single-blind, randomized study comparing the impact of different ablation approaches on long-term procedure outcome in coexistent atrial fibrillation and flutter (APPROVAL). Circulation 2013;127:1853–60. DOI: 10.1161/ CIRCULATIONAHA.113.001855; PMID: 23572499 111. Mohanty S, Natale A, Mohanty P, et al. Pulmonary Vein Isolation to Reduce Future Risk of Atrial Fibrillation in Patients Undergoing Typical Flutter Ablation: Results from a Randomized Pilot Study (REDUCE AF). J Cardiovasc Electrophysiol 2015;26:819–25. DOI: 10.1111/jce.12688; PMID: 2588432 112. Clementy N, Desprets L, Pierre B, et al. Outcomes After Ablation for Typical Atrial Flutter (from the Loire Valley Atrial Fibrillation Project). Am J Cardiol 2014;114:1361–7. DOI: 10.1016/j.amjcard.2014.07.066; PMID: 25200340 113. Pathak RK, Middeldorp ME, Lau DH, et al. Aggressive risk factor reduction study for atrial fibrillation and implications for the outcome of ablation: the ARREST-AF cohort study. 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ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Clinical Arrhythmias

Atrial Fibrillation and Anticoagulation in Hypertrophic Cardiomyopathy C Fielder Camm 1 and A John Camm 2,3 1. University of Oxford, Oxford; 2. St George’s, University of London; 3. Imperial College, London, UK

Abstract Hypertrophic cardiomyopathy (HCM) represents a common inherited cardiac disorder with well-known complications including stroke and sudden cardiac death. There is a recognised association between HCM and the development of AF. This review describes the epidemiology of AF within the HCM population and analyses the risk factors for the development of AF. It further discusses the outcomes associated with AF in this population, including the evidence in support of higher stroke risk in patients with HCM with AF compared with the general AF population. Finally, the evidence and recommendations for anticoagulation in this patient group are addressed.

Keywords Hypertrophic cardiomyopathy, atrial fibrillation, stroke, anticoagulation Disclosure: CFC has received an Academic Clinical Fellowship funded by the National Institute of Healthcare Research, and AJC has received advisory and speaker fees from Bayer, Boehringer Ingelheim, Daiichi Sankyo and Pfizer/BMS. Received: 1 February 2017 Accepted: 19 April 2017 Citation: Arrhythmia & Electrophysiology Review 2017;6(2):63–8. DOI: 10.15420/aer.2017:4:2 Correspondence: A John Camm, Professor of Clinical Cardiology, Cardiac Clinical and Academic Group, St George’s, University of London, Cranmer Terrace, London, SW17 0RE, UK. E: jcamm@sgul.ac.uk

Hypertrophic cardiomyopathy (HCM) is a common genetic cardiac disorder, with an autosomal dominant mechanism of inheritance.1,2 It has a prevalence of 1 in 500 within the general population, and is a known cause of sudden cardiac death.2,3 Recognised autosomal dominant mutations within sarcomere proteins are found in 55 % of adolescents with sporadic HCM.4 Characteristic echocardiographic features are well described;2 a left ventricular (LV) wall thickness ≥15 mm not explained by loading conditions is considered diagnostic for HCM, but diagnostic challenges exist.5 Co-existent pathologies associated with increased cardiac load can make ascertainment of the causative pathway of LV hypertrophy difficult.6 In addition, diagnosis in the late disease phase can be confused by ventricular dilatation associated with LV wall thinning.7 AF is the most common sustained arrhythmia,8 and is associated with a significantly increased risk of stroke and heart failure.9 HCM has been associated with the development of both AF and thromboembolic events.5 Indeed, 48-hour ambulatory monitoring is advised as part of the initial HCM assessment, in part, to establish whether atrial tachyarrhythmias are present.5 Atrial fibrosis has been demonstrated in some individuals with HCM, but an atrial histology similar to the HCM ventricular pathology has not been demonstrated.10 Despite the common nature of both conditions, and their considerable overlap, the role of anticoagulation in this population has not been fully investigated. This review aims to assess the evidence surrounding the development of thromboembolism in patients with HCM and AF.

Hypertrophic Cardiomyopathy and the Development of Atrial Fibrillation Although AF is common in patients with HCM, prevalence rates differ significantly between studies; prevalence has been described to be between 12 and 28 %.11–18 Eriksson et al. showed that AF developed in 12 % of patients (13/105) over a mean follow-up period of 13.6 ± 8.3

years.13 Furthermore, they found that AF was the initial disease presentation in 10 % of patients (10/105). This report of a retrospective cohort analysis does not clearly detail how AF was determined. As such, the authors may have underestimated the true prevalence of AF in this population. In a retrospective cohort (n=4,821), Guttmann et al. demonstrated an AF prevalence of 12.5 % at baseline.19 The reported prevalence found in cohorts evaluated at specialist HCM centres has been found to be significantly higher. Binder and colleagues reported an AF prevalence of 28 % in patients with apical HCM.11 This rate is supported by other registries.12,16,20 A systematic review examining AF in the HCM population included 7,381 patients in the analysis. The overall prevalence of AF in this population was 22.5 % (95% CI [20.1–24.8]).21 However, it should be noted that not all reports were included in the systematic review, including some citing lower prevalence levels. The authors also highlighted difficulties with the analysis due to heterogeneity of the study populations. Kawasaki et al. undertook prospective 24-hour Holter monitoring on patients with HCM, where those with pre-existing AF had been excluded.14 They demonstrated that 3 % of patients were shown to have AF paroxysms lasting >30 seconds. AF has been shown to be subclinical in a substantial proportion of the general population,22 this has led to concern that a similar proportion of patients with HCM and AF may be under-recognised. Robinson et al. demonstrated that in a cohort of 52 consecutive patients with HCM developing AF, 89 % had a change in symptoms with the onset of the arrhythmia.23 Similar numbers have been reported by other groups.17 In a small cohort (n=44) of patients with HCM undergoing device implantation (implantable cardioverter defibrillator [ICD], permanent pacemaker, or loop recorder), in those developing de novo AF (n=16) 88 % were asymptomatic.24

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Clinical Arrhythmias Figure 1: Key Risk Factors for the Development of Atrial Fibrillation in Patients with Hypertrophic Cardiomyopathy

e siz

Righ t-si de inv ol ve m

t en

Increasing age

Genetic elements

NT-proBNP

ark

ers

en ors

in g

Increasing age and worsening symptoms of congestive heart failure (NYHA class III or IV at diagnosis) have both been shown to be independently associated with the development of AF (OR 2.3, 95 % CI [1.4–3.7] and OR 2.8, 95 % CI [1.3–6.1], respectively).16 The prevalence of AF has been shown to increase with age in HCM cohorts; Losi et al. demonstrated an increase from 4.3 % in those <50 years of age to 13 % in those >60 years of age.18 Importantly, this group also highlights a large proportion of AF cases in an otherwise young population. An association between AF and increased age has similarly been reported in other large cohorts.25

CCF = congestive cardiac failure; HCM = hypertrophic cardiomyopathy; LA = left atrial; NT-proBNP = N-terminal pro-brain natriuretic peptide.

Risk Factors For the Presence of Atrial Fibrillation in Hypertrophic Cardiomyopathy Several risk factors for the development of AF in patients with HCM have been identified. N-terminal pro-brain natriuretic peptide (NT-proBNP) levels have been shown to positively correlate with the presence of AF at baseline.12 Prevalent AF was seen in 11 % (7 patients) in the lowest tertile of NT-proBNP levels compared with 36 % (22 patients) in the highest tertile. Retrospective analysis of a large, single-centre cohort confirmed that BNP levels are increased in patients with HCM and AF;25 this is in line with evidence supporting a significant prognostic role of NT-proBNP in predicting the development of AF.26,27 Several studies have reported an association between left atrial (LA) size and the presence of AF.28,29 Spirito et al. examined a consecutive cohort of 668 low-risk patients with HCM (no major sudden death risk factors, New York Heart Association [NYHA] class I or II and no history of AF).28 Over a median follow-up of 5.3 years, the development of AF was associated with increased baseline LA diameter with a relative risk of 4.65 (95 % CI [2.18–9.92]) in patients with an LA diameter >50 mm compared with ≤40 mm. These findings support previous work from additional groups showing a correlation between LA size and the presence of AF in patients with HCM.16–18,29–31 LA volume has been associated with AF in a cohort of 427 patients with HCM (OR 1.062, 95 % CI [1.026–1.104]).32 Tani et al. demonstrated that a maximum LA volume of ≥56 ml identified patients with HCM and paroxysmal AF with a sensitivity of 80 % and specificity of 73 %.33 Furthermore, LA volume has been shown to identify those with HCM and normal pump function who are at risk of poor outcomes (LA volume/body surface area ≥40.4 ml/m2, sensitivity 73 % and specificity 88 %), including the risk of sudden cardiac death.34 LA enlargement is commonly seen in HCM and has been suggested to be a consequence of impaired diastolic function.35

McKenna et al. demonstrated right-sided involvement in 44 % of patients with HCM.36 However, these findings have not been confirmed, and the underlying mechanism and importance remains unclear. Despite this, Doesch et al. suggest this as an important prognostic factor for the development of AF in HCM.37 In a cohort of 98 patients with HCM (38 [39 %] with AF), cardiovascular magnetic resonance revealed reduced tricuspid annular plane systolic excursion and increased right atrial size were associated with the development of AF. However, this group did not directly quantify right ventricular hypertrophy.

Obstructive phenotypic presentation is variable in HCM.16,38 It has been demonstrated in several patient cohorts that LV outflow tract obstruction (LVOTO) is associated with increased risk of AF, in line with the expected physiological outcome associated with LVOTO. Indeed, LVOTO has been suggested to have a role in LA remodelling due to increased mitral regurgitation.39 It is well recognised that the range of mutations leading to the development of HCM can significantly alter the resultant phenotype.40 As such, it has been hypothesised that differential genetic mutations may explain some element of the heterogeneity witnessed in the development of AF within the HCM population. The Arg663His (rs371898076) mutation in the myosin heavy chain beta (MYH7) gene was shown to correlate with a high prevalence of AF (46 %) in a 24-patient cohort over a 7-year follow-up period.41 Mutations in the angiotensin-converting enzyme (ACE) gene have also been associated with the development of AF in patients with HCM.42 A summary of HCM features associated with AF development is detailed in Figure 1.

The Role of Atrial Fibrillation in Hypertrophic Cardiomyopathy Outcomes Yang et al. demonstrated that AF was a risk factor for the development of cardiovascular events (a composite of sudden cardiac death, hospitalisation for heart failure, and stroke) on univariate analysis; however, on multivariate analysis, it was not found to be an independent predictor.29 In patients undergoing surgical relief of LVOTO, post-operative AF was associated with increased risk of a composite endpoint (death, appropriate ICD discharge, sudden cardiac death resuscitation, stroke and admission for congestive cardiac failure; hazard ratio [HR] 2.12, 95 % CI [1.37–3.34]).20 AF has also been found to be associated with worse survival in a cohort (N=1,069) of patients with HCM (HR 1.44, 95 % CI [1.20–1.71]).25 Analysis undertaken in a combined cohort from Italy and the USA demonstrated an increased risk of HCM-related death in patients with comorbid AF (OR 3.7, 95 % CI [1.7–8.1]).16 In a sub-group analysis, those who developed AF at ≤50 years of age had an increased risk of HCM-related mortality and progression of symptoms (1.7and 1.5-fold, respectively). Increased HCM-related mortality rates17,43

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Atrial Fibrillation in Hypertrophic Cardiomyopathy and symptom progression related to the development of AF17 have also been reported by other groups. Indeed, stroke associated with AF was found to be the cause of 13 % of HCM-related deaths in a consecutive cohort of 744 patients with HCM.44

Treatment of Atrial Fibrillation in Hypertrophic Cardiomyopathy Given the association between the development of AF and significant outcomes in HCM, prompt treatment of AF is required. In those with haemodynamic instability, electrical cardioversion is recommended,5 as with patients without HCM who develop AF.9 There is limited evidence to support specific treatment regimens for rate or rhythm control of AF in patients with HCM. Beta-blockers, diltiazem and verapamil are all recommended without significant evidence to support their efficacy in this patient group.5,9 However, given the likelihood that AF is highly symptomatic in HCM, conversion to sinus rhythm is considered beneficial. Amiodarone has been shown to be safe for use in patients with HCM,45 although long-term treatment is complicated by the sideeffect profile that is common with this medication. In addition, evidence for efficacy in this situation is derived primarily from non-randomised trials and is not overwelming.16,23,46 Disopyramide, recommended as a second-line therapy for symptomatic LVOTO,47 can be considered for the treatment of AF in patients with HCM;5 however, caution is needed in light of the potential for enhanced atrioventricular conduction and associated increased ventricular rate in AF. The use of catheter ablation in patients with HCM to prevent AF recurrence has been shown to be potentially beneficial in a number of small studies.48–50 Success rates >60 % at 1 year have been reported. However, Di Donna et al. demonstrated that despite such overall success rates, redo procedures were required in 52 % of patients and antiarrhythmic medication was continued in 54 %.49 These results are not dissimilar to those seen in the general AF population. McCready et al. demonstrated that HCM was an independent risk factor for AF recurrence following multiple procedures (HR 2.42, 95 % CI [1.06–5.55]).51

Hypertrophic Cardiomyopathy and Stroke Risk The risk of stroke in patients with HCM is well recognised, with Furlan et al. demonstrating a 7 % risk of cerebrovascular events over an average follow-up of 5.5 years.52 Incident rates of stroke in HCM, irrespective of AF diagnosis, have been estimated as 2.5 %/year.30 Compared with patients with HCM in sinus rhythm, those in AF were shown to have an eightfold increase in stroke risk (21 versus 2.6 %) in a 480-patient cohort (107 AF cases) over a follow-up period of 12.6 ± 7.7 years; thromboembolic events in patients with AF occurred on average 3.5 ± 3.4 years after AF diagnosis.16 This is supported by data from a Japanese cohort that demonstrated a 3.9-fold increased risk of stroke in patients with HCM and AF (23.0 versus 5.9 % at 5 years; p<0.01).53 High risk of stroke in the HCM population is further supported by additional groups.30,42,54–57 A meta-analysis of this topic area determined an overall annual incidence of stroke in patients with HCM and AF of 3.75 % (see Figure 2).21 However, despite the inclusion of 20 studies in this area, there were only 296 cases of thromboembolism from a pool of 6,102 HCM cases. In a large retrospective cohort study (n=4,921), Guttmann et al. demonstrated that, having excluded those with prevalent AF, 2.2 % of patients with HCM developed thromboembolic events (cerebrovascular accident [CVA], transient ischaemia attack or peripheral emboli) within 5 years.58 In addition, in patients with AF, the presence of HCM is a

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Figure 2: Incidence of Thromboembolism in Patients with Hypertrophic Cardiomyopathy and Atrial Fibrillation AF cases

TE cases

Robinson K, et al. (1990)

174

3.85 [1.67–6.02]

Shigematsu Y, et al. (1995)

7.05 [2.88–11.22]

Higashikawa M, et al. (1997)

6.65 [2.53–10.76]

Olivotto I, et al. (2001)

480

2.36 [1.40–3.33]

Trial

Incidence rate of TE (per 100 patients [95 % CI])

Doi Y (2001)

3.39 [0.42–6.37]

Maron B, et al. (2002)

900

3.27 [2.31–4.24]

Ogimoto A, et al. (2002)

138

5.49 [2.71–8.28]

Ho H, et al. (2004)

118

4.21 [1.60–6.81]

Kubo T, et al. (2009)

261

5.07 [2.50–7.63]

Maron B, et al. (2012)

2.36 [-0.91–5.64]

3.75 [2.88–4.61]

Overall (I =37.9 %; P=0.106)

3.75

Forest plot From random effect meta-analysis shows study specific incidence and pooled incidence of thromboembolism (TE). Source: modified from Guttmann et al., 2014.21 HCM = hypertrophic cardiomyopathy.

strong independent risk factor for the presence of ischaemic stroke (52.6 versus 15.3 %; p<0.001).53 This increased risk is recognised in the Japanese Circulation Society’s HCM (2012) and AF (2013) guidelines, which recommend anticoagulation in all patients with HCM and AF.59,60

Stratification of Thromboembolic Risk in Hypertrophic Cardiomyopathy Risk stratification for the incidence of stroke in AF has been a central component of guidelines issued by major cardiology societies over the past decade.9,60,61 In inividuals without HCM, this has included recognition that there is a population of individuals with AF who remain at low risk of stroke.9 All patients with HCM developing AF are considered to be at high risk of thromboembolic events. However, a consensus on what constitutes an increased risk of stroke in the HCM population has yet to be clarified. The current literature suggests several independent risk factors for the development of stroke in patients with HCM and AF (see Table 1). LA diameter, as well as being associated with the development of AF itself, has also been shown to be a risk factor for thromboembolic outcomes.17,54,58 Notably, each 1 mm increase was shown to increase the risk of stroke-related death (HR 1.10, 95 % CI [1.00–1.20]).17 Increased LA size has also been suggested as an independent risk factor for thromboembolic events in patients with HCM without diagnosed AF.54 Increasing age is a recognised risk factor for stroke both within the general population, and particularly those with AF.9 Increasing age has been shown to be associated with increased risk of thromboembolic events in patients with HCM.30,54,58 However, it should also be noted that AF has been demonstrated at significantly younger ages in patients with HCM, and a significant number of thromboembolic events occur in this younger population.30 In support of this, Olivotto et al. reported that the risk of stroke was higher in patients ≤50 years of age.16 The presence of congestive heart failure symptoms is recognised as a risk factor for cerebrovascular events in the AF population.

Clinical Arrhythmias Table 1: Independent Risk Factors, in Addition to the Presence of Atrial Fibrillation, Associated with the Development of Stroke in Patients with Hypertrophic Cardiomyopathy Citation

Strength of risk

Cohort

Risk factor

Outcome

[95 % CI]

size

(years)

Olivotto et al.16 Age at development of AF ≤50 years Stroke

HR 3.6 (95 % CI not given)

480

107

12.6 ± 7.7

Maron et al.30

Age >60 years as initial evaluation

RR 8.2 [3.9–21.6]

900

192

4.9 ± 4.3

NYHA class III or IV at initial evaluation

Thromboembolism*

Embolic stroke Benchimol CHADS2>1 LV outflow tract gradient >38 mmHg Barbosa et al.62

AF cases

CVA/TE

Follow-up

RR 2.4 [1.2–5.0]

5.9 ± 5.7

OR 7.7 [2.7–22.3] OR 5.5 [1.8–16.4]

12.3

172

Thromboembolism* HR 3.63 [1.81–7.29] 4,817 600 172 6.0 (IQR Guttmann et al.58 Prior thromboembolic event 3.0–9.7)

NYHA class III or IV

HR 2.07 [1.35–3.17]

Increasing age (per 1 year)

HR 1.03 [1.02–1.04]

LA diameter (per 1 mm increase)

HR 1.03 [1.01–1.05]

Maximum wall thickness (per 1 mm increase)

HR 1.45 [1.12–1.88]

Tian et al.17

LA diameter (per 1 mm increase)

Stroke-related death

HR 1.10 [1.00–1.20]

654

112

4.2 ± 2.8

LA diameter ≥48 mm Thromboembolism* Haruki et al.54 Age at HCM diagnosis (per 1 year increase)

HR 2.74 [1.20–6.23] HR 1.03 [1.01–1.06]

431

0†

10.7 ± 7.5

*Composite marker of CVA, transient ischaemic attack and peripheral TE. †Sub-group analysis in patients without documented AF. CVA = cerebrovascular accident; HR = hazard ratio; LA = left atrial; LV = left ventricular; OR = odds ratio; RR = relative reduction; TE = thromboembolism.

Table 2: Guideline Recommendations Regarding Anticoagulation of Patients with Hypertrophic Cardiomyopathy and Atrial Fibrillation Guideline

Issuing

Patients requiring

Anticoagulation

Strength of

body

Year

anticoagulation

agent (1st line)

recommendation

ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy5

ESC

All patients with HCM and AF

VKA

Class I

ESC guidelines for the management of AF9 ESC 2016 All patients with HCM and AF

No preference between VKA and NOAC for HCM

Class I

Guidelines for the diagnosis and treatment of HCM74

ACC/AHA

VKA

Class I

AHA/ACC/HRS guidelines for the management of patients with AF75

AHA/ACC/ 2014 All patients with HCM and AF HRS

No specification of VKA or NOAC

Class I

Guidelines for diagnosis and treatment JCS 2012 All patients with HCM and AF of patients with HCM59

No specification of VKA or NOAC

Not stated

JCS 2013 All patients with HCM and AF Guidelines for the pharmacotherapy of AF60

No specification of VKA or NOAC

Class IIa

2014

2011

All patients with HCM and AF

ACC = American College of Cardiology; AHA = American Heart Association; ESC = European Society of Cardiology; HCM, hypertrophic cardiomyopathy; HRS = Heart Rhythm Society; JCS = Japanese Circulation Society; NOAC = non-vitamin K antagonist oral anticoagulant; VKA = vitamin K antagonist.

A similar position in the HCM population is supported by Maron et al. who demonstrated that the presence of NYHA class III–IV was independently associated with increased risk of stroke.30 Using a list of pre-specified risk factors, Guttmann et al. were able to develop a risk model for predicting the development of thromboembolic events in patients with HCM.58 This model included age, presence of AF, previous thromboembolism, presence of congestive heart failure symptoms, vascular disease, LA diameter and maximal ventricular wall thickness. The authors described good correlation with the incidence of thromboembolic events. Although this model is a useful addition to the discussion of anticoagulation in this population, the complexity makes its use potentially cumbersome. Some authors have previously advised using some elements of currently or previously established risk stratification tools in the general AF population. Benchimol Barbosa et al. found that a CHADS2 score >1 was associated with increased risk of CVA and have advocated its use

as part of a score for the incidence of CVA in the HCM popuatlion.62 Inoue and colleagues, when assessing thromboembolic rates in those with non-valvular AF, have advocated a single point for the presence of HCM to the CHADS2 score;63 however, they failed to define a clear threshold at which point anticoagulation became necessary; instead assigned patients to low-, moderate- and high-risk categories. A low CHA2DS2-VASc score has been suggested as an appropriate marker for identifying little risk of thromboembolism in patients with HCM and AF. A CHA2DS2-VASc score ≤1 was associated with an annual thromboembolic incidence of 0.9 %;64 this is in line with thresholds of anticoagulation with non-vitamin K antagonist oral anticoagulants (NOACs). However the use of traditional scores in risk stratifying stroke risk in HCM is not proposed in current guidance issued by the European Society of Cardiology (ESC) or Japanese Circulation Society (JCS).5,59 This position is supported by evidence showing a poor correlation between CHA2DS2-VASc score and the development of thromboembolism in a

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Atrial Fibrillation in Hypertrophic Cardiomyopathy small sub-population of un-anticoagulated patients with HCM and AF (n=222).58 However, it should be noted that within this group there were only 21 events in total and no strong conclusions can be derived from this analysis. Given the strong burden of evidence supporting a high risk of thromboembolism in patients with HCM who develop AF, such patients should be identified early. To date, no research has undertaken the prophylactic anticoagulation of patients with HCM and highrisk features for the development of AF. However, this may be an appropriate management strategy if such a population can be adequately defined.

Choice of Anticoagulant in Patients with Hypertrophic Cardiomyopathy There is no randomised controlled trial assessing the role of anticoagulation among patients with HCM. Evidence is limited to that from small cohort studies, which show that the use of anticoagulation in patients with HCM and AF reduces the risk of thromboembolic events. Olivotto et al., in a cohort of 107 patients with HCM and AF, demonstrated a reduction of stroke from 39 % (n=11) in untreated patients to 10 % (n=6) in those treated with warfarin (p=0.001).16 This is in line with findings from a cohort of 200 patients with HCM and AF, where a reduction in the cumulative incidence of stroke was demonstrated with anticoagulation (31 % without anticoagulation [n=33] versus 18 % with warfarin [n=15]; p<0.05).30 Of note, patients on antiplatelet agents had no significant reduction in stroke risk, which is in line with findings in the general AF population.5,65 The role of anticoagulation is supported by other data showing a reduced risk of stroke when anticoagulated with warfarin (31–18 %).30 At present, no data are available from randomised controlled trials on the effectiveness of NOACs in reducing thromboembolic risk in this population. Among the four major prospective trials assessing the efficacy of NOACs versus warfarin in AF, patients with HCM were not included in the analyses.66–69 Large ‘real-world’ analyses of NOAC therapy have also failed to provide any specific discussion of patients

aron BJ, McKenna WJ, Danielson GK, et al. American M College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy. A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines. J Am Coll Cardiol 2003;42:1687–713. PMID: 14607462. Maron BJ, Gardin JM, Flack JM, et al. Prevalence of hypertrophic cardiomyopathy in a general population of young adults: echocardiographic analysis of 4111 Subjects in the CARDIA Study. Circulation 1995;92:785–9. PMID: 7641357. Koester MC. A Review of Sudden Cardiac Death in Young Athletes and Strategies for Preparticipation Cardiovascular Screening. J Athl Train 2001;36:197–204. PMID: 12937463. Morita H, Rehm HL, Menesses A, et al. Shared genetic causes of cardiac hypertrophy in children and adults. N Engl J Med 2008;358:1899–908. DOI: 10.1056/NEJMoa075463; PMID: 18403758. Authors/Task Force members, Elliott PM, Anastasakis A, et al. 2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J 2014;35:2733–79. DOI: 10.1093/eurheartj/ehu284; PMID: 25173338. Okin PM, Devereux RB, Jern S, et al. Regression of electrocardiographic left ventricular hypertrophy during antihypertensive treatment and the prediction of major cardiovascular events. JAMA 2004;292:2343–9. DOI: 10.1001/ jama.292.19.2343; PMID: 15547161. Melacini P, Basso C, Angelini A, et al. Clinicopathological profiles of progressive heart failure in hypertrophic cardiomyopathy. Eur Heart J 2010;31:2111–23. DOI: 10.1093/ eurheartj/ehq136; PMID: 20513729.

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10.

11.

12.

13.

14.

15.

16.

17.

with HCM.70,71 Noseworthy et al. examined a retrospective cohort of patients with HCM on anticoagulation and found no significant difference between NOACs and vitamin K antagonists in the rate of ischaemic stroke (HR 1.37, 95 % CI [0.40–4.67]) or major bleeding (HR 0.75, 95 % CI [0.36–1.57]).72 Furthermore, a recent post hoc subgroup analysis of the Randomised Evaluation of Long-term Anticoagulation Therapy (RE-LY) study has shown that the presence of LV hypertrophy determined by ECG criteria lead to decreased warfarin efficacy (dabigatran 150 mg versus warfarin HR 0.48, 95 % CI [0.29–0.78]).73 Although this analysis did not examine patients with HCM directly, the findings do suggest they may benefit from NOAC therapy. Given the strong evidence for their use in the AF population, NOACs have been recommended as second-line agents in patients with HCM and AF.5 However, this guidance remains unaligned between major guideline organisations. The American College of Cardiology (ACC), American Heart Association (AHA), ESC, and Heart Rhythm Society (HRS) uniformly recommend anticoagulation of all patients with HCM who develop AF (see Table 2). However, only in the most recent ESC guidelines discussing this patient group has the use of either vitamin K antagonists or NOAC anticoagulation been recommended.9

Conclusion AF represents a common comorbid condition or complication in patients with HCM. As in the general population, AF is associated with significant morbidity from thromboembolic events and consequent mortality. The risk of thromboembolic events is higher than in the general population with AF and, although some independent risk factors have been identified, it is recommended that everyone with AF and HCM should be anticoagulated to mitigate this risk. However, the lack of data derived from randomised controlled trials or large-scale cohort studies emphasises the importance of and need for prospective registries with regards to the development of AF and its associated downstream outcomes. Given the burden of AF in the HCM population, and the high risk of associated thromboembolic stroke, it is now necessary to focus on identifying patients at high-risk of developing AF such that prophylactic anticoagulation can be considered. n

iyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends in M incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation 2006;114:119–25. DOI: 10.1161/ CIRCULATIONAHA.105.595140; PMID: 16818816. 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. DOI: 10.1093/eurheartj/ehw210; PMID: 27567408. Ohtani K, Yutani C, Nagata S, et al. High prevalence of atrial fibrosis in patients with dilated cardiomyopathy. J Am Coll Cardiol 1995;25:1162–9. PMID: 7897130. Binder J, Attenhofer Jost CH, Klarich KW, et al. Apical hypertrophic cardiomyopathy: prevalence and correlates of apical outpouching. J Am Soc Echocardiogr 2011;24:775–81. DOI: 10.1016/j.echo.2011.03.002; PMID: 21511435. D’Amato R, Tomberli B, Castelli G, et al. Prognostic value of N-terminal pro-brain natriuretic Peptide in outpatients with hypertrophic cardiomyopathy. Am J Cardiol 2013;112:1190–6. DOI: 10.1016/j.amjcard.2013.06.018; PMID: 23871673. Eriksson MJ, Sonnenberg B, Woo A, et al. Long-term outcome in patients with apical hypertrophic cardiomyopathy. J Am Coll Cardiol 2002;39:638–45. PMID: 11849863. Kawasaki T, Sakai C, Harimoto K, et al. Holter monitoring and long-term prognosis in hypertrophic cardiomyopathy. Cardiology 2012;122:44–54. DOI: 10.1159/000338156; PMID: 22722267. Moon J, Shim CY, Ha JW, et al. Clinical and echocardiographic predictors of outcomes in patients with apical hypertrophic cardiomyopathy. Am J Cardiol 2011;108:1614–9. DOI: 10.1016/ j.amjcard.2011.07.024; PMID: 21890076. Olivotto I, Cecchi F, Casey SA, et al. Impact of atrial fibrillation on the clinical course of hypertrophic cardiomyopathy. Circulation 2001;104:2517–24. PMID: 11714644. Tian T, Wang Y, Sun K, et al. Clinical profile and prognostic

18.

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significance of atrial fibrillation in hypertrophic cardiomyopathy. Cardiology 2013;126:258–64. DOI: 10.1159/000354953; PMID: 24157592, Losi MA, Betocchi S, Aversa M, et al. Determinants of atrial fibrillation development in patients with hypertrophic cardiomyopathy. Am J Cardiol 2004;94:895–900. DOI: 10.1016/ j.amjcard.2004.06.024; PMID: 15464672. Guttmann OP, Pavlou M, O’Mahony C, et al. Prediction of thrombo-embolic risk in patients with hypertrophic cardiomyopathy (HCM Risk-CVA). Eur Heart J 2015;17:837–45. DOI: 10.1002/ejhf.316; PMID: 26183688. Desai MY, Bhonsale A, Smedira NG, et al. Predictors of longterm outcomes in symptomatic hypertrophic obstructive cardiomyopathy patients undergoing surgical relief of left ventricular outflow tract obstruction. Circulation 2013;128: 209–16. DOI: 10.1161/CIRCULATIONAHA.112.000849; PMID: 23770748. Guttmann OP, Rahman MS, O’Mahony C, et al. Atrial fibrillation and thromboembolism in patients with hypertrophic cardiomyopathy: systematic review. Heart 2014;100:465–72. DOI: 10.1136/heartjnl-2013-304276; PMID: 24014282. Healey JS, Connolly SJ, Gold MR, et al. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med 2012;366:120–9. DOI: 10.1056/NEJMoa1105575; PMID: 22236222. Robinson K, Frenneaux MP, Stockins B, et al. Atrial fibrillation in hypertrophic cardiomyopathy: a longitudinal study. J Am Coll Cardiol 1990;15:1279–85. PMID: 2329232. Wilke I, Witzel K, Munch J, et al. High incidence of de novo and subclinical atrial fibrillation in patients with hypertrophic cardiomyopathy and cardiac rhythm management device. J Cardiovasc Electrophysiol 2016;27:779–84. DOI: 10.1111/ jce.12982; PMID: 27060297. Siontis KC, Geske JB, Ong K, et al. Atrial fibrillation in hypertrophic cardiomyopathy: prevalence, clinical correlations, and mortality in a large high-risk population.

Clinical Arrhythmias

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fibrillation in Japanese patients with hypertrophic cardiomyopathy. J Hum Genet 2002;47:184–9. DOI: 10.1007/ s100380200021; PMID: 12166654. Maron BJ, Casey SA, Poliac LC, et al. Clinical course of hypertrophic cardiomyopathy in a regional United States cohort. JAMA 1999;281:650–5. PMID: 10029128. Maron BJ, Olivotto I, Spirito P, et al. Epidemiology of hypertrophic cardiomyopathy-related death: revisited in a large non-referral-based patient population. Circulation 2000;102:858–64. PMID: 10952953. Cecchi F, Olivotto I, Montereggi A, et al. Prognostic value of non-sustained ventricular tachycardia and the potential role of amiodarone treatment in hypertrophic cardiomyopathy: assessment in an unselected non-referral based patient population. Heart 1998;79:331–6. PMID: 9616338. Guttmann OP, Pavlou M, O’Mahony C, et al. Predictors of atrial fibrillation in hypertrophic cardiomyopathy. Heart 2017;103:672–8. Sherrid MV, Barac I, McKenna WJ, et al. Multicenter study of the efficacy and safety of disopyramide in obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2005;45:1251–8. DOI: 10.1016/j.jacc.2005.01.012; PMID: 15837258. Bunch TJ, Munger TM, Friedman PA, et al. Substrate and procedural predictors of outcomes after catheter ablation for atrial fibrillation in patients with hypertrophic cardiomyopathy. J Cardiovasc Electrophysiol 2008;19:1009–14. DOI: 10.1111/j.15408167.2008.01192.x; PMID: 18479329. Di Donna P, Olivotto I, Delcre SD, et al. Efficacy of catheter ablation for atrial fibrillation in hypertrophic cardiomyopathy: impact of age, atrial remodelling, and disease progression. Europace 2010;12:347–55. DOI: 10.1093/europace/euq013; PMID: 20173211. Gaita F, Di Donna P, Olivotto I, et al. Usefulness and safety of transcatheter ablation of atrial fibrillation in patients with hypertrophic cardiomyopathy. Am J Cardiol 2007;99:1575–81. DOI: 10.1016/j.amjcard.2006.12.087; PMID: 17531584. McCready JW, Smedley T, Lambiase PD, et al. Predictors of recurrence following radiofrequency ablation for persistent atrial fibrillation. Europace 2011;13:355–61. DOI: 10.1093/ europace/euq434; PMID: 21148171. Furlan AJ, Craciun AR, Raju NR, Hart N. Cerebrovascular complications associated with idiopathic hypertrophic subaortic stenosis. Stroke 1984;15:282–4. PMID: 6538354. Higashikawa M, Nakamura Y, Yoshida M, Kinoshita M. Incidence of ischemic strokes in hypertrophic cardiomyopathy is markedly increased if complicated by atrial fibrillation. Jpn Circ J 1997;61:673–81. PMID: 9276772. Haruki S, Minami Y, Hagiwara N. Stroke and embolic events in hypertrophic cardiomyopathy: risk stratification in patients without atrial fibrillation. Stroke 2016;47:936–42. PMID: 9276772. Doi Y, Kitaoka H. Hypertrophic cardiomyopathy in the elderly: significance of atrial fibrillation. J Cardiol 2001;37(Suppl 1): 133–8. PMID: 11433817. Ho HH, Lee KL, Lau CP, Tse HF. Clinical characteristics of and long-term outcome in Chinese patients with hypertrophic cardiomyopathy. Am J Med 2004;116:19–23. PMID: 14706661. Maron BJ, Casey SA, Haas TS, et al. Hypertrophic cardiomyopathy with longevity to 90 years or older. Am J Cardiol 2012;109:1341–7. DOI: 10.1016/j.amjcard.2011.12.027; PMID: 22381158. Guttmann OP, Pavlou M, O’Mahony C, et al. Prediction of thrombo-embolic risk in patients with hypertrophic cardiomyopathy (HCM Risk-CVA). Eur J Heart Fail 2015;17: 837–45. DOI: 10.1002/ejhf.316; PMID: 26183688. JCS Joint Working Group. Guidelines for diagnosis and treatment of patients with hypertrophic cardiomyopathy (JCS 2012) – digest version. Circ J 2016;80:753–74. DOI: 10.1253/ circj.CJ-66-0122; PMID: 26841693. JCS Joint Working Group. Guidelines for pharmacotherapy of atrial fibrillation (JCS 2013). Circ J 2014;78:1997–2021. PMID: 24965079.

61. J anuary CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/ HRS guideline for the management of patients with atrial fibrillation: executive summary. J Am Coll Cardiol 2014;64: 2246–80. DOI: 10.1161/CIR.0000000000000040; PMID: 24682348. 62. Benchimol Barbosa PR, Barbosa EC, Bomfin AS, et al. A practical score for risk stratification of embolic stroke in hypertrophic cardiomyopathy. Eur Heart J 2013;34(Suppl 1):P2969. DOI: 10.1093/eurheartj/eht309.P2969. 63. Inoue H, Nozawa T, Hirai T, et al. Accumulation of risk factors increases risk of thromboembolic events in patients with nonvalvular atrial fibrillation. Circ J 2006;70:651–6. PMID: 16723782. 64. Yang YJ, Yuan JQ, Fan CM, et al. Incidence of ischemic stroke and systemic embolism in patients with hypertrophic cardiomyopathy, nonvalvular atrial fibrillation, CHA2DS2-VASc score of </=1 and without anticoagulant therapy. Heart Vessels 2016;31:1148–53. DOI: 10.1007/s00380-015-0718-5; PMID: 26231425. 65. van Walraven C, Hart RG, Singer DE, et al. Oral anticoagulants vs aspirin in nonvalvular atrial fibrillation: an individual patient meta-analysis. JAMA 2002;288:2441–8. PMID: 12435257. 66. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51. DOI: 10.1056/NEJMoa0905561; PMID: 19717844. 67. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–92. DOI: 10.1056/NEJMoa1107039; PMID: 21870978. 68. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91. DOI: 10.1056/NEJMoa1009638; PMID: 21830957. 69. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093–104. DOI: 10.1056/NEJMoa1310907; PMID: 24251359. 70. Yao X, Abraham NS, Sangaralingham LR, et al. Effectiveness and safety of dabigatran, rivaroxaban, and apixaban versus warfarin in nonvalvular atrial fibrillation. J Am Heart Assoc 2016;5:pii: e003725. DOI: 10.1161/JAHA.116.003725; PMID: 27412905. 71. Larsen TB, Skjoth F, Nielsen PB, et al. Comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study. BMJ 2016;353:i3189. PMID: 27312796. 72. Noseworthy PA, Yao X, Shah ND, Gersh BJ. Stroke and bleeding risks in noac- and warfarin-treated patients with hypertrophic cardiomyopathy and atrial fibrillation. J Am Coll Cardiol 2016;67:3020–1. DOI: 10.1016/j.jacc.2016.04.026; PMID: 27339501. 73. Verdecchia P, Reboldi G, Angeli F, et al. Dabigatran versus warfarin in relation to the presence of left ventricular hypertrophy in patients with atrial fibrillation: The randomized evaluation of long-term anticoagulation therapy (RE-LY) study. Europace 2017; {Epub ahead of print]. DOI: 10.1093/europace/ eux022; PMID: 28520924 74. Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011;124:e783–831. DOI: 10.1161/CIR.0b013e318223e2bd; PMID: 22068434. 75. 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. Circulation 2014;130:e199–267. DOI: 10.1161/CIR.0000000000000041; PMID: 24682347.

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Device Therapy

A Review of Image-guided Approaches for Cardiac Resynchronisation Therapy Haipeng Tang, 1 Shaojie Tang 2 and Weihua Zhou 1 1. School of Computing, University of Southern Mississippi, Long Beach, MS, USA; 2. School of Automation, Xi’an University of Posts and Telecommunications, Xi’an, Shaanxi, China

Abstract Cardiac resynchronisation therapy (CRT) is a standard treatment for patients with heart failure; however, the low response rate significantly reduces its cost-effectiveness. A favourable CRT response primarily depends on whether implanters can identify the optimal left ventricular (LV) lead position and accurately place the lead at the recommended site. Myocardial imaging techniques, including echocardiography, cardiac magnetic resonance imaging and nuclear imaging, have been used to assess LV myocardial viability and mechanical dyssynchrony, and deduce the optimal LV lead position. The optimal position, presented as a segment of the myocardial wall, is then overlaid with images of the coronary veins from fluoroscopy to aid navigation of the LV lead to the target venous site. Once validated by large clinical trials, these image-guided techniques for CRT lead placement may have an impact on current clinical practice.

Keywords Cardiac resynchronisation therapy, heart failure, left ventricle, myocardial viability, mechanical dyssynchrony Disclosure: The authors have no conflicts of interest to declare. Received: 20 December 2016 Accepted: 20 January 2017 Citation: Arrhythmia & Electrophysiology Review 2017;6(2):69–74. DOI: 10.15420/aer.2016:32:2 Correspondence: Dr Weihua Zhou, School of Computing, University of Southern Mississippi, 730 East Beach Boulevard, Long Beach, MS 39560, USA

Cardiac resynchronisation therapy (CRT) is a widely-performed standard treatment for improving cardiac function and quality of life in patients with heart failure.1 After CRT, however, 30–40 % of patients do not experience improvements in left ventricular (LV) function and clinical symptoms.2–3 The key factors for increasing the response rate to CRT are identification of the optimal LV lead position and accurate lead placement at the optimal site.4–7 The optimal LV lead position is in the viable myocardial region with the latest contraction onset.8–9 Several myocardial imaging techniques have been developed to identify this position, such as echocardiography,10–11 cardiac magnetic resonance imaging (CMR)12 and nuclear imaging.13–15 Placing the LV lead in the recommended position through coronary veins is a challenge.16,17 This procedure requires high accuracy, since a difference of 20 mm in LV lead location on the myocardial wall can influence CRT response, and an incorrect LV lead pacing site may lead to greater myocardial dyssynchrony.18 This paper reviews the technical advances and clinical studies being used in image-guided LV lead placement in CRT, including the identification of optimal LV lead position and placement of the LV lead at the recommended site.

Image-guided LV Lead Placement in CRT

worse outcomes after CRT.20,21 Regardless of which condition patients present with, however, extensive scar burden can negatively impact LV functional outcomes.22–25 Recent studies show that preserved viability in the LV lead segment is related to greater LV reverse remodelling and functional benefit.25 Evaluation of myocardium viability is therefore important when predicting CRT response. The quantification and assessment of LV electrical and mechanical dyssynchrony is important in determining CRT response.3,26 The propagation of electrical activity parallels mechanical activation, so both QRS morphology and duration can reflect the dyssynchrony of LV electromechanical activity and can be regarded as electrocardiographic predictors of CRT response.27 The degree of LV electric delay, assessed based on the interval from the onset of the surface (lead II) QRS to the first major peak (positive or negative) of the left ventricle, is related to the reduction in mitral regurgitation, which contributes to the development of an electric-targeting LV lead strategy for improved CRT response.28 A true left bundle branch block (LBBB) activation pattern has a U shape and is also an important factor in predicting response to CRT.27,29 A true LBBB activation pattern is defined as a unique contraction pattern of opposing wall motion30 with apical rocking motion31 that can reflect a true LV activation delay.32 Niels et al.29 found that the U-shaped activation pattern induced by true LBBB and a QRS duration of ≥120 ms could be used as criteria to predict CRT response.

Optimal LV Lead Position Myocardial viability at the LV lead position is a key factor in enhancing CRT response rate. The quantification of scar burden in LV dyssynchrony is essential in the evaluation of CRT candidates with ischaemic cardiomyopathy (ICM) or non-ischaemic cardiomyopathy (NICM). Compared with NICM patients, the CRT response rate in ICM patients is more sensitive to the extent of scaring19,20 as these patients have more extensive and transmural myocardial fibrosis, which results in

Pacing the latest mechanical activated site may significantly reduce the total LV electromechanical activation time compared with pacing other sites on the myocardial wall.17 An animal study demonstrated that the regions with maximal resynchronisation after CRT had maximum improvements in systolic LV function. These regions are the ‘sweet spots’ and regarded as optimal regions for LV lead placement.33,34 A recent study shows that the latest activated regions may vary

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Device Therapy Figure 1: Assessment of Regional Myocardial Viability and Dyssynchrony with Gated Single Photon Emission Computed Tomography Myocardial Perfusion Imaging

Left: Dyssynchrony polar map showing the site of latest activation is the mid-anterior segment. Right: Site of latest activation is shown to be viable on the viability polar map. The optimal LV lead position is thus the mid-anterior segment. The segments next to the optimal position are suboptimal and ranked by activation delay. Source: Zhou et al., 2016.45

significantly, being on the posterolateral myocardial wall in 67 % of patients and in different regions in the remaining 33 % of patients.35 Ypenburg et al.36 make a similar observation, reporting that the latest mechanical activation is most frequently located in the lateral (33 %) and posterior segments (36 %). Several clinical trials have used echocardiography, CMR or nuclear imaging techniques to assess myocardial viability and the latest activated site in order to determine the optimal LV lead position.4,37–40 Echocardiographic techniques, such as tissue Doppler imaging, 2D and 3D speckle tracking echocardiography, are used to evaluate regional myocardial function in several clinical trials. In the prospective Targeted Left Ventricular Lead Placement to Guide Cardiac Resynchronization Therapy (TARGET) study,16 220 patients (123 with ICM and with 197 NICM, QRS ≥120 ms) were enrolled and randomly divided into two equal-sized groups. In group 1, 2D speckle tracking echocardiography was applied to determine the optimal LV lead position. The time–strain curves were generated by the movement patterns of the speckles. Starting from the onset of LV contraction in the mid and basal short-axis views, the segment containing curves with the most delayed peaks was identified as the latest activated segment. In group 1, 70 % of the latest activated sites were in the posterior and lateral segments, while 30 % were in the inferior, anterior, anteroseptal and inferoseptal segments. Scar burden was assessed by measuring the extent of the radial strain amplitude and regions with <10 % deformation amplitude were regarded to contain scarring. The LV leads in group 1 were therefore placed in the latest activated segments without scar burdens. In contrast, patients in group 2 underwent standard CRT. As a result, compared with group 2, group 1 had a higher clinical response (83 % versus 65 %, p=0.003). Of the 187 CRT candidates with heart failure (62 % ICM, QRS 159±27 ms) enrolled in the prospective Speckle Tracking Assisted Resynchronization Therapy for Electrode Region (STARTER) trial,17 treatment was guided by routine strategy (77 patients) or echocardiography (110 patients). The segment with the latest time-to-peak radial strain was considered the latest activated site. No formal quantification of myocardial scar was assessed in this study. Segments with low amplitude strain curves, implying a thin myocardial wall, and unexpected stronger acoustic reflectance were considered likely scar regions.41 These regions were

handled as missing data and not considered optimal LV lead positions. In the echo-guided group, therefore, the LV leads were placed in the latest activated sites without likely scar burdens: 76 % in lateral and posterolateral segments and 24 % in anterolateral and posterior segments. A clinical CRT response was defined as ≥15 % decrease in LV end-systolic volume (LVESV) or ≥5 % absolute increase in LV ejection fraction (LVEF). In the echo-guided group, 57 % had a decrease of ≥15 % in LVESV and 59 % had an increase of ≥5 % in LVEF; while in the routine strategy group, 35 % had a decrease of ≥15 % in LVESV and 39 % had an increase of ≥5 % in LVEF. Nuclear imaging can assess myocardial viability, mechanical dyssynchrony and LV global function in one single scan. Gated singlephoton emission-computed tomography myocardial perfusion imaging (SPECT MPI) and positron emission tomography (PET) are therefore both considered ‘one-stop shops’ in CRT guidance.4,5,13–15,40,42–44 Figure 1 shows the assessment of regional myocardial viability and mechanical dyssynchrony by gated SPECT MPI.45

SPECT MPI In a retrospective study conducted by Boogers et al.,13 SPECT MPI was used to determine the optimal LV lead position in 90 patients with advanced heart failure (QRS 161±36 ms). For each patient, a six-segment model was used to determine the latest activated site. The mean phase of every segment was calculated and the segment with the biggest value was regarded as the latest activated segment. Regions of myocardial scaring were defined as segments with <50 % tracer uptake. In consequence, the latest activated sites were located in posterior (42.2 %), lateral (23.3 %), inferior (13.3 %), anterior (15.6 %), anteroseptal (3 %) and septal (2.3 %) segments. The LV leads were placed at the latest activated sites in 52 patients (58 %, concordant) and outside the latest activated sites in 38 patients (42 %, discordant). Seventy-nine per cent of patients with concordant LV lead positions and only 26 % of patients with discordant LV lead positions had favourable CRT responses. At 6-month follow-up, significantly improved LV functions were found in patients with concordant LV lead positions; however, patients with discordant LV lead positions did not show any improvement in LV function. In a recent prospective study, Friehling et al.15 used a similar method to determine the optimal LV lead positions in 44 patients (19 with ICM and 25 with NICM, QRS 178±34 ms). The latest mechanical activated segment with acceptable myocardial viability was chosen to be the concordant LV lead position. These researchers evaluated the acute change in LV synchrony after CRT and found that it had improved in 18 patients, deteriorated in 15 patients and remained unchanged in 11 patients. Finally, it was shown that 96 % of patients with acceptable scar burden (<40 %), baseline mechanical dyssynchrony and a concordant LV lead position had a favourable acute CRT response and long-term outcome.

PET A PET study conducted by Uebleis et al.14 retrospectively compared seven responders’ LV functions with seven non-responders’ LV functions after CRT by using gated 18F-fluorodeoxyglucose (FDG) PET. All patients had a QRS ≥120 ms. They found that, compared with nonresponders, responders showed lower LVESV, LV dyssynchrony and myocardial scar burden. In addition, responders had more biventricular pacemaker leads placed in viable myocardial regions and achieved a higher response rate than non-responders.

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Image-guided Cardiac Resynchronisation Therapy In the other retrospective PET study, Lehner et al. 46 hypothesised that the probability of a favourable CRT response would be increased in cases with high amounts of ‘viable and dyssynchronous’ myocardium. Nineteen patients (seven with ICM and 12 with NICM; QRS 169±31 ms) who underwent electrocardiogram-gated FDG PET before CRT implantation were followed for 6 months. Clinical improvement of at least one New York Heart Association (NYHA) class combined with >5 % LVEF improvement was considered a favourable response to CRT. As a result, 12 patients (71 %) were identified as being responders. For each patient, the FDG uptake and phase polar maps were fused to quantify the amounts of ‘viable and synchronous’, ‘scar and synchronous’, ‘viable and dyssynchronous’ or ‘scar and dyssynchronous’ myocardium. The responders exhibited significant decreases in NYHA class and significant increases in LVEF. Furthermore, the responders tended to have a higher amount of viable and dyssynchronous myocardium compared with nonresponders before CRT.

Figure 2: Target Venous Site for Left Ventricular (LV) Lead Placement

CMR

Major LV veins were drawn on fluoroscopic venograms (left anterior oblique [LAO] and right anterior oblique [RAO]), reconstructed as a 3D structure, and fused with single photon emission-CT myocardial perfusion imaging of the LV epicardial surface. The mid part of the anterior vein (blue line) was aligned with the optimal segment (white area), so it was the target venous site. Source: Zhou et al., 2014.58

CMR cine displacement encoding with stimulated echoes can provide high-quality circumferential strain data to describe the state of mechanical dyssynchrony. Coupled with scar assessment by late gadolinium enhancement (LGE), CMR could improve upon current criteria for identifying optimal LV lead placement.47 Leyva et al.48 took advantage of LGE-CMR to guide LV lead deployment and tracked long-term outcomes after CRT. In this retrospective study, 559 patients (QRS 154±28 ms) with heart failure classified as ICM or NICM were enrolled and implanted with CRT devices, either guided or not guided by CMR. The LV lead tip and myocardial scar were localised by fluoroscopy and LGE-CMR, respectively. For data analysis, patients were divided into three groups: in group A, LV lead placement guided by CMR was paced in a scarred segment; in group B, LV lead placement guided by CMR was paced in an unscarred segment; and in group C, LV lead deployment was not guided by CMR. After a maximum of 9.1 years’ follow-up, patients in group A had higher risks of cardiovascular death or hospitalisation for heart failure compared with patients in group B. Patients in group C had intermediate risks of meeting the endpoints. A prospective study conducted by Sohal et al.49 used CMR to identify the U-shaped contraction pattern induced by true LBBB. Fifty-two patients (25 with ICM and 27 with NICM, QRS 155±24 ms) were enrolled and underwent pre-implantation CMR cine analysis using time–volume curves and contraction propagation maps generated by endocardial contour tracking software. Analogous to the pattern of LV electrical activation, the mechanical contraction pattern presenting a line of blockage in propagation from the septum to the lateral wall was regarded as a U-shaped propagation pattern. According to the presence or absence of the block line, the patients were divided into U-shaped propagation and homogenous propagation groups. The scar burdens in the two groups were evaluated by CMR respectively. Most of the LV leads were placed in the posterolateral or lateral branches of the coronary sinus in each group. As a result, the response rate of CRT in the U-shaped propagation group was significantly greater than the homogenous propagation group (80 % versus 26 %, p<0.001). Taylor et al.50 conducted a retrospective study and validated that placement of the LV lead in the viable segment with the latest

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Pre-CRT LAO

3D SPECT-vein fusion X Z

Pre-CRT RAO

Target LV venous site

activation was associated with LV reverse remodelling and positive clinical outcome after CRT. Eighty-nine patients with heart failure (QRS 179±25 ms) underwent CMR scanning before CRT. Featuretracking and LGE images were analysed. Horizontal and vertical long- and short-axis views were obtained using a segmented inversion recovery technique. The assessment of scar burden was completed by an experienced observer, who recorded the scarring in each segment using software. The latest activated segment was defined as the segment with the latest peak systolic circumferential strain within the cardiac cycle imaged. Concordance was defined as being when the LV lead was positioned in the segment with high viability and latest activation. In contrast, discordance was defined as being when the LV lead was placed in a scarred and/or activated segment. As a result, concordant and discordant LV leads were found in 44 (49 %) and 45 (51 %) patients, respectively. LV reverse remodelling was found in 30 out of 44 (68 %) patients with concordant LV leads and in 11 of 45 (24 %) patients with discordant LV leads.

Image Fusion to Aid Navigation of LV Lead Placement Placement of the LV lead at the optimal site through coronary veins on the myocardial wall is the other key factor in CRT response. The optimal LV lead position recommended by echocardiography, CMR or nuclear imaging is sited on the myocardial wall (epicardial surface), however this is not shown on X-ray fluoroscopic venograms.51 Without a clear image of the myocardial wall in fluoroscopic venograms, the implanters are unable to accurately correspond the venous anatomy with the myocardial segment containing the optimal LV lead position, which may lead to suboptimal or inappropriate LV lead placement.52 Richter et al. investigated the feasibility of a novel sensor-based electromagnetic tracking system to facilitate LV lead placement.53 Similarly, Colella et al. reported the practicality and reliability of device implantation guided by an electroanatomic navigation system in CRT.54 These techniques are limited, however, by the small sizes of the trials and lack of control groups. The other technique, image fusion, may be able to fill the gap between current imaging-guided identification of the optimal LV lead position and the practice of transvenous LV lead placement.

Device Therapy Figure 3: Left-ventricular Coronary Veins from Computed Tomography and Fluoroscopy Venograms Overlaid on the Single Photon Emission Computed Tomography Epicardial Surface Veins from CT

LMV

MCV

LMV

LMV PV

Veins from Fluoro Difference along surface

One segment of AHA 17-Segmentation Model

The differences between the veins on the epicardial surface identified by fluoroscopy and CT, as illustrated by the red lines, were used to evaluate the accuracy of the single photon emission-CT– vein fusion. AHA = American Heart Association; AV = anterior vein; Fluoro = fluoroscopy; LMV = left marginal vein; PV = posterior vein; MCV = middle cardiac vein. Source: Zhou et al., 2014.58

2D and 3D Visual Vein–Surface Correspondence Several clinical studies have integrated fluoroscopic venograms and echocardiographic images to guide LV placement. In the guided group of the TARGET trial,16 a 2D visual correspondence method was used to align the venous anatomy from steep left anterior oblique (LAO) fluoroscopic venograms with the short-axis parasternal echocardiographic view. The steep LAO fluoroscopic venograms were acquired to reveal coronary sinus anatomy approximated to the short-axis echocardiographic image, which helped operators match the appropriate vein to the optimal segment guided by echocardiography. As a result, 64 %, 26 %, and 10 % of patients had LV leads placed in recommended, suboptimal and inappropriate positions, respectively. The STARTER trial17 adopted a visual correspondence method similar to the TARGET trial to integrate the LAO fluoroscopy and echocardiographic images. It aligned the anterior lateral and posterior segments on the LAO fluoroscopy venograms with the corresponding segments on echocardiographic images. Furthermore, for correction and adjustment, the right anterior oblique venograms were used to assess the basal, middle and apical segments. However, this trial only accomplished a concordance of 30 % between the recommended segments and sites in which the LV leads were placed. Laksman et al.55 investigated the feasibility of LV lead delivery using a 3D model derived from LGE CMR. The 3D navigation model was projectively matched to intraprocedural 2D fluoroscopy to procedurally guide LV lead delivery. This procedure was accomplished by simultaneous visualisation of fluoroscopic balloon occlusive coronary venography and 3D modelling in the matched spatial orientation. Postprocedural gated CT was applied to establish the final LV lead tip location relative to the respective target segment. The 3D model-prescribed target segment and final targeted segment obtained from postprocedural CT were recorded and blindly assessed to evaluate the accuracy of the 3D navigation model. As a result, 97 % patients had their LV leads placed in targeted or adjacent segments. As a single-centre feasibility study, however, it is limited by an evaluation of clinical impact on LV lead navigation in CRT.

2D Vein–Surface Fusion Ma et al.56 used processed whole CMR data to yield an anatomical 3D model including the coronary veins. The latest activated segment and scar burden were assessed by LGE CMR. Based on the model, CRT

guidance using pre-procedural CMR data combined with live X-ray fluoroscopy was completed, in which the 3D surface showing the optimal LV lead position was manually registered on 2D live fluoroscopic venograms using multiple views of a catheter looped in the right atrium. This method provided high registration accuracy (1.2±0.7 mm); however, manual registration may influence interoperability, the 2D fusion may limit the navigability during procedural planning, and CMR tools are complicated, expensive and time-consuming to use.

Direct 3D Navigation CT venography is an anatomically-accurate and more direct method of assessing venous anatomy and guiding LV lead placement. In a trial by Sommer et al.,52 LV myocardial viability and mechanical dyssynchrony were integrated to determine the optimal segment for LV lead placement, which was then fused with cardiac CT to select the target venous site. In the trial by Ludwig et al.,57 images of SPECT–CT fusion were further manually mapped on the operative field using a commercial catheter navigator to guide the LV lead placement. Successful guidance in this clinical study was achieved in all five ICM patients and all the LV leads were placed in the latest-activated and unscarred regions. However, these CT-based navigation methods require extra imaging time and cause additional exposure to radiation.

3D Vein–Surface Fusion and Navigation A method integrating LV venous anatomy from fluoroscopy venograms with the LV epicardial surface obtained from SPECT MPI has been developed to navigate lead placement. 58 In this study, 3D LV anatomy was first reconstructed from dual-view fluoroscopic venograms. The LV epicardial surface extracted from the SPECT MPI images was fused with the venous anatomy to produce a 3D fusion model (see Figure 2) that allowed 3D navigation, such as translation, rotation and scale, to accurately identify the target venous branch and optimal site for lead placement. To test the method, a retrospective clinical study was conducted. Ten CRT patients’ fluoroscopy venograms and SPECT MPI images were fused, and CT venography was used to validate the effects of fusion. The distance between the fluoroscopic and CT veins on the SPECT epicardial surface was 4.6±3.6 mm (range: 0–16.9 mm), which is much smaller than the American Heart Association segment size (~30×30 mm 2 in the 17-segment model). A Kappa agreement value of 0.87 suggested that the segmental presence of the fluoroscopic and CT veins agreed well, as shown in Figure 3. Furthermore, a prospective study confirmed the clinical applicability of the 3D fusion toolkit and showed the advantages of image-guided LV lead placement during CRT in a catheterisation laboratory. 58 This

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Image-guided Cardiac Resynchronisation Therapy 3D fusion approach can accurately guide the LV lead to the target position and does not require additional imaging, which reduces the radiation dosage and medical cost. Based on these advantages, this method might facilitate the progress and development of a more personalised lead placement strategy. It represents a step forward and might continue to evolve once more randomised and controlled clinical trials have been carried out.34

Challenges to Overcome Echocardiography provides an excellent non-invasive and economical method by which to evaluate myocardial viability and mechanical dyssynchrony;16 however, the low accuracy of visual vein–surface correspondence and low reproducibility derived from technical and interpretative factors limit its wider clinical use. As a gold standard in scar evaluation, CMR can precisely assess myocardial viability, feasibly evaluate mechanical dyssynchrony and visualise veins;59 nevertheless it is time-consuming and expensive, which limits its extensive use in CRT. Nuclear imaging, known as the ‘one-stop shop’, can evaluate LV viability and mechanical dyssynchrony with just a single scan; however, low spatial resolution and SPECT MPI image counts are major technical barriers in guiding CRT. Insufficient trials in the past and high-costs

1. Khan FZ, Virdee MS, Fynn SP, et al. Left ventricular lead placement in cardiac resynchronization therapy: where and how? Europace 2009;11:554–61. DOI: 10.1093/europace/ eup076; PMID:19372115 2. Hawkins NM, Petrie MC, MacDonald MR, et al. Selecting patients for cardiac resynchronization therapy: electrical or mechanical dyssynchrony? Eur Heart J 2006;27:1270–81. DOI: 10.1093/eurheartj/ehi826; PMID: 16527827 3. Bax JJ, Gabe BB, Thomas HM, et al. Left ventricular dyssynchrony predicts response and prognosis after cardiac resynchronization therapy. J Am Coll Cardiol 2004;44:1834–40. DOI: 10.1016/j.jacc.2004.08.016; PMID: 15519016 4. Chen J, Boogers MM, Bax JJ, et al. The use of nuclear imaging for cardiac resynchronization therapy. Curr Cardiol Rep 2010;12:185–91. DOI: 10.1007/s11886-010-0086-9; PMID: 20425175 5. AIjaroudi W, Chen J, Jaber WA, et al. Nonechocardiographic imaging in evaluation for cardiac resynchronization therapy. Circ Cardiovasc Imaging 2011;4:334–43. DOI: 10.1161/ CIRCIMAGING.111.963504; PMID: 21586744 6. Riedlbauchova L, Brunken R, Jaber WA, et al. The impact of myocardial viability on the clinical outcome of cardiac resynchronization therapy. J Cardiovasc Electrophysiol 2009; 20:50–7. DOI: 10.1111/j.1540-8167.2008.01294.x; PMID: 18803571 7. Bose A, Kandala J, Upadhyay GA, et al. Impact of myocardial viability and left ventricular lead location on clinical outcome in cardiac resynchronization therapy recipients with ischemic cardiomyopathy. J Cardiovasc Electrophysiol 2014;25:507–13. DOI: 10.1111/jce.12348; PMID: 24350650 8. Spragg DD, Dong J, Fetics BJ, et al. Optimal left ventricular endocardial pacing sites for cardiac resynchronization therapy in patients with ischemic cardiomyopathy. J Am Coll Cardiol 2010;56:774–81. DOI: 10.1016/j.jacc.2010.06.014; PMID: 20797490 9. Murphy RT, Sigurdsson G, Mulamalla S, et al. Tissue synchronization imaging and optimal left ventricular pacing site in cardiac resynchronization therapy. Am J Cardiol 2006;97:1615–21. DOI: 10.1016/j.amjcard.2005. 12.054; PMID: 16728225 10. Becker M, Franke A, Breithardt OA, et al. Impact of left ventricular lead position on the efficacy of cardiac resynchronisation therapy: a two-dimensional strain echocardiography study. Heart 2007;93:1197–203. DOI: 10.1136/hrt.2006.095612 11. Becker M, Hoffmann R, Schmitz F. Relation of optimal lead positioning as defined by three-dimensional echocardiography to long-term benefit of cardiac resynchronization. Am J Cardiol 2007;100:11:1671–6. DOI: 10.1016/j.amjcard.2007.07.019; PMID: 18036367 12. Kronborg MB, Kim WY, Mortensen PT, et al. Non-contrast magnetic resonance imaging for guiding left ventricular lead position in cardiac resynchronization therapy. J Interv Card Electrophysiol 2012;33:1:27–35. DOI: 10.1007/s10840-011-9599-4; PMID: 21769665 13. Boogers MJ, Chen J, van Bommel RJ, et al. Optimal left ventricular lead position assessed with phase analysis on gated myocardial perfusion SPECT. Eur J Nucl Med Mol Imaging 2011;38:230–8. DOI: 10.1007/s00259-010-1621-z; PMID: 20953608 14. Uebleis C, Ulbrich M, Tegtmeyer R, et al. Electrocardiogramgated 18F-FDG PET/CT hybrid imaging in patients with

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

are have limited the development of PET imaging in spite of higher tracer counts, better spatial resolution and lower radiation exposure5 compared with SPECT MPI imaging. Although these image-guided techniques have been used to navigate LV lead placement, studies of image fusion techniques are still limited and insufficient. This gap needs to be filled if the favourable response rate to CRT is to be increased. Moreover, although a large number of CRT trials have generated promising results,60,61 large randomised prospective multicentre trials are needed to validate these emerging techniques before they can become widely implemented in clinical practice.

Conclusion Pacing of the latest activated segment without scarring can enhance the response rate of CRT. Myocardial imaging techniques, such as echocardiography, CMR and nuclear imaging, have the potential to identify the optimal LV lead position; however, research on the image fusion of coronary veins from fluoroscopy venograms and the epicardial surface from myocardial images is insufficient. Furthermore, large randomised prospective clinical trials are needed to validate these techniques for imaging-guided CRT. n

unsatisfactory response to cardiac resynchronization therapy: initial clinical results. J Nucl Med 2011;52:67–71. DOI: 10.2967/ jnumed.110.078709; PMID: 21149479 15. Friehling M, Chen J, Saba S, et al. A prospective pilot study to evaluate the relationship between acute change in left ventricular synchrony after cardiac resynchronization therapy and patient outcome using a single-injection gated SPECT protocol. Circ Cardiovasc Imaging 2011;4:532–9. DOI: 10.1161/ CIRCIMAGING.111.965459; PMID: 21772007 16. Khan FZ, Virdee MS, Palmer CR, et al. Targeted left ventricular lead placement to guide cardiac resynchronization therapy: the TARGET study: a randomized, controlled trial. J Am Coll Cardiol 2012;59:1509–18. DOI: 10.1016/j.jacc.2011.12.030; PMID: 22405632 17. Saba S, Marek J, Schwartzman D, et al. Echocardiographyguided left ventricular lead placement for cardiac resynchronization therapy: results of the Speckle Tracking Assisted Resynchronization Therapy for Electrode Region trial. Circ Heart Fail 2013;6:427–34. DOI: 10.1161/ CIRCHEARTFAILURE.112.000078; PMID: 23476053 18. Dekker AL, Phelps B, Dijkman B. Epicardial left ventricular lead placement for cardiac resynchronization therapy: optimal pace site selection with pressure-volume loops. J Thorac Cardiovasc Surg 2004;127:1641–7. DOI: 10.1016/j. jtcvs.2003.10.052; PMID: 15173718 19. Kim RJ, Wu E, Rafael A, et al. The use of contrast-enhanced magnetic resonance imaging to identify reversible myocardial dysfunction. N Engl J Med 2000;343:1445–53. DOI: 10.1056/ NEJM200011163432003; P MID: 11078769 20. Adelstein EC, Tanaka H, Soman P, et al. Impact of scar burden by single-photon emission computed tomography myocardial perfusion imaging on patient outcomes following cardiac resynchronization therapy. Eur Heart J 2011;32:93–103. DOI: 10.1093/eurheartj/ehq389; PMID: 20971745 21. Abu Daya H, Alam MB, Adelstein E, et al. Echocardiographyguided left ventricular lead placement for cardiac resynchronization therapy in ischemic vs nonischemic cardiomyopathy patients. Heart Rhythm 2014;11:614–9. DOI: 10.1016/j.hrthm.2014.01.023; PMID: 24462657 22. White JA, Yee R, Yuan X, et al. Delayed enhancement magnetic resonance imaging predicts response to cardiac resynchronization therapy in patients with intraventricular dyssynchrony. J Am Coll Cardiol 2006;48:1953–60. DOI: 10.1016/ j.jacc.2006.07.046; PMID: 17112984 23. Adelstein EC, Saba S. Scar burden by myocardial perfusion imaging predicts echocardiographic response to cardiac resynchronization therapy in ischemic cardiomyopathy. Am Heart J 2007;153:105–12. DOI: 10.1016/j.ahj.2006.10.015; PMID: 17174647 24. Auricchio A, Stellbrink C, Sack S, et al. Pacing Therapies in Congestive Heart Failure (PATH-CHF) Study Group. Longterm clinical effect of hemodynamically optimized cardiac resynchronization therapy in patients with heart failure and ventricular conduction delay. J Am Coll Cardiol 2002;39:2026–33. PMID: 12084604 25. Becker M, Zwicker C, Kaminski M, et al. Dependency of cardiac resynchronization therapy on myocardial viability at the LV lead position. J Am Coll Cardiol Img 2011;4:366–74. DOI: 10.1016/j.jcmg.2011.01.010; PMID: 21492811 26. Tanaka H, Nesser HJ, Buck T, et al. Dyssynchrony by speckle-tracking echocardiography and response to cardiac resynchronization therapy: results of the Speckle Tracking and

Resynchronization (STAR) study. Eur Heart J 2010;31:1690–700. DOI: 10.1093/eurheartj/ehq213; PMID: 20530502 27. Poole JE, Singh JP. QRS duration or QRS morphology: what really matters in cardiac resynchronization therapy? J Am Coll Cardiol 2016;67:1104–17. DOI: 10.1016/j.jacc.2015.12.039; PMID: 26940932 28. Chatterjee NA, Gold MR, Waggoner AD, et al. Longer left ventricular electric delay reduces mitral regurgitation after cardiac resynchronization therapy: mechanistic insights from the SMART-AV study (SmartDelay Determined AV Optimization: A Comparison to Other AV Delay Methods Used in Cardiac Resynchronization Therapy). Circ Arrhythm Electrophysiol 2016;9:pii:e004346. DOI: 10.1161/ CIRCEP.116.004346; PMID: 27906653 29. Risum N, Tayal B, Hansen TF, et al. Identification of typical left bundle branch block contraction by strain echocardiography is additive to electrocardiography in prediction of long-term outcome after cardiac resynchronization therapy. J Am Coll Cardiol 2015;66:631–41. DOI: 10.1016/j.jacc.2015.06.020; PMID: 26248989 30. Prinzen FW, Hunter WC, Wyman BT, et al. Mapping of regional myocardial strain and work during ventricular pacing: experimental study using magnetic resonance imaging tagging. J Am Coll Cardiol 1999;33:1735–42. PMID: 10334450 31. Voigt JU, Schneider TM, Korder S, et al. Apical transverse motion as surrogate parameter to determine regional left ventricular function inhomogeneities: a new, integrative approach to left ventricular asynchrony assessment. Eur Heart J 2009;30:959–68. DOI: 10.1093/eurheartj/ehp062; PMID: 19297386 32. Strauss DG, Selvester RH, Wagner GS. Defining left bundle branch block in the era of cardiac resynchronization therapy. Am J Coll Cardiol 2011;107: 927–34. DOI: 10.1016/ j.amjcard.2010.11.010; PMID: 21376930 33. Helm RH, Byrne M, Helm PA, et al. Three-dimensional mapping of optimal left ventricular pacing site for cardiac resynchronization. Circulation 2007;115:953–61. DOI: 10.1161/ CIRCULATIONAHA.106.643718; PMID: 17296857 34. Dilsizian V, Narula J. Finding the sweet spot for CRT. JACC Cardiovasc Imaging 2014;7:1289–90. DOI: 10.1016/ j.jcmg.2014.10.007; PMID: 25496553 35. Van de Veire N, de Sutter J, van Camp G, et al. Belgian Multicenter Registry on Dyssynchrony. Global and regional parameters of dyssynchrony in ischemic and nonischemic cardiomyopathy. Am J Cardiol 2005;95:421–3. DOI: 10.1016/ j.amjcard.2004.09.050; PMID: 15670561 36. Ypenburg C, van Bommel RJ, Delgado V, et al. Optimal left ventricular lead position predicts reverse remodeling and survival after cardiac resynchronization therapy. J Am Coll Cardiol 2008;52:1402–9. DOI: 10.1016/j.jacc.2008.06.046; PMID: 18940531 37. Donal E, de Chillou C, Magnin-Poull I, et al. Imaging in cardiac resynchronization therapy: what does the clinician need? Europace 2008;10:iii70–2. DOI: 10.1093/europace/eun229; PMID: 18955402 38. Gorcsan J III, Marek JJ, Onishi T. The contemporary role of echocardiography in improving patient response to cardiac resynchronization therapy. Curr Cardiovasc Imaging Rep 2012;5:462–72. DOI: 10.1007/s12410-012-9172-2; PMID: 24741393 39. Gorcsan J 3rd, Abraham T, Agler DA, et al. American

Device Therapy Society of Echocardiography Dyssynchrony Writing Group. Echocardiography for cardiac resynchronization therapy: recommendations for performance and reporting-a report from the American Society of Echocardiography Dyssynchrony Writing Group endorsed by the Heart Rhythm Society. J Am Soc Echocardiogr 2008;21:191–213. DOI: 10.1016/ j.echo.2008.01.003; PMID: 18314047 40. Bax JJ, Delgado V. Myocardial viability as integral part of the diagnostic and therapeutic approach to ischemic heart failure. J Nucl Cardiol 2015;22:229–45. DOI: 10.1007/s12350015-0096-5; PMID: 25733105 41. Mele D, Agricola E, Galderisi M, et al. Study Group of Echocardiography, Italian Society of Cardiology. Echocardiographic myocardial scar burden predicts response to cardiac resynchronization therapy in ischemic heart failure. J Am Soc Echocardiogr 2009;22:702–8. DOI: 10.1016/ j.echo.2009.03.009; PMID: 19423292 42. Chen J, Bax JJ, Henneman MM, et al. Is nuclear imaging a viable alternative technique to assess dyssynchrony? Europace 2008;10:101–5. DOI: 10.1093/europace/eun221; PMID: 18955389 43. Boogers MM, Chen J, Bax JJ. Myocardial perfusion single photon emission computed tomography for the assessment of mechanical dyssynchrony. Curr Opin Cardiol 2008;23:431–9. DOI: 10.1097/HCO.0b013e32830a95d5; PMID: 18670253 44. Boogers MM, Chen J, Bax JJ. Role of nuclear imaging in cardiac resynchronization therapy. Expert Rev Cardiovasc Ther 2009;7:65–72. DOI: 10.1586/14779072.7.1.65; PMID: 19105768 45. Zhou W, Garcia EV. Nuclear image-guided approaches for cardiac resynchronization therapy (CRT). Curr Cardiol Rep 2016;18:7; DOI: 10.1007/s11886-015-0687-4; PMID: 26714813 46. Lehner S, Uebleis C, Schubler F, et al. The amount of viable and dyssynchronous myocardium is associated with response to cardiac resynchronization therapy: initial clinical results using multiparametric ECG-gated [18F] FDG PET. Eur J Nucl Med Mol Imaging 2013;40:1876–83. DOI: 10.1007/s00259-

013-2516-6; PMID: 23903666 47. Bilchick KC, Kuruvilla S, Hamirani YS, et al. Impact of mechanical activation, scar, and electrical timing on cardiac resynchronization therapy response and clinical outcomes. J Am Coll Cardiol 2014;63:1657–66. DOI: 10.1016/ j.jacc.2014.02.533; PMID: 24583155 48. Leyva F, Foley P WX, Chalil S, et al. Cardiac resynchronization therapy guided by late gadolinium-enhancement cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2011;13:29. DOI: 10.1186/1532-429X-13-29; PMID: 21668964 49. Sohal M, Shetty A, Duckett S, et al. Noninvasive assessment of LV contraction patterns using CMR to identify responders to CRT. JACC Cardiovasc Imaging 2013;6:864–73. DOI: 10.1016/ j.jcmg.2012.11.019; PMID: 23735442 50. Taylor RJ, Umar F, Panting JR, et al. Left ventricular lead position, mechanical activation, and myocardial scar in relation to left ventricular reverse remodeling and clinical outcomes after cardiac resynchronization therapy: a featuretracking and contrast-enhanced cardiovascular magnetic resonance study. Heart Rhythm 2016;13:481–9. DOI: 10.1016/ j.hrthm.2015.10.024; PMID: 26498258 51. Singh JP, Klein HU, Huang DT, et al. Left ventricular lead position and clinical outcome in the multicenter automatic defibrillator implantation trial-cardiac resynchronization therapy (MADIT-CRT) trial. Circulation 2011;123:1159–66. DOI: 10.1161/CIRCULATIONAHA.110.000646; PMID: 21382893 52. Sommer A, Kronborg MB, Poulsen SH, et al. Empiric versus imaging guided left ventricular lead placement in cardiac resynchronization therapy (Imaging CRT): study protocol for a randomized controlled trial. Trials 2013;14:113. DOI: 10.1186/1745-6215-14-113; PMID: 23782792 53. Richter S, Döring M, Gaspar T, et al. Cardiac resynchronization therapy device implantation using a new sensor-based navigation system results from the first human use study. Circ Arrhythm Electrophysiol 2013;6:917–23. DOI: 10.1161/ CIRCEP.113.000066; PMID: 24002003

54. Colella A, Giaccardi M, Colella T, et al. Zero x-ray cardiac resynchronization therapy device implantation guided by a nonfluoroscopic mapping system: a pilot study. Heart Rhythm 2016;13:1481–8. DOI: 10.1016/j.hrthm.2016.03.021; PMID: 26976037 55. Laksman Z, Yee R, Stirrat J, et al. Model-based navigation of left and right ventricular leads to optimal targets for cardiac resynchronization therapy: a single-center feasibility study. Circ Arrhythm Electrophysiol 2014;7:1040–7. DOI: 10.1161/ CIRCEP.114.001729 56. Ma YL, Shetty AK, Duckett S, et al. An integrated platform for image-guided cardiac resynchronization therapy. Phys Med Biol 2012;57:2953–68. DOI: 10.1088/0031-9155/57/10/2953; PMID: 22517030 57. Ludwig DR, Menon PG, Schwartzman D. Nuclear imageguided left ventricular pacing lead navigation feasibility of a new technique. J Interv Card Electrophysiol 2015;44:273–7. DOI: 10.1007/s10840-015-0046-9; PMID: 26319647 58. Zhou W, Hou X, Piccinelli M, et al. 3D fusion of LV venous anatomy on fluoroscopy venograms with epicardial surface on SPECT myocardial perfusion images for guiding CRT LV lead placement. JACC Cardiovasc Imaging 2014;7:1239–48. DOI: 10.1016/j.jcmg.2014.09.002; PMID: 25440593 59. Leyva F. Cardiac resynchronization therapy guided by cardiac magnetic resonance. J Cardiovasc Magn Reson 2010;12:64. DOI: 10.1186/1532-429X-13-29; PMID: 21668964 60. Chung ES, Leon AR, Tavazzi L, et al. Results of the Predictors of Response to CRT (PROSPECT) Trial. Circulation 2008;117:2608–16. DOI: 10.1161/ CIRCULATIONAHA.107.743120; PMID: 18458170 61. IAEA-VISION CRT. Nuclear Cardiology in Congestive Heart Failure Value of Intraventricular Synchronism Assessment by GatedSPECT Myocardial Perfusion Imaging in the Management of Heart Failure Patients Submitted to Cardiac Resynchronization Therapy. IAEA Annual Report 2013; Additional Annex Information. International Atomic Energy Agency, 2013.

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Diagnostic Electrophysiology & Ablation

Evolution of Force Sensing Technologies Dipen Shah Division of Cardiology, Hospital Cantonal de Genève, Switzerland

Abstract In order to improve the procedural success and long-term outcomes of catheter ablation techniques for atrial fibrillation (AF), an important unfulfilled requirement is to create durable electrophysiologically complete lesions. Measurement of contact force (CF) between the catheter tip and the target tissue can guide physicians to optimise both mapping and ablation procedures. Contact force can affect lesion size and clinical outcomes following catheter ablation of AF. Force sensing technologies have matured since their advent several years ago, and now allow the direct measurement of CF between the catheter tip and the target myocardium in real time. In order to obtain complete durable lesions, catheter tip spatial stability and stable contact force are important. Suboptimal energy delivery, lesion density/ contiguity and/or excessive wall thickness of the pulmonary vein-left atrial (PV-LA) junction may result in conduction recovery at these sites. Lesion assessment tools may help predict and localise electrical weak points resulting in conduction recovery during and after ablation. There is increasing clinical evidence to show that optimal use of CF sensing during ablation can reduce acute PV re-conduction, although prospective randomised studies are desirable to confirm long-term favourable clinical outcomes. In combination with optimised lesion assessment tools, contact force sensing technology has the potential to become the standard of care for all patients undergoing AF catheter ablation.

Keywords Catheter ablation, contact force Disclosure: Professor Shah has received grant support from Biosense Webster, Boston Scientific and St Jude; advisory board and/or consultancy fees: Biosense Webster, Boston Scientific, St Jude, EP Technologies. Acknowledgement: Katrina Mountfort of Medical Media Communications (Scientific) Ltd provided medical writing and editing support to the author, funded by Biosense Webster. Received: 27 April 2017 Accepted: 2 June 2017 Citation: Arrhythmia & Electrophysiology Review 2017;6(2):75–9. DOI: 10.15420/aer.2017:8:2 Correspondence: Prof. Dipen Shah, Cardiology Division, University Hospital Geneva, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland. E: dipen.shah@hcuge.ch

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, is associated with increased risk of stroke and heart failure and is a significant global health challenge.1 Pharmacological treatments to restore sinus rhythm in patients with AF are associated with a considerable relapse rate,2,3 whereas nonpharmacological interventions, such as catheter ablation procedures, which isolate the pulmonary veins (PV) from the left atrium and prevent AF initiation, are associated with long-term (≥3 years after ablation) success rates of up to 80 % with multiple procedures.4 Rates of ablation procedures have been steadily increasing over the last decade,5 but in order for catheter ablation to become first-line treatment for AF patients, there is a need for higher and reproducible single-procedure success rates with a substantially reduced procedure time. In order to achieve this, durable transmural and contiguous radiofrequency (RF) lesions are required in concert with standardisation of the ablation strategy. An important part of the challenge is determining whether sufficient RF energy has been delivered to the appropriate local tissue site: the most common cause of failure of catheter ablation or arrhythmia recurrence is electrical reconnection of the PVs following suboptimal energy delivery,6 while excessive energy can result in overheating, local injury, perforation, fistulae, steam pops and char.7,8 Contact force (CF) between the ablation catheter tip and the target tissue is a key determinant of the locally delivered RF energy. Although applicable to other arrhythmia substrates as well, this review will mainly consider the impact of CF on procedural success of AF ablation.

Effect of Contact Force on Lesion Size A number of in vitro studies have shown that CF affects lesion size in RF catheter ablation.9,10 We described the first results of in vitro ablation with an optical fibre based real-time CF sensor equipped RF irrigation catheter showing that increased CF was associated with larger and deeper lesions despite fixed RF power.11 In 2008, a thigh muscle study confirmed that the underlying mechanism was related to increased tissue heating (see Figure 1): at high CF there was an increased incidence of steam pop, and thrombus.12 A 2010 in vitro study found that integrating CF information over time (for the first 40–60 seconds) provided a direct correlation with lesion size, again in the setting of stable fixed RF powers.13

Effect of Contact Force on Clinical Outcomes Technologies are now clinically available that allow the direct measurement of CF between the catheter tip and the target myocardium in real-time, and two CF sensing catheters have received approval by the US Food and Drug Administration for use in AF ablation. The first catheter approved was the ThermoCool® SmartTouch (Biosense Webster) irrigated tip ablation catheter (February 2014) followed by the TactiCath Quartz (St. Jude Medical) CF ablation catheter (October 2014). A growing body of clinical data, both observational and larger studies, supports their use.

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Diagnostic Electrophysiology & Ablation Figure 1: In Vitro Lesion Volume as a Function of Contact Force at Both 30 and 50 W of RF Power Showing a Linear Relationship with a Steeper Slope at 50 W Compared with 30 W

Lesion Volume (mm3)

2000

30W

1500

1052

1000

500

p <0.01

1500

p <0.01

632

50W 1542

1186

1000

906

773

683

500 445

431 271

Contact Force (g) Source: Yokoyama et al., 200812

Figure 2: SMART-AF Trial: Kaplan-Meier Curve of Time to First Atrial Fibrillation/Atrial Flutter/Atrial Tachycardia Recurrence Through 12 Months < 80 %

Probability of Atrial Arrhythmia Recurrence Free

1.0

≥ 80 %

0.9

81 %

0.8

66 %

0.7

An analysis of these and other data shows that successful PV isolation (PVI) is a function of transmurality, i.e. lesions extending through the entire thickness of the atrial wall as well as lesion continuity. Transmurality is affected by wall thickness, oedema and tissue composition, while contiguity, requiring the 3D localisation of the catheter, is affected by the lesion shape, interlesion gap and compensating for or evaluating electrode sliding. These are currently difficult parameters to measure. In this context, a varying optimal CF value has been suggested in different studies with, for example, Providencia et al. finding a mean CF <22 g indicative of poorer 12 month outcomes,17 whereas Stabile et al. found no difference in mean CF (13 ± 3.4 g versus 12 ± 4 g; p=0.32) between patients with and without arrhythmia recurrences.18 Whether these data indicate differences in tissue characteristics, RF power delivery, catheter tip stability or combinations of the above is unclear and prospective investigation using indices combining CF and other parameters (see below) may provide better results and greater safety.

0.6 0.5 0.4 0.3 0.2 0.1 0

Wilcoxon p = 0.0440 3

4 5 6 7 8 9 10 11 Time to Atrial Arrhythmia Recurrence (Months)

Source: Natale et al., 201415

The first published study of the use of CF ablation catheters in humans was the Touch+™ for Catheter Ablation (TOCCATA) study (n=77), which demonstrated that catheter ablation using real-time CF technology was safe for the treatment of supraventricular tachycardia and AF.14 In this study, a mean CF of 20 g or more correlated with an 80 % probability of AF freedom at 12-month follow-up. SMART-AF (Prospective Safety Assessment of the ThermoCool® SmartTouch® SF Family of Contact Force Sensing Catheters for the Radiofrequency Ablation Treatment of Drug Refractory Symptomatic Paroxysmal Atrial Fibrillation) was a prospective, multicentre, nonrandomised study (n=172) that assessed the safety and effectiveness of the ThermoCool SmartTouch catheter in the treatment of drug-refractory symptomatic paroxysmal AF (PAF). The 12-month freedom from AF/atrial flutter/atrial tachycardia recurrence was 72.5 %. When the CF was stable within an investigator-selected range ≥80 % of time, the success rate increased to 88 % (≥80 % of time: n=32; <80 % of time: n=73; see Figure 2).15 TOCCASTAR (Ablation Catheter Study for Atrial Fibrillation) was a prospective randomised noninferiority study that compared the TactiCath catheter with the Navistar Thermocool catheter (Biosense Webster) in patients undergoing catheter ablation of paroxysmal AF. The 12-month freedom from AF/atrial flutter/atrial tachycardia recurrence was 68 %. A prespecified analysis of TOCCASTAR investigated the impact of CF in the TactiCath cohort. Of the 145

patients treated with the TactiCath catheter, 57 % received an optimal amount of contact (90 % lesions delivered at 10–40 g of CF) and experienced a chronic treatment success rate of 85.5 % versus 72.6 % for the suboptimal CF group (p=0.043).16 These results highlight the need to standardise operating procedures so as to routinely achieve optimal CF.

As increasing CF leads to higher tissue temperatures, excessive CF can lead to collateral damage related complications. Although most studies have shown similar or even fewer complications associated with the use of real-time CF sensing catheters compared with non-CF sensing catheters, these studies have all been relatively underpowered to detect small differences in complications. Excessive CF has been associated with perforation14 and tamponade,15 and perhaps atrioesophageal fistula,19 thus underlining the importance of optimising CF.

Optimising Contact Force The CF shows significant variability in everyday use; one reason for this is the cardiac rhythm during catheter ablation. In one study (n=20), the main reasons for CF variability were identified as systolo-diastolic heart movement (29 %) and respiration (27 %), with the rest presumably due to electrode sliding unrelated to cardio-respiratory movement.20 Catheter contact stability is important and can be considered to be a combination of both temporal contact stability (which refers to degree of contact variation over time) and spatial contact stability (which refers to stability in terms of spatial localisation with respect to the endocardium).21 Realtime CF monitoring is crucial in achieving temporal stability, and by implication, transmurality, whereas accurate 3D localisation with respect to the endocardium is necessary for achieving spatial contact stability (as opposed to a fixed extracardiac/extrathoracic reference, which is currently the state of the art), which is crucial for individual lesion localisation and therefore multi-lesion contiguity.21 There are, however, other parameters beyond catheter tissue contact which are important in determining RF lesion size and contiguity. A significant consideration for obtaining complete lesions is the wall thickness of the pulmonary vein–left atrial (PV–LA) junction. In a recent study, 18 AF patients underwent wide area circumferential ablation with a target CF >10 g at a power setting of 25–30 W for 30 seconds. Of the 974 ablation points, 72 were located at dormant conduction sites and were strongly associated with thickened PV-LA junction walls

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Evolution of Force Sensing Technologies (1.02 ± 0.23 versus 0.86 ± 0.26 mm; p<0.0001) and decreased impedance fall (13.3 ± 6.4 versus 14.9 ± 7.1 ohm; p=0.0498) but not with electrogram-based information or CF. Multivariate analysis identified the thickened PV–LA junction wall as the strongest predictor of dormant conduction.22 Lesion contiguity and density are also important. A study (n=40) found that the majority of pulmonary vein reconnections (PVR), an important cause of AF recurrence after ablation, could be attributed to inadequate CF (<10 g) or long (>5 mm) interlesion distances.23 Another study (n=49) found that, in order to prevent PVR, it was necessary to complete PVI with circumferential lines without touch-up ablation, and also to create a sufficient lesion density (anterior left pulmonary vein [LPV] 1.97/cm and posterior LPV 2.01/cm) on the lines with an adequate CF (mean 14.2 g).24 As alluded to earlier, modern 3D mapping systems are important aids in providing information about spatial stability although they take into account only the catheter tip position under the assumption of static endocardium. Despite this limitation, automatic visual annotation algorithms (e.g. Visitag from Biosense, Automark from St Jude) have become popular, allowing user programmable settings of spatial stability (in time and space) during RF delivery and, combined with lesion prediction algorithms, can provide useful information about weak spots in circumferential PV isolating lesions.25

Force Sensing with RF Ablation versus Cryo-ablation A multicentre European study compared PVI by CF-guided RF with second-generation cryoballoon (CB). The procedure time was lower for the CB group than for the CF group (109.6 ± 40 versus 122.5 ± 40.7 min; p=0.003), but fluoroscopy duration and X-ray exposure showed no statistical differences (p=0.1 and p=0.22, respectively). In addition, the overall complication rate was similar in the CB and CF groups (7.3 % versus 7.1 %; p=0.93).26 In another study comparing the two techniques, 56 consecutive patients underwent a repeat ablation due to recurrent atrial tachyarrhythmias after the index PVI achieved with CF ablation (30 patients) or CB ablation (26 patients). The percentage of reconnected PVs was significantly lower following CB procedures than with CF ablation (36.1 % PVs in the CF catheter ablation group, versus 20.4 % PVs in the secondgeneration CB ablation group; p=0.01).27 However, the mean CF perreconnected vein was lower compared with the persistently isolated PVs (10.9 ± 2.7 versus 18.6 ± 3.1 g; p<0.001), indicating the potential of further reduction in PV recurrence by achieving higher CFs. The same cannot be said of CB PVI since despite the finding that late PV reconnection was associated with warmer nadir temperature (-48.9 ± 5.1 versus -51.2 ± 4.7 °C; p=0.05), no specific measures are available to address this poorer cooling, and certainly none targeted to the specific area of conduction recovery. A study performed in seven UK centres randomised patients to ablation with (n=58) or without (n=59) CF data available to the operator. PVR was assessed with adenosine at 60 minutes and all the connections were re-isolated. In the group for which CF data was available, a reduction in acute PV reconnection rates was seen (22 % versus 32 %; p=0.03) but this did not translate to a significant difference in 1-year success rates (defined as off antiarrhythmic drugs) between the two groups (49 % versus 52 %; p=0.9).28 There may be a number of reasons for this. Firstly, the dormant PV conduction was ablated at 60 minutes, thus equalising the long-term outcomes between the two groups while the analysis was only performed with the initial ablation data. PV reconnection was assessed as dichotomic rather than number of gaps or segments

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

with gaps and it is conceivable that non-CF guided PVs would have demonstrated more or wider gaps. In addition, the CF range was large, and it is unclear whether stable CF was assessed during ablation.

Lesion Assessment During Catheter Ablation It is evident that the ability to assess ablation lesion ‘quality’ during PVI would help in achieving better complete and stable lesions. Lesion assessment tools can help predict and localise electrical weak points, including actual or potential gaps with the potential of correcting these weak points with additional optimised RF energy delivery. Current diagnostic catheters allow the assessment of electrically active and conducting gaps, but provide no feedback on changes from ablation in the myocardial tissue itself and in particular lack information on whether the electrical changes – and by implication, tissue changes – are reversible or irreversible. Ideally, lesion assessment should provide information about dimensions including depth, diameter and also shape of the irreversibly necrosed tissue as well as of the zone of reversible thermal damage. Additional information of potential utility could include peak tissue and interface temperatures as well as electrogram or activation pattern changes. Direct real-time interrogation of tissue temperature could provide much of the above information but is currently not clinically achievable. Thermal ablation modelling has therefore been proposed as a means of monitoring and visualisation of the tissue response during RF ablation. In a preliminary study evaluating a comprehensive heat transfer model incorporating both conductive and resistive heat transfer as well as perfusion-mediated heat dissipation (convection), four fibre optic probes were inserted into the tissue sample at 2.5 mm and 5 mm radially away from the electrode and at 3 mm depth. Temperature measurements were simultaneously recorded from all probes during the 60-second ablation procedure at 90 °C. There was less than 5 °C difference between the model-predicted and measured temperature throughout the duration of the ablation attesting to the fidelity of thermal modelling incorporating all elements of the heat transfer equation.29 In the clinical context, combining RF energy, duration and contact parameters can allow reasonably accurate but probabilistic prediction of lesion size and therefore potential weak points within a chain of multiple contiguously delivered lesions. Force–Time Integral (FTI), the area under the real-time CF curve, can be considered the first generation lesion prediction assessment index. It was validated first in in vitro studies and against clinically available indirect parameters such as adenosine provoked dormant conduction as well as by direct restudy 3 months after initial PVI. The Efficas I study validated a minimum FTI of 400 gs as providing an 95 % likelihood of a gap-free encirclement.30 Although FTI is commonly used as a marker of ablation lesion quality it does not incorporate power, (which, in most laboratories, is either stable or varies only little) and depicts a linear, instead of the actual non-linear, relationship of lesion growth with time. In an attempt to improve the prediction of PVI success beyond that shown with FTI.13,16,30–33 RF power was incorporated into a non-linear formula, providing the so-called lesion index (LSI). This index was derived from a database of large animal (porcine and canine) ventricular lesions, which could be accurately evaluated post mortem.33 Similarly, the ablation index (AI), based on integrating RF power, duration and CF, has also been proposed as a tool to assess the quality of ablation lesions. It too has been derived from a ventricular large animal RF lesion database. In a recent study,34

Diagnostic Electrophysiology & Ablation 40 patients with paroxysmal AF underwent CF-guided PVI and the mean AI identified for each PV segment. The default power was 30 W: 25–30 W for the posterior wall and 30–35 W elsewhere. The CF ranged from 5–40 g and the RF duration from 20–40 seconds. At 2 months follow-up, late PVR was observed in 11 % of segments in 62 % of patients. The minimum AI (as well as FTI) was significantly lower in reconnected segments (308 versus 373; p<0.0001) compared with non-reconnected segments. Higher AI values were documented for anterior/roof segments than for posterior/inferior segments to prevent reconnection.34 This finding may reflect both local wall thickness differences as well as differences in catheter stability.

Other Arrhythmia Substrates The largest body of data on CF sensing is related to catheter ablation of AF. However other substrates including (but not limited to) typical cavotricuspid isthmus dependent flutter as well as both epicardial and endocardial ventricular arrhythmia substrates have been investigated. In typical flutter, low CF was implicated in longer time to achieve conduction block and increased risk of acute reconnection.35 In the ventricles, higher CFs led to larger lesions but intriguingly also provided greater electrogram information such as higher amplitudes and more frequent late potentials.36

Conclusion Another small study including 42 patients undergoing PVI used an index (ALCI) derived from depth and contiguity parameters (including CF parameters: FTI, AI and interlesion distance) to predict the weakest spot in the ablation-isolation lesion and found that minimum ALCI, significantly lower in segments with PVR (74 % versus 104 %; p<0.001), was the most accurate in identifying sites of acute as well as late (at repeat ablation) PV reconduction.25 PVR sites were also characterised by a lower minimum AI (367 versus 408 arbitrary unit [au]), and a higher maximum ILD (inter-lesion distance; 6.8 versus 5.5 mm).

Future Directions These data highlight the need for precise and accurate lesion prediction, incorporating not only CF, power and time, but also tissue thickness, high-resolution electrograms, catheter tip orientation and stability with respect to the endocardium to ensure the creation of durable optimal ablation lesions.

10.

11.

12.

13.

Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Eur Heart J 2012;33:2719–47. DOI: 10.1093/ eurheartj/ehs253; PMID: 22922413 Roy D, Talajic M, Dorian P, et al. Amiodarone to prevent recurrence of atrial fibrillation. N Engl J Med 2000;342:913–20. DOI: 10.1056/nejm200003303421302; PMID: 10738049 Crijns HJ, Van Gelder IC, Van Gilst WH, et al. Serial antiarrhythmic drug treatment to maintain sinus rhythm after electrical cardioversion for chronic atrial fibrillation or atrial flutter. Am J Cardiol 1991;68:335–41. DOI: 68:335-41; PMID: 1907089 Ganesan AN, Shipp NJ, Brooks AG, et al. Long-term outcomes of catheter ablation of atrial fibrillation: a systematic review and meta-analysis. J Am Heart Assoc 2013;2:e004549. DOI: 10.1161/jaha.112.004549; PMID: 23537812 Kneeland PP, Fang MC. Trends in catheter ablation for atrial fibrillation in the United States. J Hosp Med 2009;4:E1–5. DOI: 10.1002/jhm.445; PMID: 19753578 Cheema A, Dong J, Dalal D, et al. Incidence and time course of early recovery of pulmonary vein conduction after catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2007;18:387– 91. DOI: 10.1111/j.1540-8167.2007.00760.x; PMID: 17394453 Bohnen M, Stevenson WG, Tedrow UB, et al. Incidence and predictors of major complications from contemporary catheter ablation to treat cardiac arrhythmias. Heart Rhythm 2011;8:1661–6. DOI: 10.1016/j.hrthm.2011.05.017; PMID: 21699857 Panda NC, Cheung JW. Complications from catheter ablation of atrial fibrillation: impact of current and emerging ablation technologies. Curr Treat Options Cardiovasc Med 2014;16:344. DOI: 10.1007/s11936-014-0344-z; PMID: 25183020 Haines DE. Determinants of lesion size during radiofrequency catheter ablation: the role of electrode-tissue contact force and duration of energy delivery. J Cardiovasc Electrophysiol 1991;2:509–15. DOI: 10.1111/j.1540-8167.1991.tb01353.x Avitall B, Mughal K, Hare J, et al. The effects of electrodetissue contact on radiofrequency lesion generation. Pacing Clin Electrophysiol 1997;20:2899–910. PMID: 9455749 Shah DC, Leo G, Aebi N, et al. Evaluation of a new catheter sensor for real-time measurement of tissue contact. Heart Rhythm 2006;3:May suppl;S74. Yokoyama K, Nakagawa H, Shah DC, et al. Novel contact force sensor incorporated in irrigated radiofrequency ablation catheter predicts lesion size and incidence of steam pop and thrombus. Circ Arrhythm Electrophysiol 2008;1:354–62. DOI: 10.1161/circep.108.803650; PMID: 19808430 Shah DC, Lambert H, Nakagawa H, et al. Area under the real-time contact force curve (force-time integral) predicts radiofrequency lesion size in an in vitro contractile model.

RF catheter ablation of AF has been considered a challenging procedure, but the availability of CF sensing technology allows real-time feedback of exactly how much CF is applied at any given moment, minimising the likelihood of applying too much as well of too little force. A growing body of evidence supports the use of CF sensing technology. Real-time CF information may help to create more predictable and reliable lesions and potentially improve both the safety and efficacy of RF ablation. Despite the absence of prospective randomised clinical studies with longer follow up, RF ablation guided by real-time CF sensing has become the dominant ablation modality, particularly for catheter ablation of AF.37–39 If however, the better acute outcomes with reduction in acute electrical PV re-connection shown in medium term studies,40 is borne out in studies with appropriate longer-term follow-up, then CF sensing technology has the potential to become the recommended standard of care for all patients undergoing AF catheter ablation. n

J Cardiovasc Electrophysiol 2010;21:1038–43. DOI: 10.1111/j.15408167.2010.01750.x; PMID: 20367658 14. Kuck KH, Reddy VY, Schmidt B, et al. A novel radiofrequency ablation catheter using contact force sensing: Toccata study. Heart Rhythm 2012;9:18–23. DOI: 10.1016/j.hrthm.2011.08.021; PMID: 21872560 15. Natale A, Reddy VY, Monir G, et al. Paroxysmal AF catheter ablation with a contact force sensing catheter: results of the prospective, multicenter SMART-AF trial. J Am Coll Cardiol 2014;64:647–56. DOI: 10.1016/j.jacc.2014.04.072; PMID: 25125294 16. Reddy VY, Dukkipati SR, Neuzil P, et al. Randomized, controlled trial of the safety and effectiveness of a contact force-sensing irrigated catheter for ablation of paroxysmal atrial fibrillation: results of the TactiCath Contact Force Ablation Catheter Study for Atrial Fibrillation (TOCCASTAR) study. Circulation 2015;132:907–15. DOI: 10.1161/circulationaha.114.014092; PMID: 26260733 17. Providencia R, Marijon E, Combes S, et al. Higher contactforce values associated with better mid-term outcome of paroxysmal atrial fibrillation ablation using the SmartTouch catheter. Europace 2015;17:56–63. DOI: 10.1093/europace/ euu218; PMID: 25280910 18. Stabile G, Solimene F, Calo L, et al. Catheter-tissue contact force values do not impact mid-term clinical outcome following pulmonary vein isolation in patients with paroxysmal atrial fibrillation. J Interv Card Electrophysiol 2015;42:21–6. DOI: 10.1007/s10840-014-9947-2; PMID: 25378035 19. Black-Maier E, Pokorney SD, Barnett AS, et al. Risk of atrioesophageal fistula formation with contact-force sensing catheters. Heart Rhythm 2017; [Epub ahead of print]. DOI: 10.1016/j.hrthm.2017.04.024; PMID: 28416466. 20. Sarkozy A, Shah D, Saenen J, et al. Contact force in atrial fibrillation: role of atrial rhythm and ventricular contractions: Co-Force Atrial Fibrillation Study. Circ Arrhythm Electrophysiol 2015;8:1342–50. DOI: 10.1161/circep.115.003041; PMID: 26383774 21. Shah DC, Namdar M. Real-time contact force measurement: a key parameter for controlling lesion creation with radiofrequency energy. Circ Arrhythm Electrophysiol 2015;8:713–21. DOI: 10.1161/circep.115.002779; PMID: 26082527 22. Iso K, Okumura Y, Watanabe I, et al. Wall thickness of the pulmonary vein-left atrial junction rather than electrical information as the major determinant of dormant conduction after contact force-guided pulmonary vein isolation. J Interv Card Electrophysiol 2016;46:325–33. DOI: 10.1007/s10840-0160147-0; PMID: 27221713 23. Park CI, Lehrmann H, Keyl C, et al. Mechanisms of pulmonary vein reconnection after radiofrequency ablation of atrial fibrillation: the deterministic role of contact force and

interlesion distance. J Cardiovasc Electrophysiol 2014;25:701–8. DOI: 10.1111/jce.12396; PMID: 24575734 24. Nakamura K, Naito S, Sasaki T, et al. Predictors of chronic pulmonary vein reconnections after contact force-guided ablation: importance of completing electrical isolation with circumferential lines and creating sufficient ablation lesion densities. J Interv Card Electrophysiol 2016; [Epub ahead of print]. DOI: 10.1007/s10840-016-0164-z; PMID: 27417148 25. 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:e004867. DOI: 10.1161/circep.116.004867; PMID: 28381417. 26. Squara F, Zhao A, Marijon E, et al. Comparison between radiofrequency with contact force-sensing and secondgeneration cryoballoon for paroxysmal atrial fibrillation catheter ablation: a multicentre European evaluation. Europace 2015;17:718–24. DOI: 10.1093/europace/euv060; PMID: 25840289 27. Ciconte G, Velagic V, Mugnai G, et al. Electrophysiological findings following pulmonary vein isolation using radiofrequency catheter guided by contact-force and second-generation cryoballoon: lessons from repeat ablation procedures. Europace 2016;18:71–7. DOI: 10.1093/europace/ euv224; PMID: 26445821 28. Ullah W, McLean A, Tayebjee MH, et al. Randomized trial comparing pulmonary vein isolation using the SmartTouch catheter with or without real-time contact force data. Heart Rhythm 2016;13:1761–7. DOI: 10.1016/j.hrthm.2016.05.011; PMID: 27173976. 29. Linte CA, Camp JJ, Holmes DR, 3rd, et al. Toward modeling of radio-frequency ablation lesions for image-guided left atrial fibrillation therapy: model formulation and preliminary evaluation. Stud Health Technol Inform 2013;184:261–7. PMID: 23400167 30. Neuzil P, Reddy VY, Kautzner J, et al. Electrical reconnection after pulmonary vein isolation is contingent on contact force during initial treatment: results from the EFFICAS I study. Circ Arrhythm Electrophysiol 2013;6:327–33. DOI: 10.1161/ circep.113.000374; PMID: 23515263 31. Reddy VY, Shah D, Kautzner J, et al. The relationship between contact force and clinical outcome during radiofrequency catheter ablation of atrial fibrillation in the TOCCATA study. Heart Rhythm 2012;9:1789–95. DOI: 10.1016/j. hrthm.2012.07.016; PMID: 22820056 32. Kautzner J, Neuzil P, Lambert H, et al. EFFICAS II: optimization of catheter contact force improves outcome of pulmonary vein isolation for paroxysmal atrial fibrillation. Europace 2015;17:1229– 35. DOI: 10.1093/europace/euv057; PMID: 26041872 33. Neuzil P, Kuck K-H, Nakagawa H,et al. Lesion size index for prediction of reconnection risk following RF ablation for PVI.

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Evolution of Force Sensing Technologies

Heart Rhythm 2012;9:55:S492. 34. Das M, Loveday JJ, Wynn GJ, et al. Ablation index, a novel marker of ablation lesion quality: prediction of pulmonary vein reconnection at repeat electrophysiology study and regional differences in target values. Europace 2016;19:775-83. DOI: 10.1093/europace/euw105; PMID: 27247002 35. Kumar S, Morton JB, Lee G, et al. High incidence of low catheter-tissue contact force at the cavotricuspid isthmus during catheter ablation of atrial flutter: implications for achieving isthmus block. J Cardiovasc Electrophysiol 2015;26:826– 31. DOI: 10.1111/jce.12707; PMID: 25952766

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36. Mizuno H, Vergara P, Maccabelli G, et al. Contact force monitoring for cardiac mapping in patients with ventricular tachycardia. J Cardiovasc Electrophysiol 2013;24:519–24. DOI: 10.1111/jce.12080; PMID: 23373693 37. Afzal MR, Chatta J, Samanta A, et al. Use of contact force sensing technology during radiofrequency ablation reduces recurrence of atrial fibrillation: A systematic review and meta-analysis. Heart Rhythm 2015;12:1990–6. DOI: 10.1016/j. hrthm.2015.06.026; PMID: 26091856 38. Shurrab M, Di Biase L, Briceno DF, et al. Impact of contact force technology on atrial fibrillation ablation: a meta-

analysis. J Am Heart Assoc 2015;4:e002476. DOI: 10.1161/ jaha.115.002476; PMID: 26391136 39. Hussein AA, Barakat AF, Saliba WI, et al. Persistent atrial fibrillation ablation with or without contact force sensing. J Cardiovasc Electrophysiol 2017;28:483–8. DOI: 10.1111/jce.13179; PMID: 28185351 40. Zhou X, Lv W, Zhang W, et al. Impact of contact force technology on reducing the recurrence and major complications of atrial fibrillation ablation: A systematic review and meta-analysis. Anatol J Cardiol 2017;17:82–91. DOI: 10.14744/AnatolJCardiol.2016.7512; PMID: 28209944

Diagnostic Electrophysiology & Ablation

Percutaneous Catheter Ablation of Epicardial Accessory Pathways Eduardo Back Sternick, 1,2 Mariana Faustino, 3 Frederico Soares Correa, 1 Cristiano Pisani 4 and Maurício Ibrahim Scanavacca 4 1. Arrhythmia Unit, Biocor Instituto, Nova Lima, Brazil; 2. Medical Sciences Faculty of Minas Gerais, Belo Horizonte, Brazil; 3. Cardiology Department, Hospital Fernando Fonseca, Amadora, Portugal; 4. Arrhythmia Clinical Unit, Heart Institute, University of São Paulo Medical School, São Paulo, Brazil

Abstract Radiofrequency (RF) catheter ablation is the treatment of choice in patients with accessory pathways (APs) and Wolff–Parkinson–White syndrome. Endocardial catheter ablation has limitations, including the inability to map and ablate intramural or subepicardial APs. Some of these difficulties can be overcome using an epicardial approach performed through the epicardial venous system or by percutaneous catheterisation of the pericardial space. When a suspected left inferior or infero-paraseptal AP is refractory to ablation or no early activation is found at the endocardium, a transvenous approach via the coronary sinus is warranted because such epicardial pathways can be in close proximity to the coronary venous system. Associated congenital abnormalities, such as right atrial appendage, right ventricle diverticulum, coronary sinus diverticulum and absence of coronary sinus ostium, may also hamper a successful outcome. Percutaneous epicardial subxiphoid approach should be considered when endocardial or transvenous mapping and ablation fails. Epicardial mapping may be successful. It can guide and enhance the effectiveness of endocardial ablation. The finding of no epicardial early activation leads to a more persistent new endocardial attempt. When both endocardial and epicardial ablation are unsuccessful, open-chest surgery is the only option to eliminate the AP.

Keywords Accessory pathways, accessory pathway mapping, epicardial intravenous catheter ablation, epicardial subxiphoid catheter ablation, Wolff–Parkinson–White Disclosure: The authors have no conflicts of interest to declare. Received: 7 February 2017 Accepted: 12 May 2017 Citation: Arrhythmia & Electrophysiology Review 2017;6(2):80–4. DOI: 10.15420/AER.2017:6:2 Correspondence: Eduardo Sternick, MD, Alameda do Morro 85, T4, Ap 1900, Vila da Serra,Nova Lima, 34006083, Minas Gerais, Brazil. E: eduardosternick@gmail.com

Radiofrequency (RF) catheter ablation is currently the treatment of choice in patients with accessory pathways (APs) and Wolff– Parkinson–White syndrome, and is shown to have a success rate >95 %.1 APs usually have endocardial ventricular and atrial insertions, located close to the atrioventricular valve rings, making most endocardial catheter ablation procedures relatively straightforward and yielding a high success rate. However, this is not the case when the AP distal end is closer to the epicardial surface or its atrial or ventricular insertion is located far from the atrioventricular groove, and a small subset of patients will fail ablation procedures using a conventional endocardial approach.2,3

catheter or in the setting of Ebstein’s anomaly; proximity of the AP to vital structures, such as a coronary artery or the atrioventricular node; associated structural abnormalities, such as congenital venous system anomalies or acquired coronary system stenosis that has developed as a consequence of previous unsuccessful ablation attempts.4

Endocardial Ablation

Intravenous Mapping and Ablation

Endocardial catheter ablation has limitations, including the inability to access intramural or epicardial portions of arrhythmia circuits. Epicardial AP location was pointed to as the cause of 8 % of prolonged and failed AP ablation attempts.4 Technological improvements, such as cooled-tip, larger-tip ablation catheters, contact-force technology and different energy sources for tissue ablation have not completely solved the problem, and some arrhythmia substrates might not be accessible from the endocardium.5

AP located in the posteroseptal and left posterior areas may be difficult to ablate due to relative epicardial localisation, thickness of the myocardium, anatomic complexity of this area and coexistence of a CS diverticulum, containing a pouch and neck.7,8 CS anatomy should be carefully assessed, either by venography or CT, to rule out diverticulum, which may be present in 15–20 % of refractory posteroseptal APs. Cooled-tip catheter ablation inside the CS venous system and middle cardiac vein is effective in most epicardial posteroseptal APs. However, one has to be aware that a fast conducting AP may become a decremental AP after an ablation attempt. In this instance, the ECG may change, lacking overt preexcitation during sinus rhythm. Its correct identification is possible if a thorough programmed electrical stimulation is carried out after the ablation attempt.3,4,8,9

Several other factors may contribute to RF ablation failure: difficulties with catheter manipulation, including an inability to reach the appropriate AP site, catheter instability (particularly in right-sided AP) or inadequate tissue contact; inaccurate mapping related to AP slanting and AP localisation away from an endocardial-positioned

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Some of these difficulties can be overcome during cardiac surgery (open-chest surgery or thoracoscopy), an epicardial approach performed through epicardial vessels of the coronary sinus (CS) system or through percutaneous catheterisation of the pericardial space, as described by Sosa et al.5,6

Percutaneous Catheter Ablation of Epicardial Accessory Pathways Table 1: Worldwide Experience of Epicardial Mapping and Ablation Reference

Accessory Pathway Location

Anatomic Abnormality

Cool-tip

Success

Sapp et al., 200127

Posteroseptal

Coronary sinus diverticulum

1 Posteroseptal N N Saad et al., 200216 DePaola et al., 200428 1

Results Surgery Success ENDO guided by epicardium

Posteroseptal

Valderrábano et al., 7 Right free-wall = 5/ posteroseptal = 2 20046

2/7

ENDO guided by epicardium= 5

10 RPL = 2/ right free- Schweikert et al., wall = 3/left free20035 wall = 2/LPS = 2/MS = 1

RAA–RV diverticulum = 3

8/10

3/10

ENDO guided by epicardium= 2

RPS = 8/RP = 2/ right Scanavacca et al., 21 free-wall = 1/RAS = 1/ 20153 LPS = 1/LP = 1/ left free wall = 4/PS=3

Coronary sinus diverticulum = 2

6/21

ENDO guided by epicardium= 2

Faustino et al., 1 Posteroseptal RAA–RV diverticulum = 1 Y Y 201629

ENDO after epicardium= 5, surgery = 4

Total 42

20 (48 %)

Posteroseptal = 19, right free-wall = 9, left free-wall = 6, right posterior or posterolateral = 4

Coronary sinus diverticulum = 16 %, 15 (36 %) RAA–RV diverticulum= 10 %

13 (31 %)

Endo = endocardium; LP = left posterior; LPS = left posteroseptal; MS = midseptal; PS = posteroseptal; RAA–RV = right atrial appendage–right ventricle; RAS = right anteroseptal; RP = right posteroseptal; RPL = right posterolateral.

In 1992 Haïssaguerre et al. reported the effectiveness and safety of radiofrequency catheter ablation of left lateral APs via the mid or distal CS when endocardial approaches are unsuccessful.10 They had no significant complications, except a marked nonspecific pain during RF energy application.10 In 1993 Langberg et al. evaluated a group of patients with left-sided APs that were difficult to ablate from the endocardial surface. It was found that the absence of an AP potential during endocardial mapping in combination with a relatively large AP potential within the CS may be a useful marker of a subepicardial pathway localised in the atrioventricular groove. In this select group of patients, radiofrequency application from within the CS appears to enhance ablation efficacy.11 Morady et al. reported on a series of difficult catheter ablation cases: in three patients who were initially thought to have a right or left posteroseptal AP, the effective target site was 2–3 cm within the CS or within a posterior interventricular branch of the CS. In two patients thought to have a left lateral AP, the AP site was mapped within the CS in the region of the lateral mitral annulus. In each of these patients, AP potentials were absent or small in amplitude from the endocardium, but a relatively large potential was recorded within the CS.4 The CS has a myocardial coat with extensive connections to the left and right atria. An extension of this coat through the posterior coronary vein, the middle cardiac vein or a diverticulum neck can connect to the left ventricular epicardium and form epicardial posteroseptal and left posterior AP.1,12 CS APs (defined by earliest activation within the venous system) were identified in 36 % of patients with posteroseptal or left posterior AP in a study of a select group of patients where most had failed previous attempts at ablation; the actual incidence of such pathways should be much smaller.12 Usually CS APs have an oblique course because of the oblique orientation of the fibres connecting the CS myocardial coat with the left atrium.13 CS angiography revealed a CS diverticulum in 21 % of patients and fusiform or bulbous enlargement of the small cardiac vein, middle cardiac vein or CS in 9 % of patients.12 These venous anomalies mostly arise 1.5 cm away from the CS

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

and before the middle cardiac vein, but they can originate from the middle or posterior cardiac veins as well.1 Successful ablation of these pathways may be achieved while ablating in the diverticulum neck.1,14 A precise knowledge of the CS anatomy and its potential abnormalities, such as the presence of diverticulum or persistent left superior vena cava, as well as CS electrogram recordings, are essential for successful RF catheter ablation in patients with a prior history of multiple ablation failures or in whom successful ablation cannot be achieved.1 The presence of a negative delta wave in lead II is suggestive of an epicardial localisation of the AP (identifying a CS AP), with a sensitivity of 70 %.1 Takahashi et al.15 reported that the combination of a steep positive delta wave in lead aVR and a deep S wave in lead V6 (R wave ≤ S wave) during maximal pre-excitation had the highest specificity for identifying epicardial coronary vein posteroseptal APs, while the highest sensitivity is provided by a negative delta wave in lead II. Ablation in posteroseptal diverticula has lower success rates and is correlated with more procedural complications due to the close proximity of the epicardial coronary arteries, risk of venous perforation, tamponade, venous occlusion or heart block.1 Success can usually be improved by targeting the neck of the diverticulum, applying irrigated-tip catheters, using cryoablation or performing the subxiphoid epicardial approach.16 Although RF ablation can be done safely inside the CS, cryoablation could be a safer alternative, especially if the best ablation location is in close proximity to a coronary artery, although a higher rate of recurrences have been reported.9,17 An alternate method for mapping right-sided APs that did not stand the test of time involved the placement of a multipolar mapping catheter within the right coronary artery. In many instances, the right coronary artery is located away from the annulus and therefore provides only a limited anatomic area for mapping compared with percutaneous epicardial mapping. These multipolar 2-F or 3-F mapping catheters are no longer available. The rationale for this approach was analogous to

Diagnostic Electrophysiology & Ablation Figure 1: Percutaneous Epicardial Ablation of a Posteroseptal Accessory Pathway A

B Laboratório de Eletrofisiologia Cardíac - Biocor Instituto, Nova Lima, Minas Gerais, Brasil

Version WIN2000/XP : EP-Tracer V2. 1

5335-12

V4 EPI UNI MCV d 2 3 CS os STIM

10 mm/mV 50 mm/s

(A) Left panel: CT lateral view of the heart. The yellow line represents the course of the ablation catheter in the pericardial space from its entrance (anterior approach) to the earliest ventricular activation site at the posteroseptal region. Middle panel: Fluoro image in left anterior oblique (LAO) view during right coronary artery angiography. Note the close relationship between the ablation catheter and the posterior descending branch. Right panel: Fluoro image in right anterior oblique (RAO) view during levo-phase contrasting of the middle cardiac vein (white arrowheads). The ablation catheter tip is in close contact with the MCV. The hatched yellow line depicts the level of the annulus. The ablation catheter tip is sitting 1.5 cm below the annulus. (B) The accessory pathway was ablated within 4 seconds of radiofrequency current delivery through the cool-tip ablation catheter (black star). CS os = coronary sinus ostium; EPI = epicardium; MCV = middle cardiac vein; RF = radiofrequency; STIM = stimulus; UNI = unipolar.

the placement of a multipolar catheter within the CS for mapping left free-wall pathways.6

Percutaneous Epicardial Mapping and Ablation There are some case reports and a few series of cases about using the epicardial percutaneous subxiphoid approach to map and ablate APs (see Table 1).3

Pericardial Access Access to the epicardial space was achieved as previously described by Sosa et al.18 A subxiphoid transthoracic epicardial puncture was performed using an epidural needle. As the needle was advanced, radiographic contrast was injected to confirm entry in the epicardial space, allowing the introduction of a J-tipped wire. Absence of needle entry in the right ventricle was demonstrated by advancing a guidewire along the left heart border in the left anterior oblique view and by aspirating amber pericardial fluid. A standard sheath then was advanced over the wire. A long and deflectable sheath was substituted and advanced into the transverse sinus of the pericardium as needed to improve catheter stability.6

activation only in two cases, and ablation was ultimately successful from the endocardium but not from the epicardium.5 Cases of right atrial appendage–right ventricle AP have been described, although they represent rare situations (see Table 1).5,19–21 Misidentification of the AP location is not uncommon and successful ablation may have to be performed far from the annulus, at the atrial appendage insertion site, which is the site of the earliest ventricular activation.18 However, the atrial appendage is a difficult target for ablation, even using irrigated catheters, due to limited blood flow between the catheter and the trabeculated surface of the appendage.20 When endocardial ablation fails, a percutaneous epicardial approach has been demonstrated to be safe and effective in several case reports and can be considered an alternative to surgery.5 Left atrial appendage–left ventricle APs have recently been reported. Di Biase et al. described two adult patients with APs involving the left atrial appendage which were difficult to ablate with conventional catheter techniques.22 Mah et al. reported three paediatric patients in whom this AP was impossible to ablate percutaneously, ultimately requiring surgical intervention.23 Catheter ablation failure is likely due to the broad-based nature of the connection (requiring extensive surgical dissection) and the close proximity of the left atrial appendage to major coronary artery branches.23 In 2004, Valderábano et al. aimed to define the role of percutaneous epicardial mapping in six consecutive patients (with seven APs) referred for catheter ablation after previous attempts had failed. Endocardial and epicardial mapping were performed to identify optimal target sites for ablation. Whenever feasible, the endocardial catheter was positioned across from the epicardial catheter to compare electrograms. Epicardial RF delivery was performed only when electrograms showed that the APs were in the best epicardial sites and after endocardial RF delivery had failed. In this series, the most attractive target site for ablation was epicardial in three of the six patients, and an epicardial RF application was necessary for successful ablation in two of these patients.6 In 2015 we reviewed 21 patients referred for percutaneous epicardial AP ablation after a median of more than two previous procedures had failed.3 All patients underwent a simultaneous endocardial and epicardial approach. In six patients (28.5 %) epicardial activation was found earlier than endocardial activation and they underwent successful ablation from the epicardium. In three patients, simultaneous early activation at the epicardium and endocardium close to the mitral annulus was seen, and two of these patients were successfully ablated from the endocardium, guided by epicardial mapping. In nine patients endocardial activation was earlier than epicardial activation and in five of them subsequent endocardial or epicardial transvenous mapping and ablation resulted in AP elimination. Thus, subsequent endocardial or epicardial transvenous mapping and ablation resulted in AP elimination in seven patients (33 %). In three cases no early signals were found from endocardial or from epicardial activation.3

Clinical Experience In 2003 Schweikert et al. reported a series of previously failed catheter ablations in 48 patients who were subjected to combined epicardial–endocardial mapping. This series included 10 patients with AP-mediated tachycardia. In three of these cases, successful epicardial ablation of right atrial appendage–right ventricle epicardial APs was achieved. Of the other seven cases, epicardial mapping yielded earliest

A percutaneous epicardial subxiphoid approach should be considered when endocardial (or transvenous) mapping fails to identify a suitable ablation target or if ablation from the best site is unsuccessful, as: • Epicardial mapping can find a true epicardial AP, where ablation is successful (see Figure 1A and B). When the AP is sub-epicardial, as

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Percutaneous Catheter Ablation of Epicardial Accessory Pathways is the case of right atrial appendage–right ventricular diverticulum, an epicardial (percutaneous or surgical) approach may be the only possibility.3 The percutaneous epicardial ablation success rate is only between 28 and 33 %, however, according to different series.3,5,6 One reason is the epicardial fat – which is thicker in the vicinity of the atrioventricular annulus, covering the region where AP sits – that hampers AP ablation.5 Proximity to a major coronary artery may be another obstacle precluding epicardial AP ablation, due to safety issues. Myocardial tissue and APs that are located underneath large epicardial arteries frequently remain intact after ablation.24 • Epicardial mapping can guide and enhance the effectiveness of endocardial ablation. The identification of an early epicardial activation site works as a reference for successful endocardial ablation; patients with similar endocardium and epicardium activation times can successfully undergo endocardial ablation, according to data from the series previously presented.3 The epicardial approach allows easier and more complete mapping of the atrioventricular annulus without the anatomical restrictions of catheter manipulation from the endocardium. This approach also avoids distortion of epicardial electrograms from previous endocardial ablation attempts.6 • The finding of no early epicardial activation should lead to a more intensive and persistent endocardial attempt. In our series, five patients were successfully ablated after a further attempt at the endocardial approach (including the endocardium and coronary venous system) following epicardial mapping. We hypothesise that when pericardial mapping identifies no adequate target, the operator makes a greater effort as he or she realises that the endocardial approach is the only possibility of success.3 • When no epicardial or endocardial site with early activation is found to allow successful ablation, open-chest surgery is the only option to eliminate the AP, particularly for high-risk patients. It is important to be sure that no early activation is present during epicardial percutaneous mapping and to repeat endocardial mapping. An irrigated-tip ablation catheter should be used as it may improve results, especially in patients with coronary venous system-associated lesions. Congenital anatomical anomalies, such as CS diverticulum, venous stenosis and ostia atresia, are associated with a higher probability of requiring surgery.3

Complications and Limitations Although generally a safe procedure, subxiphoid percutaneous epicardial ablation of APs, like epicardial ablation of other arrhythmia substrates, may result in complications. Coronary injury is a matter of special concern. The procedure has the potential to damage epicardial vessels. This may occur while gaining access with the epidural needle, may be caused by the tip of the sheath or may occur during the delivery of epicardial radiofrequency current. Coronary angiography is the gold standard method for assessing the distance from the ablation site to a major coronary artery.5

ayami B, Shafiee A, Shahrzad M, et al. Posteroseptal P accessory pathway in association with coronary sinus diverticulum: Electrocardiographic description and result of catheter ablation. J Interv Card Electrophysiol 2013;38:43–9. DOI: 10.1007/s10840-012-9775-1; PMID: 23392955 Cipoletta L, Acosta J, Mont L, Berruezo A. Posterior coronary vein as the substrate for an epicardial accessory pathway. Indian Pacing Electrophysiol J 2013;13:142–7. PMID: 24086096 Scanavacca MI, Sternick EB, Pisani C, et al. Accessory atrioventricular pathways refractory to catheter ablation: Role of percutaneous epicardial approach. Circ Arrhythmia Electrophysiol 2015;8:128–36. DOI: 10.1161/CIRCEP.114.002373; PMID: 25527824

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Stavrakis et al.25 assessed 240 patients with an epicardial posteroseptal AP who had undergone ablation within the coronary venous system. The risk of coronary artery injury with radiofrequency ablation was inversely correlated with the distance between the coronary artery and the ablation site. Injury was observed in 50 %, 7 % and 0 % of patients when RF was performed within 2 mm, 3–5 mm and >5 mm of the coronary arteries. Cryoablation was found to be safe. No coronary lesions were reported, even when cryoablation was applied within 5 mm of the coronary artery. A potential advantage of the percutaneous epicardial approach is avoidance of the endovascular complications that might be encountered with conventional endocardial techniques, such as vascular injury, valve damage and embolism from coagulum or dislodged plaque during left-sided ablation procedures. Ventricular fibrillation was reported to have occurred after coronary vasospasm during catheter manipulation in one case and after severe pericardial bleeding caused by middle cardiac vein laceration in another patient.26 Another advantage is that the use of intravenous heparin, and its associated complications, could be avoided.5 A potential limitation of percutaneous pericardial instrumentation is that it should not be used in patients who have undergone prior cardiac surgery, as postoperative pericardial adhesions could limit access to the pericardial space.5 In our series,3 we did not have any major complications. In the two patients in whom the right ventricle was inadvertently punctured, pericardial haemorrhage was immediately recognised and drained, without any further complications. However, one must be aware that unusual complications may also occur, such as intra-abdominal bleeding due to puncture of the liver, hepatic haematoma, right ventricle–abdominal fistula, and right ventricular pseudoaneurysm.26 n

Clinical Perspective • A significant number of failed ablations with standard endocardial ablation methods might represent an epicardial arrhythmia substrate. • The epicardial substrate can be approached percutaneously through the cardiac venous system or through subxiphoid percutaneous epicardial access. • Percutaneous mapping in the pericardial space facilitates a successful outcome by improving the accuracy of endocardial mapping and subsequent endocardial ablation; percutaneous epicardial ablation has been successful in a minority of patients in whom this approach has been attempted. • Pericardial instrumentation is safe when performed by an experienced team. • A subset of patients may require open-chest surgery.

orady F, Strickberger SA, Man KC, et al. Reasons for M prolonged or failed attempts at radiofrequency catheter ablation of accessory pathways. J Am Coll Cardiol 1996;27:683–9. PMID: 8606282 Schweikert RA, Saliba WI, Tomassoni G, et al. Percutaneous pericardial instrumentation for endo-epicardial mapping of previously failed ablations. Circulation 2003;108:1329–35. DOI: 10.1161/01.CIR.0000087407.53326.31; PMID: 12952851 Valderrábano M, Cesario DA, Ji S, et al. Percutaneous epicardial mapping during ablation of difficult accessory pathways as an alternative to cardiac surgery. Heart Rhythm 2004;1:311–3. DOI: 10.1016/j.hrthm.2004.03.073; PMID: 15851176

orin DP, Parker H, Khatib S, Dinshaw H. Computed M tomography of a coronary sinus diverticulum associated with Wolff–Parkinson–White syndrome. Heart Rhythm 2012;9:1338–9. DOI: 10.1016/j.hrthm.2011.05.004; PMID: 21699845 8. Ho I, D’Avila A, Ruskin J, Mansour M. Percutaneous epicardial mapping and ablation of a posteroseptal accessory pathway. Circulation 2007;115:418–22. DOI: 10.1161/CIRCULATIONAHA. 106.673855 9. Guzzo G, Cosío FG, Pastor A, Núñez A. Electroanatomic study of the left atrial insertion of an epicardial accessory pathway integrating the coronary sinus. Europace 2010;12:1022–4. DOI: 10.1093/europace/euq063; PMID: 20219752 10. Haïssaguerre M, Gaita F, Fischer B, et al. Radiofrequency

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catheter ablation of left lateral accessory pathway via the coronary sinus. Circulation 1992;86:1464–8. PMID: 1423960 Langberg JJ, Man KC, Vorperian VR, et al. Recognition and catheter ablation of subepicardial accessory pathways. J Am Coll Cardiol 1993;22:1100–4. PMID: 8409047 Sun Y, Arruda M, Otomo K, et al. Coronary sinus-ventricular accessory connections producing posteroseptal and left posterior accessory pathways: Incidence and electrophysiological identification. Circulation 2002;106:1362–7. PMID: 12221053 Jackman WM, Friday KJ, Fitzgerald DM, et al. Localization of left free-wall and posteroseptal accessory atrioventricular pathways by direct recording of accessory pathway activation. Pacing Clin Electrophysiol 1989;12:204–14. PMID: 2466254 Jang SW, Rho TH, Kim DB, et al. Successful radiofrequency catheter ablation for Wolff–Parkinson–White syndrome within the neck of a coronary sinus diverticulum. Korean Circ J 2009;39:389–91. DOI: 10.4070/kcj.2009.39.9.389 Takahashi A, Shah DC, Jaïs P, et al. Specific electrocardiographic features of manifest coronary vein posteroseptal accessory pathways. J Cardiovasc Electrophysiol 1998;9:1015–25. PMID: 9817553 Saad EB, Marrouche NF, Cole CR, Natale A. Simultaneous epicardial and endocardial mapping of a left-sided posteroseptal accessory pathway associated with a large coronary sinus diverticulum: successful ablation by transection of the diverticulum’s neck. Pacing Clin Electrophysiol 2002;25:1524–6. PMID: 12418753

17. G aita F, Paperini L, Riccardi R, Ferraro A. Cryothermic ablation within the coronary sinus of an epicardial posterolateral pathway. J Cardiovasc Electrophysiol 2002;13:1160–3. PMID: 12475109 18. Sosa E, Scanavacca M, d’Avila A. A new technique to perform epicardial mapping in the electrophysiology laboratory. J Cardiovasc Electrophysiol 1996;7:531–6. PMID: 8743758 19. Wang DY, Weiner SD, Garan H, Whang W. Recurrent accessory pathway conduction in a patient with Wolff–Parkinson–White syndrome: How to ablate? Card Electrophysiol Clin 2010;12: 213–6. DOI: 10.1016/j.ccep.2010.01.005; PMID: 25632309 20. Köse S, Bas¸ arici I, Kabul KH, Barçin C. Successful percutaneous epicardial ablation of an accessory pathway located at the right atrial appendage. Turk Kardiyol Dern Ars 2011;39:579–83. PMID: 21983769 21. Lam C, Schweikert R, Kanagaratnam L, Natale A. Radiofrequency ablation of a right atrial appendageventricular accessory pathway by transcutaneous epicardial instrumentation. J Cardiovasc Electrophysiol 2000;11:1170–3. PMID: 11059983 22. Di Biase L, Schweikert RA, Saliba WI, et al. Left atrial appendage tip: an unusual site of successful ablation after failed endocardial and epicardial mapping and ablation. J Cardiovasc Electrophysiol 2010;21:203–6. DOI: 10.1111/ j.1540-8167.2009.01561.x; PMID: 19656253 23. Mah D, Miyake C, Clegg R, et al. Epicardial left atrial appendage and biatrial appendage accessory pathways. Heart Rhythm 2010;7:1740–5. DOI: 10.1016/j.hrthm.2010.08.013; PMID: 20727420 24. D’Avila A, Gutierrez P, Scanavacca M, et al. Effects of

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radiofrequency pulses delivered in the vicinity of the coronary arteries: implications for nonsurgical transthoracic epicardial catheter ablation to treat ventricular tachycardia. Pacing Clin Electrophysiol 2002;25:1488–95. PMID: 12418747 Stavrakis S, Jackman WM, Nakagawa H, et al. Risk of coronary artery injury with radiofrequency ablation and cryoablation of epicardial posteroseptal accessory pathways within the coronary venous system. Circ Arrhythmia Electrophysiol 2014;7:113–9. DOI: 10.1161/CIRCEP.113.000986; PMID: 24365648 Koruth JS, Aryana A, Dukkipati SR, et al. Unusual complications of percutaneous epicardial access and epicardial mapping and ablation of cardiac arrhythmias. Circ Arrhythm Electrophysiol 2011;4:882–8. DOI: 10.1161/ CIRCEP.111.965731; PMID: 22007036 Sapp J, Soejima K, Couper GS, Stevenson WG. Electrophysiology and anatomic characterization of an epicardial accessory pathway. J Cardiovasc Electrophysiol 2001;12:1411–28. DOI: 10.1046/j.1540-8167.2001.01411.x; PMID: 11797999 dePaola AA, Leite LR, Mesas CE. Nonsurgical transthoracic epicardial ablation for the treatment of a resistant posteroseptal accessory pathway. Pacing Clin Electrophysiol 2004;27:259–61. DOI: 10.1111/j.1540-8159.2004.00423.x; PMID: 14764183 Faustino M, Bellotti H, Hardy C, Scanavacca MI. Percutaneous epicardial access as an alternative approach for catheter ablation of a posteroseptal accessory pathway related to the coronary venous system. J Cardiovasc Electrophysiol 2016;27:754– 6. DOI: 10.1111/jce.12915; PMID: 26749380

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Diagnostic Electrophysiology & Ablation

Cardiac Electrophysiology Under MRI Guidance: an Emerging Technology Henry Chubb, 1 Steven E Williams, 1,2 John Whitaker, 1 James L Harrison, 1,2 Reza Razavi 1 and Mark O’Neill 1,2 1. King’s College London, London, UK; 2. Guy’s and St Thomas’ NHS Foundation Trust, London, UK

Abstract MR-guidance of electrophysiological (EP) procedures offers the potential for enhanced arrhythmia substrate assessment, improved procedural guidance and real-time assessment of ablation lesion formation. Accurate device tracking techniques, using both active and passive methods, have been developed to offer an interface similar to electroanatomic mapping platforms, and MR-compatible EP equipment continues to be developed. Progress to clinical implementation of these technically complex fields has been relatively slow over the last 10 years, but recent developments have led to successful clinical experience. However, further advances, particularly in harnessing the full imaging potential of CMR, are required to realise the mainstream adoption of this powerful guidance modality.

Keywords Magnetic resonance imaging, electroanatomic mapping, ablation, atrial flutter, atrial fibrillation, ventricular tachycardia Disclosure: The authors have no conflict of interest to declare. Received: 3 February 2017 Accepted: 23 May 2017 Citation: Arrhythmia & Electrophysiology Review 2017;6(2):85–3. DOI: 10.15420/aer.2017:1:2 Correspondence: Dr Henry Chubb, Division of Imaging Sciences and Biomedical Engineering, St Thomas’ Hospital, Westminster Bridge Road, London, SE1 7EH, UK. E: henry.chubb@kcl.ac.uk

Interventional magnetic resonance imaging (MRI) is a growing field, and the strength of MRI guidance for procedures rests fundamentally in the high-contrast imaging of soft tissue structures. Combined with the avoidance of radiation exposure, the potential for functional assessment and the ability to exploit MR signals for calculation of the location of interventional instruments, it is clear that the implementation of interventional MRI will continue to grow. For general cardiac interventions, the visualisation of thin, mobile structures presents particular challenges for MRI guidance. Cardiac electrophysiological (EP) procedures add a further dimension, as the accurate detection of intracardiac electrograms must be performed in a highly active electromagnetic environment. This review focuses on the technical considerations for the performance of EP procedures under MRI guidance (MR-guided EP).

Potential Benefits of MR-guided Electrophysiological Procedures MRI techniques offer a high soft-tissue contrast-to-noise ratio (CNR) in comparison with that seen with X-ray, computed tomography (CT) and ultrasound. However, the environment can present challenges and is an expensive procedure; therefore, all the benefits of MR-guided EP must be fully considered to justify the additional difficulties and expense. Broadly speaking, these benefits can be divided into three main areas: improved precision of ablation targeting (substrate identification), improved intra-procedural guidance and improved assessment of ablation lesion formation.

Substrate Identification Both ventricular and atrial arrhythmogenic substrates have been identified on cardiovascular magnetic resonance (CMR) imaging,1,2 and the implementation of CMR data regarding local myocardial characterisation is increasingly used to guide procedures. However, improvements in clinical ablation outcome with the use of CMRderived substrate information have been modest.3 MR-guided EP

presents a modality in which CMR-derived substrate could be used more accurately and intuitively to guide procedures. Ventricular substrate is generally more amenable than atrial to evaluation by CMR owing to increased wall thickness and consequent higher contrast between healthy and pathological tissue. Ventricular tachycardia (VT) in ischaemic cardiomyopathy occurs due to scar-related re-entry and scar can be visualised using late gadolinium enhancement (LGE) techniques.4,5 In particular, the scar border zone has been shown to be critical in the perpetuation of the arrhythmia and its abolition forms the basis of substrate-based VT ablation.6–8 However, caution is required in the direct extrapolation of the imaging to the electrophysiological substrate. Developments in mapping catheter technologies, using smaller and more tightly spaced electrodes, have demonstrated the importance of the fine myocardial architecture in the perpetuation of VT. Conventional LGE resolutions (typically 1.3 x 1.3 mm in-plane) are unlikely to be sufficient,9 and further work is required to establish a firm correlation between CMR-derived scar and critical isthmuses.10 Emerging data also suggest that CMR imaging may be used to guide atrial ablation procedures. Although the atrial wall is thinner, native fibrosis and ablation scar can be identified using primarily threedimensional LGE techniques.2,11 Findings from some studies have been interpreted to suggest that successful ablation of fibrotic regions, distant to the pulmonary veins (PVs), may help improve AF ablation success rates.12 Similarly, atrial re-entrant circuits can be modelled in silico based on atrial scar location and can be used to inform ablation strategies.13 Sites of PV reconnection have been identified using CMR, with successful ablation guided by the CMR-derived substrate,14 but these findings have not been replicated in all studies.15 To date, all studies that have used CMR-derived substrate identification to guide ablation have relied on fusion of the imaging to electroanatomic

Access at: www.AERjournal.com

Diagnostic Electrophysiology & Ablation Figure 1: Real-time Temperature Mapping of LV Epicardial Ablation Lesion, Using MR thermometry (Relative Tissue Temperature Mapping)

Procedural Guidance The vast majority of complex ablation procedures are performed using EAM, and procedural guidance is largely reliant on anatomic mapping techniques alone. Fusion with fluoroscopy, using techniques such as CARTOUNIVUTM (Biosense Webster) or intracardiac ultrasound (CARTOSOUNDTM [Biosense Webster]), provides a degree of structural information in addition to that derived from solely EAM. However, the anatomic information and depth of field is inferior to that achieved with CMR imaging. Detailed information on the chamber of interest and the surrounding structures such as oesophagus, coronary arteries and adjacent chambers may assist the performance of many procedures, particularly those for patients with complex congenital heart disease.20 In addition, cardiac motion derived from both respiration and the cardiac cycle can be assessed more accurately using CMR than any other imaging modality. Accurate compensation for this motion may have significant implications for guidance of energy delivery and assessment of ablation efficacy.

Lesion Evaluation

Upper six panels show colour-coded local temperature at 0–120 sec post-initiation of a 60 sec 50W radiofrequency epicardial ablation lesion, in a short-axis view (dotted lines denote limits of ventricular myocardium). Note the spread of maximum temperature from epicardium to endocardium. Lower panel shows change of temperature against time at individual voxels, the locations of which are shown on the right-hand side. IVS = interventricular septum; LV = left ventricular. Source: Images courtesy of Sebastien Roujol, King’s College London, UK.

mapping (EAM) systems.14,16,17 Software adjuncts to conventional EAM packages, such as CARTOSEGTM CT MODULE and CARTOSEGTM MR MODULE (Biosense Webster, Johnson & Johnson), facilitate the registration of imaging data to the EAM-derived anatomy. However, accurate, real-time, registration of the EAM shell and substrate data is crucial and is significantly affected by registration errors (including discrepancies in landmark identification on imaging and electrical criteria), cardiac chamber conformational changes (arising from differing loading conditions and tachyarrhythmias), and translational changes (due to patient movement, cardiac motion and respiratory motion). CMR-derived targets may typically be 2–4 mm wide for VT ablation10,18 and even smaller for atrial ablation.14,19 Small errors in registration mean that either a broad region must be ablated or critical targets left untouched, with consequent impact on safety, time and efficacy. MR-guided EP can use one of two techniques to overcome such registration errors. The first is the use of image registration within the single imaging modality, rather than trying to match electroanatomic data to imaging data, thus improving matching of landmarks. The second is the use of real-time, or near-real-time, visualisation of substrate, with the imaging performed during the same procedure. Such an approach may improve the outcome of CMR-substrate-guided ablation.

The failure to create durable transmural lesions has been held largely responsible for the high recurrence rates following many complex ablations, particularly VT and AF.21,22 CMR may be used to assess acute ablation lesions,19,23,24 but this does not necessarily mandate the performance of the procedure under MR guidance. One approach might be to perform a conventional procedure with immediate evaluation of lesions prior to removal of sheaths. Patients would undergo CMR assessment, then return to the conventional laboratory for ‘top-up’ ablation of inadequate lesions. However, many factors have inhibited such an approach. First and foremost is the absence of a specific and sensitive acute CMR signature of chronic, effective, lesion formation of sufficient precision to guide further ablation.25,26 Ventricular lesion formation is likely to be more amenable to CMR imaging, but investigations into ventricular lesion imaging are sparse in comparison with those assessing acute atrial ablation lesions. Second, intra-procedural CMR imaging requires substantial disruption: all ferromagnetic material must be removed, and almost all EAM equipment is currently incompatible with CMR imaging. Patches, catheters and most long sheaths must be removed, and, therefore, the registration of imaging to EAM for further ablation requires the procedure to restart almost from scratch. Third, few centres have the facility to move patients easily from the EP laboratory to the MR scanner and back again with sufficient sterility and safety. MR-guided EP has the potential to streamline the process of acute lesion imaging, and can allow real-time lesion formation imaging to be performed (see Figure 1). Immediate imaging presents the opportunity for early repeat ablation and even energy titration. Imaging techniques continue to be developed, but currently no single technique has been demonstrated to be robust enough for clinical implementation. With time, MR-guided EP may present the opportunity for accurate and tailored ablation lesions.

MR Compatibility of Devices The MR environment presents considerable challenges in terms of design and use of conventional procedural equipment. Interventional instruments, anaesthetic equipment and monitoring must all be capable of safe and effective operation in the demanding environment. Commercial ablation solutions frequently include non-compatible components, which are not limited to just ferromagnetic materials, and various considerations must be made.

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Cardiac Electrophysiology Under MRI Guidance Constraints Associated with the Static Magnetic Field

Figure 2: Passive Catheter Tracking

The presence of ferromagnetic materials is not absolutely contraindicated within the MR environment. However, the use of ferromagnetic materials must be carefully controlled and curtailed as far as possible. Ferromagnetic materials exhibit strong attraction along the line of the magnetic field, and torque to align the object with the field lines. Items that are fixed, such as a stent or iron doping on a catheter tip, will generally remain static within the field. However, for sensitive interventional devices, such as an EP catheter, the forces may be intolerable, and the susceptibility artefact (severely degrading imaging quality) tends to be large.

Constraints Associated with the Rapidly Switching Gradient Fields Rapidly switching gradient fields have important implications for electrically conductive materials, particularly in the vicinity of highly voltage-sensitive tissue such as myocardium. Modern gradient fields have a steepness of up to 100 mT/m, and a slew rate of up to 200 mT/m/msec.27 The gradient fields cause significant acoustic noise, may induce peripheral nerve stimulation and also cause low-level heating of tissues (low in comparison with radiofrequency [RF]induced heating). However, a further consideration for MR-guided EP is induction of current and the potential for local cardiac stimulation. Individual catheter channels must be effectively isolated from all other catheter channels to eliminate gradient-induced currents.28

Constraints Associated with the Pulsed Radiofrequency Field A high-frequency RF field is applied to perform MR imaging, which may induce high-frequency eddy currents in soft tissue and devices producing heat. The heating effect of both the electrical and magnetic components of the RF field is complex to simulate, and is largely dependent on the tuning between the transmit coil and the â&#x20AC;&#x2DC;receivingâ&#x20AC;&#x2122; device.27 Multiple tests must be performed to ensure that the worstcase scenario is included, and significant constraints may be placed on transmission lines in particular.29

An MR-compatible ablation catheter tip is visualised at the tricuspid valve annulus during a clinical ablation of the cavotricuspid isthmus for typical atrial flutter. The location of the catheter shaft is seen from IVC to RA. Ao = aorta; IVC = inferior vena cava; RA = right atrial; RV = right ventricular.

Figure 3: Screenshot of the iSuite Platform (Philips Research, Hamburg, Germany), Demonstrating Active Tracking of the Ablation (Red) and Coronary Sinus Reference (Green) Catheters

Device Tracking Device tracking within the MR environment is of paramount importance, and there are two main methods of localisation: passive and active tracking.

Passive Tracking Sequences Passive device tracking relies on the identification of the device on an imaging sequence (see Figure 2). Such an approach does not require novel technology to be developed, but it suffers from poor CNR, particularly with thicker imaging slices, and is highly time consuming. For most passive tracking purposes, a relatively high-speed imaging sequence is required to achieve imaging frame rates of at least 1 Hz. Device identification may be based on a device MR signature that is fundamentally reduced or enhanced for the imaging sequence. Signal reduction is generally achieved through magnetic susceptibility artefact (secondary to the presence of metals) or absence of signal (for non-metallic anhydrous devices). Enhanced signal may be achieved through the use of resonant RF devices30 or filling a device with an enhanced signal source such as a gadolinium-filled tube. The use of passive tracking sequences generally requires significant input from a skilled MR operator to manipulate the imaging plane to keep the device within slice. This is relatively easily achieved in

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

The right atrium has been segmented from the imaging, and is shown as a shell on the 3D projection, colour coded according to local activation time on coronary sinus pacing. Multiplanar reconstructions (MPRs), automatically aligned with ablation catheter location, are shown to the right of the 3D shell (MPR 1â&#x20AC;&#x201C;3).

narrow tubular structures lying within a single plane, such as the aorta, but is much more difficult when there is a greater degree of threedimensional movement. Thicker imaging slices (>10 mm) improve the ability to keep the device within plane, but CNR may be impaired to such a degree that the device may not be identifiable. There are also two further substantial limitations to passive tracking pertinent to MR-guided EP. The first is the difficulty in tracking more than one device at a time: EP frequently requires multiple diagnostic and ablation catheters, and the narrow MR imaging planes, in contrast to the projection view of fluoroscopy, limits the monitoring of more than one device at a time. The second limitation is the requirement to record the location of devices relative to cardiac structures. Automated image

Diagnostic Electrophysiology & Ablation Figure 4: The First Published Example of Electroanatomic Mapping-style Interface for MR-guided Electrophysiological Procedures

to signal arising more than approximately 1 mm away). High-frequency tracking sequences (>10 Hz) with a high spatial resolution (<1 mm) have been developed and shown to be robust in clinical use.28,34 The signal detected by the micro-receive coils must then be passed from catheter tip to the surface coil port at the scanner itself. As discussed, there are significant concerns regarding RF safety for long transmission lines, while they must remain capable of conducting μV MR-receive signals. Some in vivo studies have used thin, high-resistivity coaxial cable,35 optical fibres36 and modified wires,37 but have not been developed into clinical-grade devices. More recently, an approach based on miniature transformers in the device proved to provide both the required tracking robustness and RF safety,38,39 and further work has resulted in dedicated EP catheters based on this approach.40,41

Implementation Within Electroanatomic Mapping-style Interface

Mapping displays the left ventricle of a swine infarct model. Three-dimensional bipolar voltage maps using standard fluoroscopy-based CARTO (A) and the MRI-guided electrophysiology system (B) in the same animal. The maps performed by both methods demonstrate the same anterior wall myocardial scar. AP = anteroposterior; RAO = right anterior oblique; RL = right lateral. Source: adapted from Dukkipati , et al., 2008 with permission.

recognition techniques could theoretically be employed when the device tip is in-plane with sufficient CNR, enabling device localisation to be referenced to pre-defined chambers, but such a capability has not yet been demonstrated. However, passive tracking remains a useful technique, even when actively tracked devices are used (see below). At present, the number of tracked electrodes is highly limited, and therefore there is generally no information on catheter shaft or sheath location. This mirrors the earlier iterations of EAM systems, for which only the location of the catheter tip was visible. Brief runs of passive tracking sequences, preferably in imaging planes defined by the location of the actively tracked catheter tip,31 facilitate the determination of the shaft orientation. Such knowledge may be important in performing more complex catheter manipulations such as those required to reach within a pouch of the Eustachian ridge, or during retrograde access to the left ventricle. Furthermore, active tracking catheters are relatively bulky and expensive, and for simple diagnostic catheters a passive tracking solution may be more appropriate. Therefore, passive tracking remains important even in the era of an active device tracking for MR-guided EP.

Whether active or passive tracking is used for MR-guided EP interventions, it is necessary to project the location within the context of the cardiac chambers. Most studies have chosen to acquire a threedimensional balanced steady-state free precession (b-SSFP) whole heart volume at the beginning of the procedure, and then to display the location within a segmented chamber of the volume (see Figure 4).28,34,35 Manual or automated chamber segmentations have both been employed to provide an interface that closely mimics the strengths of a clinical EAM system. Passive and active tracking sequences may be interleafed, providing real-time location updates with visualisation of device position and surrounding anatomy, and the passive imaging slice position can be coordinated with catheter tip position.31 An interactive interface may also allow for the rapid switching between several MRI pulse sequences, enabling the visualisation of anatomy with different contrasts (see Figure 3). An alternative strategy has been proposed by a group from Boston, USA who have modified an impedance-based tracking system, based on EnSite™ Velocity™ (St Jude Medical), and adapted it for use within the MRI environment.42 Using a swine model, they performed diagnostic EP procedures within the MR scanner, using the voltage-based location to guide catheter manipulation. There were considerable technical challenges in terms of optimising the location signal in the MR environment, and tracking performance was impaired by the requirement for blanking of the tracking signal during the gradient field applications. However, the approach has been demonstrated to be feasible and may open the way for a truly hybrid approach, working in both conventional and MR EP laboratories during the same procedure, or for tracking of simpler devices within the MR scanner itself.

Active Tracking Sequences Active tracking of devices has been achieved using two main techniques. The first exploits the imaging gradient fields to derive device location. Electrical potentials may be induced by the timevariable magnetic fields in a set of miniature coils implanted in the device,32 and this technique has been FDA-cleared for non-cardiac MR-guided interventions (EndoScout® , Robin Medical Inc.). However, it has not been implemented in the cardiac field. The second technique is that used in MR-guided EP, and this employs a dedicated tracking sequence, detected by micro-coils within the catheter (see Figure 3). The technique was first proposed by Dumoulin et al.33 Small receive coils act to detect a highly localised spatially encoded signal from the surrounding tissue (the coils are insensitive

Electrogram Fidelity The detection of cardiac electrical activity is difficult within the MR environment, particularly in the presence of time variable gradient fields and magnetohydrodynamic (MHD) effects. MR-guided EP is currently performed with limited surface electrogram data, typically restricted to four surface electrodes (Expression, Invivo Medical), with marked distortion of many components of the ECG. Identification of the ST-segment and P-wave is often obscured, and many groups are working on improving the electrogram quality and 12-lead ECG solutions.43 There are also challenges related to the detection and transmission of the intra-cardiac electrograms (IEGMs). As for a conventional EP laboratory, IEGMs must be high-pass and low-pass filtered, often with

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Cardiac Electrophysiology Under MRI Guidance the addition of further notch filters to account for the frequency of mains electricity and other identified sources of noise. Despite filtering, however, electrical noise levels remain high in the MR environment. MHD effects have also been shown to be dependent on catheter orientation, and can result in detected voltages that are higher in late systole than at the R-wave.42 In addition, the IEGM voltage must be transmitted via a high-resistivity, RF-safe transmission line, and IEGM fidelity will need to improve significantly to enable detection of lowamplitude signals such as late diastolic potentials.28

Anaesthesia and Monitoring MR-guided EP procedures are currently longer than equivalent procedures using conventional guidance, and are performed in a noisy and potentially claustrophobic environment. Therefore, published human studies have been performed under general anaesthesia or deep sedation.28,34,44,45 Maintaining and monitoring anaesthesia in the MR-scanner room differs from conventional anaesthesia in several ways. These include the use of MR-conditional equipment and devices within the room, interference with monitoring (including ECG), and inaccessibility of the patient. MR-conditional anaesthesia equipment is commercially available, and include the Fabius® MRI (Dräger), which can be operated safely up to the 400 Gauss line. Patient monitoring requires an MR-conditional system, and the most widely employed are those manufactured by Invivo (Expression). These are relatively expensive, but provide a comprehensive range of monitoring, close to that achievable conventionally (CO2, invasive blood pressure, non-invasive blood pressure, saturations, heart rate, and respiratory rate). MR conditionality is generally restricted by power supply transformers, and in the case of the Expression is restricted to 5000 Gauss. Effective and reliable monitoring is particularly important in the context of a patient who is largely hidden from view within the scanner bore. The airway is vulnerable with no visual confirmation of endotracheal tube position, temperature is often difficult to regulate without conventional warming, and the table is relatively hard, increasing risk to pressure areas. Furthermore, the anaesthetist generally sits within the control room to avoid scanner noise and special consideration is therefore needed for effective communication with the interventional team. All these factors need to be considered carefully in the planning of interventional procedures. The final consideration is evacuation in the event of emergency, with particular focus on life-threatening arrhythmias. There is currently no commercial MR-conditional defibrillator available, although there is ongoing work to develop such capability.46 Therefore, robust protocols and training must be in place for evacuation of the patient to a safe zone for medical resuscitation if required.

Brief History of MR-guided Electrophysiological Procedures Table 1 summarises the key publications from the leading groups worldwide working in MR-guided EP. Pioneering studies by the group at John Hopkins University, led by Henry Halperin, established the benchmarks for the field in 2000 and highlighted the technical challenges that remained.47 Active tracking for EP procedures was established in vivo in 2008 by the Boston group, with the creation of an early EAM-style interface that has become the standard for ongoing MR-guided EP work (see Figure 4).35 They went on to investigate real-

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time visualisation of lesion formation,48 a challenging area that has also been investigated by a group in Utah, USA.49 Translation to clinical implementation has been difficult. The burden of proof of safety for human use for every item of equipment is high, and Nazarian et al. published the first report of a diagnostic MR-guided EP study in humans in 2008.45 MR-compatible catheters were created using a polyether block amide plastic body, copper wires and platinum electrodes. A susceptibility artefact approximately 1 mm around the catheter was used for passive position identification on two-dimensional fast gradient echo sequences, and it was possible to perform catheter mapping of a previously ablated cavo-tricuspid isthmus (CTI). Catheter position was confirmed through a combination of real-time MRI guidance and intracardiac electrograms. Electrical interference from gradient switching was suppressed through the use of 30–300 Hz bandpass filtering, allowing even the low-voltage His bundle electrogram to be identified. However, the procedures were lengthy and the studies were discontinued. The first human ablation procedure was performed by a group from Würzberg, Germany in 2012, completing a CTI ablation following two previous failed conventional procedures.50 A group from Leipzig, Germany went on to perform further CTI ablation procedures using the Imricor Vision catheter (Imricor Inc.) under passive guidance.44 Ten patients underwent MR-guided ablation, but it was only possible to achieve conduction block in one of the 10 patients using MR-guided ablation alone. The nine remaining patients required further ablation under conventional fluoroscopic guidance, and one of the main issues identified was the work-flow difficulty with passive tracking of the catheter. The first human study to use active catheter tracking was performed in 2014 in London, UK and the technology has also been demonstrated by the group in Leipzig.28,34

Radiofrequency Ablation Within the MR Environmentz RF ablation within the MR environment has been demonstrated to be safe and feasible under the correct precautions. RF ablation of liver lesions, solid tumours in the lung, kidney and symptomatic bone tumours have all been described.51 The frequency of RF ablation energy is approximately 350 kHz, which is significantly lower than the Larmor frequency in clinical scanners (64–138 MHz). However, the rectangularpulsed waveform of the ablation energy contains higher harmonics that have been shown to destroy imaging.47,52 Low-pass filtering is therefore required to maintain imaging quality, and this enables the potential for live imaging of lesion formation.

Real-time Lesion Imaging Only a small body of literature has demonstrated real-time MR imaging of cardiac lesion formation. Clearly, it can only be performed for MR-guided EP procedures, and relatively few studies have focused on this aspect of research (see Table 1). Real-time lesion imaging is attractive as it could provide a means to titrate energy delivery, potentially decreasing procedural time, increasing efficacy and reducing procedural risk. Steiner et al. first demonstrated the technical feasibility of realtime in vivo MRI of RF lesion formation for a swine paraspinal muscle ablation.53 However, it was not until 2009 that Schmidt et al. demonstrated real-time imaging of a ventricular RF lesion, using a fast T1-weighted gradient recalled echo sequence (ECG-gated, 10 mm slice

Reference

Subjects

Procedure

Magnet and platform Tracking

Tracking

Real-time Imaging

MR Sequences

Ablation (CTI) 1.5T Siemens Passive 7 Fr custom catheter Hoffmann et al., 20 swine with tuned conductor Hamburg 201058 wire loop

Interactive bSSFP (ST 6 mm, 5 fps)

None

Nordbeck et al., 8 swine Ablation (atrial 1.5T Siemens Philips Passive 7 Fr carbon fibre bSSFP, FLASH Demonstration [RA and CS] and conductors and TrueVISP of RF-induced 200952 ventricular [RV apex, (VascoMed/ (ST 8 mm, noise only His bundle]) Biotronik) 2 fps) Nordbeck et al., 9 swine Ablation (one site 1.5T Siemens Philips Passive 7 Fr carbon fibre bSSFP and None only: RA, RV, septum conductors FLASH 201154 Würzberg or coronary sinus) (VascoMed/ Biotronik Nordbeck et al., 1 human Ablation (CTI – redo 1.5T Passive 7 Fr carbon fibre Not detailed None after two failed conductors 201250 conventional (VascoMed/ ablations) Biotronik

T2W: TSE

T2W: TSE T1W: first-pass perfusion T1W: LGE at 0–120 min T2W: post-ablation

None

Proprietary N/A N/A (1.4 mm isotropic, 13 Hz) Proprietary Ventricle: FGRE AVN: early 3D LGE tracking signal (T1W: 10 mm ST) (ST 3.6 mm) (1.4 mm T1W: 3D LGE 30 min isotropic, post -gadolinium 13–15 Hz) VDT-based N/A N/A guidance

First human ablation

Imaging also performed for 24 humans postflutter ablation

Modified Ensite Velocity system

Torqueable sheath with 5 tracking coils also used

First using active tracking

First MR-guided ablation

Comments

Dukkipati et al., 14 swine Diagnostic (ventricular 1.5T GE Active 7 Fr with five substrate- 10 chronic receiver coils 200835 infarct) (St Jude Medical) Schmidt et al., 8 swine Diagnostic (7 LA) and 1.5T GE Active 8 Fr with five ablation (1 LV apex, receiver coils Boston 200948 3 AV node) (St Jude Medical) Schmidt et al., 5 swine Diagnostic (voltage- 1.5T GE VDT 8 Fr with five based device tracking receiver coils 201342 in MR environment) (St Jude Medical)

T2W: FSE T1W: early then late 2D post-gadolinium

Acute Imaging

First human MR-guided EP

7 Fr custom Fast GRE None catheter (Dacron (ST 7 mm, bodies and 5 fps) copper wires)

Manufacturer

Catheter

Nazarian et al., 10 dogs and Diagnostic (atrial [RA] 1.5T Siemens Passive + Passive: 7 Fr Irvine Interactive N/A N/A 2 humans and ventricular enhanced Medical Enhanced fast GRE 200845 [His bundle, RV apex]) passive passive: 10 Fr with (ST 10 mm, 64 MHz loop 5 fps) antenna

Lardo et al., 6 dogs Ablation (ventricular 1.5T GE Passive [RV]) 200047 Johns Hopkins

Group

Table 1: Summary of Key In Vivo MR-guided EP Publications From Leading Centres Worldwide

Diagnostic Electrophysiology & Ablation

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Reference

Subjects

Procedure

Magnet and platform Tracking

Manufacturer

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

T1W: 3D LGE at 20 min T1W: 3D LGE (2.5 mm ST)

50 % success rate (1 week follow-up)

First human ablation series (passive tracking)

Gaps ablated under MR guidance

2D = two dimensional; 3D = three dimensional; AV = atrioventricular; CTI = cavotricuspid isthmus; DIR = double inversion recovery; EP = electrophysiology; (F)GRE = (fast) gradient recalled echo; GE = General Electric; IEGM = intracardiac electrogram; LA = left atrium; LGE = late gadolinium enhancement; PV = pulmonary vein; RA = right atrium; RV = right ventricle; ST = slice thickness; T1W = T1 weighted; T2W = T2 weighted; TSE = turbo spin echo; VDT = voltage-based device-tracking.

Oduneye et al., 10 swine Diagnostic (8 healthy, 1.5T GE Active 9 Fr Vision catheter Not detailed N/A N/A 2 infarct) (Imricor) 201261 Diagnostic (ventricular 1.5T GE Active 9 Fr Vision catheter Not detailed N/A N/A Detailed IEGM Sunnybrook Oduneye et al., 6 swine infarct model) (Imricor) characterisation 201562 of scar

Ablation (PV and CTI) 1.5T Siemens Passive 9 Fr Vision catheter bSSFP (non- Nil T2W : TSE, Ganesan et al., 11 sheep (Imricor) interactive, T1W: 2D LGE at Adelaide 201260 ST 8 mm) 60 min

Eitel et al., 1 human Diagnostic (sinus 1.5T Philips Passive 9 Fr Vision catheter Interactive N/A N/A node AV node (Imricor) bSSFP 201259 conduction) Grothoff et al., 10 humans Ablation (CTI) 1.5T Philips Passive 9 Fr Vision catheter Interactive None T2W: 24 hours post- (Imricor) bSSFP ablation (3 subjects) Leipzig 201444 (ST 10 mm, 8 fps) Hilbert et al., 6 humans Ablation (CTI) 1.5T Philips Active 9 Fr Vision catheter Modified turbo None 2 subjects only: (Imricor) gradient echo, T2W: TSE with DIR 201528 15 Hz T1W: 3D LGE

Vergara et al., 6 swine Ablation (atrium 3T Siemens Active 7 Fr (SurgiVision) Spoiled GRE T2W (HASTE) [LA and RA]) (5.5 fps) 201149 Ablation (RA gaps 3T Siemens Active 8 Fr (MRI Interventions, Spoiled GRE None Utah Ranjan et al., 12 swine filled or unfilled) Irvine), four tracking (5 fps) 201219 micro-coils

T2W: TSE with DIR T1W: 3D LGE at 5, 10, 15, 20 min

First human ablation with active tracking

Comments

Modified turbo None gradient echo, 15 Hz

Acute Imaging Evaluation of RF safety

Real-time Imaging

MR Sequences

Modified turbo N/A N/A GRE, 15 Hz

Tracking

Catheter

Weiss et al., 8 swine Diagnostic 1.5T Philips Passive and 7 Fr custom active catheter, with 201141 King’s College, micro-receive London coils Chubb et al., 10 humans Ablation (CTI) 1.5T Philips Active 9 Fr Vision catheter (Imricor) 201734

Group

Table 1: Cont

Cardiac Electrophysiology Under MRI Guidance

Diagnostic Electrophysiology & Ablation thickness, one slice per 2 second acquisition).48 In the report, details regarding the results of imaging are limited to only presentation within a figure and were not quantified, but they appeared promising. Vergara et al. published a more detailed study in 2011, using T2-weighted imaging (T2W-HASTE) to detect real-time lesion formation visualisation, again in a swine model. 49 This was followed by a three-dimensional late gadolinium enhancement acquisition at 20 min. However, only 30 % of lesions could be visualised during ablation. Where lesion visualisation occurred, changes were identified within 10-15 sec of commencement of energy delivery, but lesion size was over-estimated on imaging performed at later time points during the ablation (45–60 sec after commencement). This finding is in keeping with other assessments of acute T2-weighted imaging25,26 and such early distant changes means that it is unlikely that T2-weighted imaging will prove to be specific for chronic lesion formation. An alternative strategy for real-time imaging is to leave the catheter in place and perform ‘hyper-acute’ imaging of the ablation lesion, seconds after the completion of energy delivery. The susceptibility artefact of the MR-compatible catheters is generally small, facilitating such an approach; this would enable immediate reapplication of energy if the lesion were judged inadequate.48,54 In the longer term, it is likely that real-time lesion formation imaging will rely on more novel sequences, and exploit acute physiological changes such as MR thermometry (see Figure 1).

Acute Lesion Imaging (<4 Hours) There is a great deal more evidence for acute imaging of ablation lesions, but the sensitivity and specificity of acute lesion imaging for prediction of chronic lesion formation remains controversial. Furthermore, much of the data on human ablation relates to imaging at 24 hours post ablation, which is not a clinically useful time interval. Imaging needs to be performed at the same procedure to guide further ablation, and, therefore, a maximum time interval of approximately 4 hours post ablation is considered applicable for intra-procedural acute imaging. In animal models, it has long been established that ventricular and atrial lesions can be visualised immediately following ablation.47,55 Detailed delineation of the pharmacokinetics of gadolinium within acute RF injury lesions24 has been performed, and has been correlated with nonenhanced sequences such as T2-weighted, turbo-spin echo techniques.54 First-pass hypoenhancement and native T1 sequences have been particularly promising, and Vijayakumar et al. have demonstrated the use of non-contrast T1-weighted imaging in the acute identification of chronic lesions in a canine model of ventricular scar.56 Non-contrast agent-based imaging techniques are particularly attractive as they can be repeated multiple times. Furthermore, the potential

shikaga H, Sasano T, Dong J, et al. Magnetic resonanceA based anatomical analysis of scar-related ventricular tachycardia: implications for catheter ablation. Circ Res 2007;101:939–47. DOI: 10.1161/CIRCRESAHA.107.158980; PMID: 17916777. 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. DOI: 10.1001/jama.2014.3; PMID: 24496537. Andreu D, Ortiz-Perez JT, Fernandez-Armenta J, et al. 3D delayed-enhanced magnetic resonance sequences

for toxicity related to the interaction of RF energy and gadoliniumbased contrast agents is undetermined, although gadolinium has been shown to augment lesion formation.57 Celik et al. performed a detailed study of the characterisation of acute RF lesions using native contrast, performing imaging of left ventricular lesions within 60 min of ablation in 13 pigs.23 They concluded that it was the higher ferric iron concentration in lesion core that caused a shortening of T1-relaxation time, and that this was best exploited using an inversion recovery SSFP sequence. Implementation and clinical validation in humans remains to be established.

The Financial Cost of MR-guided Electrophysiological Procedures There are currently no comprehensive commercial solutions available on the open market for MR-EP, and therefore it is not yet possible to determine cost-effectiveness. Furthermore, while technological developments are still required to leverage the full potential of MR-EP, such as detailed substrate evaluation and real-time lesion assessment, it is clear that MR-EP rests largely in the research field. In the longer term, the cost of MR-EP has the potential to trend towards that of conventional EAM-guided EP procedures. The cost calculations for the use of the main hardware item, the MRI scanner, vary widely between centres, and at our institution is approximately twice that of the operational EP catheter laboratory. Selected disposable items are not required for MR-guided ablation procedures, such as EAM patches, and may offset that cost by a small degree, particularly if fewer mapping and ablation catheters are required. However, the fundamental calculation of cost-effectiveness will rely on procedural efficacy and whether time is saved through the direct application of imaging; this can only be answered through adoption and development of the techniques.

Five-year View MR-guided EP will continue to evolve, and several investigational products are now close to achieving CE mark status. The commercial availability of an MR-compatible ablation catheter, digital amplifier stimulator and image guidance platform will make the technology more widely available and should greatly accelerate developments in the field. Longer-term mainstream adoption of MR-guidance for EP is dependent on substantial investment and co-operation of imaging and EP partners, and will also require the training of teams and individuals with crossover skills in both EP and MRI. However, if improved procedural outcomes can be demonstrated, then the technology has the potential to expand rapidly.

Conclusion MR-guided EP remains a research field in relative infancy, and advances have been slowed by the considerable technical challenges that it presents. The potential benefits, however, are substantial and research into this exciting field will accelerate greatly with the development of a robust, clinically approved, MR-guided EP system. n

improve conducting channel delineation prior to ventricular tachycardia ablation. Europace 2015;17:938–945. DOI: 10.1093/ europace/euu310; PMID: 25616406. Nazarian S, Bluemke D, Lardo AC, et al. Magnetic resonance assessment of the substrate for inducible ventricular tachycardia in nonischemic cardiomyopathy. Circulation 2005;112:2821–5. DOI: 10.1161/CIRCULATIONAHA.105.549659; PMID: 16267255. Ashikaga H, Arevalo H, Vadakkumpadan F, et al. Feasibility of image-based simulation to estimate ablation target in human ventricular arrhythmia. Heart Rhythm 2013;10:1109–16. DOI: 10.1016/j.hrthm.2013.04.015; PMID: 23608593.

arbucicchio C, Ahmad Raja N, Biase L Di, et al. High-density C substrate-guided ventricular tachycardia ablation: role of activation mapping in an attempt to improve procedural effectiveness. Heart Rhythm 2013;10:1850–8. DOI: 10.1016/ j.hrthm.2013.09.059; PMID: 24055940. Pop M, Ghugre NR, Ramanan V, et al. Quantification of fibrosis in infarcted swine hearts by ex vivo late gadoliniumenhancement and diffusion-weighted MRI methods. Phys Med Biol 2013;58:5009–28. DOI: 10.1088/0031-9155/58/15/5009; PMID: 23833042. Perez-David E, Arenal A, Rubio-Guivernau JL, et al. Noninvasive identification of ventricular tachycardia-related

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CSI 2017 – CONGENITAL, STRUCTURAL AND VALVULAR HEART INTERVENTIONS JUNE 28 – JULY 1, 2017 | FRANKFURT, GERMANY CSI Frankfurt will provide a deep dive into major topics in catheterbased therapy of congenital, structural and valvar heart disease. We look forward to welcoming adult and paediatric interventional cardiologists, cardiothoracic surgeons, anesthesiologists, nurses, technicians and any other medical specialty involved in these procedures to this annual event that has been running for over 20 years! ON THE FIRST DAY OF THE CONFERENCE THERE WILL BE THREE SIMULTANEOUS PROGRAMS: 1. CSI Focus Imaging will provide physicians involved in congenital, structural and valvar interventions with the necessary imaging tools for safe and effective performance. 2. CSI Focus Innovation is a one-of-a-kind conference that will bring together different disciplines to discuss the process of device design and development from bench to bedside. 3. CSI Focus PFO will cover everything you need to know about patent foramen ovale (PFO) closure: indication, imaging, device selection, technique and complication management.

The scientiﬁc program of CSI Frankfurt allows you to customize your learning experience according to your personal requirements: There will be three parallel main sessions at all times offering different types of learning experience, ranging from 100% live cases (Live Only), a mixture between step by step live case presentations and lectures on particular topics (Focus Live), or seminar sessions consisting of lectures and debates only. Parallel streams of adult, pediatric or mixed sessions enable you to tailor the program to your particular needs. At the same time CSI Frankfurt offers the opportunity to discover new areas of interest: You will be able to gain hands-on experience on simulators in our training hub; we will cover the newest devices, techniques and procedures and you can take this chance to explore new ﬁelds such as device therapies for heart failure. What else sets CSI Frankfurt apart from other interventional meetings? We pride ourselves on offering a personal experience to our faculty and attendees. Interaction between panel, operators and audience is encouraged at all times. We try not to take ourselves too serious – we debate with humour, question with a smile and disagree with respect. Friendships and professional relationships forged at CSI Frankfurt will last a lifetime. Come and join us at CSI 2017 and learn about the newest techniques, technology and concepts!

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German Rhythm Days 2017 Annual Meeting of the German Cardiac Societyâ&#x20AC;&#x2DC;s EP working group

Berlin, Germany 12-14 October, 2017