AER 6.4 by Radcliffe Cardiology

Arrhythmia & Electrophysiology Review Volume 6 • Issue 4 • Winter 2017

Volume 6 • Issue 4 • Winter 2017

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Management of Complications in Anticoagulated Patients with Atrial Fibrillation George D Katritsis and Demosthenes G Katritsis

At the Atrioventricular Crossroads: Dual Pathway Electrophysiology in the Atrioventricular Node and its Underlying Heterogeneities Sharon A George, N Rokhaya Faye, Alejandro Murillo-Berlioz, K Benjamin Lee, Gregory D Trachiotis and Igor R Efimov

Ablation of Atrial Fibrillation in Patients with Congenital Heart Disease Marwan M Refaat, Jad Ballout and Moussa Mansour

Minimally Invasive Epicardial Surgical Ablation Alone Versus Hybrid Ablation for Atrial Fibrillation: A Systematic Review and Meta-Analysis Charles M Pearman, Shi S Poon, Laura J Bonnett, Shouvik Haldar, Tom Wong, Neeraj Mediratta and Dhiraj Gupta

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Atrioventricular Node and Dual Pathway Physiology

Thromboembolic Risk: Shifting the Status Quo

Hybrid Ablation Surgery for Atrial Fibrillation

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Volume 6 • Issue 4 • Winter 2017

Editor-in-Chief Demosthenes Katritsis Hygeia Hospital, 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

Warren Jackman

Sunny Po

Lankenau Institute for Medical Research, Wynnewood, USA

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

Carina Blomström-Lundqvist

Pierre Jaïs

Uppsala University, Uppsala, Sweden

University of Bordeaux, CHU Bordeaux, France

Antonio Raviele

Johannes Brachmann

Josef Kautzner

Klinikum Coburg, II Med Klinik, Germany

Institute for Clinical and Experimental Medicine, Prague, Czech Republic

Pedro Brugada

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

Edward Rowland

University of Brussels, UZ-Brussel-VUB, Belgium

Pier Lambiase

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

Alfred Buxton

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

Frédéric Sacher

Beth Israel Deaconess Medical Center, Boston, USA

Samuel Lévy

Hugh Calkins

Aix-Marseille University, France

John Hopkins Medical Institution, Baltimore, USA

Cecilia Linde

David J Callans

Karolinska University, Stockholm, Sweden

University of Pennsylvania, Philadelphia, USA

Gregory YH Lip

A John Camm

University of Birmingham, UK

St George’s University of London, UK

Francis Marchlinski

Riccardo Cappato IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy

Ken Ellenbogen

University of Pennsylvania Health System, Philadelphia, USA

John Miller Indiana University School of Medicine, USA

Virginia Commonwealth University, Richmond, VA, USA

Fred Morady

Sabine Ernst Royal Brompton and Harefield NHS Foundation Trust, London, UK

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

Richard Schilling Barts Health NHS Trust, London, UK

William Stevenson Vanderbilt School of Medicine, USA

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

Panos Vardas Heraklion University Hospital, Greece

Cardiovascular Center, University of Michigan, USA

Marc A Vos

Sanjiv M Narayan

University Medical Center Utrecht, The Netherlands

Stanford University Medical Center, USA

Hein Wellens

Antwerp University and University Hospital, Antwerp, Belgium

Andrea Natale

University of Maastricht, The Netherlands

Austin, Texas

Katja Zeppenfeld

Gerhard Hindricks

Mark O’Neill

Leiden University Medical Center, The Netherlands

University of Leipzig, Germany

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

Douglas P Zipes

Carsten W Israel

Carlo Pappone

JW Goethe University, Germany

IRCCS Policlinico San Donato, Milan, Italy

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

Hein Heidbuchel

Junior Associate Editor Dr Afzal Sohaib Imperial College London, UK Managing Editor Rita Som • Production Jennifer Lucy • Design Tatiana Losinska Sales & Marketing Executive William Cadden • 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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Established: October 2012

Aims and Scope • Arrhythmia & Electrophysiology Review aims to assist time-pressured physicians to keep abreast of key advances and opinion in the arrhythmia and electrophysiology sphere. • Arrhythmia & Electrophysiology Review comprises balanced and comprehensive articles written by leading authorities, addressing the most pertinent developments in the field. • Arrhythmia & Electrophysiology Review provides comprehensive updates on a range of salient issues to support physicians in continuously developing their knowledge and effectiveness in day-to-day clinical practice. • The journal endeavours, through its timely teaching reviews, to support the continuous medical education of both specialist and general cardiologists, and disseminate knowledge of the field to the wider cardiovascular community.

Structure and Format • Arrhythmia & Electrophysiology Review is a quarterly journal comprising review articles and editorials. • The structure and degree of coverage assigned to each category of the journal is the decision of the Editor-in-Chief, with the support of the Section Editors and Editorial Board. • Articles are fully referenced, providing a comprehensive review of existing knowledge and opinion. • Each edition of Arrhythmia & Electrophysiology Review is replicated in full online at www.AERjournal.com

Frequency: Quarterly

Current Issue: Winter 2017

• Once the authors have amended a manuscript in accordance with the reviewers’ comments, the manuscript is returned to the reviewers to ensure the revised version meets their quality expectations. Once approved, the manuscript is sent to the Editor-in-Chief for final approval prior to publication.

Submissions and Instructions to Authors • Contributors are identified by the Editor-in-Chief with the support of the Section Editors and Managing Editor, and guidance from the Editorial Board. • Following acceptance of an invitation, the author(s) and Managing Editor, in conjunction with the Editor-in-Chief, formalise the working title and scope of the article. • Subsequently, the Managing Editor provides an ‘Instructions to Authors’ document and additional submission details. • The journal is always keen to hear from leading authorities wishing to discuss potential submissions, and will give due consideration to any proposals. Please contact the Managing Editor for further details: managingeditor@radcliffecardiology.com. The ‘Instructions to Authors’ information is available for download at www.AERjournal.com

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Distribution and Readership Editorial Expertise Arrhythmia & Electrophysiology Review is supported by various levels of expertise: • Overall direction from an Editor-in-Chief, supported by Section Editors and an Editorial Board comprising leading authorities from a variety of related disciplines. • Invited contributors who are recognised authorities in their respective fields. • Peer review – conducted by members of the journal’s Peer Review Board as well as other experts appointed for their experience and knowledge of a specific topic. • An experienced team of Editors and Technical Editors.

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

Call for Submissions Arrhythmia & Electrophysiology Review publishes invited contributions from prominent experts, but also welcomes speculative submissions of a superior quality. For further information on submitting an article,

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Contents Foreword

151

A Renovated Editorial Board Demosthenes Katritsis, Editor-in-Chief Hygeia Hospital, Athens, Greece

Expert Opinions

153

Premature Ventricular Contraction-induced Cardiomyopathy David J Callans Division of Cardiovascular Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA

156

Cryoballoon Ablation in Today’s Practice: Can the Left Common Ostium Be Ablated and Injury to the Right Phrenic Nerve Avoided? Gian-Battista Chierchia,1 Saverio Iacopino2 and Carlo de Asmundis1 1. Heart Rhythm Management Centre, University of Brussels, Brussels, Belgium; 2. Electrophysiology Unit, Villa Maria Cecilia Hospital, Ravenna, Italy

159

Choice of Ventricular Pacing Site: the End of Non-physiological, Apical Ventricular Pacing? Demosthenes G Katritsis Hygeia Hospital, Athens, Greece

Clinical Arrhythmias

161

Optimum Risk Assessment for Stroke in Atrial Fibrillation: Should We Hold the Status Quo or Consider Magnitude Synergism and Left Atrial Appendage Anatomy? James A Reiffel Columbia University, New York, NY, USA

167

Management of Complications in Anticoagulated Patients with Atrial Fibrillation George D Katritsis1 and Demosthenes G Katritsis2 1. Imperial College Healthcare NHS Trust, London, UK; 2. Hygeia Hospital, Greece

179

At the Atrioventricular Crossroads: Dual Pathway Electrophysiology in the Atrioventricular Node and its underlying Heterogeneities Sharon A George,1 N Rokhaya Faye,1 Alejandro Murillo-Berlioz,1,2 K Benjamin Lee,1,2 Gregory D Trachiotis2 and Igor R Efimov1 1. Department of Biomedical Engineering, The George Washington University, Washington, DC, USA; 2. Division of Cardiothoracic Surgery and Cardiothoracic Research, Veterans Affairs Medical Center, Washington, DC, USA

Diagnostic Electrophysiology and Ablation

186

Ganglionated Plexi Ablation: Physiology and Clinical Applications Stavros Stavrakis and Sunny Po University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA

191

Ablation of Atrial Fibrillation in Patients With Congenital Heart Disease Marwan M Refaat,1,2 Jad Ballout1 and Moussa Mansour3 1. Department of Internal Medicine, Cardiology Division, American University of Beirut, Lebanon; 2. Department of Biochemistry and Molecular Genetics, American University of Beirut, Lebanon; 3. Cardiac Arrhythmia Service, Massachusetts General Hospital/Harvard Medical School, Boston, USA

195

Ablation of Atrial Fibrillation Drivers Tina Baykaner, Junaid A B Zaman, Paul J Wang and Sanjiv M Narayan Stanford University, Palo Alto, California, USA

202

Minimally Invasive Epicardial Surgical Ablation Alone Versus Hybrid Ablation for Atrial Fibrillation: A Systematic Review and Meta-Analysis Charles M Pearman,1,3 Shi S Poon,1 Laura J Bonnett,4 Shouvik Haldar,5 Tom Wong,5 Neeraj Mediratta2 and Dhiraj Gupta1 1. Department of Cardiology, Liverpool Heart and Chest Hospital; 2. Department of Cardiothoracic Surgery, Liverpool Heart and Chest Hospital; 3. Division of Cardiovascular Sciences, School of Medical Sciences, Manchester Academic Health Science Centre, The University of Manchester; 4. Department of Biostatistics, University of Liverpool; 5. Heart Rhythm Centre, NIHR Cardiovascular Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust, Institute of Cardiovascular Medicine and Science, Imperial College London, UK

210

One-stage Approach for Hybrid Atrial Fibrillation Treatment Vincent Umbrain,1 Christian Verborgh,1 Gian-Battista Chierchia,2 Carlo De Asmundis,2 Pedro Brugada2 and Mark La Meir3 1. Department of Anaesthesiology and Perioperative Medicine, University Hospital Brussels, Free University of Brussels, Belgium; 2. Heart Rhythm Management Centre, University Hospital Brussels, Free University of Brussels, Belgium; 3. Department of Cardiac Surgery, University Hospital Brussels, Free University of Brussels, Belgium

217

Increasing the Single-Procedure Success Rate of Pulmonary Vein Isolation Mattias Duytschaever,1 Mark O’Neill,2,3 Martin Martinek4 1. St Jan Hospital, Bruges, Belgium; 2. St. Thomas’ Hospital, London, UK; 3. King’s College London, London, UK; 4. Elisabethinen Hospital, Linz, Austria

Letters

222

Mahaim Accessory Pathways Nikolaos Fragakis Aristotle University of Thessaloniki, Thessaloniki, Greece

223

Can We Select Patients for Prophylactic VT Ablation? Theodoros Zografos Red Cross Hospital, Athens, Greece

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European Cardiology Review Volume 12 • Issue 1 • Summer 2017

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Volume 12 • Issue 1 • Summer 2017

www.ECRjournal.com

Cardiovascular Disease in Women: Understanding Symptoms and Risk Factors Tracey Keteepe-Arachi and Sanjay Sharma

Women with Stable Angina Pectoris and No Obstructive Coronary Artery Disease: Closer to a Diagnosis Marie Mide Michelsen, Naja Dam Mygind, Daria Frestad and Eva Prescott

Cardiac Disease after Pregnancy: A Growing Problem Christina Y Aye, Henry Boardman and Paul Leeson

Health Literacy and Atrial Fibrillation: Relevance and Future Directions for Patient-centred Care Konstantinos N Aronis, Brittany Edgar, Wendy Lin, Maria Auxiliadora Parreiras Martins, Michael K Paasche-Orlow and Jared W Magnani

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Sites of Action for Antiplatelet Agents

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Foreword

A Renovated Editorial Board

ince the inauguration of Arrhythmia and Electrophysiology Review in 2012, our Editorial Board has been one of the strengths of the journal. Highly esteemed colleagues in the field of electrophysiology and arrhythmia, in general, have

honoured us by participating in the Editorial Board and actively contributing to the scientific status of the journal by submitting their work, reviewing papers, and reflecting upon our continually evolving faculty. In an era of revolutionary changes,1 it has been our institutional policy to renew our Editorial Board at predetermined time intervals; this allows us to include new motivated colleagues, and deliver long-standing members from the time-consuming tasks emanating from their commitment. The editorial staff and

myself are deeply in gratitude to all those who have supported our vision of uncompromised excellence in publishing all these years. We are all also deeply honoured by the willingness of newly invited colleagues to support our cause by joining our ranks. It is indeed a privilege and a pleasure, to welcome on board some big names in contemporary electrophysiology. Ed Rowland, Pier Lambiase, David Callans, Andrea Natale and John Miller need no introduction to our community. Most of them kindly contributed to the AER issue (6.1) dedicated to the late, and sorely missed, Mark Josephson,2â&#x20AC;&#x201C;5 and now the appearance of their names in our Editorial Board gives additional credit to the journal. I welcome them all, and look forward to a fruitful and enjoyable collaboration. n Demosthenes G Katritsis Editor-in-Chief, Arrhythmia and Electrophysiology Review Hygeia Hospital, Athens, Greece

atritsis D. Clinical Electrophysiology: A Glimpse Into K The Future. Arrhythm Electrophysiol Rev 2017;6:40. doi: 10.15420/aer.2017:6:2:ED1; PMCID: PMC5517369 Rowland E. A Gifted Teacher. Arrhythm Electrophysiol Rev 2017;6:17. DOI: 10.15420/aer.2017.6.1:PP6; PMID: 28603618

allans DJ. Mark E Josephson: Characteristics of C Leadership. Arrhythm Electrophysiol Rev 2017;6:6-8. doi: 10.15420/aer.2017.6.1:ED2; PMID: 28507737 Miller JM. Mark E Josephson: Clinical Investigator. Arrhythm Electrophysiol Rev 2017;6:9-12. doi: 10.15420/

aer.2017.6.1:ED3; PMID: 28507738 Marchlinski F. Mark E Josephson: A Tribute to His Work on Ventricular Arrhythmias. Arrhythm Electrophysiol Rev 2017;6:15-16. doi: 10.15420/aer.2017.6.1:PP4; PMID: 28630709

DOI: 10.15420/AER.2017.6.3.FO1 ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

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Expert Opinion

Premature Ventricular Contraction-induced Cardiomyopathy David J Callans Division of Cardiovascular Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA

Abstract Premature ventricular contractions (PVCs) are very common and usually do not require treatment. However, in the clinical setting of troublesome symptoms, or when PVCs trigger polymorphic ventricular tachycardia or cause cardiomyopathy, proper treatment is critical. In this review, the clinical syndrome of PVC-induced cardiomyopathy, including risk factors for development and treatment, is discussed. Although PVC-induced cardiomyopathy is typically associated with frequent PVCs there are also patients with this burden that do not develop cardiomyopathy, suggesting a differential susceptibility. Treatment often consists of catheter ablation, although antiarrhythmic medications may also provide both reduction in PVC frequency and resolution of left ventricular dysfunction.

Keywords Premature ventricular contractions, premature ventricular contraction-induced cardiomyopathy, ablation, antiarrhythmic medications, heart failure Disclosure: The authors have no conflicts of interest to declare. Received: 14 November 2017 Accepted: 16 November 2017 Citation: Arrhythmia & Electrophysiology Review 2017;6(4):153–5. DOI: 10.15420/aer.2017/6.4/EO1 Correspondence: David J Callans, 9.129 Founders Pavilion, 3400 Spruce Street, Philadelphia, PA 19104, USA. E: david.callans@uphs.upenn.edu

Premature ventricular contractions (PVCs) are very common cardiac arrhythmias, detected on up to 75 % of Holter monitors of ambulatory patients.1 Although PVCs in the setting of advanced structural heart disease have independent negative prognostic implications,2 the majority of PVCs are quite benign, associated with neither symptoms nor signals of future harm. For an important minority, PVCs represent an important medical condition that requires treatment. The three indications for treatment are symptom control, to prevent recurrence in PVC-triggered ventricular fibrillation and to potentially reduce the effects of PVC-induced cardiomyopathy. Anecdotally, there is considerable confusion regarding the application of therapy in general and catheter ablation specifically in all three of these indications. The tendency of general cardiologists seems to be undertreatment (after coronary heart disease is excluded) and the tendency of electrophysiologists may be overtreatment, particularly regarding the potential development of PVC-induced cardiomyopathy. The purpose of this review is to discuss what is understood about this syndrome, its prognosis and how catheter ablation may alter its natural history. It must be stressed that much of what follows represents my point of view, as observational studies supply most of the available data. The concept of PVC-induced cardiomyopathy was first proposed by Duffee and coworkers, who observed a small group of patients with cardiomyopathy recover normal left ventricular (LV) function after pharmacological suppression of frequent PVCs.3 The salient features of how we think of this diagnosis may be summarised as follows: (1) LV dilatation and reduction in systolic function, either in the absence of pre-existing cardiac pathology or a recognised further reduction in LV function in the setting of pre-existing heart failure; in association with (2) frequent PVCs and (3) full or partial resolution of LV dysfunction with successful treatment of PVCs.4 As in most things in medicine, the details of all of these qualifiers are important. An early description of the potential effect of catheter

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ablation on PVC-induced cardiomyopathy by Yarlagadda et al. seems prescient.5 From a group of 27 patients referred for ablation of right ventricular outflow tract PVCs, eight had depressed LV function. Although the mean PVC burden in this study was >17,000/24 h, two of the eight with depressed LV function had <6,000/24 h. Seven of the eight had successful ablation and LV function normalised in all seven. Importantly, the authors proposed that this small experience supported a differential susceptibility between patients to develop cardiomyopathy, as a clear dose response could not be established. Subsequent investigations have focused on distinguishing risk factors for the development of cardiomyopathy in patients with PVCs. This line of reasoning has been important, both to identify clinical risks and to try to “back calculate” something about the underlying mechanism. Mixed (but mostly negative) results have been observed with studies of PVC site of origin. If these studies pointed to site dependence, there would be considerable support for PVCs causing cardiomyopathy through production of dyssynchrony, analogous to the situation with right ventricular pacing. PVC morphology,6 PVC QRS duration7 and interpolation8 have been associated with PVC-induced cardiomyopathy in single-centre studies. However, most of the investigation has focused on PVC burden in observational studies of patients referred for ablation.7,9–13 A large and influential experience was presented by Baman and coworkers, who reported on 174 consecutive patients referred for PVC ablation, 54 of whom had depressed LV function.10 Patients with depressed LV function (mean ejection fraction 37 %) had significantly more PVCs than the group as a whole (33 ± 13 versus 13 ± 12 %); no patient in the low EF group had a burden less than 10 %. In an analysis of PVC frequency and ejection fraction (Figure 1), a “line in the sand” of 24 % PVC burden best separated those with LV dysfunction from normal (sensitivity 79 %, specificity 78 %). The authors concluded that although PVC-related cardiomyopathy may occur in patients with less PVCs, “in the presence of a PVC burden ≥24 %, it may

Access at: www.AERjournal.com

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Expert Opinion Figure 1: A Dot Plot Representation of the Relationship between PVC Burden and Ejection Fraction in 174 Patients Referred for PVC Catheter Ablation

(the level of resolution by echocardiography, in their opinion). However, although it is difficult to completely determine from the manuscript, it seems that only one patient developed an ejection fraction <50 %. Although anecdotal, this is in keeping with my clinical practice supplemented by conversations with many electrophysiologists – it is unusual but certainly possible to develop PVC-induced cardiomyopathy over time. Most patients are discovered at presentation, which may be a considerable but indeterminable time from PVC onset as most patients with cardiomyopathy have no specific symptoms from their PVCs. This is an expression of differential susceptibility: subjects that are susceptible develop the problem at presentation, those that are not seldom do during follow up. Guideline statements reflect this observation, and recommend conservative management and follow-up imaging for patients with frequent PVCs and preserved LV function.15 If patients develop LV dysfunction during follow up (increased LV dimension is probably more sensitive than decreased ejection fraction), then treatment with ablation medications is certainly warranted. Nonetheless, many electrophysiologists are performing PVC ablation in asymptomatic patients with normal LV function, feeling justified by high PVC burden. This is at best unproven, at worse potentially hazardous.

PVC Burden (%)

24 % 20

0 0

Ejection fraction (%) A cut-off PVC burden of 24 % distinguishes patients with and without LV dysfunction (sensitivity 79 %, specificity 78 %); however, there are patients with cardiomyopathy with lower PVC frequencies (low-left panel) and patients with higher frequency without cardiomyopathy. LV = left ventricular; PVC = premature ventricular contraction. Source: Baman, et al. Mapping and ablation of epicardial idiopathic ventricular arrhythmias from within the coronary venous system. Acknowledgement: Circ Arrhythm Electrophysiol 2010;3:274–9. http://circep.ahajournals.org/content/3/3/274

be prudent to suppress the PVCs by catheter ablation or drug therapy to avoid the development of cardiomyopathy.” In my opinion, this statement has led to unfortunate, unintended consequences. In addition to the inherent bias in referral populations (patients referred for catheter ablation would be expected to have an enriched frequency of LV dysfunction), the figure has been misinterpreted. There are certainly patients (the upper right corner of Figure 1) who have a high PVC burden and normal ejection fraction. There is limited data in unselected populations about the timedependent impact of frequent PVCs. The best data is from Niwano et al., who followed 249 patients (189 with complete follow-up data) with frequent (>1,000/24 h) PVCs from the right or left ventricular outflow tract and no discernable structural heart disease for a mean of 5.6 ± 1.7 years in the absence of treatment (except beta blockers as required for relief of symptoms).14 They segregated groups of high (>20,000), moderate (5,000–20,000) and less frequent (1,000–5,000/ 24 h) PVCs. Over follow up, 13 patients developed LV dysfunction, defined in this study as an absolute drop in ejection fraction of >6 %

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Frequent PVCs may also exacerbate a pre-existing cardiomyopathy. Many physicians struggle with causation – are the PVCs caused by the myopathy or the other way around? Although these decisions can be subtle, they are usually assisted by assessing the PVC morphology. The vast majority of PVCs are from the outflow tracts, which is an unusual location for ischemic or nonischemic pathology (excepting arrhythmogenic right ventricular cardiomyopathy). The presence of idiopathic-appearing frequent PVCs, particularly with a singular morphology, should suggest the possibility of contribution to LV dysfunction. Mountantonakis and colleagues studied 69 patients with frequent outflow tract PVCs and LV dysfunction referred for catheter ablation (ejection fraction 35 ± 9 %, ischemic heart disease excluded in all subjects).11 Twenty of these patients had a pre-existing diagnosis of non-ischemic cardiomyopathy. With successful catheter ablation, these patients also improved LV ejection fraction, but not to the same degree as those with only PVC-related cardiomyopathy (Δ LV ejection fraction 8 versus 13 %, p=0.046). In addition, lower baseline LV ejection fraction predicted a less dramatic response. Deyell et al. assessed predictors of LV recovery in 110 patients with frequent PVCs referred for ablation, 48 of whom had depressed LV function pre-procedure.7 They observed a gradient of PVC QRS duration between patients with normal LV function (134.7 ± 12.3 ms), PVC cardiomyopathy patients who recovered normal LV function (158.2 ± 8.6 ms) and those who did not (173.2 ± 12.9 ms). On multivariate analysis, the only predictor of failure to recover despite successful ablation was PVC QRS duration. The authors suggested that increases in PVC QRS duration may announce development of underlying fibrosis, which may account for the lack of reversibility. This further suggests that imaging may define possible candidates for intervention in the near future. Other groups have also found that PVC QRS duration is broader in patients with PVC-induced cardiomyopathy, suggesting a duration of ≥150 ms as a predictive indicator.16,17 Although very limited data exist to guide treatment, catheter ablation is highly effective (particularly for outflow-tract PVCs) and complications are unusual. One randomised trial in patients with outflow tract PVCs (without PVC-induced cardiomyopathy) demonstrated ablation to be superior in efficacy to metoprolol or propafenone.18 The recent ventricular arrhythmia guideline document recommends catheter

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Premature Ventricular Contractions ablation in patients with PVC-induced cardiomyopathy “for whom antiarrhythmic medications are ineffective, not tolerated, or not the patient’s preference.”15 Very limited data exist for antiarrhythmic drug treatment of PVC-induced cardiomyopathy. Although primarily a heart failure trial, in a randomised, placebo controlled study of 674 patients with heart failure (LV ejection fraction <40 %) and >10 PVCs/h, amiodarone therapy was associated with an increase in LV ejection fraction of 42 % at 2 years without an effect on mortality.19 Hyman and colleagues identified 20 patients with PVC-induced cardiomyopathy who were treated with flecainide or propafenone.20 Most patients had failed catheter ablation attempts, and coronary artery disease was excluded, but seven patients had some degree of

1. 2.

Ng GA. Treating patients with ventricular ectopic beats. Heart 2006;92:1707–12. DOI: 10.1136/hrt.2005.067843; PMID: 17041126 Bigger JT, Fleiss JL, Kleiger R, et al. The relationships among ventricular arrhythmias, left ventricular dysfunction, and mortality in the 2 years after myocardial infarction. Circulation 1984;69:250–8. DOI: 10.1161/01.CIR.69.2.250; PMID: 6690098 Duffee DF, Shen WK, Smith HC. Suppression of frequent premature ventricular contractions and improvement of left ventricular function in patients with presumed idiopathic dilated cardiomyopathy. Mayo Clinic Proc 1998;73:430–3. DOI: 10.1016/S0025-6196(11)63724-5 Cha Y-M, Lee GK, Klarich KW, Grogan M. Premature venticular contraction-induced cardiomyopathy: a treatable condition. Circ Arrhythm Electrophysiol 2012;5:229–36. DOI: 10.1161/ CIRCEP.111.963348; PMID: 22334430 Yarlagadda RK, Iwai S, Stein KM, et al. Reversal of cardiomyopathy in patients with repetitive monomorphic ventricular ectopy originating from the right ventricular outflow tract. Circulation 2005;112:1092–7. DOI: 10.1161/ CIRCULATIONAHA.105.546432; PMID: 16103234 Moulton KP, Medcalf T, Lazzara R. Premature ventricular complex morphology. A marker for left ventricular structure and function. Circulation 1990;81:1245–51. DOI: 10.1161/01. CIR.81.4.1245; PMID: 1690614 Deyell MW, Park KM, Han Y, et al. Predictors of recovery of left ventricular dysfunction after ablation of frequent ventricular premature depolarizations. Heart Rhythm 2012;9:1465–72. DOI: 10.1016/j.hrthm.2012.05.019; PMID: 22640894 Olgun H, Yokokawa M, Baman T, et al. The role of interpolation in PVC-induced cardiomyopathy. Heart Rhythm 2011;8:1046–9. DOI: 10.1016/j.hrthm.2011.02.034;

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fibrosis on MRI (<5 % of total LV mass). Treatment with flecainide or propafenone decreased mean PVC burden from 36.2 ± 3.5 to 10.0 ± 2.4 % (p<0.001) with a resultant increase in mean LV ejection fraction from 37.4 ± 2.0 to 49.0 ± 1.9 % (p<0.001). In summary, PVC-mediated cardiomyopathy requires a high index of suspicion to identify based on the presence of cardiomyopathy plus PVCs, rather than frequent PVCs in isolation. Typical patients have a high burden of PVCs with a single morphology usually from the right or left outflow tract and no history of previous structural heart disease. Successful treatment, particularly when provided relatively early in the disease process, allows recovery of LV dysfunction. n

PMID: 21376837 Bogun F, Crawford T, Reich S, et al. Radiofrequency ablation of frequent, idiopathic premature ventricular complexes: comparison with a control group without intervention. Heart Rhythm 2007;4:863–7. DOI: 10.1016/j.hrthm.2007.03.003; PMID: 17599667 Baman TS, Ilg KJ, Gupta SK, et al. Mapping and ablation of epicardial idiopathic ventricular arrhythmias from within the coronary venous system. Circ Arrhythm Electrophysiol 2010;3:274–9. DOI: ; PMID: 20400776 Mountantonakis SE, Frankel DS, Gerstenfeld EP, et al. Reversal of outflow tract ventricular premature depolarization–induced cardiomyopathy with ablation: effect of residual arrhythmia burden and preexisting cardiomyopathy on outcome. Heart Rhythm 2011;8:1608–14. DOI: 10.1016/j.hrthm.2011.04.026; PMID: 21699837 Yokokawa M, Good E, Crawford T, et al. Recovery from left ventricular dysfunction after ablation of frequent premature ventricular complexes. Heart Rhythm 2013;10:172–5. DOI: 10.1016/j.hrthm.2012.10.011; PMID: 23099051 Zhong L, Lee YH, Huang XM, et al. Relative efficacy of catheter ablation vs antiarrhythmic drugs in treating premature ventricular contractions: a single-center retrospective study. Heart Rhythm 2014;11:187–93. DOI: 10.1016/j.hrthm.2013.10.033; PMID: 24157533 Niwano S, Wakisaka Y, Niwano H, et al. Prognostic significance of frequent premature ventricular contractions originating from the ventricular outflow tract in patients with normal left ventricular function. Heart 2009;95:1230–7. DOI: 10.1136/ hrt.2008.159558; PMID: 19429571 Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017

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AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Heart Rhythm 2017; DOI: 10.1016/j.hrthm.2017.10.036; epub ahead of press. Yokokawa M, Kim HM, Good E, et al. Impact of QRS duration of frequent premature ventricular complexes on the development of cardiomyopathy. Heart Rhythm 2012;9:1460–4. DOI: 10.1016/j.hrthm.2012.04.036; PMID: 22542704 Del Carpio Munoz F, Syed FF, Noheria A, et al. Characteristics of premature ventricular complexes as correlates of reduced left ventricular systolic function: study of the burden, duration, coupling interval, morphology and site of origin of PVCs. J Cardiovasc Electrophysiol 2011;22:791–8. DOI: 10.1111/j.1540-8167.2011.02021.x; PMID: 21332870 Ling Z, Liu Z, Su L, et al. Radiofrequency ablation versus antiarrhythmic medication for treatment of ventricular premature beats from the right ventricular outflow tract: prospective randomized study. Circ Arrhythm Electrophysiol 2014;7:237–3. DOI: 10.1161/CIRCEP.113.000805; PMID: 24523413 Singh SN, Fletcher RD, Fisher SG, et al. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. N Engl J Med 1995;333:77–82. DOI: 10.1056/ NEJM199507133330201; PMID: 7539890 Hyman MC, Supple G, Lin D, McNaughton N, Troutman G, Callans DJ, Marchlinski FE, Frankel DS. Use of class 1C antiarrhythmic drugs in patients with PVC-induced cardiomyopathy. Presented at Heart Rhythm Scientific Sessions 2017, Chicago, 12 May 2017. Heart Rhythm 2017; 14(5): S375. Abstract C-PO04-122. http://www.heartrhythmjournal. com/article/S1547-5271(17)30428-9/pdf

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Cryoballoon Ablation in Today’s Practice: Can the Left Common Ostium Be Ablated and Injury to the Right Phrenic Nerve Avoided? Gian-Battista Chierchia, 1 Saverio Iacopino 2 and Carlo de Asmundis 1 1. Heart Rhythm Management Centre, University of Brussels, Brussels, Belgium; 2. Electrophysiology Unit, Villa Maria Cecilia Hospital, Ravenna, Italy

Abstract Cryoballoon ablation is rapidly gaining popularity among electrophysiologists in the setting of pulmonary vein isolation for the treatment of AF. The first part of the following review focuses on the feasibility and clinical outcome of this technique in patients exhibiting a left common ostium. In the second part, we discuss how to predict and prevent the most common complication related to cryoballoon ablation: right phrenic nerve palsy.

Keywords Cryoballoon, second-generation cryoballoon, pulmonary vein isolation, left common ostium, phrenic nerve palsy Disclosure: Dr Gian-Battista Chierchia and Dr Carlo de Asmundis receive teaching, proctoring and speaker fees from Medtronic. Dr Chierchia receives speaker fees from Biosense Webster. Received: 19 November 2017 Accepted: 25 November 2017 Citation: Arrhythmia & Electrophysiology Review 2017;6(4):156–8. DOI: 10.15420/aer.2017.6.4EO2 Correspondence: Gian-Battista Chierchia, Heart Rhythm Management Centre, Vrij Universiteit Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium. E: gbchier@yahoo.it

Pulmonary vein (PV) isolation is currently an established treatment for drug-resistant AF.1 A left common PV (LCPV) is present in 9–83 % of the patients, depending on the definition used,2,3 and counts as the most frequent PV variation, followed by a right accessory middle vein. In recent years, cryoballoon (CB) ablation has emerged as a valid alternative to traditional point-by-point radiofrequency ablation.4,5 However, mainly due to its geometrical shape the use of the CB in the setting of LCPVs is still under evaluation. In fact, a successful ablation with the CB is tightly related to an optimal occlusion. In addition, one might advocate that in the setting of a LCPV the CB might create a distal lesion leaving the antrum largely unablated. Although, initial experiences with the first-generation CB (Arctic FrontTM Cardiac Cryoballoon, Medtronic, USA) reported deceiving results in patients presenting this anatomical variant6 if compared with individuals exhibiting a normal PV drainage pattern, clinical outcomes with the current second-generation CB (CB-Adv [Arctic Front Advance Cryoballoon, Medtronic, USA]) might greatly differ. In fact, the CB-Adv has been launched on the market with significant technological improvements if compared with its predecessor.7 During the cryoablation the refrigerant gas is ejected in the balloon through holes known as ‘refrigerant jets’. In the CB-Adv the number of refrigerant jets has been doubled and have been positioned more distally on the catheter’s shaft. These modifications have led to more homogeneous and circumferential lesions around the PV antrum if compared with the first-generation device.8,9 This translated in significantly better clinical outcomes,10 probably due to a higher rate of permanent PV isolation in the long term.11 Recently, Ströker et al.12 analysed the impact of an LCPV on clinical outcome in patients undergoing CB-Adv ablation as an index procedure. In a total of 476 patients, 146 presenting LCPV (study cohort; LCPV+) and 287 with normal PV drainage pattern (control group; LCPV-), were matched in a 1:1 ratio based on propensity

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scores, which resulted in two balanced groups of 146 patients each. All patients underwent a pre-procedural CT scan and the presence of a common PV ostium was defined as a coalescence of inferior and superior PV ≥5 mm before the insertion into the left atrium (LA). Furthermore, LCPV were subdivided according to the length of the common trunk. Specifically, a short common PV trunk was defined when the distance from the ostium to the bifurcation was 5–15 mm, and a long common trunk when this distance was >15 mm.12 During the procedure, full occlusion and acute isolation could be achieved in all LCPVs without additional focal tip ablation. Importantly, no significant difference was noted in terms of AF recurrence rate in LCPV+ versus LCPV- patients (46/146 [31 %] versus 39/146 [27 %], respectively, p=0.4), on a mean follow up of 19 months. Of note, within LCPV+ patients the recurrence rate did not differ between short and long common trunks. Recently, Heeger et al.13 analysed the same issue in a multicentre trial. In a total cohort of 670 patients having undergone CB-Adv as an index ablation in three German centres between 2012 and 2016, 74 individuals exhibited a LCPV. The latter were matched with a control group presenting with a normal PV drainage pattern and analysed on a mean follow up of 1.9 ± 0.9 years. Interestingly, all procedural parameters such as procedural duration, fluoroscopy exposure, number of freezes per vein, rate of acute isolation and rate of complications, among others, did not differ between both groups. Most importantly, clinical outcome in terms of AF recurrence was not worse in the LCPV group. In fact, a total of 47 of 73 patients (64 %) of LCPV group and 49 of 74 patients (66 %) of the control group remained in sinus rhythm (p=0.820). The slightly lower overall success rate in this study compared with Ströker et al. findings might be explained by the higher proportion of patients presenting with persistent AF. We believe that these promising findings might be due to the wide and homogeneous lesions achieved by the CB-Adv, which might extend proximally and successfully ablate a large portion of the PV antrum.

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Cryoballoon Ablation: Can Phrenic Nerve Injury Be Avoided? A recent publication by Kenisberg et al.14 analysed the extension of the lesions after CB-Adv ablation by means of electroanatomical mapping showing that the lesions extended proximally in the PV antra affecting a large portion of the posterior wall of the LA. However, although all abovementioned studies seem to confirm the ability of the CB to successfully isolate the LCPV, a recent article by Shigeta et al.15 concluded that on a midterm follow up of 454 ± 195 days the clinical outcome of ablation of AF with the CB was worse in patients with an LCPV than in those without (77 % versus 89 %; p=0.02). The authors hypothesised this difference was due to a distal lesion in the antrum that left the proximal portion largely unablated proven by electroanatomical mapping. Although we strongly believe that the LCPV can be successfully approached with the CB-Adv, future prospective multicentre trials are needed to shed light on this controversial issue. Right phrenic nerve paralysis (PNP) is the most frequent complication occurring during CB16–18 when ablating the right sided PVs, specifically the right superior PV (RSPV). This is due to the proximity of the phrenic nerve (PN) to this anatomical structure. Although this adverse effect is usually transient and virtually always resumes within weeks after the procedure, persistence of PNP has been described in the literature.19 Traditionally, PN function is evaluated by manual palpation of the patient’s abdomen to monitor the excursion of the right hemidiaphragm. Furthermore, albeit the use of increasingly sophisticated monitoring strategies aiming at the prevention of this complication, PNP still seems to occur in a small but non-negligible number of patients. Therefore, pre- and intraprocedural indicators helping to identify patients being potentially more at risk for this complication are warranted. A recent publication by Mugnai et al.20 analysed the temperature drop behaviour in the setting of phrenic nerve injury (PNI). In a large cohort of 550 patients with an incidence of PNI, 40 individuals (7.3 %) experienced PNI during ablation in the RSPV. Fortunately, only four (0.7 %) did not resolve until discharge and one (0.2 %) still persisted at 23 months. Interestingly patients with PNI exhibited significantly lower temperatures at 20, 30 and 40 s after the beginning of the cryoapplication in the RSPV (p=0.006, p=0.003 and p=0.003, respectively). Also, the temperature drop expressed as delta temperature/delta time was also significantly higher in patients with PNI. Importantly, a low temperature during the early phases of the freezing cycle (less than -38°C at 40 s) predicted PNI with a sensitivity of 80.5 %, a specificity of 77 % and a negative predictive value of 97.9 %. Another factor predicting PNI is the position of the CB in the RSPV. In this setting, Saitoh et al.21 analysed the position of the CB in relation to the cardiac silhouette in the anteroposterior (AP) projection. Anatomical studies conducted on human cadavers consistently showed that after descending almost vertically along the right brachiocephalic vein, the PN continues along the right anterolateral surface of the superior vena cava (SVC). It then progresses inferiorly along the pericardium overlying the right aspect of the right atrial wall.12 Therefore, in this setting the AP projection might be the ideal fluoroscopic view to delineate the right lateral border of the cardiac silhouette and consequently the right PN course. The authors

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retrospectively analysed the fluoroscopic position of the CB in AP in a cohort of 165 patients having undergone AF ablation. They concluded that the incidence of PNI in the RSPV significantly increased in case of more distal positioning of the CB relative to the cardiac shadow and that such a simple and straightforward intraprocedural indicator might encourage the operators to attempt occluding this vein more proximally to avoid PNI. Pre-procedural anatomical evaluation by the means of a CT scan might also play an important role in predicting PNI. In a recent article Ströker et al.22 meticulously analysed the influence of the RSPV size and its drainage angle in the setting of this complication. The authors concluded that pre-procedural anatomic assessment of right PVs is useful in evaluating the risk of PNI and that ostial vein area and external RSPV–LA angle measurement showed excellent predictive value for PNI at the RSPV. Given these considerations it seems mandatory to avoid ablating the RSPV with the CB distally positioned in the vessel. An easy and straightforward technique that guarantees a more proximal lesion in the antrum was first described by Casado-Arroyo et al. in 2012.23 The ‘proximal seal’ manoeuvre consists in initially obtaining a complete occlusion of the vein demonstrated by dye injection. Then, while injecting contrast, the CB-Adv is retrieved slowly to a more proximal position until a small leak is observed. Cryoenergy application is then started, and dye injection is continued in the very first seconds of the application when it is still possible. During freezing, the balloon volume increases (up to 5 % of the initially inflated balloon—from 26.5 to 28 mm) and the internal pressure grows from 2.0–3.0 psi to a maximum of 17.7 psi, resulting in a ‘stiffer’ and less compliant balloon. In some cases, this is sufficient to eliminate the leak and obtain full occlusion without further repositioning. If a residual leak remains, small pressure to the balloon is applied in the early stages of cryoenergy delivery to eliminate it and occlude the vein. In this setting, a larger and less compliant balloon and the small pressure applied to the device in the PV ostium bare a significantly lower chance of creating a more distal lesion in the vessel. This manoeuvre led to a dramatic reduction in incidence of PNI as observed by the authors in their study. Finally, although manual palpation of the diaphragmatic contraction during PN pacing in the SVC is the most common and straightforward method to avoid this complication during ablation in the right-sided veins, other methods such as the compound motor action potential24–26 or the analysis of the femoral venous pressure waveform27,28 have been thoroughly described in the literature as techniques aiming at the intensity monitoring of diaphragmatic contractility. Both methods reproducibly showed their capacity in predicting impending PNP in multiple studies available in today’s literature. Although, significant progress has been achieved in preventing this complication, it still remains the most frequently associated adverse event related to this procedure. Therefore, all efforts should be used to avoid PNP when performing CB ablation. Ultimately, a more proximal lesion in the PV antrum might also reduce other complications related to distal positioning of the balloon, such as bronchial haemorrhage.29 n

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aïssaguerre M, Jaïs P, Shah DC, et al. Spontaneous initiation H of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998;339:659–66. DOI: 10.1056/ NEJM199809033391003; PMID: 9725923 2. Thorning C, Hamady M, Liaw JV, et al. CT evaluation of pulmonary venous anatomy variation in patients undergoing catheter ablation for atrial fibrillation. Clin Imaging 2011;35:1–9. DOI: 10.1016/j.clinimag.2009.11.005; PMID: 21237413 3. Jongbloed MR, Dirksen MS, Bax JJ, et al. Atrial fibrillation: multi-detector row CT of pulmonary vein anatomy prior to radiofrequency catheter ablation—initial experience. Radiology 2005;234:702–9. DOI: 10.1148/radiol.2343031047; PMID: 15665218 4. Kuck KH, Brugada J, Fürnkranz A, et al. Cryoballoon or radiofrequency ablation for paroxysmal atrial fibrillation. N Engl J Med 2016;374:2235–45. DOI: 10.1056/NEJMoa1602014; PMID: 27042964 5. Andrade JG, Khairy P, Guerra PG, et al. Efficacy and safety of cryoballoon ablation for atrial fibrillation: a systematic review of published studies. Heart Rhythm 2011;8:1444–51. DOI: 10.1016/j.hrthm.2011.03.050; PMID: 21457789 6. Kubala M, Hermida JS, Nadji G, et al. Normal pulmonary veins anatomy is associated with better AF-free survival after cryoablation as compared to atypical anatomy with common left pulmonary vein. Pacing Clin Electrophysiol 2011;34:837–43. DOI: 10.1111/j.1540-8159.2011.03070.x; PMID: 21418249 7. Fürnkranz A, Bordignon S, Dugo D, et al. Improved 1-year clinical success rate of pulmonary vein isolation with the second-generation cryoballoon in patients with paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol 2014;25:840–4. DOI: 10.1111/jce.12417; PMID: 24654794 8. Metzner A, Reissmann B, Rausch P, et al. One-year clinical outcome after pulmonary vein isolation using the secondgeneration 28-mm cryoballoon. Circ Arrhythm Electrophysiol 2014;7:288–92. DOI: 10.1161/CIRCEP.114.001473; PMID: 24610797 9. Chierchia GB, Di Giovanni G, Ciconte G, et al. Secondgeneration cryoballoon ablation for paroxysmal atrial fibrillation: 1-year follow-up. Europace 2014;16:639–44. DOI: 10.1093/europace/eut417; PMID: 24478116 10. Lemes C, Wissner E, Lin T, et al. One-year clinical outcome after pulmonary vein isolation in persistent atrial fibrillation using the second-generation 28 mm cryoballoon: a retrospective analysis. Europace 2016;18:201–5. DOI: 10.1093/ europace/euv092; PMID: 25995389

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11. A ndrade JG, Dubuc M, Guerra PG, et al. Pulmonary vein isolation using a second-generation cryoballoon catheter: a randomized comparison of ablation duration and method of deflation. J Cardiovasc Electrophysiol 2013;24:692–8. DOI: 10.1111/ jce.12114; PMID: 23489648 12. Ströker E, Takarada K, de Asmundis C, et al. Secondgeneration cryoballoon ablation in the setting of left common pulmonary veins: procedural findings and clinical outcome. Heart Rhythm 2017;14:1311–18. DOI: 10.1016/j. hrthm.2017.06.019; PMID: 28625928 13. Heeger CH, Tscholl V, Wissner E, et al. Acute efficacy, safety, and long-term clinical outcomes using the second-generation cryoballoon for pulmonary vein isolation in patients with a left common pulmonary vein: a multicenter study. Heart Rhythm 2017;14:1111–18. DOI: 10.1016/j.hrthm.2017.05.003; PMID: 28495652 14. Kenigsberg DN, Martin N, Lim HW, et al. Quantification of the cryoablation zone demarcated by pre- and postprocedural electroanatomic mapping in patients with atrial fibrillation using the 28-mm second-generation cryoballoon. Heart Rhythm 2015;12:283–90. DOI: 10.1016/j.hrthm.2014.11.012; PMID: 25460865 15. Shigeta T, Okishige K, Yamauchi Y, et al. Clinical assessment of cryoballoon ablation in cases with atrial fibrillation and a left common pulmonary vein. J Cardiovasc Electrophysiol 2017;28:1021–27. DOI: 10.1111/jce.13267; PMID: 28570019 16. Kuck KH, Fürnkranz A. Cryoballoon ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2010;21:1427–31. DOI: 10.1111/j.1540-8167.2010.01944.x; PMID: 21091966 17. Andrade JG, Khairy P, Guerra PG, et al. Efficacy and safety of cryoballon ablation for atrial fibrillation: a systematic review of published studies. Heart Rhythm 2011;8:1444–51. DOI: 10.1016/j.hrthm.2011.03.050; PMID: 21457789 18. Sorgente A, Chierchia GB, de Asmundis C, et al. Cryoballoon ablation of atrial fibrillation: state of the art 10 years after its invention. Recent Pat Cardiovasc Drug Discov 2010;5:177–83. DOI: 10.2174/157489010793351917; PMID: 20874670 19. Casado-Arroyo R, Chierchia GB, Conte G, et al. Phrenic nerve paralysis during cryoballoon ablation for atrial fibrillation: a comparison between the first- and second-generation balloon. Heart Rhythm 2013;10:1318–24. DOI: 10.1016/j. hrthm.2013.07.005; PMID: 23891574 20. Mugnai G, de Asmundis C, Velagic V, et al. Phrenic nerve injury during ablation with the second-generation cryoballoon: analysis of the temperature drop behaviour in a large cohort

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of patients. Europace 2016;18:702–9. DOI: 10.1093/europace/ euv346; PMID: 26564954 Saitoh Y, Ströker E, Irfan G, et al. Fluoroscopic position of the second-generation cryoballoon during ablation in the right superior pulmonary vein as a predictor of phrenic nerve injury. Europace 2016;18:1179–86. DOI: 10.1093/europace/ euv362; PMID: 26614521 Ströker E, de Asmundis C, Saitoh Y, et al. Anatomic predictors of phrenic nerve injury in the setting of pulmonary vein isolation using the 28-mm second-generation cryoballoon. Heart Rhythm 2016;13:342–51. DOI: 10.1016/j.hrthm.2015.10.017; PMID: 26573972 Casado-Arroyo R, Chierchia GB, Conte G, et al. Phrenic nerve paralysis during cryoballoon ablation for atrial fibrillation: a comparison between the first- and second-generation balloon. Heart Rhythm 2013;10:1318–24. DOI: 10.1016/j. hrthm.2013.07.005; PMID: 23891574 Franceschi F, Koutbi L, Gitenay E, et al. Electromyographic monitoring for prevention of phrenic nerve palsy in secondgeneration cryoballoon procedures. Circ Arrhythm Electrophysiol 2015;8:303–7. DOI: 10.1161/CIRCEP.115.002734; PMID: 25740826 Franceschi F, Dubuc M, Guerra PG, Khairy P. Phrenic nerve monitoring with diaphragmatic electromyography during cryoballoon ablation for atrial fibrillation: the first human application. Heart Rhythm 2011;8:1068–71. DOI: 10.1016/j. hrthm.2011.01.047; PMID: 21315843 Franceschi F, Koutbi L, Mancini J, et al. Novel electromyographic monitoring technique for prevention of right phrenic nerve palsy during cryoballoon ablation. Circ Arrhythm Electrophysiol 2013;6:1109–14. DOI: 10.1161/ CIRCEP.113.000517; PMID: 24114777 Ghosh J, Singarayar S, Kabunga P, McGuire MA. Subclavian vein pacing and venous pressure waveform measurement for phrenic nerve monitoring during cryoballoon ablation of atrial fibrillation. Europace 2015;17:884–90. DOI: 10.1093/europace/ euu341; PMID: 25488959 Mugnai G, de Asmundis C, Ströker E, et al. Femoral venous pressure waveform as indicator of phrenic nerve injury in the setting of second-generation cryoballoon ablation. J Cardiovasc Med (Hagerstown) 2017;18:510–17. DOI: 10.2459/ JCM.0000000000000418; PMID: 27341195 van Opstal JM, Timmermans C, Blaauw Y, Pison L. Bronchial erosion and hemoptysis after pulmonary vein isolation by cryoballoon ablation. Heart Rhythm 2011;8:1459. DOI: 10.1016/j. hrthm.2010.06.024; PMID: 20601153

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Choice of Ventricular Pacing Site: the End of Non-physiological, Apical Ventricular Pacing? Demosthenes G Katritsis Hygeia Hospital, Athens, Greece

Keywords Pacing site, ventricular physiology, atrioventricular block, apical pacing, His-bundle pacing Disclosure: The author has no conflict of interest to declare. Received: 12 October 2017 Accepted: 15 October 2017 Citation: Arrhythmia & Electrophysiology Review 2017;6(4):159–60. DOI: 10.15420/aer.2017.6.4:EO3 Correspondence: Demosthenes G Katritsis, Hygeia Hospital, Erithrou Stavrous 4, Athens 15123, Greece. E: dkatrits@dgkatritsis.gr

The ideal pacing site in the ventricle(s) of patients with atrioventricular (AV) block has been debated for years. Despite considerable technological advances, the optimal ventricular pacing site to mimic normal human ventricular physiology and attain the best haemodynamic response remains elusive.1 Prolonged ventricular dyssynchrony induced by long-term right ventricular (RV) apical pacing is associated with deleterious left ventricular (LV) remodelling and the deterioration of both LV diastolic and systolic function.2–4 The adverse effects of long-term RV apical pacing has led to tremendous interest in alternate pacing options. RV septal pacing sites are probably beneficial by means of intraventrcular synchrony and LV function5,6 and specific His-bundle pacing is a promising option, with acute results comparable to these of cardiac resynchronisation therapy.1,7,8 Biventricular pacing may also be superior,9 especially in patients with reduced LV ejection fraction. In the Biventricular versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block (BLOCK-HF) trial, biventricular was preferable to RV pacing in the presence of LV ejection fraction <50 % and AV block, but the potential for increased LV lead-related complications should be considered.10 Interestingly, in crossover comparisons His-bundle pacing has been demonstrated to effect an equivalent cardiac resynchronisation pacing response, because it generates truly physiological ventricular activation, as evidenced in part by the identical morphology between normallyconducted and -paced QRS complexes.8 Theoretically, therefore, a mid-septal position should be the optimum site, at least in patients without a previous anteroseptal myocardial infarction. Why, then, has no benefit over apical pacing been definitively shown in randomised, comparative studies?11,12 There are reasons to believe that the main problem with these trials is their relatively limited follow-up times. Deleterious apical pacing takes years to express its adverse effects on ventricular remodelling and follow-up periods of <10 years may not be indicative. In the same manner, tachycardiainduced cardiomyopathies need several years to express their adverse impact on ventricular function.13

ijayaraman P, Bordachar P, Ellenbogen KA. The continued V search for physiological pacing. Where are we now? J Am Coll Cardiol 2017;69:3099–114. DOI: 10.1016/j.jacc.2017.05.005; PMID: 28641799.

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Figure 1: Mapping of Ventricular Electrical Activation SPONTANEOUS ACTIVATION

RV PACING

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LV RV LEAD DYSSYNCHRONY

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124 ms

LV LEAD

Electrocardiographic maps (CardioInsight Technologies Inc.) of a single heart failure patient presenting with a narrow QRS duration (115 ms) during spontaneous conduction (left), RV pacing (middle) and biventricuolar pacing (BVP, right). He was resynchronised (+ His ablation) because he demonstrated episodes of rapidly-conducted atrial fibrillation. For comparison purposes, all maps refer to the same relative scale of 124 ms. The spontaneous activation is driven by the His–Purkinje system and results in short LV and total ventricular activation times (55 and 60 ms, respectively). VDD (80 ms atrioventricular delay) and RV apical pacing results in major alteration of the ventricular activation, with lengthening of both the LV and total ventricular activation times (104 ms). The addition of a LV posterolateral pacing site to apply BVP reduces the LV activation time (88 ms) but not the total activation time (103 ms) compared with RV pacing. Comparison with spontaneous activation shows that BVP does not fully reverse the conduction impairment induced by RV pacing. This figure demonstrates the detrimental effect of apical RV pacing on different levels of ventricular dyssynchrony and the beneficial, but incomplete, effect of BVP, causing an intermediate level of dyssynchrony between the narrow QRS interval and RV pacing. LAO = left anterior oblique view; Left Lat = left lateral view; LV = left ventricular; RV = right ventricular. Reproduced with permission from Vijayaraman, et al., 2017.1

There is a need to avoid unnecessary apical RV pacing in patients with normal intrinsic AV conduction or intermittent AV block, especially in those at risk for heart failure. If we attempt to imitate nature through artificial pacing, we should get as close as possible to the normal conduction pathway in the ventricles, by targeting the His bundle. My personal view is that we certainly need randomised trials with a reasonably prolonged follow-up to explore this important issue. This might put the death-stone on the concept of non-physiological, apical ventricular pacing. n

ang F, Zhang Q, Chan JY, et al. Deleterious effect of right F ventricular apical pacing on left ventricular diastolic function and the impact of pre-existing diastolic disease. Eur Heart J 2011;32:1891–9. DOI: 10.1093/eurheartj/ehr118;

PMID: 21531741. Zhang XH, Chen H, Siu CW, et al. New-onset heart failure after permanent right ventricular apical pacing in patients with acquired high-grade atrioventricular block and normal left

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Expert Opinion

ventricular function. J Cardiovasc Electrophysiol 2008;19:136–41. DOI: 10.1111/j.1540-8167.2007.01014.x; PMID: 18005026. Cicchitti V, Radico F, Bianco F, et al. Heart failure due to right ventricular apical pacing: the importance of flow patterns. Europace 2016;18:1679–88. DOI: 10.1093/europace/euw024; PMID: 27247008. Shimony A, Eisenberg MJ, Filion KB, Amit G. Beneficial effects of right ventricular non-apical vs. apical pacing: a systematic review and meta-analysis of randomized-controlled trials. Europace 2012;14:81–91. DOI: 10.1093/europace/eur240; PMID: 21798880. Weizong W, Zhongsu W, Yujiao Z, et al. Effects of right ventricular nonapical pacing on cardiac function: a metaanalysis of randomized controlled trials. Pacing Clin Electrophysiol 2013;36:1032–51. DOI: 10.1111/pace.12112; PMID: 23438131. Sharma PS, Dandamudi G, Naperkowski A, et al. Permanent

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His-bundle pacing is feasible, safe, and superior to right ventricular pacing in routine clinical practice. Heart Rhythm 2015;12:305–12. DOI: 10.1016/j.hrthm.2014.10.021; PMID: 25446158. 8. Lustgarten DL, Crespo EM, Arkhipova-Jenkins I, et al. His-bundle pacing versus biventricular pacing in cardiac resynchronization therapy patients: A crossover design comparison. Heart Rhythm 2015;12:1548–57. DOI: 10.1016/j. hrthm.2015.03.048; PMID: 25828601. 9. Chan JY, Fang F, Zhang F, et al. Biventricular pacing is superior to right ventricular pacing in bradycardia patients with preserved systolic function: 2-year results of the PACE trial. Eur Heart J 2011;32:2533–40. DOI: 10.1093/eurheartj/ ehr336. PMID: 21875860 10. Curtis AB, et al. Biventricular pacing for atrioventricular block and systolic dysfunction. N Engl J Med 2013;368:1585–93. DOI:

10.1056/NEJMc1306998; PMID: 23924013. 11. J anousek J, van Geldorp IE, Krupicˇ ková S, et al. Working Group for Cardiac Dysrhythmias and Electrophysiology of the Association for European Pediatric Cardiology. Permanent cardiac pacing in children: choosing the optimal pacing site: a multicenter study. Circulation 2013;127:613–23. DOI: 10.1161/ CIRCULATIONAHA.112.115428; PMID: 23275383. 12. Kaye GC, Linker NJ, Marewick T, et al. Protect-Pace Trial Investigators. Effect of right ventricular pacing lead site on left ventricular function in patients with high-grade atrioventricular block: results of the Protect-Pace study. Eur Heart J 2015;36:856–62. DOI: 10.1093/eurheartj/ehu304; PMID: 25189602. 13. 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.

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Clinical Arrhythmias

Abstract Thromboembolic stroke and systemic embolism are generally agreed to be the major morbidity/mortality concerns for patients with AF. However, the risk of thromboembolism is not the same for all AF patients. Both AF and comorbidities must interact synergistically to create the risk for thromboembolism. But, is the synergism dichotomous – AF present or absent, comorbid disorder present or absent – or does synergism have magnitude, depending on the number and severity of the associated disorders and the amount of time one is in AF? This review discusses the current risk-score contributors and options for assessing risk of thromboembolism in AF patients, and what their combined roles might be. Also covered is the consideration of left atrial appendage anatomy in this context.

Keywords Stroke, risk assessment, atrial fibrillation, CHADS2, CHA2DS2-VASc, ABC Score, ATRIA Score Disclosure: In the past 36 months, Dr Reiffel has received grant support for work related to atrial fibrillation from Medtronic and Janssen; support for advisory consultation from Medtronic, Janssen, Acesion, InCardia Therapeutics, Sanofi, and Portola; and has served on speakers’ bureaus for Janssen and Boehringer Ingelheim. Received: 2 October 2017 Accepted: 9 October 2017 Citation: Arrhythmia & Electrophysiology Review 2017;6(4):161–6. DOI: 10.15420/aer.2017.33.1 Correspondence: James A Reiffel. E: jar2@columbia.edu

Thromboembolic stroke and systemic embolism are generally agreed to be the major morbidity/mortality concerns for patients with AF. However, the risk of thromboembolism (TE) is not the same for all AF patients. While ECG rhythm strips of patients with AF are generally indistinguishable, it has long been known that AF in younger patients without co-morbid factors (“lone AF”) carries an extremely low risk for TE, whereas AF in older patients in the presence of specific comorbidities carries a high TE risk.1,2 Thus, AF alone cannot sufficiently explain the risk. However, it has also been long known that older patients with conditions such as hypertension, diabetes and atherosclerotic disease also have an important risk for stroke, even in the absence of AF,3,4 but that these same conditions in the presence of AF have been associated with a two to seven times greater risk of stroke than when AF is absent.5 Thus, the comorbidities themselves also do not fully explain the total risk. Consequently, both AF and comorbidities must interact synergistically to magnify the risk for TE. But, is the synergism dichotomous – AF present or absent, comorbid disorder present or absent – or does synergism have magnitude, depending on the number and severity of the associated disorders and the amount of time one is in AF (AF burden, AFB)? I believe the latter is the case and that clinical trials addressing this point are warranted. Moreover, left atrial appendage (LAA) anatomy and the risk for stasis therein may also be a contributory factor to cardioembolic risk in AF. Thus, the line from AF to stroke is far from straight. To best understand the risk for TE in patients with AF, both synergism and the magnitude of the underlying components must be recognised. Historically, based on the presence of specific comorbidities, we have determined the risk for TE in AF patients as being either high enough to warrant prophylactic chronic oral anticoagulation (OAC) or too low

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to justify the risk of OAC-associated bleeding. A decade or so ago, such risk was assessed by determining the CHADS2 score (Table 1), congestive heart failure, a history of hypertension, age 75 years or higher, diabetes (each 1 point), or prior thromboembolic event, e.g. ischemic stroke (2 points), and the paradigm was to determine from the score calculated which AF patients were at high enough risk to warrant OAC – generally agreed to be a score of 2 or more.2 More recently, as we have recognised that stroke is much more likely to be fatal or debilitating than is bleeding, and as we have developed newer oral anticoagulants with preferable efficacy and safety profiles as compared to warfarin, the paradigm has shifted. We now ask which AF patients are at too low a score to warrant avoidance of OAC, with the rest having OAC indicated, and current guidelines1,2 recommend the CHA2DS2-VASc score (Table 1), congestive heart failure, history of hypertension, age 65–74 years (each 1 point) or 75 years and above (2 points), vascular disease and female gender (each 1 point) to make this determination. A score of 0 or 1 being low; OAC being generally recommended for a score of 1 or above (excluding female gender alone).1 Importantly, neither CHADS2 nor CHA2DS2-VASc require symptoms of AF to be present; they are based on readily ascertainable clinical history, demographics and routinely assessed measurements (blood pressure, blood sugar), and they are easy to calculate. With this move towards offering prophylactic OAC to more AF patients, we must ask ourselves if our current approach is sufficient or if it can be improved still further. I believe it can. First, by recognising that additional considerations might be applied to the AF patients with a CHA2DS2-VASc score of 0 or 1 – as we know that even these patients have some risk of TE – and second, by recognising that we may further improve our selectivity if we utilise an understanding of the magnitude

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Clinical Arrhythmias Table 1: Risk Factor Scoring Systems for Stroke in Patients with AF Risk Factor

CHADS2 CHA2DS2-VASc ABC ATRIA

Age*

X X

Hypertension X X X Heart failure

Diabetes mellitus

Prior stroke/TIA

Vascular disease

Female gender

Proteinuria X Renal failure (estimated glomerular filtration rate)

NT-proBNP

cTn-hs

*Age is quantitative in each system, with more points for older age. cTn-hs = high-sensitivity cardiac troponin; NT-proBNP = N-terminal pro b-type natriuretic peptide; TIA = transient ischemic attack.

synergism that exists between AF and comorbidities in generating TE risk (Figure 1) and laboratory values that may reflect it. That such an interplay exists is not entirely a new concept. We have known for years that the risk of stroke with AF increases with age6 – one of the factors in both the CHADS2 and CHA2DS2-VASc scoring systems. Moreover, that such an interplay should also hold true for other important comorbidities is a concept that I detailed in an editorial in 2016.7

AF Burden Several recent sources of evidence suggest that AF burden has importance in determining the likelihood of a thromboembolic event. Botto and colleagues,8 for example, assessed the interaction between AFB and CHADS2 factors with respect to risk for embolic stroke. They assessed AFB in three groups: no AF, AF>5 min and AF>24 h. There were no substantial differences in the frequency of each AFB duration group within any of the CHADS2 component groups. The rate of TE events increased linearly with the presence and duration of AF, so too as the CHADS2 score increased from 0 to 1 to 2. Notably, the patients with a CHADS2 score of 0 were at low risk, even if they had long-lasting AF, as were patients with a CHADS2 score of 1 if AFB was >5 min but <24 h, and patients with a CHADS2 score of 2 if they had no AF. By contrast, patients with a CHADS2 score of 3 or higher demonstrated high risk, even without AF being recorded, as did patients with a CHADS2 score of 2 if they had AF >5 min. Similar (though not identical) to this were the observations of Van Gelder et al. who reported events with implanted device-detected AF in a population with a mean CHADS2 score of 2.3 using the groups: no subclinical AF (no AF or AF<6 min), AF of 6 min to 6 h, AF of 6–24 h and AF >24 h.9 The stroke rates in the first three groups were not significantly different, with hazard ratios of 1, 0.93 and 1.39, respectively, whereas the AF >24 h group had a hazard ratio of 3.86 compared with the no subclinical AF group. Likewise, Boriani and Pettorelli reported that although a device-detected maximum daily burden of AF of at least 5–6 min was associated with an increase in the risk of stroke, the risk was particularly increased if the daily AFB was at least 1 h.10 Consistent with the above, using 14-day continuous ambulatory recordings to document AF of at least 30 s, Go et al. demonstrated that during follow up the rate of validated thromboembolic events off anticoagulants was 2.52/100 patient-years, with a higher crude

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rate with greater AF burden.11 After adjustment for ATRIA stroke risk score (see below), there was a 9 % increase in the odds of TE per 10 % increase in AFB, which was borderline significant. Likewise, Ganesan et al. reported that morbidity and mortality with AF were both higher in patients with non-paroxysmal AF than in patients with paroxysmal AF, but with no differences in bleeding rates.12 If the increased adverse events were due to more advanced comorbidities in the non-paroxysmal patients, then it would be expected that they would also have higher bleeding rates – which they did not. Thus, the mere presence versus absence of AF is not enough of a consideration, especially in those with lower CHA2DS2-VASc scores. Here, a score of 1 plus a high AFB probably justifies OAC, whereas a similar score with only brief, infrequent AF may not. Unfortunately, we are not yet sophisticated enough to accurately determine what threshold of AFB is important at any specific comorbidity magnitude, although we can understand the concept of the interaction (Figure 1). Lower AFB may be enough to trigger clot formation when the number and severity of comorbidities (and hence their effect on the atria) is high, whereas a greater AFB, such as 24 h or more, may be necessary with a lower CHA2DS2-VASc score.

Magnitude of Comorbidities Determining how the number and degree of comorbidities is related to TE risk is not as easy as it is for AFB. Certainly, the CHA2DS2-VASc score relates well to the number of contributory comorbidities, but only age is considered in any quantitative way. Yet, if one considers pathophysiologically how disease can contribute to thrombus formation in the left atrium, the process cannot simply be “all or none”. Multiple factors interplay in this process, including both stasis of blood from left atrial anatomical alterations and mechanical dysfunction, as well as abnormal coagulation factors – many of which relate to abnormal endothelial function. Mechanical dysfunction can result from structural remodelling with histopathological alterations in the diseased atrial wall, such as fibrosis, infiltration or inflammation, with the first of these occurring commonly and progressively with age and with disorders that increase LA pressure and volume, resulting in an atrial cardiomyopathy.13–15 A tachycardic myopathic component from AF itself is then an additive contributor. Numerous abnormal coagulation factors have been described in both diseased and fibrillating atria, as well as systemically in AF patients. They include an increased ratio of procoagulant factors versus normal anticoagulant factors, only a few of which are affected by antiplatelet agents. The latter may explain why aspirin is not comparable to OAC in the prevention of TE in at-risk patients with AF. More specifically, reports of coagulation alterations during AF include increases in: factor VII, fibrinogen, D-dimer, prothrombin fragment 1.2, thrombin–antithrombin complexes, thrombin generation, plasminogen activator inhibitor-1, von Willebrand factor, P-selectin, β-thromboglobulin, platelet factor 4, soluble CD40 ligand and superoxides in the left atrial appendage (which degrade nitrous oxide).16–24 Logically, more numerous or advanced comorbidities will have a greater impact on the structural and electrophysiological remodelling that enhances the frequency and duration of AF as well as on the severity of endothelial dysfunction and abnormal coagulation factors. That this is likely the case can be gleaned from the Framingham risk score data and its relationship to 5-year stroke risk. In 2003, Wang and colleagues reported on the risk of stroke or death versus the height of systolic blood pressure and the presence and number of specific additional factors, including diabetes, smoking, prior MI and

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Stroke Risk Assessment in Atrial Fibrillation left ventricle (LV) hypertrophy by ECG, stratified by age.25 There was a steady and age-related increase in the risk of stroke or death as the systolic blood pressure rose from 130 to 170 and as the number of comorbidities increased – from approximately 10 % to over 50 % in 60 year olds and from approximately 25 % to over 70 % in 70 year olds. Similarly, the yearly risk of stroke has been shown to increase in AF patients as the degree of systolic LV dysfunction increases by echocardiography,26–28 and the yearly risk of major cardiovascular and cerebrovascular events has been shown to increase progressively as the degree of left atrial fibrosis (demonstrated by left atrial gadolinium enhancement severity) increases.29 These are quantitative rather than present/absent determinants. Finally, with respect to endothelial dysfunction and its enhanced propensity for thrombogenesis, Lim et al. showed that there is a “significant stepwise increase in endothelial dysfunction measured by asymmetric-dimethylarginine from controls to lone AF to AF with comorbidities (p<0.001)”.30

Figure 1: Thromboembolic Synergism

Importantly, many of these structural and coagulation changes do not normalise with the restoration of sinus rhythm by drug therapy or by ablation. Rhythm normality does not necessarily mean functional or rheological normality. Both the AFFIRM and RACE trials reported more strokes in patients in their rhythm control arms than in their rate control arms.31,32 This is considered to have resulted from higher rates of OAC reduction or discontinuation upon presumption of maintained sinus rhythm by the patients’ physicians, and unrecognised (subclinical) recurrences of paroxysmal AF in these patients. However, incomplete reverse remodelling must also be considered. Using magnetocardiography, Lehto et al. demonstrated that magnetocardiographically detected atrial electrophysiological alterations in persistent AF diminish during maintained sinus rhythm after cardioversion, but only incompletely.33

Thromboembolic synergism: Atrial abnormalities from disease pathophysiology and atrial fibrillation burden

Increasing AF burden

Very low risk

Very high risk

Increasing severity of co-morbidities (CHA2DS2-VASc)

Increasing risk of embolism

Thromboembolic synergism: Atrial abnormalities from disease pathophysiology and atrial fibrillation burden

Increasing AF

Very low risk

Low

burden Mod-high

Sc) s (CHA2DS2-VA

tie ty of co-morbidi Increasing severi Low

Increasing

Mod-high

Highest risk

Lo and Chen reported only partial reversal of structural remodelling after return to sinus rhythm.34 In their study of mitral stenosis patients with AF pre-existing their cardioversion and commissurotomy, Fan and colleagues reported the recovery course of electrical remodelling to be prolonged and heterogeneous in AF patients, and that regional conduction abnormalities were irreversible.35 In patients who underwent ablation for their AF, Masuda et al. reported that increased left atrium (LA) ablation lesions, better LA ejection fraction and paroxysmal AF were associated with worsening of LA function post-ablation as compared to pre-ablation, rather than improvement.36 Using MRI and magnetic resonance spectroscopy, Wijesurendra et al. reported that LA function did not normalise post-ablation, regardless of both recovery of sinus rhythm and freedom from AF.37 Finally, Kusa et al. noted that LA appendage flow velocity remained low in 22 % of their post-ablation patients, even after 6 months of sinus rhythm, and that a CHA2DS2-VASc score of 2 or more was an independent predictor of low LA appendage flow velocity.38 These observations support the consideration of AF synchronously with any associated structural abnormalities when considering OAC, and that the latter may not only persist but may increase with some forms of rhythm control. They also support the current recommendation that OAC generally be continued in AF patients, even if sinus rhythm is restored with an antiarrhythmic drug or ablation, if the CHA2DS2-VASc score would warrant it and if AF was still present.

bolism

risk of em

AF = Atrial fibrillation Low (mild) co-morbidity with moderately high AF burden (red triangle region) or moderately high co-morbidity with low AF burden (purple rectangle region) should each have more risk than low AF burden with no or mild co-morbidity (far left of figure). High AF burden with severe co-morbidity should have the greatest risk (far right of figure). Assessment may be best done by combining consideration of atrial abnormalities from disease pathophysiology and AF burden. (A) AF burden plus increasing severity of comorbidities combine to produce thromboembolic risk. (B) Expansion of the concepts in (A).

Biomarkers

and the like,39–42 and therefore would have to be increased in patients with higher CHA2DS2-VASc scores and higher stroke risk, it is of interest that in the dabigatran versus warfarin AF trial where this was examined, troponin I and NT-proBNP levels were additive to the CHADS2 score in correlating with stroke and systemic embolism, pulmonary embolism, myocardial infarction and non-hemorrhagic vascular death.40 The biomarkers raised the c-statistic for these endpoints from 0.68 to 0.72 (p<0.0001). At a minimum, as greater biomarker abnormalities may correlate with comorbidity severity, they may be one way to reflect comorbidity magnitude and it may be appropriate to consider OAC in patients with a low CHA2DS2-VASc score but in whom such biomarkers are abnormal – especially if in the setting of a comorbidity factor aside from age and gender. At least a prospective interventional trial to this point is worth considering.

In addition to the above considerations, there is growing evidence that the presence of abnormal biomarker activity may also correlate with the risk for TE in patients with AF. Although one might assume that biomarker abnormalities would simply reflect the degree of comorbidity severity, such as LV dysfunction, hypertrophy, inflammation, fibrosis

Moreover, an alternative risk score method utilising biomarkers has already been proposed and evaluated. In 2016, Oldgren, Hijazi and colleagues reported on the development and validation of a biomarker-based stroke risk score: the ABC score.43,44 This score includes

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Clinical Arrhythmias Figure 2: How to use Risk Scores to Determine Whether to Anticoagulate a Patient with AF How To Use Risk Scores to Determine Whether to Anticoagulate AF Risk Factor Score

Therapy

CHADS2 = 6 CHADS2 = 5 Anticoagulation

CHADS2 = 4 CHADS2 = 3

scoring method has not yet been widely adapted. Moreover, its relative performance against CHADS2 or CHA2DS2-VASc appears to depend on population specifics, such as prior stroke rates.47 Nonetheless, I think both systems may be appropriate to consider in patients in whom CHA2DS2-VASc itself does not suggest a certain indication for OAC but concern may exist (Figure 2). Consider, for example, a 62-year-old man with hypertension associated with LV hypertrophy and diastolic dysfunction but no other CHA2DS2-VASc factors, or a 42-year-old diabetic man with moderate renal insufficiency but no other CHA2DS2-VASc factors. If each had a high AFB, I would likely start OAC, but if AFB were low, consideration of the ABC score or ATRIA score may be quite helpful in the decision.

CHADS2 = 2 CHADS2 = 1

CHADS2 = 0

Consider ABC score or ATRIA score as guide ?

CHA2DS2-VASc

ASA or nothing

If the CHADS2 score is 2 or higher, oral anticoagulation is indicated, and one need not riskstratify any further. If the CHADS2 score is <2, the CHA2 DS2-VASc score should be used, with oral anticoagulation if 2 or higher. If the CHA2 DS2-VASc score is 0, anticoagulation is not necessary, but if it is 1 (excluding female gender on its own), then additional risk scoring methods might be useful, including the ABC system and the ATRIA system.

age, biomarkers (N-terminal fragment B-type natriuretic peptide [BNP] and high-sensitivity cardiac troponin) and clinical history (prior stroke) (Table 1) and is calculated from a nomogram using a sliding scale for each of the components. The ABC score achieved slightly higher c-indices than CHA2DS2-VASc. Nonetheless, this scoring system has not yet been widely used or recommended in major guidelines – in part, perhaps, because the biomarker values are not routinely assessed in most clinical care settings and because it requires use of nomogram for its determination rather than a simple, quick calculation using easy to recall point values of 1 or 2. However, because currently used risk scoring systems are practical but still somewhat limited in their stroke prediction accuracy, biomarkers might improve our assessments. In addition to BNP or pro-BNP and troponin measurements, D-dimer, inflammatory growth differentiation factor-15, micro-RNAs, galectin-3 (which correlates with myocardial fibrosis), C-reactive protein (inflammation) and determinants that reflect renal dysfunction (creatinine, cystatin C) have also been considered for use. With respect to considering renal status in risk assessment, higher risk for TE in AF patients has been demonstrated to be inversely related to estimated glomerular filtration rate.45 Accordingly, Singer et al. have reported on an additional approach, the ATRIA score,46 as an alternative with a greater C-index than they found with CHADS2 or CHA2DS2-VASc. The ATRIA score (Table 1) is based on age, female gender, diabetes mellitus, heart failure, hypertension, proteinuria and estimated glomerular filtration rate stratified by the presence or absence of prior stroke. Without a prior stroke, points are assigned as: 6 for age 85 years and above, 5 for age 75–84 years, 3 for age 65–74 years, 0 for age <65 years, and 1 each for female gender, diabetes, congestive heart failure, hypertension, proteinuria and an estimated glomerular filtration rate <45cc/min or end-stage renal disease. With a prior stroke, the points are the same except: 9 for age 85 years and above, 7 for age 75–84 years, 7 for age 65–74 years and 8 for age <65 years. A score of 0–5 points is considered low risk, 6 points is considered risk and 7–15 points is considered high risk. Thus, simplistically, it adds renal dysfunction to the components used in the CHADS2 system. As with the ABC score approach, the ATRIA

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Left Atrial Appendage Anatomy and Function Coupled with considerations of the magnitude of comorbidities, there is a growing set of data to suggest that left atrial appendage anatomy may be an additional factor to consider in determining TE risk in patients with AF. However, the data is somewhat conflicting and its role in assessing whether or not to anticoagulate a patient with a low CHA2DS2-VASc score is not yet clear. For example, Di Biase et al. proposed a LA appendage anatomic pattern scheme to stratify risk for TE in AF patients.48 Four major patterns were described: cactus, windsock, chicken wing and cauliflower. Patients with chicken wing morphologies were felt to be at lower risk for stroke than those with other patterns, especially cauliflower. Concordantly, Petersen et al. reported that non-chicken wing morphologies were associated with lower LAA emptying velocity and higher prevalence of spontaneous echo contrast than chicken wing morphology, irrespective of the underlying type of AF.49 Relatedly, over a decade ago Goldman et al. demonstrated that the annualised rate of cardioembolic events in AF increased as peak LAA flow velocity decreased.50 However, somewhat in contrast, Anselmino et al. reported that windsock, cauliflower and chicken wing morphologies were independently related to the risk of silent cerebral ischemia by imaging.51 The descriptive shape of the LAA may not be the only LAA feature that plays a role in TE risk. In a two-case report series, Kreidieh and Valderrabano suggested that an elongated, narrow LA appendage that tapered slowly into a pointed tip – “a rare variant of the commonly classified chicken wing morphology” – had a specifically notable risk for TE.52 Khurram et al. reported that smaller LA orifice diameters and more LAA trabeculation independently correlated with higher stroke risk.53 Yamamoto et al. reported that the number of lobes, rather than the descriptive pattern, may be the determinant of LAA TE risk.54 In a prospectively enrolled population of 633 consecutive patients (of whom 594 had evaluable transesophageal echocardiograms), multivariate analysis revealed CHADS2 score (p=0.002), LV ejection fraction (p=0.01), degree of spontaneous echo contrast (p=0.02), LA volume (p=0.02) and number of LAA lobes (p<0.001) to be independently associated with LAA thrombus. Most patients with LAA thrombus (94.4 %) had three or more lobes, whereas thrombus was observed in only 2 of 296 patients (0.7 %) with 1 or 2 lobes. In an analogous manner, Korhonen et al.55 assessed LA appendage morphology by cardiac CT in 111 patients with suspected cardiogenic stroke without known AF. The distribution of morphology types differed significantly between the matched stroke and control groups. Cactus and windsock were less common in the stroke patients than in the controls, whereas chicken wing and especially cauliflower were more common in the stroke patients. Similarly, increased LA appendage volumes were larger in the stroke patients, and single-lobed appendages were overrepresented in the stroke patients. Thus, the number and size of the lobes and

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Stroke Risk Assessment in Atrial Fibrillation their orifices may be more important contributory features than the shape the lobes take. While the consideration of LA appendage anatomy and risk for TE clearly needs further investigation and clarification, it seems likely that any alteration in which emptying is impaired, flow is impaired and stasis is increased should relate to risk for clot formation within the appendage. However, as LA appendage anatomical patterns require imaging to ascertain, we are not yet ready to add them to our risk stratification consideration for patients with a low CHA2DS2-VASc score.

Conclusion We have come a long way in understanding: (1) those factors that promote the risk of TE in patients with AF, and (2) that we can utilise this understanding in a way to determine when the risk of TE is high enough to warrant prophylactic OAC – most of the time. However, the value of quantitative mechanistic synergism and utilising AF burden, laboratory means and imaging means to quantify associated tissue and coagulation pathophysiology so as to improve selectivity in our decision has not yet been adequately appreciated. Clinical trials to test the importance and validity of these considerations are necessary. Thus, we still have a road on which we must continue travelling. Or, as a fortune cookie I was recently served for dessert said: “thromboembolic risk – there is still more to know.” n

7. 8.

10.

11.

12.

13.

14.

irchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines K for the management of atrial fibrillation developed in collaboration with EACTS. Europace 2016;18:1609–78. DOI: 10.1093/europace/euw295; PMID: 27567465 January CT, Wann S, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1–76. DOI: 10.1016/j.jacc.2014.03.022; PMID: 24685669 Li L, Yin GS, Geraghty OC, et al. Incidence, outcome, risk factors, and long-term prognosis of cryptogenic transient ischaemic attack and ischaemic stroke: a population-based study. Lancet Neurol 2015;14: 903–13. DOI: 10.1016/S14744422(15)00132-5 Uehara T, Bang OY, Kim JS, et al. Risk factors. Front Neurol Neurosci 2016;40:47–57. DOI: 10.1159/000448301; PMID: 27960158 Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22:983–88. DOI: 10.1161/01.STR.22.8.983; PMID: 1866765 Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: implications for rhythm management and stroke prevention: the Anticoagulation and Risk factors In Atrial fibrillation (ATRIA) study. JAMA 2001;285:2370–5. DOI: 10.1001/jama.285.18.2370 Reiffel J. If it were only that simple. Eur Heart J 2016;37:1603–05. DOI: 10.1093/eurheartj/ehw014; PMID: 26984857 Botto G, Padeletti L, Santini M, et al. Presence and duration of atrial fibrillation detected by continuous monitoring: crucial implications for the risk of thromboembolic events. J Cardiovasc Electrophys 2009;20:241–48. DOI: 10.1111/j.15408167.2008.01320.x; PMID: 19175849 Van Gelder IC, Healey JS, Crijns HJGM, et al. Duration of device-detected subclinical atrial fibrillation and occurrence of stroke in ASSERT. Eur Heart J 2017;38:1339–44. DOI: 10.1093/ eurheartj/ehx042; PMID: 28329139 Boriani G, Pettorelli D. Atrial fibrillation burden and atrial fibrillation type: clinical significance and impact on the risk of stroke and decision making for long-term anticoagulation. Vasc Pharmacol 2016;83:26–35. DOI: 10.1016/j.vph.2016.03.006; PMID: 27196706 Go AS, Reynolds K, Yang J, et al. Burden of atrial fibrillation and thromboembolism risk: the RHYTHM Study. Heart Rhythm 2016;15(5,Suppl):S82. DOI: 10.1016/j.jrthm.2016.03.026 Ganesan AN, Chew D, Hartshorne T, et al. The impact of atrial fibrillation type on the risk of thromboembolism, mortality, and bleeding: a systematic review and meta-analysis. Eur Heart J 2016;37:1591-1602. DOI: 10.1093/eurheartj/ehw007; PMID: 26888184 Burashnikov A, Antzelevitch C. Pathophysiology of atrial fibrillation. In: Kowey P, Piccini JP, Naccarelli G, Reiffel JA (eds). Cardiac Arrhythmias, Pacing, and Sudden Death. Switzerland: Springer International Publishing, 2017;15–25. DOI: 10.1007/978-3-319-58000-5_2 Guichard JB, Nattel S. Atrial cardiomyopathy: a useful notion

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15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

The fortune inside indicates that we still have more to learn about thromboembolism in AF.

Clinical Perspective • R isk for thromboembolism in AF is determined by both the amount of AF and the presence and magnitude of contributing comorbidities. • Current risk-scoring methods do not adequately consider the magnitude synergism of the AF and comorbidity interaction. • Current risk-scoring approaches can be used in combination to better determine who is at lowest risk, not requiring anticoagulation. • Left atrial appendage morphology may also be considered in risk-assessment.

in cardiac disease management of a passing fad? J Am Coll Cardiol 2017;70:756–65. DOI: 10.1016/j.jacc.2017.06.033; PMID: 28774383 Calenda BW, Fuster V, Halperin JL, et al. Stroke risk assessment in atrial fibrillation: risk factors and markers of atrial myopathy. Nature Rev Cardiol 2016;13:549–59. DOI: 10.1038/nrcardio.2016.106; PMID: 27383079 Rubanenko A, Shchukin Y, Tereshina O, et al. Haemostatic and genetic factors associated with left atrial appendage thrombosis in patients with permanent atrial fibrillation. Eur Heart J 2017;38(Suppl1):767. DOI: 10.1093/eurheartj/ehx504. P3587 Gustafsson C, Blomback M, Britton M, et al. Coagulation factors and the increased risk of stroke in atrial fibrillation. Stroke 1990;21:47–51. DOI: 10.1161/01.STR.21.1.47; PMID: 2105543 Ederhy S, Di Angelantonio E, Mallat Z, et al. Levels of circulating procoagulant microparticles in nonvalvular atrial fibrillation. Am J Cardiol 2007;100:989–94. DOI: 10.1016/ j.amjcard.2007.04.040; PMID: 17826384 Weymann A, Sabashnikov A, Ali-Hasan-Al-Saegh S, et al. Predictive role of coagulation, fibrinolytic, and endothelial markers in patients with atrial fibrillation, stroke, and thromboembolism: a meta-analysis, meta-regression, and systematic review. Med Sci Monitor Basic Res 2017;23:97–104. PMID: 28360407 Chooudhury A, Chung I, Blann A, et al. Elevated platelet microparticle levels in nonvalvular atrial fibrillation: relationship to p-selectin and antithrombotic therapy. Chest 2007;131:809–15. DOI: 10.1378/chest.06-2039; PMID: 17356097 Heeringa J, Conway DS, van der Kuip DA, et al. A longitudinal population-based study of prothrombotic factors in elderly subjects with atrial fibrillation: the Rotterdam Study 1990– 1999. J Thromb Haemost 2006;4:1944–49. DOI: 10.1111/j.15387836.2006.02115.x; PMID: 16824187 Marin F, Roldan V, Lip GY. Fibrinolytic function and atrial fibrillation. Thromb Res 2003;109:233–40. DOI: 10.1016/S00493848(03)00259-7 Sohara H, Amitani S, Kurose M, et al. Atrial fibrillation activates platelets and coagulation in a time-dependent manner: a study in patients with paroxysmal atrial fibrillation. J Am Coll Cardiol 1997;29:106–12. DOI: 10.1016/S0735-1097(96)00427-5 Cai H, Li Z, Goette A, et al. Downregulation of endocardial nitric oxide synthase expression and nitric oxide production in atrial fibrillation: potential mechanisms for atrial thrombosis and stroke. Circulation 2002;106:2854–8. DOI: 10.1161/01.CIR.0000039327.11661.16; PMID: 12451014 Wang TJ, Massaro JM, Levy D, et al. A risk score for predicting stroke or death in individuals with new-onset atrial fibrillation in the community: the Framingham Heart Study. JAMA 2003;290:1049–56. DOI: 10.1001/jama.290.8.1049; PMID: 12941677 Atrial Fibrillation Investigators. Echocardiographic predictors of stroke in patients with atrial fibrillation: a prospective study of 1066 patients from 3 clinical trials. Arch Intern Med 1998;158:1316–20. DOI: 10.1001/archinte.158.12.1316 Vazini SM, Larson MG, Benjamin EJ, et al. Echocardiographic predictors of nonrheumatic atrial fibrillation: The Framingham

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DOI: 10.1161/CIRCULATIONAHA.108.816082; PMID: 19255343 46. S inger DE, Chang Y, Borowsky LH, et al. A new risk scheme to predict ischemic stroke and other thromboembolism in atrial fibrillation: the ATRIA study stroke risk score. J Am Heart Assoc 2013;2:e000250. DOI: 10.1161/JAHA.113.000250 47. Aspberg S, Chang Y, Atterman A, et al. Comparison of the ATRIA, CHADS2, and CHA2DS2-VASc stroke risk scores in predicting ischaemic stroke in a large Swedish cohort of patients with atrial fibrillation. Eur Heart J 2016;37:3203–10. DOI: 10.1093/eurheartj/ehw077; PMID: 26941204 48. Di Biase L, Santangeli P, Anselmino M. Does the left atrial appendage morphology correlate with the risk of stroke in patients with atrial fibrillation? Results from a multicenter study. J Am Coll Cardiol 2012;60:531–8. DOI: 10.1016/ j.jacc.2012.04.032; PMID: 22858289 49. Petersen M, Roehrich A, Balzer J, et al. Left atrial appendage morphology is closely associated with specific echocardiographic flow pattern in patients with atrial fibrillation. Europace 2015;17:539–45. DOI: 10.1093/europace/ euu347; PMID: 25491111 50. Goldman ME, Pearce LA, Hart RG, et al. Pathophysiologic correlated of thromboembolism in nonvalvular atrial fibrillation: I. Reduced flow velocity in the left atrial appendageThe Stroke Prevention in Atrial Fibrillation

(SPAF-111) Study. J Am Soc Echocardio 1999;12:1080–7. DOI: 10.1016/S0894-7317(99)70105-7 51. A nselmino M, Scaglione M, Di Biase L. Left atrial appendage morphology and silent cerebral ischemia in patients with atrial fibrillation. Heart Rhythm 2014;11:2–7. DOI: 10.1016/ j.hrthm.2013.10.020; PMID: 24120872 52. Kreidieh B, Valderrabano M. Malignant left atrial appendage morphology and embolization risk in atrial fibrillation. Heart Rhythm Case Rep 2015;1:406–10. DOI: 10.1016/j.hrcr.2015.02.016; PMID: 26918230 53. Khurram IM, Dewire J, Mager M. Relationship between left atrial appendage morphology and stroke in patients with atrial fibrillation. Heart Rhythm 2013;10:1843–9. DOI: 10.1016/ j.hrthm.2013.09.065; PMID: 24076444 54. Yamamoto M, Seo Y, Kawamatsu N, et al. Complex left atrial appendage morphology and left atrial appendage thrombus formation in patients with atrial fibrillation. Circ Cardiovasc Imaging 2014;7:337–43. DOI: 10.1161/CIRCIMAGING.113.001317; PMID: 24523417 55. Korhonen M, Muuronen A, Mustonen P, et al. Left atrial appendage morphology in patients with suspected cardiogenic stroke without known atrial fibrillation. Plos One 2015;10:e0118822. DOI: 10.1371/journal.pone.0118822; PMID: 25751618

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Clinical Arrhythmias

Management of Complications in Anticoagulated Patients with Atrial Fibrillation George D Katritsis 1 and Demosthenes G Katritsis 2 1.Imperial College Healthcare NHS Trust, London, UK; 2. Hygeia Hospital, Athens, Greece

Abstract Oral anticoagulation is mandatory for patients at high risk of thromboembolism, but the risk of bleeding should also be taken into account. Direct oral anticoagulants are now recommended for non-valvular AF as a potential alternative to warfarin. In this article we discuss methods to assess the anticoagulant effect of these agents, specific and general antidotes, and management of complications such as embolic and haemorrhagic stroke, and significant bleeding.

Keywords Atrial fibrillation, anticoagulation, ischaemic stroke, bleeding Disclosure: The authors have no conflicts of interest to declare. Received: 21 July 2017 Accepted: 27 July 2017 Citation: Arrhythmia & Electrophysiology Review 2017;6(4):167–78. DOI: 10.15420/aer.2017.23.1 Correspondence: Demosthenes G Katritsis, Hygeia Hospital, Erithrou Stavrous 4, Athens 15123, Greece. E: dkatrits@dgkatritsis.gr

Atrial fibrillation (AF) is associated with a fivefold increased risk for stroke, a twofold increased risk for dementia, and a tripling of risk for heart failure,1,2,3 while AF genetic risk is strongly associated with cardioembolic stroke.4 In the Framingham Heart Study the percentage of strokes attributable to AF increases steeply from 1.5 % at 50–59 years of age to 23.5 % at 80−89 years of age.5,6 In the Danish National Patient Registry, the 5-year risk of stroke for men aged 50 years with no risk factors was 1.1 %, and with AF alone without additional risk factors 2.5 %, with the great majority not being anticoagulated. In men aged 70 years, the corresponding risks were 4.8 % and 6.6 %.7 Approximately 24 % of all strokes are due to AF,3 and 10 % of ischaemic strokes are associated with AF first diagnosed at the time of stroke.8 Numbers of AF-related incident ischaemic strokes at age ≥80 years have trebled over the last 25 years, despite the introduction of anticoagulants, and are projected to treble again by 2050.9 In addition, extracranial systemic embolic events constitute 11.5 % of clinically recognised thromboembolic events in patients with AF, and are associated with a high morbidity and mortality, comparable to that of ischaemic stroke.10 AF is the main cause of coronary embolism, being independently associated with an increased risk of myocardial infarction, especially non-ST-elevation myocardial infarction (NSTEMI) in women.11,12 Oral anticoagulation, therefore, is mandatory for patients at high risk of thromboembolism as expressed by a CHA2DS2VASc score >2, but the risk of bleeding, assessed by various schemes such as the HAS-BLED, ATRIA, HEMORR2HAGES, and ORBIT,13,14 should also be taken into account. Low risk patients (score 0 for male and 1 for female) have a low risk of stroke (<1 % per year) and may be left without anticoagulation, since the benefit of anticoagulation does not outweigh the bleeding risk (net clinical benefit).15 Anticoagulation in patients with one stroke risk factor (CHA2DS2VASc score 1 for men and 2 in women) should be individualised since there is a significant increase in events rate in the presence of an additional risk factor.16–19 Direct oral anticoagulants (DOAC) are now

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recommended for non-valvular AF as a potential alternative to warfarin (see Tables 1 and 2).20

Assessment of Anticoagulant Effect and Antidotes of Specific Agents Warfarin The efficacy of the treatment with warfarin is directly related to the time in therapeutic range (TTR), that is, the percent time with international normalised ratio (INR) between 2.0 and 3.0. A target threshold TTR exists (estimated between 58 % and 65 %), below which there appears to be little benefit of oral anticoagulant (OAC) over antiplatelet therapy.21 The SAMe-TT2R2 [Sex (female); Age, 60 years; Medical history (more than two comorbidities); Treatment (interacting drug, e.g. Amiodarone); Tobacco use (doubled), and Race (doubled)] score is useful in identifying individuals who will not have good INR control (score ≥2).22 For excessive INR in the absence of bleeding, the American College of Chest Physicians (ACCP) guidelines recommend oral vitamin K (phytomenadione, 1–2.5 mg) only when INR is >10.23 IV vitamin K (1–2 mg) may also be given, although at 24 h oral vitamin K produces similar results. Oral dose is 2.5 mg or 1–2 mg of the IV preparation in a cup of orange juice. In the presence of major bleeding, four-factor prothrombin complex concentrate (4-PCC) is preferred to fresh frozen plasma since >1500 ml of fresh frozen plasma are needed to achieve a meaningful increase in coagulation factor levels.24 In a trial for reversal of VKA-associated major bleeding, the reported efficacy of 4-PCCs was 72 %, with 8 % thrombotic events, and 6 % mortality.25 The additional use of vitamin K 5 to 10 mg administered by slow IV injection is helpful in this setting.26

Dabigatran Diluted thrombin time and ecarin clotting time or chromogenic assay are precise methods to assess the anticoagulant effect of dabigatran, but these methods are time-consuming and not widely available.27

Access at: www.AERjournal.com

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Clinical Arrhythmias Table 1: Oral Anticoagulants for Atrial Fibrillation

Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban

Dose Variable once daily 150 twice daily 20 mg once daily 5 mg twice daily 110 twice daily if CrCl 15 mg once daily 2.5 mg twice daily <50 ml/min or >75 years if CrCl 15–30 ml/min if two criteria of: of age 75 mg twice daily • Cr ≥1.5 mg/dL, if CrCl 15–30 ml/min ≥80 years • Body weight ≤60 kg

60 mg once daily 30 mg once daily if CrCl ≤ 50 ml

Target

Vitamin K-dependent factors

Thrombin (Factor II)

Factor Xa

Half-life

40 h

12 h

9 h

12 h

10 h

Renal clearance 0 80 % 60 %

25 % 40 %

Onset of action inhibition

3–5 h

1 h

2 h

3 h

Anticoagulation INR 2–3 monitoring

Not required

Interactions

P-gp

P-gp; CYP3A4

Andexanet alfa; ciraparantag; PCCs/aPCCs

Multiple

Antidote Vitamin K Idarucizumab; PCCs/ aPCCs

Dabigatran is eliminated via the P-glycoprotein (P-gp) transporter, while the Xa inhibitors are eliminated via P-gp and cytochrome P450 (CYP) 3A4 activity. Their dosage should be reduced with co-administration of P-gp or CYP3A4 inhibitors, and they should be used with caution or avoided with administration of P-gp or CYP3A4 inducers. P-gp inhibitors include verapamil, diltiazem, amiodarone, dronedarone, quinidine, erythromycin, clarithromycin, ketoconazole, intraconazole, voriconazole, posaconazole, cyclosporine, grapefruit juice. P-gp inducers include rifampicin, St. John’s wort, carbamazepine, phenytoin, phenobarbital and trazodone. CYP3A4 inhibitors include ketoconazole, intraconazole, voriconazole, posaconazole, fluconazole, chloramphenicol, clarithromycin, HIV protease inhibitors (e.g. ritonavir, atanazavir), verapamil and diltiazem. CYP3A4 inducers include phenytoin, carbamazepine, phenobarbital, rifampicin, and St. John’s wort (Hypericum perforatum). aPCC = activated prothrombin complex concentrate; PCC = prothrombin complex concentrate. Source: Katritsis, et al., 2016.75 Credit: p.589 Table 53.19, p.590 Table 53.20 & p.591 Table 53.22 from Chapter 53 ‘Atrial Fibrillation’ from Clinical Cardiology: Current Practice Guidelines, Updated Edition by Katritsis, D.G., Gersh, B.J. & Camm, A.J. (2016). Free permission Author’s own material, appr. HPL. By permission of Oxford University Press.

Individual NOAC Interactions The dose of dabigatran or edoxaban should be reduced in patients taking verapamil. No dose reduction is needed in patients taking rivaroxaban with verapamil. Apixaban does not interact with amiodarone or verapamil. Dabigatran is contraindicated in combination with dronedarone. Edoxaban 30 mg should be used in patients on dronedarone. Source: Diene, et al. Choosing a particular oral anticoagulant and dose for stroke prevention in individual patients with non-valvular atrial fibrillation: part 2. Eur Heart J 2017;38(12):860-868. By permission of Oxford University Press/European Society of Cardiology 41

Activated partial thromboplastin time (aPTT) and prothrombin time (PT), measured in samples soon after the last dose, are prolonged by dabigatran but the correlation is not linear to guide dosage.28 However, in the presence of a normal aPTT, dabigatran is unlikely to contribute to bleeding, and aPTT can be used in emergencies as a rough estimate.29 Specific antidotes are under study.30,31 Idarucizumab, a monoclonal antibody fragment, completely reverses the anticoagulant effect of dabigatran within minutes and has been shown to be effective in initial clinical trials (2.5 g IV infusions no more than 15 min apart).32–34 In patients with acute major bleeding the reported efficacy was 71 %, with 10 % thrombotic events, and a mortality of 12 %.32 Idarucizumab for reversal of dabigatran was approved by the FDA in October 2015. Ciraparantag binds in a similar way to the new oral factor Xa inhibitors, and to dabigatran, but further clinical experience is needed. Non-specific haemostatic agents are prothrombin complex concentrates (PCCs) and activated prothrombin complex concentrates (aPCCs). PCCs are plasma-derived products that contain 3 (factors II, IX, and X) or 4 (addition of factor VII) clotting factors in addition to variable amounts of heparin and the natural coagulation inhibitors protein C and protein S. aPCC contains mostly activated factor VII along with mainly non-activated factors II, IX, and X. Recombinant activated factor VII may also reverse the effect of non-vitamin K antagonist oral anticoagulants (NOAC) but increases the risk of thromboembolic effects by >1 %.31,35

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In emergencies, gastric lavage in recent drug ingestion, haemodialysis, oral charcoal within 2 h following dabigatran ingestion, desmopressin, packed red cells in anaemia, platelet transfusions in patients receiving concurrent antiplatelet therapies, and fresh frozen plasma in the presence of dilutional coagulopathy or disseminated intravascular coagulation may also be tried as general measures.36 Prothrombin complex concentrates (PCCs and aPCCs) are more effective than fresh frozen plasma but they carry an absolute increase of thromboembolic events of 1 %.31

Factor Xa Inhibitors Antifactor Xa assays may be used as an estimate of the anticoagulant effect. 27 aPTT and PT are prolonged by Xa inhibitors, but cannot be used to guide dosage since the correlation is not linear.28 Diluted prothrombin time appears as the best test to use in emergency situations.29 Andexanet alfa, a recombinant protein that binds and sequesters factor Xa inhibitors has been successfully tried for apixaban and rivaroxaban (ANNEXA trials).37,38 It is given as 300 mg IV bolus that can be followed by an infusion of 4mg/min for 120 min. In patients with acute major bleeding the reported efficacy was 79 %, with 18 % thrombotic events, and a mortality of 15 % reported.38 Ciraparantag, (IV bolus of 100–300 mg), a synthetic molecule that binds specifically to unfractionated heparin and low-molecular-weight heparin, reversed edoxaban within 10–30 min,39 and is under study.

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Complications in Anticoagulated Patients with AF Table 2: New Anticoagulants Versus Warfarin in Nonvalvular Atrial Fibrillation Trial

Dose of NOAC

NOAC (%/y)

RELY

Dabigatran 110 mg twice daily

Stroke/systemic embolism 1.53 1.69 0.34

Warfarin (%/y)

Dabigatran 150 mg twice daily

1.11

ROCKET-AF

Rivaroxaban 15–20 mg once dailya

2.1 2.4

ARISTOTLE

Apixaban 2.5–5 mg twice dailyb 1.27c 1.60c 0.01

1.69

p-value

<0.001 0.12

ENGAGE-AF-TIMI 48

Edoxaban 60 mg once daily

Edoxaban 30 mg once dailyd 2.04

RELY

Dabigatran 110 mg twice daily

Intracranial haemorrhage 0.12 0.38

<0.001

Dabigatran 150 mg twice daily

0.10

<0.001

1.57

1.8

0.08

1.8

0.1

0.38

ROCKET-AF

Rivaroxaban 15–20 mg once daily

0.5

0.7

0.02

ARISTOTLE

Apixaban 2.5–5 mg twice daily

0.24

0.47

<0.001

ENGAGE-AF-TIMI 48

Edoxaban 60 mg once daily

0.26

0.47

<0.001

Edoxaban 30 mg once daily

0.16

0.47

<0.001

RELY

Dabigatran 110 mg twice daily

Major bleeding 2.71

3.36

<0.003

Dabigatran 150 mg twice daily

3.11

3.36

0.31

ROCKET-AF

Rivaroxaban 20 mg once daily

3.6

3.4

0.58

ARISTOTLE

Apixaban 2.5–5 mg twice daily

2.13

3.09

<0.001 <0.001

ENGAGE-AF-TIMI 48

Edoxaban 60 mg once daily

2.75

3.43

Edoxaban 30 mg once daily

1.61

3.43 <0.001

RELY ROCKET-AF ARISTOTLE ENGAGE-AF-TIMI 48

Dabigatran 110 mg twice daily Dabigatran 150 mg twice daily Rivaroxaban 20 mg once daily Apixaban 2.5–5 mg twice daily Edoxaban 60 mg once daily Edoxaban 30 mg once daily

Total mortality 3.75 3.64 4.5 3.52 3.99 3.80

4.13 4.13 4.9 3.94 4.35 4.35

0.13 0.051 0.15 0.047 0.08 0.006

a = 15 mg once daily if CrCl 40–49 ml/min; b = 2.5 mg twice daily if ≥2 of the following: age ≥80 y, BW <60 kg, creatinine ≥1.5 mg/dl; c = This number Includes both embolic and haemorrhagic strokes; d = 30 mg once daily if CrCl 30–50 ml/min, BW <60 kg, concomitant verapamil or quinidine; BW: body weight, CrCl: creatinine clerance; NOAC = nonvitamin K antagonist oral anticoagulants. Source: Katritsis, et al., 2016. Credit: p.589 Table 53.19, p.590 Table 53.20 & p.591 Table: 53.22 from Chapter 53 ‘Atrial Fibrillation’ from Clinical Cardiology: Current Practice Guidelines, Updated Edition by Katritsis, D.G., Gersh, B.J. & Camm, A.J. (2016). Free permission Author’s own material, appr. HPL. By permission of Oxford University Press.

Xa inhibitors are not removed by dialysis, being protein bound. Gastric lavage in recent drug ingestion, and platelet and fresh frozen plasma transfusions may also been tried as general measures. As noted, PCCs and aPCCs are more effective but they carry an absolute increase of thromboembolic events of 1 %.31

Management of Stroke Ischaemic Stroke Patients presenting within 4.5 h after the onset of ischaemic stroke should be considered for IV rt-PA (0.9 mg/kg, with 10 % bolus, and the remainder over 60 min, maximum dose 90 mg). Diffusionweighted magnetic resonance imaging and non-enhanced computed tomography are the most sensitive and specific methods for detecting ischaemic stroke and excluding intracerebral haemorrhage.40 They are necessary before intravenous rtPA to exclude intracranial haemorrhage (absolute contraindication) and to determine whether CT hypodensity of haemorrhage or MRI hyperintensity of ischaemia are present. Anticoagulation does not increase the risk of intracerebral haemorrhagic complications when INR is ≤1.7.41 In patients who present with stroke while taking new anticoagulants, if the aPTT is prolonged in a patient taking dabigatran or the prothrombin time with an Xa inhibitor, it should be assumed that the patient is anticoagulated, and thrombolysis should probably not be administered.40 However, in recent studies on patients with a ischaemic stroke and a NOAC taken within the last 48 h, thrombolysis with rt-PA or intra-arterial treatment had similar risk of symptomatic intracranial haemorrhage to that in

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patients on subtherapeutic VKA treatment (INR <1.7) or in those without previous anticoagulation.42,43 Criteria for fibrinolysis are presented in Table 3 and recommendations for secondary stroke prevention in Table 4 and Figure 1. Of note, age >80 years is not an exclusion criterion, provided it can be given within the first 3 h. Tenecteplase (0.25 mg/kg, administered as a single bolus, with a maximum dose of 25 mg), a more fibrin-selective agent, is superior to alteplase in patients subjected to fibrinolysis within 6 h after the onset of ischaemic stroke,44 but this was not verified in another comparison within 4.5 h after stroke.45 Anticoagulants and antiplatelet agents should be withheld the first 24 h following fibrinolysis. Labetalol (10–20 mg IV over 1–2 min, may repeat 1 time), or nicardipine (5 mg/h IV, titrate up by 2.5 mg/h every 5–15 min, maximum 15 mg/h) are recommended only when the blood pressure exceeds 180/110 mmHg.40 However, in patients who are not candidates for fibrinolysis, blood pressure lowering in acute stroke is not established to be useful with systolic blood pressure of 140 to 220 mmHg and without evidence of nonstroke end-organ damage, with the possible exception of an early (<6 h) BP lowering strategy.46 Thus, treatment of hypertension in this setting should be individualised. In patients who are candidates for fibrinolysis a pre-treatment BP <180/110 mmHg is mandatory. Fibrinolysis offers recanalisation rate of <50 %, and large thrombi in vessels such as the distal internal carotid artery or the first segment of the middle cerebral artery respond poorly.47 Intra-arterial, catheterbased treatment administered within 6 h after acute ischaemic stroke

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Clinical Arrhythmias Table 3: Management of Acute Ischaemic Stroke AHA/ASA 2013 Guidelines on Acute Ischemic Stroke. Inclusion and Exclusion Characteristics of Patients with Ischemic Stroke who Could Be Treated with IV rtPA Within 3 Hours from Symptom Onset Inclusion criteria Diagnosis of ischaemic stroke causing measurable neurological deficit Onset of symptoms <3 h before beginning treatment Aged ≥18 years Exclusion criteria Significant head trauma or prior stroke in previous 3 months Symptoms suggest subarachnoid haemorrhage Arterial puncture at non-compressible site within previous 7 days History of previous intracranial haemorrhage Recent intracranial or intraspinal surgery Elevated blood pressure (systolic ≥185 mmHg or diastolic ≥110 mmHg) Active internal bleeding Acute bleeding diathesis, including, but not limited to: Platelet count ≤100 000/mm3 Heparin received within 48 hours, resulting in abnormally elevated aPTT greater than the upper limit of normal Current use of anticoagulant, with INR >1.7 or PT >15 s Current use of direct thrombin inhibitors or direct factor Xa inhibitors with elevated sensitive laboratory tests (such as aPTT, INR, platelet count, and ECT; TT; or appropriate factor Xa activity assays) Blood glucose concentration <5O mg/dL (2.7 mmol/L) CT demonstrates multilobar infarction (hypodensity >1/3 cerebral hemisphere) Relative exclusion criteria Recent experience suggests that under some circumstances—with careful consideration and weighting of risk to benefit—patients may receive fibrinolytic therapy despite 1 or more relative contraindications. Consider risk to benefit of IV alteplase administration carefully if any of these relative contraindications are present: Only minor or rapidly improving stroke symptoms (clearing spontaneously) Pregnancy Seizure at onset with postictal residual neurological impairments Major surgery or serious trauma within previous 14 days Recent gastrointestinal or urinary tract haemorrhage (within previous 21 days) Recent acute myocardial infarction (within previous 3 months) 1. The checklist includes some FDA-approved Indications and contraindications for administration of IV alteplase for acute ischaemlc stroke. Recent guideline, revisions have modified the original FDAapproved Indications. A physician with expertise in acute stroke care may modify this list. Onset time is defined as either the witnessed onset of symptoms or the time last known normal If symptom onset was not witnessed. In patients without recent use of oral anticoagulants or heparin. treatment with IV alteplase can be initiated before availability of coagulation test results but should be discontinued If INR is >1.7 or PT is abnormally elevated by local laboratory standards. In patients without, history of thrombocytopenia, treatment with IV alteplase can be initiated before availability of platelet count but should be discontinued if platelet count is <100 000/mm3. aPTT = indicates activated partial thromboplastin time; CT = computed tomography; ECT ecarin clotting time; FDA = Food and Drug Administration; INR = international normalized ratio; IV = Intravenous; PT = partial thromboplastin time; and TT = thrombin time. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Source: 77Jauch, et al. AHA/ASA 2013 Guideline for the Early Management of Patients With Acute Ischemic Stroke Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013;44:870– 947. http://stroke.ahajournals.org/content/44/3/870

2015 AHA/ASA Focused Update of the 2013 Guidelines for the Early Management of Patients with Acute Ischemic Stroke (A Summary of Recommendations) Endovascular Interventions 1. Patients eligible for intravenous r-tPA should receive IV r-tPA even if endovascular treatments are being considered.

I-A

2. Patients should receive endovascular therapy with a stent retriever if they meet all the following criteria: a. Prestroke mRS score 0–1; b. Acute ischaemic stroke receiving IV r-tPA within 4.5 h of onset according to guidelines from professional medical societies; c. Causative occlusion of the ICA or proximal MCA (M1); d. Age ≥18 years; e. NIHSS score ≥6; f. ASPECTS ≥6; and g. Treatment can be initiated (groin puncture) within 6 h of symptom onset.

I-A

3. To ensure benefit, reperfusion to TICI grade 2b/3 should be achieved as early as possible and within 6 h of stroke onset.

I-B-R

4. When treatment is initiated beyond 6 h from symptom onset, the effectiveness of endovascular therapy is uncertain for patients with acute ischaemic stroke who have causative occlusion of the ICA or proximal MCA (M1).

IIb-C

5. Endovascular therapy with stent retrievers completed within 6 h of stroke onset in carefully selected patients with anterior circulation occlusion who have contraindications to intravenous r-tPA.

IIa-C

6. Use of endovascular therapy with stent retrievers for carefully selected patients with acute ischaemic stroke in whom treatment can be initiated (groin puncture) within 6 h of symptom onset and who have causative occlusion of the M2 or M3 portion of the MCAs, anterior cerebral arteries, vertebral arteries, basilar artery, or posterior cerebral arteries.

IIb-C

7. Endovascular therapy with stent retrievers may for some patients <18 years of age with acute ischaemic stroke who have demonstrated large-vessel occlusion in whom treatment can be initiated (groin puncture) within 6 hours of symptom onset.

IIb-C

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Complications in Anticoagulated Patients with AF 2015 AHA/ASA Focused Update of the 2013 Guidelines for the Early Management of Patients with Acute Ischemic Stroke (A Summary of Recommendations): Cont. Endovascular Interventions 8. Endovascular therapy with stent retrievers for patients with acute ischaemic stroke in whom treatment can be initiated (groin puncture) within 6 h of symptom onset and who have prestroke mRS score >1, ASPECTS <6, or NIHSS score <6 and causative occlusion of the ICA or proximal MCA (M1).

IIb-B-R

9. Observing patients after IV r-tPA to assess for clinical response before pursuing endovascular therapy is not recommended.

III-B-R

10. Use of stent retrievers in preference to the MERCI device.

I-A

The use of mechanical thrombectomy devices other than stent retrievers may be reasonable in some circumstances.

IIb-B-NR

11. Use of a proximal balloon guide catheter or a large-bore distal-access catheter rather than a cervical guide catheter alone in conjunction with stent retrievers may be beneficial.

IIa-C

12. The technical goal of the thrombectomy procedure should be a TICI grade 2b/3 angiographic result to maximize the probability of a good functional clinical outcome.

I-A

Use of salvage technical adjuncts, including intra-arterial fibrinolysis, to achieve these angiographic results if completed within 6 h of symptom onset.

IIb-B-R

13. Angioplasty and stenting of proximal cervical atherosclerotic stenosis or complete occlusion at the time of thrombectomy may be considered, but the usefulness is unknown.

IIb-C

14. Initial treatment with intra-arterial fibrinolysis for carefully selected patients with major ischaemic strokes of <6 h duration caused by occlusions of the MCA.

I-B-R

A clinically beneficial dose of intra-arterial r-tPA is not established, and r-tPA does not have FDA approval for intra-arterial use. Thus, endovascular therapy with stent retrievers is recommended over intra-arterial fibrinolysis as first-line therapy.

I-E

15. Intra-arterial fibrinolysis initiated within 6 h of stroke onset in carefully selected patients who have contraindications to the use of IV r-tPA.

IIb-C

16. Favour conscious sedation over general anaesthesia during endovascular therapy for acute ischaemic stroke.

IIb-C

Imaging 1. Emergency imaging of the brain before any specific treatment for acute stroke is initiated. In most instances, nonenhanced CT will provide the necessary information to make decisions about emergency management.

I-A

2. If endovascular therapy is contemplated, a noninvasive intracranial vascular study during the initial imaging evaluation should not delay IV r-tPA if indicated.

I-A

3. The benefits of additional imaging beyond CT and CTA or MRI and MRA such as CT perfusion or diffusion- and perfusion-weighted imaging for selecting patients for endovascular therapy are unknown.

IIb-C

ASPECTS = Alberta Stroke Program Early CT Score; CT = computed tomography; CTA = computed tomography angiography; FDA = Food and Drug Administration; ICA = internal carotid artery; MCA = middle cerebral artery; MRA = magnetic resonance angiography; MRI = magnetic resonance imaging; mRS = modified Rankin Scale; NIHSS = National Institutes of Health Stroke Scale; r-tPA = recombinant tissue-type plasminogen activator; TICI = thrombolysis in cerebral infarction. Source: Powers, et al. 201575. Credit: American Heart Association, Inc.

Table 4: ESC 2016 Guidelines on Atrial Fibrillation. Recommendations for Secondary Stroke Prevention Anticoagulation with heparin or LMWH immediately after an ischaemic stroke is not recommended.

III-A (harm)

In TIA or stroke while on anticoagulation, adherence to therapy should be assessed and optimized.

IIa-C

Figure 1: Initiation or Continuation of Anticoagulation in Atrial Fibrillation Patients After a Stroke or Transient Ischaemic Attack Patient with atrial fibrillation and acute TIA or ischaemic stroke Exclusion of intracerebral bleeding by CT or MRI

In moderate-to-severe ischaemic stroke while on anticoagulation, IIa-C anticoagulation should be interrupted for 3–12 days based on a multidisciplinary assessment of acute stroke and bleeding risk. Following a stroke, aspirin should be considered for secondary prevention until the initiation or resumption of oral anticoagulation.

IIa-B

Systemic thrombolysis with rtPA is not recommended if the INR is above 1.7 (or, for patients on dabigatran, if aPTT is outside normal range).

III-C (Harm)

NOACs are preferred to VKAs or aspirin in AF patients with a previous stroke.

I-B

After TIA or stroke, combination therapy of OAC and an antiplatelet is not recommended.

IIII-B (harm)

After intracranial haemorrhage, oral anticoagulation in patients with AF may be reinitiated after 4–8 weeks provided the cause of bleeding or the relevant risk factor has been treated or controlled.

IIb-B

aPTT = activated partial thromboplastin time; AF = atrial fibrillation; INR = international normalized ratio; LMWH = low-molecular weight heparin; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulation; rtPA = recombinant tissue plasminogen activator; TIA = transient ischaemic attack; VKA = vitamin K antagonist. Source: Kirchhof, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37:2893–962. Published with permission of the European Society of Cardiology.

using aspiration and stent retrievers has improved neurologic recovery, and reduced mortality compared to IV fibrinolysis, especially in the presence of a proximal cerebral arterial occlusion, and a small infarct or salvageable brain tissue on CT.48 It can be delivered with or without

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TIA

Mild stroke (NIHSS <8)

Moderate stroke (NIHSS 8–15)

Severe stroke (NIHSS ≥16)

Consider additional clinical factors favouring early / delayed initiation of OAC Factors favouring early initiation of OAC:

Factors favouring delayed initiation of OAC:

Low NIHSS (<8): Small/no brain infarction on imaging High recurrence risk, e.g. cardiac thrombus on echo No need for percutaneous endoscopic gastrostomy No need for carotid surgery No haemorrhagic transformation Clinically stable Young patient Blood pressure is controlled

Start OAC

1 day after acute event

3 days after acute event

High NIHSS (≥8): Large/moderate brain infarction on imaging Needs gastrostomy or major surgical intervention Needs carotid surgery Haemorrhagic transformation Neurologically unstable Elderly patient Uncontrolled hypertension

Evaluate haemorrhagic transformation by CT or MRI at day 6

Evaluate haemorrhagic transformation by CT or MRI at day 12

6 days after acute event

12 days after acute event

This approach is based on consensus rather than prospective data. AF = atrial fibrillation; CT = computed tomography; MRI = magnetic resonance imaging; NIHSS = National Institutes of Health stroke severity scale (available at http://www.strokescenter.org/wp-content/ uploads/2011/08/NIH_Stroke_Scale.pdf); OAC = oral anticoagulation; TIA = transient ischaemic attack. Source: Kirchhof, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37:2893–962. Published with permission of the European Society of Cardiology.

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Clinical Arrhythmias Figure 2: Initiation or Resumption of Anticoagulation in Atrial Fibrillation Patients After an Intracranial Bleed

Figure 3: Management of Active Bleeding in Patients Receiving Anticoagulation

Patient with AF suffering from an intracranial bleed on OAC If acute event: establish intensity of anticoagulation (see bleeding flow chart)

Patient with active bleeding

Compress bleeding sites mechanically Contra-indication for OAC

Consider further information to allow informed judgement Factors supporting withholding of OAC:

Factors supporting reinitiation of OAC:

Bleeding occured on adequately dosed NOAC or in setting of treatment interruption or underdosing Older age Uncontrolled hypertension Cortical bleed Severe intracranial bleed Multiple microbleeds (e.g. >10) Cause of bleed cannot be removed or treated Chronic alcohol abuse Need for dual antiplatelet therapy after PCI

Bleeding occured on VKA or in setting of overdose Traumatic or treatable cause Younger age Well controlled hypertension Basal ganglia bleed No or mild white matter lesions Surgical removal of subdural haematoma Subarachnoid bleed: aneurysm clipped or coiled High-risk of ischaemic stroke

Patient or next of kin choice informed by multidisciplinary team advice

Assess haemodynamic status, blood pressure, basic coagulation parameters, blood count, and kidney function

Obtain anticoagulation history (last NOAC / VKA dose)

VKA Delay VKA until INR <2

Add symptomatic treatment: Fluid replacement Blood transfusion Treat bleeding cause (e.g. gastroscopy)

NOAC Minor

Moderate-severe

Consider to add Vitamin K (1–10mg) i.v.

No stroke protection (no evidence)

LAA occlusion (IIbC)

Initiate or resume OAC, choosing an agent with low intracranial bleeding risk, after 4−8 weeks (IIbB)

This approach is based on consensus opinion and retrospective data. In all patients, evaluation by a multidisciplinary panel is required before treatment (stroke physician/ neurologist, cardiologist, neuroradiologist, and neurosurgeon). AF = atrial fibrillation; LAA = left atrial appendage; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulation; PCI = percutaneous coronary intervention; VKA = vitamin K antagonist. Source: Kirchhof, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37:2893–962. Published with permission of the European Society of Cardiology.

Table 5: ESC 2016 Guidelines on Atrial Fibrillation. Recommendations for Management of Bleeding Blood pressure control in hypertensive patients

IIa-B

When dabigatran is used, a reduced dose (110 mg twice daily) in patients >75 years to reduce the risk of bleeding.

IIb-B

In patients at high-risk of gastrointestinal bleeding, a VKA or another NOAC preparation should be preferred over dabigatran 150 mg twice daily, rivaroxaban 20 mg once daily, or edoxaban 60 mg once daily.

IIa-B

Avoid alcohol excess in all AF patients considered for OAC.

IIa-C

Genetic testing before the initiation of VKA therapy is not recommended.

III-b (no benefit)

Reinitiation of OAC after a bleeding event in all eligible patients by a multidisciplinary AF team, considering different anticoagulants and stroke prevention interventions, improved management of factors that contributed to bleeding, and stroke risk.

IIa-B

In AF patients with severe active bleeding events, interrupt OAC therapy until the cause of bleeding is resolved.

I-C

AF = atrial fibrillation; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulation; VKA = vitamin K antagonist. Source: Kirchhof, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37:2893–962. Published with permission of the European Society of Cardiology.

concomitant IV fibrinolysis, and preliminary data suggest that they might be useful up to 8 h49 or even 12 h50 after symptoms onset. Re-initiation of anticoagulation following a non-fibrinolysed ischaemic stroke should be within 14 days after the onset of symptoms (AHA/ASA

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Consider PCC and FFP Consider replacement of platelets where appropriate

Delay NOAC for 1 dose or 1 day

Add symptomatic treatment: Fluid replacement Blood transfusion Treat bleeding cause (e.g. gastroscopy) Consider to add oral charcoal if recently ingested NOAC

Severe or life-threatening

Consider specific antidote, or PCC if no antidote available Consider replacement of platelets where appropriate

Institutions should have an agreed procedure in place. FFP = fresh frozen plasma; INR = international normalized ratio; i.v. = intravenous; NOAC = non-vitamin K antagonist oral anticoagulant; PCC = prothrombin complex concentrated; VKA = vitamin K antagonist. Source: Kirchhof, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37:2893–962. Published with permission of the European Society of Cardiology.

2014 GL for prevention of stroke IIa-B), since the risk of early recurrence is as high as 8 %.50 In patients with a TIA, anticoagulation can be initiated 1 day after the onset of neurological symptoms, 3 days following small, non-disabling infarcts, 5–7 days following moderate infarcts, and 12–14 days following severe strokes.52,41 In the presence of high risk for haemorrhagic conversion (i.e. large infarct, haemorrhagic transformation on initial imaging, uncontrolled hypertension, or haemorrhage tendency), it is reasonable to delay initiation of oral anticoagulation beyond 14 days (AHA/ASA 2014 GL for prevention of stroke IIa-B).51 If anticoagulation is unsuitable or not feasible, dual antiplatelet therapy is recommended for secondary prevention (Clopidogrel With Aspirin in Acute Minor Stroke or Transient Ischemic Attack [CHANCE] trial).53 Since dabigatran 150 mg twice daily resulted in a significant reduction in both ischaemic and haemorrhagic stroke, should the acute ischaemic stroke occur while the patient is taking dabigatran 110 mg twice daily, or rivaroxaban or apixaban (neither of which significantly reduced ischaemic stroke compared with warfarin, in their respective trials), the use of dabigatran 150 mg twice daily instead, may be reasonable, but no direct data exist.54 Elective non-cardiac surgery may best be avoided for 9 months following a stroke, if possible.55

Intracerebral Haemorrhage In the case of intracerebral haemorrhage, reversal of anticoagulation (INR <1.3) is needed with vitamin K 10 mg IV, to be repeated if the INR remains >1.4 at 24–48 h.56 If INR remains >1.4, four-factor PCCs are preferred to fresh frozen plasma. In patients receiving a DOAC, a specific antidote such as idarucizumab for dabigatran and andexanet alfa for Xa inhibitors

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Complications in Anticoagulated Patients with AF Figure 4: Whether to Interrupt and How to Interrupt for Vitamin K Antagonists

WHETHER TO INTERRUPT

Assess patient bleed risk checklist

Bleed risk considered increased if any 1 of the following: major bleed or ICH <3 months; quantitative or qualitative platelet abnormality, including aspirin use, INR above therapeutic range: prior bleed during previous bridging or similar procedure.

VKA THERAPY

CONSIDERATIONS

Yes

Procedural bleed risk? Not clinically important or low

Intermediate or high

Procedural bleed risk? Not clinically important or low

Uncertain

Perform the procedure uninterrupted.

GUIDANCE

Increased patient bleed risk?

Perform the procedure uninterrupted.

Use clinical judgment: Persistent concern for bleeding?

Exit the pathway.

Yes

INTERRUPT

CONSIDERATIONS

Uncertain

Insufficient data on best practices; likely interrupt but consult with proceduralists.

Exit the pathway.

GUIDANCE

Intermediate or high

INTERRUPT

WHEN TO INTERRUPT INR measurement 5–7 days prior to procedure? Supratherapeutic

Goal level (2.0 to 2.5 or 2.0 to 3.0)

Subtherapeutic

Discontinue ≥5 days before procedure depending on current INR, time to procedure, and desired INR for procedure; recheck INR 24 hours before procedure.

Discontinue 5 days before procedure depending on current INR, time to procedure and desired INR for procedure; recheck INR 24 hours before procedure.

Discontinue 3-4 days before procedure; recheck INR 24 hours before procedure if a normal INR is desired.

DOAC — direct oral anticoagulant ICH — intracranial hemorrhage INR — international normalized ratio VKA — vitamin K antagonist

CONTINUE TO

WHETHER TO BRIDGE

Credit: Reprinted from Doherty, et al. 2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients With Nonvalvular Atrial Fibrillation: A Report of the American College of Cardiology Clinical Expert Consensus Document Task Force. J Am Coll Cardiol. 2017;69:871–98. With permission from the Journal of the American Society of Cardiology.

are preferable, but if not available four-factor PCCs should be used. Protamine (1 mg for every 100 units of unfractionated heparin [UFH]) is used for unfractionated as well as for LMW heparin, and cryoprecipitate should be administered to patients who have received thrombolytics. Platelet transfusions are not recommended for patients who take antiplatelet agents, unless neurosurgical procedures are needed.56 Intensive treatment to lower the blood pressure with a target systolic level of <180 mmHg is recommended,57 but there has been evidence

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that values <160–140 mmHg may reduce haematoma enlargement and improve functional outcomes.58,59 After documentation of cessation of bleeding, low-dose heparin may be started 1–4 days from onset.57 The timing of resumption of oral anticoagulant is controversial (Figure 2). However, it may be started within 2 weeks since it is associated with a significant reduction in ischaemic stroke/all-cause mortality rates.60 DOAC are probably preferred if the haemorrhage happened on warfarin. In Asian patients, where the prevalence of intracranial haemorrhage is

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Clinical Arrhythmias Figure 5: Whether to Bridge and How to Bridge for Direct Oral Anticoagulants and Vitamin K Antagonists

WHETHER TO BRIDGE

CHA2DS2-VASc 1-4 (annualized stroke risk <5 %), no prior TE Moderate:

Type of anticoagulant? DOAC

Assess patient thrombotic risk definitions: Low:

CHA2DS2-VASc 5-6 (annualized stroke risk 5-10 %) or prior TE more than 3 months previously High: CHA2DS2-VASc 7+ (annualized stroke risk >10 %) or prior TE within 3 months

VKA

Thrombotic risk?

CONSIDERATIONS

Low

Recent TE <3 months?

Consider delaying procedure.

Yes

Exit the pathway.

No 1

Increased patient bleed risk?

Yes

Prior stroke or TIA?

Major bleed or ICH <3 months?

Bleed risk considered increased if any 1 of the following: major bleed or ICH <3 months; quantitative or qualitative platelet abnormality including aspirin use, INR above therapeutic range: prior bleed from previous bridging

High

Moderate

Yes

Assess patient bleed risk checklist

Yes

No Address other factors: ASA, high INR, Also consider bleed history.

GUIDANCE

Use of parenteral agent not indicated.

Likely bridge

Likely do not bridge

DO NOT BRIDGE

Likely bridge

Indication for bridging; strongly consider parenteral agent.

Likely do not bridge

USE CLINICAL JUDGMENT

BRIDGE

CONSIDERATIONS No

CrCl ≥30?

Heparin allergy or recent HIT? Yes

Administer therapeutic UFH or LMWH.

GUIDANCE

HOW TO BRIDGE

Yes

Use clinical judgment UFH Start UFH when the INR is <2 or after omitting 2-3 doses of the OAC if the INR is not measured. Discontinue >4 hours prior to the procedure and if the aPTT is the normal range.*

High stroke risk and increased bleed risk? Yes

Follow local protocol for management of HIT and heparin allergy.

Consider individualized strategies such as using prophylactic/low-dose parenteral anticoagulant, or postoperative bridging only.

LMWH Start LMWH when the INR is <2 or after omitting 2-3 doses of the OAC if the INR is not measured. Discontinue >12-24 hours prior to the procedure based on renal function and whether you are administering it once daily or q12 hours.

*if the aPPT is not in the normal range, delay the procedure and recheck the aPTT every 2 hours until it is in the normal range.

PERFORM THE PROCEDURE aPTT = activated partial thromboplastin time assay; ASA = acetylsalicylic acid (aspirin); DOAC = direct oral anticoagulant; HIT = heparin-induced thrombocytopenia; ICH = intracranial hemorrhage; INR = international normalised ratio; LMWH = low-molecular-weight heparin; OAC = oral anticoagulation; TE = thromboembolic event; TIA = transient ischemic attack; UFH = unfractionated heparin; VKA = vitamin K antagonist. Reprinted from Doherty, et al. 2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients With Nonvalvular Atrial Fibrillation: A Report of the American College of Cardiology Clinical Expert Consensus Document Task Force. J Am Coll Cardiol. 2017;69:871–98. With permission from the Journal of the American Society of Cardiology

much higher than in non-Asians, warfarin was found beneficial following an event only in patients with CHA2DS2-VASc score ≥6.61

Management of Bleeding Antidotes and general measures as discussed, are summarised in Table 5 and Figure 3. Recent data suggest that anticoagulation should be restarted following discharge after an episode of GI bleeding.62 However, this study was too small for definitive conclusions.

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Perioperative Anticoagulation Warfarin Usually major surgical procedures require an INR of at least <1.5. Warfarin has a half-life of 36–42 h and should be stopped for 3–4 days before surgery when the INR is <2 and 5 days when it is >2 (Figure 4).63 In urgent cases oral or IV vitamin K (1–2 mg) may be considered. In need of urgent reversal, prothrombin plasma concentrate may also be added, and is preferable to fresh frozen plasma.64 Bridging to UFH

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Complications in Anticoagulated Patients with AF Table 6: AHA/ACC 2017 Update of the 2014 Guidelines on Valve Disease. Bridging Therapy for Prosthetic Heart Valves Continuation of VKA with a therapeutic INR in patients with mechanical heart valves undergoing minor procedures (such as dental extractions or cataract removal).

I-C

Temporary interruption of VKA, without bridging agents while the INR is subtherapeutic, in patients with a bileaflet mechanical AVR and no other risk factors for thrombosis who are undergoing invasive or surgical procedures.

I-C

Bridging anticoagulation therapy during the time interval when the INR is subtherapeutic preoperatively on an individualized basis, with the risks of bleeding weighed against the benefits of thromboembolism prevention, for patients who are undergoing invasive or surgical procedures with a

IIa-C-LD

1) mechanical AVR and any thromboembolic risk factor, 2) older-generation mechanical AVR, or 3) mechanical MVR Fresh frozen plasma or prothrombin complex concentrate in patients with mechanical valves receiving VKA therapy for emergency noncardiac surgery or invasive procedures.

IIa-C

AVR = aortic valve replacement; INR = international normalised ratio; MVR = mitral valve replacement; VKA = vitamin K antagonist. Source: Nishimura, et al., 2017.79 Credit: American Heart Association, Inc

Table 7: EHRA 2015: Last Intake of Non-vitamin K Antagonist Oral Anticoagulant Before Elective Surgical Intervention No Important Bleeding Risk and/or Adequate Local Haemostasis Possible: Perform 12–24 h After Last Intake Dabigatran

Apixaban/Rivaroxaban

Low risk

High risk

Low risk

High risk

CrCI ≥80 ml/min

≥24

≥48

≥24

≥48

CrCI 50–80 ml/min

≥36

≥72

≥24

≥48

CrCI 30–50 ml/min

≥48

≥96

≥24

≥48

CrCI 15–30 ml/min

not indicated

≥36

≥48

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. Source: Katritsis, et al., 2016.Credit: p.589 Table 53.19, p.590 Table 53.20 & p.591 Table: 53.22 from Chapter 53 ‘Atrial Fibrillation’ from Clinical Cardiology: Current Practice Guidelines, Updated Edition by Katritsis, D.G., Gersh, B.J. & Camm, A.J. (2016). Free permission Author’s own material, appr. HPL. By permission of Oxford University Press.

ACC 2017: Recommended Durations for Withholding Direct Oral Anticoagulants Based on Procedural Bleed Risk and Estimated CrCI When There Are No Increased Patient Bleed Risk Factors CrCl, mL/min

Dabigatran

Apixaban, Edoxaban, Rivaroxaban

≥80 50–79 30–49 15–29 <15

≥30 15–29

Estimated drug half-life, h 13 15 18 27 30 (off dialysis) 6–15 Apixaban: 17 Edoxaban: 17 Rivaroxaban: 9

<15 Apixaban: 17 (off dialysis) Edoxaban 10–17 (off dialysis) Rivaroxaban: 13 (off dialysis)

Procedural bleed risk Low ≥24 h ≥36 h ≥48 h ≥72 h No data. Consider ≥24 h ≥36 h measuring dTT and/or withholding ≥96 h. Uncertain, intermediate, ≥48 h ≥72 h ≥96 h ≥120 h No data. Consider ≥48 h or high measuring dTT.

No data. Consider measuring agent-specific anti Xa level and/or withholding ≥48 h

No data. Consider measuring agentspecific anti Xa level and/or withholding ≥72 h.

NOTE: The duration for withholding is based upon the estimated direct oral anticoagulants’ half-life withholding times of 2 to 3 half-lives for low procedural bleeding risk and 4 to 5 drug halflives for uncertain, intermediate, or high procedural bleeding risk. CrCl = creatinine clearance; dTT = dilute thrombin time. Credit: Reprinted from Doherty, et al. 2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients With Nonvalvular Atrial Fibrillation: A Report of the American College of Cardiology Clinical Expert Consensus Document Task Force. J Am Coll Cardiol. 2017;69:871–98. With permission from the Journal of the American Society of Cardiology.

or LMWH that is discontinued ≥12 h before and restarted 24 h after the operation, has been recommended only in patients with certain mechanical heart valves and high risk of thrombosis (Figure 5 and Table 6). In a recent meta-analysis, however, heparin bridging for invasive procedures and surgery in patients receiving vitamin K antagonists for AF, prosthetic heart valves, or VTE conferred a greater than five-fold increased risk for bleeding, whereas the risk of thromboembolic events was not significantly different between bridged and non-bridged patients.65 The use of therapeutic dose LMWH

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was associated with an increased risk of bleeding compared with prophylactic or intermediate dose.65 Thus, bridging is not required, especially in patients at low risk of thrombosis.66–68 In the continuedwarfarin group, the INR in the day of surgery should be ≤3, except for patients with one or more mechanical valves, for whom an INR ≤3.5 or less is permitted (Bridge or Continue Coumadin for Device Surgery Randomised Controlled Trial [BRUISECONTROL] trial).67 In patients with AF, normal renal function and platelet count platelet count >100 × 109/L, even major surgery can be safely accomplished with warfarin

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Clinical Arrhythmias Figure 6: Whether to Interrupt, and How to Interrupt for Direct Oral Anticoagulants

CONSIDERATIONS

WHETHER TO INTERRUPT DOAC THERAPY

1 No

Increased patient bleed risk?

Yes

Procedural bleed risk? No clinically important risk

Low

Uncertain, intermediate, or high

GUIDANCE

Perform the procedure uninterrupted, but time it at DOAC interval trough

CONSIDERATIONS

INTERRUPT

GUIDANCE

Assess patient bleed risk checklist Bleed risk considered increased if any 1 of the following: major bleed or ICH <3 months; quantitative or qualitative platelet abnormality, including aspirin use; prior bleed during previous bridging.

INTERRUPT

Type of DOAC DTI

FXa inhibitor

WHEN TO INTERRUPT

Type of DOAC DTI

FXa inhibitor

Measure Crcl

CrCI <15 15-29 30-49 50-79 ≥80

Discontinue No data; consider dTT and/or ≥96 hrs. ≥72 hrs ≥48 hrs ≥36 hrs ≥24 hrs

CrCI <15

15-29 ≥30

Discontinue No data; consider anti Xa level and/or ≥48 hrs. ≥36 hrs ≥24 hrs

Crcl — creatinine clearance DTI — direct thrombin inhibitor (dabigatran) dTT — dilute thrombin time assay DOAC — direct oral anticoagulant

CrCI <15 15-29 30-49 50-79 ≥80

Discontinue No data; consider dTT. ≥120 ≥96 hrs ≥72 hrs ≥48 hrs

CrCI <30

≥30

Discontinue No data; consider anti Xa level and/or ≥72 hrs. ≥48 hrs

Insufficient data on best practices. Interrupt at least as long as determined by CrCI (Table 2) and possibly longer. Use clinical judgment.

PARENTERAL BRIDGING NOT INDICATED FOR DOACS.

FXa inhibitor — Factor Xa inhibitor (apixaban, edoxaban, rivaroxaban) ICH — intracranial hemorrhage INR — international normalized ratio VKA — vitamin K antagonist

Perform the procedure and continue to “How to Restart.”

cessation without bridging when the INR is <1.8 (Effectiveness of Bridging Anticoagulation for Surgery [BRIDGE] trial). Warfarin is then resumed the evening after the procedure.68 There are limited data on safety of cardiac surgery or other major surgery with a very high risk of thromboembolism and bleeding, in patients who are on warfarin. Currently, these patients are bridged with heparin prior to surgery. In the need of emergent coronary artery bypass grafting

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(CABG), fresh frozen plasma and vitamin K may be used to reduce the risk of bleeding.

Non-vitamin K Anticoagulants Preoperative interruption of DOAC depends on the risk of bleeding and renal function (Table 7 and Figure 6)52,63,69 In low-risk patients with normal renal function 24–48 h interruption of dabigatran and

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Complications in Anticoagulated Patients with AF 24 h interruption of Xa inhibitors is sufficient. In patients at high bleeding risk dabigatran is interrupted 120 h (CrCl <30 ml/min) to 48 h (CrCl >80 ml/min), and Xa inhibitors 72 h (CrCl <30 ml/min) to 48 (CrCl >30 ml/min).63 There has been recent evidence that continuation or short-interruption of DOAC are safe strategies for most invasive procedures.70 Bridging with heparin is, on most occasions, not necessary and may increase the risk of bleeding.70 In an analysis of data from the Randomised Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, interruption of dabigatran (2 days) or warfarin (5 days) for allowance of surgery was not associated by a significant occurrence of stroke and systemic embolism although heparin bridging was used in <80 % of patients on dabigatran, and major bleeding was not different in the two treatment groups.71 However, discontinuation of rivaroxaban in the ROCKET AF trial for at least 3 days was associated with a higher incidence of stroke compared to discontinuation of warfarin.72 Thus, in patients with a CHADS2DS2VASC score >4, i.e. >5 % annual risk of stroke, bridging therapy with LMWH should be considered. Procedures with low haemorrhagic risk (dental extraction, skin biopsy, cataract surgery) can be safely performed without interruption of NOACs, especially if carried out 12 h after last dosing. For pacemaker and ICD implantation a 24-h discontinuation with re-initiation 48 h after implantation (24 h in patients with a CHADS2DS2VASC score >4) is recommended.73,52 If urgent surgery or intervention is required, the risk of bleeding must be weighed against the clinical need for the procedure. Dilute TT for

10.

11.

12.

13.

14.

15.

iccini JP, et al. Clinical course of atrial fibrillation in older P adults: the importance of cardiovascular events beyond stroke. Eur Heart J 2014;35:250–6. DOI: 10.1093/eurheartj/ eht483; PMID: 24282186. Santangeli P, et al. Atrial fibrillation and the risk of incident dementia: a meta-analysis. Heart Rhythm. 2012;9:1761-8. DOI: 10.1016/j.hrthm.2012.07.026; PMID: 22863685 Sposato LA, et al. Diagnosis of atrial fibrillation after stroke and transient ischaemic attack: a systematic review and meta-analysis. Lancet Neurol 2015;14:377–87. DOI: 10.1016/ S1474-4422(15)70027-X; PMID: 25748102. Lubitz SA, et al. Genetic risk prediction of atrial fibrillation. Circulation 2016. 135;14:1311-20. DOI: 10.1161/ CIRCULATIONAHA.116.024143; PMID: 27793994. Wolf PA, et al. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22:983–8. PMID: 1866765. Quinn GR, et al. Wide variation in reported rates of stroke across cohorts of patients with atrial fibrillation. Circulation 2016. DOI: 10.1161/CIRCULATIONAHA.116.024057; PMID: 27799272. Christiansen CB, et al. Atrial fibrillation and risk of stroke: a nationwide cohort study. Europace 2016;18:1689–97. DOI: 10.1093/europace/euv401; PMID: 26838693. Freedman B, et al. Screening for atrial fibrillation: A Report of the AF-SCREEN International Collaboration. Circulation 2017;135:1851–67. DOI: 10.1161/ CIRCULATIONAHA.116.026693; PMID: 28483832. Yiin GS, et al. Age-specific incidence, outcome, cost, and projected future burden of atrial fibrillationrelated embolic vascular events: a population-based study. Circulation 2014;130:1236–44. DOI: 10.1161/ CIRCULATIONAHA.114.010942; PMID: 25208551. Bekwelem W, et al. Extracranial systemic embolic events in patients with nonvalvular atrial fibrillation: incidence, risk factors, and outcomes. Circulation 2015;132:796–803. DOI: 10.1161/CIRCULATIONAHA.114.013243; PMID: 26224811. Soliman EZ, et al. Atrial fibrillation and risk of ST-segmentelevation versus non-ST-Segment-elevation myocardial infarction: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation 2015;131:1843–50. DOI: 10.1161/ CIRCULATIONAHA.114.014145; PMID: 25918127. Shibata T, et al. Prevalence, clinical features, and prognosis of acute myocardial infarction attributable to coronary artery embolism. Circulation 2015;132:241–50. DOI: 10.1161/ CIRCULATIONAHA.114.015134; PMID: 26216084. Roldan V, et al. Predictive value of the HAS-BLED and ATRIA bleeding scores for the risk of serious bleeding in a “real-world” population with atrial fibrillation receiving anticoagulant therapy. Chest 2013;143:179–84. DOI: 10.1378/ chest.12-0608; PMID: 22722228. O’Brien EC, et al. The ORBIT bleeding score: a simple bedside score to assess bleeding risk in atrial fibrillation. Eur Heart J 2015;36:3258–64. DOI: 10.1093/eurheartj/ehv476; PMID: 26424865. Lip GY. How to manage occult atrial fibrillation detected on

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16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

dabigatran and anti-Xa assays for rivaroxaban and apixaban are used to assess anticoagulant activity. aPTT and PT may also be used as rough estimates of the anticoagulant activity of dabigatran and rivaroxaban, respectively.28 Sensitive PT may be used as a rough estimate of the antocoagulation intensity of all FXa inhibitors. Specific coagulation test (dTT for dabigatran; chromogenic assays for FXa inhibitors) can also be considered, but no clinical experience exists.52 Surgery or intervention should be deferred, if possible, until at least 12 h and ideally 24 h after the last dose. Non-specific antihaemorrhagic agents, such as recombinant human activated factor VIIa or prothrombin complex concentrates should not be given for prophylactic reversal due to their uncertain benefit-risk.74 Re-initiation of these agents should be delayed for 24–48 h and once complete haemostasis is assured, since within 1–2 h of re-initiation the patient will be anticoagulated. For procedures with immediate and complete haemostasis NOACs can be resumed 6–8 h after the intervention.52 n

Clinical Perspective • Patients on anticoagulation for atrial fibrillation are still at risk of ischaemic stroke, and may also develop haemorrhagic complications. • Prompt diagnosis and therapy is necessary for these conditions. • Specific antidotes are now available for the new, direct oral anticoagulants.

long-term monitoring. Circulation 2016;133:1290–95. DOI: 10.1161/CIRCULATIONAHA.115.016797; PMID: 27022040. Friberg L, et al. Benefit of anticoagulation unlikely in patients with atrial fibrillation and a CHA2DS2-VASc score of 1. J Am Coll Cardiol 2015;65:225–32. DOI: 10.1016/j. jacc.2014.10.052; PMID: 25614418. Lip GY, et al. Oral anticoagulation, aspirin, or no therapy in patients with nonvalvular AF with 0 or 1 stroke risk factor based on the CHA2DS2-VASc score. J Am Coll Cardiol 2015;65:1385–94. DOI: 10.1016/j.jacc.2015.01.044; PMID: 25770314. Lip GY, et al. Stroke prevention in atrial fibrillation: a systematic review. JAMA 2015;313:1950–62. DOI: 10.1001/ jama.2015.4369; PMID: 25988464. Andreotti F, et al. Antithrombotic therapy in the elderly: expert position paper of the European Society of Cardiology Working Group on Thrombosis. Eur Heart J 2015;36:3238-3249. DOI: 10.1093/eurheartj/ehv304; PMID: 26163482. Kovacs RJ, et al. Practical management of anticoagulation in patients with atrial fibrillation. J Am Coll Cardiol 2015;65:1340–60. DOI: 10.1016/j.jacc.2015.01.049; PMID: 25835447. Connolly SJ, et al. Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range. Circulation 2008;118:2029–37. DOI: 10.1161/ CIRCULATIONAHA.107.750000; PMID: 18955670. Apostolakis S, et al. Factors affecting quality of anticoagulation control among patients with atrial fibrillation on warfarin: the SAMe-TT(2)R(2) score. Chest 2013;144:1555– 63. DOI: 10.1378/chest.13-0054; PMID: 23669885. Guyatt GH, et al. Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:7S–47S. DOI: 10.1378/chest.1412S3; PMID: 22315257. Garcia DA, et al. Reversal of warfarin: case-based practice recommendations. Circulation 2012;125:2944–7. DOI: 10.1161/ CIRCULATIONAHA.111.081489; PMID: 22689931. Sarode R, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasmacontrolled, phase IIIb study. Circulation 2013;128:1234–43. DOI: 10.1161/CIRCULATIONAHA.113.002283; PMID: 23935011. Holbrook A, et al. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e152S–184S. DOI: 10.1378/chest.11-2295; PMID: 22315259. Weitz JI, et al. Urgent need to measure effects of direct oral anticoagulants. Circulation 2016;134:186–8. DOI: 10.1161/ CIRCULATIONAHA.116.022307; PMID: 27436877. Cuker A, et al. Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol 2014;64:1128–39. DOI: 10.1016/j.jacc.2014.05.065; PMID: 25212648.

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Clinical Arrhythmias

At the Atrioventricular Crossroads: Dual Pathway Electrophysiology in the Atrioventricular Node and its Underlying Heterogeneities Sharon A George, 1 N Rokhaya Faye, 1 Alejandro Murillo-Berlioz, 1,2 K Benjamin Lee, 1,2 Gregory D Trachiotis 2 and Igor R Efimov 1 1. Department of Biomedical Engineering, The George Washington University, Washington, DC, USA; 2. Division of Cardiothoracic Surgery and Cardiothoracic Research, Veterans Affairs Medical Center, Washington, DC, USA

Abstract The atrioventricular node (AVN) is a complex structure that performs a variety of functions in the heart. The AVN is primarily an electrical gatekeeper between the atria and ventricles and introduces a delay between atrial and ventricular excitation, allowing for efficient ventricular filling. The AVN is composed of several compartments that safely transmit electrical excitation from the atria to the ventricles via the fast or slow pathways. There are many electrophysiological differences between these pathways, including conduction time and electrical refractoriness, that increase the predisposition of the atrioventricular junction to arrhythmias such as atrioventricular nodal re-entrant tachycardia. These varied electrophysiological characteristics of the fast and slow pathways stem from their unique structural and molecular composition (tissue and cellular geometry, ion channels and gap junctions). This review summarises the structural and molecular heterogeneities of the human AVN and how they result in electrophysiological variations and arrhythmias.

Keywords Atrioventricular junction, dual-pathway electrophysiology, connexin, optical mapping, ion channels Disclosure: The authors have no conflicts of interest to declare. Received: 22 August 2017 Accepted: 2 November 2017 Citation: Arrhythmia & Electrophysiology Review 2017;6(4):179–85. DOI: 10.15420/aer.2017.30.1 Correspondence: Igor Efimov, The George Washington University, 800 22nd Street NW, Washington, DC 20052, USA. E: efimov@gwu.edu

More than 100 years have passed since the atrioventricular node (AVN) was first discovered by Sunao Tawara1 and described as a “Knoten” of tissue located at the proximal end of the Bundle of His (BoH).2 Despite the numerous advances in knowledge regarding the structure and function of the AVN, there are still several controversies that need to be addressed in both clinical and scientific settings. The AVN is located in the paraseptal endocardium of the right atrium, at the apex of the Triangle of Koch, formed by the ostium of the coronary sinus, the tendon of Todaro and the tricuspid valve.3 Morphologically, the AVN can be subdivided into the lower nodal bundle and compact node (CN). From the lower nodal bundle, the rightward inferior nodal extension (INE) spreads along the tricuspid valve toward the coronary sinus and the leftward nodal extension spreads from the CN along the Tendon of Todaro.4 Similar to the sinoatrial node, AVN has the potential for pacemaker activity; however, there are significant differences between the activities of the two nodes. The normal AVN firing rate is 20–60 bpm compared with the 60–100 bpm of the sinoatrial node. 5 One unique characteristic of pacemaker cells in the sinoatrial node and AVN is the process of diastolic depolarisation. An increased permeability to cations slowly depolarises the cell membrane. When the membrane potential rises and reaches the threshold for activation of the “funny current” (I f), Na + and K+ permeability increase, which then triggers an action potential (AP). The upstroke of the AP is mainly due to Ca 2+ influx, as opposed to myocytes where Na + plays a crucial role during upstroke. Finally, K+ efflux is responsible for repolarisation. 6,7

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It has been well established that there are two functional conduction pathways in the atrioventricular junction: the slow pathway (SP) and the fast pathway (FP).8–12 The presence of these dual pathways was suggested as early as 1909, as evidenced by the dual AV nodal structure illustrated in DeWitt’s 3D wax reconstruction of the conduction system (Figure 1A).13 Anatomically, the SP is located in the INE while the anatomical substrate for the FP is less well defined. It is has been postulated to be in the transitional cell (TC) layers around the CN.14 Under normal conditions, excitation travels anterogradely through both the FP and SP. The wavefront through the FP reaches the BoH earlier than that through the SP due to the difference in anatomical distance and excites this region. The wavefront through the SP then reaches the refractory tail of the FP and is annihilated. This conduction pathway is illustrated in Figure 1B.15,16 Atrioventricular nodal re-entrant tachycardia (AVNRT) is the most common supraventricular tachycardia, accounting for greater than 50 % of all supraventricular tachycardias.17,18 It results from the formation of re-entry circuits between the AVN, at least two atrionodal connections or pathways, and a component of the atrial myocardium. The two atrionodal pathways, FP and SP, have historically been used to classify the type of AVNRT as SP-FP, FP-SP or SP-SP, depending on the direction of the re-entrant circuit and pathways involved.19 However, this classification could lead to confusion as these anatomical pathways are not consistent between patients. A newer approach to classify AVNRT was implemented by Katritsis and Josephson,18 depending on conduction times between the atria, BoH and ventricles. Briefly, AVNRT is classified as typical (SP-FP) or atypical (FP-SP, SP-SP).

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Clinical Arrhythmias Figure 1: Dual Pathway Electrophysiology of AVN SP

SP Atrium

Atrium

FP BoH Normal beat (S1)

BoH Premature beat (S2)

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(A) Stereoscope photograph of a wax 3D model by Lydia DeWitt13 showing dual AVN pathways. (B) Dual pathways of electrical wavefront propagation between the atria and BoH during normal beat (left) and during a premature beat (right) resulting in a re-entrant arrhythmia. AVN = atrioventricular node; BoH = Bundle of His; FP = fast pathway; SP = slow pathway. Acknowledgement: DeWitt L. Observations on the sino-ventricular connecting system of the mammalian heart. Anat Rec 1909;3:475–97. DOI: 10.1002/ar.1090030902. Copyright: Wiley

Most episodes of AVNRT will terminate with simple vagal maneuvres or pharmacological agents such as adenosine or non-dihydropyridine calcium channel blockers (verapamil and diltiazem).19 For chronic, recurrent arrhythmia, transcatheter ablation is a well-accepted technique that uses a minimally invasive method to ablate the lesions at the inferior or midpart of the triangle of Koch.20 In modern literature, this method has success rates of 93–98 % without recurrence.20–22 Many studies have identified the underlying molecular and structural causes for AVNRT and the efficacy of ablating the SP. This review summarises the structural, molecular and functional differences between the dual AVN pathways in humans.

Structural Heterogeneity The components of the AVN are morphologically different in terms of cell shape, cell size and myofibril density. Of these factors, cell shape and size have previously been reported to alter electrophysiological variables such as conduction velocity (CV). Briefly, larger cells promote faster macroscopic CV through a given region and vice versa. The morphological heterogeneity in the AVN cells could partly account for the dual pathway electrophysiology. Studies on human AVN cells have reported two cell types within the AVN and the surrounding tissue. The FP is composed of longer cells of larger diameter while the SP is composed of shorter cells that have smaller diameter. Additionally, the number of myofibrils in the SP closer to the coronary sinus is less and progressively increases toward the CN. The cells in the CN were also reported to show fewer striations relative to surrounding cells. In contrast, the BoH is composed of elongated cells. Cellular morphology is also closely linked to intercalated discs that are cell–cell junctions with several important cellular coupling proteins. While the atrial myocytes (AM) and ventricular myocytes (VM) are composed of long, brick-shaped cells with many bifurcations and highly developed intercalated discs, the AVN cells have fewer bifurcations with underdeveloped intercalated discs.

Molecular Heterogeneity Gap Junctions Intercellular electrical coupling at the intercalated discs is achieved through gap junctions, which form pores that connect neighboring myocytes and allow for electrical and chemical communication between them. Gap junctions are hexameric protein structures that are formed by connexins (Cx) and their conductance varies depending on the Cx isoform.23–25 In the AVN, the most commonly expressed isoforms are Cx40 (large conductance) and Cx43 (medium conductance), followed

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by a relatively low-level expression of Cx45 (small conductance) and possibly Cx30.2/31.9 (ultra-small conductance).26 The AVN has a very complex yet unique distribution of these various Cx isoforms that facilitate its numerous functions. Several groups have studied Cx expression patterns in the human AVN.11,27,28 Total protein and mRNA levels of Cx40, Cx43 and/or Cx45 were assessed qualitatively and quantitatively in these studies. Representative Cx43 immunolabelled sections are shown in Figure 2B, alongside their serially sectioned histological images (Figure 2A). AM and the BoH express both Cx43 and Cx40 proteins and mRNA in large levels. These Cx proteins are also expressed in TC, albeit at lower levels. The CN, however, has very high Cx40 expression with almost no Cx43. Penetrating bundle (PB) cells express large amounts of Cx40 but low levels of Cx43. INE also has high Cx40 expression; however, Cx43 expression in INE is different in the left nodal extension compared with the right nodal extension. Although the right nodal extension is usually longer in humans and has more Cx43, the left nodal extension is shorter (sometimes absent) and has very low C43 expression. The left nodal extension connects to the CN and forms a substrate for very slow conduction that could potentially sustain re-entrant arrhythmias within the AVN. Interestingly, the left nodal extension was also reported to be longer in pathological states such as dilated cardiomyopathy.11,27,28 The expression profile for Cx43 in the human AVN is shown in Figure 2C. To summarise, although Cx43 is highly expressed in the atrial and ventricular myocardium, its expression levels progressively drop off as we move into the central AVN region. In contrast, Cx40 is highly expressed in the AVN region and its expression levels drop off as we move away from the nodal cells to the AM and VM. Therefore, the expression profile of Cx40 is roughly opposite to that of Cx43. Finally, Cx45 and Cx30.2/31.9 are ubiquitously expressed at very low levels or are not present in the AVN.29 This heterogeneous expression pattern of Cxs within the AVN has several functional consequences. While on a larger scale, conduction slows within the AVN, resulting in AV delay, heterogeneous Cx expression is associated with dual-pathway electrophysiology. The dual pathways (FP and SP) paradoxically support relatively slower and faster conduction of electrical excitation, respectively. Conduction velocity is slower along the FP with lower Cx43 expression, and vice versa. Interestingly, higher Cx40 expression within the AVN does not correspond to faster CV. This could be due to a number of reasons, such as: (1) even though Cx40 protein is present, it may not form functional gap junction channels; or (2) conduction is further modulated by other ion channel protein expression and function.

Ion Channels Each different cell type in the AV junction has its own electrical signature, that is, its AP. The AP morphology, duration and propagation are a result of the unique ion channel expression profile of the underlying tissue. The AVN, with its multiple cell types, is thus a collage of ion channel proteins and the expression profile of this complex structure is detailed below and summarised in Figure 3.

HCN Channels The hyperpolarisation-activated channels or HCN channels are responsible for the “funny current” (If) in pacemaker cells and account for the automaticity of these cells.30,31 In the AVN AP, they contribute to the diastolic depolarisation phase. Four isoforms, HCN1, HCN2, HCN3 and HCN4, are present in the human AVN.32 Of these, HCN4 is the

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At the Atrioventricular Crossroads: Dual Pathway Electrophysiology Figure 2: AVN Cx43 Expression Profile Superior

Cx43

His

CFB

BoH

300 µm Cx43

LNB

CFB Cx43

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His

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TC CFB

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Mid Cx43

Low Cx43

Serial sections processed for (A) histology and (B) Cx43 immunolabelling from the human AVN taken from three separate planes.11 (C) These planes of sectioning are indicated by the blue lines in the Cx43 expression profile schematic. AM = atrial monocytes; AVN = atrioventricular node; BoH = Bundle of His; CFB = central fibrous body; CN = compact node; Cx = connexin; INE = inferior nodal extension; L = leftward extension; LNB = lower nodal bundle; R = rightward extension; TC = transitional cells; TV = tricuspid valve; VM = ventricular monocytes; VS = ventricular septum. Acknowledgement: Hucker WJ, McCain ML, Laughner JI, et al. Connexin 43 expression delineates two discrete pathways in the human atrioventricular junction. Anat Rec 2008;291:204–15. http://onlinelibrary.wiley.com/doi/10.1002/ar.20631/full

most abundant isoform. HCN4 mRNA was significantly higher in the CN, INE and PB cells relative to AM and VM, where they were mostly absent. HCN4 protein was also demonstrated to be upregulated in the CN and localised at the sarcolemma of these cells. HCN1 mRNA was predominantly expressed in the CN but its levels were low elsewhere. HCN2 and HCN3 were uniformly expressed throughout the myocardium and AVN cells; however, the latter was expressed at very low levels.27,28

Figure 3: AVN Ion Channel Expression Profile

AVN - AM AVN - VM Atrial layer

AVN

Sodium Channels Sodium channels are responsible for the fast upstroke of the AP and excitation of the myocytes. Several isoforms of sodium channels are expressed in the human heart and in the AVN region.33 Mutations in sodium channels result in AVN arrhythmias such as AVN block.34 Nav1.5 is the most abundantly expressed sodium channel isoform in the heart. The expression of Nav1.5 at the protein and mRNA level is high in AM and VM, very low to absent in the CN and INE and intermediate in the connecting layers of TC and PB.27,28 The neuronal sodium channel Nav1.1 is also expressed in the AVN cells and is most highly expressed in the INE and PB cells. It is uniformly distributed at lower levels through other cell types. Finally, studies have also reported low-level mRNA expression of Nav1.3, Nav1.4, Nav1.6 and Nav1.7.27,28 In the absence of a large sodium channel density in the AVN region, other ion channels such as calcium channels take over the cellular excitation and contribute to the upstroke of the AP.35

Tbx3 HCN1 Nav1.5 Cav1.2 Cav1.3 Cav3.1 NCX1 RyR2 Kv1.5 ERG Kir3.1

CFB

TV VS

Calcium Channels Calcium channels are the major drivers of depolarisation in the pacemaker cells of the AVN and sinoatrial node.35,36 The slow influx of calcium ions through voltage-gated calcium channels gives the AVN APs their characteristic slow upstroke. Two types of calcium channels are present in the AVN: L-type and T-type calcium channels.

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2 mm The expression levels of various ion channel mRNAs in the AM, AVN and VM. The table indicates the change in the given mRNA between the AVN and the AM and VM. AM = atrial monocytes; AVN = atrioventricular node; CFB = central fibrous body; TV = tricuspid valve; VS = ventricular septum.

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Clinical Arrhythmias Figure 4: Conduction Through the Dual AVN Pathways A

1.26 mV

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(A) Electrograms11 showing different conduction delays from the atria through FP or SP to BoH during a basic versus premature beat, highlighting the heterogenic electrophysiology of the dual AVN pathways. (B) Activation pattern during a regular beat showing atrial excitation (left), dual AVN pathway excitation (middle) and BoH excitation (right).16 (C) Activation pattern during a reentrant arrhythmia that propagates retrogradely through FP (left) and anterogradely through SP (right) as indicated by white dotted lines.16 AVN = atrioventricular node; BoH = Bundle of His; CS = coronary sinus; EGM = electrogram; FP = fast pathway; IAS = interatrial septum; IVS = interventricular septum; SP = slow pathway; TA = tricuspid valve annulus. Acknowledgements: (A) Hucker WJ, McCain ML, Laughner JI, et al. Connexin 43 expression delineates two discrete pathways in the human atrioventricular junction. Anat Rec 2008;291:204–15. http://onlinelibrary.wiley.com/doi/10.1002/ar.20631/full; (B,C) Fedorov VV, Ambrosi CM, Kostecki G, et al. Anatomic localization and autonomic modulation of atrioventricular junctional rhythm in failing human hearts. Circ Arrhythmia Electrophysiol 2011;4:515–25. http://circep.ahajournals.org/content/circae/4/4/515.full.pdf

The expression profiles of their various isoforms are summarised in Figure 3. These channels are responsible for the L-type and T-type calcium currents (ICa,L and ICa,T), respectively. Cav1.2, an L-type calcium channel, is the most abundantly expressed calcium ion channel in the AM and VM. It is also expressed in the AVN cells but at much lower levels.28,37 In the absence of sodium channels, it has been theorised that ion channels with a more negative activation threshold are required for cellular excitation. Cav1.3, another L-type calcium channel, meets this requirement.38 Cav1.3 mRNA is expressed at significantly higher levels in the human AVN, particularly in the INE, CN and PB regions, relative to AM and VM.27,28 Together, Cav1.2 and Cav1.3 contribute to ICa,L in the AVN.

proposed that the purpose of calcium handling proteins in AVN (and sinoatrial node) cells is primarily to regulate the calcium clock and the pacemaking function of these cells.40 The level of sodium calcium exchanger isoform 1 mRNA was reported to be similar in AVN tissue relative to AM and VM; however, there was a slight upregulation in the CN and a small downregulation in the INE regions specifically.27,28 The sarcoplasmic reticulum calcium release and uptake channel expression was also previously investigated. While Greener et al.28 reported a lower abundance of ryanodine receptor 2 in AVN cells versus myocytes, Dobrzynski et al.27 reported an increase in ryanodine receptor 2 mRNA but a decrease in ryanodine receptor 2 protein in human AVN relative to VM. Ryanodine receptor 3 mRNA expression was higher in the TC and INE cells but similar elsewhere. Finally, the expression of the sarcoplasmic reticulum calcium pump SERCA2a mRNA was uniform throughout the AM, VM and AVN cells.27,28

Potassium Channels Potassium channels are responsible for repolarisation of the cardiac cells. Based on the specific current they contribute to, they can be divided into three components: transient outward potassium current (Ito), delayed rectifier currents and inward rectifier current (IK1).41 Ito is responsible for the repolarisation during phase 1 of the AP. The major contributor to Ito in humans is voltage-dependent potassium channel Kv4.3.35,42 The expression of Kv4.3 mRNA in the human AVN is similar to the working myocardium. Other Ito contributors, such as Kv1.4 and Kv4.2, have significantly higher expression in the CN and PB relative to the working myocardium.27,28 Delayed rectifier potassium currents are ––of three types: ultra-rapid delayed rectifier (IK,ur), rapid delayed rectifier (IK,r) and slow delayed rectifier (IK,s). The ion channels associated with these currents are Kv1.5, human ether-a-go-go (hERG) and KvLQT (the LQT-like subfamily of voltage gated potassium channels), respectively.41,43 Kv1.5 mRNA expression was high in the AM but very less in the AVN cells and VM. hERG mRNA expression in the AM, AVN cells and VM were reported to be uniform by Greener et al.28 but Dobrzynski et al.27 reported that hERG mRNA expression was significantly higher in VM. Finally, KvLQT was uniformly expressed in AM, VM and all AVN regions except for the INE where it was significantly reduced.27,28 IK1 is responsible for maintaining the resting membrane potential (RMP) in most cardiac cells. However, the major IK1 ion channel, Kir2.1, is significantly reduced in the AVN, which could account for its more positive RMP.27,28,44,45 Other potassium channel isoforms responsible for IK1 are more uniformly distributed in the AM, AVN and VM.27,28

Autonomic Nervous System

Calcium Handling Proteins

Both sympathetic and parasympathetic nervous systems exert control over the AVN.16,46 Sympathetic innervation is achieved through the beta-adrenergic receptors (AR), which when stimulated can increase the rate of junctional rhythm in the human AVN.16 The mRNA of the two most commonly expressed beta-AR isoforms, beta1-AR and beta2-AR, are expressed throughout the AVN region at similar levels. The expression profile is mostly uniform between the AM, VM and AVN regions, except for a slightly lower abundance of beta1-AR expression in the PB and beta2-AR expression in the INE.27,28

In the working myocardium, the primary purpose of calcium handling proteins in the cells is for facilitating contraction. However, this is not the case in the nodal and conduction system cells. It has been

Parasympathetic innervation in the human AVN is achieved by the activation of the acetylcholine-activated potassium channel current

Cav3.1 and Cav3.3 are the major T-type calcium ion channels in the human AVN. Cav3.2 mRNA was reported to be undetectable in the human heart.39 Cav3.1 is highly expressed in the AVN, particularly in CN, PB and INE cells, at levels significantly higher than in AM and VM.27,28 Cav3.3 has a more uniform distribution through the AVN region and its expression is also comparable to AM and VM.27,28

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At the Atrioventricular Crossroads: Dual Pathway Electrophysiology Figure 5: Schematic of the AVN FP and SP Superior

BoH

Posterior

(IK,Ach). These channels are heteromers that are formed by the Kir3.1 and Kir3.4 potassium channel isoforms and are upregulated in the CN and PB cells.27,28 This could be an indication of the importance of parasympathetic stimulation of the AVN. Activation of the IK,Ach channels can then reduce AV junctional rhythm rate in the AVN.16

Inferior

Thus, the AVN is under very tight autonomic control that can modulate its conduction and pacemaking properties, which determine AV delay and AV functional rhythm, respectively. Therefore, even though it is not the lead pacemaker in a healthy heart, autonomic control of the AVN is crucial to maintain normal conduction delays (<0.1 ms) that allow sufficient time for ventricular filling and also prevent re-entrant arrhythmias.16,47

CFB

CN VM

NB LNB

In addition to AV junctional rhythm rate, autonomic innervation can alter the lead pacemaker site within the human AVN.16 It has been reported that during control conditions, the intrinsic pacemaker site is at the proximal end of the BoH. When the AVN is treated with isoproterenol (sympathetic stimulation), the leading pacemaking site shifts to the CN region. This could be a result of the heterogeneous beta-ARs in this region. Similarly, when the human AVN is treated with acetylcholine (parasympathetic stimulation), the leading pacemaker site shifts to the TC area.

AM TT

TC ToK K CS

Functional Heterogeneity The vast differences in molecular profiles of the AVN and its surrounding region underly the complex electrophysiological heterogeneities of the human AVN. The pacemaking capability, dual conduction pathways, refractory period variations and the other specialised functions and characteristics of the AVN stem from its unique structural and molecular composition. A few of these distinct features are discussed in detail here.

Action Potential The differences in ion channel expression can result in differing AP morphologies in various compartments of the AVN. This morphological variation was observed by optical mapping of the human AVN.15,16 These AP morphologies closely match those recorded by patch clamping of the rabbit AVN, which also reported varying RMP and even major ionic currents contributing to the AVN AP.44 For example, while the AM and VM RMPs were more negative, the AVN cells had an RMP of around –50 mV. TC, which are intermediate cells between AM and AVN cells, had an RMP similar to atrial cells (–70 mV) whereas PB cells have an RMP closer to that of CN cells. These RMP variations closely follow the expression of the IK1 channels, which are responsible for maintaining a negative RMP. These channels are greatly downregulated in CN cells. The maximum rate of rise of the action potential (dV/dtmax) was also different between these cells.44 The expression profile of sodium and calcium ion channels underlie this phenomenon. Specifically, in AM and VM, which have higher Nav1.5 expression levels and INa as the major depolarising current, a much higher dV/dtmax (80–100 V/s) was recorded. In contrast, in AVN cells with very low Nav1.5 and high Cav3.1 expression, ICa,L is the major depolarising current. This results in a small dV/dtmax (4–6 V/s) and gives the AVN cells their characteristic slow AP upstroke. TC cells had an intermediate dV/dtmax (22 V/s), possibly due to a mix of both types of currents.

NE INE

FP SP Re-entry path

Summary of the various anatomical structures that constitute the AVN and its dual conduction pathways: FP and SP. Dashed red lines indicate speed of conduction through the various structures, closely spaced lines indicate slower conduction velocity and widely space lines indicate faster conduction velocity. Varying action potential morphology schematised in purple. SP-FP reentrant pathway highlighted by orange arrow. AM = atrial myocytes; AVN = atrioventricular node; BoH = Bundle of His; CFB = central fibrous body; CN = compact node; CS = coronary sinus; FP = fast pathway; INE = inferior nodal extension; LNB = lower nodal bundle; SP = slow pathway; ToK = Triangle of Koch; TT = tendon of Todaro; TV = tricuspid valve; VM = ventricular myocytes.

Phase 2 or the plateau phase was not very pronounced in these APs. AP duration heterogeneity was possibly due to the delayed rectifier potassium channel distribution, specifically hERG. However, TC and PB cells had AP durations closer to that of AM.

Refractoriness Another important electrophysiological difference within the different regions of the AVN is refractoriness or the time interval after an AP over which the cell cannot be re-excited. It has been demonstrated that the components of the SP have a shorter refractory period than those of the FP.48,49 One interesting result of this property was previously reported by electrograms recorded from the human AVN illustrated in Figure 4A.15 During atrial pacing using an S1S2 protocol, electrograms were recorded from the BoH. At shorter S2 intervals, the amplitude of the BoH electrogram was reduced and the delay between S2 and the recorded electrogram was increased. This indicates the switch in the conduction path from FP to SP at shorter pacing intervals, due to prolonged refractoriness of the FP. It also suggests the presence of two different compartments in the proximal BoH, which produce His electrograms of different amplitudes (FP: 1.26 mV versus SP: 0.14 mV).

Conduction Velocity Finally, AVN cells also had significantly shorter AP durations relative to AM and VM (113 ms relative to 155 or 215 ms, respectively).44

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The AVN acts as the gatekeeper of electrical excitation between the atrial and ventricular tissue. Due to its unique ion channel and gap

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Clinical Arrhythmias junctional expression profiles, the conduction of electrical excitation is slow in the AVN relative to the working myocardium.16 Additionally, there is CV heterogeneity even within the compartments of the AVN.10,15,16 The various molecular heterogeneities described above underlie these differences and give rise to the FP and SP of AVN conduction. During a normal beat, atrial excitation precedes AVN excitation as shown in Figure 4B (Left). The excitation wavefront then moves through the AVN, anterogradely through both the FP and SP (Figure 4B, Middle); however, excitation reaches the BoH earlier through the FP relative to the SP. This is then followed by BoH activation (Figure 4B, Right) and eventually ventricular activation.16 It is crucial to state here that the terminology of FP and SP does not refer to the CV through these structures. Paradoxically, the FP, which includes the TC and CN, is associated with slower CV relative to the SP which includes the INE. The terminology arises from the conduction delay through these structures. For example, even though CV is relatively faster through the SP, due to its increased anatomic dimension, it takes longer for excitation to reach the BoH through this pathway. Similarly, CV is slower through the FP but due to its shorter dimension, excitation reaches the BoH more quickly through this pathway.50

Arrhythmias Abnormal activation sequences or rhythms through this complex nodal structure can result in the development of a re-entrant rotor within the dual conduction pathway of the AVN. This then gives rise to arrhythmias such as AVNRT.16 Optical mapping of the AVN during an SP-FP AVNRT episode is demonstrated in Figure 4C where the wavefront propagates retrogradely up the FP and then anterogradely through the SP. Other types of arrhythmias such as AV block can be a result of ion channel mutations.34 In these cases, the propagation

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of electrical excitation between the atria and the ventricles is either completely or partially blocked.

Summary The schematic in Figure 5 illustrates the complex electrophysiological heterogeneities of the AVN, which include a dual conduction pathway involving varying CVs through the AVN and markedly different AP morphologies. The FP is the route of excitation wavefront propagation during a regular beat whereas the SP overtakes in the case of a premature beat or other AVN defects. This can then generate AVN arrhythmias such as AVNRT in which the excitation wavefront is trapped between the FP and SP and triggers excitation into the atria and BoH at a faster rate (tachycardia). This review highlights some of the key structural and molecular variants that underlie this complex electrophysiology and its predisposition to arrhythmias due to slight variations in normal activity. Concluding in the words of the poet Robert Frost, ‘I [conduction] took the road [pathway] less travelled by, And that has made all the difference [arrhythmia].’ n

Clinical Perspective • C haracterisation of atrioventricular node morphology will allow for the development of more efficient targeted pharmacological therapy for different types of arrhythmias. • Better understanding of the electrophysiological pathways in the heart is crucial in developing precise diagnostic and ablation strategies. • Identifying gene expression levels of these specific ion channels may allow for early identification of patients who are more likely to develop arrhythmias in the future.

10.1002/ca.20700; PMID: 18773472 15. H ucker WJ, Nikolski VP, Efimov IR. Optical mapping of the atrioventricular junction. J Electrocardiol 2005;38:121–5. DOI: 10.1016/j.jelectrocard.2005.06.024; PMID: 16226086 16. Fedorov VV, Ambrosi CM, Kostecki G, et al. Anatomic localization and autonomic modulation of atrioventricular junctional rhythm in failing human hearts. Circ Arrhythmia Electrophysiol 2011;4:515–25. DOI: 10.1161/CIRCEP.111.962258; PMID: 21646375 17. Katritsis DG, Josephson ME. Differential diagnosis of regular, narrow-QRS tachycardias. Heart Rhythm 2015;12:1667–76. DOI: 10.1016/j.hrthm.2015.03.046; PMID: 25828600 18. Katritsis DG, Josephson ME. Classification of electrophysiological types of atrioventricular nodal re-entrant tachycardia: A reappraisal. Europace 2013;15:1231–40. DOI: 10.1093/europace/eut100; PMID: 23612728 19. Nawata H, Yamamoto N, Hirao K, et al. Heterogeneity of anterograde fast-pathway and retrograde slow-pathway conduction patterns in patients with the fast-slow form of atrioventricular nodal reentrant tachycardia: electrophysiologic and electrocardiographic considerations. J Am Coll Cardiol 1998;32:1731–40. DOI: 10.1016/S07351097(98)00433-1; PMID: 9822103 20. Goette A, Kalman JM, Aguinaga L, et al. EHRA/HRS/APHRS/ SOLAECE expert consensus on atrial cardiomyopathies: definition, characterization, and clinical implication. Hear Rhythm 2017;14:e3–40. DOI: 10.1016/j.hrthm.2016.05.028; PMID: 27320515 21. Katritsis DG, Marine JE, Contreras FM, et al. Catheter ablation of atypical atrioventricular nodal reentrant tachycardia. Circulation 2016;134:1655–63. DOI: 10.1161/ CIRCULATIONAHA.116.024471; PMID: 27754882 22. Drago F, Placidi S, Righi D, et al. Cryoablation of AVNRT in children and adolescents: early intervention leads to a better outcome. J Cardiovasc Electrophysiol 2014;25:398–403. DOI: 10.1111/jce.12339; PMID: 24303941 23. Van Veen TAB, Van Rijen HVM, Opthof T. Cardiac gap junction channels: modulation of expression and channel properties. Cardiovasc Res 2001;51:217–29. DOI: 10.1016/S00086363(01)00324-8; PMID: 11470461 24. Vozzi C, Dupont E, Coppen SR, et al. Chamber-related differences in connexin expression in the human heart. J Mol Cell Cardiol 1999;31:991–1003. DOI: 10.1006/jmcc.1999.0937; PMID: 10336839 25. Revel JP, Yancey SB, Nicholson B, Hoh J. Sequence diversity of gap junction proteins. Ciba Found Symp 1987;125:108–27. PMID: 3030671 26. Boyett MR, Inada S, Yoo S, et al. Connexins in the sinoatrial and atrioventricular nodes. Adv Cardiol 2006;42:175–97.

DOI: 10.1159/000092569; PMID: 16646591 27. D obrzynski H, Atkinson A, Borbas Z, Ambrosi CM, Efimov IR. Molecular investigation into the human atrioventricular node in heart failure. Anat Physiol 2015;5:164. DOI: 10.4172/21610940.1000164; PMID: 14563715 28. Greener ID, Monfredi O, Inada S, et al. Molecular architecture of the human specialised atrioventricular conduction axis. J Mol Cell Cardiol 2011;50:642–51. DOI: 10.1016/j. yjmcc.2010.12.017; PMID: 21256850 29. Kreuzberg MM, Liebermann M, Segschneider S, et al. Human connexin31.9, unlike its orthologous protein connexin30.2 in the mouse, is not detectable in the human cardiac conduction system. J Mol Cell Cardiol 2009;46:553–9. DOI: 10.1016/j.yjmcc.2008.12.007; PMID: 19168070 30. Verkerk AO, Wilders R. Pacemaker activity of the human sinoatrial node: effects of HCN4 mutations on the hyperpolarization-activated current. Europace 2014;16:384–95. DOI: 10.1093/europace/eut348; PMID: 24569893 31. DiFrancesco D. Pacemaker mechanisms in cardiac tissue. Annu Rev Physiol 1993;55:455–72. DOI: 10.1146/annurev. physiol.55.1.455; PMID: 7682045 32. Furst O, D’Avanzo N, Fürst O, D’Avanzo N. Isoform dependent regulation of human HCN channels by cholesterol. Sci Rep 2015;5:14270. DOI: 10.1038/srep14270; PMID: 26404789 33. Zimmer T, Haufe V, Blechschmidt S. Voltage-gated sodium channels in the mammalian heart. Glob Cardiol Sci Pract 2014;2014:449–63. DOI: 10.5339/gcsp.2014.58; PMID: 25780798 34. Wang DW. Clinical, genetic, and biophysical characterization of SCN5A mutations associated with atrioventricular conduction block. Circulation 2002;105:341–6. DOI: 10.1161/ hc0302.102592; PMID: 11804990 35. Inada S, Hancox JC, Zhang H, Boyett MR. One-dimensional mathematical model of the atrioventricular node including atrio-nodal, nodal, and nodal-His cells. Biophys J 2009;97:2117– 27. DOI: 10.1016/j.bpj.2009.06.056; PMID: 19843444 36. Noma A, Irisawa H, Kokobun S, et al. Slow current systems in the A-V node of the rabbit heart. Nature 1980;285:228–9. DOI: 10.1038/285228a0; PMID: 7374774 37. Gaborit N, Le Bouter S, Szuts V, et al. Regional and tissue specific transcript signatures of ion channel genes in the non-diseased human heart. J Physiol 2007;582:675–93. DOI: 10.1113/jphysiol.2006.126714; PMID: 17478540 38. Zhang Q, Timofeyev V, Qiu H, et al. Expression and roles of Cav1.3 (α1D) L-Type Ca2+ channel in atrioventricular node automaticity. J Mol Cell Cardiol 2011;50:194–202. DOI: 10.1016/j. yjmcc.2010.10.002; PMID: 20951705

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At the Atrioventricular Crossroads: Dual Pathway Electrophysiology

39. C handler NJ, Greener ID, Tellez JO, et al. Molecular architecture of the human sinus node insights into the function of the cardiac pacemaker. Circulation 2009;119: 1562–75. DOI: 10.1161/CIRCULATIONAHA.108.804369; PMID: 19289639 40. Bogdanov KY, Vinogradova TM, Lakatta EG. Sinoatrial nodal cell ryanodine receptor and Na+–Ca2+ exchanger: molecular partners in pacemaker regulation. Circ Res 2001;88:1254–8. DOI: 10.1161/hh1201.092095; PMID: 11420301 41. Snyders DJ. Structure and function of cardiac potassium channels. Cardiovasc Res 1999;42:377–90. DOI: 10.1016/S00086363(99)00071-1; PMID: 10533574 42. Mitcheson JS, Hancox JC. Characteristics of a transient outward current (sensitive to 4-aminopyridine) in Ca2+tolerant myocytes isolated from the rabbit atrioventricular node. Pflugers Arch 1999;438:68–78. DOI: 10.1007/ s004240050881; PMID: 10370089

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43. M itcheson JS, Hancox JC. An investigation of the role played by the E-4031-sensitive (rapid delayed rectifier) potassium current in isolated rabbit atrioventricular nodal and ventricular myocytes. Pflugers Arch 1999;438:843–50. DOI: 10.1007/s004249900118; PMID: 10591073 44. Munk A a, Adjemian RA, Zhao J, et al. Electrophysiological properties of morphologically distinct cells isolated from the rabbit atrioventricular node. J Physiol 1996;493:801–18. DOI: 10.1113/jphysiol.1996.sp021424; PMID: 8799901 45. Kokubun S, Nishimura M, Noma A, Irisawa H. Membrane currents in the rabbit atrioventricular node cell. Pflügers Arch Eur J Physiol 1982;393:15–22. DOI: 10.1007/BF00582385; PMID: 6283467 46. Lister JW, Stein E, Kosowsky BD, et al. Atrioventricular conduction in man. Am J Cardiol 1965;16:516–23. DOI: 10.1016/0002-9149(65)90028-7; PMID: 5834472 47. Prystowsky EN, Jackman WM, Rikenberger RL, et al. Effect

of autonomic blockade on ventricular refractoriness and atrioventricular nodal conduction in humans. Evidence supporting a direct cholinergic action on ventricular muscle refractoriness. Circ Res 1981;49:511–8. DOI: 10.1161/01.RES.49.2.511; PMID: 7249285 48. Chiou CW. Effects of continuous enhanced vagal tone on dual atrioventricular node and accessory pathways. Circulation 2003;107:2583–8. DOI: 10.1161/01.CIR.0000068339.04731.4D; PMID: 12743004 49. Philippon F, Plumb VJ, Kay GN. Differential effect of esmolol on the fast and slow AV nodal pathways in patients with AV nodal reentrant tachycardia. J Cardiovasc Electrophysiol 1994;5:810–7. DOI: 10.1111/j.1540-8167.1994.tb01119.x; PMID: 7874326 50. Hucker WJ, Sharma V, Nikolski VP, Efimov IR. Atrioventricular conduction with and without AV nodal delay: two pathways to the bundle of His in the rabbit heart. Am J Physiol Hear Circ Physiol 2007;293;H1122–30. DOI: 10.1152/ajpheart.00115.2007; PMID: 17496219

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Diagnostic Electrophysiology and Ablation

Ganglionated Plexi Ablation: Physiology and Clinical Applications Stavros Stavrakis and Sunny Po University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA

Abstract Ganglionated plexi (GP), consisting of conglomerations of autonomic ganglia on the epicardial surface of the heart, have been shown to play a significant role in different arrhythmias, including atrial fibrillation. GP ablation has become an adjunctive procedure in the treatment of atrial fibrillation, while it has been used successfully in preliminary studies in vasovagal syncope. This review will present the current data on the physiology and clinical applications of GP ablation in the treatment of atrial fibrillation and other diseases.

Keywords Ganglionated plexi, ablation, atrial fibrillation, vasovagal syncope Disclosure: The authors have no conflicts of interest to declare. Received: 31 July 2017 Accepted: 18 October 2017 Citation: Arrhythmia & Electrophysiology Review 2017;6(4):186–90. DOI: 10.15420/aer2017.26.1 Correspondence: Stavros Stavrakis, E: stavros-stavrakis@ouhsc.edu

There are numerous conglomerations of autonomic ganglia on the epicardial surface of the heart, known as ganglionated plexi (GP). These GP have been shown to play a significant role in different arrhythmias, including AF. As such, GP ablation has become an adjunctive procedure in the treatment of AF. This review will present the current data on the significance of GP in arrhythmogenesis and will discuss the role of GP ablation in the treatment of AF and other diseases.

GP Anatomy and Physiology The heart is innervated by both the extrinsic (central) and the intrinsic cardiac autonomic nervous system (CANS). The extrinsic CANS consists of the ganglia in the brain or along the spinal cord, where the cell bodies reside, as well as their axons en route to the heart. The intrinsic CANS is comprised of an extensive epicardial neural network of nerve axons, interconnecting neurons and clusters of autonomic ganglia, known as GP, not only on the atria, but also on both ventricles. These GP, most of which are embedded within epicardial fat pads, vary in size, from those that contain just a few neurons, to those that contain over 400 neurons.1,2 Notably, the highest density of autonomic innervation is found at the posterior wall of the left atrium, particularly at the pulmonary vein–atrial junction.2 Several studies have demonstrated that the GP are composed of a heterogeneous population of neurons, including efferent, afferent and interconnecting neurons, the latter group comprising the majority of the neural elements within the GP.3 From a physiological point of view, GP contain both sympathetic and parasympathetic elements, as well as a variety of neuropeptides and neuromodulators, including calcitonin gene-related peptide, vasoactive intestinal polypeptide, substance P and nitric oxide.4,5 The role of each of these neuropeptides has not been fully elucidated. Importantly, the GP serve as the communication centers between the intrinsic and the extrinsic CANS, coordinating the response to afferent and efferent neural trafficking, to control regional electrophysiological, vascular and contractile function.6 Anatomically, the four major atrial GP are located in close association to the pulmonary veins (PVs) and each innervate one of the four PVs, as well as the surrounding atrial myocardium.1,2 These GP can be

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identified during electrophysiological study by applying high-frequency stimulation (HFS) (20 Hz) at the respective anatomical locations.7,8 A positive response is defined as an increase in the R–R interval by >50 % during AF8 (Figure 1A). Based on the response to HFS and their location in reference to PVs, the Oklahoma group renamed the major atrial GP for better communication among clinical electrophysiologists. The anterior right GP is located immediately anterior to the right superior PV and often extends inferiorly, to the region anterior to the right inferior PV (Figure 1B). The superior left GP is located at the roof of the left atrium, 1–2 cm medial to the left superior PV (Figure 1B). The right and left inferior GP are located at the inferior aspect of the posterior wall of the left atrium, 2–3 cm below the right and left PVs, respectively (Figure 1B).8 The ligament of Marshal, located between the left atrial appendage and the left superior PV, also contains autonomic neurons. There are multiple interconnections among the GP, converging to the sinus node and atrioventricular (AV) node through the anterior right GP and inferior right GP, respectively.9 Similar neural pathways connecting the GP with the PVs, AV node and sinus node exist in humans.10

GP Ablation for AF Recent experimental and clinical studies have established the important role that the intrinsic CANS plays in the initiation and maintenance of AF.11 Variations in autonomic tone in humans12 and hyperactivity of the GP in ambulatory dogs13 are commonly observed before episodes of paroxysmal AF. In canine models of AF, GP electrical stimulation that did not excite the atrial myocardium (20 Hz, 0.1 ms pulse width) and produced focal firing from the PVs,14 while injection of acetylcholine into the GP induced, within minutes, focal firing originating from the adjacent PV and sustained AF.15 In addition, it has been shown that PV myocytes have cellular electrophysiological properties distinctive from the adjacent atrium, which facilitate the induction of AF. In these experiments, a shorter action potential duration and greater sensitivity to autonomic stimulation of canine PVs led to triggered firing, similar to the focal firing observed in patients with paroxysmal AF.16,17 Moreover, the autonomic neural activity recorded from the anterior right GP increased hour by hour during 6 h of rapid atrial pacing, suggesting

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Ganglionated Plexi Ablation

Autonomic denervation is common following PV isolation and has been associated with decreased risk of AF recurrence.20,23,24 Using differential PV isolation and GP ablation, Lemola et al. demonstrated that intact PVs are not needed to maintain experimental vagal AF, whereas ablation of GP prevents AF.25 The same group of investigators showed that PVs play a minor role in AF induced by chronic rapid atrial pacing, whereas intact GP play an important role in AF maintenance in the presence of rapid atrial pacing-induced remodelling.26 It should be noted, however, that the specific neural elements within the GP (efferent, afferent or interconnecting neurons) that are responsible for the beneficial effects of GP ablation remain to be determined. Clinical studies showing that complete electrical isolation of the PVs may not be necessary for maintenance of sinus rhythm support the aforementioned experimental data.27–30 These investigations suggest that the interruption of axons from these hyperactive GP to the adjacent PVs may also contribute to procedural success. It cannot be overemphasised that PV isolation transects at least three of four major atrial GP at the PV–atrial junction (Figure 1B) and numerous autonomic nerves. Thus, the contribution of autonomic denervation to the efficacy of PV isolation cannot be overlooked.

Figure 1: Identification of GP in the Electrophysiology Lab

a stand-alone procedure32–34 support the notion that GP play an important role in the pathogenesis of AF. In these studies, the overall success in eliminating AF was increased with the addition of GP ablation by approximately 25 %,8,31 whereas GP ablation alone in patients with either paroxysmal or persistent AF was successful in 71–86 % of the patients.32–34 The largest randomised clinical trial aiming to answer the question of whether the addition of GP ablation to PV isolation improves the success of AF ablation in patients with paroxysmal AF and whether GP ablation alone is as effective as PV isolation was recently published.35 In this study, 242 patients with paroxysmal AF were randomised to conventional PV isolation, PV isolation plus GP ablation and GP ablation alone and were followed for at least 2 years. Freedom from atrial tachyarrhythmias was achieved in a similar number of patients in the PV isolation and GP ablation groups (56 % and 48 %, respectively), and in a significantly greater number of patients in the PV isolation plus GP ablation group (74 %; p=0.004 by log-rank test), lending further support to the important role of intrinsic CANS in the pathophysiology of AF (Figure 2A). Despite our better understanding of the anatomy and physiology of the major atrial GP, the best GP ablation technique remains to be determined. GP ablation can be performed either empirically, at their presumed anatomical locations,35 or the GP can be identified by applying highfrequency stimulation, as described by the Oklahoma group.8 A major limitation of GP ablation is that despite their consistent location adjacent to the PV–atrial junction, the extent of each “hyperactive” GP that needs to be ablated to treat AF is largely unknown. It should be noted that while the vagal response to HFS is relatively specific, it lacks sensitivity.36 In an attempt to define the best GP ablation technique, Pokushalov et al. randomised 80 paroxysmal AF patients to: (1) selective GP ablation

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Off

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that GP may provide not only the trigger for AF initiation, but also the substrate for AF maintenance.18 In support of this notion, GP ablation reversed acute autonomic remodelling (shortening of atrial effective refractory period and increased inducibility of AF) induced by 6 h of rapid atrial pacing in a canine model of AF.19 Therefore, targeting the GP with ablation in humans appears to be a promising strategy.

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(A) High-frequency stimulation during atrial fibrillation elicits a “vagal” response, indicated by prolongation of R–R interval and drop in arterial blood pressure. (B) The anatomical location of the major atrial GP, based on the response to high-frequency stimulation, as seen in the right anterior oblique projection (left panel), anteroposterior projection (middle panel) and posteroanterior projection (right panel). ARGP = anterior right ganglionated plexus; aVL = an ECG lead; GP = ganglionated plexi; I = an ECG lead; ILGP = inferior left ganglionated plexus; IRGP = inferior right ganglionated plexus; LAA = left atrial appendage; LIPV = left inferior pulmonary vein; LOM = Ligament of Marshal; LSPV = left superior pulmonary vein; RIPV = right inferior pulmonary vein; RSPV = right superior pulmonary vein; RV = right ventricle; SLGP = superior left ganglionated plexus.

guided by vagal responses induced by HFS (20 Hz); and (2) ablation of GP selected by their presumed anatomical locations.33 AF free rates at a mean of 13 months of follow up were 42.5 % in patients with highfrequency stimulation-guided GP ablation and 77.5 % in patients with anatomic GP ablation (p=0.02). This difference may be explained by the fact that significantly more radiofrequency applications were delivered in the latter group, covering a larger area for each GP. Another possible explanation is that continuous HFS identifies GP sites with inputs to the AV node (a positive HFS response is essentially an AV nodal response), whereas logically it makes more sense to target GP with inputs to the PVs, as PV ectopy is widely accepted as the predominant trigger for paroxysmal AF.11 HFS synchronised to the local atrial refractory period resulting in activation of the autonomic neural elements, as previously described in animals37 and humans,10 may produce better results, although this technique requires further research. Moreover, it should be noted that HFS without concomitant GP ablation has been shown to increase early but not late recurrences in patients with persistent AF.38 While the debate regarding the best substrate modification techniques in addition to PV isolation in patients with persistent AF continues,39,40 GP ablation has also been used in this patient population. In a randomised study including 264 patients with persistent or long-standing persistent AF, GP ablation as an adjunct to PV isolation resulted in higher rates of sinus rhythm maintenance at 3 years (49 %) compared to PV isolation plus left atrial linear lesions (34 %)41 (Figure 2B). In addition, left atrial tachycardias were less common with PV isolation plus GP ablation than with PV isolation plus linear lesions. In another study, GP ablation alone in patients with drug-refractory long-standing persistent AF resulted in less optimal results (38 % sinus rhythm maintenance at 2 years).42 Collectively, these studies provide further support to the autonomic hypothesis for AF, which states that GP hyperactivity is most important in the early stages of AF, while its importance may diminish with progression of the disease to more advance stages and the development of atrial remodelling and fibrosis.36

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Diagnostic Electrophysiology and Ablation Figure 2: Results of Randomised Controlled Trials using GP Ablation B

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(A) Comparison of GP ablation alone versus GP ablation plus PVI versus PVI alone in patients with paroxysmal atrial fibrillation. (B) Comparison of PVI plus GP ablation versus PVI plus LL in patients with persistent atrial fibrillation. GP = ganglionated plexi; LL = linear lesions; PVI = pulmonary vein isolation.

Surgical techniques have also used the combination of PV isolation with GP ablation.43 Minimally invasive thoracoscopic surgical ablation procedures combining epicardial PV isolation with GP ablation have been shown to achieve freedom from atrial tachyarrhythmias of approximately 80 %, without major adverse cardiac events, at 1 year of follow up.44–46 However, a recent large randomised controlled trial of surgical GP ablation in patients with either paroxysmal or persistent AF and enlarged atria (43 % patients with left atrial volume index >40 mL/ m2) or prior failed catheter ablation (25 % patients) showed no benefit of adjunctive GP ablation in this patient population and increased complication rates.47 The lack of benefit of GP ablation in this patient population with advanced AF can be explained by the notion that the role of the intrinsic CANS in the pathogenesis of AF diminishes over time, with atrial remodelling and fibrosis having a more prominent role as the disease progresses.36 Another plausible explanation is that AF is a heterogeneous disease, and the current classification to paroxysmal and persistent AF does not distinguish between the different electrophysiological substrates responsible for AF in each patient. In the future, it may be possible to develop biomarkers, including recordings from single neuron recordings from the GP,48 which would provide a mechanistic approach to AF ablation in each patient, such as those who would mostly benefit from GP ablation. This approach in turn may provide the basis for patient-tailored AF treatment.

GP Ablation for Vasovagal Syncope Vasovagal syncope is the most common form of neurally mediated syncope.49 Although the pathophysiology of vasovagal syncope is still controversial, the current thought is that it is related to prolonged orthostatic stress, which causes increased peripheral venous pooling with a subsequent fall in venous return to the heart, which in turn results in activation of ventricular mechanoreceptors and a sudden increase in the afferent neural traffic to the brain. The final result is sympathetic withdrawal and parasympathetic enhancement, which manifests as hypotension (vasodepressor type), bradycardia (cardioinhibitory type) and syncope.49 Thus, vasovagal syncope is a disorder caused by an abnormally amplified autonomic reflex involving both sympathetic

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and parasympathetic components. The treatment of vasovagal syncope includes beta-blockers, alpha-agonists, mineralocorticoids, selective serotonin reuptake inhibitors and dual-chamber pacemaker implantation, but studies of these modalities has provided mixed results.49,50 In contrast to pharmacological therapy and pacemaker implantation, GP ablation for vasovagal syncope provides a means of targeting the root of the problem, which includes disturbances of the intrinsic CANS.51 GP ablation for vasovagal syncope was first introduced by Yao et al., who reported their initial experience on 10 patients with highly symptomatic vasovagal syncope.52 Selective highfrequency stimulation-guided GP ablation resulted in an impressive amelioration of their prodromal symptoms and no recurrence of syncope over 30 months of follow up.52 The therapeutic effects were attributed to autonomic (parasympathetic) denervation, as indicated by an increase in the mean heart rate and a decrease in the highfrequency component of the heart rate variability 3 and 12 months after ablation.52 It should be noted that all 10 patients received “partial autonomic denervation”, as GP were ablated only in the presence of a positive HFS response. This approach resulted in three, six and one patients receiving one, two and three GP ablations, respectively, with the left superior GP being the mostly commontly ablated GP.52 The same group recently reported their long-term results of GP ablation in a larger cohort of patients with vasovagal syncope.53 In this study, 57 consecutive patients with highly symptomatic vasovagal syncope received either anatomical (sequential ablation of all four major atrial GP in their presumed anatomical locations) or high-frequency stimulation-guided GP ablation. During a mean of 36 months of follow up, 91 % of patients remained syncope-free and prodromes were markedly attenuated.53 There were no differences between anatomical and high-frequency stimulation-guided GP ablation in terms of syncope or prodromes, while anatomical GP ablation resulted in a signiﬁcant decrease in the procedure and ﬂuoroscopy time.53 Similar results were obtained by Pachon et al., who performed extensive right and left atrial ablation guided by spectral analysis for “AF nests” to achieve vagal denervation in patients with vasovagal syncope (40 of 43 patients free of syncope

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Ganglionated Plexi Ablation after a mean of 45 months of follow up).54 Although the extent of GP ablation required to treat vasovagal syncope remains to be detemined, collectively, these results indicate that GP ablation is an effective and safe treatment option for patients with refractory vasovagal syncope and call for further randomised controlled trials to confirm the efficacy of this novel treatment.

The Future of GP Ablation GP ablation appears to be a safe and efficacious adjunctive technique to improve outcomes of PV isolation in patients with paroxysmal AF. In addition, promising results were obtained with GP ablation in patients with vasovagal syncope. Nonetheless, some important questions remain unanswered. First, the long-term (e.g. 5 years) outcomes of GP ablation have not been studied. Second, the mechanism by which GP ablation results in improved outcomes is not completely understood. Although autonomic innervation returns approximately 3–6 months after GP ablation in patients with AF,24 GP ablation improves outcomes up to 24 months after the procedure.35 These results are consistent with a recent autonomic neuromodulation study, in which botulinum toxin injection into the epicardial fat pads in patients undergoing cardiac surgery led to a marked decrease in the incidence of atrial tachyarrhythmias both at 30 days and 1 year of follow up, despite recovery of heart rate variability parameters indicating reinnervation

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rmour JA, Murphy DA, Yuan BX, et al. Gross and A microscopic anatomy of the human intrinsic cardiac nervous system. Anat Rec 1997;247:289–98. DOI: 10.1002/(SICI)10970185(199702)247:2<289::AID-AR15>3.0.CO;2-L Pauza DH, Skripka V, Pauziene N, Stropus R. Morphology, distribution, and variability of the epicardiac neural ganglionated subplexuses in the human heart. Anat Rec 2000;259:353–82. DOI: 10.1002/1097-0185(20000801)259:4<353::AID-AR10> 3.0.CO;2-R Shivkumar K, Ajijola OA, Anand I, et al. Clinical neurocardiology defining the value of neuroscience-based cardiovascular therapeutics. J Physiol 2016;594:3911–54. DOI: 10.1113/JP271870; PMID: 27114333 Hoover DB, Isaacs ER, Jacques F, et al. Localization of multiple neurotransmitters in surgically derived specimens of human atrial ganglia. Neuroscience 2009;164:1170–9. DOI: 10.1016/j. neuroscience.2009.09.001; PMID: 19747529 Steele PA, Gibbins IL, Morris JL, Mayer B. Multiple populations of neuropeptide-containing intrinsic neurons in the guineapig heart. Neuroscience 1994;62:241–50. DOI: 10.1016/03064522(94)90327-1 Armour JA. Cardiac neuronal hierarchy in health and disease. Am J Physiol Regul Integr Comp Physiol 2004;287:R262–71. DOI: 10.1152/ajpregu.00183.2004; PMID: 15271675 Lemery R, Birnie D, Tang AS, et al. Feasibility study of endocardial mapping of ganglionated plexuses during catheter ablation of atrial fibrillation. Heart Rhythm 2006;3:387–96. DOI: 10.1016/j.hrthm.2006.01.009; PMID: 16567283 Po SS, Nakagawa H, Jackman WM. Localization of left atrial ganglionated plexi in patients with atrial fibrillation. J Cardiovasc Electrophysiol 2009;20:1186–9. DOI: 10.1111/j.1540-8167.2009.01 515.x; PMID: 19563367 Hou Y, Scherlag BJ, Lin J, et al. Ganglionated plexi modulate extrinsic cardiac autonomic nerve input: effects on sinus rate, atrioventricular conduction, refractoriness, and inducibility of atrial fibrillation. J Am Coll Cardiol 2007;50:61–8. DOI: 10.1016/j. jacc.2007.02.066; PMID: 17601547 Malcolme-Lawes LC, Lim PB, Wright I, et al. Characterization of the left atrial neural network and its impact on autonomic modification procedures. Circ Arrhythm Electrophysiol 2013;6:632–40. DOI: 10.1161/CIRCEP.113.000193; PMID: 23580743 Nishida K, Datino T, Macle L, Nattel S. Atrial fibrillation ablation: translating basic mechanistic insights to the patient. J Am Coll Cardiol 2014;64:823–31. DOI: 10.1016/j. jacc.2014.06.1172; PMID: 25145528 Bettoni M, Zimmermann M. Autonomic tone variations before the onset of paroxysmal atrial fibrillation. Circulation 2002;105:2753–9. DOI: 10.1161/01.CIR.0000018443.44005.D8; PMID: 12057990 Choi EK, Shen MJ, Han S, et al. Intrinsic cardiac nerve activity and paroxysmal atrial tachyarrhythmia in ambulatory dogs. Circulation 2010;121:2615–23. DOI: 10.1161/ CIRCULATIONAHA.109.919829; PMID: 20529998 Scherlag BJ, Yamanashi W, Patel U, et al. Autonomically induced conversion of pulmonary vein focal firing into atrial fibrillation. J Am Coll Cardiol 2005;45:1878–86. DOI: 10.1016/j. jacc.2005.01.057; PMID: 15936622

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after approximately 6 months.55 Further insight into this unexpected long-term benefit was provided by a recent animal study, in which temporary suppression of major atrial GPs by botulinum toxin injection prevented autonomic remodelling and resulted in long-term suppression of AF up to 3 months.56 Specifically, the parasympathetic neural elements in GP and the sympathetic neural elements in atrial myocardium were reduced by botulinum toxin. These results highlight the critical role of GP in AF progression. Finally, the optimal technique to perform GP ablation as well as the extent of GP ablation required to improve outcomes remain to be determined. Further research needs to be directed toward identifying those patients who are most likely to benefit from GP ablation, and the extent of GP ablation required to improve outcomes. Direct visualisation of the GP using I-123-metaiodobenzylguanidine imaging57 may provide an innovative way to assess the autonomic tone before ablation, the extent of atrial denervation, and correlate with clinical outcomes. Given that many other arrhythmias are related to autonomic imbalance, including inappropriate sinus tachycardia and outflow tract ventricular premature complexes and/or tachycardia, GP ablation may offer an alternative way to target these diseases with fewer side effects. Further studies are warranted to investigate the utility of GP ablation in these conditions. n

15. P o SS, Scherlag BJ, Yamanashi WS, et al. Experimental model for paroxysmal atrial fibrillation arising at the pulmonary vein-atrial junctions. Heart Rhythm 2006;3:201–8. DOI: 10.1016/j. hrthm.2005.11.008; PMID: 16443537 16. Patterson E, Lazzara R, Szabo B, et al. Sodium-calcium exchange initiated by the Ca2+ transient: an arrhythmia trigger within pulmonary veins. J Am Coll Cardiol 2006;47:1196– 206. DOI: 10.1016/j.jacc.2005.12.023; PMID: 16545652 17. Patterson E, Po SS, Scherlag BJ, Lazzara R. Triggered firing in pulmonary veins initiated by in vitro autonomic nerve stimulation. Heart Rhythm 2005;2:624–31. DOI: 10.1016/j. hrthm.2005.02.012; PMID: 15922271 18. Yu L, Scherlag BJ, Sha Y, et al. Interactions between atrial electrical remodeling and autonomic remodeling: how to break the vicious cycle. Heart Rhythm 2012;9:804–9. DOI: 10.1016/j.hrthm.2011.12.023; PMID: 22214613 19. Lu Z, Scherlag BJ, Lin J, et al. Atrial fibrillation begets atrial fibrillation: autonomic mechanism for atrial electrical remodeling induced by short-term rapid atrial pacing. Circ Arrhythm Electrophysiol 2008;1:184–92. DOI: 10.1161/ CIRCEP.108.784272; PMID: 19808412 20. Pappone C, Santinelli V, Manguso F, et al. Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibrillation. Circulation 2004;109:327–34. DOI: 10.1161/01.CIR.0000112641.16340.C7; PMID: 14707026 21. Tan AY, Li H, Wachsmann-Hogiu S, et al. Autonomic innervation and segmental muscular disconnections at the human pulmonary vein-atrial junction: implications for catheter ablation of atrial-pulmonary vein junction. J Am Coll Cardiol 2006;48:132–43. DOI: 10.1016/j.jacc.2006.02.054; PMID: 16814659 22. Verma A, Saliba WI, Lakkireddy D, et al. Vagal responses induced by endocardial left atrial autonomic ganglion stimulation before and after pulmonary vein antrum isolation for atrial fibrillation. Heart Rhythm 2007;4:1177–82. DOI: 10.1016/j.hrthm.2007.04.023; PMID: 17765618 23. Scherlag BJ, Nakagawa H, Jackman WM, et al. Electrical stimulation to identify neural elements on the heart: their role in atrial fibrillation. J Interv Card Electrophysiol 2005;13(Suppl1):37–42. DOI: 10.1007/s10840-005-2492-2; PMID: 16133854 24. Scanavacca M, Pisani CF, Hachul D, et al. Selective atrial vagal denervation guided by evoked vagal reflex to treat patients with paroxysmal atrial fibrillation. Circulation 2006;114:876–85. DOI: 10.1161/CIRCULATIONAHA.106.633560; PMID: 16923757 25. Lemola K, Chartier D, Yeh YH, et al. Pulmonary vein region ablation in experimental vagal atrial fibrillation: role of pulmonary veins versus autonomic ganglia. Circulation 2008;117:470–7. DOI: 10.1161/CIRCULATIONAHA.107.737023; PMID: 18195170 26. Nishida K, Maguy A, Sakabe M, et al. The role of pulmonary veins vs autonomic ganglia in different experimental substrates of canine atrial fibrillation. Cardiovasc Res 2011;89:825–33. DOI: 10.1093/cvr/cvq332; PMID: 20962102 27. Lemola K, Oral H, Chugh A, et al. Pulmonary vein isolation as an end point for left atrial circumferential ablation of atrial fibrillation. J Am Coll Cardiol 2005;46:1060–6. DOI: 10.1016/j. jacc.2005.05.069; PMID: 16168292

28. S tabile G, Turco P, La Rocca V, et al. Is pulmonary vein isolation necessary for curing atrial fibrillation? Circulation 2003;108:657–60. DOI: 10.1161/01.CIR.0000086980.42626.34; PMID: 12900336 29. Kuck KH, Hoffmann BA, Ernst S, et al. Impact of complete versus incomplete circumferential lines around the pulmonary veins during catheter ablation of paroxysmal atrial fibrillation: results from the Gap-Atrial Fibrillation-German Atrial Fibrillation Competence Network 1 Trial. Circ Arrhythm Electrophysiol 2016;9:e003337. DOI: 10.1161/CIRCEP.115.003337; PMID: 26763226 30. Jiang RH, Po SS, Tung R, et al. Incidence of pulmonary vein conduction recovery in patients without clinical recurrence after ablation of paroxysmal atrial fibrillation: mechanistic implications. Heart Rhythm 2014;11:969–76. DOI: 10.1016/j. hrthm.2014.03.015; PMID: 24632180 31. Katritsis DG, Giazitzoglou E, Zografos T, et al. Rapid pulmonary vein isolation combined with autonomic ganglia modification: a randomized study. Heart Rhythm 2011;8:672–8. DOI: 10.1016/j. hrthm.2010.12.047; PMID: 21199686 32. Pokushalov E, Romanov A, Artyomenko S, et al. Left atrial ablation at the anatomic areas of ganglionated plexi for paroxysmal atrial fibrillation. Pacing Clin Electrophysiol 2010;33:1231–8. DOI: 10.1111/j.1540-8159.2010.02800.x; PMID: 20546147 33. Pokushalov E, Romanov A, Shugayev P, et al. Selective ganglionated plexi ablation for paroxysmal atrial fibrillation. Heart Rhythm 2009;6:1257–64. DOI: 10.1016/j. hrthm.2009.05.018; PMID: 19656736 34. Pokushalov E, Turov A, Shugayev P, et al. Catheter ablation of left atrial ganglionated plexi for atrial fibrillation. Asian Cardiovasc Thorac Ann 2008;16:194–201. DOI: 10.1177/021849230801600304; PMID: 18515667 35. Katritsis DG, Pokushalov E, Romanov A, et al. Autonomic denervation added to pulmonary vein isolation for paroxysmal atrial fibrillation: a randomized clinical trial. J Am Coll Cardiol 2013;62:2318–25. DOI: 10.1016/j. jacc.2013.06.053; PMID: 23973694 36. Stavrakis S, Nakagawa H, Po SS, et al. The role of the autonomic ganglia in atrial fibrillation. JACC Clinical Electrophysiol 2015;1:1–13. DOI: 10.1016/j.jacep.2015.01.005; PMID: 26301262 37. Sha Y, Scherlag BJ, Yu L, et al. Low-level right vagal stimulation: anticholinergic and antiadrenergic effects. J Cardiovasc Electrophysiol 2011;22:1147–53. DOI: 10.1111/j. 1540-8167.2011.02070.x; PMID: 21489033 38. Sairaku A, Yoshida Y, Kamiya H, et al. High-frequency stimulation of the atria increases early recurrence following pulmonary vein isolation in patients with persistent atrial fibrillation. Heart Rhythm 2012;9:1386–92. DOI: 10.1016/j. hrthm.2012.05.014; PMID: 22583843 39. Verma A, Jiang CY, Betts TR, et al. Approaches to catheter ablation for persistent atrial fibrillation. N Engl J Med 2015;372: 1812–22. DOI: 10.1056/NEJMoa1408288; PMID: 25946280 40. Providencia R, Lambiase PD, Srinivasan N, et al. Is there still a role for complex fractionated atrial electrogram ablation in addition to pulmonary vein isolation in patients with paroxysmal and persistent atrial fibrillation? Meta-analysis of 1415 patients. Circ Arrhythm Electrophysiol 2015;8:1017–29. DOI: 10.1161/CIRCEP.115.003019; PMID: 26082515

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Diagnostic Electrophysiology and Ablation 41. P okushalov E, Romanov A, Katritsis DG, et al. Ganglionated plexus ablation vs linear ablation in patients undergoing pulmonary vein isolation for persistent/long-standing persistent atrial fibrillation: a randomized comparison. Heart Rhythm 2013;10:1280–6. DOI: 10.1016/j.hrthm.2013.04.016; PMID: 23608592 42. Pokushalov E, Romanov A, Artyomenko S, et al. Ganglionated plexi ablation for longstanding persistent atrial fibrillation. Europace 2010;12:342–6. DOI: 10.1093/europace/euq014; PMID: 20173210 43. Fragakis N, Pantos I, Younis J, et al. Surgical ablation for atrial fibrillation. Europace 2012;14:1545–52. DOI: 10.1093/ europace/eus081 44. Edgerton JR, Brinkman WT, Weaver T, et al. Pulmonary vein isolation and autonomic denervation for the management of paroxysmal atrial fibrillation by a minimally invasive surgical approach. J Thorac Cardiovasc Surg 2010;140:823–8. DOI: 10.1016/j.jtcvs.2009.11.065; PMID: 20299028 45. Yilmaz A, Geuzebroek GS, Van Putte BP, et al. Completely thoracoscopic pulmonary vein isolation with ganglionic plexus ablation and left atrial appendage amputation for treatment of atrial fibrillation. Eur J Cardiothorac Surg 2010;38:356–60. DOI: 10.1016/j.ejcts.2010.01.058; PMID: 20227287 46. Krul SP, Driessen AH, van Boven WJ, et al. Thoracoscopic video-assisted pulmonary vein antrum isolation, ganglionated plexus ablation, and periprocedural confirmation of ablation

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53. S un W, Zheng L, Qiao Y, et al. Catheter ablation as a treatment for vasovagal syncope: long-term outcome of endocardial autonomic modification of the left atrium. J Am Heart Assoc 2016;5:e003471. DOI: 10.1161/JAHA.116.003471; PMID: 27402231 54. Pachon JC, Pachon EI, Cunha Pachon MZ, et al. Catheter ablation of severe neurally meditated reflex (neurocardiogenic or vasovagal) syncope: cardioneuroablation long-term results. Europace 2011;13:1231–42. DOI: 10.1093/europace/eur163; PMID: 21712276 55. Pokushalov E, Kozlov B, Romanov A, et al. Long-term suppression of atrial fibrillation by botulinum toxin injection into epicardial fat pads in patients undergoing cardiac surgery: one-year follow-up of a randomized pilot study. Circ Arrhythm Electrophysiol 2015;8:1334–41. DOI: 10.1161/ CIRCEP.115.003199 56. Lo LW, Chang HY, Scherlag BJ, et al. Temporary suppression of cardiac ganglionated plexi leads to long-term suppression of atrial fibrillation: evidence of early autonomic intervention to break the vicious cycle of “AF begets AF”. J Am Heart Assoc 2016;5:e003309. DOI: 10.1161/JAHA.116.003309; PMID: 27381759 57. Lemery R, Ben-Haim S, Wells G, Ruddy TD. I-123Metaiodobenzylguanidine imaging in patients with atrial fibrillation undergoing cardiac mapping and ablation of autonomic ganglia. Heart Rhythm 2017;14:128–32. DOI: 10.1016/j.hrthm.2016.08.038; PMID: 28007094

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Diagnostic Ablation and Electrophysiology

Ablation of Atrial Fibrillation in Patients with Congenital Heart Disease Marwan M Refaat, 1,2 Jad Ballout 1 and Moussa Mansour 3 1. Department of Internal Medicine, Cardiology Division, American University of Beirut, Lebanon; 2. Department of Biochemistry and Molecular Genetics, American University of Beirut, Lebanon; 3. Cardiac Arrhythmia Service, Massachusetts General Hospital/Harvard Medical School, Boston, USA

Abstract With improved surgical techniques and medical management for patients with congenital heart diseases, more patients are living longer and well into adulthood. This improved survival comes with a price of increased morbidity, mainly secondary to increased risk of tachyarrhythmias. One of the major arrhythmias commonly encountered in this subset of cardiac patients is AF. Similar to the general population, the risk of AF increases with advancing age, and is mainly secondary to the abnormal anatomy, abnormal pressure and volume parameters in the hearts of these patients and to the increased scarring and inflammation seen in the left atrium following multiple surgical procedures. Catheter ablation for AF has been shown to be a very effective treatment modality in patients with refractory AF. However, data and guidelines regarding catheter ablation in patients with congenital heart disease are not well established. This review will shed light on the procedural techniques, success rates and complications of AF catheter ablation in patients with different types of CHD, including atrial septal defects, tetralogy of Fallot, persistent left superior vena cava, heterotaxy syndrome and atrial isomerism, and Ebstein anomaly.

Keywords Atrial fibrillation, catheter ablation, congenital heart disease, atrial septal defect, tetralogy of Fallot, persistent left superior vena cava, Ebstein anomaly, atrial isomerism Disclosure: The authors have no conflicts of interest to declare. Received: 13 July 2017 Accepted: 18 October 2017 Citation: Arrhythmia & Electrophysiology Review 2017;6(4):191–4. DOI: 10.15420/2017.2017.15.1 Correspondence: Moussa Mansour, Massachusetts General Hospital, Cardiac Arrhythmia Service, 55 Fruit Street, Boston, MA, USA. E: mmansour@mgh.harvard.edu

Although there is no formal database of adults with congenital heart disease (CHD) in the United States, the prevalence and incidence of CHD can be estimated and extrapolated from data in the Canadian providence.1 As such, the prevalence of CHD in the United States has been estimated in 2010 to be around 2.4 million people (1.4 million adults and 1 million children), with an incidence of between four and 10 per 1,000. Forty-five per cent of these adults have mild disease, 37 % have moderate disease, and 14 % have severe disease.1–3 Furthermore, the prevalence of patients living with CHD has been increasing secondary to the improvements in surgical techniques and medical management over the past few decades. Mortality secondary to CHD is highest during infancy and childhood declining gradually with age to reach a steady state between 15 and 65 years. It is higher in men than women.4 One of the most important causes of morbidity in patients with CHD is the development of cardiac arrhythmias, in particular tachyarrhythmias. These result from multiple surgical scars, haemodynamic abnormalities and structural defects that create arrhythmogenic substrates.5 In fact, about 11 % of patients with CHD develop atrial arrhythmias (intra-atrial reentrant tachycardia [IART] and AF), with the risk being higher in patients with right-sided heart lesions.6 The most common arrhythmia in patients with CHD is IART that occurs secondary to reentrant circuits in the right atrium. AF is a less common cause of atrial arrhythmia in CHD, but its prevalence is increasing in these patients because of improved survival to older age.5 The 2014 American College of Cardiology/American Heart Association/ Heart Rhythm Society guidelines for the management of AF

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describe medical therapies including rate control, rhythm control and anticoagulation, with radiofrequency catheter ablation mainly reserved for patients who are refractory or intolerant to treatment with antiarrhythmic medication.7 Here in this review we describe the efficacy, technical limitations and common complications of radiofrequency catheter ablation for AF in patients with different types of CHD.

Atrial Septal Defect Patients with atrial septal defect (ASD) are prone to developing different types of atrial arrhythmias. These include atrial flutter, atrial tachycardia and – most commonly – AF. Just as in the general population, the incidence of AF in patients with ASD increases with age. Since ASD is usually asymptomatic early on because of the absence of signs and symptoms, many patients may present with AF before correction of the defect. Although correction of the ASD prevents recurrence of most cases of paroxysmal AF, this is not the case in patients with persistent AF.8,9

AF Catheter Ablation in Patients with ASD Catheter ablation has been one of the primary treatment strategies for patients with AF and ASD. Several reports have described the different approaches to perform this procedure, along with success rates and possible complications. Nie et al.10 described catheter ablation in patients with uncorrected ASD via direct access through the defect when feasible. Success rates were similar to those in matched patients without ASD. The procedure can also be performed in patients who have already had their ASDs closed. This has been described by Lakkireddy et al.11 and Santangeli et al.12 In these patients, CT

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Diagnostic Ablation and Electrophysiology scanning can be useful in defining the anatomy, location of the closure device and any calcifications around the site of closure. Intracardiac echocardiography can also be very helpful in determining a suitable site for transseptal puncture through the native septum. However, in some cases access through the native septum is not feasible. Santangeli et al. have described access into the left atrium (LA) through the closure device.12 In this study, because the device increases resistance to access directly via the transseptal sheath, the authors reported that extra steps of dilation of the access site were required. The needle was introduced into the LA through the device. Once the needle was in the LA, a dilator (8 Fr in this case) was introduced over the needle. The needle was removed and a guide wire introduced into the left pulmonary vein. Then the dilator was removed and a larger dilator (11 Fr in this case) introduced over the wire. This sequential dilation allowed the transseptal catheter to be advanced through the stiff closure device into the LA. When transseptal access is done through the native septum, total procedure time, fluoroscopy time and transseptal time are not significantly between patients with corrected ASD compared with those without an ASD.11 However, when the LA is accessed through the occlusion device, more time is required to puncture and dilate the device to allow the transseptal sheath to pass, and as such total procedure time, fluoroscopy time and transseptal time are significantly increased compared with access through the native septum.12 The success rate of the procedure is similar between patients with ASD and patients without ASD, and between patients who had LA access through the native septum compared with patients who had access through the device.11,12 Arrhythmia-free survival rates >14 months after the procedure in patients with ASD range between 56 % and 77 %, and are not significantly different from those seen in patients without ASD undergoing catheter ablation for AF.10–12 While Santangeli et al.12 successfully demonstrated that transseptal access through the occlusion device is feasible, several concerns have been raised. In an accompanying editorial commentary by Demosthenes Katritsis, it was argued that a transoesophageal echocardiogram should have been used after the procedure to confirm there was no residual shunt secondary to the puncture.13 The issue of device dislodgement was also raised. The concern was mainly that smaller devices and inadequately supported large devices are more likely to dislodge as a result of forces exerted by large sheaths. Therefore, an atrial-septal rim of >5 mm should be present for safe access through the device. Another point that the author made is that Santangeli et al. performed the device puncture only in patients with the Amplatzer device and therefore that the safety of this procedure with other devices (e.g., Cardioseal) is unknown. Finally, it was argued that access through a native septum via a large sheath or via double puncture has been associated with a 20–30 % rate of iatrogenic ASDs. Hence, it was recommended that patients should be carefully selected for this procedure and that the procedure should be performed in symptomatic patients with high AF burden only 6 months or more following the device insertion.13 Reported adverse effects of catheter ablation in patients with ASDs in the literature include mild pericardial effusion, haematoma formation, acute heart failure, and transient ischaemic attack. All reported complications resolved and patients achieved full recovery. 11,12 Therefore radiofrequency catheter ablation for AF is a technically feasible procedure in patients with ASD closure devices. Efficacy is similar to that in patients without ASD, and it is a safe procedure with minimal complications. However, special care should be taken when

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selecting patients with closure devices and AF, especially when access through the device is contemplated.

Tetralogy of Fallot Tetralogy of Fallot (ToF) is the most common cyanotic congenital heart defect, with an estimated incidence in the range of 0.23–0.63 cases per 1,000 live births.14 Surgical techniques for the correction of ToF have improved dramatically since the first operation was performed in 1955 and patients are living well into adulthood. With increased survival, increased morbidity secondary to long-term complications of ToF is seen. Atrial and ventricular arrhythmias are major contributors to long-term morbidity from ToF.15–17 It is estimated that the total arrhythmia burden in patients with ToF ranges from 30–43 %,14,15 with atrial arrhythmias being more common than ventricular arrhythmias.15,18 The most common atrial arrhythmia in younger patients (aged <45 years) is IART. However, with age, the incidence of AF increases and exceeds IART making it the most common atrial arrhythmia in patients aged >55 years.15–17

AF Catheter Ablation in Tetralogy of Fallot Unlike in patients with ASDs, limited data exist for radiofrequency catheter ablation for AF in patients with ToF. In a retrospective study by Philip et al.19 attempted ablation in one patient with ToF and AF failed secondary to difficulties reaching the LA. In a study by Ezzat et al.17 describing ablation in ToF patients with tachyarrhythmias, the most common arrhythmia was cavo-tricuspid-dependent tachyarrhythmia with only four patients presenting with, or having induced AF during the electrophysiology study. Of those four cases, only two left-sided procedures were performed (wide area circumferential ablation of the pulmonary veins and complex fractionated electrogram ablation). Thus, the effectiveness of radiofrequency ablation of AF in this cohort of ToF patients could not be assessed. More studies are needed to study the efficacy of this treatment modality in ToF patients, particularly those with AF.

Persistent Left Superior Vena Cava Although persistent left superior vena cava (PLSVC) is the most common congenital anomaly affecting thoracic venous structures, it is quite a rare disorder with a prevalence of 0.1–3 % in the general population.20–22 PLSVC results when the left cardinal vein fails to obliterate into the ligament of Marshall during the foetal period. The PLSVC drains into the right atrium after joining a dilated coronary sinus. In rare cases, PLSVC may be associated with absence of a right SVC.20,21,23,24 It is thought that the PLSVC contains remnant pacemaker tissues from foetal development. These tissues can be a source of ectopy that can initiate AF.25

AF Catheter Ablation in PLSVC Because PLSVC is an uncommon condition, studies on AF ablation in patients with PLSVC are mainly case series or case reports. Hsu et al.25 reported their experience with five patients who had refractory AF and PLSVC. All patients underwent pulmonary vein isolation (PVI), followed by isolation of the PLSVC. On follow-up, three of the five patients were arrhythmia free, one had an unsuccessful PLSVC isolation and AF recurrence and one did not have recurrence of AF but required two further procedures for atrial flutter. In another study by Elayi et al., six patients with refractory AF and PLSVC were studied. After PVI and PLSVC isolation, none of the six patients had recurrence of AF on follow-up. While the above two studies reported PLSVC isolation after the patients had undergone PVI, Anselmino et al.22 reported success in keeping two patients free of AF with only PLSVC isolation without PVI.

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Ablation of Atrial Fibrillation in Patients with Congenital Heart Disease Figure 1: Patient with PLSVC who Underwent AF Catheter Ablation

Figure 2: Patient with Ebstein Anomaly who Underwent Pulmonary Vein Isolation A

A: CARTO map; B: intracardiac tracings showing pulmonary vein isolation.

with complex CHD such as atrial isomerism, the use of more advanced techniques and equipment such as magnetic navigation to guide the ablation procedure may provide better dexterity and easier access to the desired locations in the heart, possibly leading to better outcomes.26

Ebstein Anomaly

A: CARTO map; B: transseptal puncture; C: normal sinus rhythm during isolation of the right pulmonary vein; D: isolation of the PLSVC; E: no reconnection after administration of adenosine. PLSVC = persistent left superior vena cava.

Patients with Ebstein anomaly are predisposed to AF. PVI by catheter ablation can be successfully done in this group of patients. We report a 38 year old with repaired Ebstein anomaly and AF who underwent PVI at another hospital. The patient had recurrent arrhythmia with reconnection of the right inferior pulmonary vein that was isolated (see Figure 2).

Other Congenital Heart Defects Most studies described above showed that there are two sites of connection between the PLSVC and the myocardium.21,22,25 One connection is located proximally at the junction of the PLSVC and the coronary sinus, and another connection to the LA located higher up along the PLSVC. Ablation of only one of these sites is not sufficient to completely electrically isolate the PLSVC and both sites should be ablated. Complications during this procedure include cardiac tamponade and left phrenic nerve palsy. Overall, PLSVC isolation as a treatment for refractory AF in this population subset seems to be feasible. However, caution should be practiced during radiofrequency energy delivery to avoid injury to nearby structures such as the circumflex coronary artery and the left phrenic nerve. Figure 1 shows images of the electroanatomical mapping, fluoroscopy images, and electrophysiological tracings in one of our patients with PLSVC who underwent AF catheter ablation.

Heterotaxy and Atrial Isomerism Atrial isomerism is a rare disorder, but improved surgical procedures have resulted in improved survival and more patients are living into adulthood. Just like in other types of CHD, improved survival into adulthood is associated with an increased burden of arrhythmia. Suman-Horduna et al.26 reported eight patients with atrial isomerism and atrial tachyarrhythmias. These included twin atrioventricular nodal reentrant tachycardia, atrial tachycardia and AF. Out of the two patients with AF who underwent PVI, one patient remained arrhythmia free on follow-up, while the other developed paroxysmal episodes of atrial tachycardia and AF. No conclusion can be drawn regarding PVI for AF in patients with heterotaxy syndrome because of the very small number of patients. However, the above mentioned study pointed out that in patients

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AF is seen in other congenital heart defects that include aortic stenosis and single ventricle after the Fontan operation.27 For Fontan patients who have AF, the atrial MAZE can be extended to the LA with a variation of the Cox procedure and with a recurrence rate <12 %. Surgical ablation with Fontan has a combined mortality or need for postoperative heart transplant risk that exceeds 5 %.27

Conclusion With improved surgical methods and medical management, patients with CHD are living well into adulthood. This increased survival is associated with increased morbidity secondary to many factors, with arrhythmias being major players in this regard. Atrial arrhythmias including AF are common and tend to become refractory to medical treatment as patients live longer. Catheter ablation for AF can be successfully performed in patients with CHD, and despite the lack of large multicentre controlled trials, available data point to the safety and efficacy of this method in this group of patients. The procedure can be challenging and adjunctive ablation of non-pulmonary vein triggers is often needed in addition to PVI. n

Clinical Perspective: • A dult CHD puts patients at increased risk of AF and the electrophysiologist in a treatment dilemma. • Catheter ablation for AF is a very appealing modality in patients with ACHD especially because treatment with antiarrhythmic drugs in this group may be ineffective or may carry a higher risk of adverse effects. • Because solid evidence and guidelines are lacking for AF ablation in ACHD, more studies are needed to establish the safety and efficacy of this technique in this group, and patients should undergo careful evaluation and selection.

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hatt AB, Foster E, Kuehl K, et al. Congenital heart disease B in the older adult: a scientific statement from the American Heart Association. Circulation 2015;131:1884–931. DOI: 10.1161/ CIR.0000000000000204; PMID: 25896865 Gilboa SM, Devine OJ, Kucik JE, et al. Congenital Heart Defects in the United States: Estimating the Magnitude of the Affected Population in 2010. Circulation 2016;134:101–9. DOI: 10.1161/ CIRCULATIONAHA.115.019307; PMID: 27382105 Benjamin EJ, Blaha MJ, Chiuve SE, et al. Heart Disease and Stroke Statistics-2017 Update: A Report From the American Heart Association. Circulation 2017;135:e146–e603. DOI: 10.1161/CIR.0000000000000485; PMID: 28122885 Boneva RS, Botto LD, Moore CA, et al. Mortality associated with congenital heart defects in the United States: trends and racial disparities, 1979-1997. Circulation 2001;103:2376–81. DOI: 10.1161/01.CIR.103.19.2376; PMID: 11352887 Sherwin ED, Triedman JK, Walsh EP. Update on interventional electrophysiology in congenital heart disease: evolving solutions for complex hearts. Circ Arrhythm Electrophysiol 2013;6:1032–40. DOI: 10.1161/CIRCEP.113.000313; PMID: 24129205 Bernier M, Marelli AJ, Pilote L, et al. Atrial arrhythmias in adult patients with right- versus left-sided congenital heart disease anomalies. Am J Cardiol 2010;106:547–51. DOI: 10.1016/j. amjcard.2010.03.068; PMID: 20691314 January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/ HRS Guideline for the Management of Patients With Atrial Fibrillation. A Report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014;64:e1–e76. DOI: 10.1016/j.jacc.2014.03.022; PMID: 24685669 Wi J, Choi J-Y, Shim J-M, et al. Fate of Preoperative Atrial Fibrillation After Correction of Atrial Septal Defect. Circ J 2013;77:109–15. DOI: 10.1253/circj.CJ-12-0550; PMID: 23075753 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

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10. N ie JG, Dong JZ, Salim M, et al. Catheter ablation of atrial fibrillation in patients with atrial septal defect: long-term follow-up results. J Interv Card Electrophysiol 2015;42:43–9. DOI: 10.1007/s10840-014-9958-z; PMID: 25504269 11. Lakkireddy D, Rangisetty U, Prasad S, et al. Intracardiac echo-guided radiofrequency catheter ablation of atrial fibrillation in patients with atrial septal defect or patent foramen ovale repair: a feasibility, safety, and efficacy study. J Cardiovasc Electrophysiol 2008;19:1137–42. DOI: 10.1111/j.15408167.2008.01249.x; PMID: 18662188 12. Santangeli P, Di Biase L, Burkhardt JD, et al. Transseptal access and atrial fibrillation ablation guided by intracardiac echocardiography in patients with atrial septal closure devices. Heart Rhythm 2011;8:1669–75. DOI: 10.1016/j. hrthm.2011.06.023; PMID: 21703215 13. Katritsis DG. Transseptal puncture through atrial septal closure devices. Heart Rhythm 2011;8:1676–7. DOI: 10.1016/j. hrthm.2011.06.025; PMID: 21712023 14. Wu M-H, Lu C-W, Chen H-C, 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 15. Decker JA, Kim JJ. Management of arrhythmias in patients with a tetralogy of Fallot. Cardiol Young 2013;23:888–95. DOI: 10.1017/S1047951113001789; PMID: 24401263 16. 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 17. Ezzat VA, Ryan MJ, O’Leary J, et al. Radiofrequency ablation of atrial tachyarrhythmias in adults with tetralogy of Fallot predictors of success and outcome. Cardiol Young 2017; 27:284–93. DOI: 10.1017/S1047951116000482; PMID: 27225323 18. Le Gloan L, Khairy P. Management of arrhythmias in patients with tetralogy of Fallot. Curr Opin Cardiol 2011;26:60–5. DOI: 10.1097/HCO.0b013e328341381a; PMID: 21076290 19. Philip F, Muhammad KI, Agarwal S, Natale A, Krasuski RA. Pulmonary vein isolation for the treatment of drugrefractory atrial fibrillation in adults with congenital heart

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disease. Congenit Heart Dis 2012;7:392–9. DOI: 10.1111/j.17470803.2012.00649.x; PMID: 22469422 Wissner E, Tilz R, Konstantinidou M, et al. Catheter ablation of atrial fibrillation in patients with persistent left superior vena cava is associated with major intraprocedural complications. Heart Rhythm 2010;7:1755–60. DOI: 10.1016/j. hrthm.2010.08.005; PMID: 20708711 Elayi CS, Fahmy TS, Wazni OM, et al. Left superior vena cava isolation in patients undergoing pulmonary vein antrum isolation: Impact on atrial fibrillation recurrence. Heart Rhythm 2006;3:1019–23. DOI: 10.1016/j.hrthm.2006.05.024; PMID: 16945794 Anselmino M, Ferraris F, Cerrato N, et al. Left persistent superior vena cava and paroxysmal atrial fibrillation: the role of selective radio-frequency transcatheter ablation. J Cardiovasc Med (Hagerstown) 2014;15:647–52. DOI: 10.2459/ JCM.0000000000000144; PMID: 24978664 Maruyama M, Ino T, Miyamoto S, et al. Characteristics of the electrical activity within the persistent left superior vena cava: Comparative view with reference to the ligament of Marshall. J Electrocardiol 2003;36:53–7. DOI: 10.1054/ jelc.2003.50004; PMID: 12607196 Liu H, Lim KT, Murray C, Weerasooriya R. Electrogram-guided isolation of the left superior vena cava for treatment of atrial fibrillation. Europace 2007;9:775–80. DOI: 10.1093/europace/ eum118; PMID: 17557767 Hsu LF, Jais P, Keane D, et al. Atrial fibrillation originating from persistent left superior vena cava. Circulation 2004;109:828–32. DOI: 10.1161/01.CIR.0000116753.56467.BC; PMID: 14757689 Suman-Horduna I, Babu-Narayan SV, Ueda A, et al. Magnetic navigation in adults with atrial isomerism (heterotaxy syndrome) and supraventricular arrhythmias. Europace 2013;15:877–85. DOI: 10.1093/europace/eus384; PMID: 23355132 Walsh EP. Interventional electrophysiology in patients with congenital heart disease. Circulation 2007; 115:3224–34. DOI: 10.1161/CIRCULATIONAHA.106.655753; PMID: 17592091

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Diagnostic Electrophysiology and Ablation

Ablation of Atrial Fibrillation Drivers Tina Baykaner, Junaid A B Zaman, Paul J Wang and Sanjiv M Narayan Stanford University, Palo Alto, California, USA

Abstract Pulmonary vein isolation (PVI) is central to ablation approaches for atrial fibrillation (AF), yet many patients still have arrhythmia recurrence after one or more procedures, despite evolving technologies for PVI. Ablation of localised AF drivers, which lie outside the pulmonary veins in many patients, is a practical approach that has been shown to improve success by many groups. Such localised drivers lie in atrial regions shown mechanistically to sustain AF in optical mapping and clinical studies of human AF, as well as computational and animal studies. Clinical studies now verify rotational activation by multiple mapping approaches in the same patients, at sites where ablation terminates persistent AF. This review article provides a mechanistic and clinical rationale to ablate localised drivers, and describes successful techniques for their ablation as well as pitfalls to avoid, which may explain discrepancies between results from some centres. We hope that this review will serve as a platform for future improvements in the patient-tailored ablation for complex arrhythmias.

Keywords Atrial fibrillation, ablation, rotors, computer mapping Disclosure: This work was supported by grants from the National Institutes of Health to Sanjiv M Narayan (HL83359, HL103800). Sanjiv M Narayan is co-author of intellectual property owned by the University of California Regents and licensed to Topera Inc., and has held equity in Topera. Sanjiv M Narayan reports consulting fees and honoraria from the American College of Cardiology, Medtronic, St. Jude, Abbott and UpToDate. Paul J. Wang reports Honoraria/Consultant from Janssen, St. Jude Medical, Amgen, Medtronic; Fellowship support from Biosense Webster, Boston Scientific, Medtronic, St. Jude Medical; Clinical studies from Medtronic, Siemens, Cardiofocus, ARCA; and Stock options from Vytronus. Received: 3 August 2017 Accepted: 9 November 2017 Citation: Arrhythmia & Electrophysiology Review 2017;6(4):195–201. DOI: 10.15420/2017:28:1 Correspondence: Tina Baykaner, Stanford University, 780 Welch Road MC 5773, Stanford, CA 94305, USA; E: tina4@stanford.edu

Treatment of atrial fibrillation (AF) classically focuses on eliminating triggers near and from the pulmonary veins, which may initiate AF. However, the 1–2 year success rate of pulmonary vein isolation (PVI) remains 40–50 % for persistent AF1,2 and 50–65 % for paroxysmal AF,3–5 while supplementary linear lesions or extensive ablation at electrogram-targets have had disappointing results and may not improve the success of pulmonary vein isolation.1,2,6 In recent years, focal or rotational drivers for AF have gained increasing attention as ablation targets. This approach is now supported by wide evidence ranging from optical mapping of animal and human AF7,8 (Figure 1) to several multicentre non-randomised clinical trials of AF driver ablation, yet the paucity of randomised trials in this area still remains a shortcoming.9–14 In this review, we hope to provide an overview of the mechanistic and clinical foundation of localised drivers of human AF, technical factors explaining why they may be revealed by some but not all mapping approaches, and potential explanations for why some clinical ablation studies have been disappointing despite promising results at many independent centres.

Mechanisms of Initiation of Human AF Triggers such as ectopic beats,15 bursts of atrial tachycardia16 or varying autonomic balance17,18 may dynamically initiate AF, despite a static atrial architecture, including fibrosis.19 Dynamics in the physiology of atrial repolarisation and conduction can explain how triggers initiate AF. Ectopic beats, such as triggers from pulmonary veins, can produce dramatic oscillations of left atrial action potential duration (APD). 16,20,21 The steep curve relating APD to diastolic

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interval (time between beats) leads to drastically shortened APD, lengthening subsequent diastolic interval, producing APD alternans and wavebreak, facilitating reentry and AF. These dynamics likely interact with atrial anatomy and/or fibrosis, explaining studies in which triggers dynamically formed spiral wave reentry at spatially conserved sites22,23 that initiated AF.

Mechanisms of Maintenance of Human AF Once AF is initiated by triggers from pulmonary veins or other sites, two central hypotheses may explain how disorganised wavefronts in AF are sustained. The multi-wavelet hypothesis shows disorganised activity that generates new wavelets in a stochastic fashion, such that no specific atrial region or structural element, e.g. fibrosis distribution is not critical to the maintenance of AF.24 In this hypothesis, extensive ablation should limit the critical mass for wave propagation and increase freedom from AF, although this has been contradicted by recent multicentre trials1,2,6 and by suboptimal results in some surgical studies that limit critical mass.1,2,6,25 An alternative hypothesis is that preferential regions of the atria can act as functional drivers for AF, manifest electrically in the form of spiral waves or focal activation patterns whose wave-fronts break down resulting in fibrillatory conduction. This hypothesis can reconcile the paradox of limited ablation terminating persistent AF in some patients,26–28 while extensive, untargeted ablation of left atrial regions (that may miss a driver region) being ineffective in others.1,2,29 This mechanism is supported by optical mapping, which remains the gold standard for mapping of fibrillatory conduction (Figure 1) and uses video imaging of voltage-sensitive dyes, coupled with phase, activation

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Diagnostic Electrophysiology and Ablation Figure 1: Optical Mapping of Fibrillatory Conduction from an AF Driver A

B x

250 200 150

100 50 0

–x 0

2 Time (s)

LA phase map

5 mm

–π

2.5 mm

y-coordinate 5 mm

2 Sec

+π Phase

x-coordinate

A: High Resolution optical action potentials obtained from explanted fibrillating tissue; B: Snapshot of phase movie of a fibrillating rabbit ventricle, showing rotors as red to blue phase angles, and phase singularities as dark black dots where all phases (colors) converge; C: Rotor meandering and fractionation during AF in isolated sheep heart. On the left, a left atrial phase snapshot demonstrates reentry in the left atrium (LA) free wall. The inset shows the time–space trajectory of the phase singularity, while the x and y coordinate signals are shown on the right. Adapted from Gray, et al., 1999 (A,C) and Zlochiver, et al., 2008 (C).

or other signal processing approaches to produce high spatial and temporal resolution maps of AF. Figure 1A illustrates rapid irregular action potentials at one anatomic site mapped optically. Figure 1B plots such action potentials across the cardiac surface in fibrillation. Each color represents phase (from activation to repolarization) such that rotations can be traced through the color spectrum (from red to blue, i.e. from early to late in the activation cycle). Points in the atrium where activation and repolarszation meet, i.e. around which an entire cycle can be traced, have undefined phase and are termed phase singularities (PS) which may represent rotor cores.30 Rotors are not fixed like reentry around an obstacle, but may precess in limited areas with complex trajectories (Figure 1C).31,32 This again distinguishes them from leading circle reentry, where the circuit is stabilised spatially around a depolarised core and which is not typically anchored to a region. Fibrillation driven by a rotational source may terminate when the source collides with a boundary, does not have enough “elbow room” to spin, or via other mechanisms.

Mapping AF: Applying Basic Science to Patients Despite data in favour of rotational or focal drivers for human AF, there is an active debate on this issue with studies, predominantly using classical activation mapping, not showing any stable rotational drivers in AF. This has highlighted a central issue in AF – that results and mechanisms may differ markedly depending on the mapping approach used. This differs from mapping of organised rhythms (e.g. atrial flutter), which yield similar findings regarding the underlying arrhythmia mechanism for different mapping methods. One specific difficulty with mapping fibrillatory waves is that an electrode antenna may capture several local and far-field waves. There are few means of separating these a priori except by knowledge of refractory period, and the traditional methods of visually ‘selecting’ local signals may be incorrect33 and alter reported mechanisms. Another difficulty is that activity changes in both temporal and spatial aspects rapidly within AF, which challenges mapping.

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It became clear in early studies that unipolar, bipolar and MAP signals in AF differ dramatically,33 with examples of signals that appeared local in bipolar recordings actually being far-field, i.e. they lay within repolarisation indicated by the MAP.33 This may explain why optical maps of AF, which are based on local action potentials, show rotational drivers of AF in nearly all studies, while traditional electrode based AF activation maps mostly show only disordered activity.8,34,35 These findings, combined with data on conduction velocity and validation of mechanisms by patientspecific targeted ablation, led to Focal Impulse and Rotor Mapping/ Modulation (FIRM).27,36,37 An example of a stable right atrial AF driver and a left atrial focal source is shown in Figure 2, where basket catheters are used to identify localised AF drivers. Theoretically, baskets can resolve 1–2 cm diameter reentry circuits in human AF as predicted by Allessie et al., and shown in human optical maps of AF.7,38 Conversely, if electrodes are too closely spaced to map fibrillatory conduction, calculated wave propagation may fall within measurement error. For instance, for atrial conduction velocity in AF patients of 40 cm/sec,39,40 reported errors in assigning onset time in AF (≈5–10 ms) translate to a distance of 2–4 mm (=40×0.005 to 40×0.010). Closer electrode separation than this may attempt to identify circuits within measurement noise, and will have less confidence. A related issue is that closely spaced electrode arrays typically cover small distances simultaneously, which may also miss the 1–2 cm diameter circuits in human AF, noted in optical maps.7,41

Reconciling Differences Between Mapping Studies of AF Rotational Drivers Since long-term ablation success varies dramatically between centres even for a well-defined, anatomic guided technique, such as, due to numbers of lesions, their durability, disease progression and other factors, reconciling differences in AF mapping may be assisted by other study designs.42 On the basis that sites where ablation terminates persistent AF may have mechanistic relevance, we have recently systematically compared maps created by different techniques for analysing the same raw electrographic data in cases of clear termination of persistent AF by ablation, as part of the international COMParison of Algorithms for Rotational Evaluation in AF (COMPAREAF) study (NCT02997254).43 Figure 3 shows a patient in whom limited ablation before PVI terminated persistent AF to sinus rhythm. In panels C–E, detailed analysis of raw AF electrograms prior to ablation revealed sustained rotational activation by three methods. Of these methods, traditional activation maps of AF electrograms may be confused by spurious deflections, perhaps reflecting far field, and often showed only disorder at AF termination sites where phase and combined phase/activation maps showed rotations.

Long-term Outcomes of AF Driver-Guided Ablation Multiple studies now exist on the outcomes of AF driver ablation (Table 1), with FIRM being the most widely applied technique. As with most new approaches, while initial reports were promising, some recent reports have been disappointing, such as Buch et al. reporting 21 % success and Steinberg et al. 12 % success. These results are surprisingly low since these series included many patients with paroxysmal AF and also performed PVI.44,45 Table 1 summarises studies in a total cohort of 1181 patients undergoing AF driver ablation in addition to PVI. Of these patients, 78 % had non-paroxysmal AF, and the overall single procedure freedom from

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Ablation of Atrial Fibrillation Drivers Figure 2: A,B: Isochronal Activation Map of a Right Atrial Atrial Fibrillation Rotor and a Left Atrial Focal Source; C: Three Successive Still Frame Images of AF Sources Demonstrated on Focal Impulse and Rotor Mapping (FIRM) Movies with Top Panel Showing a Counterclockwise AF Rotor and the Bottom Panel Showing a Focal Source for AF A

Time=1 cycle

Stable RA rotor during AF

ECG V1 CS

Repetitive focal source during AF

ECG V1 CS

Figure 3: Comparing Atrial Fibrillation Mapping Methods in the Same Patient, where Ablation Terminates Persistent Atrial Fibrillation Multiple Methods to Map AF Termination Site

Traditional activation tags (-dV/dt)

Phase maps with sustained complete rotations

Activation + phase (FIRM) sustained complete rotations

Site of AF termination*

C AF termination during ablation I

<75% 160 cycle

140 120

V1 V6

ABL

180

ABL d

Traditional map - partial rotations D

100

AF Termination

80 60

B CS 9.10

C 8

D E F G H A B C

8 7 6 5 4 3 2 1

A: Example of a 65-year-old patient with localised ablation near the right superior pulmonary vein carina prior to PVI which terminates persistent AF to sinus rhythm; B,C: Traditional activation maps show only a partial rotation (75Â % of cycle, orange to light blue) which may not explain AF termination by ablation in this region; D,E: Phase maps by an independent method and activation plus phase maps (focal impulse and rotor mapping [FIRM]; activation in gray scale, phase in red) each revealed sustained rotations at the site where ablation terminates AF. Ablation site was identified prospectively by FIRM mapping.

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Diagnostic Electrophysiology and Ablation Table 1: Summary of Atrial Fibrillation Driver Ablation Studies Year Author

Study

Study Type of

Type of

Persistent Re-do

Type

Size

Driver

Ablation

Freedom Freedom

Ablation Termination from

from

(n) Mapping (months) AF AF/AT 2012 Narayan

Multi- center, controlled

Driver+PVI FIRM

9.1

0.85

0.42

0.56

0.82

0.71

2014 Haissaguerre Single center, case series

193

Driver+PVI ECVUE

12.0

1.00

0.20

0.79

0.80

0.64

2015 Sommer

1820 Driver+PVI FIRM

–

0.90

0.50

0.05

0.85

0.80

2015 Tomassoni Single center, case series

Driver+PVI FIRM

16.0

0.76

0.46

0.39

0.95

0.75

2015 Rashid

Single center, case series

Driver+PVI FIRM

7.7

0.77

0.48

0.28

0.82

0.79

2015 Tilz

Single center, case series

Driver+PVI FIRM

13.0

0.60

–

0.24

0.72

0.52

2015 Hummel

Single center, case series

Driver+PVI FIRM

26.7

0.68

0.41

–

0.73

–

6.0

0.61

–

0.39

–

0.65

Single center, case series

2015 Prystowsky Single center, case series

193 Driver+PVI FIRM

2015 Kuklik

Single 18 Driver+PVI Phase+ center, case Dyssynchrony series

n/a

1.00

0.00

0.41

0.65

–

2016 Spitzer

Single center, case series

Driver+PVI FIRM

12.0

1.00

0.09

0.73

0.69

2016 Buch

Multi- center, case series

Driver+PVI

18.0

0.44

0.67

0.26

0.37

0.21

2016 Steinberg

Single center, case series

Driver+PVI FIRM

18.7

0.83

0.72

0.12

0.24

0.12

2017 Miller

Single center, case series

170 Driver+PVI FIRM

15.0

0.63

0.43

0.39

0.87

0.70

2017 Balouch

Single center, case series

Driver+PVI FIRM

12.0

1.00

0.52

0.30

0.54

0.39

2017 Kis

Single center, case series

Driver+PVI FIRM

12.0

1.00

0.53

0.68

–

0.69

2017 Wilber

Single center, case series

131 Driver+PVI FIRM

–

0.73

0.34

0.51

–

0.77

2017 Knecht

Multi-centre, 118 case series

12.0

1.00

0.00

0.72

0.77

0.39

Driver+PVI

FIRM

ECVUE

Single procedure, acute and long-term outcomes of AF driver ablation when added to pulmonary vein isolation are presented.11,12,14,27,45,52–55,57–64

AF and from AF/all atrial arrhythmias was 76 % and 62 %, respectively. It is noted that reading AF rotational/focal source maps and/or guiding ablation accordingly are novel skills and not learned as part of traditional PVI. Indeed, lower success was seen in studies listed in Table 1 that had fewer cases per operator, and in patients studied early (pre-2013) when no automatic tools were available to interpret maps to assist the operator in this early learning phase. Recent analyses confirm the incremental benefit of adding AF driver ablation to PVI, and

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there are several multicenter trials ongoing which may provide more clarity on this issue.46 In most studies, AF drivers arise in diverse locations, overall with 25–40 % near pulmonary veins, 25–40 % elsewhere in the left atrium, and 25–40 % in the right atrium. Body surface mapping (ECVUE) show similar AF driver distributions but in larger regions,11 which may represent greater ‘meander’ in projecting from the heart to the

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Ablation of Atrial Fibrillation Drivers torso.47 In multiple studies, right atrial drivers are mostly in the free wall, posterolateral to the right atrial appendage, and rarely near the superior vena cava or cavotricuspid isthmus. AF drivers are present in higher numbers and more widely distributed in patients with persistent than paroxysmal AF.27 Atrial fibrillation rotational/focal driver sites have been compared to complex fractionated atrial electrogram (CFAE), and AF driver site areas are typically smaller than areas covered by CFAE. However, the concordance between AF drivers and CFAE differs between studies that may reflect differences in identifying CFAE or true differences between methods. FIRM identified sites do not show a specific CFAE grade or voltage fingerprint,27 i.e. CFAE arise at some AF driver sites but are prevalent elsewhere. Conversely, sites identified by body surface mapping could be related to CFAE.48 At the current time, electrogram markers for AF drivers are the subject of intense research.

Figure 4: Reported Pearls and Pitfalls in Atrial Fibrillation Source Ablation

Suboptimal

Optimal

Poor basket coverage

Multiple basket positions

Basket prolapsed to LV

Good basket position

Sparse ablation lesions

Dense ablation lesions

Practical Approach in Ablation of AF Drivers Core components required for effective driver-guided ablation include an effective broad-area mapping of both atria, precise identification of drivers to target, and ensuring full elimination of target areas. Each of these components is fertile for technical improvement, and may explain much of the heterogeneity in outcomes between centres. The FIRM approach to widely map the atria uses multipolar contact basket catheters to analyze many wave-fronts at the same time. In the right atrium, the basket catheter is unsheathed in the superior vena cava (SVC) and slowly retracted into the right atrial body. Slight clockwise or counterclockwise torque is applied for optimal deployment. Particular care is required if a right atrial pacing lead is present, rotating the basket so that splines span the lead rather than displace it, and typically advancing from the inferior vena cava rather than pulling down from the SVC. In left atrium, the basket is unsheathed in the left superior pulmonary vein and slowly retracted into the atrial body. Slight clockwise or counterclockwise torque may help achieve optimal basket deployment, maximising endocardial contact with the fewest splines over the mitral valve orifice. Alternatively, the basket catheter can be carefully ‘reflected’ off the carina of the left pulmonary veins. Figure 4 shows examples of optimal and suboptimal basket placement. Various basket sizes and types are available from an increasing number of vendors. We select the most appropriate basket size based on atrial size from intracardiac echocardiography or computed tomography. Figure 4B shows a suboptimal basket positioning that could be identified with fluoroscopic landmarks.49 Importantly, comprehensive atrial coverage may not be possible with a single basket position. Repeat maps after repositioning to sample previously poorly covered regions may help to reveal residual AF drivers. Successful driver ablation should fully cover the affected driver areas, and contact force sensing catheters may help in this regard. Incomplete coverage may explain lower success rates in some AF driver ablation studies. For instance, Figure 4C shows sparse lesions that may not have eliminated drivers in the long-term, even if AF terminates acutely.50 Incompletely eliminated driver regions may cause recurrent post-ablation AF or atrial tachycardia (AT). Thus, it is critical to ablate the entire affected region, although the science on how much atrium to ablate has yet to be fully established.

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A: Insufficient basket coverage of the left atrium (left), multiple basket positions in the left atrium, which remains the method of choice in large atria (right); B: Inadvertent LV prolapse of the basket – conical shape, anterolateral to CS, ventricular electrograms (left), good basket position covering atrium well (right); C: (left) Sparse lesions over AF driver area (Adapted from Gianni et al., 201665), (right) dense lesions in a report with more successful outcomes (Adapted from Sommer at al., 2016).53

Finally, AF driver-guided ablation does not appear to increase complication rates over traditional ablation alone,51 and is likely not pro-arrhythmic.12,44,52–56 In summary, the endpoint of AF driver ablation is the elimination of sustained rotational or focal activity that lie in conserved spatial locations. This endpoint is achievable in most patients, and may be superior to historical endpoints of AF termination. Lack of AF termination may reflect many mechanisms, including residual AF driver, but clinical results have been promising even in such patients if drivers are eliminated.

Limitations of AF Driver Mapping While basic and translational science for AF drivers is mature, additional studies are required to reconcile technical differences in mapping for individual patient types. Clinically, large multicentre randomised trials are currently not available, but are ongoing. A learning curve exists in optimum basket placement, interpretation of AF maps, and ablation guidance based on maps. Each of these elements is a subject both for technical innovation and for clinical studies.

Conclusion Evidence continues to mount that human AF is maintained by rotational and focal sources, and that targeting these areas may improve outcomes over PVI alone. We have outlined the scientific rationale for AF driver ablation, and practical strategies for ablation associated with

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Diagnostic Electrophysiology and Ablation promising outcomes in multicentre studies. Analysis of less promising studies suggests that suboptimal basket placement, resulting in greater difficulty in reading maps and in targeting ablation, and early learning curve experience may explain at least some of these discrepancies. Future improvements in AF driver ablation may be facilitated by better computational interpretation of AF maps, comparative studies between potentially complementary mapping approaches, and improvements in basket design. Combined mechanistic and imaging studies may enable better and functional classification of AF that may enable better patient tailoring of AF ablation. Ultimately, a better mechanistic and clinical understanding of AF may pave the way for novel drug discovery or regenerative therapies for AF. This is an exciting prospect. n

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erma A, Jiang CY, Betts TR, et al. Approaches to catheter V ablation for persistent atrial fibrillation. N Engl J Med 2015;372:1812–22. DOI: 10.1056/NEJMoa1408288; PMID: 25946280. Wong KC, Paisey JR, Sopher M, et al. No Benefit OF Complex Fractionated Atrial Electrogram (CFAE) Ablation in Addition to Circumferential Pulmonary Vein Ablation and Linear Ablation: BOCA Study. Circ Arrhythm Electrophysiol 2015;8:1316–24. DOI: 10.1161/CIRCEP.114.002504; PMID: 26283145. Calkins H. Demonstrating the value of contact force sensing: more difficult than meets the eye. Circulation 2015;132:901–3. DOI: 10.1161/CIRCEP.114.002504; PMID: 26283145. Dukkipati SR, Cuoco F, Kutinsky I, et al. Pulmonary vein isolation using the visually guided laser balloon: A prospective, multicenter, and randomized comparison to standard radiofrequency ablation. J Am Coll Cardiol 2015;66:1350–60. DOI: 10.1016/j.jacc.2015.07.036; PMID: 26383722. Kuck KH, Brugada J, Furnkranz A, et al. Cryoballoon or radiofrequency ablation for paroxysmal atrial fibrillation. N Engl J Med 2016;374:2235–45. DOI: 10.1056/NEJMoa1602014; PMID: 27042964. Vogler J, Willems S, Sultan A, et al. Pulmonary vein isolation versus defragmentation: The CHASE-AF clinical trial. J Am Coll Cardiol 2015;66:2743–52. DOI: 10.1016/j.jacc.2015.09.088; PMID: 26700836. Hansen BJ, Zhao J, Csepe TA, et al. Atrial fibrillation driven by micro-anatomic intramural re-entry revealed by simultaneous sub-epicardial and sub-endocardial optical mapping in explanted human hearts. Eur Heart J 2015;36:2390–401. DOI: 10.1093/eurheartj/ehv233; PMID: 26059724. Pandit SV and Jalife J. Rotors and the dynamics of cardiac fibrillation. Circ Res 2013;112:849–62. DOI: 10.1161/ CIRCRESAHA.111.300158; PMID: 23449547 PMCID: PMC3650644. Narayan SM, Baykaner T, Clopton P, et al. Ablation of rotor and focal sources reduces late recurrence of atrial fibrillation compared with trigger ablation alone: extended follow-up of the CONFIRM trial (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation). J Am Coll Cardiol 2014;63:1761–8. DOI: 10.1016/j.jacc.2014.02.543; PMID: 24632280; DOI: 10.1016/j.jacc.2014.02.543. Miller MA, Gangireddy SR, Doshi SK, et al. Multicenter study on acute and long-term safety and efficacy of percutaneous left atrial appendage closure using an epicardial suture snaring device. Heart Rhythm 2014;11;1853–9. DOI: 10.1016/j. hrthm.2014.07.032; PMID: 25068574. Haissaguerre M, Hocini M, Denis A, et al. Driver domains in persistent atrial fibrillation. Circulation 2014;130:530–8. DOI: 10.1161/CIRCULATIONAHA.113.005421; PMID: 25028391. Rashid H and Sweeney A. Approaches for focal impulse and rotor mapping in complex patients: A US private practice perspective. J Innovations Card Rhythm Management 2015; 6:2193–98. DOI:10.19102/icrm.2015.061104 Tomassoni G, Duggal S, Muir M, et al. Long-term follow-up of FIRM-guided ablation of atrial fibrillation: A single center experience. The Journal of Innovations in Cardiac Rhythm Management. 2015;6:2145–51. Miller JM, Kalra V, Mithilesh DK, et al. Clinical benefit of ablating localized sources for human atrial fibrillation: The Indiana University FIRM Registry. J Am Coll Cardiol 2017; 69:1247–56. DOI: 10.1016/j.jacc.2016.11.079; PMID: 28279291. Haissaguerre M, Jais P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998;339:659–6. DOI: 10.1056/ NEJM199809033391003; PMID: 9725923. Narayan SM, Bode F, Karasik PL, et al. Alternans of atrial action potentials as a precursor of AF. Circulation 2002;106:1968–73. PMID: 12370221. Patterson E, Po SS, Scherlag BJ, et al. Triggered firing in pulmonary veins initiated by in vitro autonomic nerve stimulation. Heart Rhythm 2005;2:624–31. DOI: 10.1016/j. hrthm.2005.02.012; PMID: 15922271. Katritsis DG, Giazitzoglou E, Zografos T, et al. Rapid pulmonary vein isolation combined with autonomic ganglia modification: a randomized study. Heart Rhythm 2011;8:672–8. DOI: 10.1016/j. hrthm.2010.12.047; PMID: 21199686.

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Clinical Perspective • A F drivers have been shown in animal and human optical mapping studies, as well as using several new mapping technologies. • Studies demonstrate promising outcomes with rotor ablation when added to pulmonary vein isolation. • Future improvements to the field would include better automated interpretation of AF maps, comparative studies between mapping approaches that may be complementary, and improved basket designs.

19. E ngelman ZJ, Trew ML and Smaill BH. Structural heterogeneity alone is a sufficient substrate for dynamic instability and altered restitution. Circ Arrhythm Electrophysiol 2010;3:195–203. DOI: 10.1161/CIRCEP.109.890459; PMID: 20133934. 20. Narayan SM, Kazi D, Krummen DE, et al. Repolarization and activation restitution near human pulmonary veins and atrial fibrillation initiation: a mechanism for the initiation of atrial fibrillation by premature beats. J Am Coll Cardiol 2008;52:1222– 30. DOI: 10.1016/j.jacc.2008.07.012; PMID: 18926325. 21. Narayan SM, Franz MR, Clopton P, et al. Repolarization alternans reveals vulnerability to human atrial fibrillation. Circulation 2011;123:2922–30. DOI: 10.1161/ CIRCULATIONAHA.110.977827;PMID: 21646498. 22. Gonzales MJ, Vincent KP, Rappel W-J, et al. Structural contributions to fibrillatory rotors in a patient-derived computational model of the atria. Europace 2014;16:iv3-iv10. DOI: 10.1093/europace/euu251; PMID: 25362167. 23. 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. 24. Moe GK, Rheinboldt W, Abildskov J. A computer model of atrial fibrillation. Am Heart J 1964;67:200–220. PMID: 14118488. 25. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/ HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014;64: e1–76. DOI: 10.1016/j.jacc.2014.03.022; PMID: 24685669. 26. Herweg B, Kowalski M, Steinberg JS. Termination of persistent atrial fibrillation resistant to cardioversion by a single radiofrequency application. Pacing Clin Electrophysiol 2003;26:1420–3. PMID: 12822761. 27. Narayan SM, Krummen DE, Shivkumar K, et al. Treatment of atrial fibrillation by the ablation of localized sources: CONFIRM trial. J Am Coll Cardiol 2012;60:628–36. DOI: 10.1016/j. jacc.2012.05.022; PMID: 22818076. 28. Shivkumar K, Ellenbogen KA, Hummel JD, et al. Acute termination of human atrial fibrillation by identification and catheter ablation of localized rotors and sources: first multicenter experience of focal impulse and rotor modulation (FIRM) ablation. J Cardiovasc Electrophysiol 2012;23:1277–85. DOI: 10.1111/jce.12000; PMID: 23130890. 29. Haissaguerre M, Hocini M, Sanders P, et al. Catheter ablation of long-lasting persistent atrial fibrillation: clinical outcome and mechanisms of subsequent arrhythmias. J Cardiovasc Electrophysiol 2005;16:1138–47. DOI: 10.1111/j. 1540-8167.2005.00308.x; PMID: 16302893. 30. Gray RA, Pertsov AM, Jalife J. Spatial and temporal organization during cardiac fibrillation. Nature 1998;392:75–8. DOI: 10.1038/32164; PMID: 9510249. 31. Davidenko JM, Pertsov AV, Salomonsz R, et al. Stationary and drifting spiral waves of excitation in isolated cardiac muscle. Nature 1992;355:349–51. DOI: 10.1038/355349a0; PMID: 1731248. 32. Zlochiver S, Yamazaki M, Kalifa J, et al. Rotor meandering contributes to irregularity in electrograms during atrial fibrillation. Heart Rhythm 2008;5:846–54. DOI: 10.1016/j. hrthm.2008.03.010; PMID: 18534369. 33. Narayan SM, Wright M, Derval N, et al. Classifying fractionated electrograms in human atrial fibrillation using monophasic action potentials and activation mapping: evidence for localized drivers, rate acceleration and non-local signal etiologies. Heart Rhythm 2011;8:244–53. DOI: 10.1016/j. hrthm.2010.10.020; PMID: 20955820. 34. Allessie MA, de Groot NM, Houben RP, et al. Electropathological substrate of long-standing persistent atrial fibrillation in patients with structural heart disease: longitudinal dissociation. Circ Arrhythm Electrophysiol 2010; 3:606–15. DOI: 10.1161/CIRCEP.109.910125; PMID: 20719881. 35. Lee S, Sahadevan J, Khrestian CM, et al. Simultaneous biatrial high-density epicardial mapping of persistent and longstanding persistent AF in patients: New insights into the mechanism of Its maintenance. Circulation 2015;132:2108–17. DOI: 10.1161/CIRCULATIONAHA.115.017007; PMID: 26499963.

36. N arayan SM, Krummen DE, Rappel W-J. Clinical mapping approach to identify rotors and focal beats in human atrial fibrillation. J Cardiovasc Electrophysiol 2012;23:447–54. DOI: 10.1111/j.1540-8167.2012.02332.x; PMID: 22537106. 37. Narayan SM, Krummen DE, Enyeart MW, et al. Computational mapping approach identifies stable and long-lived electrical rotors and focal sources in human atrial fibrillation. PLos One 2012;7:e46034. DOI: 10.1371/journal.pone.0046034; PMID: 23049929. 38. Allessie MA, Bonke FIM, Schopman FJG. Circus movement in rabbit atrial muscle as a mechanism of tachycardia. III: the “leading circle” concept: a new model of circus movement in cardiac tissue without the involvement of an anatomical obstacle. Circ Res 1977;41:9–18. PMID: 862147. 39. Lalani G, Schricker A, Gibson M, et al. Atrial conduction slows immediately before the onset of human atrial fibrillation: a bi-atrial contact mapping study of transitions to atrial fibrillation. J Am Coll Cardiol 2012;59:595–606. DOI: 10.1016/j. jacc.2011.10.879; PMID: 22300695. 40. Schricker A, Rostamian A, Lalani G, et al. Human atrial fibrillation initiates by organized not disorganized mechanisms. Circ Arrhythm Electrophysiol 2014;7:816–24. DOI: 10.1161/CIRCEP.113.001289; PMID: 25217042. 41. Zhao J, Hansen BJ, Csepe TA, et al. Integration of highresolution optical mapping and 3-dimensional microcomputed tomographic imaging to resolve the structural basis of atrial conduction in the human heart. Circ Arrhythm Electrophysiol 2015;8:1514–7. DOI: 10.1161/CIRCEP.115.003064; PMID: 26671938. 42. 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. 43. Alhusseini M, Vidmar D, Meckler GL, et al. Two independent mapping techniques identify rotational activity patterns at sites of local termination during persistent atrial fibrillation. J Cardiovasc Electrophys 2017;28:615–22. DOI: 10.1111/jce.13177; PMID: 28185348. 44. Buch E, Share M, Tung R, et al. Long-term clinical outcomes of focal impulse and rotor modulation for treatment of atrial fibrillation: a multi-center experience. Heart Rhythm 2016;13:636–41. DOI: 10.1016/j.hrthm.2015.10.031; PMID: 26498260. 45. Steinberg JS, Shah Y, Bhatt A, et al. Focal impulse and rotor modulation: acute procedural observations and extended clinical follow-up. Heart Rhythm 2016;14:192–7. DOI: 10.1016/j. hrthm.2016.11.008; PMID: 27826130. 46. Ramirez FD, Birnie DH, Nair GM, et al. Efficacy and safety of driver-guided catheter ablation for atrial fibrillation: A systematic review and meta-analysis. J Cardiovasc Electrophysiol 2017. DOI: 10.1111/jce.13313; PMID: 28800192. 47. Rodrigo M, Guillem MS, Climent AM, et al. Body surface localization of left and right atrial high frequency rotors in atrial fibrillation patients: a clinical-computational study. Heart Rhythm 2014;11:1584–91. DOI: 10.1016/j.hrthm.2014.05.013; PMID: 24846374. 48. Zahid S, Cochet H, Boyle PM, et al. Patient-derived models link re-entrant driver localization in atrial fibrillation to fibrosis spatial pattern. Cardiovasc Res 2016;110:443–54. DOI: 10.1093/ cvr/cvw073; PMID: 27056895. 49. Benharash P, Buch E, Frank P, et al. Quantitative analysis of localized sources identified by focal impulse and rotor modulation mapping in atrial fibrillation. Circ Arrhythm Electrophysiol 2015;8:554–61. DOI: 10.1161/CIRCEP.115.002721; PMID: 25873718. 50. Gianni C, Di Biase L, Deneke T, et al. Acute and short-term outcomes in persistent and long-standing persistent patients undergoing rotors only ablation (Abstract). Heart Rhythm 2015;12:PO01–58. 51. Krummen DE, Baykaner T, Swarup V, et al. Multicenter procedural safety of FIRM ablation (Abstract). Europace 2016. 52. Tomassoni G, Duggal S, Muir M, et al. Long-term follow-up of FIRM-guided ablation of atrial fibrillation: A single-center experience. J Innovations Card Rhythm Management 2015;6:2145–51. DOI: 10.1016/j.jacep.2016.10.006. 53. Sommer P, Kircher S, Rolf S, et al. Successful repeat catheter ablation of recurrent longstanding persistent AF with rotor

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elimination as the procedural endpoint: A case series. J Cardiovasc Electrophysiol 2016;27:274–80. DOI: 10.1111/ jce.12874; PMID: 26527103. 54. Spitzer SG, Karolyi L, Rammler C, et al. Treatment of recurrent non-paroxysmal atrial fibrillation using focal impulse and rotor mapping (FIRM)-guided rotor ablation: early recurrence and long-term outcomes. J Cardiovasc Electrophysiol 2017; 28:31–38. DOI: 10.1111/jce.13110; PMID: 27766704. 55. Tilz RR, Lin T, Rillig A, et al. Focal impulse and rotor modulation for the treatment of atrial fibrillation: locations and one year outcomes of human rotors identified using a 64-electrode basket catheter. J Cardiovasc Electrophysiol 2017;28:367–74. 10.1111/jce.13157 56. Miller JM, Das MK, Jain R, et al. Clinical benefit of ablating localized sources for human atrial fibrillation: the Indiana University FIRM Registry. J Am Coll Cardiol 2017;69:1247–56. DOI: 10.1016/j.jacc.2016.11.079; PMID: 28279291.

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fibrillation ablation outcomes. Clin Cardiol 2017;40:383–89. DOI: 10.1002/clc.22674; PMID: 28120392. Kis Z, Theuns D, Bhagwandien R, et al. Type and rate of atrial fibrillation termination due to rotational activity ablation combined with pulmonary vein isolation. J Cardiovasc Electrophys 2017;28:862–9. DOI: 10.1111/jce.13240; PMID: 28471019. Wilber D. FIRM ablation as an adjunct to pulmonary vein isolation. Western AF Symposium, Park City, UT. 2017. Knecht S, Sohal M, Deisenhofer I, et al. Multicentre evaluation of non-invasive biatrial mapping for persistent atrial fibrillation ablation: the AFACART study. Europace 2017;19:1302–9. DOI: 10.1093/europace/euw168; PMID: 28204452. Gianni C, Mohanty S, Di Biase L, et al. Acute and early outcomes of FIRM-guided rotors-only ablation in patients with non-paroxysmal atrial fibrillation. Heart Rhythm 2016;13:830–5. DOI: 10.1016/j.hrthm.2015.12.028; PMID: 26706193.

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Minimally Invasive Epicardial Surgical Ablation Alone Versus Hybrid Ablation for Atrial Fibrillation: A Systematic Review and Meta-Analysis Charles M Pearman, 1,3 Shi S Poon, 1 Laura J Bonnett, 4 Shouvik Haldar, 5 Tom Wong, 5 Neeraj Mediratta 2 and Dhiraj Gupta 1 1. Department of Cardiology, Liverpool Heart and Chest Hospital; 2. Department of Cardiothoracic Surgery, Liverpool Heart and Chest Hospital; 3. Division of Cardiovascular Sciences, School of Medical Sciences, Manchester Academic Health Science Centre, The University of Manchester; 4. Department of Biostatistics, University of Liverpool; 5. Heart Rhythm Centre, NIHR Cardiovascular Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust, Institute of Cardiovascular Medicine and Science, Imperial College London, UK

Abstract Maintaining sinus rhythm in patients with non-paroxysmal AF is an elusive goal. Some suggest that hybrid ablation, combining minimally invasive epicardial surgical ablation with endocardial catheter ablation, may be more effective than either modality alone. However, randomised trials are lacking. We investigated whether hybrid ablation is more effective than epicardial ablation alone at preventing recurrent AF by performing a systematic review and meta-analysis. The review was prospectively registered with PROSPERO (CRD42016043389). MEDLINE and EMBASE were searched for studies of standalone minimally invasive epicardial ablation of AF and/or hybrid ablation, identifying 41 non-overlapping studies comprising 2737 patients. A random-effects meta-analysis, meta-regression and sensitivity analysis were performed. Single-procedure survival free from atrial arrhythmias without antiarrhythmic drugs was similar between epicardial-alone and hybrid approaches at 12 months (epicardial alone 71.5 %; [95 % CI 66.1–76.9], hybrid 63.2 %; [95 % CI 51.5–75.0]) and 24 months (epicardial alone 68.5 %; [95 % CI 57.7–79.3], hybrid 57.0 %; [95 % CI 33.6–80.4]). Freedom from atrial arrhythmias with AADs and rates of unplanned additional catheter ablations were also similar between groups. Major complications occurred more often with hybrid ablation (epicardial alone 2.9 %; [95 % CI 1.9–3.9], hybrid 7.3 %; [95 % CI 4.2–10.5]). Meta-regression suggested that bipolar radiofrequency energy and thoracoscopic access were associated with greater efficacy, but adjusting for these factors did not unmask any difference between epicardial-alone and hybrid ablation. Hybrid and epicardial ablation alone appear to be equally effective treatments for AF, although hybrid ablation may be associated with higher complication rates. These data derived from observational studies should be verified with randomised data.

Keywords Atrial fibrillation, ablation, minimally invasive, surgical, hybrid, convergent, complications, trans-diaphragmatic, monopolar Disclosure: Charles Pearman was supported by a clinical lectureship from the National Institute for Health Research. Laura Bonnett was supported by a post-doctoral research fellowship (PDF-2015-08-044) from the National Institute for Health Research. Shouvik Haldar, Tom Wong and Dhiraj Gupta were supported by the National Institute of Health Research grant EME 12/127/127. Received: 14 August 2017 Accepted: 7 November 2017 Citation: Arrhythmia & Electrophysiology Review 2017;6(4):202–9. DOI: 10.15420/aer/2017.29.2 Correspondence: Charles Pearman, Department of Cardiology, Liverpool Heart and Chest Hospital, Thomas Drive, Liverpool, L14 3PE, UK. E: charles.pearman@manchester.ac.uk.

The goal of arrhythmia eradication in AF continues to be elusive for cardiac electrophysiologists. Although endocardial radiofrequency (RF) catheter ablation is more effective than pharmacological management at maintaining sinus rhythm,1 it is far from perfect, especially in patients with non-paroxysmal AF.2 In an attempt to address this, attention has turned back to the surgical ablation that preceded catheterbased approaches. While the initial open-chest Cox-Maze procedure generated high success rates, the complexity and invasiveness of this procedure limited its widespread adoption. As surgical techniques evolved and the traditional cut-and-sew method of surgical ablation was replaced with device-based lesion formation, the complication rate substantially improved.3 Aiming to preserve efficacy while reducing complication rates and recovery time, several minimally invasive surgical techniques have been described varying in access site, ablation energy source, and lesion set. These aims may not have been fully met, as a recent review found that that using modern techniques, a full Cox-Maze performed on cardiopulmonary bypass had an equally low complication rate as minimally invasive procedures3.

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Initial reports suggest that minimally invasive epicardial surgical ablation may be more effective than endocardial catheter ablation, 4–6 albeit with a higher risk of complications. Why should ablation from the epicardial surface be more effective? Epicardial ablation using bipolar RF increases the likelihood of fully transmural atrial lesions that reduce the chance of electrical reconnection, 7 although transmural lesions occur less frequently using monopolar RF. 8 Furthermore, the left atrial appendage can be both physically and electrically isolated during surgical ablation, reducing the risk of thromboembolism and possibly recurrent arrhythmias.9 The disadvantages of surgical ablation relate to difficulties accessing some regions of the atria (the cavotricuspid and mitral isthmuses and the superior aspect of the pulmonary veins with a transdiaphragmatic approach). However, these regions are easily accessible by endocardial catheter ablation. To exploit the benefits of epicardial and endocardial ablation, some groups therefore advocate a ‘hybrid’10 or ‘convergent’11 approach and routinely combine these techniques.

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Efficacy of Epicardial Versus Hybrid Ablation for AF Despite the theoretical advantages of a hybrid approach, it is uncertain whether hybrid ablation is more effective than epicardial ablation alone in practice, as no randomised controlled trials (RCTs) have addressed this question. While a single cohort study suggested that hybrid ablation was more effective,12 two others did not find a difference,13,14 potentially stemming from differences in the surgical techniques and lesions sets used. We asked whether, in patients with AF, the outcomes from hybrid ablation differ from those from minimally invasive surgical epicardial ablation alone with respect to freedom from atrial arrhythmias at 12 and 24 months, major complication rates and the need for additional unplanned catheter ablations. Because of the absence of RCTs, we addressed these questions by performing a systematic review and meta-analysis of all studies reporting the outcomes of these procedures.

Figure 1: Study Selection Diagram MEDLINE and EMBASE searched from start -1/11/2016 for: ("atrial fibrillation" OR "AF" ) AND ("surgical" OR "hybrid" OR "thoracoscopic" OR "pericardioscopic" OR "endoscopic" or "minimally invasive" OR "minimal invasive" OR "less invasive") AND ("ablation" OR "pulmonary vein isolation" OR "PVI" OR “radiofrequency”).

1530 records identified through searching MEDLINE

105 records identified through searching EMBASE (MEDLINE journals excluded)

1 record identified through other sources

1636 records screened

1532 records excluded as failed to meet inclusion criteria

104 full text articles assessed for eligibility

63 full-text articles excluded

Methods A comprehensive description of the methods used can be found in the supplemental materials (available online at www.aerjournal. com). The Preferred Reporting Items For Systematic Reviews and Meta-analyses15 and Meta-analysis Of Observational Studies In Epidemiology16 guidelines for reporting meta-analyses were followed. A protocol for the meta-analysis was prospectively recorded in the PROSPERO registry (CRD42016043389).

Search Strategy Relevant studies were identified by interrogating the MEDLINE and EMBASE databases including studies from the start of records to 1st November 2016. Additional studies were identified by scanning reference lists of included studies and existing reviews. The search strategy can be found in Figure 1. Shortlisted papers and reasons for exclusion can be found in the Supplemental Materials, available online.

Outcome Measures The pre-specified primary outcome was survival free from any atrial arrhythmia (AF, typical or atypical atrial flutter, left or right atrial tachycardia) without antiarrhythmic drugs (AADs) at 12 and 24 months. Secondary outcomes included survival free from any atrial arrhythmias with or without AADs, survival free from AF with or without AADs, need for repeat catheter ablation, and rate of major complications. A list of all data fields extracted can be found in Supplemental Table 1.

Eligibility and Exclusion Criteria RCTs, cohort studies and case series published in peer-reviewed journals including at least one cohort of ≥10 patients undergoing minimally invasive epicardial ablation of AF using RF energy were eligible for inclusion. Studies were excluded if patients underwent concomitant cardiac surgery or routine sternotomy, used non-RF energy sources, were not published as full-text articles, or contained patients overlapping an already included study. Studies in which the planned treatment was a combination of minimally invasive surgical ablation with endocardial catheter ablation and in which both aspects of the ablation were completed in >75 % of patients were included in the ‘hybrid’ group. The endocardial ablation could be performed either simultaneously with the epicardial ablation or as a staged procedure up to 3 months later, as no difference in outcome has been shown between simultaneous and staged hybrid ablation.17 Studies in which catheter ablation was not performed routinely but was performed ad hoc in cases of recurrent arrhythmia

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• Overlapping patients (33) • <12 months follow up (9) • No data at specified timepoints (9) • Concomitant cardiac surgery (8) • Non-RF energy source (3) • Routine sternotomy (1)

41 studies included in quantitative synthesis See Supplemental Table 4 (available online) for details of all excluded full text articles.

were included in the ‘epicardial only’ group. Studies that fell into neither of these categories were excluded.

Statistical Methods Data analysis was performed by a statistician (LB). Based on the sampling frame that comprised diverse populations of patients, pooled estimates were obtained for each outcome for epicardialalone and hybrid ablation via the DerSimonian and Laird method using a random-effects model. Differences between epicardial alone and hybrid ablations were judged to be different if 95 % CIs for the respective pooled estimates did not overlap.18 Baseline demographics were compared using two-tailed T-tests for normally distributed continuous data and Chi-squared tests for categorical data. Meta-regression was used to examine the impact of several clinical covariates on the effect size of both primary outcomes. Study quality and risk of bias within studies were assessed using a modified version of published criteria1,19 for measuring the quality of case series (Supplemental Table 3). Risk of publication bias across studies was assessed using Funnel plots and Eggers’ test.18 Analyses were performed using R version 3.2.3.20

Results The search strategy generated 1636 abstracts (see Figure 1). Fortyone studies comprising a total of 2737 patients met the inclusion criteria (median number of patients per study 52, range 12–240). The commonest reason for excluding studies was overlapping patient cohorts (Supplemental Table 4). Five RCTs and two cohort studies compared minimally invasive surgical ablation against another treatment (catheter ablation 4–6,21 (n=4), medical management 22,23 (n=2), open chest surgical ablation24 (n=1); in these studies the minimally invasive surgical arm was treated as a single case series. Two RCTs and one cohort study compared surgical ablation techniques (+/− ganglionic plexus ablation25 (n=1), +/− left atrial appendage exclusion 26 (n=1), immediate versus delayed hybrid ablation17 (n=1); in these studies the two arms were combined to

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Diagnostic Electrophysiology and Ablation Table 1: Demographics of Patients Included in Studies Demographic

Epicardial alone

Hybrid

Mean (SD)

(30 series,

(12 series,

Difference (p-value)

2132 patients)

605 patients)

Age (years)

59.1 (4.1)

60.5 (2.9)

0.22

Gender (male) (%)

69.6 (11.6)

76.5 (13.8)

0.16

LA diameter (mm)

46.0 (4.2)

48.7 (2.8)

0.02

LV ejection fraction (%)

56.6 (4.4)

54.4 (4.8)

0.24

BMI (kg/m2)

28.6 (3.0)

29.7 (2.1)

0.35

CHADS score

1.2 (1.0)

1.2 (0.2)

0.80

Prior catheter ablation (%)

28.6 (25.9)

28.7 (33.4)

0.99

Paroxysmal AF (%)

43.6 (33.3)

9.3 (16.1)

<0.001

Persistent AF (%)

30.0 (28.6)

35.7 (30.0)

0.58

Longstanding persistent AF (%)

26.4 (37.3)

55.2 (34.7)

0.03

Duration of AF (years)

5.0 (2.1)

5.0 (1.3)

0.99

BMI = body mass index; LA = left atrial; LV = left ventricular. Values in bold denote statistically significant differences.

form a single case series for the primary analysis but treated as separate series for the meta-regression where appropriate. One cohort study compared hybrid with epicardial-alone ablation13 and in this study the two arms treated as separate case series. Thirty studies were single-arm case series. Forty-one studies therefore yielded 42 case series. Combined, the demographics of the patients included in the studies of epicardial ablation alone were broadly similar to those included in the studies of hybrid ablation (Table 1, Supplemental Table 5). However, studies of hybrid ablation included patients with greater left atrial diameters, a greater proportion of patients with longstanding persistent AF and correspondingly fewer patients with paroxysmal AF. These discrepancies were addressed and adjusted for in sensitivity analyses.

Clinical Outcomes Studies showed heterogeneity across all outcomes and therefore a random-effects model was used. The pooled estimates for the prespecified primary outcome of survival free from any atrial arrhythmias without AADs showed marked heterogeneity (I2), but were similar between epicardial-alone and hybrid approaches at 12 months (epicardial alone 71.5 %; [95 % CI 66.1–76.9]; I2 86 %, hybrid 63.2 %; [95 % CI 51.5–75.0]; I2 89 %, see Figure 2A) and 24 months (epicardial alone 68.5 %; [95 % CI 57.7–79.3]; I2 87 %, hybrid 57.0 %; [95 % CI 33.6–80.4]; I2 92 %, see Figure 2B). Survival free from any atrial arrhythmias with or without AADs was also similar at 12 months (epicardial alone 78.4 %; [95 % CI 72.9–83.9]; I 2 87 %, hybrid 76.9 %; [95 % CI 66.6–87.3]; I 2 90 %, see Supplemental Figure 1) and 24 months (epicardial alone 77.1 %; [95 % CI 67.5–86.6]; I 2 82 %, hybrid 65.2 %; [95 % CI 39.0–91.4]; I 2 95 %, see Supplemental Figure 2), as was AF-free survival with or without AADs at 12 months (epicardial alone 84.0%; [95 % CI 79.5–88.4]; I 2 70 %, hybrid 90 %; [95 % CI 83.0–97.1]; I 2 90 %, see Supplemental Figure 3) and 24 months (epicardial alone 87.2 %; [95 % CI 81.2–93.3]; I 2 0.0 %, hybrid 93.1 %; [95 % CI 87.2–99]; I 2 0.0 %, see Supplemental Figure 4).

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The rate of major complications defined as a composite of death, stroke/transient ischemic attack, major bleeding, pericardial effusion requiring drainage, atrio-oesophageal fistula, and sternotomy showed somewhat narrower heterogeneity than the primary outcome, and was significantly higher in the hybrid ablation group (epicardial alone 2.8 %; [95 % CI 1.8–3.9]; I2 52 %, hybrid 7.3 %; [95 % CI 4.2–10.5]; I2 54 %, see Supplemental Figure 5 and Supplemental Table 7). Similar numbers of additional unplanned catheter ablations were performed in each group (epicardial alone 7.2 %; 95 % CI [4.9–9.6]; I2 51 %, hybrid 7.1 %; 95 % CI [2.8–11.4]; I2 81 %, see Supplemental Figure 6).

Meta-Regression We next explored possible causes for the marked heterogeneity in reported success rates by performing a univariable meta-regression on the primary outcome (Table 2). Studies using monopolar RF reported lower success rates than those using bipolar RF (OR 0.79; [95 % CI 0.70–0.88] at 12 months). Lower success rates were also seen when trans-diaphragmatic access was compared with thoracoscopic access (OR 0.72; [95 % CI 0.61–0.86] at 12 months). We investigated the surgical techniques used by grouping studies according to primary lesion set (pulmonary vein isolation [PVI], PVI and box lesion, PVI and box lesion and right atrial [RA] ablation [see Supplemental Table 2), ganglionic plexus ablation, left atrial appendage exclusion, and whether conduction block was verified. Studies in which >50 % of participants underwent left atrial appendage exclusion reported higher success rates (OR 1.15; [95 % CI 1.04–1.27] at 12 months). Neither the proportion of participants with paroxysmal AF nor the duration of ambulatory monitoring in the first 12 months were associated with the primary outcome. We also performed a meta-regression on the major complication rate (Table 1). Higher rates of major complications were associated with hybrid ablation (OR 1.03; [95 % CI 1.01–1.05]), trans-diaphragmatic access (OR 1.05; [95 % CI 1.00–1.11]), more extensive lesion sets (OR 1.04; [95 % CI 1.02–1.06] for PVI alone versus PVI and box lesion and RA ablation), and left atrial appendage exclusion (OR 1.03; [95 % CI 1.01–1.05]).

Sensitivity Analysis As our primary analysis suggested that hybrid ablation was no more effective than epicardial ablation alone, we next performed sensitivity analyses to assess the robustness of our conclusions (Supplemental Table 8). We first addressed the disparity in demographics by performing a sensitivity analysis including only studies in which no more than 20 % of participants had paroxysmal AF, a value which in our experience is representative of the case mix of thoracoscopic ablation in the UK.27 This analysis removed all demographic differences including the proportion of participants with paroxysmal AF (epicardial alone 1.8 %; [95 % CI 0.0–6.8], hybrid 3.3 %; [95 % CI 0.0–9.1]; p=0.55) and mean left atrial diameter (epicardial alone 49.3 mm; [95 % CI 44.5–54.1], hybrid 49.1 mm; [95 % CI 46.7–51.7]; p=0.88). This analysis did not unmask any differences between groups (epicardial alone 73 %; [95 % CI 62–85], hybrid 63 %; [95 % CI 51–76]). We also used this sensitivity analysis to reassess the meta-regression. Lesion sets

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Efficacy of Epicardial Versus Hybrid Ablation for AF Figure 2: Forest Plot Showing the Primary Outcome of Atrial Arrhythmia-free Survival Without Antiarrhythmic Drugs A Author (year) Abo-Salem (2013)† Bagge (2009) Bauer (2009) Beaver (2016) Boersma (2011) Compier (2016)† De Maat (2013) Doty (2012) Driessen (2016) Edgerton (2010) Fengsrud (2016) Gersak (2012) Geuzebroek (2016) Janusauskas (2016)* Kasirajan (2012) Krul (2014) Mcclelland (2007) Oudeman (2015) Pojar (2014)* Pokushalov (2013) Probst (2015) Romanov (2016) Santini (2012) Sirak (2012)‡ Wagner (2015)* Wang (2014) Weimar (2012) Zheng (2013)

Epi-alone / hybrid

Patients

Event free survival

Eligible patients

Epicardial Epicardial Epicardial Epicardial Epicardial Epicardial Epicardial Epicardial Epicardial Epicardial Epicardial Epicardial Epicardial Epicardial Epicardial Epicardial Epicardial Epicardial Epicardial Epicardial Epicardial Epicardial Epicardial Epicardial Epicardial Epicardial Epicardial Epicardial

33 43 54 12 61 25 86 32 240 52 15 32 82 91 118 36 21 20 41 32 60 176 22 229 15 103 89 139

17 15 25 11 40 17 42 10 158 33 8 21 30 48 102 27 14 12 24 26 45 125 16 109 12 79 42 99

29 33 38 12 61 23 59 25 227 52 15 29 45 91 118 36 21 15 33 32 59 173 22 114 15 103 51 138 I2 = 86 %

Bulava (2015)* de Asmundis (2016) Edgerton (2016)† Gehi (2013) Gersak (2016) Krul (2014) La Meir (2012) Mahapatra (2011) Muneretto (2012) On (2015) Osmancik (2016)* Richardson (2016)

Hybrid Hybrid Hybrid Hybrid Hybrid Hybrid Hybrid Hybrid Hybrid Hybrid Hybrid Hybrid

51 64 24 101 76 36 19 15 24 79 33 83

43 31 4 33 37 30 7 12 16 35 21 45

50 46 24 77 61 36 19 14 22 47 29 79 I2 = 89 %

20 %

40 %

60 %

80 %

100 %

Atrial arrhythmia free survival at 12 m off AADs

Epi-alone / hybrid

Patients

Event free survival

Eligible patients

Abo-Salem (2013)† De Maat (2013) Doty (2012) Janusauskas (2016)* Pojar (2014)* Santini (2011) Sirak (2012) Wagner (2015)* Wang (2014) Weimar (2012) Zheng (2013)

Epicardial Epicardial Epicardial Epicardial Epicardial Epicardial Epicardial Epicardial Epicardial Epicardial Epicardial

33 86 32 91 41 22 229 14 103 89 139

13 28 3 45 32 7 34 8 77 17 82

27 39 13 85 37 10 37 11 103 19 138

Bulava (2015)* de Asmundis (2016) Edgerton (2016)† Gersak (2016) Muneretto (2012) Osmancik (2016)*

Hybrid Hybrid Hybrid Hybrid Hybrid Hybrid

51 64 24 76 24 33

39 7 3 36 15 7

49 11 24 58 21 13

Author (year)

I2= 87 %

I2= 92 % 0%

20 % 40 % 60 % 80 % Atrial arrhythmia free survival at 24 m off AADs

100 %

A: 12 months. B: 24 months. Supplemental references64–104; *additional data obtained following personal communication with authors; †outcome adjusted to include deceased patients; ‡ reported as outcome at 13 months. AADs = antiarrhythmic drugs.

more extensive than pulmonary vein isolation were not associated with higher success rates (OR 0.99; [95 % CI 0.77–1.23]) even in studies including predominantly persistent AF, and continued to be associated with higher complication rates (OR 1.05; [95 % CI 1.00–1.11]). As access site and energy source were each associated with success, we assessed the effect of including only studies that used

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thoracoscopic access and bipolar RF. Despite this, no difference was seen in the primary outcome at 12 months (epicardial alone 73 %; [95 % CI 67–79], hybrid 75 %; [95 % CI 65–85]). While many studies defined success according to American College of Cardiology/American Heart Association/European Society of Cardiology (ACC/AHA/ESC) guidelines, some used weaker definitions such as point

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Diagnostic Electrophysiology and Ablation Table 2: Meta-regression Analysis

12-month success p-value

Major complications

OR (95 % CI)

Procedure

Epicardial alone

Hybrid

0.92 (0.84–1.02)

1.03 (1.01–1.05)

Access

Thoracoscopic

Mini-thoracotomy

0.92 (0.82–1.04)

0.19

0.99 (0.97–1.01)

0.51

Trans-diaphragmatic

0.72 (0.61–0.86)

<0.001

1.05 (1.00–1.11)

0.04

Mixed

0.99 (0.80–1.23)

0.9

1.04 (0.98–1.10)

0.09

Energy Source

Bipolar

Monopolar

0.79 (0.70–0.88)

<0.001

1.02 (0.98–1.06)

0.18

Mixed

0.99 (0.74–1.33)

0.95

1.38 (1.11–1.71)

<0.001

Lesion set category

PVI only

PVI + LA Box lesion

1.01 (0.90–1.14)

0.8

1 (0.98–1.02)

0.86

PVI + LA Box + RA ablation

0.97 (0.86–1.09)

0.59

1.04 (1.02–1.06)

<0.001

0.14

OR (95 % CI)

False

True

1.06 (0.96–1.17)

0.99 (0.97–1.01)

Left atrial appendage exclusion

False

True

1.15 (1.04–1.27)

0.01

1.03 (1.01–1.05)

Conduction block checked

False

True

1.02 (0.87–1.19)

1 (0.96–1.04)

0.78

0.01

Ganglionic plexus ablation 0.21

p-value

0.4

0.02

0.84

Ambulatory monitoring duration

<48 hours

48 hours–7 days

0.98 (0.84–1.15)

0.81

1.01 (0.97–1.05)

0.43

>7 days

0.99 (0.85–1.16)

0.95

1.02 (0.98–1.06)

0.33

Prevalence of paroxysmal AF

1.03 (0.92–1.16)

0.63

0.98 (0.96–1.00)

0.1

PVI = pulmonary vein isolation; LA = left atrial; RA = right atrial. Values in bold denote statistically significant differences.

prevalence of AF. Furthermore, some studies performed prolonged periods of ambulatory monitoring or implantable loop recorders while others performed little or none. Including only studies that explicitly defined success according to ACC/AHA/ESC guidelines28 did not reveal any differences in the primary outcome (epicardial-alone 74 %; [95 % CI 68–81], hybrid 62 %; [95 % CI 47–78]), neither did including only studies in which participants underwent >7 days of ambulatory monitoring (epicardial alone 75 %; [95 % CI 67–84], hybrid 61 %; [95 % CI 45–77]). Similar results were seen in outcomes at 24 months (Supplemental Table 9). Having found that a hybrid ablation strategy was associated with higher rates of major complications, we assessed the validity of our statistical methods by adjusting the fixed value added to series with zero events. Hybrid ablation was associated with increased complications rates without overlap of CIs at a range of added fixed values from 0.05 to 1. When we assessed the complication rate including only studies employing the most effective technique of thoracoscopic access and bipolar RF the magnitude of difference in complication rate was similar but the lower statistical power rendered the difference non-significant (epicardial alone 2.8 %; [95 % CI 1.5–4.1], hybrid 6.6 %; [95 % CI 3.2–10.0]).

Study Quality and Risk of Bias Studies were generally of variable quality (Figure 3A). While six of 41 studies met all eight quality assessment criteria, 23 passed five

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to seven. Thirteen studies met four or fewer criteria. Thirteen of 41 studies reported detailed inclusion and exclusion criteria. Twenty of 41 studies were unrepresentative of usual practice, including large proportions of participants with paroxysmal AF. Thirty-seven of 41 studies defined outcomes adequately. Twenty-eight of 41 studies reported and explained loss to follow up, and in 8/41 studies >10 % of patients were lost to follow up. Only 17/41 studies recruited prospectively and 30/41 recruited consecutive patients. Thirty-nine of 41 studies reported relevant prognostic factors. Funnel plots and Egger’s test were used to assess the risk of publication bias. For studies of epicardial ablation alone, Egger’s test suggested a risk of publication bias, although visual assessment of the Funnel plot was not unduly concerning (Figure 3B). For studies of hybrid ablation, the risk of publication bias was low (Figure 3C). The numbers of studies meeting all quality inclusion criteria were too small to permit meaningful comparisons between groups.

Discussion The main findings are that: (1) minimally invasive surgical epicardial ablation and hybrid ablation of AF are both effective; (2) success rates are similar between these groups; (3) hybrid ablation is associated with higher rates of major complications; (4) monopolar RF and trans-diaphragmatic access are associated with lower success rates;

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Efficacy of Epicardial Versus Hybrid Ablation for AF

Epicardial

Bauer (2009)

Epicardial

Beaver (2016)

Epicardial

Boersma (2011)

Epicardial

Compier (2016)

Epicardial

De Maat (2013)

Epicardial

Doty (2012)

Epicardial

Driessen (2016)

Epicardial

Edgerton (2010)

Epicardial

Fengsrud (2016)

Epicardial

Gersak (2012)

Epicardial

Geuzebroek (2016)

Epicardial

Janusauskas (2016)

Epicardial

Kasirajan (2012)

Epicardial

Krul (2014)

Epicardial

Ma (2015)

Epicardial

Mcclelland (2007)

Epicardial

Oudeman (2015)

Epicardial

Pojar (2014)

Epicardial

Pokushalov (2013)

Epicardial

Probst (2015)

Epicardial

Romanov (2016)

Epicardial

Santini (2011)

Epicardial

Sirak (2012)

Epicardial

Wagner (2015)

Epicardial

Wang (2014)

Epicardial

Wang (2014)

Epicardial

Weimar (2012)

Epicardial

Zheng (2013)

Epicardial

Bulava (2015) de Asmundis (2016)

Hybrid Hybrid

Edgerton (2016)

Hybrid

Gehi (2013)

Hybrid

Gersak (2016)

Hybrid

Krul (2014)

Hybrid

La Meir (2012)

Hybrid

Mahapatra (2011)

Hybrid

Muneretto (2012)

Hybrid

On (2015)

Hybrid

Osmancik (2016)

Hybrid

Richardson (2016)

Hybrid

Prognostic factors

Consecutive

Prospective

Loss to FU <10 %

Outcome defined

Epicardial alone 0 p = 0.02

0.05 Standard error

Epicardial

Bagge (2009)

0.1

0.15 25 %

75 %

50 %

100 %

Arrhythmia free survival at 12 m

Hybrid

0 p = 0.57

0.04 Standard error

Abo-Salem (2013)

Representative

Eligiblitly criteria

Loss to FU explained

Figure 3: Assessment of Study Quality and Risk of Bias

0.08

0.12 25 %

50 %

75 %

100 %

Arrhythmia free survival at 12 m

A: Study quality assessment. Green boxes indicate that this study passed this criterion and red boxes indicate failure. B: Funnel plot of studies of epicardial ablation alone. C: Funnel plot of studies of hybrid ablation. P-values refer to Egger’s test of likelihood of publication bias.

and (5) with the exception of left atrial appendage exclusion, lesion sets that were more extensive than pulmonary vein isolation are not associated with higher success rates.

Hybrid and Epicardial-Alone Ablation are Both Effective in Preventing Recurrent AF Similar to previous reviews of minimally invasive surgical ablation of AF, we found that both hybrid and epicardial-alone approaches are effective,3,29 although our estimates of success of 72 % and 63 % at 12 months and 69 % and 57 % at 24 months for epicardial-alone and hybrid strategies,

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respectively, are more conservative than some previous reviews. Different estimates could arise for several reasons. Firstly, many studies report outcomes at last follow up. Although mean follow up in these groups may exceed 12 months, inclusion of patients with shorter follow up is likely to overestimate success rates. We have reported data at specific timepoints to minimise this bias. We took great care to only include non-overlapping studies, reducing the risk of bias arising from including duplicate patients from successful high-volume centres. We also included deceased patients in the follow up denominators for all studies even if these patients were excluded from the headline figure in the original manuscripts.

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Diagnostic Electrophysiology and Ablation Hybrid Ablation Offers Little Advantage Over Epicardial Ablation Alone and is Associated with Higher Complication Rates Hybrid ablation did not offer higher success rates at 12 or 24 months. No differences were seen when all studies were included or when the disparities in operative technique, patient demographics, definitions of success, or duration of ambulatory monitoring were controlled for in sensitivity analyses. Furthermore, even though all patients receiving hybrid ablation underwent at least one catheter ablation, the need for additional catheter ablations beyond the planned procedure did not decrease with a hybrid strategy. While no significant difference was seen between groups, the numerically lower success rates seen in the hybrid group appear to have been driven by those studies which employed trans-diaphragmatic access and monopolar RF. Meta-regression identified trans-diaphragmatic access and monopolar RF as being predictive of lower success. In addition, the sensitivity analysis excluding studies that used these techniques showed near-identical success rates between hybrid and epicardial-alone ablation. Whilst failing to provide a clinical benefit, hybrid ablation was associated with more major complications. The difference in complications was largely driven by more patients suffering from major bleeding and pericardial effusions requiring drainage, as expected from the additional vascular access and trans-septal puncture obligated by hybrid ablation. This finding is in keeping with a previous systematic review,3 which showed that the complication rate from hybrid ablation was higher than that seen from the full Cox-Maze ablation performed on cardiopulmonary bypass. The absolute complication rates reported should be interpreted with caution, as the sensitivity analysis using only series obtained from arms of randomised trials suggested that complication rates could be double that reported amongst the case series as a whole.

Monopolar RF and Trans-diaphragmatic Access are Associated with Lower Success Rates Corroborating a previous cohort study,30 monopolar RF was less effective than bipolar RF at preventing recurrent atrial arrhythmias, potentially because transmural ablation lesions are seen less frequently following monopolar than bipolar RF in animal studies.8 Furthermore, trans-diaphragmatic access was less effective than thoracoscopic access. This may be partly because studies employing trans-diaphragmatic access used monopolar RF. However, as transdiaphragmatic access limits ablation of the superior aspects of the pulmonary veins, this technique may impair complete pulmonary vein isolation, the cornerstone of successful AF ablation. Relying on one continuous box lesion to encircle all veins means that failure at even a single point along this long ablation line may cause electrical reconnection of all veins. Despite these shortcomings, trans-diaphragmatic access may have a role for patients with poor respiratory reserve for whom the single lung ventilation required for thoracoscopic ablation may be hazardous.

More Extensive Lesion Sets do Not Increase Success Rates Pulmonary vein isolation alone was as effective as more extensive ablation. Neither ganglionic plexus ablation, creation of a box lesion set, nor right atrial ablation were associated with higher success rates at 12 or 24 months. This supports randomised data from the

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AtrialÂ Fibrillation Ablation and Autonomic Modulation via Thoracoscopic Surgery (AFACT) study25 showing that that the addition of ganglionic plexus ablation to surgical pulmonary vein isolation did not improve outcomes. These findings were consistent across the primary analysis and within a sensitivity analysis minimising the inclusion of patients with paroxysmal AF. Isolation of the left atrial appendage was associated with greater success at 12 months. Although a similar effect size was found at 24 months, a significant difference was not seen at this timepoint. This uncertainty reflects the controversy in the existing literature. While the Effect of Empirical Left Atrial Appendage Isolation on Long-term Procedure Outcome in Patients With Persistent or Longstanding Persistent Atrial Fibrillation Undergoing Catheter Ablation (BELIEF) trial9 suggested that left atrial appendage (LAA) electrical isolation decreased AF recurrence following catheter ablation, Romanov et al.26 found no benefit to LAA ligation during surgical ablation.

Limitations This meta-analysis is based on case series and therefore is at greater risk of bias than randomised data. Furthermore, the majority of studies were graded only moderate in quality. However, we believe that our approach is valid as randomised data are not currently available to answer this question. Moreover, prior meta-analyses of case series in the field of ablation for AF have given results consistent with RCTs.19 As the data were not sourced from RCTs there are inevitable differences in the demographics between study groups. Hybrid studies included more patients with longstanding persistent AF, which may underestimate the relative efficacy of hybrid ablation. However, controlling for these differences using a sensitivity analysis including only studies in which <20Â % of patients had paroxysmal AF abolished all differences in baseline demographics without revealing any differences in success rates. Despite this, it is possible that residual unmeasured confounders remain, potentially leaving the hybrid ablation group with a patient cohort with more advanced disease and hiding a true benefit from this procedure. While the mandate for surgical ablation of AF is greatest in patients with longstanding persistent AF, our pre-specified primary analysis also included studies with a high prevalence of paroxysmal AF, potentially overestimating the success rates of surgical ablation. However, the sensitivity analysis including only studies with <20Â % paroxysmal AF showed that success rates were similar to those when all studies were included. The definition of minimally invasive surgery used here included access via thoracoscopy, trans-diaphragmatic pericardioscopy and mini-thoracotomy. While some argue that mini-thoracotomy is not minimally invasive, lengths of stay and rates of complications were similar between these three methods (Supplemental Table 9) suggesting that mini-thoracotomy is no more invasive than other modes of access. Complication reporting was highly variable, and underreporting of complications may have been present. To reduce the risk that underreporting might influence a comparison between groups, the definition of major complications used here was relatively narrow, including only the complications most likely to be reported. As a result,

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Efficacy of Epicardial Versus Hybrid Ablation for AF the true incidence of complications using a broader definition such as the Ottawa Thoracic Morbidity and Mortality classification system31 may be higher.

Conclusions Minimally invasive surgical ablation offers a chance of freedom from the potentially disabling symptoms of AF, at least in the medium term. Epicardial ablation alone appears to be as effective as hybrid ablation and may be associated with fewer complications, although complications may have been underreported in some case series. The highest success rates are associated with thoracoscopic ablation using bipolar RF energy including isolation of the left atrial appendage. These analyses, based upon data predominantly from case series of generally moderate quality, need to be verified with randomised trials. n

ynn GJ, Das M, Bonnett LJ, et al. Efficacy of catheter ablation W for persistent atrial fibrillation: a systematic review and metaanalysis of evidence from randomized and nonrandomized controlled trials. Circ Arrhythm Electrophysiol 2014;7:841–52. DOI: 10.1161/CIRCEP.114.001759; PMID: 25132078 2. Brooks AG, Stiles MK, Laborderie J, et al. Outcomes of long-standing persistent atrial fibrillation ablation: a systematic review. Heart Rhythm 2010;7:835–46. DOI: 10.1016/j. hrthm.2010.01.017; PMID: 20206320 3. Je HG, Shuman DJ, Ad N. A systematic review of minimally invasive surgical treatment for atrial fibrillation: a comparison of the Cox-Maze procedure, beating–heart epicardial ablation, and the hybrid procedure on safety and efficacy. Eur J Cardiothorac Surg 2015;48:531–540; discussion 540–31. DOI: 10.1093/ejcts/ezu536; PMID: 25567961 4. Boersma LV, Castella M, van Boven W, et al. Atrial fibrillation catheter ablation versus surgical ablation treatment (FAST): a 2-center randomized clinical trial. Circulation 2012;125(1):23–30. DOI: 10.1161/CIRCULATIONAHA.111.074047; PMID: 22082673 5. Wang S, Liu L, Zou C. Comparative study of video-assisted thoracoscopic surgery ablation and radiofrequency catheter ablation on treating paroxysmal atrial fibrillation: a randomized, controlled short–term trial. Chin Med J (Engl) 2014;127:2567–70. PMID:25043068 6. Pokushalov E, Romanov A, Elesin D, et al. Catheter versus surgical ablation of atrial fibrillation after a failed initial pulmonary vein isolation procedure: a randomized controlled trial. J Cardiovasc Electrophysiol 2013;24:1338–43. DOI: 10.1111/ jce.12245; PMID: 24016147 7. Voeller RK, Zierer A, Lall SC, et al. Efficacy of a novel bipolar radiofrequency ablation device on the beating heart for atrial fibrillation ablation: a long-term porcine study. J Thorac Cardiovasc Surg 2010;140:203–8. DOI: 10.1016/j. jtcvs.2009.06.034; PMID: 20122702 8. Schuessler RB, Lee AM, Melby SJ, et al. Animal studies of epicardial atrial ablation. Heart Rhythm 2009;6(12 Suppl):S41–45. DOI: 10.1016/j.hrthm.2009.07.028; PMID: 19959142 9. Di Biase L, Burkhardt JD, Mohanty P, et al. Left Atrial Appendage Isolation in Patients With Longstanding Persistent AF Undergoing Catheter Ablation: BELIEF Trial. J Am Coll Cardiol 2016;68:1929–40. DOI: 10.1016/j.jacc.2016.07.770; PMID: 27788847 10. Bulava A, Mokracek A, Hanis J, et al. Sequential hybrid procedure for persistent atrial fibrillation. J Am Heart Assoc 2015;4:e001754. DOI: 10.1161/JAHA.114.001754; PMID: 25809548 11. Gersak B, Zembala MO, Muller D, et al. European experience of the convergent atrial fibrillation procedure: multicenter

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Clinical Perspective • M aintenance of sinus rhythm is difficult to achieve in patients with persistent or longstanding persistent atrial fibrillation. • Minimally invasive surgical ablation offers a 70 % chance of freedom from atrial arrhythmias at 12 months, at the cost of a complication rate of 2–10 % depending on the technique used. • Hybrid ablation is no more effective than epicardial ablation alone but is associated with a higher rate of major complications. • While left atrial appendage exclusion is associated with higher success rates, lesion sets more extensive than pulmonary vein isolation do not improve outcomes. • Trans-diaphragmatic access and monopolar energy source are associated with inferior outcomes.

outcomes in consecutive patients. J Thorac Cardiovasc Surg 2014;147:1411–6. DOI: 10.1016/j.jtcvs.2013.06.057; PMID: 23988287 Kiser AC, Landers MD, Boyce K, et al. Simultaneous catheter and epicardial ablations enable a comprehensive atrial fibrillation procedure. Innovations (Phila) 2011;6:243–7. DOI: 10.1097/IMI.0b013e31822ca15c; PMID: 22437982 Krul SP, Pison L, La Meir M, et al. Epicardial and endocardial electrophysiological guided thoracoscopic surgery for atrial fibrillation: a multidisciplinary approach of atrial fibrillation ablation in challenging patients. Int J Cardiol 2014;173:229–35. DOI: 10.1016/j.ijcard.2014.02.043; PMID: 24630384 La Meir M, Gelsomino S, Luca F, et al. Minimally invasive surgical treatment of lone atrial fibrillation: early results of hybrid versus standard minimally invasive approach employing radiofrequency sources. Int J Cardiol 2013;167: 1469–75. DOI: 10.1016/j.ijcard.2012.04.044; PMID: 22560495 Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta–analyses: the PRISMA statement. PLoS Med 2009;6:e1000097. DOI: 10.1371/journal. pmed.1000097; PMID: 19621072 Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000;283:2008–12. DOI: 10.1001/JAMA.283.15.2008; PMID: 10789670 Richardson TD, Shoemaker MB, Whalen SP, et al. Staged versus simultaneous thoracoscopic hybrid ablation for persistent atrial fibrillation does not affect time to recurrence of atrial arrhythmia. J Cardiovasc Electrophysiol 2016;27:428–34. DOI: 10.1111/jce.12906; PMID: 26725742 Higgins JPT, Green S (eds). Cochrane Handbook for Systematic Reviews of Interventions. Hoboken, NJ: Wiley-Blackwell, 2008. DOI: 10.1002/9780470712184 Chambers D, Rodgers M, Woolacott N. Not only randomized controlled trials, but also case series should be considered in systematic reviews of rapidly developing technologies. J Clin Epidemiol 2009;62:1253–60.e1254. DOI: 10.1016/j. jclinepi.2008.12.010; PMID: 19349144 R Core Team. R: A language and environment for statistical computing. 2016. Available at: www.R–project.org (accessed 16 November 2016) Mahapatra S, LaPar DJ, Kamath S, et al. Initial experience of sequential surgical epicardial–catheter endocardial ablation for persistent and long–standing persistent atrial fibrillation with long-term follow-up. Ann Thorac Surg

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2011;91:1890–8. DOI: 10.1016/j.athoracsur.2011.02.045; PMID: 21619988 Beaver TM, Hedna VS, Khanna AY, et al. Thoracoscopic Ablation With Appendage Ligation Versus Medical Therapy for Stroke Prevention: A Proof-of-Concept Randomized Trial. Innovations (Phila) 2016;11:99–105. DOI: 10.1097/ IMI.0000000000000226; PMID: 26914668 Fengsrud E, Wickbom A, Almroth H, et al. Total endoscopic ablation of patients with long-standing persistent atrial fibrillation: a randomized controlled study. Interact Cardiovasc Thorac Surg 2016;23:292–8. DOI: 10.1093/icvts/ivw088; PMID: 27068249 Gersak B, Kiser AC, Bartus K, et al. Importance of evaluating conduction block in radiofrequency ablation for atrial fibrillation. Eur J Cardiothorac Surg 2012;41:113-118. PMID: 21680193 Driessen AH, Berger WR, Krul SP, et al. Ganglion Plexus Ablation in Advanced Atrial Fibrillation: The AFACT Study. J Am Coll Cardiol 2016;68:1155–65. DOI: 10.1016/j.jacc.2016.06.036; PMID: 27609676 Romanov A, Pokushalov E, Elesin D, et al. Effect of left atrial appendage excision on procedure outcome in patients with persistent atrial fibrillation undergoing surgical ablation. Heart Rhythm 2016;13:1803–9. DOI: 10.1016/j.hrthm.2016.05.012; PMID: 27180620 Pearman CM, Todd D, King R, et al. The procedural complication rates and short–term success rates of thoracoscopic AF ablation during the institutional learning curve. EP Europace 2016;18:Suppl 2,ii13–ii17. Fuster V, Ryden LE, Cannom DS, et al. 2011 ACCF/AHA/ HRS focused updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation. J Am Coll Cardiol 2011;57:e101–98. DOI: 10.1016/j. jacc.2010.09.013; PMID: 21392637 Gelsomino S, Van Breugel HN, Pison L, et al. Hybrid thoracoscopic and transvenous catheter ablation of atrial fibrillation. Eur J Cardiothorac Surg 2014;45:401–7. DOI: 10.1093/ ejcts/ezt385; PMID: 23904136 La Meir M, Gelsomino S, Luca F, et al. Minimally invasive thoracoscopic hybrid treatment of lone atrial fibrillation: early results of monopolar versus bipolar radiofrequency source. Interact Cardiovasc Thorac Surg 2012;14:445–50. DOI: 10.1093/ icvts/ivr142; PMID: 22228287 Seely AJ, Ivanovic J, Threader J, et al. Systematic classification of morbidity and mortality after thoracic surgery. Ann Thorac Surg 2010;90:936–42; discussion 942. DOI: 10.1016/j. athoracsur.2010.05.014; PMID: 20732521

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Diagnostic Electrophysiology and Ablation

One-stage Approach for Hybrid Atrial Fibrillation Treatment Vincent Umbrain, 1 Christian Verborgh, 1 Gian-Battista Chierchia, 2 Carlo De Asmundis, 2 Pedro Brugada 2 and Mark La Meir 3 1. Department of Anaesthesiology and Perioperative Medicine, University Hospital Brussels, Free University of Brussels, Belgium; 2. Heart Rhythm Management Centre, University Hospital Brussels, Free University of Brussels, Belgium; 3. Department of Cardiac Surgery, University Hospital Brussels, Free University of Brussels, Belgium

Abstract The one-stage approach for hybrid atrial fibrillation involves the simultaneous and close cooperation of different medical specialties. This review attempts to describe its challenging issues, exposing a plan to balance thrombotic risk and bleeding risk. It describes the combined surgical-electrophysiological procedure. Specific topics, involving hemodynamic, fluid and respiratory management during surgery are considered, and problems related to postoperative pain are surveyed.

Keywords Atrial fibrillation, hybrid surgery, radiofrequency ablation, pain Disclosure: Mark La Meir might have a financial interest in this publication. He also consults for AtriCure. Received: 19 September 2017 Accepted: 16 November 2017 Citation: Arrhythmia & Electrophysiology Review 2017;6(4):210–6. DOI: 10.15420/2017.36.2 Correspondence: Vincent Umbrain, Department of Anaesthesiology and Perioperative Medicine, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium. E: Vincent.umbrain@uzbrussel.be

The current option for refractory treatment for atrial fibrillation (AF) includes hybrid AF-surgery.1–2 The hybrid approach was originally a combination of mini-invasive surgical epicardial evaluation and ablation, as well as endocardial electrophysiologist (EP) catheter ablation with the intention of creating a lesion set to cure AF.3 In the search for greater efficacy with less patient invalidation, different surgical and EP approaches have been developed. Variable timing between the epicardial approach and EP endocardial procedure has also emerged. Potential risks (Table 1) and claimed conversion rates to sinus rhythm after hybrid AF treatment vary from 27 to 94 %.4–13 The large variation in success rate is probably due to differences in patient selection between centres, staging and surgical technical approaches, lesion sets, periprocedural care and endpoints, energy sources, and choice of endpoints used after the procedure. Experience and technical improvements, as well as a search for greater value-based healthcare treatment of AF has led us to develop a one-stage hybrid method described in this manuscript. For refractory AF, our team recommends a combination of minimal invasive epicardial evaluation and ablation, together with EP mapping and ablation on the beating heart in a single procedure. The suggested epicardial technique involves mostly surgical unilateral left thoracoscopic evaluation and ablation approach, while the EP maps and ablates throughout the endocard after a percutaneous femoral approach during the procedure. Sometimes, depending on the patient’s antecedents, the epicard is approached with either a sequential, bilateral or unilateral right thoracoscopy.4 We believe that a one-stage approach provides unique and important advantages for patients compared to a two-stage procedure (Table 2). The approach for hybrid AF surgery involves some particularities and challenging issues that require specific attention from the medical specialities involved. The purpose of this review is to describe our

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standard approach as follows: determine optimum timing of the last anticoagulant administration during the preoperative visit to minimise thrombus risk in the left atrial appendix and bleeding risk during surgery; expose respiratory management of prolonged sequential bilateral or unilateral thoracoscopy, hereby optimising oxygen delivery but reducing the risk of atelectasis; interpret haemodynamic control problems related to thoracoscopy, diastolic dysfunction with loss of atrial kick and decreased venous return by ablation on the pulmonary veins; show optimal positioning for surgery to facilitate access of the epicardial radio-ablation procedure; point out specific problems related to postoperative pain, its localization and treatment options; touch on the potential consequences of left atrial appendix clipping on fluid administration during and after surgery; and comment on early feeding problems after surgery.

Hybrid Method Team In practice, hybrid AF-surgery may be considered a joint venture of different medical specialities requiring close cooperation and immediate presence of a cardiologist, electrophysiologist, cardiac surgeon, anaesthesiologist, immediate care holders (nurses of the ward, operating room, high care or intensive care team, acute pain team), respiratory care specialists and pain doctors. The cardiopulmonary bypass department is also informed and on standby due to a <1.6 % risk of conversion to sternotomy with eventual repair under cardiopulmonary bypass.11

Patient Preoperative Visit An in-depth preoperative visit focusing on the patient’s rhythm history and their cardiovascular risk factors often allows estimation of probability of conversion to sinus rhythm and duration of surgery. The factors affecting success rate are prior duration of AF, size of left atrial dilatation11 and prior treatment of comorbidity factors such

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One-stage Approach for Hybrid Atrial Fibrillation Table 1: Incidence of Complications for Hybrid Atrial Fibillation Surgery 1 Endocardial catheter endovascular ablation complications: Life-threatening complications: Peri-procedural death Oesophageal injury (perforation/fistula) Peri-procedural stroke (including TIA/air embolism) Cardiac tamponade Severe complications Pulmonary vein stenosis Persistent phrenic nerve palsy Vascular complications

Figure 1: Enhanced Postoperative Pain Treatment Options for Hybrid Atrial Fibrillation Surgery

Paracetamol <0.2 % <0.5 % <1 % 1–2 %

Multimodal analgesia

Postoperative pain strategy

Thoracic para vertebra block

<1 % 1–2 % 2–4 %

Intravenous systemic opiates Wound infiltration

Thoracic epidural COX1-2 blockers

Other severe complications 1 % Other moderate or minor complications Unknown significance Asymptomatic cerebral embolism (silent stroke) Radiation exposure

1–2 % 5–20 %

Epicardial complications of thoracoscopic atrial fibrillation surgery Conversion to sternotomy Pacemaker implantation Drainage for pneumothorax Pericardial tamponade Transient ischaemic attack Asymptomatic cerebral embolism

0–1.6 % 0–3.3 % 0–3.3 % 0–6.0 % 0–3.0 % Unknown

Table 2: One-stage Hybrid Procedure: Advantages and Disadvantages Advantages Value-based atrial fibrillation treatment Single hospital stay Communication between EP and surgeon: • Confirm endocardially performed conduction block of epicardial ablation lines • Guide endocardially/epicardially ablation resting epicardial/endocardially substrates • Discuss best isolation of potentially remaining substrates of activity Limited tamponade risk Reduced phrenic nerve damage Disadvantages Restraints on logistic organisation (timing, space) Peri-myocyte oedema following epicardial ablation and potentially more difficult assessment for the electrophysiologist

as arterial hypertension, valvular heart disease, obesity, chronic obstructive pulmonary disease, chronic kidney disease and obesity before surgery.1 As surgery often requires sequential single-lung ventilation, anamnesis of former pulmonary afflictions is recorded. Postoperative choices of enhanced pain treatment after surgery, with consideration of multimodel therapeutic strategy14 (use of diverse analgesic compounds to reduce opiate consumption; see Figure 1) and particular choices should be discussed during the preoperative visit. The benefits and risks of treating postoperative pain using intravenous, epidural or paravertebral approaches are explained.15–20 Local anaesthetics with or without opioids are used for the epidural or paravertebral approach. A morphine or piritramide opiate pump is used for the intravenous route. A choice is made in light of the patient’s history and preferences, and experience of the anaesthetist (Table 3). Of concern in this choice is coagulation status just before surgery. The

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exact timing of discontinuation of anticoagulants before surgery is discussed in Table 4. Briefly, the aim is to find a window of opportunity between risk of bleeding with existing coagulation guidelines during surgery,21–25 and increased risk of thrombi generation in the left atrial appendix of patients with AF and an enlarged left atrium with decreased blood flow velocities. This is not always an easy task. Most guidelines for stopping anticoagulants apply to general surgery and not specifically to AF patients scheduled for hybrid AF surgery, where the left atrial appendix will be mobilised and ultimately stapled. If there is doubt of coagulation status, an assessment of the patient’s coagulation status just before incision with TEG/ROTEM monitoring, when available, may reduce the risk of epidural or paravertebral bleeding with subsequent medullar compression.26–28 However, the exact value of using this method of monitoring in this context is insufficiently studied and needs to be further investigated.29 A detailed, yet gentle explanation to patients about the goal and surgical technique is often helpful in reducing preoperative anxiety and sympathetic activity. In most cases, the patient’s preference is a patient-controlled intravenous or thoracic epidural technique. A paravertebral block is eventually used as a postoperative rescue issue for patients with refractory pain after patient-controlled intravenous pain when administration of non-steroidal anti-inflammatory agents is not indicated. Both epidural and paravertebral block with catheter insertion in AF patients under anticoagulant treatment present a threat challenge to the anaesthesiologist as inserting the needle or catheter may lacerate a blood vessel and subsequently create a risk of medullar compression.29 In normal circumstances the risk for neuraxial haematoma is estimated to be between 1 in 220 000 and 1 in 320 000. Short new oral anticoagulant (NOAC) discontinuation times may increase this risk. Multiple neuraxial puncture attempts should, therefore, be avoided in patients with spinal abnormalities or with other underlying hereditary or acquired coagulation disorders. Patients are informed of the need for radial artery catheter for beatto-beat blood pressure monitoring during surgery and insertion of a jugular venous catheter for eventual continuous administration of inotropic support during or immediately after surgery.

Anaesthetic Approach Before Surgery Preparation of anaesthesia before surgery (see the preoperative checklist in Table 5) includes radial artery monitoring set, eventual epidural catheter set, patient-controlled intravenous or epidural pump device, intubation equipment for left and/or right-sided thoracoscopy through selective left endobronchial intubation by endotracheal intubation with a bronchial blocker or EZ-blocker under fibrescopic control, central venous catheter set, norepinephrine, and possibly dobutamine pump.

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Diagnostic Electrophysiology and Ablation Table 3: Advantages/Disadvantages of Enhanced Postoperative Analgesia Approaches

All patients receive antibiotic prophylaxis before incision. A repeat dose is given for surgeries lasting for more than 4 h.

Systemic opiate pump (IV approach)*

Anaesthetic specificities for hybrid surgery involve control of perioperative haemodynamic and ventilatory stability and postoperative pain control.

Advantages Disadvantages Immediate analgesic effect

Incomplete pain relief Higher incidence of postoperative nausea or vomiting Higher incidence of constipation Itching Respiratory depression risk requesting monitoring Sedative effect Opiate tolerance, opiate-induced hyperalgesia Coagulation alteration is not an issue

Epidural pump (TEA)* Advantages Disadvantages Accepted gold standard Bilateral block Reliable, dense block May reduce supraventricular arrhythmias Sympatholytic effect block Technical failure possibility Lower reported incidence of chronic pain development

Hypotension (total spinal/subdural block) Dural puncture risk Urinary retention Catheter problems (kinking/obstruction)

Relative contraindications Coagulation disorder Restless anxious tense patient Emotive, vagal syncope-risk patient Neurologic impairment/lesions Access problems due to former pathology/back/vertebra problems Percutaneous paravertebral block (unilateral orbilateral paravertebral thoracic approach)* Advantages Disadvantages Equally (?) reliable block Unilateral block Requires experienced regular practitioner Pleural puncture risk (0.8–1 %) More local anaesthetic toxicity (7 %)

Catheter threading migration/dislodgement, kinking Tendency for reduced incidence of sideeffects Epidural or intrathecal catheter spread Local anaesthetic spread to epidural or intrathecal space

Relative contraindications Restless, anxious, tense patient Emotional, vagal syncope-risk patient Neurologic impairment/lesions Access problems due to former pathology/back problems *Patient-controlled, with or without background basal infusion.

All patients receive a bladder catheter. Temperature recording with active patient warming (Bair Hugger or analogue) to maintain core temperature (bladder temperature) above 35.5°C is favoured. External and internal defibrillator pads and a same-day checked defibrillator are needed. The immediate vicinity of a primed cardiopulmonary bypass (CPB) machine is checked for possible repair of pulmonary vein or left atrium laceration under cardiopulmonary bypass.

The ventilation settings are adapted to single-lung ventilation request during surgery. For single-lung ventilation tidal volumes are decreased (from 7–8 ml/kg to 5–6 ml/kg ideal bodyweight), respiratory frequency increased (from 14 to 20/min or more depending on initial basal respiratory rate). High versus low positive end-expiratory pressure (PEEP)-levels, when needed, are prudently increased depending on their impact on blood pressure and pulse oxygen saturation. Often, a permissive attitude to hypercapnia with arterial carbon dioxide levels of 50 mmHg is accepted. Alveolar recruitment is performed depending on patient blood pressure, pulse saturation and surgical consent. Particular attention should be given to alveolar recruitment when changing sides if a two-stage sequential thoracoscopy is performed. An enhanced incidence of hypotension due to diastolic dysfunction, loss of atrial kick, carbon dioxide insufflation in the thoracic, mediastinal and pericardial cavities, and effect of surgery during ablation on pulmonary venous return is frequently observed after onset of single-lung ventilation. Carbon dioxide insufflation pressure during thoracoscopy should be adapted to blood pressure and limited to 8 mmHg or less to avoid a tamponade effect. Judicious titration of phenylephrine, noradrenaline or dobutamine is often requested. Impaired or restrictive diastolic function, sequential one-lung ventilation with clipping of the left atrial appendage and consequent altered postoperative atrial natriuretic hormone levels justifies reasoned and restricted fluid administration. Fluid administration is adapted to current guidelines30–32 and eventual surgical blood loss. As in most cases, blood loss is minimal and blood products can be avoided. Fluid administration starts with a balanced crystalloid solution set at 2 ml/kg per h and is further adapted in function of transoesophageal echocardiography imaging. However, a tendency to restrain fluids is observed in later stapling of the left atrial appendage. In general, total fluid administration given during surgery ranges from 500 to 1000 ml.

Patient Positioning Patient positioning for surgery involves opening the space on the front axillary line to provide optimal access to the fourth and fifth intercostal space with an inflatable balloon placed below the patient’s back. The balloon is inflated for improved access and widening of the intercostal opening with consideration to the pressure exerted on the cervical lordosis and the possible hyperextension in the lumbar area. Both arms are flexed and placed sideways to the operation table to widen the operative area. A radial artery catheter is preferred as a brachial artery catheter often leads to greater kinking or obstruction in patients positioned with flexed elbows (Figure 2). The area surrounding the sternum is kept electrode-free for a worst-case scenario with unforeseen bleeding leading to sternotomy (Figure 3).

Surgery Anaesthetic drugs are determined by the patient’s antecedents and anaesthetist’s habits or preferences and include opioids, propofol/etomidate, non-depolarizing muscle relaxants (rocuronium, cisatracurium) and inhalational anaesthetics (isoflurane, sevoflurane).

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Epicardial Approach Hybrid AF-surgery consists of a combined thoracoscopic epicardial and endovascular endocardial approach. The epicardial approach consists of left and possibly right thoracoscopy. Briefly, a 6 mm camera port is

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One-stage Approach for Hybrid Atrial Fibrillation placed in the fifth intercostal space at the mid-axillary line and in the sixth or seventh intercostal space anterior axillary line. A 5 mm working port is placed in the third intercostal space anterior axillary line. The pericardium is opened anterior to the phrenic nerve and transverse and oblique sinuses, and is bluntly dissected. A bipolar RF-clamp is used for antral isolation of both pairs of pulmonary veins with four to six applications. Afterwards, a bipolar RF pen or linear pen device is used to perform a roof line and inferior line connecting, respectively, on both superior and inferior pulmonary veins to create the box lesion for posterior left atrial wall isolation. Box lesion ablation is completed when the right atrium is dilated with two additional ablation lines: one line with the use of the clamp encircling the vena cava superior and a bicaval line using the pen and connecting both caval veins. In most patients, the left atrial appendix appendage is also clipped. Communication between the surgeon and anaesthetist is important as pulmonary venous return is sometimes hindered during ablation. Subsequent hypotension and lowered oxygen saturation levels are treated with norepinephrine titration, higher inspired oxygen levels as indicated, and surgical repositioning.

Electrophysiology Percutaneous femoral electrophysiological examination and ablation includes the insertion of a decapolar coronary sinus catheter under fluoroscopy and a trans-septal puncture for placing a long 8-Fr sheath under combined guidance of TEE and fluoroscopy. The patient is heparinised after the trans-septal puncture with a heparin dose of 1,000 IU/10 kg bodyweight to obtain a target activated clotting time >300s. Eventual heparin increments are given to maintain ACT values. A circular mapping catheter and a radiofrequency (RF) ablation catheter are used with an open, irrigated 3.5 mm tip to create a detailed electro-anatomic map of the left atrium. The ‘epicardial box lesion’ ablation block is controlled endocardially by checking the entry and exit block of the pulmonary veins alongside the posterior wall of the left atrium. The circular mapping catheter is used to evaluate the entry block of the pulmonary veins and the posterior left atrial box, and is defined as the absence of atrial bipolar signs. The exit block checks the pulmonary veins or the posterior wall during pacing with an output of 10 mA and a pulse width of 2 ms without conduction to the left atrium. If either block is not present, additional endocardial ablation is performed to close the conduction gaps. A radiofrequency power-controlled mode with a power limit of 35 W with maximal temperature of 48°C is used until block achievement.

Table 4: Discontinuation Times of Oral Anticoagulants, Low Molecular Weight Heparins and Antiplatelet Medications Vitamin K antagonists Warfarin: discontinue 5 d before procedure Acenocoumarol: discontinue 3 d before procedure Fenprocoumon: discontinue for 5–6 d before procedure New oral anticoagulants Dabigatran: stop 3–4 d before procedure, first postoperative dose 24 h after needle placement and 6 h after neuraxial or paravertebral catheter removal Rivaroxaban: stop 3 d before procedure, first postoperative dose 24 h after needle placement and 6 h post catheter removal Apixaban: stop 3 d before procedure, first postoperative dose 24 h after needle placement and 6 h post catheter removal Edoxaban: stop 3 d before procedure, first postoperative dose 24 h after needle placement and 6 h post catheter removal Low molecular weight heparins Discontinue 12 h before surgery Antiplatelet medications Aspirin, other NSAIDs Continue until surgery Thienopyridines Clopidogrel: discontinue 5–7 d before surgery Prasugrel: discontinue 7–10 d before surgery Ticlopidine: discontinue 10 d before surgery Ticargrelor: discontinue 5–7 d before surgery

Table 5: Preoperative Anaesthesia Checklist Peripheral Line (Plasmalyte® 1000 ml) Arterial line and catheter set Central line (bi or triple lumen) Urinary catheter and collector bag Ventilator check Cross-matched blood presence in blood bank in refrigerator Endobronchial blocker, bronchial blocker or EZ-blocker; fiberscope and light spot Defibrillator check Transoesophageal echocardiography machine check Coagulation monitoring check: presence of activated coagulation time machine, TEG/Sonoclot/ROTEM device Temperature monitoring probes and active warming device Positioning pads/foam Presence of extracorporeal machine pump and perfusion department Noradrenaline pump and eventually dobutamine pump

A cavo-tricuspid isthmus endocardial or a mitral line ablation is added in the presence of a flutter or a mitral isthmus dependent flutter, respectively, during the procedure. If despite these epicardial and endocardial ablations AF persists, left and right continuous fractionated atrial electrogram mapping/ablation is performed. Target sites are defined as the fastest local repetitive electrical activity, multicomponent fragmented signals or as activation delay between the distal and proximal bipolar electrodes covering most the cycle length. The endpoint of ablation coincides with a regular or disappeared local signal, conversion to sinus rhythm or the presence of stable atrial flutter. Patients who do not convert to sinus rhythm during hybrid AF ablation are cardioverted. In sinus rhythm, all ablation lines are then revisited to confirm bidirectional conduction using the standard criteria. The pericardium is approximated with a stitch, and a chest tube is placed in one or both pleural cavities depending on the approach.

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TEG/ROTEM device check Anaesthetic and antibiotic drugs

Perioperative Management Pain Triggers Postoperative pain treatment after hybrid surgery for AF presents interesting challenges with a fluctuating variability of localisation and intensity. This is explained by nerve sensitisation induced at several places by the surgical approach combined with the endocardial and pericardial radiofrequency-ablation procedure (Figure 1). The first potential cause of postoperative pain, and often the first reported, is related to neural activation in the pleural cavities. This is caused by the insertion of intercostal ports, insufflation of carbon dioxide (which cannot always be totally removed at the end of surgery)

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Diagnostic Electrophysiology and Ablation Figure 2: Patient Installation Before Incision for One-Stage Hybrid AF Surgery with Flexed Elbows to Free Intercostal Space at the Mid-axillary Line

The second possible pain course is by neural activation and sensitisation of several (epicardial) heart nerve endings during the radiofrequency ablation approach. Possibly implicated and sensitised nerves are the phrenic nerve(s), pericardiophrenic nerve, epicardial nerve and intrinsic cardiac nerves, which regroup in a ganglionated plexus located in fat pads. At the atrial level three plexi are described: a superior left atrial plexus disposed over the superior veno-atrial junction, a posterolateral plexus laying over the lateral atrial wall and the left inferior veno-atrial junction and a posteromedial plexus overlying the right veno-atrial junctions. Signals from the heart are transmitted by primary sensory neurons. The afferent fibres originating from the heart travel as sympathetic and parasympathetic nerves and transmit information to the central nervous system about the activities of the heart or the occurrence of tissue injury, the latter through nociceptive fibres. These signals also generate autonomic reflexes, which allow regulation of organ function. Some of the signals, for instance pain signals, can be transmitted to cortical centres and become conscious. Nociceptive fibres are mostly associated with sympathetic fibres. Their cell bodies are found in spinal ganglia and likely end in the posterior roots of the spinal cord, where they synapse in second-order nociceptive neurons. Nociceptive visceral fibres are much less numerous than the nociceptive somatic fibres and usually end at more levels in the spinal cord, thus generating less specific and localised pain sensation. Afferent primary sensory fibres associated with parasympathetic nerve fibres are more involved in regulatory reflexes of system/organ activities. These nerve fibres are mainly associated with the vagal nerve, but several visceral cranial afferent fibres travel with the glossopharyngeal nerve or facial nerve and fibres of the pelvic nerves. The cell bodies of these afferent fibres are found in ganglia associated with these parasympathetic nerves. Primary sensory neurons then project onto second-order visceral sensory neurons located in the medulla oblongata, the nucleus of the solitary tract and other nuclei.33â&#x20AC;&#x201C;34

Figure 3: Patient Installation Just Before Incision with Free Sternum and Possible Access to Bilateral Incision

Reported pain sensation after radiofrequency ablation can vary. Most often, a persistent dull type of cardiac pain is reported, but severe, sharp, diffuse heart pain is also possible. This type of pain may be associated with altered ST-segment elevations on ECG-recordings and troponin elevations, and is induced by regional pericarditis radiofrequency. This is to be differentiated from coronary embolisation of left atrial thrombus, ablation damage to the left circumflex artery and pericardial blood effusion. Pericarditis pain is treated with aspirin, NSAIDs, or colchicine when appropriate, often in combination with intravenous opioid administration.35 Whether preoperative central sensitisation induced by the presence of a long-standing AF, young age, extent of radiofrequency ablation or ongoing long-lasting anxiety potentiate this postoperative pericarditis pain is still unknown.

or the presence of thoracic drains in one or both pleural cavities. Pain symptoms are specifically respiratory (inspiratory) and drain-related. In case of shoulder pain, inadequate CO2 removal with secondary phrenic nerve irritation should be considered. Of importance for the long term, the intercostal nerves may be pressurised by the 5-mm ports in patients with narrow intercostal distances and rarely progress to intercostal nerve neuropathic pain.

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A third possible source of pain is of epigastric or oesophageal origin. Its causes are dual. The reported incidence of inflammation of the anterior oesophageal wall secondary to the RF-ablation on the antrum of the pulmonary veins is 47Â %.36 This oesophageal inflammation may also be related, albeit to a lower extent, to TEE insertion and manipulation for exclusion of the presence of thrombi in the left atrial appendix just before surgery.37 Whether preoperative central sensitisation induced by the presence of a long-standing AF, young age, extent of radiofrequency ablation or ongoing and long-lasting anxiety, depression or catastrophising behaviour potentiate this severe postoperative pericarditis pain is unknown.

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One-stage Approach for Hybrid Atrial Fibrillation Figure 4: Factors Related to Postoperative Pain After Hybrid AF Surgery Shoulder

CO2 insufflation related pain Cardiac pain

Intercostal nerve neuralgia

Pericarditis

Esopheal nerve sensitisation

Intercostal distances

Radiofrequency-induced ablation related pain Thoracic incisions

Prior Central sensitisation by AF?

HYBRID AF SURGERY PAIN

Surgery

Drains

Pleural nerve sensitisation Trocards

Epigastric pain Anxiety

Cardiac Nerve irritation

Throat pain

Pericardiophrenic Intubation: tube, TEE

Phrenic Epicardial

Catastrophising Depression

Establishing the difference between cardiac pain and stomach/ oesophageal pain is sometimes difficult as both the posterior wall of the left atrium and the pulmonary veins share some common efferent nociceptive nerves. In our experience, its onset is later than pain reported that is related to pleural or pericardial neural sensitisation. Discrete oesophageal dysphagia or slow oesophageal food descent often mentioned with resumption of solid fluid intake may be part of this nervous sensitisation. A gastroscopy performed after surgery may help exclude pain of oesophageal or gastric origin.

Pain Control Pain treatment in our institution starts with paracetamol given before incision and continued for 24–48 h. A surgical infiltration of the wound and the intercostal nerves with ropivacaine is accomplished before closure of the laparoscopic incision sites. Pain control is further enhanced with either an intravenous opioid or an epidural pump with local anaesthetics started 30 min before skin closure. The patient-controlled IV pump consists of either a morphine or piritramide pump. Depending on the VAS scales and patient’s complaints, a background continuous infusion is eventually added. Most pain complaints after surgery decrease drastically after thoracic drain removal. In some patients, however, pain persists for another week. Further pain relief is provided when possible or indicated with intravenous NSAIDs, selective COX-2 inhibitors, tramadol, or morphine/oxycodone. When pain treatment is refractory a paravertebral block is eventually performed.

Postoperative Management Cardiac Management Patients are monitored for eventual arrhythmia relapses, coronary vasospasm, circumflex coronary artery damage by radiofrequency and coronary thrombus embolisation for 24 h in intensive care.

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For patients with suspected RF-induced pericarditis, regular ECGs and troponin measurements are performed. After ICU discharge some patients are placed under continuous telemetric monitoring. Transthoracic echocardiography is requested and performed to exclude post-procedure pericardial effusion. Low molecular weight heparins are started the evening after surgery. NOACs and oral anticoagulants are re-initiated on the third postoperative day and continued for 3 months. The left atrial appendix is stapled to reduce the stroke incidence after hybrid AF surgery.38–39 Closure of the left atrial appendix leads to lower atrial natriuretic peptide levels and consequently higher risk of fluid retention in the immediate postoperative days. Careful postoperative fluid administration with regular patient weighing is therefore indicated in the first weeks after surgery. A one-month diuretic treatment is usually used to bridge the period before the right atrial appendix or the brain compensates with the patient’s personal natriuretic peptide production at our hospital.40

Follow-up Clinical follow-up by the cardiologist and/or surgeon with a physical examination, electrocardiogram and 24-h Holter monitoring is implemented at 3, 6 and 12 months following hybrid surgery. A gentle cardiac rehabilitation program following the procedure is encouraged.

Conclusion Hybrid AF-surgery is a promising therapy for patients refractory to AF-treatment. An integrated approach involving different teams may lead to improved success rate and increased patient satisfaction. Differentiation of the several possible pain triggers, whether thoracic, cardiac or gastro-esophageal in origin, can help resolve observed versatile postoperative pain. n

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Diagnostic Electrophysiology and Ablation 1.

irchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for K the management of atrial fibrillation developed in collaboration with EACTS: The Task Force for the management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC Endorsed by the European Stroke Organisation (ESO). Eur J Cardiothorac Surg 2016;50:1–88 DOI: 10.1093/ejcts/ezw313; PMID:27663299. 2. Lawrance CP, Henn MC, Damiano RJ Jr. Surgical ablation for atrial fibrillation: techniques, indications, and results. Curr Opin Cardiol 2015;30:58–64. DOI 10.1097/ HCO.0000000000000125; PMID: 25389650. 3. Pak HN, Hwang C, Lim HE, Kim JS, Kim YH. Hybrid epicardial and endocardial ablation of persistent or permanent atrial fibrillation: a new approach for difficult cases. J Cardiovasc Electrophysiol 2007;18:917-23. DOI:10.1111/ j.1540-8167.2007.00882.x; PMID:17573836. 4. Pison L, La Meir M, van Opstal J, Blaauw Y, Maessen J, Crijns HJ. Hybrid thoracoscopic surgical and transvenous catheter ablation of atrial fibrillation. J Am Coll Cardiol 2012;60: 54–61. DOI: 10.1016/j.jacc.2011.12.055; PMID: 227 42400. 5. Krul SP, Driessen AH, van Boven WJ, et al. Thoracoscopic video-assisted pulmonary vein antrum isolation, ganglionated plexus ablation, and periprocedural confirmation of ablation lesions: first results of a hybrid surgical-electrophysiological approach for atrial fibrillation. Circ Arrhythm Electrophysiol 2011;4:262–70. DOI: 10.1161/CIRCEP.111.961862; PMID:21493960. 6. La Meir M, Gelsomino S, Lorusso R, et al. The hybrid approach for the surgical treatment of lone atrial fibrillation: one-year results employing a monopolar radiofrequency source. J Cardiothorac Surg 2012;7:71. DOI: 10.1186/1749-8090-7-71; PMID: 22812613. 7. Muneretto C, Bisleri G, Bontempi L, Curnis A. Durable staged hybrid ablation with thoracoscopic and percutaneous approach for treatment of long-standing atrial fibrillation: a 30-month assessment with continuous monitoring. J Thorac Cardiovasc Surg 2012;144:1460–5. DOI: 10.1016/ j.jtcvs.2012.08.069; PMID: 23062968. 8. Gehi AK, Mounsey JP, Pursell I, et al. Hybrid epicardialendocardial ablation using a pericardioscopic technique for the treatment of atrial fibrillation. Heart Rhythm 2013;10:22–8. DOI: 10.1016/j.hrthm.2012.08.044; PMID: 23064043. 9. Krul SP, Pison L, La Meir M, et al. Epicardial and endocardial electrophysiological guided thoracoscopic surgery for atrial fibrillation: a multidisciplinary approach of atrial fibrillation ablation in challenging patients. Int J Cardiol 2014;173:229–35. DOI: 10.1016/j.ijcard.2014.02.043; PMID:24630384. 10. Je HG, Shuman DJ, Ad N. A systematic review of minimally invasive surgical treatment for atrial fibrillation: a comparison of the Cox-Maze procedure, beating-heart epicardial ablation, and the hybrid procedure on safety and efficacy. Eur J Cardiothorac Surg 2015;48:531–40. DOI: 10.1093/ejcts/ezu536; PMID:25567961. 11. De Asmundis C, Chierchia GB, Mugnai G, et al. Midterm clinical outcomes of concomitant thoracoscopic epicardial and transcatheter endocardial ablation for persistent and long-standing persistent atrial fibrillation: a single-centre experience. Europace 2016:19:58–65. DOI: 10.1093/europace/ euw026; PMID: 27247011.

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12. H u QM, Li Y, Xu CL, et al. Analysis of risk factors for recurrence after video-assisted pulmonary vein isolation of lone atrial fibrillation results of 5 years of follow-up. J Thorac Cardiovasc Surg 2014;148:2174–80. DOI: 10.1016/ j.jtcvs.2013.10.054; PMID: 24698564. 13. Vroomen M, Pison L. Hybrid ablation for atrial fibrillation: a systematic review. J Interv Electrophysiol 2016;47:265–74. DOI: 10.1007/s10840-016-0183-9; PMID: 27613183. 14. Buvanendran A, Kroin JS. Multimodal analgesia for controlling acute postoperative pain. Curr Opin Anaesthesiol 2009;22:588–93. DOI: 10.1097/ ACO.0b013e328330373a; PMID: 19606021. 15. Freise H, Van Aken HK. Risks and benefits of thoracic epidural anesthesia. Br J Anaesth 2011;107:859–68. DOI: 10.1093/bja/ aer339; PMID: 22058144. 16. Pöpping DM, Elia N, Van Aken HK, et al. Impact of epidural analgesia on mortality and morbidity after surgery: systematic review and meta-analysis of randomized controlled trials. Ann Surg 2014;259:1056–67. DOI: 10.1097/ SLA.0000000000000237; PMID: 24096762. 17. Block BM, Liu SS, Rowlingson AJ, et al. Efficacy of postoperative epidural analgesia: a meta-analysis. JAMA 2003;290:2455–63. DOI: 10.1001/jama290.18.2455; PMID: 14612482. 18. Teeter EG, Kumar PA: Pro Thoracic epidural is superior to paravertebral block for open thoracic durgery. J Cardiothorac Vasc Anesth 2015;29:1717–9. DOI: 10.1053/j.jvca.2015.06.015; PMID: 26386502. 19. Krakowski JC, Arora H. Con: thoracic epidural is not superior to paravertebral block for open thoracic surgery. J Cardiothorac Vasc Anesth. 2015;29:1720–2. DOI: 10.1053/ j.jvca.2015.06.012; PMID:26386503. 20. Zhang X, Shu L, Lin C, et al. comparison between intraoperative two-space injection thoracic paravertebral block and wound infiltration as a component of multimodal analgesia for postoperative pain management after video-assisted thoracoscopic lobectomy: a randomized controlled trial. J Cardiothorac Vasc Anesth 2015;29:1550–6. DOI: 10.1053/ j.jvca.2015.06.013; PMID:26409920. 21. Horlocker TT, Wedel DJ, Rowlingson JC, et al. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine Evidence Based Guidelines (Third Edition) Reg Anesth Pain Med 2010;35:64–101. PMID: 20052816. 22. Horlocker TT. Regional Anesthesia in the patient receiving antithrombotic and antiplatelet therapy Br J Anesth 2011;107: i96–i106. DOI: 10.1093/bja/aer381; PMID: 22156275. 23. Neal JM, Barrington MJ, Brull R, et al. Second ASRA Practice Advisory on Neurologic Complications Associated with Regional Anesthesia and Pain Medicine: Executive Summary 2015 JC. Reg Anesth Pain Med 2015;40:401–30. DOI: 10.1097/ AAP.0000000000000286; PMID: 26288034. 24. Weitz JI, Hirsh J, Samama MM. New antithrombotic drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133:234S–256S. DOI: 10.1378/chest.08-0673; PMID: 18574267. 25. Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors in development.

Clin Pharmacokinet 2009;48:1–22. DOI: 10.2165/0003088200948010-00001; PMID 19071881. 26. J akoi A, Kumar N, Vaccaro A, Radcliff K. Perioperative coagulopathy monitoring. Musculoskeletal Surgery 2014; 98,1–8. DOI: 10.1007/s12306-013-0307-7; PMID: 24281819. 27. Petricevic M, Konosic S, Biocina B, et al. Bleeding risk assessment in patients undergoing elective cardiac surgery using ROTEM® platelet and multiplate® impedance aggergometry. Anaesthesia. 2016;71: 636–47. DOI: 10.1111/ anae.13303; PMID: 26763378. 28. Lee GC, Kicza AM, Liu KY et al. Does rotational thromboelastometry (ROTEM) improve prediction of bleeding after cardiac surgery? Anesth Analg 2012;115:499–506. DOI: 10.1213/ANE.0b013e31825e7c39; PMID: 22713683. 29. Dubois V, Dincq AS, Douxfils J, et al. Perioperative management of patients on direct oral anticoagulants. Thromb J 2017;15:14. DOI: 10.1186/s12959-017-0137-1; PMID: 28515674. 30. Woodcock TE, Woodcock TM. Revised Starling equation and the glycocalyx model of transvalvular fluid exchange: an improved paradigm for prescribing intravenous fluid therapy. Br J Anaesth 2012;108:384–94. DOI: 10.1093/bja/aer515; PMID: 22290457. 31. Miller TE, Raghunathan K, Gan TJ. State of the art fluid management in the operating room. Best Pract Res Clin Anaesthesiol 2014;28:261–73. DOI: 10.1016/j.bpa.2014.07.003; PMID: 252089. 32. Miller TE, Roche AM, Mythen M. Fluid management and goaldirected therapy as an adjunct to Enhanced Recovery After Surgery (ERAS). Can J Anaesth 2015;62:158–68. DOI: 10.1007/ s12630-014-0266-y; PMID 25391735. 33. Battipaglia I and Lanza GA. Autonomic innervation of the heart. In: Slart RHJA, Tio RA, Elsinga PH, Schwaiger M (eds). Role of Molecular Imaging. Berlin: Springer, 2015;2–11. 34. Suraj K. Innervation of the heart an invisible grid with a black box. Trends in Cardiovasc Med 2016;26: 245–57. DOI: 10.1016/ j.tcm.2015.07.001; PMID: 26254961. 35. Orme J, Eddin M, Loli A. Regional pericarditis status post cardiac ablation: a case report. North Am J Med Sci 2014;6:481–3. DOI: 10.4103/1947-2714.141653; PMID: 25317395. 36. Schmidt M, Nölker G, Marschang H, et al. Incidence of oesophageal wall injury post-pulmonary vein antrum isolation for treatment of patients with atrial fibrillation. Europace 2008; 10: 205–9. DOI: 10.1093/europace/eun001; PMID: 18256125. 37. Purza R, Ghosh SB, Walker C, et al. Transesophageal echocardiography complications in adult cardiac surgery: a retrospective cohort study. Ann Thorac Surg 2017;103:795–802. DOI: 10.1016/j.athoracsur.2016.06.073; PMID: 27646612. 38. Di Biase L, Burkhardt JD, Mohanty P, et al. Left atrial appendage: an underrecognized trigger site of atrial fibrillation. Circulation 2010;122:109–18. DOI: 10.1161/ CIRCULATIONAHA.109.928903; PMID: 27788847. 39. Emmert MY, Puippe G, Baumüller S, et al. Safe, effective and durable epicardial left atrial appendage clip occlusion in patients with atrial fibrillation undergoing cardiac surgery: first long-term results from a prospective device trial. Eur J Cardiothorac Surg 2014;45:126–31. DOI: 10.1093/ejcts/ ezt204; PMID: 23657550. 40. Majunke N, Sandri M, Adams V, et al. Atrial and brain natriuretic peptide secretion after percutaneous closure of the left atrial appendage with the watchman device. J Invasive Cardiol 2015;27:448–52. PMID: 25999139.

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Diagnostic Electrophysiology and Ablation

Increasing the Single-Procedure Success Rate of Pulmonary Vein Isolation Mattias Duytschaever, 1 Mark O’Neill, 2,3 Martin Martinek 4 1. St Jan Hospital, Bruges, Belgium; 2. St. Thomas’ Hospital, London, UK; 3. King’s College London, London, UK; 4. Elisabethinen Hospital, Linz, Austria

Abstract To improve the single-procedural success and long-term outcomes of catheter ablation techniques for AF, there is a need for durable, contiguous and transmural lesions encircling the pulmonary veins (PV). Measurement of contact force (CF) between the catheter tip and the target tissue can optimise ablation procedures. A new approach to obtain single-procedure durable PV isolation (PVI) using the latest CF technology combined with the CARTO VISITAG™ Module with Ablation Index (Biosense Webster) has been shown in small studies to almost eliminate recurrence of paroxysmal AF at 1-year follow up and to make PVI procedures more reproducible. The use of a standardised workflow is expected to increase the reproducibility of results and to increase the efficiency of PVI procedures.

Keywords Catheter ablation, contact force, pulmonary vein isolation, CARTO VISITAG™ Module, ablation index Disclosure: Mark O’Neill has received research support, honoraria and consulting fees from Biosense Webster; and research support, honoraria and consulting fees from Abbott/St Jude. Mattias Duytschaever has received honoraria for presentation and consulting from Biosense Webster. Acknowledgement: The authors are grateful to the technical editing support provided by Katrina Mountfort of Medical Media Communications (Scientific) Ltd, which was funded by Biosense Webster. Received: 16 October 2017 Accepted: 18 November 2017 Citation: Arrhythmia & Electrophysiology Review 2017;6(4):ePub: 217–21. DOI: 10.15420/aer.2017.38/1 Correspondence: Mattias Duytschaever, St Jan Hospital, Ruddershove 10, Bruges, Belgium 8000 Bruges. E: Mattias.Duytschaever@azsintjan.be

The most common sustained cardiac arrhythmia is AF, which is associated with increased risk of stroke and heart failure, and represents a significant global health burden.1 Pulmonary vein isolation (PVI) is the standard treatment for symptomatic, drug resistant paroxysmal and persistent AF.2 Radiofrequency (RF) ablation, the most widely used ablation technique, aims to achieve circumferential ipsilateral PVI by creating contiguous and transmural point-by-point lesions.3 However, pulmonary vein (PV) reconnection following ablation leads to AF recurrences, necessitating repeat ablations, putting patients at increased risk of complications and decreasing the cost-effectiveness of the procedure. Rates of ablation procedures have risen over the last decade,4 but in order for catheter ablation to become standard first-line treatment for AF patients, there is a need for higher and reproducible single-procedure success rates. CARTO VISITAG™ Module with Ablation Index (Biosense Webster) is a new technology providing visual lesion representation based on the integration of power, contact force and time parameters to be displayed on the CARTO® 3 System (Biosense Webster). This index was developed to simplify and standardise the workflow for ablating patients with paroxysmal AF (PAF) and support electrophysiologists using the CARTO SMARTTOUCH™ Technology (Biosense Webster) in reproducing their own successful ablation strategy to achieve PVI. This article will review the literature on optimising efficacy and outcomes with the use of contact force (CF), describe the ‘CLOSE’ protocol – an ablation strategy guided by the CARTO VISITAG Module with Ablation Index – and discuss the need for a reproducible and standard RF ablation strategy.

Contact Force: A Critical Determinant of Lesion Size RF current at the electrode tissue interface leads to tissue injury. Although RF current cannot be measured directly, RF power and

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duration can be measured and altered. Because equivalent power and duration applications do not give equivalent lesion sizes, lesion size cannot be reliably assessed in real time. CF is a key parameter to controlling lesion size. It has been clearly demonstrated that CF is a determinant of lesion size; at constant power, tissue temperature and lesion size increased with CF. In addition, the incidence of steam pop and thrombus increased with CF.5 Shah et al.6 have examined the delivery of RF energy during constant contact at 20 g, variable contact with a 20 g peak and 10 g nadir and intermittent contact with a 20 g peak and 0 g nadir with loss of contact. The area under the CF curve was calculated as the force-time integral (FTI). The measured FTI was highest during constant contact, intermediate during variable contact and lowest during intermittent contact and correlated linearly with lesion volume. An estimation of lesion size was possible by combining CF and the duration of RF delivery.6 Ikeda et al. assessed the relationship between lesion size and CF by measuring electrogram amplitude, impedance and electrode temperature in a beating canine heart.7 At constant power and duration of RF delivery, lesion size increased significantly with increasing CF (p<0.01). There was a poor correlation between peak electrode temperature and lesion size. The decrease in impedance during the RF application correlated well with lesion size for lesions in the left ventricle but less well for lesions in the right ventricle.7 Therefore, CF is a critical determinant of lesion size. Increasing CF at constant power increases lesion size. Steam pops are uncommon at CFs <20 g and RF power/duration levels used in the clinical setting. The appropriate CF needed to achieve transmurality with 25–30 W delivery in the thin-walled atrium is lower than for the ventricle.

Access at: www.AERjournal.com

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Diagnostic Electrophysiology and Ablation Table 1: Available Force-sensing Technologies Sensor position

Temporal

Technology

resolution

IntelliSense®

4 Hz

Mechanical resistance

Within extravascular

Validation

Calibration

Units

Using ICE, fluoro

Required

Grams

(Hansen Medical) to catheter pulsing

segment of

proprietary sheath

within sheath

in canines

Electric Coupling Measure of catheter- None; two indifferent Not specified, Evaluation during Zeroing and ECI, ohms Index (ECI; tip tissue electric patches required real-time curve human PV calibration St Jude Medical) coupling derived from generated isolation required three terminal circuit model of global impedance TaciCath™ (St Jude Medical)

Originally Distal catheter tip: 50 Hz Bench, in vivo microdeformation juxtaposed to tip animal, clinical transduced by FBG electrode optical fibre sensor; currently transduced by white light intermittently through optical fibres

ThermoCool Electromagnetic SMARTTOUCH® transduction of catheter tip electrode (Biosense microdeflection Webster)

Zeroing Grams required, auto- zero effective thereafter

Distal catheter tip: 40 Hz Bench, in vivo Zeroing Grams transmitter coil animal, clinical required attached to electrode with three location sensors proximal to spring

Comments Accuracy angle-dependent; best results perpendicular to tissue Influenced by tissue characteristics, tissue healing and overall impedance fluctuation during procedure; orientation independent, nonmechanical parameter Tip orientationindependent CF measurement, sheath constraint effect possible

Tip orientation-independent CF measurement, sheath constraint effect warning, electromagnetic interference warning

CF = contact force; ECI = Electric Coupling Index; FBG = Fiber Bragg Grating; ICE = intracardiac ultrasound; PV pulmonary veins. Acknowledgement: 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. https://doi.org/10.1161/CIRCEP.115.002779

Clinical Impact of Contact Force Technologies Currently tested modalities include the IntelliSense® force sensing technology8 (Hansen Medical), Electric Coupling Index (ECI; St Jude Medical), TactiCath™ (St Jude Medical) and ThermoCool SMARTTOUCH® (Biosense Webster) catheters (see Table 1). Assessment of ECI remains challenging. It requires scaling to the individual patient and is repeated every 30 minutes; therefore, it is difficult to compare between patients. In addition, ECI and the nature of its changes during tissue contact are not completely understood. It lacks precise distinction between levels of contact, and may be challenging to interpret at sites of previous ablation injury or spontaneous atrial fibrosis. Both the TactiCath and ThermoCool SMARTTOUCH have been demonstrated to be highly accurate in assessing tip-tissue contact, albeit using quite different force assessment technologies.9 A systematic review and meta-analysis of nine non-randomised studies involving 1,148 patients aimed to evaluate the clinical impact of CF technology. The primary endpoint was relative risk of AF recurrence at follow up. RF duration, total procedure length and fluoroscopy exposure were assessed as secondary outcomes. Compared with standard technology, the use of CF technology showed a 37 % reduction (relative risk [RR] 0.63; p=0.01) in AF recurrence at a median follow up of 12 months and a 7.3-minute reduction (p=0.03) in RF use during ablation. However, there was no significant difference in total procedure length and fluoroscopy exposure between the two groups.10 This analysis also included small early studies. A multicentre study of 600 patients evaluated the impact of CF-sensing technology on medium-term outcome of AF ablation. First-time AF ablation procedures employing CF-sensing catheters from four centres were matched retrospectively to those without CF-sensing catheters in a 1:2 manner by type of AF. The primary outcome measure was freedom from recurrence of atrial arrhythmia, with fluoroscopy

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time as a secondary outcome measure. A total of 600 AF ablation procedures (200 using CF and 400 using non-CF catheters) were performed. Of these, 46 % were PAF, 36 % persistent AF and 18 % longlasting persistent AF. The follow-up duration was 10.0–11.4 months. Similar complication rates were reported in both groups. The use of a CF-sensing catheter independently predicted clinical success in ablating PAF, but not non-PAF. In all cases, the use of CF catheters was associated with reduced fluoroscopy time.11 Further insights can be derived from non-comparative studies. The first published study of the use of CF-ablation catheters in humans was the Touch+™ for Catheter Ablation (TOCCATA) study. Patients with PAF underwent PVI using the TactiCath catheter. All patients (n=5) treated with an average CF of <10 g experienced recurrences, whereas 80 % of the patients treated with an average CF of >20 g (n=10) were free from AF recurrence at 12 months. The investigators concluded that CF achieved correlates with clinical outcome.12 In the prospective, multicentre, 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 (SMART-AF) study, 160 of 172 enrolled patients from 21 centres underwent AF ablation using the ThermoCool SMARTTOUCH catheter. The majority of procedures employed between 10–25 g. Investigators remained within their individually defined prespecified ranges 73.3 ± 18.4 % of the time. Success rate after 1 year follow up was 74 % when the operator remained in the preset CF range. This improved to 81 % when the investigator stayed within their preselected CF range ≥80 % of the time. Further subanalysis showed that when the CF was within investigator selected range ≥85 % of the time, success rate increased to 88 %.13 Stable CF during RF ablation increases the likelihood of 12-month success.

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Optimising Outcomes in Pulmonary Vein Isolation What About Randomised Trials? The importance of optimal contact has been demonstrated in the prospective randomised non-inferiority Ablation Catheter Study for Atrial Fibrillation (TOCCASTAR) study, which compared the TactiCath catheter with a non-CF-sensing catheter (NAVISTAR® ThermoCool®; Biosense Webster) in 300 patients undergoing catheter ablation of PAF.14 When the CF arm was stratified into optimal CF (≥90 % ablations with ≥10 g) and non-optimal CF groups, effectiveness was achieved in 75.9 % versus 58.1 %, respectively (p=0.018). In a recent randomised trial performed at seven UK centres, 117 patients undergoing first-time PAF ablation were randomised to ablation with (CF-on) or without (CF-off) CF data available to the operator. A reduction in acute PV reconnection rates was seen in the CF-on group (22 % versus 32 %, p=0.03) but there was no significant difference in 1-year success rates (49 % versus 52 %, p=0.9). Furthermore, there was no difference in major complication rates, procedural times and fluoroscopy times. The investigators concluded that CF data availability as used in this study was associated with improved catheter control but did not impact on the clinical outcome. This confirms that CF is only one of multiple factors that determine lesion efficacy and safety.15 Three other small prospective randomised studies have compared CF versus non-CF-sensing catheter ablation. These studies have shown that some operators are able to estimate CF with a high degree of accuracy when CF information is not available and may explain why, when the CF information was available, none of these studies demonstrated a statistically significant improvement in long-term outcomes.16–18 Despite the lack of superiority demonstrated by randomised studies, some experts consider their personal experience with CF catheters to be so favourable they would “consider it almost unethical to perform an AF RF ablation with a non-CF-sensing catheter”.19 It is possible that the failure to demonstrate unequivocal benefit can be explained by study design, variability in the catheter and mapping systems used and the absence of target guidelines at the procedural outset. In addition, the operators in the trial were highly skilled.19 Furthermore, although catheter-tissue contact is the single most important determinant of RF lesion formation to which there is access in the electrophysiology laboratory, consistency and contiguity of lesions is more important than absolute level of contact per lesion above a threshold. Objective lesion representation tools such as CARTO VISITAG Module with Ablation Index could provide the means to translate biophysical parameters including CF into a reproducible and reliable delivery of RF lesion sets.

Towards A Standardised Protocol For Durable PVI: The CLOSE Protocol The CLOSE protocol is a point-by-point approach aiming to enclose PVs with contiguous and optimised RF lesions (Figure 1). This protocol was based upon a prior study from El Haddad et al.20 In this study 42 CF-guided PVI procedures were analysed with the aim of identifying determinants of acute and late gaps after CF-guided PV encircling. Each circle was subdivided into 10 segments. For each segment, the weakest link in the circle was determined. Two independent predictors of durable segments were identified: ablation index (AI) and interlesion distance (ILD). This study suggests that gaps are determined by insufficient lesion depth and/or discontiguity within the deployed RF circle. Vice versa, combining ILDmax ≤6 mm and AImin ≥400 (posterior)/550 (anterior) was associated with a 93 % specificity to predict durable segments (Figure 2).20

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Figure 1: The CLOSE Protocol

The ‘CLOSE’ protocol is a point-by-point RF approach aiming to enclose the PVs with contiguous and optimised RF lesions

PV = pulmonary vein; RF = radiofrequency.

It was therefore hypothesised that an RF strategy aiming to enclose the PVs with strict criteria for lesion depth and ILD would lead to durable PV isolation.21 This CLOSE protocol was evaluated in >400 patients with PAF. The protocol involved creating one prespecified circle enclosing the veins. This was nephroid-shaped (towards the carina) (Figure 3) and 10–12 cm at the perimeter per circle. Ablation was performed where the atrial myocardium connects to the PV sleeve, and typically with a >2 cm distance between the ablated anterior and posterior carina. Lesions were closely spaced: an ILDmax ≤6 mm, based on previous study findings20,22,23 and energy (35 W) was delivered to reach a minimal AI ≥400 at the posterior wall and ≥550 at the anterior wall. The AI target was reduced to 300 (corresponding to an application of only 11–12 seconds) in the event of signs of oesophageal injury (pain during local anaesthesia or temperature probe heating during general anaesthesia). The procedural endpoint was not PVI per se but a perfect circle leading invariably to PVI. More specifically, the CLOSE protocol is performed using the ThermoCool SMARTTOUCH and LASSO® catheter (Biosense Webster). Before RF was undertaken, the circle was pre-designed around the veins based on anatomy, CF, local electrograms and position of the LASSO catheter. Using the CARTO VISITAG Module and respiratory gating, the lesion marker settings were based upon stability (3 mm for 8 seconds) and force (30 % >4 g). Procedures were carried out under sedation or general anaesthesia. A point-by-point contiguous line was created to enclose the PVs. During RF, a size tag 3 mm and real-time ruler were employed. Power settings were as high as reasonably achievable with a maximum of 35 W (30 cc cooling). Following ipsilateral encircling, ILD and AI criteria were systematically verified. The ultimate goal was enclosing the circle with the exact required quantity of RF tags, around 30 per circle (corresponding to an RF time of approximately 15 minutes). Recently, procedural- and 1-year outcome in 130 patients with PAF were reported by Taghji et al.21 An unprecedented high rate of acute durable PV isolation (98 % adenosine-proof isolation) was paralleled by excellent 1-year outcome. At 12 months, freedom from documented AF/ atrial tachycardia (AT)/ atrial flutter (AFL) was reported in 92.3 % of all patients.21 Recurrence was defined as any AF, AT or AFL >30 seconds on Holter ECGs at 3, 6 and 12 months. Subgroup analysis showed that freedom from documented AF/AT/ AFL in patients off antiarrhythmic drug therapy (n=104) was 91.3 %; freedom from documented AF/AT/AFL in patients on antiarrhythmic drug therapy (n=26) was 96.2 %.

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Diagnostic Electrophysiology and Ablation Figure 2: Determinants of Gap in Contact Force-Guided Pulmonary Veins Encircling AI and ILD are independent predictors of durable segment Segments with tags all with ILDmax ≤ 5 mm p = 0.014

Anterior wall

Posterior wall

800

700

600

500

400

300

100

2 N=7

Segments without PVR

Posterior wall

N = 275

N = 164

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200

p < 0.001

Inter-lesion distance (ILDmax)

Ablation index (AImin)

Segments with tags all with AImin > 417 (post) or AImin > 550 (ant)

N=5

Segments without PVR

Segments with PVR

Combining ILDmax ≤ 6 mm and AImin ≥ 400/550 is associated with a 93 % specificity to predict durable segments AI = ablation index; ant = anterior; ILD = interlesion distance; post = posterior; PVR = pulmonary vein reconnection. Adapted from El Haddad, et al., 2017.20

Figure 3: The CLOSE Study: Pulmonary Vein Isolation Protocol The CLOSE Protocol: Recipe and Ingredients

AI 550

AI 400*

AI 550

ILD ≤ 6 mm

Posterior

*AI 300 if signs of oesophageal injury. AI = ablation index; ILD = interlesion distance.

Among 235 patients in a safety cohort (130 in the pilot study and 105 in a follow-up study) complications were reported in only three cases (1.2 %). These comprised one transient ischaemic attack-like event (0.42 %), one symptomatic PV stenosis (operator error; 0.42 %) and one femoral artery pseudo aneurysm requiring surgery. No incidences of steam pops, death, stroke or tamponade were reported. Several other studies evaluating the efficiency, safety and efficacy of CLOSE are ongoing. The ongoing Evaluation of Ablation Index and VISITAG

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Use for PVI in Patients with PAF (VISTAX) study aims to evaluate an AIand ILD-guided enclosing strategy in over 300 PAF patients. The study began early in 2017 and is being performed in 19 European centres. The CLOSE-Guided Pulmonary Vein Isolation as Cure for Paroxysmal Atrial Fibrillation? (CLOSE to CURE) study is a single-centre, patient-controlled trial evaluating CLOSE-guided PVI in 105 PAF patients.24 A subcutaneous loop recorder monitors the patients 2 months before until 3 years after PVI. The last enrolment was in April 2017. The patients are not taking antiarrhythmic drug therapy and oral anticoagulants are stopped when there is absence of arrhythmia, low stroke risk and absence of atrial scar. In summary, an ablation strategy guided by the CARTO VISITAG Module with Ablation Index and respecting strict criteria of lesion contiguity and lesion depth results in a significant improvement in acute PVI durability and a high single-centre-procedure, arrhythmiafree survival at 1 year (92.3 %). Because of the standardised workflow to reach an objective procedural endpoint, reproducible results are expected across centres and operators.

Conclusion A growing body of evidence supports the efficacy and safety of CF-sensing technology. To optimise clinical outcomes in PVI, there is a need for a standard RF ablation procedure. Consistency and lesion contiguity are essential in such a procedure. An objective lesion assessment prediction tool such as CARTO VISITAG Module with Ablation Index is also important to achieve a significant improvement in acute PVI durability and a high rate of arrhythmia-free survival at 1 year (92.3 %). The use of a standardised workflow is expected to increase the reproducibility of results across

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Optimising Outcomes in Pulmonary Vein Isolation centres and operators, and to increase efficiency of PVI procedure. It should be emphasised that the current approach is limited to only paroxysmal, not necessarily persistent, AF beyond PVI. 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 Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design. Europace 2012;14:528–606. DOI: 10.1093/europace/eus027; PMID: 22389422 Ouyang F, Bänsch D, Ernst S, et al. Complete isolation of left atrium surrounding the pulmonary veins: new insights from the double-Lasso technique in paroxysmal atrial fibrillation. Circulation 2004;110:2090–6. DOI: 10.1161/01. CIR.0000144459.37455.EE; PMID: 15466640 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 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. J Cardiovasc Electrophysiol 2010;21:1038–43. DOI: 10.1111/j.15408167.2010.01750.x; PMID: 20367658 Ikeda A, Nakagawa H, Lambert H, et al. Relationship between catheter contact force and radiofrequency lesion size and incidence of steam pop in the beating canine heart: electrogram amplitude, impedance, and electrode temperature are poor predictors of electrode-tissue contact force and lesion size. Circ Arrhythm Electrophysiol 2014;7:1174–80. DOI: 10.1161/CIRCEP.113.001094; PMID: 25381331 Dello Russo A, Fassini G, Casella M, et al. Simultaneous assessment of contact pressure and local electrical coupling

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The next challenge in PV ablation is to maintain this high durability while avoiding overshoot. Only then will the unique advantage of PV ablation be exploited to its full potential. n

index using robotic navigation. J Interv Card Electrophysiol 2014;40:23–31. DOI: 10.1007/s10840-014-9882-2; PMID: 24633546 Bourier F, Hessling G, Ammar-Busch S, et al. Electromagnetic Contact-Force Sensing Electrophysiological Catheters: How Accurate is the Technology? J Cardiovasc Electrophysiol 2016;27:347–50. DOI: 10.1111/jce.12886; PMID: 26643010 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 Jarman JW, Panikker S, Das M, et al. Relationship between contact force sensing technology and medium-term outcome of atrial fibrillation ablation: a multicenter study of 600 patients. J Cardiovasc Electrophysiol 2015;26:378–84. DOI: 10.1111/ jce.12606; PMID: 25546580 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 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 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 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 Kimura M, Sasaki S, Owada S, et al. Comparison of lesion formation between contact force-guided and non-guided

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circumferential pulmonary vein isolation: a prospective, randomized study. Heart Rhythm 2014;11:984–91. DOI: 10.1016/j. hrthm.2014.03.019; PMID: 24657428 Nakamura K, Naito S, Sasaki T, et al. Randomized comparison of contact force-guided versus conventional circumferential pulmonary vein isolation of atrial fibrillation: prevalence, characteristics, and predictors of electrical reconnections and clinical outcomes. J Interv Card Electrophysiol 2015;44:235–45. DOI: 10.1007/s10840-015-0056-7; PMID: 26387117 Pedrote A, Arana-Rueda E, Arce-Leon A, et al. Impact of contact force monitoring in acute pulmonary vein isolation using an anatomic approach. A randomized study. Pacing Clin Electrophysiol 2016;39:361–9. DOI: 10.1111/pace.12811; PMID: 26768692 Calkins H. Demonstrating the value of contact force sensing: more difficult than meets the eye. Circulation 2015;132:901–3. DOI: 10.1161/CIRCULATIONAHA.115.018354; PMID: 26260735 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 Taghji P, El Haddad M, Phlips T, et al. Evaluation of a strategy aiming to enclose the pulmonary veins with contiguous and optimized radiofrequency lesions in paroxysmal atrial fibrillation. JACC Clin Electrophysiol 2017; DOI: 10.1016/j. jacep.2017.06.023; epub ahead of press. 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 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 CLOSE-Guided Pulmonary Vein Isolation as Cure for Paroxysmal Atrial Fibrillation? (CLOSE to CURE) Study. 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT02925624 (accessed 5 July 2017).

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Letter

Mahaim Accessory Pathways

Citation: Arrhythmia & Electrophysiology Review 2017;6(4):222. DOI: 10.15420/aer.2017.6.4:L1 Correspondence: Nikolaos Fragakis, Aristotle University of Thessaloniki, Thessaloniki, Greece, E: fragakis.nikos@googlemail.com

Dear Sir, I read with great interest the review article ‘Mahaim Accessory Pathways’ by D. Katritsis, et al.,1 in a past issue of Arrhythmia & Electrophysiology Review (AER 6(1):29-32). In this concise paper a systematic approach to electrophysiological diagnosis and differential diagnosis of these rare, but characteristic, pathways is presented. As the authors point out, pathways with Mahaim characteristics can be atriofascicular, atrioventricular, nodofascicular and nodoventricular, depending on their variable proximal and distal insertions. In my opinion, nodoventricular and nodofascicular pathways deserve special interest because they are often associated with regular wide complex tachycardia, which is difficult to differentiate from ventricular tachycardia (VT). Mahaim accessory pathways during tachycardia may exhibit atrioventricular dissociation since the atria are not integral to the circuit. Although this helps to rule out other forms of decremental pathways, mediated atrioventricular tachycardias may also be confused with VT, especially in nodoventricular tachycardias which often display a wide broad QRS complex tachycardia implying ventricular tachycardia. One criterion that distinguishes nodoventricular and nodofascicular tachycardia from intramyocardial VT is that QRS fusion from atrial activation during tachycardia is not possible in the first case wheras it is possible during VT.2,3 Therefore thorough observation during clinical tachycardia for possible fusion beats may provide the hallmark for the origin of tachycardia and may help significantly in the ablation procedure. Furthermore, induction of fusion systole with atrial extrasystoles during tachycardia is also very useful for distinguishing between these two tachycardias. Nikolaos Fragakis Assistant Professor of Cardiology, Aristotle University of Thessaloniki, Thessaloniki, Greece

1. 2. 3.

Katritsis DG, Wellens HJ, Josephson MA. Mahaim Accessory Pathways. Arrhythmia & Electrophysiology Review 2017;6(1):29–32. doi: 10.15420/aer.2016:35:1; PMID: 28507744 Tchou P, Lehmann MH, Jazayeri M, Akhtar M. Atriofascicular connection or a nodoventricular Mahaim fiber? Electrophysiologic elucidation of the pathway and associated reentrant circuit. Circulation 1988;77:837–48. Grogin HR, Lee RJ, Kwasman M, et al. Radiofrequency catheter ablation of atriofascicular and nodoventricular Mahaim tracts. Circulation 1994;90:272–81

Authors’ reply: We thank Professor Fragakis for his kind words regarding our article on Mahaim pathways.1 We do concur with his comments. Demonstration of fusion is indeed a criterion of VT diagnosis, in general, and he is very right to point it out. Mahaim pathways are typical examples of electrophysiology entities that demand analytical and constructive thinking that may not always be found in our current era of computerised, video-game-like approaches. They also keep reminding us of the relevance and importance of the profound article by our sorely missed friend Mark Josephson: learn electrophysiology.2 Demosthenes G Katritsis, Hygeia Hospital, Greece Hein J J Wellens, University of Maastricht, The Netherlands

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Katritsis DG, Wellens HJ, Josephson MA. Mahaim Accessory Pathways. Arrhythmia & Electrophysiology Review 2017;6(1):29–32. doi: 10.15420/aer.2016:35:1; PMID: 28507744 Josephson ME. Electrophysiology at a crossroads. Heart Rhythm 2007;4:658–61. DOI: 10.1016/j.hrthm.2006.12.045; PMID: 17467638

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Letter

Can We Select Patients for Prophylactic VT Ablation?

Citation: Arrhythmia & Electrophysiology Review 2017;6(4):223–4. DOI: 10.15420/aer.2017.6.4.L2 Correspondence: Theodoros Zografos, MD, PhD, Red Cross Hospital, Athens, Greece. E: theodoroszografos@gmail.com

Dear Sir, I read with great interest the elegant review by Mukherjee and colleagues on prophylactic VT ablation in the latest issue of the journal (AER 6(3)125-8).1 The concept is indeed revolutionary, and should extend the boundaries of interventional electrophysiology. However, such an approach cannot be feasible without rationalising patient selection. Current guidelines’ recommendations, based on the results of primary sudden cardiac death prevention trials, mainly the Multicenter Automatic Defibrillator Implantation Trial–II (MADIT-II)2 and the Sudden Cardiac Death in Heart Failure (SCD-Heft)3 trials, use the left ventricular ejection fraction (LVEF) as a sole criterion for the propensity to sudden cardiac death. However, LVEF alone has limited sensitivity,4 and low specificity5 for arrhythmic versus non-arrhythmic cardiac death. Further risk stratification is crucial in this respect, and the issue of electrophysiology study (EPS) should not be ignored. In a recent review, the induction of sustained VT has been associated with a two- to three-fold increased risk of arrhythmia-related death in post-infarction patients with non-sustained VT.6 EPS has a sensitivity of 58.1 % and a specificity of 69.5 %, albeit with significant heterogeneity between the included studies. We think that in ischaemic patients with LVEF ≤35 %, EPS may be of value in identifying patients at high risk of future arrhythmic events, and should be useful as a risk stratifier in this setting. Such an approach might help focusing our attempts for prophylactic ablation on patients with a proven propensity, not just the substrate, for VT. If prophylactic VT ablation can ever become a clinical reality, effective selection of candidates is imperative. Theodoros Zografos, Red Cross Hospital, Athens, Greece

1. 2. 3. 4. 5. 6.

Mukherjee RK, O’Neill L, O’Neill MD. Prophylactic catheter ablation for ventricular tachycardia: are we there yet? Arrhythm Electrophysiol Rev 2017;6:125–8. DOI: 10.15420/aer.2017:17:1; PMID: 29018520 Moss AJ, Zareba W, Hall WJ, et al.; Multicenter Automatic Defibrillator Implantation Trial II Investigators. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346:877–83. DOI: 10.1056/NEJMoa013474; PMID: 11907286 Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225–37. DOI: 10.1056/NEJMoa043399; PMID: 15659722 Solomon SD, Zelenkofske S, McMurray JJ, et al. Sudden death in patients with myocardial infarction and left ventricular dysfunction, heart failure, or both. N Engl J Med 2005;352:2581–8. DOI: 10.1056/NEJMoa043938; PMID: 15972864. Every N, Hallstrom A, McDonald KM, et al. Risk of sudden versus nonsudden cardiac death in patients with coronary artery disease. Am Heart J 2002;144:390–6. Katritsis DG, Zografos T, Hindricks G. Electrophysiology testing for risk stratification of patients with ischemic cardiomyopathy: a call for action. Europace (In press)

Authors’ Reply: We would like to thank Dr Zografos for his interest in our review ‘Prophylactic catheter ablation for ventricular tachycardia: are we there yet?’ We agree with the author that risk predictive models for sudden cardiac death need to be improved in patients with ischaemic cardiomyopathy and that electrophysiology study (EPS) may have a crucial role to play in this regard. The value of EPS may not only be limited to improved risk stratification, but could also inform selection criteria for catheter ablation and assess the response to anti-tachycardia pacing, which could be useful for determination of future device programming.1 There is some evidence that in patients early after myocardial infarction, an LVEF ≤30 % or LVEF 31–35 % with NYHA II–III heart failure and inducible VT at EPS is associated with a decreased survival free of death or arrhythmia.2 However, in those patients who were EPS-negative with impaired LVEF, there was no significant difference compared with control patients with

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Letter LVEF >40 %, suggesting the existence of a cohort of lower-risk patients with LVEF ≤30 % post myocardial infarction. The concern with EPS, however, has been its negative predictive value, with non-inducible patients in the Multicentre Automatic Defibrillator Implantation II population having a higher risk of VF than in inducible patients, although a combined arrhythmic endpoint of VT or VF was lower.3 The negative predictive value of EPS appears to be dependent on the VT induction protocol used.2 We also know that the addition of fibrosis detection by late gadolinium enhancement cardiac magnetic resonance may add value to risk stratification tools for the propensity of sudden cardiac death in this population. In a multivariate analysis of a large group of patients with sustained or non-sustained VT, the presence of LV fibrosis was an independent predictor of adverse outcomes (composite of cardiac death/arrest, new episode of sustained VT or appropriate implantable cardioverter defibrillator [ICD] discharge).4 Perhaps the best strategy for patient selection for prophylactic catheter ablation may be a personalised approach incorporating data from cardiac imaging and electrophysiological testing. A recent proof-of-concept report constructed personalised models of post-infarct hearts using MRI and computational modelling, and appeared to outperform several existing clinical metrics in assessing the propensity to future arrhythmic events.5 We agree with the author of the letter that further work is warranted investigating EPS as a risk stratification tool for sudden cardiac death and in selecting patients for prophylactic VT ablation; however, the primary outcomes of the major VT ablation clinical trials are survival from ICD therapies or time to VT/VF recurrence. Without more robust arrhythmic risk stratification tools it would be difficult to justify performing a prophylactic VT ablation, with its associated risks, in patients who either do not have an ICD or have never received any therapies from their device. Rahul K Mukherjee, Division of Imaging Sciences and Biomedical Engineering, King’s College London, UK Louisa O’Neill, Division of Imaging Sciences and Biomedical Engineering, King’s College London, UK Mark D O’Neill, Department of Cardiology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK

1. 2. 3. 4. 5.

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Mitchell LB. The role of the transvenous catheter electrophysiology study in the evaluation and management of ventricular tachyarrhythmias associated with ischemic heart disease. Card Electrophysiol Rev 2002;6:458–62. Zaman S, Narayan A, Thiagalingam A, et al. Long-term arrhythmia-free survival in patients with severe left ventricular dysfunction and no inducible ventricular tachycardia after myocardial infarction. Circulation 2014;129:848–54. DOI: 10.1161/CIRCULATIONAHA.113.005146; PMID: 24381209. Daubert JP, Zareba W, Hall J, et al. Predictive value of ventricular arrhythmia inducibility for subsequent ventricular tachycardia or ventricular fibrillation in Multicenter Automatic Defibrillator Implantation Trial (MADIT) II patients. J Am Coll Cardiol 2006;47:98–107. DOI: 10.1016/j.jacc.2005.08.049; PMID: 16386671. Dawson DK, Hawlisch K, Prescott G, et al. Prognostic role of CMR in patients presenting with ventricular arrhythmias. J Am Coll Cardiol Cardiovas Imag 2013;6:335–44. DOI: 10.1016/j. jcmg.2012.09.012; PMID: 23433931. Arevalo HJ, Vadakkumpadan F, Guallar E, et al. Arrhythmia risk stratification of patients after myocardial infarction using personalized heart models. Nat Commun 2016;7:11437. DOI: 10.1038/ncomms11437; PMID: 27164184.

Access at: www.AERjournal.com

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