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Markers of atrial remodeling and invasive treatment of atrial fibrillation

Berger, W.R.

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Wouter Berger

Markers of atrial rem

odeling and invasive treatment of atrial fibrillation

Wouter Berger

UITNODIGINGVoor de openbare verdediging

van het proefschrift:

Markers of atrial remodeling and

invasive treatment of atrial fibrillation

doorWouter R. Berger

Rooseveltlaan 246-21078 NZ [email protected]

Donderdag 9 januari 2020 om 14:00 uur

in de Agnietenkapel Universiteit van AmsterdamOudezijds Voorburgwal 231

te Amsterdam

Aansluitend bent u van harte uitgenodigd voor de receptie in het

nabijgelegen café:De Brakke Grond

Nes 43, Amsterdam

PARANIMFEN

Florine Berger [email protected]

Volkert Poulie [email protected]

MARKERS OF ATRIAL REMODELINGAND INVASIVE TREATMENT OF ATRIAL FIBRILLATION

Wouter Berger

ColofonCover design, layout and printing by Optima Grafische Communicatie (www.ogc.nl)ISBN: 978-94-6361-361-3

Financial support by the Dutch Heart Foundation for the publication of this thesis is gratefully acknowledged.

Additional financial support for printing of this thesis was kindly provided by Academic Medical Center – University of Amsterdam, Stichting Wetenschappelijk Onderzoek Interne Geneeskunde OLVG, Research B.V. Cardiologie OLVG, AtriCure, Bayer Nederland B.V., Daiichi-Sankyo Nederland B.V., Boehringer-Ingelheim B.V., Servier Nederland Farma B.V., Vrest B.V. and ChipSoft B.V.

Copyright © by Wouter Rudolph Berger. All rights reserved. Any authorized reprint or use of this material is prohibited. No part of this thesis may be reproduced, stored or transmitted in any form or by any means, without written permission of the author or, when appropriate, of the publishers of the publications

MARKERS OF ATRIAL REMODELINGAND INVASIVE TREATMENT OF ATRIAL FIBRILLATION

ACADEMISCH PROEFSCHRIFT

ter verkrijging van de graad van doctoraan de Universiteit van Amsterdam op gezag van de Rector Magnificus

prof. dr. ir. K.I.J. Maexten overstaan van een door het College voor Promoties ingestelde commissie,

in het openbaar te verdedigen in de Agnietenkapel

op donderdag 9 januari 2020, te 14.00 uur

door

Wouter Rudolph Bergergeboren te Rotterdam

PROMOTIECOMMISSIE:

Promotores: Prof. dr. J.R. de Groot AMC-UvA Prof. mr. dr. B.A.J.M. de Mol AMC-UvA

Overige leden: Prof. dr. L.V.A. Boersma AMC-UvA Prof. dr. Y.M. Pinto AMC-UvA Prof. dr. J.P.S. Henriques AMC-UvA Prof. dr. M. Mariani Rijksuniversiteit Groningen Dr. M.J.W. Götte Vrije Universiteit Amsterdam Dr. J.S.S.G. de Jong OLVG

Faculteit der Geneeskunde

“The shortest distance between two points is often unbearable”Charles Bukowski

Voor mijn ouders

CONTENTS

Chapter 1. General introduction and outline of the thesis 9

Part I. Invasive treatment strategies for the treatment of patients with advanced atrial fibrillation

Chapter 2. Persistent atrial fibrillation: A systematic review and meta-analysis of invasive strategies.

23

International Journal of Cardiology 2019

Chapter 3. Ganglion plexus ablation in advanced atrial fibrillation: The AFACT study.

61

Journal of the American College of Cardiology 2016

Chapter 4. Additional ganglion plexus ablation during thoracoscopic ablation of advanced atrial fibrillation. Intermediate follow-up of the AFACT study.

81

JACC: Clinical Electrophysiology 2019

Chapter 5. Electrophysiologically guided thoracoscopic surgery for advanced atrial fibrillation: Five-year follow-up.

101

Journal of the American College of Cardiology 2017

Part II. Quality of life after invasive treatment of patients with atrial fibrillation

Chapter 6. Documented atrial fibrillation recurrences after pulmonary vein isolation are associated with diminished quality of life.

119

Journal of Cardiovascular Medicine 2016

Chapter 7. Quality of life improves after thoracoscopic surgical ablation of advanced atrial fibrillation. Results of the AFACT study.

137

Journal of Thoracic Cardiovascular Surgery 2018

Part III. Determinants of the substrate of advanced atrial fibrillation: the role of atrial fibrosis

Chapter 8. Atrial fibrosis and conduction slowing in the left atrial appendage of patients undergoing thoracoscopic surgical ablation.

159

Circulation: Arrhythmia and Electrophysiology 2015

Chapter 9. The change in circulating Galectin-3 predicts absence of atrial fibrillation after thoracoscopic surgical ablation.

177

Europace 2018

Chapter 10. Summary and future perspectives. 195

Chapter 11. Samenvatting en toekomstperspectieven. 205

AppendicesList of publications 219Contributing authors 222Portfolio 224Dankwoord 226Curriculum vitae 230

Chapter 1General Introduction and Outline of the Thesis

10 Chapter 1

Atrial FibrillationAtrial fibrillation (AF) is the most common cardiac arrhythmia in man, with a higher incidence in older patients. As the median age of the population is increasing world-wide, the number of patients with AF is growing, with population projections in large international cohorts estimating the prevalence to have doubled by 2060.1

Patients with AF have an increased morbidity and mortality.2 In particular, these patients have a five time higher risk of stroke. AF is also associated with an increased risk of heart failure, renal failure and cognitive impairment.3-6 Because these patients are frequently admitted to the hospital, AF causes an high burden on healthcare costs. The average costs of an AF patient in the chronic phase is $640 per patient per month.7 These costs will grow with the increasing prevalence of patients with AF, imposing high financial and economic burden, which is predicted to increase dramatically in the future. Therefore, adequate treatment of AF is essential in order to alleviate this high burden on society.

Classification atrial fibrillationAF is characterized by chaotic depolarization of the atrial cardiomyocytes resulting in irregular RR intervals and absence of P-waves on the electrocardiogram. Symptoms of AF may consist of (but are not limited to) palpitations, fatigue, dyspnea and chest pain, while AF can also be asymptomatic. The clinical progression of AF has been defined in four stages.8 The rhythm disorder usually starts as paroxysmal AF with episodes that are typically short and self-terminating within 7 seven days. When episodes have a dura-tion of more than 7 days, it is classified as persistent AF. Episodes of AF usually do not terminate spontaneously in patients with persistent AF. In longstanding persistent AF, episodes last more than one year, but rhythm control may be still pursued. Finally, in pa-tients with permanent AF, the arrhythmia is accepted, the patients is in a constant state of AF and rate control is applied. This classification is based on consensus for simplicity and on clinical relevance.9

Atrial remodelingAF is a progressive disease and its progression varies between patients. Clinical signs not always correlate with the underlying process of the disease (figure). The pathophysi-ological process of AF is complex because of its multifactorial character. Multiple experi-mental as well as clinical studies have shown that AF begets AF.10,11 Increasing AF burden leads to electrical, structural and autonomic remodeling of the atria, creating a substrate that is favorable for sustaining AF perpetuation. Alteration of the expression or activity of ion channels causes electrical atrial remodeling characterized by shortening of the atrial effective refractory period, atrial conduction slowing and action potential duration shortening. During AF atrial enlargement, development of fibrosis and reduced atrial

1

General Introduction 11

contractility may exist, described as structural remodeling. These changes may explain in part the progressive character of the disease in which AF progresses to a more sustained form over time. In this thesis, we frequently use the term ‘advanced atrial fibrillation’. This is defined as AF in patients with either persistent AF, enlarged left atria, a history of previous catheter ablation or a combination of these factors. With this classification we aim to better select patients with progression of the underlying substrate and who are often more difficult to treat. However, additional markers for progression of the atrial substrate would help to identify subgroups of patients that can benefit from a specific treatment strategy and might provide more individualized therapeutic opportunities, improve prognostication or provide preventive opportunities in patient with AF.

The role of the autonomic nervous system in atrial fibrillationAnother important modulator of the electrophysiological characteristics of the atria is the autonomic nervous system (ANS). The heart is extensively innervated and regulated by the ANS through its sympathetic and parasympathetic branches.12 The ANS is divided in the extrinsic nervous system that refers to brainstem and cardiac preganglionic fibers and comprises sympathetic nerves and vagus nerves, and the intrinsic nervous system,

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

12 Chapter 1

which consists of the epicardial ganglionated plexi (GP), residing in epicardial fat pads and related nerve fibers connecting them. The anatomy of the ANS and its function and modulation in arrhythmias have been extensively reviewed before.13,14 Studies show that simulation of the GPs triggers ectopy from the pulmonary veins (PV) in animals and humans, consequently triggering AF.15 PV ectopy is caused by activation of the acetylcholine activated potassium current as a result of parasympathetic stimulation, resulting in shortening of the action potential and by increasing calcium release from the sarcoplasmic reticulum as a result of sympathetic stimulation.16 Furthermore, GP stimulation affect local and global left atrial conduction time, consistent with a predomi-nantly parasympathetic effect.17 Therefore, hyperactivity of the GPs causes shortening of the action potential and increased burden of AF.18 Targeting the autonomic influence by ablating the GPs and, by doing so, taking away the inhibitory action of the extrinsic nervous system could decrease the burden of AF. This conjecture forms the rationale for the AFACT-trial, described in chapter 3.

Treatment of atrial fibrillationThe treatment of AF is based on three pillars: 1) Reducing the cardiovascular risk by using lifestyle changes and medication, such as anti-hypertensive and cholesterol low-ering drugs, 2) Prevention of thrombo-embolic events with anticoagulants in patients with a CHA2DS2-VASC score ≥1 (or ≥2 in women) and 3) Treatment of the arrhythmia with either rate control, which is aimed at controlling the ventricular rate, while accepting AF or rhythm control, aimed at achieving and maintaining sinus rhythm.8,19

Two seminal randomized controlled trials, comparing rate control with rhythm con-trol, did not show a difference in mortality or quality of life.20,21 However, some critical side notes are relevant when interpreting these results. The studies were performed before the era of ablation therapy and the non-superiority of rhythm control might be caused by the side effects of anti-arrhythmic drugs, since anti-arrhythmic drugs can have pro-arrhythmic effects.22,23 Furthermore, it was hypothesized that patients in sinus rhythm would no longer have an indication for anticoagulation therapy. However, many events in the rhythm control group were related to stroke.24 Long-term results of the AF-FIRM trial showed that in patients in whom sinus rhythm maintained during follow-up mortality was lower than in the rate control group.25 Finally, the mean age of the study populations was relatively high.

The current guidelines indicate rhythm control for symptomatic AF patients.26 It is also applied in young patients, patients with a short history of AF or patients with heart failure. Rhythm control can be achieved using different strategies: 1) Class I or III anti-arrhythmic drugs, with 44 – 67% of patients free of AF recurrence at one year27 2) electrical or pharmacological cardioversion, with 50% of patients free of AF after one year28 or 3) invasive treatment with catheter or surgical ablation.

1


Invasive treatment of atrial fibrillationWhen antiarrhythmic medication to achieve rhythm control fails, invasive treatment of AF may be considered. The first invasive techniques that were developed to treat AF where surgical techniques that were based on the interruption of macro-reentrant waves in the atria. In 1987, James Cox and his team developed a technique that involved multiple incisions across the left and right atria, preventing reentrant circuits to form.29 This was called the Maze procedure and was further developed into the Cox-Maze III procedure resulting in high success rates, with 97% of patients free of AF at long-term follow-up.30 To date, this technique remains the golden standard for surgical AF ablation. A drawback of the Cox-Maze procedure is its complexity and technical difficulty and a considerable number of complications, including mortality and pacemaker implanta-tions.31 For that reason, the procedure did not gain widespread acceptance and the results are difficult to reproduce.

In 1998, a landmark study by Michel Haissaguerre and colleagues, demonstrated that AF could be attributed to atrial ectopy arising from the junction between the pulmonary veins and the atrial antrum, and ablating these triggers could eliminate AF.32 This study formed the basis of many different catheter ablation techniques, in which isolation of the pulmonary veins is the cornerstone.26 Different studies have showed superiority of catheter ablation over anti-arrhythmic drugs in terms of efficacy and quality of life.33,34 However, success rates of catheter ablation vary largely.35 The efficacy of AF ablation is usually defined as freedom of AF after ablation and therefore highly depends on the frequency and intensity of arrhythmia monitoring during follow-up. Outcome of AF ablation also depends on patients characteristics, such as comorbidities, left atrial size and type of atrial fibrillation, and ablation techniques. Furthermore, isolation of the pulmonary veins is not always complete and often redo-procedures are necessary. Long term results of catheter ablation are poor with success rates of 20-29% after a single procedure and 45-67% after multiple procedures.36-38

It is important to note that the most relevant indication for AF ablation is reduction of symptoms, instead of eliminating episodes of AF. Moreover, since guidelines recom-mend to continue anticoagulant treatment after ablation, absence of AF after ablation has no implication for antithrombotic treatment. Quality of life questionnaires provide a useful reflection of symptom change. Therefore, assessment of quality of life has an increasingly important role in the evaluation of outcomes of AF ablation.

Ablation approaches not targeting the pulmonary veinsWhile paroxysmal AF may be caused by triggers only, the atrial substrate in patients with persistent AF has more abnormalities and pulmonary vein isolation alone might not be sufficient. In attempt to modify the atrial substrate, a wide range of different strategies have been used, with a large variation in success rates. One of these strategies

14 Chapter 1

is to create linear ablation lines in the atria similar to those advocated with Cox-Maze procedure.39 The efficacy in preventing AF recurrence of these additional linear lines remain controversial.40 Targeting non-PV triggers have been showed to eliminate AF.41

Complex fractionated atrial electrograms (CFAE) potentially represent the atrial substrate. Ablation of CFAEs usually results in extensive ablation and results are not uniform.42,43

Novel strategies have been developed, such focal impulse and rotor ablation, that aim at electrophysiologically mapping foci and rotors during AF.44 The first results of these techniques are promising.45 Finally, targeting the components of the autonomic nervous system by ablating the GPs appears to be successful in eliminating AF. Studies investigating the role of this autonomic substrate modulation on top of PVI showed mixed results.46,47 A study by Katritsis et al. showed a beneficial effect of endocardial GP ablation compared to PVI alone in patients with paroxysmal AF, albeit that the amount of radiofrequency ablation was also higher in the group of patients that underwent PVI and GP ablation during catheter ablation.48 The dogma that PVI alone is insufficient for persistent AF is challenged in the STAR AF II-trial, showing no difference in efficacy between PVI alone versus PVI with more extensive ablation in persistent AF patients.49

Thoracoscopic treatment of atrial fibrillationWhile catheter ablation is often the first choice in patients who are refractory to anti-arrhythmic drugs, new surgical ablation techniques have been developed. In 2005, Wolf et al. described a minimally-invasive technique that attempts to combine the high suc-cess rates of the maze procedure with the safety of catheter ablation by performing a mini-thoracotomy to apply epicardial pulmonary vein isolation.50 This technique was further developed into a totally thoracoscopic approach by Yilmaz et al.51 The first stud-ies investigating this minimally-invasive surgical ablation technique showed promising results with success rates of 69% after a single procedure, but in several studies high rates of atrial tachycardia were reported during follow-up.52,53 Therefore, hybrid approaches were designed where cardiothoracic surgeons collaborate with electrophysiologists to confirm conduction block and perform additional ablation when needed.54-56

The FAST-trial was the first randomized trial that compared thoracoscopic AF ablation with catheter ablation in patients with previously failed catheter ablation or with severely enlarged left atria.57 This study showed superiority of thoracoscopic ablation, however, at the cost of more procedural complications. An advantage of thoracoscopic ablation is that ablation is performed under direct vision, while catheter ablation depends on navi-gating systems and fluoroscopy. Furthermore, the left atrial appendage can be removed, potentially decreasing the risk of thrombo-embolic events after ablation, although it remains unclear if this decreases stroke incidence.58 An additional potential advantage

1


is that the GPs can be ablated, which are located in epicardial fat pads and cannot be ablated endocardially without more atrial myocardial ablation.

Outline of the thesisThe first part of this thesis focuses on invasive treatment of AF, in particular thoraco-scopic ablation. In chapter 2 we systematically review the literature on randomized controlled trials that investigated efficacy and safety outcomes of catheter or minimally-invasive surgical ablation. We included 6 studies on minimally-invasive surgical ablation and 57 studies on catheter ablation that reported outcome after 1 year follow-up and performed meta-analyses in order to, indirectly, compare both treatment strategies. In chapter 3 we present the results of the AFACT-trial. In this randomized controlled trial, we compared GP ablation on top of an epicardial ablation set versus the same epicardial ablation set without GP ablation. The AFACT-trial included 240 patients with advanced AF and was conducted in the Academic Medical Center. In chapter 4 we describe the results of the AFACT trial after intermediate follow-up, regarding freedom of AF and AF burden. Chapter 5 presents the long-term results of the first 66 patients who underwent thoracoscopic ablation for paroxysmal or persistent AF in the Academic Medical Center.

The second part of this thesis focuses on quality of life after AF ablation. In chapter 6 we investigate the relation between AF recurrences, documented on 24-hour holter or ECG, and quality of life in 99 patients who underwent catheter ablation. In chapter 7 we present a sub study of the AFACT-trial regarding the quality of life after thoracoscopic ablation with or without GP ablation.

Part 3 of this thesis focuses on the role of atrial fibrosis in AF patients. The effect of the fibrotic substrate on electrophysiological properties have not been studied in human. In chapter 8 we study the effect of interstitial fibrosis on conduction velocity in the left atrial appendages of patients with AF. Determining the amount of fibrosis in the clinical setting remains challenging. Galectin-3 is a mediator of cardiac fibrosis and is currently used as a marker for progression of heart failure. In chapter 9, we study the concentration of Galectin-3 in serum and left atrial tissue of patients who underwent thoracoscopic AF ablation. Furthermore, we follow the change of Galactin-3 concentra-tions over time in these patients to investigate if serum Galectin-3 reflects alterations of the arrhythmogenic atrial substrate and if Galectin-3 has prognostic implications and might therefore be useful as biomarker.

Finally, chapter 10 summarizes the main findings of the thesis and provides future perspectives for the treatment of advanced AF.

16 Chapter 1

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18. Lo LW, Scherlag BJ, Chang HY, Lin YJ, Chen SA, Po SS. Paradoxical long-term proarrhythmic effects after ablating the “head station” ganglionated plexi of the vagal innervation to the heart. Heart rhythm 2013;10:751-7.

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1


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22. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991;324:781-8.

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31. Weimar T, Schena S, Bailey MS, et al. The cox-maze procedure for lone atrial fibrillation: a single-center experience over 2 decades. Circulation Arrhythmia and electrophysiology 2012;5:8-14.

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18 Chapter 1

39. Ernst S, Ouyang F, Lober F, Antz M, Kuck KH. Catheter-induced linear lesions in the left atrium in patients with atrial fibrillation: an electroanatomic study. J Am Coll Cardiol 2003;42:1271-82.

40. Chae S, Oral H, Good E, et al. Atrial tachycardia after circumferential pulmonary vein ablation of atrial fibrillation: mechanistic insights, results of catheter ablation, and risk factors for recurrence. J Am Coll Cardiol 2007;50:1781-7.

41. Lin WS, Tai CT, Hsieh MH, et al. Catheter ablation of paroxysmal atrial fibrillation initiated by non-pulmonary vein ectopy. Circulation 2003;107:3176-83.

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43. Wong KC, Paisey JR, Sopher M, et al. No Benefit of Complex Fractionated Atrial Electrogram Ablation in Addition to Circumferential Pulmonary Vein Ablation and Linear Ablation: Benefit of Complex Ablation Study. Circ Arrhythm Electrophysiol 2015;8:1316-24.

44. Narayan SM, Krummen DE, Shivkumar K, Clopton P, Rappel WJ, Miller JM. Treatment of atrial fibril-lation by the ablation of localized sources: CONFIRM (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation) trial. J Am Coll Cardiol 2012;60:628-36.

45. Narayan SM, Baykaner T, Clopton P, et al. Ablation of rotor and focal sources reduces late recur-rence 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.

46. Pokushalov 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 fibril-lation: a randomized comparison. Heart rhythm 2013;10:1280-6.

47. Mikhaylov E, Kanidieva A, Sviridova N, et al. Outcome of anatomic ganglionated plexi ablation to treat paroxysmal atrial fibrillation: a 3-year follow-up study. Europace 2011;13:362-70.

48. Katritsis DG, Pokushalov E, Romanov A, et al. Autonomic denervation added to pulmonary vein isolation for paroxysmal atrial fibrillation: a randomized clinical trial. Journal of the American College of Cardiology 2013;62:2318-25.

49. Verma A, Jiang CY, Betts TR, et al. Approaches to catheter ablation for persistent atrial fibrillation. The New England journal of medicine 2015;372:1812-22.

50. Wolf RK, Schneeberger EW, Osterday R, et al. Video-assisted bilateral pulmonary vein isolation and left atrial appendage exclusion for atrial fibrillation. The Journal of thoracic and cardiovascu-lar surgery 2005;130:797-802.

51. 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.

52. Krul SP, Driessen AH, Zwinderman AH, et al. Navigating the mini-maze: systematic review of the first results and progress of minimally-invasive surgery in the treatment of atrial fibrillation. Int J Cardiol 2013;166:132-40.

53. Kron J, Kasirajan V, Wood MA, Kowalski M, Han FT, Ellenbogen KA. Management of recurrent atrial arrhythmias after minimally invasive surgical pulmonary vein isolation and ganglionic plexi abla-tion for atrial fibrillation. Heart Rhythm 2010;7:445-51.

54. 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.

1


55. Krul SP, Pison L, La Meir M, et al. Epicardial and endocardial electrophysiological guided thoraco-scopic surgery for atrial fibrillation: a multidisciplinary approach of atrial fibrillation ablation in challenging patients. Int J Cardiol 2014;173:229-35.

56. de Groot JR, Berger WR, Krul SPJ, van Boven W, Salzberg SP, Driessen AHG. Electrophysiological Evaluation of Thoracoscopic Pulmonary Vein Isolation. J Atr Fibrillation 2013;6:899.

57. 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;125:23-30.

58. Johnsrud DO, Melduni RM, Lahr B, Yao X, Greason KL, Noseworthy PA. Evaluation of anticoagula-tion use and subsequent stroke in patients with atrial fibrillation after empiric surgical left atrial appendage closure: A retrospective case-control study. Clin Cardiol 2018;41:1578-82.

Part IInvasive treatment strategies for

the treatment of patients with advanced atrial fibrillation

Chapter 2Persistent Atrial Fibrillation: A Systematic Review and Meta-analysis of Invasive Strategies

Wouter R. Berger *Eva R. Meulendijks *Jacqueline Limpens

Nicoline W.E. van den BergJolien Neefs

Antoine H.G. DriessenSébastien P.J. Krul

Wim Jan P. van BovenJoris R. de Groot

* These authors contributed equally

Int J Cardiol. 2019 Mar 1;278:137-143

24 Chapter 2

AbstRAct

BackgroundPersistent atrial fibrillation (AF) is associated with higher stroke and mortality risk than paroxysmal AF (pAF). Outcomes of catheter or surgical ablation are worse in patients with persistent AF than in pAF, and the optimal invasive rhythm control strategy has not been established.

PurposeWe provide a contemporary systematic overview on efficacy and safety of catheter and minimally-invasive surgical ablation for persistent AF.

MethodsWe systematically searched EMBASE, MEDLINE and CENTRAL from inception to July 2018 for randomized trials on surgical and catheter ablation, and included all study arms on persistent AF. Outcome was AF freedom after ≥12 months follow-up without AAD use. Random effects models were used to calculate proportions with 95%-confidence inter-vals. Safety consisted of adverse events during treatment and follow-up.

ResultsWe included 6 studies on minimally-invasive surgical ablation and 56 on catheter ab-lation, involving 7624 patients with persistent AF. AF Freedom at 12 months was 69% (95%CI 64-74%) after surgical and 51% (95%CI 46-56%) after catheter ablation. More severe procedural adverse events occurred with surgery than with catheter ablation.

ConclusionsIn persistent AF patients, minimally-invasive surgical ablation is associated with more procedural complications, but higher AF freedom. As adverse events after surgical abla-tion appear more severe than in catheter ablation, a patient-tailored therapy choice is warranted.

2

Invasive treatment of persistent AF 25

IntRoductIon

Persistent Atrial Fibrillation (PeAF) is associated with higher AF burden and higher stroke and mortality risk compared to paroxysmal AF (pAF).1 Approximately 50% of AF patients have peAF.2 However, despite the considerable prevalence and higher stroke risk of this particular AF group, there is no consensus on the optimal invasive strategy for PeAF, contrary to paroxysmal atrial fibrillation (pAF). The aggregate evidence for the efficacy of catheter ablation for peAF is weaker than for pAF.3,4

The total number of patients with AF is increasing and estimated at>8 million in the USA by 2050 and 14 to 17 million in Europe by 2030.2,5 Furthermore, AF is associated with decreased quality of life, a fivefold increased risk of stroke, increased risk of heart failure and dementia and mortality.6,7 Annual AF costs are estimated between $6 to $26 billion dollars in the USA and €6.2 billion in five European countries.8,9 Hence, AF imposes a large and increasing burden on health and on healthcare systems10, largely caused by treatment.

When restoration of sinus rhythm is required in patients with paroxysmal AF, refrac-tory for anti-arrhythmic drugs (AAD), pulmonary vein isolation (PVI) through catheter ablationis indicated, and a large body of evidence supports this therapy. Some studies advocate catheter ablation as first line treatment in pAF, without prior use of AAD.11-14 However, evidence is limited, and essentially insufficient to proof that catheter ablation is the optimal invasive strategy for maintaining sinus rhythm in PeAF patients. Moreover, the frequent need for multiple catheter ablations in PeAF patients may have impact on the cumulative risk and burden of procedural complications. Minimally-invasive surgical techniques are therefore increasingly being employed in peAF patients.15

The current literature on catheter ablation for the treatment of PeAF has recently been reviewed.16 Whether sinus rhythm is restored most effectively with catheter abla-tion or minimally-invasive surgical ablation in peAF is uncertain. Limited randomized comparisons exist on these treatment strategies. Similarly, how complication rates of both strategies compare is unknown. However, as the population of patients with PeAF is large and growing, and despite the scarce data, the need for a systematic overview of the available evidence is evident. We therefore provide a contemporary overview, and conducted two meta-analyses on rhythm control interventions for peAF. We describe efficacy and safety using all randomized study arms on minimally-invasive surgical and catheter ablation.

26 Chapter 2

Methods

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines.17 The protocol was registered in the International Prospective Register of Systematic Reviews, registration number: CRD42015026621.

Search StrategyA medical information specialist (J.L.) performed a comprehensive search in OVID MED-LINE, OVID EMBASE and CENTRAL (the Cochrane Central Register of Controlled Trials from inception to July 5th 2018. Supplemental Table S1 displays the complete MEDLINE search strategy.

The search strategy consisted of controlled terms and text words for the concepts of AF persistence and the two interventions (catheter and minimally-invasive surgical ablation). A broad search filter was applied to identify all randomized controlled trials (RCTs). We cross-checked reference lists and citing articles of identified relevant papers and adapted the search in case of additional relevant studies. The bibliographic records retrieved were imported and de-duplicated in ENDNOTE X7©.

Study selection and critical appraisalTwo investigators (W.R.B and E.R.M.) independently screened studies for eligibility using Covidence©, 2015. Inclusion criteria were: PeAF or longstanding peAF (LPeAF). Studies on patients with paroxysmal or permanent AF exclusively were excluded, as were stud-ies not written in English. Studies comprising patients with both paroxysmal and PeAF were included when peAF or LPeAF data was extractable for efficacy, defined as freedom of AF or any atrial tachycardia. We included different catheter ablation strategies includ-ing: radiofrequency, cryoballoon, or any other type of AF ablation. Minimally-invasive surgical ablation studies that used both mini-thoracotomy and (hybrid) thoracoscopy were allowed, however, concomitant AF ablation during open-chest cardiac surgery was excluded. Supplemental Table S2 details in- and exclusion criteria. When studies reported serial data on the same cohort, the study with the largest number of patients was included. Abstract, case reports, reviews were excluded. The Cochrane Collabora-tion Tool for assessing risk of bias18 was applied for all RCTs.

Data collection and analysisBaseline and procedure characteristics, follow-up design and duration, and data on ef-ficacy and safety were independently extracted by two investigators (W.R.B. and E.R.M.). Disagreements were resolved by consensus or by consultation of a third reviewer (J.R.d.G.). Efficacy rates at 12 months were extracted. All AF freedom definitions reported

2


by the original articles were accepted, provided that at least one electrocardiographic recording was performed during ≤12 months follow-up.

We extracted the following pre-specified adverse events: death, procedure-related death, thrombo-embolism, bleeding, hemothorax, cardiac tamponade, sternotomy, pacemaker implantation, phrenic nerve paralysis, atriaoesophageal fistula, pulmonary vein stenosis, pneumothorax, pericarditis, (non-embolic) neurologic event, ventricular arrhythmia, bradycardia, atrioventricular block, thyroid dysfunction, infection, gastroin-testinal- and hepatic complications.

Sensitivity analysesIn the catheter ablation group, we performed a sensitivity analysis for PVI ablation alone, and PVI+additional lesions. Furthermore, we performed sensitivity analyses comparing (i) studies reporting AF freedom at 12 months vs. at >12 months, (ii) those reporting AF freedom in PeAF vs. LPeAF patients, (iii) those reporting AF freedom following the HRS/EHRA/ECAS expert consensus statement vs. those using alternative outcome19, (iv) those published before 2010 vs. between 2010-2015 vs 2016-2018, (v) those report-ing on studies with <100 vs. >100 patients, (vi) those reporting on studies with mean study population age<60 vs. >60 years, (vii) those reporting on studies where mean left atrial diameter <47mm vs. >47mm or where left atrial volumes index was <38mL/m2 vs. >38mL/m2.

Statistical analysisWe used ‘meta’ package in R for Windows version 3.2.4 and SPSS for Windows (IBM) version 23. Meta-analyses were performed to calculate proportions (rates) with cor-responding 95%-confidence intervals (CI). Random-effects modelling was used, taking into account the heterogeneity of effects estimates across the studies. Heterogeneity was assessed by Q-statistics and I². A P-value<0.05 for the Q-statistic defined statistical significance. An I² >40% indicated substantial heterogeneity. Meta-regression analyses were conducted testing the relation between publication year and efficacy outcomes. For continuous data, sample size-weighted means and standard deviations of sample means were calculated. Categorical data were described in percentages. Funnel plots were used to assess publication bias.

Results

Search Results and Risk of BiasSupplemental Figure S3 shows the flowchart of included studies. We identified 1,016 unique publications. After exclusion based on title and abstract, 158 articles were re-

28 Chapter 2

trieved for full-text analysis. The study arms on patients with PeAF were extracted from 60 articles that met our inclusion criteria, of which 2 articles provided study arms for both catheter and minimally-invasive surgical ablation, comprising 56 catheter and 6 minimally-invasive surgical ablation RCTs. Supplemental Figure S4 shows the risk-of-bias scores. Only two studies had all quality criteria, the remainder had >1 criterium for bias. Supplemental Table S5 shows reference lists of the included studies.

Patient characteristicsTable 1 displays the patient characteristics of the catheter ablation- and minimally-invasive surgical ablation-studies. The studies overall described 9710 patients, of whom 7624 with PeAF or LPeAF. Numerically, the majority of patients were male, had enlarged atria and had an AF duration >12 months. The comorbidities of the study subjects were not consistently reported among the study arms, hence caution should be taken com-paring comorbidities from Table 1.

Treatment characteristicsPulmonary veins were isolated in all 56 catheter ablation-studies. In 97% of the treat-ment arms, radiofrequency energy was used. The following additional lesions in 94 treatment arms were described: none (n=16), ganglion plexus ablation (n=3), complex fractionated atrial electrogram (CFAE) ablation (n=36), cavotricuspid ablation (n=32), mitral isthmus ablation (n=44), additional left atrial roof line (n=43), left posterior wall ablation (n=1) or right atrial ablation (n=7).

PVI was performed in all 8 treatment arms of minimally-invasive surgical ablation studies. Additional lesions were the following: ganglion plexus ablation (n=3), additional left atrial lines (roof line n=4, inferior line n=2, mitral isthmus line n=1, trigone line n=3 respectively) or other additional ablations. Two studies described a hybrid approach, where electrophysiologists collaborate with the surgeon for mapping and ablation. Supplemental Tables S6 and S7 summarize study and treatment characteristics re-spectively.

AF monitoring during follow-upPost-procedural rhythm monitoring varied strongly between studies. All studies used Holter monitoring, a combination of Holter and ECG or continuous rhythm monitoring during follow-up, except for one catheter ablation study that used only ECGs. Figure 1 summarizes AF absence rates for the different meta-analyses, using the endpoint defini-tion and monitoring strategy of the original studies.

2


Table 1. Characteristics of patients with AF undergoing catheter ablation or minimally-invasive surgical ablation.

Baseline CharacteristicsCatheter Ablation Surgical Ablation

t N Mean(Range)

t N Mean(Range)

Total patients

Mean age,y 110 9710 59.0 (50-69) 8 557 59.8 (56-67)

Mean duration of AF since diagnosis, m 95 8691 46.3 (9-96) 7 545 58.0 (48-89)

Mean LA size, mm 87 7721 45.0 (39-51) 7 545 44.8 (42-47)

Mean LV ejection fraction, % 85 7980 56.6 (22-65) 7 545 54.3 (48-58)

Mean BMI 48 5218 27.6 (23-34) 7 545 27.9 (27-30)

t n/N % t n/N %

Sex

Male 107 7181/9480 76 7 400/557 72

Female 107 2299/9480 24 7 157/557 28

AF Type

Persistent 110 4501/9710 46 7 366/557 66

Persistent/Longstanding 110 398/9710 0.04 7 7/557 1

Longstanding 110 2337/9710 24 7 15/557 3

Comorbid conditions

History of PVI 18 80/1305 6 3 59/161 37

Structural Heart Disease 43 756/5933 13 6 29/464 6

Valvular Heart Disease 29 236/3664 6 1 1/36 3

Hypertension 86 4203/8027 52 7 222/496 45

Diabetes Mellitus 76 820/6415 13 6 39/460 8

Coronary Artery Disease 57 393/3633 12 4 35/416 8

History of MI 6 51/2313 2 3 13/276 5

Stroke / TIA 41 444/5286 8 7 49/496 10

COPD 5 18/275 7 1 2/36 6

CHA2DS2-VASc -score

CHA2DS2-VASc = 0 14 531/1352 39 4 177/389 46

CHA2DS2-VASc = 1 12 504/1234 41 3 93/301 31

CHA2DS2-VASc ≥ 2 13 1293/3179 41 6 148/513 29

NYHA-Class

NYHA I 5 359/444 81 -- -- --

NYHA II 6 83/470 18 -- -- --

NYHA III 3 16/470 3 -- -- --

NYHA IV 3 1/444 0 -- -- --

30 Chapter 2

51%58%

69%71%

n=7502

n=3133

n=339 n=196

0

25

50

75

100

CAw/oAAD

CAw/ or w/o

AAD

SAw/oAAD

SAw/ or w/o

AAD

Free

dom

of A

F re

curr

ence

(%)

Figure 1.Freedom of AF after both treatment strategies for persistent atrial fibrillationAF, atrial fibrillation; CA, catheter ablation; SA, minimally-invasive surgical ablation; w/o, without; w/, with; AAD, antiarrhythmic drugs.

Table 1. Characteristics of patients with AF undergoing catheter ablation or minimally-invasive surgical ablation. (continued)

Baseline CharacteristicsCatheter Ablation Surgical Ablation

t n/N % t n/N %

Anti-arrhythmic Drugs

Class IA 5 67/410 16 2 6/240 3

Class IC 12 243/1148 21 2 81/240 34

Class III 35 1030/2502 41 3 122/301 41

Beta-blockers 16 850/1387 61 2 122/240 51

Digoxin 10 163/1030 16 2 30/240 13

Anticoagulants

Anti-Platelets 9 331/2992 11 2 15/240 6

OAC 9 2702/2992 90 2 240/240 100

t indicates No. of treatment groups reporting characteristics, n; No. of patients with this characteristic, LA; left atrium,LV; left ventricle, BMI; body mass index, AF; atrial fibrillation, PVI; pulmonary vein isolation, MI; myocardial infarction, TIA; transient ischemic attack, COPD; chronic obstructive pulmonary disease, NYHA: New York Heart Association, OAC; oral anticoagulants.

2


Randomized trials directly comparing treatment strategiesTwo RCTs were performed on minimally-invasive surgical versus catheter ablation in 67 patients with persistent AF.20,21 These studies showed a numerically, but not statistically higher AF freedom after surgical ablation compared to catheter ablation (OR 2.58, 95%CI 0.83-8.03).

AF freedom after 12 months; Catheter ablationForty-one studies with 7502 PeAF or LPeAF patients, reported outcome after catheter ablation without AAD after 12 months. AF freedom was 51% (95%CI 46-56%)(Figure 2A). With AAD use allowed, AF freedom increased to 58% (95%CI 54-63%) in 29 studies (3133 patients). In patients with peAF, AF freedom after PVIalone was 53% (95%CI 42-62%) without AAD and 57% (95%CI 46-67%) with AAD. AF freedom after PVI+additional lesions was 49% (95%CI 42-55%) without and 55% (95%CI 50-60%) with AAD. The blank-ing period, during which arrhythmia episodes are considered no recurrence, ranged from 0-3 months.

AF freedom after 12 months; Minimally-Invasive Surgical AblationIn 5 randomized trials on minimally-invasive surgical ablation (339 patients), AF freedom was 69% (95%CI 64-74%), after 12 months, without AAD (Figure 2B). Three studies (196 patients) reported outcome with and without AAD, AF freedom increased to 71% with AAD. The blanking period ranged from 0-3 months.

Heterogeneity and Sensitivity analysesAll meta-analyses demonstrated heterogeneity (I2>40%). Despite, sensitivity analysis demonstrated similar outcomes in peAF patients (50%, (95%CI 42-58)) vs. LPeAF (51% (95%CI 44-58%)) after catheter ablation. Only one minimally-invasive surgical ablation reported outcome in LPeAF patients. No difference in AF freedom was found between studies that reported according to the HRS/EHRA/ECAS consensus statement (i.e. serial Holter monitoring and reporting every recurrence of atrial tachyarrhythmia lasting >30 seconds as a recurrence), versus those that did not.

No difference was found between studies that reported on patients ≥60 years com-pared to study patients<60 years (Supplemental Figure S8). Furthermore, there was no difference when studies were divided according to study population size, publication year or left atrial dimensions.

Meta-regression testing for the relation between publication year and outcome showed higher efficacy rates in more recent catheter ablation-studies (p=0.03), but not minimally-invasive surgical ablation-studies. Funnel plots showed publication bias in catheter ablation-studies, but not in minimally-invasive surgical ablation-studies (Supplemental Table S9).

32 Chapter 2

Study

Random effects modelHeterogeneity: I 2 = 92%p < 0.01

Calo et al. 2006Nilsson et al. 2006Arentz et al. 2007Gaita et al. 2008Oral et al. 2008 Caponi et al. 2010Corrado et al. 2010 Estner et al. 2011Boersma et al. 2012Dixit et al. 2012Kumagai et al. 2013 Pokushalov et al. 2013 Pokushalov et al. 2013 Jones et al. 2013Han et al. 2014Mamchur et al. 2014Pokushalov et al. 2014 Ullah et al. 2014Wang et al. 2014 Dong et al. 2015Kim et al. 2015Kobori et al. 2015 Mohanty et al. 2015Verma et al. 2015 Vogler et al. 2015 Wong et al. 2015 Bassiouny et al. 2016 Di Biase et al. 2016Singh et al. 2016Wynn et al. 2016 Di Biase et al. 2016Ammar−Busch et al. 2017Fink et al. 2017Huang et al. 2017Kim et al. 2017Kircher et al. 2017Schmidt et al. 2017Wang et al. 2017 Yang et al. 2017 Conti et al. 2018Wang et al. 2018

n

7502

129 23 43 79 66

112 395 106 26

156 100 264 14 24

119 83 45

116 124 146 120

2113 112 589 143 130 100 102 195 79

173 90

118 90

137 58

134 96

229 124 400

0 20 40 60 80 100

Mean

AF Freedom (%)

AF Freedom (%)

51.0

38.817.451.232.927.350.969.937.734.644.975.041.735.770.863.962.740.025.942.763.773.359.650.032.150.351.529.077.551.863.342.226.735.670.053.353.471.665.669.961.350.0

95%−CI

[46.4; 55.5]

[30.3; 47.7][ 5.0; 38.8]

[35.5; 66.7][22.7; 44.4][17.0; 39.6][41.3; 60.5][65.1; 74.4][28.5; 47.7][17.2; 55.7][36.9; 53.0][65.3; 83.1][35.7; 47.9][12.8; 64.9][48.9; 87.4][54.6; 72.5][51.3; 73.0][25.7; 55.7][18.2; 34.8][33.9; 51.9][55.3; 71.5][64.5; 81.0][57.5; 61.7][40.4; 59.6][28.3; 36.0][41.9; 58.8][42.6; 60.4][20.4; 38.9][68.1; 85.1][44.5; 59.0][51.7; 73.9][34.7; 49.9][17.9; 37.0][27.0; 44.9][59.4; 79.2][44.6; 61.9][39.9; 66.7][63.2; 79.1][55.2; 75.0][63.5; 75.7][52.1; 69.9][45.0; 55.0]

Weight

100%

2.6%1.4%2.2%2.4%2.3%2.6%2.7%2.5%1.8%2.6%2.4%2.7%1.4%1.7%2.5%2.4%2.2%2.5%2.6%2.6%2.5%2.8%2.6%2.8%2.6%2.6%2.5%2.4%2.7%2.4%2.6%2.4%2.5%2.4%2.6%2.3%2.5%2.5%2.7%2.6%2.8%

Study

Random effects modelHeterogeneity: I 2 = 0% ,p = 0.53

Pokushalov et al. 2013 Fengsrud et al. 2016 Romanov et al. 2016 Driessen et al. 2016 Beaver et al. 2016

n

339

12 15

173132

7

0 20 40 60 80 100

Mean

AF Freedom (%)

AF Freedom (%)

69.4

75.080.072.364.471.4

95%−CI

[64.3; 74.1]

[42.8; 94.5][51.9; 95.7][64.9; 78.8][55.6; 72.5][29.0; 96.3]

Weight

100.0%

3.2%3.4%

48.8%42.6%

2.0%

Study



n

339

12 15

173132

7

0 20 40 60 80 100

Mean

AF Freedom (%)

AF Freedom (%)

69.4

75.080.072.364.471.4

95%−CI

[64.3; 74.1]

[42.8; 94.5][51.9; 95.7][64.9; 78.8][55.6; 72.5][29.0; 96.3]

Weight

100.0%

3.2%3.4%

48.8%42.6%

2.0%

Study



n

339

12 15

173132

7

0 20 40 60 80 100

Mean

AF Freedom (%)

AF Freedom (%)

69.4

75.080.072.364.471.4

95%−CI

[64.3; 74.1]

[42.8; 94.5][51.9; 95.7][64.9; 78.8][55.6; 72.5][29.0; 96.3]

Weight

100.0%

3.2%3.4%

48.8%42.6%

2.0%

Figure 2.Forest plots showing rates of AF freedom of persistent AF patients 12 months after (A) catheter ablation or (B) minimally-invasive surgical ablation

A

B

2


Safety outcomesTable 2 displays adverse events and complications following catheter and minimally-invasive surgical ablation.

Adverse events after catheter ablation were infrequent. Mortality during the study course was 1.1%, procedure-related death 0.1%. The commonest complications were pacemaker implantations (0.9%), any bleeding (1.7%) and pericarditis (1.4%). Thrombo-embolic events occurred in 0.7% of patients.

Mortality was 1.1%; procedure-related death 0% after minimally-invasive surgical ab-lation. Pulmonary vein stenoses were not reported. Combined major and minor bleed-ing rate was 7.7% and 8 patients (1.6%) were converted to sternotomy. Pneumothorax occurred in 6.1% of patients and 2.7% required pacemaker implantation. Thrombo-embolic events occurred in 1.4%. Taken together, particularly irreversible adverse events occurred more frequently after minimally-invasive surgery than after catheter ablation.

Table 2. Safety outcomes for patients with AF after catheter ablation or minimally-invasive surgical abla-tion.

Safety OutcomesCatheter Ablation Surgical Ablation

studies n/N % studies n/N %

Mortality

Overall death 17 38/3264 1.1 4 5/464 1.1

Prodecure- related death 15 3/3052 0.1 4 0/464 0

Thrombo-embolic event 29 53/7169 0.7 6 8/557 1.4

Bleeding

Small bleeding 34 124/7515 1.7 2 21/272 7.7

Hemathorax 1 1/80 1.3 3 6/448 1.3

Cardiac Tamponade 36 81/8090 1.0 2 2/301 0.6

Sternotomy -- -- 4 8/489 1.6

Phrenic nerve paralysis 5 9/2934 0.3 1 2/240 0.8

LA-esophageal fistula 9 7/3937 0.2 -- -- --

Pulmonary vein stenosis 11 14/1690 0.8 -- -- --

Pneumothorax -- -- 4 31/509 6.1

Pericarditis 10 54/3981 1.4 -- -- --

Atrioventricular block 1 1/230 0.4 -- -- --

QT-prolongation -- -- -- -- --

Pacemaker implantation 2 3/345 0.9 2 8/301 2.7

Thyroid dysfunction 1 1/230 0.4 -- --

Gastro-intestinal complications 2 7/2286 0.3 -- -- --

Infection (pneumonia, urinary tract infection etc.) 3 21/2754 0.7 2 3/301 1.0

n; No. of patients with adverse events, N; No. of patients evaluated in studies reporting this adverse event, %; percent of patients with adverse event of interest.

34 Chapter 2

dIscussIon

We performed a comprehensive systematic review, using all treatment arms of ran-domized controlled trails available to date. We included both catheter ablation- and minimally-invasive surgical ablation-studies and show that in patients with peAF: 1) Minimally-invasive surgery is associated with numerically more irreversible adverse events than catheter ablation 2) AF freedom after 12 months is 69% in randomized studies on minimally-invasive surgical ablation compared to 51% in catheter ablation studies. In patients with or without AAD, AF freedom was 58 % in catheter ablation studies, and 71% in minimally-invasive surgical ablation studies. These numbers do not reflect direct treatment comparisons, but the confidence intervals did not overlap. Procedural complications are reported inconsistently and cannot be compared directly between both invasive strategies. The higher procedural complications rate reported in minimally-invasive surgical ablation seems to accompany higher efficacy rates.

Treatment StrategiesInherent to our aim to include all available data, patient characteristics, endpoint report-ing and follow-up strategy varied among the included publications.

Our aim was to numerically estimate efficacy and safety of different treatment mo-dalities. However, as studies generally did not compare different strategies directly, care must be taken in comparing absolute numbers.

While PVI remains the cornerstone of invasive AF treatment. However, different com-binations of additional lesion sets and energy sources were applied, resulting in consid-erable variation among studies. The dogma that PVI alone is insufficient for PeAF was challenged in the STAR-AF-2 trial, randomizing PeAF patients to PVI alone, PVI + linear ablation or PVI+CFAE ablation.3 No difference in efficacy was found in that study. In our meta-analysis on catheter ablation studies, sensitivity analysis showed no difference in AF freedom after PVI alone compared to PVI + additional lesions, with AF freedom after PVI alone being slightly higher than PVI + additional lesions (53% vs 49% respectively). A recent meta-analysis reported even higher success rates (67%) after a single PVI proce-dure, but this study also included cohort studies and allowed for AAD use.22

Contrarily, another meta-analysis supported combining PVI with additional ablations in PeAF.23

Minimally-invasive surgical ablation was developed to combine the success rates of the (open heart surgery) Cox-Maze procedure with a less invasive intervention.

Epicardial PVI is usually performed with RF energy through clamps around the PVs.Furthermore, additional left, and right, atrial ablation lines can be created with linear

devices and the left atrial appendage can be removed, possibly reducing stroke risk.15

2


New approaches need to be evaluated in clinical trials and treatment of concomitant diseases is important adjunct to ablation strategies.24

Clinical ImplicationsGuidelines designate class IA indications for AAD class I and III and for catheter abla-tion in patients with symptomatic (paroxysmal) AF, reflecting the current (randomized) literature.4,19,25 RCTs in PeAF patients showed higher AF freedom with catheter ablation compared to AAD.26,27 In general the ESC and the HRS/EHRA/ECAS consensus document are more conservative on the indication for stand-alone minimally-invasive surgery to treat AF, potentially because of the higher complication rate.

The variation among the studies was large, and insufficient direct comparison between invasive treatment strategies for peAF is available. AF freedom was significantly higher in the minimally-invasive surgical ablation-group than in the catheter ablation-group. This effect was further enhanced when AAD use was permitted during follow-up. The majority of the 5 RCTs with 7 treatment arms on minimally-invasive surgical ablation studies were small and/or single-center studies, whereas larger, more frequently multi-center RCTs were available on catheter ablation. Potentially, the minimally-invasive surgery studies reflect dedicated programs in specialized centers.

Two RCTs directly compared minimally-invasive surgical ablation to catheter ablation in patients with paroxysmal or PeAF, with a prior failed catheter ablation or hypertension and enlarged left atria (potentially representing a more advanced patient group), and showed higher AF freedom in minimally-invasive surgical ablation, at the cost of more procedural complications.20,21 The number of peAF patients in these studies was low, but the results of both studies were consistent with the data in this review.

We describe efficacy rates after the index procedure, notwithstanding that patients may have had previous ablations. A. single catheter ablation procedure may often not be sufficient, and multiple procedures combined with AAD can increase success to 69%16, numerically comparable with the success rates of minimally-invasive surgical ablation. Furthermore, the increasing safety of catheter ablation over time, makes a multiple procedure approach feasible.19 However, adverse events rates for minimally-invasive surgical ablation are similarly improving.

The characteristics and timing of adverse events vary between the included studies. Procedure related death was similarly infrequent in both strategies. However, irrevers-ible complications, such as sternotomy, pacemaker implantation, phrenic nerve paraly-sis and thrombo-embolic events appeared more frequent in minimally-invasive surgical ablation. However, these patients more often had high CHA2DS2-VASc -scores. In general, the extent of reporting of adverse events in all studies included in our meta-analyses was limited in both treatment strategies, and most studies did not meet the criteria of complete reporting of complications resulting in permanent injury, death, requiring

36 Chapter 2

interventions or hospitalization.19 However, these are the published data available on peAF.

Generalizability and limitationsA limitation of our analysis is the heterogeneity between the different studies and treatment strategies. Different catheter ablation strategies were studied, while the mini-mally-invasive surgical ablation strategies are relatively uniform. Also, there are only two prospective, randomized studies comparing both treatment strategies. Furthermore, only studies on catheter ablation with >40 patients were included in this analysis, since a plethora of randomized studies was available in this treatment arm, while studies on minimally-invasive surgical ablation are small, with only two studies with >40 patients with PeAF. However, omitting minimally-invasive studies with <40 patients did not change our conclusions on procedural efficacy. Despite the high and growing preva-lence of PeAF, the data reported here are the only aggregate data available for clinical decision making. Using detailed inclusion criteria, and including all available evidence, we attempted to select equivalent studies reporting outcome after PeAF treatment.

We performed extensive sensitivity analyses to detect concomitant conditions driving the results reported, and found no differences among subgroups that alter our main conclusions. However, more recent catheter ablation studies seemed more efficacious. Consistent reporting procedural outcome and complications, such as advocated by the HRS/EHRA/ECAS consensus statement remains of utmost importance.19 The definitions of peAF and LPAF evolved over time, and have not been used similarly strictly across studies. Furthermore, we appreciate that peAF is a clinical classification that poorly reflects AF temporal persistence.28

AF freedom is defined as absence of any atrial arrhythmia (AF, atrial flutter and atrial tachycardia) lasting >30 seconds, without AAD use. 19 The majority of studies included in our meta-analyses employed this endpoint. Studies included in our meta-analyses used different monitoring protocols, varying between continuous monitoring to only one ECG at 12 months follow-up. This may limit direct comparison and emphasizes the necessity for consistency in monitoring and outcome reporting. Evidently, contempo-rary rhythm follow-up is more extensive than before, and more often includes long term rhythm monitoring. For the particular case of peAF, continuous monitoring may be less relevant than for pAF.

Therefore, and despite the limitations listed here, this systematic review comprising more than 7500 patients with peAF, provides the most comprehensive available evi-dence on the invasive treatment to date.

2


conclusIons

Minimally-invasive surgery for peAF is associated with more severe complications than catheter ablation, although underreporting of adverse events appeared present in all included studies. Minimally-invasive surgical ablation appears more efficacious in restoring sinus rhythm than catheter ablation, however the number of randomized studies directly comparing both treatment strategies is limited and cohorts are small.

38 Chapter 2

RefeRences 1. Steinberg BA, Hellkamp AS, Lokhnygina Y, et al. Higher risk of death and stroke in patients

with persistent vs. paroxysmal atrial fibrillation: results from the ROCKET-AF Trial. Eur Heart J 2015;36:288-96.

2. Zoni-Berisso M, Lercari F, Carazza T, Domenicucci S. Epidemiology of atrial fibrillation: European perspective. Clin Epidemiol 2014;6:213-20.

3. Verma A, Jiang CY, Betts TR, et al. Approaches to catheter ablation for persistent atrial fibrillation. N Engl J Med 2015;372:1812-22.

4. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrilla-tion developed in collaboration with EACTS. Eur Heart J 2016;37:2893-962.

5. Naccarelli GV, Varker H, Lin J, Schulman KL. Increasing prevalence of atrial fibrillation and flutter in the United States. Am J Cardiol 2009;104:1534-9.

6. Singh-Manoux A, Fayosse A, Sabia S, et al. Atrial fibrillation as a risk factor for cognitive decline and dementia. Eur Heart J 2017;38:2612-8.

7. Leong DP, Eikelboom JW, Healey JS, Connolly SJ. Atrial fibrillation is associated with increased mortality: causation or association? Eur Heart J 2013;34:1027-30.

8. Kim MH, Johnston SS, Chu BC, Dalal MR, Schulman KL. Estimation of total incremental health care costs in patients with atrial fibrillation in the United States. Circ Cardiovasc Qual Outcomes 2011;4:313-20.

9. Ringborg A, Nieuwlaat R, Lindgren P, et al. Costs of atrial fibrillation in five European countries: results from the Euro Heart Survey on atrial fibrillation. Europace 2008;10:403-11.

10. Wolowacz SE, Samuel M, Brennan VK, Jasso-Mosqueda JG, Van Gelder IC. The cost of illness of atrial fibrillation: a systematic review of the recent literature. Europace 2011;13:1375-85.

11. Cosedis Nielsen J, Johannessen A, Raatikainen P, et al. Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation. N Engl J Med 2012;367:1587-95.

12. Wazni OM, Marrouche NF, Martin DO, et al. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a randomized trial. JAMA 2005;293:2634-40.

13. Morillo CA, Verma A, Connolly SJ, et al. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of paroxysmal atrial fibrillation (RAAFT-2): a randomized trial. JAMA 2014;311:692-700.

14. Wilber DJ, Pappone C, Neuzil P, et al. Comparison of antiarrhythmic drug therapy and radiofre-quency catheter ablation in patients with paroxysmal atrial fibrillation: a randomized controlled trial. JAMA 2010;303:333-40.


16. Clarnette JA, Brooks AG, Mahajan R, et al. Outcomes of persistent and long-standing persistent atrial fibrillation ablation: a systematic review and meta-analysis. Europace 2017.

17. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 2009;62:1006-12.

18. Higgins J. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. https://handbook-5-1.cochrane.org/: Cochrane Collab.; 2011.

19. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation. Heart Rhythm 2017;14:e275-e444.

2



21. Pokushalov E, Romanov A, Elesin D, et al. Catheter versus surgical ablation of atrial fibrillation af-ter a failed initial pulmonary vein isolation procedure: a randomized controlled trial. J Cardiovasc Electrophysiol 2013;24:1338-43.

22. Voskoboinik A, Moskovitch JT, Harel N, Sanders P, Kistler PM, Kalman JM. Revisiting pulmonary vein isolation alone for persistent atrial fibrillation: A systematic review and meta-analysis. Heart Rhythm 2017;14:661-7.

23. Wynn GJ, Das M, Bonnett LJ, Panikker S, Wong T, Gupta D. Efficacy of catheter ablation for persis-tent atrial fibrillation: a systematic review and meta-analysis of evidence from randomized and nonrandomized controlled trials. Circ Arrhythm Electrophysiol 2014;7:841-52.

24. Kirchhof P, Calkins H. Catheter ablation in patients with persistent atrial fibrillation. Eur Heart J 2017;38:20-6.

25. Calkins H, Reynolds MR, Spector P, et al. Treatment of atrial fibrillation with antiarrhythmic drugs or radiofrequency ablation: two systematic literature reviews and meta-analyses. Circ Arrhythm Electrophysiol 2009;2:349-61.

26. Di Biase L, Mohanty P, Mohanty S, et al. Ablation Versus Amiodarone for Treatment of Persistent Atrial Fibrillation in Patients With Congestive Heart Failure and an Implanted Device: Results From the AATAC Multicenter Randomized Trial. Circulation 2016;133:1637-44.

27. Mont L, Bisbal F, Hernandez-Madrid A, et al. Catheter ablation vs. antiarrhythmic drug treatment of persistent atrial fibrillation: a multicentre, randomized, controlled trial (SARA study). Eur Heart J 2014;35:501-7.

28. Charitos EI, Purerfellner H, Glotzer TV, Ziegler PD. Clinical classifications of atrial fibrillation poorly reflect its temporal persistence: insights from 1,195 patients continuously monitored with im-plantable devices. J Am Coll Cardiol 2014;63:2840-8.

40 Chapter 2

Supplemental table S1. Search strategyDatabase(s): Ovid MEDLINE(R) Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to PresentSearch Strategy: 2018-07-05

# Searches Results

1 Atrial Fibrillation/ 46762

2 ((atria* or atrium or auricular) adj6 fibril*).tw,kf,ot. 61392

3 AF.tw,kf. and (flutter or fibril?at* or arr?yth?m* or atrial or atrium or atria).mp. 21540

4((recurr* or persistent* or long-dur* or long-stand* or longstand* or long-last* or longlast* or prolonged or continuing or chronic* or refractory or non-valv* or nonvalv* or nonparoxysm* or non-paroxysm*) adj3 AF).tw.

7019

5 (LPAF or LSPAF or LSP-AF or PsAF or Ps-AF or R-AF or PerAF or Per-Af or CPAF).tw. 448

6 or/1-5 [AF] 70977

7(exp animals/ or (animal* or pig or pigs or porcine or pup or pups or dog or dogs or canine or bitch* or ((cat or cats) not AMIO-CAT) or feline or rodent* or rabbit* or rat or rats or mice or mouse or murine).ti,ot.) not humans/

4578994

8 6 not 7 [ human AF ] 67911

9

(controlled clinical trial/ or randomized controlled trial/ or random allocation/ or double-blind method/ or single-blind method/ or (randomi?ed or placebo* or randomly or (random adj2 allocat*) or ((random* or controlled) adj2 (study or trial)) or ((singl* or doubl* or treb* or tripl*) adj (blind*3 or mask*3))).tw,kf. or trial.ti.) not ((cochrane or systematic review* or clinical evidence or EBM).jw. or editorial/ or (systematic* adj3 (review or literature)).ti. or (search* adj12 (literature* or ((electronic or medical or biomedical) adj3 database*) or exhaustiv* or systematic* or medline or pubmed or embase or psychinfo or (CENTRAL and cochrane) or “Central Register of Controlled Trials”)).tw. or (((conferenc* or congress*).hw. or review/ or meta-analysis/ or (meta analy* or metaanaly* or meta?analy*).ti,ot. or (systematic* adj3 (review or literature)).tw,kf.) not (controlled clinical trial/ or randomized controlled trial/ or ((random* and trial) or (controlled adj2 trial)).ti,ot.))) [Filter for RCTs not reviews/conf abstracts]

1020521

10 8 and 9 [ RCTs on human AF ] 5701

11(persistent or long-stand* or longstand* or long-last* or longlast* or nonparoxysm* or non-paroxysm*).tw,kf.

270030

12 ((AF or fibril?at*) adj3 ((long adj2 durat*) or continuing or refractory)).tw,kf. 1318

13 ((AF or atrial fibri?lat*) adj2 duration* adj5 (months or years)).tw. 292

14 ((chronic* or advanced or sustained or continuous) adj3 (atrial fibril* or AF)).tw,kf. 4090

15 ((chronic* or advanced or sustained or continuous) adj fibril*).tw,kf. 66

16 (LPAF or LSPAF or LSP-AF or PsAF or Ps-AF or R-AF or PerAF or Per-Af or CPAF).tw. 448

17(((prior or earlier or drug or treatment* or therap* or AAD or anti-arr?yt?m* or anticonver* or anti-conver*) adj6 fail*) not ((prior or earlier or drug or treatment* or therap* or AAD or anti-arr?yt?m* or anticonver* or anti-conver*) adj6 heart fail*)).tw,kf.

105384

18 ((“after electrical cardiover*” or “after cardioversion*”) adj5 (atrial fibrillat* or AF)).tw,kf. 504

19 (maint* adj2 sinus r?yt?m adj3 “after conver*”).tw. 30

20 or/11-19 [persistent] 376608

21 20 and 10 [ RCTs on human PsAF (persistent AF) ] 1272

2


Search Strategy: 2018-07-05 (continued)

# Searches Results

22 Catheter Ablation/ 28291

23 Cryosurgery/ 12150

24(ablat* or cryoablat* or cryoballoon* or cryomaze or radiofrequency or RFA or RFCA).tw,kf.

110260

25 ((pulmonary vein* or PV or ganglion* plex* or GP) adj6 (isolat* or discon*)).tw,kf. 4741

26 (PVI or PVAI or CPVI or mCPVI or EIPVI or SRI).tw,kf. 9871

27((box or ring or circum* or electric or atri* or wall* or catheter* or transcathet*) adj4 isolat*).tw,kf.

11455

28 or/22-27 [ I CAB catheter ablation] 143536

29 21 and 28 [ I = RCTs on PsAF + CAb] 473

30 Minimally Invasive Surgical Procedures/ 22388

31 exp Thoracoscopy/ 12585

32 (video-assist* or videothoracoscop* or thoracoscop* or VATS).tw,kf. 18505

33 (min* adj3 invasiv*).tw,kf. 62247

34 ((surgic* or operativ*) adj3 ablat*).tw,kf. 2907

35(((mini* or epicard* or epimyocard* or endoscop*) adj6 (cox or maze)) or minimaze).tw,kf.

385

36 ((dallas or box) adj2 l?esion*).tw,kf. 98

37 ((endo* or percutan* or cath* or transcath*) adj4 epicard* adj10 hybrid).tw,kf. 45

38((epimyocard* or epicardial*) adj6 (surg* or operat* or stapling or probe or probes or ablat* or isolat* or guided or pulmonary vein* or PVI or PVAI or CPVI or ganglionat* plex* or GP)).tw,kf.

1864

39(endoscop* adj2 (surg* or operat* or stapling or probe or probes or ablat* or isolat* or guided or pulmonary vein* or PVI or PVAI or CPVI)).tw,kf.

24824

40 or/30-39 [ II = MIS] 113991

41 21 and 40 [ II = RCTs on PsAF + MIS ] 61

42 29 or 41 [ I II RCTs on PsAF - CAb & MIS ] 475

43 remove duplicates from 42 [ I II RCTs on PsAF - CAb & MIS -deduplicated ] 475

42 Chapter 2

Supplemental table S2. Inclusion and exclusion criteria

CriteriumCatheter Ablation

Surgical Ablation

Randomized controlled trials + +

Observational studies - -

Letters, comments, reviews, meta-analyses, abstracts, case reports - -

Study not in English - -

Animal/in vitro studies - -

> 15% patients <18 - -

< 40 patients in study - +

Patients having (Longstanding) Persistent AF defined according to expert consensus or guidelines + +

Previous PVI + +

Success rates not specified for (Longstanding) Persistent AF only - -

Follow-up without ECG and/or Holter monitoring - -

Minimum follow-up reported (months) 12 12

Study details missing - -

PVI not performed - -

Non-thoracoscopic procedure (apart from small thoracotomy) n/a -

Concomitant to open surgical intervention n/a -

.

2


OVID EMBASE

650 records

CENTRAL

584 records

OVID MEDLINE

540 records

1016 titles andabstracts

158 full-text articles ofpotential interest

60 studies included

CA-group

56 studies

SA-group

6 studies

Duplicate removal 758 records removed

858 excluded based on titleand abstract

98 full-text articles excluded:- 39 conference abstracts- 25 efficacy not specifically described for peAF- 1 incomplete follow-up- 9 no RCTs- 1 language other than english- 2 no outcomes of interest- 9 duplicates- 1 reviews, study designs, comments- 6 fewer than 40 patients (for AAD or CA studies)- 1 overlapping data- 2 no patient population of interest- 1 no full text- 1 article retracted

Supplemental figure S3.Flowchart for study selectionCA; catheter ablation, SA; minimally-invasive surgical ablation; RCT; randomized controlled trial, PeAF; per-sistent atrial fibrillation. AAD; anti-arrhythmic drugs.

44 Chapter 2

Arentz et al. 2007 Atienza et al. 2014 Bansch et al. 2013 Bassiouny et al. 2016 Boersma et al. 2012 Calo et al. 2006

Caponi et al. 2010 Corrado et al. 2010Di Biase et al. 2016 Dixit et al. 2012 Dong et al. 2015 Elayi et al. 2008 Estner et al. 2011 Fassini et al. 2005Gaita et al. 2008 Gu et al. 2012

Han et al. 2014

Kim et al. 2015 Kobori et al. 2015Kumagai et al. 2013Lim et al. 2012 Lin et al. 2014 Mamchur et al. 2014Mohanty et al. 2015 Mont et al. 2014 Nilsson et al. 2006Oral et al. 2008 Pokushalov et al. 2013Pokushalov et al. 2013Pokushalov et al. 2014Singh et. al 2016 Turco et al. 2007 Ullah et al. 2014

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Verma et al. 2010 Verma et al. 2014 Verma et al. 2015 Vogler et al. 2015Wang X et al. 2014

Wang Y et al. 2013

Willems et al. 2006

Wong et al. 2015 Wynn et al. 2016

Ammar-Busch 2017

Kim et al. 2017

Wang et al. 2017Conti et al. 2018 Wang et al. 2018

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Driessen et al. 2016

Beaver et al. 2017

Fengsrud et al. 2016 Pokushalov et al. 2013Romanov et al. 2016

Huang et al. 2017

Fink et al. 2017

Kircher et al. 2 017

Pappone et al. 2018

Schmidt et al. 2017

Jones et al. 2017

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2


Supplemental table S5. Studies included in meta-analysesA. Studies included in the Catheter Ablation Meta-analysis 1. Ammar-Busch S, Bourier F, Reents T et al. Ablation of Complex Fractionated Electrograms With or

Without ADditional LINEar Lesions for Persistent Atrial Fibrillation (The ADLINE Trial). J Cardiovasc Electrophysiol 2017;28:636-641.

2. Arentz T, Weber R, Burkle G et al. Small or large isolation areas around the pulmonary veins for the treatment of atrial fibrillation? Results from a prospective randomized study. Circulation 2007;115:3057-63.

3. Atienza F, Almendral J, Ormaetxe JM et al. Comparison of radiofrequency catheter ablation of drivers and circumferential pulmonary vein isolation in atrial fibrillation: a noninferiority random-ized multicenter RADAR-AF trial. J Am Coll Cardiol 2014;64:2455-67.

4. Bansch D, Bittkau J, Schneider R et al. Circumferential pulmonary vein isolation: wait or stop early after initial successful pulmonary vein isolation? Europace 2013;15:183-8.

5. Bassiouny M, Saliba W, Hussein A et al. Randomized Study of Persistent Atrial Fibrillation Ablation: Ablate in Sinus Rhythm Versus Ablate Complex-Fractionated Atrial Electrograms in Atrial Fibrilla-tion. Circ Arrhythm Electrophysiol 2016;9:e003596.

6. Boersma LV, Castella M, van Boven W et al. Atrial fibrillation catheter ablation versus surgical abla-tion treatment (FAST): a 2-center randomized clinical trial. Circulation 2012;125:23-30.

7. Calo L, Lamberti F, Loricchio ML et al. Left atrial ablation versus biatrial ablation for persistent and permanent atrial fibrillation: a prospective and randomized study. J Am Coll Cardiol 2006;47:2504-12.

8. Caponi D, Corleto A, Scaglione M et al. Ablation of atrial fibrillation: does the addition of three-dimensional magnetic resonance imaging of the left atrium to electroanatomic mapping improve the clinical outcome?: a randomized comparison of Carto-Merge vs. Carto-XP three-dimensional mapping ablation in patients with paroxysmal and persistent atrial fibrillation. Europace 2010;12:1098-104.

9. Conti S, Weerasooriya R, Novak P et al. Contact force sensing for ablation of persistent atrial fibril-lation: A randomized, multicenter trial. Heart Rhythm 2018;15:201-208.

10. Corrado A, Bonso A, Madalosso M et al. Impact of systematic isolation of superior vena cava in addition to pulmonary vein antrum isolation on the outcome of paroxysmal, persistent, and per-manent atrial fibrillation ablation: results from a randomized study. J Cardiovasc Electrophysiol 2010;21:1-5.

11. 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;68:1929-1940.

12. Di Biase L, Mohanty P, Mohanty S et al. Ablation Versus Amiodarone for Treatment of Persistent Atrial Fibrillation in Patients With Congestive Heart Failure and an Implanted Device: Results From the AATAC Multicenter Randomized Trial. Circulation 2016;133:1637-44.

13. Dixit S, Marchlinski FE, Lin D et al. Randomized ablation strategies for the treatment of persistent atrial fibrillation: RASTA study. Circ Arrhythm Electrophysiol 2012;5:287-94.

14. Dong JZ, Sang CH, Yu RH et al. Prospective randomized comparison between a fixed ‘2C3L’ approach vs. stepwise approach for catheter ablation of persistent atrial fibrillation. Europace 2015;17:1798-806.

15. Elayi CS, Verma A, Di Biase L et al. Ablation for longstanding permanent atrial fibrillation: results from a randomized study comparing three different strategies. Heart Rhythm 2008;5:1658-64.

46 Chapter 2

16. Estner HL, Hessling G, Biegler R et al. Complex fractionated atrial electrogram or linear ablation in patients with persistent atrial fibrillation--a prospective randomized study. Pacing Clin Electro-physiol 2011;34:939-48.

17. Fassini G, Riva S, Chiodelli R et al. Left mitral isthmus ablation associated with PV Isolation: long-term results of a prospective randomized study. J Cardiovasc Electrophysiol 2005;16:1150-6.

18. Fink T, Schluter M, Heeger CH et al. Stand-Alone Pulmonary Vein Isolation Versus Pulmonary Vein Isolation With Additional Substrate Modification as Index Ablation Procedures in Patients With Persistent and Long-Standing Persistent Atrial Fibrillation: The Randomized Alster-Lost-AF Trial (Ablation at St. Georg Hospital for Long-Standing Persistent Atrial Fibrillation). Circ Arrhythm Electrophysiol 2017;10.

19. Gaita F, Caponi D, Scaglione M et al. Long-term clinical results of 2 different ablation strate-gies in patients with paroxysmal and persistent atrial fibrillation. Circ Arrhythm Electrophysiol 2008;1:269-75.

20. Gu J, Liu X, Tan H et al. Extensive antiarrhythmic drugs after catheter ablation of persistent atrial fibrillation. Acta Cardiol 2012;67:407-14.

21. Han SW, Shin SY, Im SI et al. Does the amount of atrial mass reduction improve clinical outcomes after radiofrequency catheter ablation for long-standing persistent atrial fibrillation? Comparison between linear ablation and defragmentation. Int J Cardiol 2014;171:37-43.

22. Huang X, Chen Y, Huang Y et al. Clinical efficacy of irrigated catheter application of amiodarone during ablation of persistent atrial fibrillation. Clin Cardiol 2017;40:1333-1338.

23. Jones DG, Haldar SK, Hussain W et al. A randomized trial to assess catheter ablation versus rate control in the management of persistent atrial fibrillation in heart failure. J Am Coll Cardiol 2013;61:1894-903.

24. Kim JS, Shin SY, Na JO et al. Does isolation of the left atrial posterior wall improve clinical outcomes after radiofrequency catheter ablation for persistent atrial fibrillation?: A prospective randomized clinical trial. Int J Cardiol 2015;181:277-83.

25. Kim TH, Uhm JS, Kim JY, Joung B, Lee MH, Pak HN. Does Additional Electrogram-Guided Ablation After Linear Ablation Reduce Recurrence After Catheter Ablation for Longstanding Persistent Atrial Fibrillation? A Prospective Randomized Study. J Am Heart Assoc 2017;6.

26. Kircher S, Arya A, Altmann D et al. Individually tailored vs. standardized substrate modification during radiofrequency catheter ablation for atrial fibrillation: a randomized study. Europace 2017.

27. Kobori A, Shizuta S, Inoue K et al. Adenosine triphosphate-guided pulmonary vein isolation for atrial fibrillation: the UNmasking Dormant Electrical Reconduction by Adenosine TriPhosphate (UNDER-ATP) trial. Eur Heart J 2015;36:3276-87.

28. Kumagai K, Sakamoto T, Nakamura K, Hayano M, Yamashita E, Oshima S. Pre-procedural predic-tion of termination of persistent atrial fibrillation by catheter ablation as an indicator of reverse remodeling of the left atrium. Circ J 2013;77:1416-23.

29. Liang JJ, Muser D, Santangeli P. Approaches to Catheter Ablation of Nonparoxysmal Atrial Fibril-lation. Curr Treat Options Cardiovasc Med 2018;20:39.

30. Lim TW, Koay CH, See VA et al. Single-ring posterior left atrial (box) isolation results in a different mode of recurrence compared with wide antral pulmonary vein isolation on long-term follow-up: longer atrial fibrillation-free survival time but similar survival time free of any atrial arrhythmia. Circ Arrhythm Electrophysiol 2012;5:968-77.

2


31. Lin YJ, Chang SL, Lo LW et al. A prospective and randomized comparison of limited versus exten-sive atrial substrate modification after circumferential pulmonary vein isolation in nonparoxysmal atrial fibrillation. J Cardiovasc Electrophysiol 2014;25:803-812.

32. Mamchur SE, Mamchur IN, Khomenko EA, Bokhan NS, Scherbinina DA. ‘Electrical exclusion’ of a critical myocardial mass by extended pulmonary vein antrum isolation for persistent atrial fibril-lation treatment. Interv Med Appl Sci 2014;6:31-9.

33. Mohanty S, Di Biase L, Mohanty P et al. Effect of periprocedural amiodarone on procedure out-come in patients with longstanding persistent atrial fibrillation undergoing extended pulmonary vein antrum isolation: results from a randomized study (SPECULATE). Heart Rhythm 2015;12:477-483.

34. Mont L, Bisbal F, Hernandez-Madrid A et al. Catheter ablation vs. antiarrhythmic drug treatment of persistent atrial fibrillation: a multicentre, randomized, controlled trial (SARA study). Eur Heart J 2014;35:501-7.

35. Nilsson B, Chen X, Pehrson S, Kober L, Hilden J, Svendsen JH. Recurrence of pulmonary vein con-duction and atrial fibrillation after pulmonary vein isolation for atrial fibrillation: a randomized trial of the ostial versus the extraostial ablation strategy. Am Heart J 2006;152:537 e1-8.

36. Oral H, Chugh A, Good E et al. Randomized evaluation of right atrial ablation after left atrial abla-tion of complex fractionated atrial electrograms for long-lasting persistent atrial fibrillation. Circ Arrhythm Electrophysiol 2008;1:6-13.

37. Pappone C, Ciconte G, Vicedomini G et al. Clinical Outcome of Electrophysiologically Guided Ablation for Nonparoxysmal Atrial Fibrillation Using a Novel Real-Time 3-Dimensional Map-ping Technique: Results From a Prospective Randomized Trial. Circ Arrhythm Electrophysiol 2018;11:e005904.

38. 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.

39. Pokushalov E, Romanov A, Katritsis DG et al. Renal denervation for improving outcomes of cath-eter ablation in patients with atrial fibrillation and hypertension: early experience. Heart Rhythm 2014;11:1131-8.

40. Pokushalov 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 fibril-lation: a randomized comparison. Heart Rhythm 2013;10:1280-6.

41. Schmidt B, Neuzil P, Luik A et al. Laser Balloon or Wide-Area Circumferential Irrigated Radiofre-quency Ablation for Persistent Atrial Fibrillation: A Multicenter Prospective Randomized Study. Circ Arrhythm Electrophysiol 2017;10.

42. Singh SM, d’Avila A, Kim YH et al. The modified stepwise ablation guided by low-dose ibutilide in chronic atrial fibrillation trial (The MAGIC-AF Study). Eur Heart J 2016;37:1614-21.

43. Turco P, De Simone A, La Rocca V et al. Antiarrhythmic drug therapy after radiofrequency catheter ablation in patients with atrial fibrillation. Pacing Clin Electrophysiol 2007;30 Suppl 1:S112-5.

44. Ullah W, McLean A, Hunter RJ et al. Randomized trial comparing robotic to manual ablation for atrial fibrillation. Heart Rhythm 2014;11:1862-9.

45. Verma A, Jiang CY, Betts TR et al. Approaches to catheter ablation for persistent atrial fibrillation. N Engl J Med 2015;372:1812-22.

46. Verma A, Mantovan R, Macle L et al. Substrate and Trigger Ablation for Reduction of Atrial Fibril-lation (STAR AF): a randomized, multicentre, international trial. Eur Heart J 2010;31:1344-56.

48 Chapter 2

47. Verma A, Sanders P, Champagne J et al. Selective complex fractionated atrial electrograms targeting for atrial fibrillation study (SELECT AF): a multicenter, randomized trial. Circ Arrhythm Electrophysiol 2014;7:55-62.

48. Vogler J, Willems S, Sultan A et al. Pulmonary Vein Isolation Versus Defragmentation: The CHASE-AF Clinical Trial. J Am Coll Cardiol 2015;66:2743-2752.

49. Wang M, Zhao Q, Ding W, Cai S. Comparison of Direct Current Synchronized Cardioversion to Ibutilide-Guided Catheter Ablation for Long-Term Sinus Rhythm Maintenance After Isolated Pulmonary Vein Isolation of Persistent Atrial Fibrillation. Am J Cardiol 2017;119:1997-2002.

50. Wang XH, Li Z, Mao JL, He B. A novel individualized substrate modification approach for the treat-ment of long-standing persistent atrial fibrillation: preliminary results. Int J Cardiol 2014;175:162-8.

51. Wang YL, Liu X, Tan HW et al. Evaluation of linear lesions in the left and right atrium in ablation of long-standing atrial fibrillation. Pacing Clin Electrophysiol 2013;36:1202-10.

52. Wang YL, Liu X, Zhang Y et al. Optimal endpoint for catheter ablation of longstanding persistent atrial fibrillation: A randomized clinical trial. Pacing Clin Electrophysiol 2018;41:172-178.

53. Willems S, Klemm H, Rostock T et al. Substrate modification combined with pulmonary vein isolation improves outcome of catheter ablation in patients with persistent atrial fibrillation: a prospective randomized comparison. Eur Heart J 2006;27:2871-8.

54. Wong KC, Paisey JR, Sopher M et al. No Benefit of Complex Fractionated Atrial Electrogram Ablation in Addition to Circumferential Pulmonary Vein Ablation and Linear Ablation: Benefit of Complex Ablation Study. Circ Arrhythm Electrophysiol 2015;8:1316-24.

55. Wynn GJ, Panikker S, Morgan M et al. Biatrial linear ablation in sustained nonpermanent AF: Results of the substrate modification with ablation and antiarrhythmic drugs in nonpermanent atrial fibrillation (SMAN-PAF) trial. Heart Rhythm 2016;13:399-406.

56. Yang B, Jiang C, Lin Y et al. STABLE-SR (Electrophysiological Substrate Ablation in the Left Atrium During Sinus Rhythm) for the Treatment of Nonparoxysmal Atrial Fibrillation: A Prospective, Multicenter Randomized Clinical Trial. Circ Arrhythm Electrophysiol 2017;10.

57. Yu HT, Shim J, Park J et al. Pulmonary Vein Isolation Alone Versus Additional Linear Ablation in Pa-tients With Persistent Atrial Fibrillation Converted to Paroxysmal Type With Antiarrhythmic Drug Therapy: A Multicenter, Prospective, Randomized Study. Circ Arrhythm Electrophysiol 2017;10.

B. Studies included in the Minimally-invasive Surgical Ablation Meta-analysis 1. 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.

2. Boersma LV, Castella M, van Boven W et al. Atrial fibrillation catheter ablation versus surgical abla-tion treatment (FAST): a 2-center randomized clinical trial. Circulation 2012;125:23-30.

3. Driessen AHG, Berger WR, Krul SPJ et al. Ganglion Plexus Ablation in Advanced Atrial Fibrillation: The AFACT Study. J Am Coll Cardiol 2016;68:1155-1165.

4. Fengsrud E, Wickbom A, Almroth H, Englund A, Ahlsson A. Total endoscopic ablation of patients with long-standing persistent atrial fibrillation: a randomized controlled study. Interact Cardio-vasc Thorac Surg 2016;23:292-8.

5. 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.

6. 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.

2


Supp

lem

enta

l tab

le S

6. S

tudy

cha

ract

eris

tics

A. C

athe

ter A

blat

ion

stud

ies

Stud

ySe

ttin

gPa

tien

ts

in s

tudy

Pati

ents

w

ith

(L)P

eAF

AF

type

Trea

tmen

t mod

alit

ies

Effica

cy(o

n/off

AA

D)

Endp

oint

defi

niti

on

Follo

w-

up(m

onth

s)Fo

llow

-up

met

hod

HRS

gu

idel

ines

fo

llow

ed

Am

mar

-Bus

chet

al.

2017

sing

le90

90Pe

AF

LPeA

F

PVI +

CFA

E +

addi

tiona

l lin

es v

s. PV

I +

CFA

E24

/90

(27%

) off

AF/

AFL

/AT

recu

rren

ce (o

n EC

G

or >

30

seco

nds

on 2

4h-H

olte

r)12

ECG

, Hol

ter

yes

Are

ntz

et a

l. 20

07si

ngle

110

43Pe

AF

PVI v

s PV

I22

/43

(51%

) off

AF/

AFL

/AT

recu

rren

ce (o

n EC

G

or >

30

seco

nds

on 2

4h-H

olte

r)15

ECG

, hol

ter

yes

Atie

nza

et a

l. 20

14m

ulti

230

117

PeA

FPV

I vs

PVI +

add

ition

al

lines

77/1

17 (6

6%) o

nA

F/A

FL/A

T re

curr

ence

(on

ECG

or

> 3

0 se

cond

s on

24h

-Hol

ter)

12EC

G, h

olte

r n

o

Bans

chet

al.

2013

sing

le10

737

PeA

FPV

I vs

PVI

20/3

7 (5

4%) o

nA

F/A

FL/A

T re

curr

ence

12EC

G, h

olte

r n

o

Bass

ioun

yet

al.

2016

sing

le90

90Pe

AF,

LPeA

F

PVA

I + a

dditi

onal

line

s vs

PVA

I + a

dditi

onal

lin

es29

/90

(32%

) off

AF/

AFL

/AT

recu

rren

ce (o

n EC

G

or >

30

seco

nds

on 2

4h-H

olte

r)12

ECG

, hol

ter

yes

Boer

sma

et a

l. 20

12m

ulti

124

26Pe

AF

PVI v

s SA

9/2

5 (3

6%) o

ffA

F/A

FL/A

T re

curr

ence

(on

ECG

or

> 3

0 se

cond

s on

24h

-Hol

ter)

12EC

G, h

olte

r y

es

Calo

et a

l. 20

06si

ngle

8043

PeA

F, LP

eAF

PVI +

add

ition

al li

nes

vs P

VI +

add

ition

al

lines

PeA

F 20

/43

(47%

) on,

13

/44

(30%

) off

LPeA

F 16

/37

(43%

) on

, 9/3

7 (2

4%) o

ffA

F/A

FL/A

T re

curr

ence

(on

ECG

or

> 3

0 se

cond

s on

24h

-Hol

ter)

14EC

G, h

olte

rye

s

Capo

niet

al.

2010

sing

le29

911

2Pe

AF

PVI +

add

ition

al li

nes

vs P

VI +

add

ition

al

lines

63/1

12 (5

6%) o

n,48

/114

(42%

) off

AF/

AFL

/AT

recu

rren

ce (o

n EC

G

or >

30

seco

nds

on 2

4h-H

olte

r)12

ECG

, hol

ter

yes

Cont

iet

al.

2018

mul

ti12

812

8Pe

AF

LPeA

FPV

I CFS

blin

ded

vs. P

VI

CFS

guid

ed87

/122

(71%

) on,

76/1

24 (6

1%) o

ffA

F/A

FL/A

T re

curr

ence

(on

ECG

or

> 3

0 se

cond

s on

24h

-Hol

ter)

12EC

G, h

olte

rye

s

Corr

ado

et a

l. 20

10si

ngle

320

160

PeA

F, LP

eAF

PVI v

s PV

I + a

dditi

onal

lin

es

57/7

5 (7

6%) o

n,LP

eAF

58/8

5 (6

8%)

offEp

isod

ic A

F lo

nger

than

30

seco

nds

12EC

G, h

olte

r n

o

50 Chapter 2

2


Supp

lem

enta

l tab

le S

6. S

tudy

cha

ract

eris

tics

A. C

athe

ter A

blat

ion

stud

ies

(con

tinue

d)

Stud

ySe

ttin

gPa

tien

ts

in s

tudy

Pati

ents

w

ith

(L)P

eAF

AF

type

Trea

tmen

t mod

alit

ies

Effica

cy(o

n/off

AA

D)

Endp

oint

defi

niti

on

Follo

w-

up(m

onth

s)Fo

llow

-up

met

hod

HRS

gu

idel

ines

fo

llow

ed

Di B

iase

et a

l. 20

16m

ulti

203

203

PeA

FPV

I vs

Am

ioda

rone

122/

203

(60%

) off

AF/

AFL

/AT

recu

rren

ce (o

n EC

G

or >

30

seco

nds

on 2

4h-H

olte

r)12

ECG

, hol

ter

yes

Di B

iase

et a

l. 20

16m

ulti

173

173

LPeA

F

Exte

nsiv

e ab

latio

n +

LAA

isol

atio

n vs

. Ex

tens

ive

abla

tion

73/1

73 (4

2%) o

ffA

F/A

FL/A

T re

curr

ence

(on

ECG

or

> 3

0 se

cond

s on

24h

-Hol

ter)

12EC

G, h

olte

rye

s

Dix

itet

al.

2012

sing

le15

615

6Pe

AF

PVI +

add

ition

al li

nes

vs P

VI +

add

ition

al

lines

92/1

61 (6

4%) o

n,71

/156

(46%

) off

Any

doc

umen

ted

arrh

ythm

ia

recu

rren

ce12

ECG

yes

Don

get

al.

2015

sing

le14

614

6Pe

AF,

LPeA

FPV

I + a

dditi

onal

line

s vs

PVI

93/1

46 (6

4%) o

ffA

F/A

FL/A

T re

curr

ence

(on

ECG

or

> 3

0 se

cond

s on

24h

-Hol

ter)

12EC

G, h

olte

r y

es

Elay

iet

al.

2008

mul

ti 1

4414

4LP

eAF

PVI v

s PV

I + a

dditi

onal

lin

es54

/144

(51%

) on

Epis

odes

of A

F/AT

that

last

ed

mor

e th

an 1

min

dur

ing

the

follo

w-u

p pe

riod.

12EC

G, h

olte

r n

o

Estn

eret

al.

2011

sing

le11

610

6Pe

AF,

LPeA

F

PVI +

add

ition

al li

nes

vs P

VI +

add

ition

al

lines

44/1

16 (3

8%) o

ff

Free

dom

from

any

sym

ptom

atic

at

rial t

achy

arrh

ythm

ia a

fter

the

last

abl

atio

n pr

oced

ure

12H

olte

r y

es

Fass

ini

et a

l.200

5si

ngle

187

61Pe

AF

PVI v

s PV

I + a

dditi

onal

lin

es34

/61

(56%

) on

Doc

umen

ted

sus-

tain

ed A

F re

curr

ence

12H

olte

r n

o

Fink

et a

l. 20

17si

ngle

118

118

PeA

F,LP

eAF

PVI v

s PV

I + s

ubst

rate

m

odifi

catio

n66

/118

(56%

) on

42/1

18 (3

6%) o

ffA

F/A

FL/A

T re

curr

ence

(on

ECG

or

> 3

0 se

cond

s on

24h

-Hol

ter)

12ye

s

Gai

taet

al.

2008

sing

le20

420

4Pe

AF

PVI +

add

ition

al li

nes

vs P

VI31

/79

(39%

) off

AF/

AFL

/AT

recu

rren

ce (o

n EC

G

or >

30

seco

nds

on 2

4h-H

olte

r)12

Hol

ter

yes

Gu

et a

l. 20

12si

ngle

172

123

PeA

F

PVI +

add

ition

al li

nes

vs P

VI +

add

ition

al

lines

43/1

23 (3

5%) o

nA

F/A

FL/A

T re

curr

ence

(on

ECG

or

> 3

0 se

cond

s on

24h

-Hol

ter)

12EC

G, h

olte

r N

o

50 Chapter 2

2


Supp

lem

enta

l tab

le S

6. S

tudy

cha

ract

eris

tics

A. C

athe

ter A

blat

ion

stud

ies

(con

tinue

d)

Stud

ySe

ttin

gPa

tien

ts

in s

tudy

Pati

ents

w

ith

(L)P

eAF

AF

type

Trea

tmen

t mod

alit

ies

Effica

cy(o

n/off

AA

D)

Endp

oint

defi

niti

on

Follo

w-

up(m

onth

s)Fo

llow

-up

met

hod

HRS

gu

idel

ines

fo

llow

ed

Han

et a

l. 20

14si

ngle

119

119

LPeA

F

PVI +

add

ition

al li

nes

vs P

VI +

add

ition

al

lines

76/1

19 (6

4%) o

ffA

F/A

FL/A

T re

curr

ence

(on

ECG

or

> 3

0 se

cond

s on

24h

-Hol

ter)

12EC

G, h

olte

r y

es

Hua

nget

al.

2017

sing

le90

90Pe

AF

PVI +

am

ioda

rone

vs

. PVI

63/9

0 (7

0%) o

ffA

F/A

FL/A

T re

curr

ence

(on

ECG

or

> 3

0 se

cond

s on

24h

-Hol

ter)

15EC

G, H

olte

rye

s

Jone

set

al.

2013

mul

ti52

52LP

eAF

PVI +

ste

pwis

e ab

latio

n vs

rate

co

ntro

l17

/24

(72%

) off

AF/

AFL

/AT

recu

rren

ce (o

n EC

G

or >

30

seco

nds

on 2

4h-H

olte

r)12

ECG

, hol

ter

yes

Kim

et a

l. 20

14si

ngle

120

120

PeA

F

PVI +

add

ition

al li

nes

vs P

VI +

add

ition

al

lines

88/1

20 (7

3%) o

ffD

ocum

ente

d A

F or

atr

ial fl

utte

r12

Hol

ter

No

Kim

et a

l. 20

17si

ngle

137

137

LPeA

F

PVI +

add

ition

al li

nes

vs.

PVI +

add

ition

al li

nes

vs.

PVI +

add

ition

al

lines

+ C

FAE

84/1

37 (6

1%) o

n,73

/137

(53%

) off

AF/

AFL

/AT

recu

rren

ce (o

n EC

G

or >

30

seco

nds

on 2

4h-H

olte

r)12

ECG

, hol

ter

yes

Kirc

her

et a

l. 20

17si

ngle

124

61Pe

AF

PVI +

line

ar a

blat

ion

vs. P

VI +

line

ar

abla

tion

+ lo

w v

olta

ge

area

34/5

8 (5

9%) o

n31

/58

(53%

) off

AF/

AFL

/AT

recu

rren

ce (o

n EC

G

or >

30

seco

nds

on 2

4h-H

olte

r)12

Hol

ter

yes

Kobo

riet

al.

2015

mul

ti21

1369

3Pe

AF,

LPeA

F

PVI +

add

ition

al li

nes

vs P

VI +

add

ition

al

lines

413/

750

(55%

) off

AF/

AFL

/AT

recu

rren

ce (o

n EC

G

or >

30

seco

nds

on 2

4h-H

olte

r)12

ECG

, hol

ter

Yes

Kum

agai

et a

l. 20

13si

ngle

100

100

PeA

F, LP

eAF

PVI v

s PV

I + a

dditi

onal

lin

es75

/100

(75%

) on

AF

> 1

min

on

ECG

12EC

G, h

olte

r N

o

Lim

et a

l. 20

12si

ngle

220

85Pe

AF,

LPeA

F

PVI +

add

itona

l lin

es

vs P

VI +

add

ition

al

lines

56/8

5 (6

6%) o

nA

F/A

FL/A

T re

curr

ence

(on

ECG

or

> 3

0 se

cond

s on

24h

-Hol

ter)

12EC

G, h

olte

r N

o

52 Chapter 2

Supp

lem

enta

l tab

le S

6. S

tudy

cha

ract

eris

tics

A. C

athe

ter A

blat

ion

stud

ies

(con

tinue

d)

Stud

ySe

ttin

gPa

tien

ts

in s

tudy

Pati

ents

w

ith

(L)P

eAF

AF

type

Trea

tmen

t mod

alit

ies

Effica

cy(o

n/off

AA

D)

Endp

oint

defi

niti

on

Follo

w-

up(m

onth

s)Fo

llow

-up

met

hod

HRS

gu

idel

ines

fo

llow

ed

Lin

et a

l. 20

14si

ngle

120

86Pe

AF,

LPeA

F

PVI +

add

ition

al li

nes

vs P

VI +

add

ition

al

lines

48/8

6 (5

6%) o

n

Free

dom

from

any

sym

ptom

atic

at

rial a

rrhy

thm

ia a

fter

a s

ingl

e pr

oced

ure

15EC

G, h

olte

rno

Mam

chur

et a

l. 20

14si

ngle

120

120

PeA

F, LP

eAF

GP

abla

tion

vs P

VI52

/83

(63%

) off

Com

plet

e ab

senc

e of

AF

epis

odes

on

daily

ECG

re

cord

ing

16EC

G, h

olte

r N

o

Moh

anty

et a

l. 20

15m

ulti

112

112

LPeA

F

PVI +

add

ition

al li

nes

vs P

VI +

add

ition

al

lines

65/1

12 (5

8%) o

n,56

/112

(50%

) off

Free

dom

from

AF,

atria

l flut

ter,

or a

tria

l tac

hyca

rdia

32EC

G, h

olte

rye

s

Mon

tet

al.

2014

mul

ti14

698

PeA

F

PVI +

add

ition

al

lines

vs

Flec

aini

de/

Am

ioda

rone

59/9

8 (6

0%) o

nA

F/A

FL/A

T re

curr

ence

(on

ECG

or

> 3

0 se

cond

s on

24h

-Hol

ter)

12EC

G, h

olte

r N

o

Nils

son

et a

l. 20

06si

ngle

100

100

PeA

FPV

I vs

PVI

17/1

00 (1

7%) o

ff

Free

dom

from

recu

rren

t sy

mpt

omat

ic A

F af

ter P

V is

olat

ion

12EC

G, h

olte

r N

o

Ora

let

al.

2008

sing

le85

66LP

eAF

PVI +

add

ition

al li

nes

vs P

VI +

add

ition

al

lines

18/6

6 (2

7%) o

ffA

F/A

FL/A

T re

curr

ence

(on

ECG

or

> 3

0 se

cond

s on

24h

-Hol

ter)

17H

olte

rYe

s

Papp

one

et a

l. 20

18si

ngle

8181

PeA

FPV

I vs.

PVI +

RRA

ab

latio

n50

/81

(62%

) on

AF/

AFL

/AT

recu

rren

ce (o

n EC

G

or >

30

seco

nds

on 2

4h-H

olte

r)12

ECG

, hol

ter

yes

Poku

shal

ovet

al.

2013

sing

le64

14Pe

AF

PVI +

add

ition

al li

nes

vs S

A5/

14 (3

6%) o

ffA

F% >

0.5

was

cla

ssifi

ed a

s A

F re

curr

ence

s.12

Cont

inuo

us

mon

itorin

g Y

es

Poku

shal

ovet

al.

2013

sing

le26

426

4Pe

AF,

LPeA

F

PVI +

add

ition

al li

nes

vs P

VI +

add

ition

al

lines

PeA

F 87

/181

(48%

) off LP

eAF

23/8

3 (2

8%)

off A

F% >

0.5

was

cla

ssifi

ed a

s A

F re

curr

ence

s.12

Cont

inuo

us

mon

itorin

g Y

es

2


Supp

lem

enta

l tab

le S

6. S

tudy

cha

ract

eris

tics

A. C

athe

ter A

blat

ion

stud

ies

(con

tinue

d)

Stud

ySe

ttin

gPa

tien

ts

in s

tudy

Pati

ents

w

ith

(L)P

eAF

AF

type

Trea

tmen

t mod

alit

ies

Effica

cy(o

n/off

AA

D)

Endp

oint

defi

niti

on

Follo

w-

up(m

onth

s)Fo

llow

-up

met

hod

HRS

gu

idel

ines

fo

llow

ed

Poku

shal

ovet

al.

2014

sing

le80

45Pe

AF

PVI v

s PV

I + R

enal

de

nerv

atio

n18

/45

(40%

) off

AF/

AFL

/AT

recu

rren

ce (o

n EC

G

or >

30

seco

nds

on 2

4h-H

olte

r)12

ECG

, hol

ter

yes

Schm

idt

et a

l. 20

17m

ulti

134

134

PeA

FLa

ser b

allo

on P

VI v

s. PV

I with

RF

96/1

34 (7

2%) o

ffA

F/A

FL/A

T re

curr

ence

(on

ECG

or

> 3

0 se

cond

s on

24h

-Hol

ter)

12EC

G, h

olte

rYe

s

Sing

het

al.

2016

mul

ti20

020

0Pe

AF

PVI +

add

itona

l lin

es

+ Ib

utili

de v

s PV

I +

addi

tiona

l lin

es11

5/18

9 (6

1%) o

n,10

1/18

9 (5

3%) o

ffA

F/A

FL/A

T re

curr

ence

(on

ECG

or

> 3

0 se

cond

s on

24h

-Hol

ter)

12EC

G, h

olte

rYe

s

Turc

oet

al.

2007

sing

le10

7 4

3Pe

AF

PVI +

add

ition

al li

nes

vs P

VI +

add

ition

al

lines

25/4

3 (5

9%) o

n N

ot s

peci

fied

12EC

G, h

olte

r N

o

Ulla

het

al.

2014

sing

le15

749

PeA

F, LP

eAF

PVI +

add

ition

al li

nes

vs P

VI +

add

ition

al

lines

30/1

15 (2

6%) o

ffA

F/A

FL/A

T re

curr

ence

(on

ECG

or

> 3

0 se

cond

s on

24h

-Hol

ter)

12EC

G, h

olte

rye

s

Verm

aet

al.

2010

mul

ti10

036

PeA

FCF

AE

vs P

VI v

s PV

I +

addi

tiona

l lin

es14

/23

(61%

) on

AF/

AFL

/AT

recu

rren

ce (o

n EC

G

or >

30

seco

nds

on 2

4h-H

olte

r)12

ECG

, hol

ter

No

Verm

aet

al.

2014

mul

ti77

48Pe

AF

PVI +

add

ition

al li

nes

vs P

VI +

add

ition

al

lines

17/4

8 (3

5%) o

nA

F/A

FL/A

T re

curr

ence

(on

ECG

or

> 3

0 se

cond

s on

24h

-Hol

ter)

12EC

G, h

olte

r N

o

Verm

aet

al.

2015

mul

ti58

958

9Pe

AF

PVI v

s PV

I + a

dditi

onal

lin

es22

0/54

9 (4

0%) o

n,17

7/54

9 (3

2%) o

ffA

F/A

FL/A

T re

curr

ence

(on

ECG

or

> 3

0 se

cond

s on

24h

-Hol

ter)

18EC

G, h

olte

r Y

es

Vogl

eret

al.

2015

sing

le20

514

3Pe

AF

PVI v

s PV

I + a

dditi

onal

lin

es80

/132

(61%

) on,

67/1

32 (5

1%) o

ffA

F/A

FL/A

T re

curr

ence

(on

ECG

or

> 3

0 se

cond

s on

24h

-Hol

ter)

12EC

G, h

olte

rye

s

Wan

get

al.

2013

sing

le21

014

0LP

eAF

PVI +

add

ition

al li

nes

vs P

VI +

add

ition

al

lines

74/1

40 (5

3%) o

n

Any

recu

rren

ce o

f atr

ial

arrh

ythm

ias

afte

r a s

ingl

e pr

oced

ure

32EC

G, h

olte

rno

54 Chapter 2

Supp

lem

enta

l tab

le S

6. S

tudy

cha

ract

eris

tics

A. C

athe

ter A

blat

ion

stud

ies

(con

tinue

d)

Stud

ySe

ttin

gPa

tien

ts

in s

tudy

Pati

ents

w

ith

(L)P

eAF

AF

type

Trea

tmen

t mod

alit

ies

Effica

cy(o

n/off

AA

D)

Endp

oint

defi

niti

on

Follo

w-

up(m

onth

s)Fo

llow

-up

met

hod

HRS

gu

idel

ines

fo

llow

ed

Wan

get

al.

2014

sing

le12

412

4LP

eAF

PVI +

add

ition

al li

nes

vs P

VI +

add

ition

al

lines

69/1

24 (5

6%) o

n,53

/124

(43%

) off

AF/

AFL

/AT

recu

rren

ce (o

n EC

G

or >

30

seco

nds

on 2

4h-H

olte

r)12

Hol

ter

Yes

Wan

get

al.

2017

sing

le96

96LP

eAF

PVI +

dire

ct

card

iove

rsio

n vs

. PVI

+

ibut

ilide

63/9

6 (6

7%) o

ffA

F/A

FL/A

T re

curr

ence

(on

ECG

or

> 3

0 se

cond

s on

24h

-Hol

ter)

12EC

G, h

olte

rye

s

Wan

get

al.

2018

sing

le40

040

0LP

eAF

PVI +

CFA

E +

linea

r ab

latio

n vs

. PVI

+ C

FAE

+ lin

ear a

blat

ion

200/

400

(50%

) off

AF/

AFL

/AT

recu

rren

ce (o

n EC

G

or >

30

seco

nds

on 2

4h-H

olte

r)12

ECG

, hol

ter

yes

Will

ems

et a

l. 20

06si

ngle

6262

PeA

FPV

I vs

PVI +

add

ition

al

lines

28/6

2 (4

5%) o

nA

F/A

FL/A

T re

curr

ence

(> 3

0 se

cond

s on

Tele

-ECG

)12

Tele

-ECG

Yes

Won

get

al.

2015

mul

ti13

013

0Pe

AF,

LPeA

F

PVI +

add

ition

al li

nes

vs P

VI +

add

ition

al

lines

67/1

30 (5

2%) o

ffA

ny A

F/A

FL/A

T re

curr

ence

12EC

G, h

olte

rYe

s

Wyn

net

al.

2016

mul

ti13

079

PeA

FPV

I vs

PVI +

add

ition

al

lines

77/1

22 (6

3%) o

ffA

F/A

FL/A

T re

curr

ence

(on

ECG

or

> 3

0 se

cond

s on

24h

-Hol

ter)

12EC

G, h

olte

rYe

s

Yang

et a

l. 20

17m

ulti

229

229

PeA

F,LP

eAF

PVI +

CTI

+ L

VA v

s. PV

I +

addi

tiona

l lin

es +

de

frag

men

tatio

n16

0/22

9 (7

0%) o

ffA

F/A

FL/A

T re

curr

ence

(on

ECG

or

> 3

0 se

cond

s on

24h

-Hol

ter)

18EC

G, h

olte

rYe

s

Yu et a

l. 20

17m

ulti

113

113

PeA

FPV

I vs.

PVI +

line

ar

abla

tion

86/1

13 (7

6%) o

nA

F/A

FL/A

T re

curr

ence

(on

ECG

or

> 3

0 se

cond

s on

24h

-Hol

ter)

18EC

G, h

olte

rye

s

AF,

atria

l fibr

illat

ion;

PeA

F, pe

rsis

tent

atr

ial fi

brill

atio

n; L

PeA

F, lo

ngst

andi

ng p

ersi

sten

t atr

ial fi

brill

atio

n; A

FL, a

tria

l flut

ter;

AT, a

tria

l tac

hyca

rdia

; ECG

, ele

ctro

card

iogr

am;

HRS

, hea

rt rh

ythm

soc

iety

; PVI

, pul

mon

ary

vein

isol

atio

n; V

ATS-

PVI,

vide

o as

sist

ed th

orac

osco

pic

pulm

onar

y ve

in is

olat

ion

2


B. M

inim

ally

-inva

sive

Sur

gica

l Abl

atio

n st

udie

s

Stud

ySe

ttin

gPa

tien

ts

in s

tudy

Pati

ents

w

ith

(L)P

eAF

AF

type

Trea

tmen

t mod

alit

ies

Effica

cy (o

n/off

A

AD

)En

dpoi

nt d

efini

tion

Follo

w-

up(m

onth

s)Fo

llow

-up

met

hod

HRS

gu

idel

ines

fo

llow

ed

Beav

eret

al.

2016

Sing

le23

7Pe

AF

LPeA

FVA

TS-P

VI6/

7 (8

6%) o

n5/

7 (7

1%) o

ffN

orm

al s

inus

rhyt

hm a

t 12

mon

ths

12EC

GN

o

Boer

sma

et a

l. 20

12m

ulti

124

16Pe

AF

VATS

-PVI

9/16

(56%

) on

AF/

AFL

/AT

recu

rren

ce (o

n EC

G

or >

30

seco

nds

on 2

4h-H

olte

r)12

ECG

, hol

ter

No

Drie

ssen

et a

l. 20

16si

ngle

240

143

PeA

FH

ybrid

VAT

S-PV

I with

vs

with

out G

P85

/132

(64%

) off

AF/

AFL

/AT

recu

rren

ce (o

n EC

G

or >

30

seco

nds

on 2

4h-H

olte

r)12

ECG

, hol

ter

Yes

Feng

srud

et a

l.201

6si

ngle

3615

LPeA

FVA

TS-P

VI12

/15

(80%

) off

AF

epis

odes

of >

30 s

econ

ds o

r on

ECG

12EC

G, h

olte

rN

o

Poku

shal

ovet

al.

201

3si

ngle

6412

PeA

FVA

TS-P

VI9/

12 (7

5%) o

ffA

F% >

0.5

was

cla

ssifi

ed a

s A

F re

curr

ence

s12

Cont

inuo

us

mon

itorin

gYe

s

Rom

anov

et a

l. 20

16m

ulti

176

176

PeA

F

PVI +

Box

lesi

on v

sPV

I + b

ox le

sion

+ L

AA

ex

cisi

on12

6/17

3 (7

3%) o

n12

5/17

3 (7

2%) o

ffA

F/A

FL/A

T re

curr

ence

(on

ECG

or

> 3

0 se

cond

s on

24h

-Hol

ter)

12EC

G, h

olte

rYe

s

AF,

atria

l fibr

illat

ion;

PeA

F, pe

rsis

tent

atr

ial fi

brill

atio

n; L

PeA

F, lo

ngst

andi

ng p

ersi

sten

t atr

ial fi

brill

atio

n; A

FL, a

tria

l flut

ter;

AT, a

tria

l tac

hyca

rdia

; ECG

, ele

ctro

card

iogr

am;

HRS

, hea

rt rh

ythm

soc

iety

; PVI

, pul

mon

ary

vein

isol

atio

n; V

ATS-

PVI,

vide

o as

sist

ed th

orac

osco

pic

pulm

onar

y ve

in is

olat

ion

56 Chapter 2

Supplemental Table S7. Treatment characteristics for catheter- and minimally-invasive surgical ablation

Catheter Ablation(t=79, n=4854)

Surgical Ablation(t=33, n=1094)

Procedure Characteristics t n (%) t n (%)

Pulmonary Vein Isolation 110 7183 (100) 8 388 (100)

Additional Lesions:

Roof Lesion 43 3034 (42) 4 170 (45)

Inferior Lesion 7 276 (4) 2 25 (7)

Mitral Isthmus Lesion 44 2680 (37) 1 12 (3)

Cavotricuspid Isthmus Lesion 32 2539 (35) 0 0 (0)

Trigone Lesion -- -- 3 152 (40)

CFAE Ablation 36 2531 (35) 0 0 (0)

GP Ablation 3 250 (5) 3 102 (27)

Right Atrial Ablation 7 450 (8) 0 0 (0)

2


Supplemental figure S8.Sensitivity analyses(A) studies reporting AF freedom at 12 months vs. later than 12 months, (B) those reporting AF freedom in persistent atrial fibrillation (AF) vs. longstanding persistent AF patients, (C) those reporting AF freedom following the HRS/EHRA/ECAS expert consensus statement vs. those that used a different outcome defini-tion, (D) those that were published before 2010 vs in 2010 or later, (E) those reporting on studies with <100 patients vs. >100 patients, (F) those reporting on studies where the mean age of the study population was <60 vs. > 60 years, (G) those reporting on studies where the mean left atrial (LA) diameter of the study population was <47mm vs. > 47mm or where left atrial volumes index (LAVI) was <38mL/m2 vs >38mL/m2

58 Chapter 2

Supplemental figure S9.Funnel Plots(A) Catheter ablation meta-analysis. (B) Minimally-invasive Surgical ablation meta-analysis

Chapter 3Ganglion Plexus Ablation in Advanced Atrial Fibrillation: The AFACT Study

Antoine H.G. Driessen *Wouter R. Berger *

Sébastien P.J. KrulNicoline W.E. van den Berg

Jolien NeefsFemke R. Piersma

Dean R.P.P. Chan Pin YinJonas S.S.G. de Jong

Wim Jan P. van BovenJoris R. de Groot


J Am Coll Cardiol. 2016; 13;68:1155-65

62 Chapter 3

AbstRAct

BackgroundPatients with long duration of atrial fibrillation (AF), enlarged atria, or failed catheter ablation have advanced AF and may require more extensive treatment than pulmonary vein isolation.

ObjectivesThe aim of this study was to investigate the efficacy and safety of additional ganglion plexus (GP) ablation in patients undergoing thoracoscopic AF surgery.

MethodsPatients with paroxysmal AF underwent pulmonary vein isolation. Patients with persis-tent AF also received additional lines (Dallas lesion set). Patients were randomized 1:1 to additional epicardial ablation of the 4 major GPs and Marshall’s ligament (GP group) or no extra ablation (control) and followed every 3 months for 1 year. After a 3-month blanking period, all antiarrhythmic drugs were discontinued.

ResultsTwo hundred forty patients with a mean AF duration of 5.7 ± 5.1 years (59% persistent) were included. Mean procedure times were 185 ± 54 min and 168 ± 54 min (p = 0.015) in the GP (n = 117) and control groups (n = 123), respectively. GP ablation abated 100% of evoked vagal responses; these responses remained in 87% of control subjects. Major bleeding occurred in 9 patients (all in the GP group; p < 0.001); 8 patients were man-aged thoracoscopically, and 1 underwent sternotomy. Sinus node dysfunction occurred in 12 patients in the GP group and 4 control subjects (p = 0.038), and 6 pacemakers were implanted (all in the GP group; p = 0.013). After 1 year, 4 patients had died (all in the GP group, not procedure related; p = 0.055), and 9 were lost to follow-up. Freedom from AF recurrence in the GP and control groups was not statistically different whether patients had paroxysmal or persistent AF. At 1 year, 82% of patients were not taking antiarrhythmic drugs.

ConclusionsGP ablation during thoracoscopic surgery for advanced AF has no detectable effect on AF recurrence but causes more major adverse events, major bleeding, sinus node dysfunction, and pacemaker implantation.

3

AFACT study: Thoracoscopic GP ablation for AF 63

IntRoductIon

The most common arrhythmia, atrial fibrillation (AF) is associated with increased mor-bidity and mortality. Ablation is indicated for patients remaining symptomatic despite a trial with antiarrhythmic drugs (AADs).1,2 Therefore, catheter ablation and stand-alone thoracoscopic surgery are increasingly being used. The arrhythmogenic trigger from the pulmonary veins (PVs) is the target for ablation in patients with paroxysmal AF without concomitant atrial or cardiac disease; the mechanism is less well established in patients with advanced AF, defined as persistent AF, enlarged left atria, or previously failed catheter ablation. Various treatment strategies have been advocated, combining more extensive myocardial ablation and ablation of non-PV and non-myocardial targets, including stepwise catheter ablation approaches3, in which PV isolation (PVI) is followed by linear left atrial (LA) ablation, ablation of continuous fractionated atrial electrograms4, or ablation of rotors.5 As it has become clear that the autonomous nervous system plays a central role in initiating AF and in atrial autonomic remodeling6,7, partial atrial denerva-tion through ablation of the major autonomic ganglion plexus (GP), either alone or in combination with PVI, has been pursued.8,9

GP stimulation promotes AF by a combined parasympathetic and sympathetic action resulting in action potential duration (APD) shortening and increased sarcoplasmic reticulum calcium release in PV myocardium, allowing early after-depolarizations to emerge and trigger AF.10 Aside from AF induction, GP stimulation affects local and global LA conduction time, consistent with a predominantly parasympathetic effect.11 Thus, the stimulation of the autonomic nerves within the GPs, beyond triggering AF, may also have a proarrhythmic effect on the atrial myocardium that perpetuates the arrhythmia.11

Studies investigating the role of GP ablation in addition to PVI have demonstrated mixed results8,12,13, as have nonrandomized studies during concomitant cardiac sur-gery.14,15 The GPs reside in epicardial fat pads and cannot be ablated endocardially without (much) more atrial myocardial ablation. This may induce post-ablation atrial tachycardias (ATs). However, more rigorous myocardial ablation around the PVs may also lower the chance of reconnection. Second, most studies have focused on patients with paroxysmal AF with few cardiovascular comorbidities. Epicardial ablation during thoracoscopic surgery for AF may allow more selective GP ablation without ablating the underlying atrial myocardium; however, only observational data on thoracoscopic GP ablation are available.16-19

The aim of the prospective, randomized, controlled AFACT (Atrial Fibrillation Ablation and Autonomic Modulation via Thoracoscopic Surgery) study was to investigate epicar-dial GP ablation during thoracoscopic surgery for advanced AF. We hypothesized that GP ablation in these patient results in a higher percentage of freedom from AF, without inducing more periprocedural or late complications.

64 Chapter 3

Methods

AFACT is a single-center study, performed at the Academic Medical Center in Amster-dam, that enrolled patients between April 2010 and January 2015. The study conformed to the Declaration of Helsinki and was approved by the Institutional Review Board. All patients provided written informed consent.

Pre-operative workupThe inclusion and exclusion criteria are listed in the Online Appendix. All patients had electrocardiographic documentation of AF and underwent the following pre-operative tests: non-triggered cardiac magnetic resonance imaging angiography for LA anatomy, 24-h Holter recording for AF burden and rate control assessment, transthoracic echo-cardiography for LA diameter and volume (determined using the Simpson method), spirometry for vital capacity and forced expiratory volume in 1 second to assess the ability to undergo perioperative single-lung ventilation, and treadmill testing to exclude clinically significant coronary artery disease (followed by coronary angiography when appropriate). Hepatic and renal failure, as well as clinically relevant anaemia, were excluded. All patients were adequately anticoagulated with vitamin K antagonists or non–vitamin K oral anticoagulant agents (NOAC) ≥4 weeks prior to surgery.

Randomization was computer guided and performed in blocks with varying block sizes at the time of pericardial opening. With 110 patients in each arm (α = 0.8, 2-sided signifi-cance level = 0.05), AFACT was powered to detect a 17.5% difference in AF absence after 1 year, on the basis of previous studies.16,20,21 We enrolled 240 patients to allow for about 10% of patients not completing follow-up.

Surgical procedureThe surgical procedure has been described previously.16 In short, bilateral video-assisted thoracoscopy was performed. Oral anticoagulant agents were discontinued 2 days be-fore surgery, and transesophageal echocardiography excluded LA thrombi before the atria were manipulated. All patients underwent PVI, specifically, ≥6 radiofrequency ap-plications to the PV antrum, until a conductance drop within 10 s was observed (Isolator Synergy clamp, AtriCure, West Chester, Ohio). In patients with persistent AF, additional LA ablation lines were made, specifically, a Dallas lesion set involving a superior line connecting the right and left antral PVI and left fibrous trigone line, connecting the superior line to the left fibrous trigone at the aortic annular level (Isolator Transpolar pen or Coolrail linear pen. AtriCure).22 All ablation lines were extensively tested for bidi-rectional block with epicardial electrodes connected to an electrophysiologic system in the operating theater, as reported earlier.16,23,24 The LA appendage was excluded using

3


an endoscopic stapler. Patients stayed in the recovery room for 3 to 6 h and were admit-ted to the ward afterward. Thorax drains were removed within 24 h, and patients were usually discharged on postoperative day 3.

GP ablationBefore any PV or linear ablation, the anterior right (located in the epicardial fat pad anterior to the right superior and inferior PVs) and inferior right (located in the fat pad inferior to the right inferior PV, extending to the inferior side of the LA posterior wall) GPs were localized using anatomic landmarks and high-frequency stimulation (HFS). The GP between the superior caval vein and aorta was not ablated or tested. Online Figure 1 shows the location of the main GPs (posterior LA view). A positive HFS response was defined as ≥50% increase in the R-R interval. HFS was delivered using a bipolar ablation pen (Isolator Transpolar pen) with cycle length 60 ms, 16 Hz, pulse width 1.0 ms, and output incrementing from 1 to 25 mA.

In patients randomized to GP ablation, GPs were subsequently ablated. Notably, ablation on the basis of anatomic landmarks was performed when HFS did not evoke a vagal response. On the left side, the superior left and inferior left GPs (located in the fat pads on the LA roof, medial to the left superior PV, and inferior to the left inferior PV, extending toward the LA posterior wall) were identified similarly and ablated in these patients. The ligament of Marshall (between the pulmonary artery and the left superior PV) was subsequently dissected. In both groups, HFS of the 4 major GPs was repeated after all ablation was complete to confirm the absence or presence of a vagal response. Additional GP ablation was applied when necessary.

Clinical follow-upAll patients were treated with colchicine 0.5 mg once daily from the first post-operative day for 30 days to prevent pericarditis. Follow-up at 10 days after discharge was for wound control. Clinical follow-up for endpoints was performed every 3 months with a clinical visit, electrocardiography, and 24-h Holter monitoring. Symptomatic patients were en-couraged to obtain additional rhythm recording. The first 3 months formed a blanking period, during which recurrences of AF or other atrial arrhythmias were not considered recurrence. All AADs were discontinued after 3 months. When AF was present at the 3-month visit, electric cardioversion was performed. Anticoagulation was discontinued only in patients with CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke, transient ischemic attack, or thromboembolism, vascular disease, age 65–74 years, sex category [female]) scores of 0 (or 1 when based solely on sex) at 6 months.1

66 Chapter 3

Endpoint definitionThe efficacy endpoint was freedom from AF or any atrial tachyarrhythmia lasting ≥30 s, documented on electrocardiography, Holter monitoring, or pacemaker or implantable cardioverter-defibrillator electrogram, without AAD use, as per the guidelines.

Safety endpoints included any procedure-related complication, stroke, and bleeding. Major complications were defined as those causing hospital admission within 30 days, inability to complete the procedure, or permanent injury or death. An independent clinical endpoint committee, whose members were unaware of study assignment, adju-dicated all efficacy and safety endpoints.

Statistical analysisStatistical analysis was performed with SPSS version 23.0 (IBM, Armonk, New York) and R version 3.2.1 for Windows (R Foundation for Statistical Computing, Vienna, Austria). Continuous values are expressed as mean ± SD. Categorical variables are expressed as numbers and percentages. The Mann-Whitney U test, paired Student t test, and Fisher exact test were used for comparisons. For freedom from AF recurrence, event-free sur-vival was plotted and estimated by Kaplan-Meier curves. Clinical parameters associated with AF recurrence were studied using univariate and stepwise multivariate analysis in a Cox regression model. All variables with p values <0.10 in univariate analysis, plus 3 well-established risk factors for AF recurrence (left ventricular ejection fraction, AF dura-tion, and previous PVI) were entered into the multivariate regression. A p value <0.05 indicated statistical significance.

Results

Of 318 patients screened, 240 provided written informed consent. Patients were ran-domized 1:1 to standard thoracoscopic ablation (n = 123) or additional GP ablation (n = 117) (Figure 1). Patients were 60 ± 8 years of age, and 73% were men. Overall, 68% had enlarged left atria (LA volume index [LAVI] >33 ml/m2), and 43% had severely enlarged left atria (LAVI ≥40 ml/m2). AF was present for 4 years (interquartile range: 2 to 8 years; range: 1 to 35 years). Nearly one-quarter of patients had undergone previous catheter ablation; only 26 patients (11%) had normal left atria and no persistent AF or previous ablation. Baseline characteristics were balanced (Table 1).

Surgical procedure and complicationsThe procedure durations were 185 ± 54 min in the GP group and 168 ± 54 min in the control group (p = 0.015). The difference was driven by procedures in patients with par-oxysmal AF (PVI alone: 144 ± 40 min vs. 127 ± 38 min; p = 0.04). There was no difference

3


in procedure duration when additional LA lines were performed for persistent AF (GP 205 ± 49 min vs. control 202 ± 40 min; p = 0.609).

Isolation of all PVs was confirmed by demonstration of entry and exit block as previ-ously described. (23, 24) Block across all LA lines was confirmed with differential pacing. After ablation, HFS-evoked vagal response was absent in 100% of patients in the GP group, whereas a residual vagal response could be provoked in at least 1 GP in 87% of control patients (p < 0.001).

Major bleeding occurred in 9 patients (LAVI 40.3 ± 11.6 ml/m2, which was not different from patients without bleeding; p = 0.833), all in the GP group (p < 0.001). Bleeding was managed thoracoscopically in 8 patients, resulting in termination of the procedure and thoracoscopic reoperation after several weeks in 4 patients, and in 3 patients, at least 1 of the LA lines could not be completed. Furthermore, 1 major bleed consisted of

Figure 1.Study flowchartFrom the original 318 patients screened, data for analysis of the primary endpoint were available for 117 patients in the control group and 110 in the ganglion plexus (GP) ablation group. AF; atrial fibrillation, LVEF; left ventricular ejection fraction.

68 Chapter 3

Table 1. Baseline characteristics

All NO GP ablation GP ablation(n=240) (n=123) (n=117) p-value

BaselineAge (mean±SD) 59.9±8.2 60.2±8.2 59.5±8.2 0.525Male gender (n, %) 175 (73) 91 (74) 84 (72) 0.813BMI, (mean±SD) 27.3±3.9 27.1±3.5 27.6±4.3 0.283Left Atrial Diameter (mm, mean±SD) 42.2±5.6 42.3±5.5 42.1±5.6 0.740LAVI (ml/m2, mean±SD) 39.4±11.8 40.3±13.0 38.3±10.4 0.198LVEF (%, mean±SD) 49.6±14.4 51.2±9.1 47.9±18 0.071Creatinin, (µmol/L, mean±SD) 85±18 83±17 87±19 0.115Previous catheter PVI, (n, %) 56 (23) 30 (24) 26 (22) 0.780Myocardial Infarction, (n, %) 11 (5) 8 (7) 3 (3) 0.263Previous PCI, (n, %) 29 (12) 14 (11) 15 (13) 0.866

AF CharacteristicsAF Duration (years), median [IQR] 4 [2-8] 5 [2-10] 4 [2-6] 0.063ParoxysmalAF , (n, %) 98 (41) 55 (45) 43 (37) 0.238Persistent AF, (n, %) 142 (59) 68 (55) 74 (63) 0.238CHA2DS2VASc (mean±SD, (range)) 1.4±1.3 (0-7) 1.4±1.3 (0-7) 1.4±1.2 (0-6) 0.770CHA2DS2VASc 0, (n, %) 67 (28) 34 (28) 33 (28) 1CHA2DS2VASc 1, (n, %) 76 (32) 38 (31) 38 (33) 0.890CHA2DS2VASc ≥ 2, (n, %) 97 (40) 51 (41) 46 (39) 0.793Congestive heart failure, (n, %) 12 (5) 5 (4) 7 (6) 0.700Hypertension, (n, %) 102 (43) 54 (44) 48 (41) 0.749Diabetes, (n, %) 16 (7) 8 (7) 8 (7) 1Stroke/TIA/Embolus, (n, %) 19 (8) 10 (8) 9 (8) 1Vascular disease, (n, %) 25 (10) 14 (11) 11 (9) 0.771Female gender, n (%) 65 (27) 33 (27) 33 (28) 0.813Age ≥ 65, years (n, %) 67 (28) 36 (29) 31 (27) 0.738Age ≥ 75 years, (n, %) 2 (1) 1 (1) 1 (1) 1

MedicationAnticoagulants, Acenocoumarol, (n, %) 182 (76) 87 (71) 96 (82) 0.007 Fenprocoumon, (n, %) 27 (11) 16 (13) 11 (9) 0.419 NOAC, (n, %) 30 (13) 20 (16) 10 (9) 0.081 Antiplatelets, (n, %) 15 (7) 7 (6) 8 (7) 0.793Anti-arrhythmic drugs, Class IA, (n, %) 6 (3) 2 (2) 4 (4) 0.516 Class IC, (n, %) 81 (34) 41 (33) 40 (34) 0.843 Class II, (n, %) 122 (51) 56 (45) 66 (56) 0.261 Class III, (n, %) 92 (38) 48 (39) 44 (37) 0.264 Class IV, (n, %) 32 (13) 20 (16) 12 (10) 0.367 Digoxin, (n, %) 30 (13) 16 (13) 14 (12) 0.618 Any AAD, (n, %) 234 (98) 118 (96) 116 (99) 0.214

Values are mean±SD, n (%) or median (interquartile range), unless otherwise indicated.AAD = antiarrhythmic drug; AF = atrial fibrillation; BMI = body mass index; CHA2DS2-VASc = congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke, transient ischemic attack, or thromboembolism, vascular disease, age 65 -74 years, sex category (female); GP = ganglion plexus; LA = left atrial; LAVI = left atrial volume index; LVEF = left ventricular ejection fraction; NOAC = nonvitamin K oral anticoagulant drug; PCI = percutaneous coronary intervention; PVI = pulmonary vein isolation; TIA = transient ischemic attack.

3


thoracoscopic access-port bleeding, necessitating a second thoracoscopic procedure. In 1 patient, a sternotomy was needed after trocar perforation of the right ventricle and the left anterior descending coronary artery, resulting in tamponade followed by ster-notomy with suturing of the perforation and arterially grafting the left anterior descend-ing coronary artery. Minor bleeds, all managed thoracoscopically without affecting the procedure, occurred in 12 patients, 6 in each group (p = 1.00).

Hospital stayAverage hospital admission lasted 5.3 ± 2.1 days (range: 2 to 15 days) and 5.0 ± 1.8 days (range: 3 to 14 days) in the GP and control groups, respectively (p = 0.242). Symptomatic sinus node dysfunction, necessitating admission to the cardiac medium care unit, treat-ment with isoprenaline, and/or (temporary) pacing occurred in 12 GP patients and 4 control subjects (p = 0.038). Pacemakers were implanted in 3 patients for sinus node dysfunction with asystolic pauses during admission. Shortly after discharge, another 3 pacemakers were implanted because of sinus node dysfunction: syncope in 2 patients and postopera-tive total atrioventricular (AV) block in 1 patient. All 6 pacemakers were implanted in GP patients (p = 0.013). These patients had no pre-existing conduction disorders, apart from 1 with first-degree AV block (P-Q interval 210 ms). Major procedure-related complications occurred in 22 GP patients and 10 control subjects (p = 0.022) (Table 2).

Follow-upFour patients died during follow-up, none procedure related and all in the GP group (p = 0.055) (Table 3). One-year follow-up was incomplete for 9 patients (4%), who were considered lost to follow-up. Complete information on the primary endpoint was as-certained in 227 patients (95%). AF recurrences during the blanking period were noted in 40 of 117 GP patients and 36 of 123 control patients (p = 0.407), with cardioversions performed in 25 and 28 patients, respectively.

At 1-year follow-up, no AF recurrences were observed in 70.9% and 68.4% of patients in the GP and control groups (p = 0.696) (Central Illustration) and 82% of patients were off AADs. Cardioversions were performed in 22 and 21 patients, respectively. There were no differences according to clinical AF type; AF was absent in 80.0% and 74.5% (p = 0.512) of patients with paroxysmal AF and 65.7% and 62.9% (p = 0.767) of those with persistent AF in the GP and control groups, respectively (Figure 2). In subgroup analysis, there were no differences between GP ablation and control (Figure 3).

AT was the most common recurrent arrhythmia and occurred significantly more often in patients in the GP group (78.1% AT and 21.9% AF) than in the control group (51.4% AT and 48.6% AF) (p = 0.026).

There were no differences in mean heart rate on Holter monitoring at baseline or 3-month follow-up. After discontinuation of AADs, mean heart rate on Holter monitor-

70 Chapter 3

Table 2. Adverse Events After Thoracoscopic Ablation for Atrial Fibrillation

Adverse Event (n, %) NO GP ablation GP ablation

(n=123) (n=117) p-value

Procedure related, major*

Total 10 (8) 22 (19) 0.022

Bleeding 0 (0) 9 (8) 0.001

Sternotomy 0 (0) 1 (1) 0.488

Tamponade 1 (1) 0 (0) 1

Phrenic Paralysis 2 (2) 0 (0) 0.498

Sinus node dysfunction 4 (3) 12 (10) 0.038

Pacemaker implantation 0 (0) 6 (5) 0.013

Pneumothorax 3 (2) 1 (1) 0.622

Pneumonia 1 (1) 2 (2) 0.614

Stroke 0 (0) 1 (1) 0.488

Haemathorax 0 (0) 1 (1) 0.488

Pleural Effusion 2 (2) 1 (1) 1

Pericarditis 0 (0) 1 (1) 0.488

Procedure related, minor†

Total 12 (10) 10 (9) 0.825

Bleeding (minor) 6 (5) 6 (5) 1

Hypothermia during surgery 1 (1) 0 (0) 1

Pneumothorax 3 (2) 1 (1) 0.622

Urinary Tract Infection 0 (0) 2 (2) 0.237

Pleural Effusion 0 (0) 1 (1) 0.488

Pericarditis 2 (2) 1 (1) 1

Non-procedure related, major*

Total 4 (3) 10 (9) 0.101

Death 0 (0) 4 (3) 0.055

PCI during follow-up 2 (2) 1 (1) 1

Haemathorax 0 (0) 1 (1) 0.488

Pleural Effusion 2 (2) 4 (3) 0.677

Non-procedure related, minor†

Total 1 (1) 1 (1) 1

Pneumonia 1 (1) 1 (1) 1

Values are n (%).Abbreviations as in Table 1.* Major adverse events are defined as causing (prolongation of ) hospital admission within 30 days, inability to complete the procedure, or permanent injury or death.† Minor adverse events are defined as complications that did not result in termination of the procedure or permanent injury.

3


0 2 4 6 8 10 120

20

40

60

80

100

Paroxysmal AF

Follow−up (months)

Fre

edom

of A

F R

ecur

renc

e (%

)

No GP ablationGP ablation

p=0.512

0 2 4 6 8 10 120

20

40

60

80

100

Persistent AF


Fre

edom

of A

F R

ecur

renc

e (%

)


p=0.767

Figure 2.Primary endpointThe primary endpoint of atrial fibrillation (AF) recurrence within 1 year was not significantly different be-tween ganglion plexus (GP) ablation and control groups for the overall population (Central illustration, panel A), (A) patients with paroxysmal AF (n=98), or (B) patients with persistent AF (n=141).

Figure 3.Subgroup analysis: Ganglion plexus ablation efficacyThere were no subgroups in which ganglion plexus (GP) ablation added to thoracoscopic ablation was as-sociated with less atrial fibrillation (AF) recurrence during follow-up. CHA2DS2-VASc = congestive heart fail-ure, age ≥75 years, diabetes mellitus, prior stroke, transient ischemic attack, or thromboembolism, vascular disease, age 65-74 years, sex category (female); CI = confidence interval; LA = left atrial; PVI = pulmonary vein isolation.

A B

72 Chapter 3

ing increased by 5.5 ± 19.2 beats/min versus 2.6 ± 17.7 beats/min at 6 months (p = 0.013) and by 6.4 ± 19.2 beats/min versus 2.3 ± 16.1 beats/min at 9 months (p = 0.004) in the GP and control groups, respectively.

At 1 year, mean heart rate did not differ from baseline in either groups, although of-fice heart rate during follow-up was higher in the GP group than in control subjects during follow-up (data not shown). Univariate and multivariate regression analysis was performed on AF recurrence (Figure 4). LAVI was the only determinant of AF recurrence (hazard ratio: 1.38 per 10-ml increase; 95% confidence interval: 1.03 to 1.83; p = 0.029) that remained significant in multivariate analysis.

Univariate

Age

Gender

AF Type

Ganglion Plexus Ablation

AF Duration

Left Atrial Volume Index

Left Ventricular Ejection Fraction

History of PVI

BMI

Hypertension

Diabetes Mellitus

CHA2DS2−VASc-score

Multivariate

Age

AF Type

AF Duration

LA Volume Index

Left Ventricular Ejection Fraction

History of PVI


HR

1.03

1.28

1.86

0.93

0.92

1.44

0.91

1.23

1.22

1.24

0.96

1.17

1.07

1.52

0.90

1.38

1.05

1.51

1.10

95% CI

[1.00−1.06]

[0.80−2.04]

[1.16−2.98]

[0.60−1.43]

[0.59−1.44]

[1.09−1.89]

[0.75−1.11]

[0.78−2.04]

[0.75−1.98]

[0.80−1.91]

[0.38−2.36]

[0.99−1.38]

[0.82−1.47]

[0.90−2.55]

[0.48−1.29]

[1.02−1.84]

[0.85−1.30]

[0.87−2.55]

[0.88−1.33]

P−value

0.072

0.299

0.001

0.734

0.725

0.009

0.343

0.344

0.419

0.341

0.923

0.066

0.532

0.116

0.345

0.040

0.673

0.144

0.476

0 0.5 1 1.5 2 2.5 3Hazard Ratio

Figure 4.Determinants of atrial fibrillation recurrenceAll variables with p-values <0.10 in univariate analysis plus 3 well-established risk factors for atrial fibrilla-tion (AF) recurrence (AF duration, left ventricular ejection fraction, and history of previous pulmonary vein isolation (PVI)) were included in the multivariate model. BMI = body mass index; HR = hazard ratio; other abbreviations as in Figure 3.

3


dIscussIon

The first randomized study of GP ablation in thoracoscopic surgery, AFACT is the largest study to date of minimally invasive AF surgery. Our study demonstrated that in patients with advanced AF, of whom 68% had enlarged LAs, GP ablation did not reduce AF recur-rence (Central Illustration). GP ablation was associated with more major procedural complications (19% vs. 8%), in particular bleeds leading to termination of the procedure or sternotomy, and significantly more pacemaker implantations because of sinus node dysfunction and AV block. Additionally, recurrences were more often ATs in the GP group than in control subjects. There was no difference in AF recurrence rates during the so-called blanking period between groups.

The various hierarchical levels of extrinsic (nuclei and axonal fields in the brain), in-trathoracic (spinal cord ganglia), and intrinsic (major GP and the atrial neural network, consisting of axons and smaller ganglia extending from these) autonomous nervous systems are interdependently connected but can function independently once discon-nected. Injection of cholinergic agents into the GPs, electric stimulation of nerves, and pacing-induced AF produce proarrhythmic autonomic hyperactivity10,25, leading to shortening of the atrial and PV APD (parasympathetic effect) and increases intracellular [Ca2+] (sympathetic effect), resulting in triggered firing and induction of AF.10 GP stimu-lation also directly affects atrial myocardial electrophysiology in a proarrhythmic man-ner, consistent with a predominantly parasympathetic action.11 Disconnecting extrinsic

0 2 4 6 8 10 120

20

40

60

80

100


Fre

edom

of A

F R

ecur

renc

e (%

)


p=0.696

0

5

10

15

20

Major Procedure

Related

p=0.022

Minor Procedure

Related

Major Non-procedure

Related

Minor Non-procedure

Related

p=0.825p=0.101

p=1

Adve

rse

Even

ts (%

)

Central illustration.Thoracoscopic ganglion ablation for atrial fibrillation: efficacy and safety(A). Efficacy of GP ablation (B). Adverse events associated with GP ablationIn a comparison of groups that did or did not undergo ganglion plexus (GP) ablation in addition to pulmo-nary vein isolation for advanced atrial fibrillation (AF), the primary endpoint of AF recurrence at 1 year was not statistically different (A). The addition of GP ablation did produce significantly more major procedure-related adverse events (B), which occurred in 19% of patients in the GP ablation group versus 8% in the control group (p = 0.022).

A B

74 Chapter 3

from intrinsic cardiac innervation resulted in shortened regional refractory periods in dogs and an increased burden of AF or AT starting after 4 to 5 weeks.26

Thus, removing the inhibitory effect of the extrinsic on the intrinsic autonomous car-diac innervation causes proarrhythmic GP hyperactivity, which provides the rationale for GP ablation. Indeed, Katritsis et al.8 demonstrated fewer recurrences in patients with paroxysmal AF randomized to catheter ablation of 4 major GP areas and Marshall’s ligament in addition to PVI compared with either treatment in isolation. An anatomic approach to GP ablation conferred less AF recurrence than an evoked vagal response–based localization.27 These were catheter ablation studies, and it cannot be discerned whether these effects were caused by GP ablation or by more atrial myocardial abla-tion, resulting in more rigorous PVI.8 Observational thoracoscopic studies showed that GP ablation combined with PVI conferred a high rate of freedom from AF.16 However, in advanced AF, when electric, structural, and autonomic remodeling has occurred, GP ablation would be expected to be ineffective.28 Many minimally invasive studies reported observational evidence on procedures where PVI (with or without LA lines) was standardly combined with ablation of the GPs,16-19 but a systematic review found no benefit of GP ablation in this setting, which may relate to the advanced nature of AF in these patients and autonomic remodeling.29 Indeed, Mao et al.30 demonstrated that 8 weeks after GP ablation in dogs, APD was shorter than in sham-operated animals, and AF inducibility increased. In contrast, the acute effect of GP ablation results in APD prolongation and decreased AF inducibility but coincides with abundant reinnerva-tion of the atrium, which may promote AF inducibility. Such reinnervation might have contributed to our findings, supported by the observation that increased heart rate (on Holter monitoring) in the GP group was no longer present after 1 year. Similarly, there is abundant clinical evidence for structural and autonomic remodeling and increased non-PV triggers in advanced and long-standing AF.6,7,31

AFACT randomized patients with advanced AF, undergoing thoracoscopic surgery for AF. There was no difference in AF recurrence in the entire population or in subgroups with paroxysmal or persistent AF. It has been suggested that autonomic hyperactivity, occurring over the hierarchical gradient from the GP via the axonal field to the atrial neu-ral network, is responsible for this.32 Instead, we observed more major bleeding in the GP ablation group. Whereas these bleeds may not be caused directly by GP ablation, more rigorous surgical dissection in the patients randomized to GP ablation and the longer procedure time might have promoted bleeding. Indeed, several bleeds occurred during positioning of the ablation clamp around the right PVs, just after dissection and ablation of the anterior right and inferior right GP. Patients with major bleeding did not have larger LAs. Eight of 9 major bleeds could be managed thoracoscopically but resulted in termination of the procedure and resumption after weeks or in an inability to subsequently complete the ablation lines.

3


Furthermore, GP ablation more often resulted in conduction disorders requiring prolonged monitoring or isoprenaline therapy as well as pacemaker implantation in 6 patients (vs. 0 control subjects). As the procedural endpoint of GP ablation is not defined, and the absence of HFS-evoked vagal response merely shows the interruption of the trajectory between GP and end organs (i.e., sinus node or AV node), it can be questioned whether denervation was complete in the GP ablation group or, conversely, whether there was no inadvertent GP ablation during PVI or ablation of additional lines in the control group. We found that a residual HFS-evoked vagal response of at least 1 GP was present in 87% of control patients compared with 0% in the GP ablation patients. Moreover, there was an increase in heart rate in the GP group, reaching statistical signifi-cance after 6 and 9 months, but not in the control group. Finally, sinus node dysfunction occurred significantly more frequently in the GP group, as did pacemaker implantation, indicating that the autonomic modulation was indeed different among groups. The observation that recurrences constituted AT (as opposed to AF) more frequently in the GP groups might point to more inadvertent myocardial ablation during GP targeting, despite an epicardial approach.

AF recurrence was absent in 76.8% and 64.4% of patients with paroxysmal and per-sistent AF, respectively, without the use of AADs after a single thoracoscopic procedure. These were slightly higher recurrence rates than in our earlier study in less affected patients and higher than those reported for full maze surgery with cardiopulmonary bypass and biatrial ablation.16,33 An earlier systematic review reported 69% freedom from AF (without the use of AADs) after minimally invasive surgery.29 AFACT’s single-procedure surgical ablation results compared favourably with catheter ablation in this group of patients.3

Study limitationsThe optimal lesion set in this setting remains a matter of debate and might have af-fected outcomes in AFACT. Similarly, progression of the underlying disease might have contributed to AF recurrence.34 These hypotheses were not tested systematically, be-cause AFACT tested GP ablation on top of a systematic AF ablation protocol.

conclusIon

GP ablation on top of PVI and additional LA lines in patients with advanced AF did not reduce AF recurrence but resulted in more major procedural complications, in particular major bleeds and pacemaker implantations. Therefore, GP ablation should not be per-formed in these patients.

76 Chapter 3

AcknowledgeMents

The authors acknowledge Wim ter Smitte and Carel Kools for excellent technical assis-tance.

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3. Scherr D, Khairy P, Miyazaki S, et al. Five-year outcome of catheter ablation of persistent atrial fibrillation using termination of atrial fibrillation as a procedural endpoint. Circ Arrhythm Electro-physiol 2015;8:18-24.

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22. Edgerton JR, Jackman WM, Mack MJ. A new epicardial lesion set for minimal access left atrial maze: the Dallas lesion set. Ann Thorac Surg 2009;88:1655-7.

23. de Groot JR, Driessen AH, Van Boven WJ, et al. Epicardial confirmation of conduction block dur-ing thoracoscopic surgery for atrial fibrillation--a hybrid surgical-electrophysiological approach. Minim Invasive Ther Allied Technol 2012;21:293-301.


25. Po SS, Scherlag BJ, Yamanashi WS, et al. Experimental model for paroxysmal atrial fibrillation aris-ing at the pulmonary vein-atrial junctions. Heart Rhythm 2006;3:201-8.

26. Lo LW, Scherlag BJ, Chang HY, Lin YJ, Chen SA, Po SS. Paradoxical long-term proarrhythmic effects after ablating the “head station” ganglionated plexi of the vagal innervation to the heart. Heart Rhythm 2013;10:751-7.

27. Pokushalov E, Romanov A, Shugayev P, et al. Selective ganglionated plexi ablation for paroxysmal atrial fibrillation. Heart Rhythm 2009;6:1257-64.

28. Ausma J, Litjens N, Lenders MH, et al. Time course of atrial fibrillation-induced cellular structural remodeling in atria of the goat. J Mol Cell Cardiol 2001;33:2083-94.


30. Mao J, Yin X, Zhang Y, et al. Ablation of epicardial ganglionated plexi increases atrial vulnerability to arrhythmias in dogs. Circ Arrhythm Electrophysiol 2014;7:711-7.

31. Di Biase L, Burkhardt JD, Mohanty P, et al. Left atrial appendage: an underrecognized trigger site of atrial fibrillation. Circulation 2010;122:109-18.

32. Shen X, Scherlag BJ, He B, Sun J, Mei G, Po SS. The Role of the Atrial Neural Network In Atrial Fibrillation: The Metastatic Progression Hypothesis. J Atr Fibrillation 2013;6:882.

33. Weimar T, Schena S, Bailey MS, et al. The cox-maze procedure for lone atrial fibrillation: a single-center experience over 2 decades. Circ Arrhythm Electrophysiol 2012;5:8-14.

34. Kottkamp H. Human atrial fibrillation substrate: towards a specific fibrotic atrial cardiomyopathy. Eur Heart J 2013;34:2731-8.

3


onlIne AppendIx. InclusIon And exclusIon cRIteRIA

Patients could be included in the study if they agreed to undergo thoracoscopic abla-tion because of persistent AF, enlarged left atria (left atrial volume index (LAVI) >33 ml/m2, previously failed catheter ablation, or patient preference, and had failed at least 1 class Ic or III AAD, were 18 to 80 years old, and had a life expectancy ≥2 years.

Exclusion criteria were: unable or unwilling to take AADs; catheter ablation for AF within the preceding 4 months; myocardial infarction within the preceding 2 months; cerebrovascular accident (any sudden neurological deficit lasting ≥24 h, with or without pathological computed tomographic cerebrum) within the preceding 6 months; New York Heart Association (NYHA) III/IV heart failure, NYHA II or III/IV heart failure with recent hospitalization for decompensation (unless related to or aggravated by AF); left ventricular ejection fraction (LVEF) <35%; documented carotid stenosis >80%; planned cardiac surgery for other purposes than AF alone; active infection; pregnant or being of childbearing potential without adequate anticonception; requiring AADs for ventricular arrhythmias; documentation of an intracardiac mass or thrombus; being unable to un-dergo transesophageal echocardiography (TEE); previous thoracic radiation; comorbid conditions possessing undue risks for general anesthesia or thoracoscopic port access; or being unwilling/unable to adhere to the follow-up protocol.

Online figure 1.Anatomical localization of the major ganglion plexiThis posterior view of the left and right atrium displays the anatomical location of each major ganglion plexus (GP) and the ligament of Marshall (LOM). ARGP = anterior right GP; ILGP = inferior left GP; IRGP = inferior right GP; IVC = inferior caval vein; LIPV = left inferior PV; LSPV = left superior PV; PA = pulmonary artery; PV = pulmonary vein; RIPV = right inferior PV; RSPV = right superior PV; SLGP = superior left GP; SVC = superior caval vein.

Chapter 4Additional Ganglion Plexus Ablation During Thoracoscopic Surgical Ablation of Advanced Atrial Fibrillation: Intermediate Follow-up of the AFACT Study

Wouter R. Berger *Jolien Neefs *

Nicoline W.E. van den BergSébastien P.J. KrulElise M. van PraagFemke R. Piersma

Jonas S.S.G. de JongWim-Jan P. van BovenAntoine H.G. Driessen

Joris R. de Groot


JACC Clin Electrophysiol. 2019 Mar;5(3):343-353.

82 Chapter 4

AbstRAct

BackgroundThe AFACT study randomized patients with advanced atrial fibrillation (AF) to thoraco-scopic AF ablation with or without additional ganglion plexus (GP) ablation. At 1 year, there was no difference in AF freedom between the groups, but autonomic modification may exert beneficial effects during longer follow-up

MethodsPatients underwent thoracoscopic pulmonary vein isolation, with additional left atrial lines in persistent AF patients, and were randomized 1:1 to ablation of the 4 major GP and Marshall ligament or no GP ablation (control). Patients were followed every 3 months up to 18 months and at 24 months. After an initial 3-month blanking period, all antiarrhythmic drugs were discontinued.

ResultsThe authors randomized 240 patients (age 59 ± 8 years, 73% men, 68% enlarged left atrium, 60% persistent AF), of whom 228 patients (95%) completed follow-up. Freedom of any atrial tachyarrhythmia did not differ significantly between the GP group (55.6%) and control group (56.1%) (p = 0.91), with no difference in paroxysmal (p = 0.60) or persistent AF patients (p = 0.88). Documented AF recurrences were similar between treatment arms: 11.8% (GP) versus 11.0% (control) had >3 recurrences/year (p = 0.82). More persistent AF patients (17.0%) than paroxysmal (3.2%) had >3 recurrences per year (p < 0.01). Despite this, 78% of patients were off antiarrhythmic drugs after 2 years. No procedural-related complications occurred in the second year.

ConclusionsAdditional GP ablation during thoracoscopic surgery for advanced AF does not affect freedom of AF recurrence. As GP ablation is associated with more major procedural complications, it should not routinely be performed.

4

AFACT: 2-year follow up 83

IntRoductIon

Invasive treatment strategies with either catheter or (minimally invasive) surgical abla-tion are indicated in patients with symptomatic atrial fibrillation (AF), who have failed at least 1 trial of antiarrhythmic drug Class I or III.1 Pulmonary vein isolation (PVI) is the cornerstone in the invasive treatment of AF, but it may be insufficient for persistent or advanced AF (paroxysmal or persistent AF, with enlarged left atria or previously failed catheter ablation).2 However, the benefit of additional lesion sets remains a matter of debate, especially after the STAR-AF II (Substrate and Trigger Ablation for Reduction of Atrial Fibrillation Trial) showed that additional ablation lines do not affect success rates after ablation.3 Therefore, additional research is needed to elucidate the optimal AF ablation strategy, because an effective strategy reduces AF-related hospitalization, stroke, and mortality rates and increases quality of life.4,5

The autonomic nervous system has been shown to play a central role in the initiation and perpetuation of AF. More specifically, stimulation of the ganglion plexus (GP) induces rapid ectopic activity from the PV, a process that critically depends on vagally induced action potential shortening and sympathetically driven sarcoplasmic reticulum calcium release.6 Also, stimulation of the GP results in myocardial conduction slowing in addition to sinus arrest and atrioventricular block.7 Clinical evidence suggests that ablation of the GP adds to AF freedom and is more efficacious when based on anatomical landmarks than when based on high-frequency stimulation (HFS) of the atrial neurons.8,9 It has been demonstrated that in patients with paroxysmal AF, endocardial ablation of the GP when added to PVI resulted in higher rates of AF absence during follow-up.10 However, from that study, it seemed that the differential effect of additional GP ablation increased with longer follow-up. Also, whereas most evidence of GP ablation has been obtained in patients with paroxysmal AF, the role of GP ablation in modifying the arrhythmogenic substrate in patients with advanced AF is less clear, and autonomic modulation may actually be proarrhythmogenic in more diseased substrates.11,12

The AFACT (Atrial Fibrillation Ablation and Autonomic Modulation via Thoracoscopic Surgery) study was designed to investigate the role of ablation of the autonomic GP in addition to thoracoscopic ablation of advanced AF.13 The main results of the study were that additional GP ablation does not increase AF freedom at 1 year of follow-up. On the contrary, GP ablation was associated with significantly more sinus node dysfunction, pacemaker implantations, and peri-procedural bleeding. Despite this, it is unknown whether GP ablation exerts intermediate effects that may relate to the reinnervation of the atrium or the absence thereof.14,15 Therefore, we report the 2-year clinical outcome of efficacy and safety measures of additional GP ablation in the AFACT study.

84 Chapter 4

Methods

The AFACT study was a single-center, prospective, randomized trial comparing efficacy and safety of additional GP ablation to PVI and left atrial lines in patients with advanced paroxysmal or persistent AF undergoing thoracoscopic surgery for AF. The study was registered at clinicaltrials.gov (NCT01091389) and approved by the Institutional Review Board of the Academic Medical Center. All patients provided written informed consent. The inclusion and exclusion criteria as well as the main clinical results have been pub-lished previously.13 In brief, patients 18 to 80 years of age with advanced AF undergoing thoracoscopic surgical ablation were eligible for inclusion. Advanced AF was defined as paroxysmal or persistent AF, with enlarged left atria or previously failed catheter ablation. Main exclusion criteria were prior catheter ablation within the preceding 4 months, New York Heart Association class IV heart failure, a history of radiation therapy on the thorax, and long-standing persistent AF. All patients (N = 240) were subjected to bilateral thoracoscopic PVI (≥6 radiofrequency applications to the PV antrum with the AtriCure Isolator Synergy bipolar radiofrequency ablation clamp [Mason, Ohio]). In patients with persistent AF, additional left atrial ablation lines were performed conform-ing to the Dallas lesion set.16,17 The left atrial appendage was excised using a stapler device. At the time of opening of the pericardium, patients were randomized to either additional ablation of the 4 major GP and Marshall ligament (n = 117) or no additional GP ablation (control group, n = 123). Evoked vagal responses were tested before and after GP and left atrial ablation in all patients. GP were localized based on anatomical landmarks as well as based on HFS-evoked response. In both groups, HFS of the 4 major GPs was repeated after all ablation was complete to confirm the absence or presence of a vagal response. Additional GP ablation was applied when necessary. As described previously (13), this method resulted in an absence of HFS-evoked vagal response in 100% of patients in the GP group, whereas a residual vagal response could be provoked in at least 1 GP in 87% of control patients (p < 0.001).

Clinical follow-upThe efficacy and safety of GP ablation at 2-year follow-up was a pre-specified secondary endpoint of the AFACT study. Patients were followed for 2 years with outpatient visits, electrocardiograms (ECG) and 24-h Holter monitors at 3, 6, 9, 12, 15, 18, and 24 months. Patients were encouraged to obtain additional rhythm recording when symptomatic, and all recorded ECG and Holter data in referral hospitals were collected and included in the rhythm-monitoring analysis. AF recurrences were defined according to the defini-tion in the Heart Rhythm Society/European Heart Rhythm Association/European Cardiac Arrhythmia Society consensus document, as were any episode of AF, atrial tachycardia, or atrial flutter documented on ECG or on 24-h Holter lasting >30 s.2

4


A blanking period of 3 months after the procedure was instituted during which atrial tachyarrhythmia recurrences were not included in the clinical endpoints.1 After the blanking period, all antiarrhythmic drugs were discontinued, unless the patient remained to have AF. Anticoagulants were continued in all patients with a CHA2DS2-VASc (Congestive Heart Failure, Hypertension, Age ≥75 Years, Diabetes Mellitus, Prior Stroke or Transient Ischemic Attack or Thromboembolism, Vascular Disease, Age 65 to 74 Years, Sex) score ≥1 (unless solely based on female sex), irrespective of the (presumed) absence of AF or the exclusion of the left atrial appendage, and according to current guidelines.1 Procedural adverse events were defined as major when causing (prolonga-tion of ) hospital admission within 30 days.

The number of documented AF recurrences, paroxysmal and persistent, was assessed by the cumulative number of documented episodes of AF, atrial tachycardia, or atrial flutter documented on ECG or on 24-h Holter lasting >30 s per patient. Patients with an AF recurrence were categorized as: 1) a single AF recurrence; 2) some recurrences (1 to 3 episodes/year); or 3) many recurrences (>3 episodes/year or permanent AF) during follow-up. Recurrences requiring cardioversion or with spontaneous conversion were calculated similarly.

Statistical analysisRandomization methods and the power calculation have been published before.13 Patients who were lost to follow-up were censored at the latest outpatient clinic visit. Continuous values were expressed as mean ± SD. Categorical variables were expressed as numbers and percentages. The Mann-Whitney U test, Wilcoxon signed-rank test, and Student’s t-test were used for comparisons. For the primary endpoint, freedom of AF recurrence, event-free survival was plotted and estimated by Kaplan-Meier curves. Intention-to-treat and per-protocol analyses were both performed. Repeated measure-ment analysis with mixed analysis of variance was used to compare heart rates recorded with 24-hour Holter monitoring over time and paired Student’s t-test was used to compare heart rates at individual follow-up points with baseline heart rates. Clinical parameters associated with AF recurrence were studied using univariate and stepwise multivariate analysis in Cox proportional hazard models and expressed as hazard ratios (HRs) with corresponding 95% confidence intervals (CIs). A p value of <0.05 was consid-ered statistically significant. Statistical analysis was performed with SPSS version 23.0, (IBM, Armonk, New York) and R (version 3.2.1 for Windows, R Foundation for Statistical Computing, Vienna, Austria).

86 Chapter 4

Results

Study populationTwo-hundred-and-forty patients were randomized. Mean age at the time of the proce-dure was 59 ± 8 years, 73% were men, and mean left atrial volume index was 39 ± 12 ml/m2. Left atria were enlarged (>33 ml/m2) in 68% and severely enlarged (≥40 ml/m2) in 43% of patients. Fifty-six patients (23%) had 1 or more previous catheter ablations, and 143 patients (60%) had persistent AF. Baseline demographics are detailed in Table 1. In total, 228 patients (95%; GP ablation group n = 110; control group n = 118) completed follow-up. Two procedures were aborted (both in the GP ablation group), 4 patients died within the first year after the procedure (all in the GP ablation group, not procedure-related), and 6 patients were lost to follow-up at 2 years (1 in the GP ablation group, 5 in the control group).

Surgical procedure and complicationsProcedural characteristics have been described previously.13 In short, PVI was performed in all patients. In the GP group, HFS-evoked vagal response was absent in 100% of pa-tients, whereas residual vagal response could be provoked in 87% of patients without GP ablation (p < 0.001). Adverse events related to the procedure have also been pub-lished previously: clinically relevant sinus node dysfunction (12 vs. 4 patients; p = 0.038), procedural bleeding (9 vs. 0 patients; p < 0.001), and pacemaker implantation (6 vs. 0 patients; p = 0.013) were more frequent in patients allocated to GP ablation or control, respectively. Aside from those, no procedural-related complications occurred during the second year of follow-up.

AF recurrences and treatment allocationIn the intention-to-treat analysis, freedom of any atrial tachyarrhythmia lasting longer than 30 s was 55.6% and 56.1% in the GP and control groups, respectively, after 2 years (log rank p = 0.91) (Figure 1A). Similarly, the per-protocol analysis resulted in a freedom of atrial tachyarrhythmias of 54.5% and 54.2% in the GP and control groups, respectively (log rank p = 0.96). Similar to the entire cohort, GP ablation did not affect freedom from AF in patients with paroxysmal AF (AF freedom in 70.7% vs. 66.1%, respectively; log rank p = 0.60) (Figure 2A), nor in patients with persistent AF (AF freedom in 50.0% vs. 47.8%, respectively; log rank p = 0.88) (Figure 2B). Despite recurrences in some, 78% of patients were not using antiarrhythmic medication at 2 years.

Seventy-five patients (31.2%) had their first AF recurrence during the first year of follow-up, 35 patients (29.9%) in the GP group and 40 (32.5%) in the control group. In another 29 patients (12.1%), AF recurred first in the second year of follow-up after tho-racoscopic AF ablation, in 15 patients (12.2%) in the GP group and 14 patients (11.9%)

4


in the control group. The lack of efficacy of GP ablation was consistent across subgroup analysis based on age, sex, AF type (i.e., paroxysmal or persistent AF), indexed left atrial volume, AF duration, CHA2DS2-VASc score, and history of previous catheter ablation for AF (Figure 3).

Table 1. Baseline characteristics of patients undergoing ganglion plexus ablation and control subjects.

No GP ablation(n=123)

GP ablation(n=117)

Baseline

Age (mean±SD) 60.2±8.2 59.5±8.2

Male gender (n, %) 91 (74) 84 (72)

BMI, (mean±SD) 27.1±3.5 27.6±4.3

Left Atrial Diameter (mm, mean±SD) 42.3±5.5 42.1±5.6

LAVI (ml/m2, mean±SD) 40.3±13.0 38.3±10.4

LVEF (%, mean±SD) 51.2±9.1 47.9±18

Previous catheter PVI, (n, %) 30 (24) 26 (22)

Myocardial infarction, (n, %) 8 (7) 3 (3)

Previous PCI, (n, %) 14 (11) 15 (13)

AF Characteristics

AF duration (years), median [IQR] 5 [2-10] 4 [2-6]

Paroxysmal AF, (n, %) 56 (46) 41 (35)

Persistent AF, (n, %) 67 (55) 76 (66)

CHA2DS2VASc (mean±SD, (range)) 1.4±1.3 (0-7) 1.4±1.2 (0-6)

CHA2DS2VASc 0, (n, %) 34 (28) 33 (28)

CHA2DS2VASc 1, (n, %) 38 (31) 38 (33)

CHA2DS2VASc ≥ 2, (n, %) 51 (41) 46 (39)

Congestive heart failure, (n, %) 5 (4) 7 (6)

Hypertension, (n, %) 55 (44) 49 (41)

Diabetes, (n, %) 8 (7) 8 (7)

Stroke/TIA/Embolus, (n, %) 10 (8) 9 (8)

Vascular disease, (n, %) 15 (11) 10 (9)

Female gender, (n, %) 32 (27) 33 (28)

Age ≥ 65, years, (n, %) 37 (29) 31 (27)

Age ≥ 75 years, (n, %) 1 (1) 1 (1)

Values are mean ± SD, n (%), median (interquartile range), or mean ± SD (range).AF, atrial fibrillation; BMI, body mass index; CHA2DS2VASc, congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism, vascular disease, age 65-74 years, sex; GP, ganglion plexus; LAVI, left atrial volume index; LVEF, left ventricle ejection fraction; PCI, percutaneous coronary intervention; PVI, pulmonary vein isolation; TIA, transient ischemic attack.

88 Chapter 4

Type of atrial tachyarrhythmia recurrenceDuring 2-year follow-up, 104 patients had atrial tachyarrhythmia recurrences, of which 53 (51%) were atrial tachycardia (AT) and 51 (49%) were AF recurrences (p = 0.85). In the GP group, numerically more recurrences of AT (n = 30) than AF (n = 20) occurred (p = 0.16), whereas there was a trend toward the opposite relation in the control group, AT (n = 23) versus AF (n = 31; p = 0.28).

During the second year of follow-up, there were 9 AT compared with 6 AF recurrences in the GP group (p = 0.44). In the control group, more AT (n = 10) than AF (n = 4) recur-rences were documented, although they were not significantly different (p = 0.11).

0 6 12 18 240

20

40

60

80

100


Free

dom

of A

F R

ecur

renc

e (%

)


Log Rank p=0.91

No. at riskNo GP ablation 123 103 80 73 54 GP ablation 117 95 78 69 55

GP ablation no GP ablation

Patie

nts

(%)

0

20

40

60

80

100

54.5

62.7

88.2

54.2

63.5

88.9

No AF reccurence<1 AF reccurence / year1-3 AF reccurences / year>3 AF reccurences / year

Figure 1.Freedom of AF recurrence and AF burden by randomization(A) Freedom of atrial fibrillation (AF) recurrences (percentage) in the ganglion plexus (GP) ablation and control group of the total cohort. (B) AF burden following thoracoscopic ablation of advanced AF with and without additional GP ablation.

0 6 12 18 240

20

40

60

80

100Paroxysmal AF


Free

dom

of A

F R

ecur

renc

e (%

)

Log Rank p=0.60


No. at riskNo GP ablation 56 51 42 38 29 GP ablation 41 38 32 28 24

0 6 12 18 240

20

40

60

80

100Persistent AF


Free

dom

of A

F R

ecur

renc

e (%

) Log Rank p=0.88

No. at riskNo GP ablation 67 52 38 35 25GP ablation 76 57 46 38 31


Figure 2.Freedom of AF recurrence in paroxysmal or persistent AFFreedom of AF recurrences (percentages) in the GP ablation and control groups in paroxysmal (A) or persis-tent (B) AF patients. Abbreviations as in Figure 1.

A B

A B

4


Documented atrial tachyarrhythmia recurrencesThe number of documented AF recurrence after thoracoscopic surgical AF ablation is displayed in Figure 1B. After 2 years, 11.4% of the total study population had >3 AF recurrences per year or permanent AF, 11.8% in the GP group versus 11.0% in the control group (p = 0.82). This was mainly driven by patients with persistent AF, of whom 17.0%

SubgroupSubgroupSubgroupSubgroup

All

Age

<60 yr

>60 yr

Sex

Male

Female

AF type

Paroxysmal

Persistent

LA volume index

<33 ml/m2

34−40 ml/m2

>40 ml/m2

AF Duration

<5 yr

>5 yr

CHA2DS2−VASC−score

0

1

2

>2

History of PVI

Yes

No

Hazard Ratio (95% CI)

1.02

0.78

1.34

0.99

1.09

0.83

1.02

1.21

0.82

1.04

1.24

0.74

0.43

1.17

1.55

1.32

1.21

1.00

[0.70−1.50]

[0.43−1.44]

[0.82−2.18]

[0.62−1.57]

[0.56−2.11]

[0.40−1.70]

[0.64−1.60]

[0.54−2.69]

[0.37−1.83]

[0.61−1.78]

[0.75−2.03]

[0.40−1.40]

[0.18−1.08]

[0.63−2.20]

[0.71−3.37]

[0.54−3.19]

[0.59−2.49]

[0.64−1.56]

P−value

0.91

0.44

0.25

0.96

0.81

0.60

0.95

0.65

0.63

0.88

0.40

0.36

0.07

0.62

0.27

0.54

0.60

0.99

0 0.5 1 1.5 2 2.5 3

Favors No GP ablation Favors GP ablation

240

121

119

175

65

97

143

72

60

103

146

94

67

75

60

38

56

183

No. of Patients

Figure 3.HR of AF recurrencesSubgroup analysis of hazard ratio (HR) (95% confidence interval [CI]) of AF recurrence. CHA2DS2VASc, con-gestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient ischemic at-tack or thromboembolism, vascular disease, age 65-74 years, sex; LA, left atrial; pulmonary vein isolation; other abbreviations as in Figure 1.

90 Chapter 4

had >3 AF recurrences or permanent AF, 14.1% in the GP group versus 20.3% in the con-trol group (p = 0.32) (Figure 4A). More than 3 AF recurrences or permanent AF occurred in 3.2% of patients with paroxysmal AF at randomization, 7.7% in the GP group versus 0% in the control group (p = 0.02) (Figure 4B). The percentage of patients with a single or some recurrences was similar in both treatment groups (p = 0.73). The recurrences were mostly recorded on ECG (65.4%), which included ECG during standard follow-up (28.9%) and indicated by symptoms (71.1%), whereas in 34.6%, the recurrences were recorded by Holter monitoring.

Predictors of AF recurrenceFigure 5 shows the univariate and multivariate analysis of clinical determinants of AF recurrence, regardless of randomization. AF type (i.e., paroxysmal or persistent AF) at the time of surgery was independently associated with AF recurrence (HR: 1.44; 95% CI: 1.12 to 2.67; p = 0.01). Also, left atrial volume index (classified as <33 ml/m2, 34 to 40 ml/m2 or >40 ml/m2) was independently associated with AF recurrence (HR: 1.28; 95%: 1.00 to 1.64; p = 0.04). Age, history of previous PVI and CHA2DS2-VASc scores were associated with AF recurrence in univariate analysis, but this association did not hold in multivariate analysis.

Effect of GP ablation on heart rateIn a repeated measurement analysis, the mean heart increased significantly over time (F [4.39, 487.50] = 2.46, p=0.04). There was no interaction between the change in heart rate over time and randomization group (p = 0.61). Also, the maximum and minimum heart rate changed significantly over time (F4.83, 564.95 = 12.47, p < 0.01 and F5.22,


Patie

nts

(%)

0

20

40

60

80

100

69.2

74.3

92.2

100

79.6

64.8

Paroxysmal AF



Patie

nts

(%)

0

20

40

60

80

100

46.5

56.4

86.0

45.3

50.0

79.7

Persistent AF


Figure 4.AF recurrences in GP and control groupsNumber of documented AF recurrences in the GP ablation and control groups in patients with paroxysmal (A) or persistent (B) AF. Abbreviations as in Figure 1.

A B

4


615.58 = 35.00, p < 0.01, respectively), independent of randomization (p = 0.88 and p = 0.46, respectively).

At individual follow-up points, only at the 9-month follow-up was the mean heart rate significantly higher in the GP ablation group (76.0 ± 12.4 vs. 79.5 ± 10.3 in the control group, p = 0.04) (Table 2). Meanwhile, the minimal heart rate at individual follow-up points was numerically higher in the GP group, although this was only significant at 9-month follow-up (59.0 ± 9.3 vs. 56.0 ± 10.9 in the control group, p = 0.04) (Table 2). Maximally achieved heart rate was similar between the GP and control groups at all follow-up points.

Table 3 displays the change of heart rate at individual follow-up points compared with baseline in a paired analysis. In the GP ablation group, mean heart rate was significantly

Univariate

Age (years)

Gender (female)

AF Type (persistent)

Ganglion Plexus Ablation

AF Duration (years)

Left Atrial Volume Index (ml/m2)

Left Ventricular Ejection Fraction (%)

History of PVI

BMI (kg/m2)

Hypertension

Diabetes Mellitus


Multivariate

Age (years)

AF Type (persistent)

LA Volume Index (ml/m2)

History of PVI


HR

1.35

1.34

1.98

1.02

0.97

1.38

0.99

1.34

1.20

1.21

1.27

1.19

1.20

1.72

1.28

1.44

1.08

95% CI

[1.08−1.69]

[0.89−2.01]

[1.30−3.01]

[0.70−1.50]

[0.66−1.44]

[1.10−1.75]

[0.83−1.16]

[0.88−2.05]

[0.79−1.82]

[0.83−1.78]

[0.59−2.74]

[1.03−1.37]

[0.93−1.55]

[1.12−2.67]

[1.00−1.64]

[0.92−2.23]

[0.91−1.29]

P−value

<0.01

0.16

<0.01

0.91

0.89

<0.01

0.86

0.18

0.40

0.39

0.54

0.02

0.17

0.01

0.04

0.11

0.36

0 0.5 1 1.5 2 2.5 3Hazard Ratio

Figure 5.Cox regression analyses of risk of AF recurrenceUnivariate and multivariate Cox regression analyses of clinical determinants of risk of AF recurrence regard-less of randomization. BMI = body mass index, other abbreviations as in Figures 1 and 3.

92 Chapter 4

higher compared with baseline rate at 6 and 9 months (both p < 0.01). These differences did not persist over the duration of the follow-up. In the control group, there was no significant difference in mean heart rate at follow-up points compared with baseline rate. However, the minimum heart rate increased in both groups, and at the same time, the maximum heart rate decreased significantly.

Table 2. Mean, minimum and maximum heart rate (beats per minute) recorded with 24-holter monitoring in patients undergoing ganglion plexus (GP) ablation and controls.

Baseline 3-monthFU

6-monthFU

9-monthFU

12-monthFU

15-monthFU

18-monthFU

24-monthFU

Mean Heart Rate

No GP ablation 74.4±17.7 74.0±16.4 77.7±12.9 76.0±12.4 75.1±11.3 74.8±12.0 74.2±11.3 73.2±12.6

GP ablation 72.8±17.8 75.0±10.3 80.1±11.8 79.5±10.3 75.3±11.1 78.0±15.3 76.8±10.3 74.7±10.9

p-value 0.54 0.60 0.18 0.04 0.91 0.10 0.09 0.37

Minimum Heart Rate

No GP ablation 46.9±11.4 55.5±9.6 56.9±9.8 56.0±10.9 54.8±9.9 54.4±9.2 54.8±9.3 53.5±10.1

GP ablation 45.3±7.9 57.5±8.4 59.6±8.6 59.0±9.3 57.0±12.4 56.7±8.6 57.3±7.9 55.9±8.1

p-value 0.25 0.11 0.05 0.04 0.19 0.09 0.05 0.07

Maximum Heart Rate

No GP ablation 137.0±40.9 108.7±25.8 118.7±24.8 122.0±28.4 122.6±26.4 117.3±22.2 119.0±22.1 116.3±25.2

GP ablation 131.1±35.6 111.4±25.9 118.9±20.7 122.5±21.9 119.6±25.1 117.2±27.3 117.9±21.9 121.1±23.2

p-value 0.31 0.46 0.95 0.89 0.44 0.98 0.74 0.16

Values are mean ± SD.FU, follow-up; GP, ganglion plexus.

4


dIscussIon

The AFACT study was the first randomized study investigating the benefit of additional GP ablation in patients with advanced AF undergoing thoracoscopic surgery.13 Here we present the intermediate-term efficacy and safety outcomes.

AF recurrence by treatment allocationSimilar to the results of the main publication at 1 year, additional GP ablation does not reduce AF recurrences during 2 years of follow-up. This is regardless of AF type at randomization, although patients with paroxysmal AF had fewer AF recurrences than patients with persistent AF did. This is in contrast to earlier studies on GP ablation in addition to PVI, which concluded that the treatment effects increase over time.10,18 It has been suggested that heterogeneity of patient characteristics within our study, for example, inclusion of both patients with paroxysmal AF and persistent AF, and patients with prior catheter ablation might have caused a neutral effect at 1 year of follow-up,

Table 3. Change of heart rate (beats/minute) during follow-up compared with baseline in GP ablation patients and control subjects.

Mean Heart Rate Minimum Heart Rate Maximum Heart Rate

Change vsbaseline

p Change vs baseline

p Change vsbaseline

p

No GP ablation

3 months 2.0 (-12.5 – 12.0) 0.71 8.0 (3.0 – 14.0) <0.01 -16.5 (-57.8 – 1.0) <0.01

6 months 4.0 (-10.5 – 16.5) 0.07 11.0 (4.0 – 18.5) <0.01 -12.0 (-59.0 – 10.5) <0.01

9 months 5.0 (-9.0 – 14.0) 0.35 8.5 (2.0 – 17.0) <0.01 -6.5 (-54.5 – 20.0) <0.01

12 months 5.0 (-8.3 – 14.0) 0.54 9.0 (2.0 – 15.0) <0.01 -3.0 (-51.3 – 20.8) <0.01

15 months 2.0 (-10.8 – 14.0) 0.93 8.0 (3.0 – 14.3) <0.01 -5.0 (-58.3 – 13.2) <0.01

18 months 4.0 (-9.0 – 12.3) 0.97 9.0 (0.0 – 14.0) <0.01 -11.5 (-56.8 – 17.0) <0.01

24 months 1.0 (-10.5 – 11.0) 0.41 7.0 (0.0 – 14.0) <0.01 -7.0 (-53.3 – 13.3) <0.01

GP ablation

3 months 6.0 (-11.0 – 16.0) 0.31 14.0 (7.0 – 18.3) <0.01 -17.0 (-50.0 – 5.0) <0.01

6 months 7.0 (-8.5 – 20.8) <0.01 15.0 (7.5 – 22.5) <0.01 -18.0 (-41.8 – 16.0) <0.01

9 months 10.0 (-7.0 – 21.0) <0.01 12.0 (7.5 – 22.5) <0.01 -5.0 (-39.0 – 19.0) 0.07

12 months 5.0 (-10.0 – 14.0) 0.63 10.0 (4.0 – 19.0) <0.01 -18.5 (-46.0 – 13.0) <0.01

15 months 7.0 (-9.5 – 17.5) 0.29 10.0 (3.5 – 19.0) <0.01 -11.5 (-43.8 – 16.5) <0.01

18 months 6.0 (-9.0 – 17.0) 0.23 13.0 (5.5 – 19.0) <0.01 -14.5 (-43.0 – 17.8) 0.01

24 months 6.0 (-10.5 – 15.3) 0.43 12.0 (5.0 – 18.0) <0.01 -4.0 (-41.0 – 20.0) 0.03

Values are median (interquartile range).GP, ganglion plexus.

94 Chapter 4

which plausibly could be different at longer follow-up.19 Nevertheless, our results dem-onstrate no difference in AF recurrence during longer follow-up. Also, subgroup analysis did not reveal a subpopulation with potential beneficial (or detrimental) effect of GP ablation on AF.

Importantly, the thoracoscopic approach toward GP ablation differs from catheter techniques, as it reaches to the GP from the epicardium. This may allow for better lo-calization and exposure of GP when compared with endocardial catheter ablation. In the latter approach, theGP cannot be ablated without concomitantly ablating the myocardium in between the endocardial catheter and the epicardially located GP. It can-not be excluded that the better outcome of additional GP ablation reported by Katritsis et al.10 is partially the consequence of more thorough PVI, as total ablation time was indeed significantly longer in the GP + PVI group. In the present study, both anatomic landmarks (i.e., epicardial fat pads) and HFS were used to localize the GP. All ablation lines and efficacy of GP ablation were thoroughly confirmed using entry and exit block, differential pacing, and repeat HFS of the areas of the GP, as previously described.20 After GP ablation, HFS-evoked vagal response was indeed absent in 100% of the patients. In patients not allocated to GP ablation, a vagal response could still be evoked in 87% of patients (p < 0.001).

The lack of efficacy of GP ablation may also be due to a more progressed AF substrate. Patients included in the present study had advanced AF and their arrhythmogenic substrates may have been different to those in patients with paroxysmal AF in whom a benefit of additional GP ablation was demonstrated earlier.10 In patients with advanced AF, progressed atrial remodeling may even be associated with a proarrhythmogenic ef-fect when subjected to GP ablation. 11,12 It is similarly likely that autonomic modification adds little in already progressed autonomic, electrical, and structural remodeling of the atrium. Furthermore, PVI itself may block the possibility for the GP to trigger the PV firing and therefore reduces the risk for AF in both study groups.21

Number of documented AF recurrencesWe report that the number of documented AF recurrences, measured as number of AF recurrences per year, was generally low and similar between patients who underwent additional GP ablation compared with the control subjects. This is consistent with an earlier report on long-term outcome of thoracoscopic ablation in advanced AF.22 A substantial part of the patients in whom thoracoscopic ablation was unsuccessful ac-cording to the consensus criteria of outcome definition, had fewer than 1 documented episode per year (i.e., only 1 episode in total) of recurrent AF at 2-year follow-up. Of note, we did not quantify the number of documented AF episodes before the intervention, because such an analysis would require estimation of days in AF rather than the number of episodes. Furthermore, we did not perform continuous monitoring during follow-up,

4


but collected all rhythm recordings that were performed in a comprehensive follow-up. In addition, we collected all recordings performed during visits because of symptoms, while realizing that short, asymptomatic AF episodes may have been missed using this method. Whereas all patients were highly symptomatic before thoracoscopic surgery, merely 11% of the patients remained to have frequent, symptomatic, recurrences after treatment. It can be advocated that, reporting a measure of AF burden is clinically more meaningful than a Kaplan-Meier representation of the results, as advocated by the Heart Rhythm Society/European Heart Rhythm Association/European Cardiac Arrhythmia Society consensus document.2 Indeed, assigning the same weight to a single episode of 31 s, as to the development of permanent AF, underestimates the clinical impact AF recurrences may have. Aside from that, the main indication for invasive treatment of AF is formed by reducing AF-related symptoms. We have previously shown in the same cohort that patients with a single recurrence of AF have the same improvement in qual-ity of life as patients without a recurrence, whereas multiple recurrences are associated with lack of quality of life improvement.22 The clinical implication of a single or few AF recurrences is further underscored by the observation that a high percentage, 78%, of patients had discontinued antiarrhythmic drugs at 2 years of follow-up.

Importantly, as there is no consequence for the discontinuation of anticoagulation in patients with a presumed successful ablation, health-related quality of life and medica-tion use are relevant clinical outcomes.

Role of additional left atrial lesionsAF recurrences were more prevalent in patients with persistent AF at randomization than in those with paroxysmal AF. This may be due to a more progressed substrate, but also the ablation strategy was different. Patients with paroxysmal AF were treated with epicardial PVI alone, whereas a roof (superior) line and trigone line were ablated in patients with persistent AF. Conduction block across these lines was confirmed with pacing manoeuvres, but evidently acute block does not per se predict persistence of conduction block over time. Also, there were patients with confirmed lack of conduc-tion block due to anatomical restrictions. Aside from that, there remains discussion on the optimal ablation strategy in persistent AF patients, as STAR-AF II demonstrated that additional ablation of GP, complex fractionate atrial electrograms, or left atrial lines was not associated with better outcome than PVI alone.3 Also, it has been demonstrated that more lines are associated with a higher chance of reconnection along any of those lines.23 Hence, the optimal lesion set in these patients remains to be determined.

Evidence for autonomic modification during intermediate-term follow-upIt has been suggested that parasympathetic denervation may recover due to atrial neu-ral resprouting and hyper reinnervation. 8,24 This has been demonstrated in humans and

96 Chapter 4

confirmed by imaging.25 We did not test for reinnervation during follow-up; however, we found similar heart rates at 1 and 2 years in both groups, after an initial significantly increased heart rate in the GP group at 6 and 9 months. This suggests that the effect of GP ablation is diminished on the long term, which may point at reinnervation of the GP or other adaptive mechanisms. Contrary to that observation, minimum heart rate was numerically, but not significantly higher, in the GP group during the complete follow-up, which also holds for the control group. Furthermore, the decrease in maximum heart rate was less in the GP ablation group than in the control group.

Of note, the changes in heart rate may also be in part due to the discontinuation of antiarrhythmic medication, including beta-blockers from 3 months of follow-up onward in both groups.

Procedure-related complicationsIn addition to the previously published procedural complications, no further adverse effects that could be attributed to the procedure or strategy were encountered during the second year of follow-up. However, during the first year, GP ablation was associated with more major complications (19% vs. 8%).13

Study limitationsThe number of documented episodes of AF recurrences was assessed, but the study protocol did not include continuous rhythm monitoring. Hence, the actual AF burden may have been underestimated, most importantly with regard to asymptomatic epi-sodes of AF. However, serial rhythm monitoring by at least 7 24-h Holter monitors was conducted as demanded in the study. The chosen approach did allow for a symptom-driven calculation of the AF burden, as well as an estimation of asymptomatic episodes, as 53.4% of recurrent AF episodes were captured on standardly performed ECG or Holter monitoring. Of note, the amount and duration of rhythm monitoring used in the present study comprises a comprehensive follow-up, beyond what the guidelines recommend following AF surgery.2

Next, it was not possible to assess burden of AF at baseline, because that would have required a strategy of determining the days in AF to avoid a single episode of AF of minutes-long duration being counted similarly as an ongoing episode for months. This made a definite comparison of AF burden before and after surgery impossible.

conclusIons

GP ablation added to PVI and left atrial lines during thoracoscopic AF surgery does not affect 2-year freedom of AF recurrence. Documented AF recurrences during 2 years of

4


follow-up were very modest (maximum of 3 AF recurrences per year) in almost 90% of patients and were not different among patients with or without GP ablation. The increased heart rate induced by GP ablation normalized after more than 9 months of follow-up. Major procedural complications occurred more frequently in patients as-signed to GP ablation, but there were no further complications during follow-up. Hence, and in the absence of benefit, ablation of the GP should not routinely be performed.

98 Chapter 4

RefeRences 1. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrilla-

tion developed in collaboration with EACTS. European heart journal 2016;37:2893-962. 2. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus

statement on catheter and surgical ablation of atrial fibrillation: Executive summary. Europace 2018;20:157-208.


4. Srivatsa UN, Danielsen B, Amsterdam EA, et al. CAABL-AF (California Study of Ablation for Atrial Fibrillation): Mortality and Stroke, 2005 to 2013. Circulation Arrhythmia and electrophysiology 2018;11:e005739.

5. Wokhlu A, Monahan KH, Hodge DO, et al. Long-term quality of life after ablation of atrial fibril-lation the impact of recurrence, symptom relief, and placebo effect. Journal of the American College of Cardiology 2010;55:2308-16.

6. 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.

7. Krul SP, Meijborg VM, Berger WR, et al. Disparate response of high-frequency ganglionic plexus stimulation on sinus node function and atrial propagation in patients with atrial fibrillation. Heart rhythm 2014;11:1743-51.

8. Pokushalov E, Romanov A, Shugayev P, et al. Selective ganglionated plexi ablation for paroxysmal atrial fibrillation. Heart rhythm 2009;6:1257-64.

9. Pokushalov E, Romanov A, Artyomenko S, Turov A, Shirokova N, Katritsis DG. Left atrial ablation at the anatomic areas of ganglionated plexi for paroxysmal atrial fibrillation. Pacing Clin Electro-physiol 2010;33:1231-8.


11. Lo LW, Scherlag BJ, Chang HY, Lin YJ, Chen SA, Po SS. Paradoxical long-term proarrhythmic effects after ablating the “head station” ganglionated plexi of the vagal innervation to the heart. Heart rhythm 2013;10:751-7.

12. Ausma J, Litjens N, Lenders MH, et al. Time course of atrial fibrillation-induced cellular structural remodeling in atria of the goat. J Mol Cell Cardiol 2001;33:2083-94.

13. Driessen AHG, Berger WR, Krul SPJ, et al. Ganglion Plexus Ablation in Advanced Atrial Fibrillation: The AFACT Study. Journal of the American College of Cardiology 2016;68:1155-65.

14. Sakamoto S, Schuessler RB, Lee AM, Aziz A, Lall SC, Damiano RJ, Jr. Vagal denervation and rein-nervation after ablation of ganglionated plexi. The Journal of thoracic and cardiovascular surgery 2010;139:444-52.

15. Oh S, Zhang Y, Bibevski S, Marrouche NF, Natale A, Mazgalev TN. Vagal denervation and atrial fibrillation inducibility: epicardial fat pad ablation does not have long-term effects. Heart rhythm 2006;3:701-8.



4


18. Pokushalov 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 fibril-lation: a randomized comparison. Heart rhythm 2013;10:1280-6.

19. Michaud GF, Kumar S. Surgical Ganglionic Plexus Ablation in Atrial Fibrillation: Is All Hope Lost for the Plexus? Journal of the American College of Cardiology 2016;68:1166-8.


21. Jiang RH, Jiang CY, Sheng X, et al. Marked suppression of pulmonary vein firing after circumfer-ential pulmonary vein isolation in patients with paroxysmal atrial fibrillation: is pulmonary vein firing an epiphenomenon? Journal of cardiovascular electrophysiology 2014;25:111-8.

22. Driessen AHG, Berger WR, Bierhuizen MFA, et al. Quality of life improves after thoracoscopic surgical ablation of advanced atrial fibrillation: Results of the Atrial Fibrillation Ablation and Autonomic Modulation via Thoracoscopic Surgery (AFACT) study. The Journal of thoracic and cardiovascular surgery 2018;155:972-80.

23. Mun HS, Joung B, Shim J, et al. Does additional linear ablation after circumferential pulmonary vein isolation improve clinical outcome in patients with paroxysmal atrial fibrillation? Prospective randomised study. Heart 2012;98:480-4.

24. Wang X, Zhang M, Zhang Y, et al. Long-Term Effects of Ganglionated Plexi Ablation on Electro-physiological Characteristics and Neuron Remodeling in Target Atrial Tissues in a Canine Model. Circulation Arrhythmia and electrophysiology 2015;8:1276-83.

25. Buckley U, Rajendran PS, Shivkumar K. Ganglionated plexus ablation for atrial fibrillation: Just because we can, does that mean we should? Heart rhythm 2017;14:133-4.

Chapter 5Electrophysiologically Guided Thoracoscopic Surgery for Advanced Atrial Fibrillation: 5-Year Follow-up

Antoine H.G. Driessen *Wouter R. Berger *

Dean R.P.P. Chan Pin YinFemke R. Piersma

Jolien NeefsNicoline W.E. van den Berg

Sébastien P.J. KrulWim Jan P. van Boven

Joris R. de Groot


Published as letter. Article in full in manuscript

J Am Coll Cardiol. 2017 Apr 4;69(13):1753-1754

102 Chapter 5

AbstRAct

BackgroundElectrophysiologically guided, thoracoscopic surgery may be employed to treat patients with advanced symptomatic atrial fibrillation (AF), usually with severely enlarged left atria or long AF duration, previous ablation and refractory to antiarrhythmic drugs (AAD). Data on efficacy of this procedure during long term follow-up is lacking. We therefore assessed AF freedom at 5 years in consecutive patients with advanced paroxysmal or persistent AF following a single thoracoscopic procedure.

MethodsPatients were followed-up prospectively with ECGs and 24-hour Holter monitoring every 3 months, and when symptoms were reported, for 2 years after the procedure. All patients were invited for a follow-up visit after 5 years. Additionally, all medical charts, clinical data, all ECGs and Holters from referring hospitals, obtained during the entire follow-up, were reviewed.

ResultsSixty-six consecutive patients (49 men, mean age 57±8 years, mean left atrial volume index 36±12 ml/m2) underwent thoracoscopic surgery for paroxysmal (n=33) or persis-tent advanced AF (n=33) between 2008 and 2010. ECG and clinical data were complete in all. Fifty-eight patients (88%) attended the 5-year visit after 66 (60-82) months. Of all patients (n=66), 33 (50%) were free of AF recurrence, without AAD. Seventy-four percent of patients had no or <1 AF recurrence/year, 91% had no or <3 recurrences. More than 3 AF recurrences/year or permanent AF was documented in 9% of all patients; 6% in paroxysmal and 12 % in persistent AF. At 5 years, 88% of patients had sinus rhythm, 30% were prescribed AAD.

ConclusionsThoracoscopic surgery for advanced AF is associated with complete absence of AF, without AAD use, in 50% of patients after a single surgical procedure at 5 years. At that time 88% of patients had sinus rhythm and 70% discontinued AAD. Only 9% of patients had frequent AF recurrences or permanent AF.

5

5-year follow up of thoracoscopic ablation for AF 103

IntRoductIon

Atrial fibrillation (AF) affects 30 million subjects worldwide and its incidence and prevalence of AF are expected to double over the forthcoming decades.1,2 Many patients suffer from AF symptoms. Therefore, after the unsuccessful trial of at least one class 1 or class 3 antiarrhythmic drug (AAD), symptomatic patients may qualify for catheter or surgical ablation.3 The seminal discovery that AF is often triggered from the pulmonary veins resulted in a plethora of ablation approaches aiming at isolating the pulmonary veins from the left atrium.4 Whereas catheter ablation is increasingly being employed worldwide, the surgical Cox-Maze procedure, reported to have highly successful out-comes, was never adopted on a large scale due to its surgical complexity, invasiveness and associated morbidity and even mortality, and the available evidence is derived from a few expert centers.5,6

Thoracoscopic surgical approaches have been developed to combine the reported ef-ficacy of the Cox-Maze procedure with a less invasive approach.7,8 One randomized study comparing thoracoscopic ablation with catheter ablation in patients with recurrent AF after previous ablation, enlarged left atrium with or without hypertension demonstrated absence of AF after one year in 36.5 and 65.6% of patients undergoing catheter and surgical ablation respectively, at the cost of more peri-procedural complications with surgery.9 Endocardial and epicardial hybrid approaches, where the surgeon is guided by electrophysiological confirmation of ablation lesions, seem to yield higher rates of absence of AF (79% after one year in a retrospective study) than thoracoscopic surgery alone, without increasing the rates of peri-procedural complications.8,10,11

Procedural complications associated with catheter ablation of AF, albeit fewer than with surgery, occur in 6.4%, more frequently than generally assumed.12 Using variable definitions and variable follow-up periods, a meta-analysis showed absence of AF after a single catheter procedure in 57% of patients after a median follow-up of 9 months.13 However, this number may be lower in real life.14 Despite the increasing global uptake of catheter ablation as a primary invasive therapy of atrial fibrillation, longer-term follow-up data is limited and the results are very modest at best. The most experienced centers report freedom of AF after a single procedure of 29% in patients with mainly paroxysmal AF and normally sized left atria after 5 years.15 After up to 7 procedures, this number increased to 63%. Similarly, the group in Hamburg shows freedom of AF of 47% in paroxysmal and 20% in persistent AF after a single procedure, whereas after multiple procedures 79% and 45% were free from AF respectively after a 5-year follow-up period, with approximately 25% of patients continuing anti-arrhythmic medication.16,17

Currently, data on long-term follow-up of patients undergoing thoracoscopic surgery for AF are not available. We investigated the single surgical procedure efficacy of totally thoracoscopic, electrophysiologically guided, surgery for patients with advanced AF,

104 Chapter 5

that is, usually persistent, with severely enlarged left atria or long AF duration, after 5 years of follow-up.

Methods

All patients with paroxysmal, persistent or longstanding persistent AF who underwent thoracoscopic surgery for AF at our center between 2008 and the end of 2010 were included. Persistent and longstanding persistent AF were combined for this analysis and reported as persistent AF. All patients had symptomatic AF, refractory or intolerant to at least one class I or III AAD. All patients consented to the surgical procedure. The cur-rent study and follow-up after 5 years conformed to the Declaration of Helsinki and was approved by the Institutional Review Board of the Academic Medical Center. All study subjects provided written informed consent.

Surgical ProcedureThe surgical procedure has been described previously.8 In short, after deflation of the right lung, a videoscope and surgical instruments were introduced through 3 trocars. The pericardium was opened. Entry and exit block of the right pulmonary veins were tested using a custom made epicardial mapping electrode, before and after ablation with the AtriCure IsolatorR Synergy™ bipolar RF ablation clamp.18 At least 6 RF applica-tions were delivered. The four main Ganglion Plexus (GP) were localized as described previously8 and were subsequently ablated. Patients included in the prospective AFACT study were per protocol randomized to GP ablation or no GP ablation.19 After closing the pericardium, the procedure was repeated on the left side.

All patients were treated with pulmonary vein isolation, in patients with persistent AF, a superior line connecting both antral pulmonary vein isolation islands, an inferior line in certain patients, and a left fibrous trigone line, connecting the superior line to the left fibrous trigone were made.20 All ablation lines were tested for bidirectional block as reported earlier.8,18 The left atrial appendage (LAA) was removed using an endoscopic stapler.

Patients were admitted to the recovery room for 3-6 hours and to the ward afterwards. Thorax drains were removed within 24 hours and patients were discharged usually on the third postoperative day.

Follow-upAll patients were followed up prospectively with clinical visits, 12-lead ECG and 24-hour Holter at 3, 6, 9, 12, 15, 18 and 24 months in our center. Patients were encouraged to have additional rhythm recordings obtained when symptomatic. All AAD were discontinued

5


3 months after surgery. Anticoagulants were continued in all patients with a CHA2DS-

2VASc score≥1 (unless solely based on female gender), irrespective of the (presumed) absence of AF or the exclusion of the LAA.3 After 2 years, patients were followed in a non-standardized manner by their referring cardiologist. For this 5-year follow-up analysis, all patients were invited for a standardized office visit, physical examination and 12-lead ECG. Additionally, demographic and clinical data were collected through medical chart review and consultations with referring physicians. All ECGs and 24-hour Holter data obtained during this period were collected and included in the current analysis. The municipal administration confirmed that all patients were still alive. At 5-year follow-up, patients were explicitly asked for AF symptoms, cardioversion or ablation procedures over the preceding years, and, where pertinent, electrocardiographic evidence for AF recurrence was collected. Figure 1 displays the follow-up strategy.

Outcome definitionAF absence was defined as the absence of any atrial arrhythmia>30 seconds without the use of AADs.21 The first 3 months following surgery formed a blanking period, during which recurrences of AF or other atrial arrhythmias were not considered a recurrence. In addition to the Kaplan-Meier analysis of AF absence, we investigated the actual rhythm at the 5-year follow-up visit, and analysed patients with <1, <3 or ≥3 AF recurrences/year.

As a consequence of the protocol, where all AADs were discontinued after 3 months, there were no patients on AAD treatment without any AF recurrence. Those patients without AF recurrences after restarting AAD following their index post procedural recur-

//

VisitECG

Holter

VisitECG

HolterEchoMRI

VisitECG

Holter

VisitECG

Holter

VisitECG

Holter

3 6 9 12 15

VisitECG

Holter

18

VisitECG

Holter

24

VisitECG

60

Retrospective data collection:- all ECGs- all Holters- all cardioversion data- all redo ablation data

Thoracoscopic procedure

Retrospective

Prospective

VisitECG

HolterEcho MRI

Follow-up (months)

Figure 1.Study flow chartFlow chart of the study. ECG and Holter data were prospectively collected during the first 2 years of follow-up. Patients returned for a 5-year follow-up visit, and all ECGs and Holters performed in the time between were collected.

106 Chapter 5

rence were considered to be free of AF with the use of AAD. We performed univariable and multivariable analysis of clinical parameters associated with AF recurrence.

Statistical AnalysisStatistical analysis was performed with SPSS version 23.0 and R version 3.2.1 for Windows. Continuous values are expressed as mean (±SD). Categorical variables are expressed as numbers and percentages. The Mann-Whitney U and Wilcoxon tests were used for comparisons. For the primary endpoint, AF freedom, event-free survival was plotted and estimated by Kaplan-Meier curves. Clinical parameters associated with AF recurrence were studied using univariable and stepwise multivariable analysis in a Cox regression models. A p-value of <0.05 was considered statistically significant.

Results

Sixty-six consecutive patients with advanced paroxysmal or persistent AF underwent thoracoscopic surgery for AF between January 2008 and December 2010. Mean age of the patients was 57.4±8.9 years (range 38-76), and 49 (74%) were male. Thirty-three (50%) patients had paroxysmal, 31 persistent and 2 long standing persistent AF. Twenty-nine patients (44%) had a history of at least one previous percutaneous catheter ablation. Median duration of AF was 5 (range 1-25) years. Mean left atrial volume was 35.9±11.9 ml/m2, 30 patients had an enlarged (>33 ml/m2) of whom 16 had a severely enlarged (≥40 ml/m2) left atrium. Baseline demographics are detailed in Table 1.

Surgical ProcedureIsolation of all PVs was achieved in 100% of patients. Additional lines were ablated in patients with persistent AF. The LAA was excised in 65 patients (98.5%). In one patient, the size and anatomy was deemed unsafe for exclusion. Periprocedural adverse events occurred in 18 patients (27%, Table 2). Of note, all three sternotomies were performed in the first 20 patients, indicating a learning curve of the surgeon and the team as these included our first procedures, and have been reported earlier.8

Follow-upElectrocardiographic and clinical data were collected from 66 patients (100%). Fifty-eight patients attended the clinical follow-up visit with ECG. Of the remaining, 7 refused the follow-up visit and 1 could not be traced, although his ECG and clinical data were collected from the referring hospital. Median follow-up was 66 months (60-82). 51/58 patients (88%) were in sinus rhythm at the clinical follow-up. Thirty percent of patients were using AAD. At 5 years, all patients were alive, and none had experienced a stroke or systemic embolism.

5



n=66

General characteristics

Age, years 57.4±7.9 (38-77)

Male, n (%) 49 (74)

Body mass index, (kg/m2) 27.8±5.4

Left Atrial Diameter (mm)

Left Atrial Volume Index (mL/m2) 35.9±11.9

Left ventricular Ejection Fraction (%)

Creatinin (µmol/L, mean±SD)

Previous catheter PVI, n (%) 29 (44)

Myocardial Infarction

AF Characteristics

AF duration, years, median (range) 5 (1-25)

Paroxysmal, n (%) 33 (50)

Persistent, n (%) 33 (50)

CHA2DS2VASc-score (mean).

Congestive heart failure, n (%) 1 (2)

Hypertension, n (%) 21 (32)

Age ≥ 75, n (%) 2 (3)

Diabetes, n (%) 1 (2)

Stroke/TIA/Embolus, n (%) 4 (6)

Vascular disease, n (%) 2 (3)

Female gender, n (%) 12 (18)

Age ≥ 65, n (%) 12 (18)

CHA2DS2VASc-score = 0, n (%) 27 (41)


CHA2DS2VASc-score ≥ 2, n (%) 13 (20)

Medication

Anti-arrhythmic medication

Class IA, n (%) 3 (5)

Class IC, n (%) 19 (29)

Class II, n (%) 29 (44)

Class III, n (%) 32 (48)

Class IV, n (%) 3 (5)

Digoxin, n (%) 4 (6)

Anticoagulants

Coumarins, n (%) 66 (100)

Antiplatelets, n (%) 3 (5)

PVI, pulmonary vein isolation; AF, atrial fibrillation; TIA, transient ischemic attack

108 Chapter 5

Absence of AFFigure 2 shows the Kaplan-Meier curve for absence of AF without the use of AAD (21). No AF recurrence was documented, and all AAD remained discontinued in 67% of patients with paroxysmal and in 33% of patients with persistent AF respectively after 5 years. Absence of AF in the entire cohort was 73%, 61%, 52%, 52%, 50% after 1, 2, 3, 4 and 5 years. Excluding patients in whom a previous catheter ablation proved unsuc-cessful resulted in absence of AF in 60 % of patients after 5 years (76% in paroxysmal and 38% in persistent AF). AAD were restarted in 20 patients with recurrences (30%, 6 with paroxysmal and 14 with persistent AF), of whom 3 did not experience any other AF

Table 2. Procedural complications

Procedural adverse events n, (%)

Sternotomy 3 (15)

Sinus node dysfunction 3 (7)

Pacemaker implant 1 (2)

Pneumothorax 1 (5)

Pneumonia 2 (4)

Procedural bleeding, thoracoscopically managed 2 (4)

Late Bleeding, requiring intervention 4 (9)

0 1 2 3 4 5

0

20

40

60

80

100

Follow−up (years)

Free

dom

of A

F/AT

/AFL

Rec

urre

nce

(%)

Number at risk 66 48 38 32 32 29

Figure 2.Kaplan-Meier of absence of AF recurrence, without AADKaplan-Meier analysis of absence of AF recurrence, without the use of anti-arrhythmic drugs, after a single thoracoscopic procedure.

5


recurrence thereafter. Hence, AF absence with or without AAD was 55% in the combined cohort and 67% and 42% in patients with paroxysmal or persistent AF respectively.

Recurrence of AFThe recurrent atrial tachyarrhythmia in 33 patients was AF in 67%, atrial tachycardia in 24% and atrial flutter in 9%. AF recurrence was detected with symptom-driven ECG recording in 64%, clinical visit in 9% and Holter in 27% of patients. One patient was classified a recurrence based on a single atrial tachycardia lasting 31 seconds on Holter, without any other clinical or electrocardiographic evidence of recurrence during the rest of the follow-up. Similarly, another patient experienced AF recurrence during an episode hyperthyroidism and had no further recurrences during the course of follow-up. Of the patients classified with AF recurrences, four underwent a redo catheter ablation procedure for AF and two others for typical right atrial flutter, all of whom experienced AF recurrences thereafter.

Figure 3 displays AF burden during 5 years of follow-up. Seventy-four percent of all patients had no or <1 AF recurrence/year, 91% had no or <3 AF recurrences/year. Nine percent of patients had >3 recurrences/year or permanent AF. Of patients with parox-ysmal AF, 91% had no or <1, and 94% no or <3 AF recurrences/year. Of patients with persistent AF 58% had no or <1, and 88% had no or <3 AF recurrences/year.

Figure 4 shows the univariable and multivariable analysis of clinical determinants of AF recurrence. AF type (i.e. paroxysmal or persistent) at the time of surgery was as-sociated with AF recurrence (HR 2.28, 95% confidence interval 1.09 – 4.74, p<0.028). Interestingly, also a history of one or more previous catheter ablations was associated with AF recurrence (HR 1.44, 95% confidence interval 1.02 – 2.05, p<0.041). Left atrial volume was enlarged in a large proportion of patients and not associated with long-term AF absence.

dIscussIon

We, for the first time, report 5-year outcomes of thoracoscopic, electrophysiologically guided ablation of advanced AF. Using a rigorous follow-up protocol and endpoint defi-nition, with all patients prospectively followed for two years, 88% of patients returned for an outpatient visit at 5 years. All available electrocardiographic and clinical data were collected for 100% of the entire cohort, we show that 50% of patients (67% with parox-ysmal and 33% with persistent AF) discontinued AAD and had no AF recurrence after a single thoracoscopic procedure at 5 years. After 5 years, and irrespective of recurrent episodes, 88% of patients were in sinus rhythm.

110 Chapter 5

All PAF PersAF

Patie

nts

(%)

0

20

40

60

80

100

949191

74

50

67

88

58

33

Figure 3.AF burdenNumber of AF episodes/year, first bar: all patients; second bar: patients with paroxysmal AF; third bar: pa-tients with persistent AF. White tinted: no AF recurrence without the use of AAD; light blue tinted: <1 AF recurrence/year; intermediaite blue tinted: 1-3 AF recurrences / year; dark blue tinted: ≥3 AF recurrences/year or permanent AF. Numbers indicate the cumulative percentage.

Univariable

AF Type

Age (years)

Female Gender

BMI (kg/m²)

AF Duration

LAVI (ml/m²)

Previous PVI

Multivariable

AF Type

Previous PVI

HR

2.54

1.02

1.44

1.02

1.02

0.98

1.52

2.23

1.43

95% CI

[1.23−5.25]

[0.98−1.06]

[0.68−3.02]

[0.96−1.09]

[0.96−1.09]

[0.95−1.02]

[1.09−2.12]

[1.11−4.82]

[1.01−2.03]

P−value

0.012

0.366

0.338

0.512

0.485

0.413

0.014

0.025

0.042

0 1 2 3 4 5Hazard Ratio

Figure 4.Univariable and multivariable regression of determinants of AF recurrenceUnivariable and multivariable regression of determinants of AF recurrence. BMI = body mass index; LAVI = left atrial volume index; PVI = pulmonary vein isolation.

5


Seventy-four percent of patients experienced no or <1 recurrent episodes/year, 91% had no or<3 recurrences/year and only 9% had ≥3 recurrences/year or permanent AF. We further show that AF type (i.e. paroxysmal or persistent) at the time of surgery is associated with AF recurrence, and that patients with prior catheter ablations have a higher chance of AF recurrence during 5 years of follow-up. Previous catheter ablation was a predictor for AF recurrence and exclusion of those patients resulted in AF absence in 60% of patients naive to invasive therapy at 5 years.

Procedural complicationsThe number of periprocedural complications in this cohort is high, with 3 sternotomies for uncontrolled bleeding. Boersma et al. reported similar complication rates for thora-coscopic surgery for AF. However, most of the complications described here have been reported previously in an analysis of the one-year results of this procedure.8 (8) Indeed, all sternotomies occurred in the first 20 procedures, strongly suggesting a learning curve for both surgeon and team when the procedure was first introduced at our center. In the AFACT study the total number of major procedural complications was approximately 50% lower with one sternotomy in 240 patients.19

However, thoracoscopic surgery is associated with a longer hospital stay and more periprocedural complications than catheter ablation, albeit that with multiple catheter procedures the number of complications may accumulate.

Relation with other surgical and catheter techniquesUsing the most stringent definition of outcome, 50% of the entire cohort had no single AF recurrence and discontinued all AAD, and 88% had sinus rhythm at 5 years. The initial publications of the Cox-Maze procedure reported success rates >95%, but the means of follow-up were looser than contemporary methods.22

Using contemporary follow-up methods, Weimar et al. reported 82% and 83% freedom of AF after two years for the Cox-maze 3 and 4 respectively.5 Using repetitive Holter re-cordings in 144 patients (in 88% the Cox-Maze procedure was performed, the remainder were treated with a more limited approach), Ad et al. demonstrate AF absence in 63,5% of patients.23 At 5 years, 71% of patients had sinus rhythm and did not use AAD. Of note, this patient cohort was a selection of the 300 patients that were eligible for this analysis, as the majority of these patients had insufficient rhythm recordings. Henn et al. describe 576 patients (41% paroxysmal AF) who underwent a Cox-Maze procedure between 2002 and 2014; 5-year follow-up was available for 139 patients, of whom 52% had prolonged monitoring. Fifty-nine percent of patients with a stand-alone procedure, were free of AF without AAD at 5 years.24 Although these rates seem slightly higher than in our study, we report complete data from consecutive patients, who all were prospectively followed for two years, and in whom all ECGs and Holters performed thereafter were retrieved and

112 Chapter 5

included in the analysis. Approximately 2/3 of recurrences were derived from symptom driven ECGs, and Holter recording detected 27% of recurrences only. In addition, we verified in every patient that no cardioversion or catheter ablation had been performed elsewhere. At 5 years, 88% of the patients in this study were in sinus rhythm, compared to 71% in the cohort of Ad et al..23

Our analysis of AF burden shows that 74% and 91% of patients had no or <1 or no or<3 AF recurrences/year respectively, indicating a very high percentage of clinical success.21 With a less invasive approach, only 9% of our patients had frequent AF recurrence or permanent AF. In the available randomized studies, employing variable lesion patterns, lower success rates have been reported for concomitant maze surgery,25,26 with a consid-erably higher percentage of complications.27

Similarly, the groups in Bordeaux and Hamburg report AF absence in only 29 and 47% of patients with mostly or exclusively paroxysmal AF after 5 years, which increased to 63 and 79% after multiple (up to seven in selected patients) procedures.15,17 In persistent AF, single procedure result was 20%, increasing up to 45% after multiple procedures.16 Also here the follow-up protocol was less rigorous than employed in the current study. Hence, and despite that this study is not a randomized comparison of techniques, the efficacy of thoracoscopic surgery for advanced AF appears similar to Cox-Maze surgery and superior to that achieved with catheter ablation. In multivariable analysis, previous catheter ablation and persistent AF were associated with AF recurrence at five years. This differs from the one-year results of the AFACT study, where LAVI was the only predictor for AF recurrence.19

Role of Lesion set and Energy SourceAll patients in this cohort underwent a standardized approach with bilateral thora-coscopic pulmonary vein isolation using a bipolar radiofrequency clamp.8 In patients with persistent AF, additional lines conforming to the Dallas lesion set were added to the procedure20 and in most patients GPs were ablated. Pulmonary vein isolation alone may be insufficient for treating more advanced AF, but which additional lesion set is preferred remains matter of debate. Different lesion patterns are being employed, also in randomized clinical trials.25,26 There is, to the best of our knowledge, no randomized trial comparing the Cox-Maze with alternative lesion sets. Recent data from the STAR-AF 2 trial demonstrated that adding additional ablation was ineffective compared to PVI alone.28 Contrary to a fixed lesion set, there is vast evidence on stepwise procedures where the lesion patterns are driven by periprocedural AF conversion or organiza-tion.29 Taken together, as of to date there is no consensus in clinical practice, nor in the literature, on which approach is superior in the treatment of advanced paroxysmal or persistent AF. All patients in the current cohort were treated using the same ablation platform, and the lesion set was prospectively and consistently tailored to the clinical AF

5


type. A different lesion set or energy source, however, could have resulted in different rate or time course of AF recurrences.

LimitationsThis study is a single center study, including our very first experience with this procedure. Most of the complications reported here have been published previously.8 Therefore, the reported adverse events during surgery may be an overestimation of the true com-plication risk. This hypothesis is supported by the notion that virtually all complications occurred in the first 20 procedures, and that data from the AFACT trial show far lesser surgical complications.19

Data were collected prospectively in a standardized manner for 2 years, and subse-quently retrospectively for the time period between 2 and 5 years (Figure 1). During the first two years 24-hour Holters were performed every 3 months, and we invited every patient back to our hospital for a clinical visit and ECG, and specifically inquired on AF recurrence or cardioversions. With this, our study still provides the most comprehen-sive data set on 5 years follow-up of surgical AF ablation currently available. We can, however, not exclude that we missed asymptomatic episodes of AF, but our follow-up protocol conforms to, and is in fact more rigorous than, the consensus.21 Furthermore, by performing ECGs at the 5-year clinical visit we ruled out asymptomatic permanent AF. In addition, all Holter recordings and ECGs performed after two years were collected and included in this analysis.

conclusIon

Thoracoscopic, electrophysiologically guided surgery for advanced AF is associated with AF absence and discontinuation of AAD in 50% of patients during a follow-up period of ≥5 years. At 5 years, 88% of patients had sinus rhythm. Seventy-four percent of patients had no or <1 AF recurrence/year, 91% had no or <3 recurrences.

More than 3 AF recurrences/year or permanent AF was documented in 9% of all patients. Persistent AF and a history of previous catheter ablations were independently associated with AF recurrence.

114 Chapter 5

RefeRences 1. Chugh SS, Havmoeller R, Narayanan K, et al. Worldwide epidemiology of atrial fibrillation: a Global

Burden of Disease 2010 Study. Circulation 2014;129:837-47. 2. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national

implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Fac-tors in Atrial Fibrillation (ATRIA) Study. JAMA 2001;285:2370-5.

3. Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Europace 2010;12:1360-420.

4. Haissaguerre M, Jais P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. The New England journal of medicine 1998;339:659-66.

5. Weimar T, Schena S, Bailey MS, et al. The cox-maze procedure for lone atrial fibrillation: a single-center experience over 2 decades. Circulation Arrhythmia and electrophysiology 2012;5:8-14.

6. Cox JL, Schuessler RB, D’Agostino HJ, Jr., et al. The surgical treatment of atrial fibrillation. III. De-velopment of a definitive surgical procedure. The Journal of thoracic and cardiovascular surgery 1991;101:569-83.

7. Wolf RK, Schneeberger EW, Osterday R, et al. Video-assisted bilateral pulmonary vein isolation and left atrial appendage exclusion for atrial fibrillation. The Journal of thoracic and cardiovascu-lar surgery 2005;130:797-802.

8. 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. Circulation Arrhythmia and electrophysiology 2011;4:262-70.


10. Krul SP, Pison L, La Meir M, et al. Epicardial and endocardial electrophysiological guided thoraco-scopic surgery for atrial fibrillation: a multidisciplinary approach of atrial fibrillation ablation in challenging patients. Int J Cardiol 2014;173:229-35.

11. Pison L, La Meir M, van Opstal J, Blaauw Y, Maessen J, Crijns HJ. Hybrid thoracoscopic surgical and transvenous catheter ablation of atrial fibrillation. Journal of the American College of Cardiology 2012;60:54-61.

12. Deshmukh A, Patel NJ, Pant S, et al. In-hospital complications associated with catheter ablation of atrial fibrillation in the United States between 2000 and 2010: analysis of 93 801 procedures. Circulation 2013;128:2104-12.


14. Van Brabandt H, Neyt M, Devos C. Effectiveness of catheter ablation of atrial fibrillation in Belgian practice: a cohort analysis on administrative data. Europace 2013;15:663-8.

15. Weerasooriya R, Khairy P, Litalien J, et al. Catheter ablation for atrial fibrillation: are results main-tained at 5 years of follow-up? Journal of the American College of Cardiology 2011;57:160-6.

16. Tilz RR, Rillig A, Thum AM, et al. Catheter ablation of long-standing persistent atrial fibrillation: 5-year outcomes of the Hamburg Sequential Ablation Strategy. Journal of the American College of Cardiology 2012;60:1921-9.

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17. Ouyang F, Tilz R, Chun J, et al. Long-term results of catheter ablation in paroxysmal atrial fibrilla-tion: lessons from a 5-year follow-up. Circulation 2010;122:2368-77.





22. Prasad SM, Maniar HS, Camillo CJ, et al. The Cox maze III procedure for atrial fibrillation: long-term efficacy in patients undergoing lone versus concomitant procedures. The Journal of thoracic and cardiovascular surgery 2003;126:1822-8.

23. Ad N, Holmes SD, Stone LE, Pritchard G, Henry L. Rhythm course over 5 years following surgical ablation for atrial fibrillation. Eur J Cardiothorac Surg 2015;47:52-8; discussion 8.

24. Henn MC, Lancaster TS, Miller JR, et al. Late outcomes after the Cox maze IV procedure for atrial fibrillation. The Journal of thoracic and cardiovascular surgery 2015;150:1168-76, 78 e1-2.

25. Budera P, Straka Z, Osmancik P, et al. Comparison of cardiac surgery with left atrial surgical abla-tion vs. cardiac surgery without atrial ablation in patients with coronary and/or valvular heart disease plus atrial fibrillation: final results of the PRAGUE-12 randomized multicentre study. European heart journal 2012;33:2644-52.

26. Gillinov AM, Gelijns AC, Parides MK, et al. Surgical ablation of atrial fibrillation during mitral-valve surgery. The New England journal of medicine 2015;372:1399-409.

27. Buber J, Luria D, Sternik L, et al. Left atrial contractile function following a successful modified Maze procedure at surgery and the risk for subsequent thromboembolic stroke. Journal of the American College of Cardiology 2011;58:1614-21.


29. Scherr D, Khairy P, Miyazaki S, et al. Five-year outcome of catheter ablation of persistent atrial fibrillation using termination of atrial fibrillation as a procedural endpoint. Circulation Arrhythmia and electrophysiology 2015;8:18-24.

Part IIQuality of life after invasive

treatment of patients with atrial fibrillation

Chapter 6Documented Atrial Fibrillation Recurrences After Pulmonary Vein Isolation are Associated with Diminished Quality of Life

Wouter R. BergerSébastien P.J. KrulJoy A. van der Pol

Pascal F.H.M. van DesselChantal E. ConrathArthur A.M. Wilde

Joris R. de Groot

J Cardiovasc Med 2016, 17:201–20

120 Chapter 6

AbstRAct

AimsPulmonary vein isolation (PVI) aims at eliminating symptomatic atrial fibrillation. In this regard, the most relevant indication for this procedure is the reduction of symptoms and improvement of quality of life (QoL) in patients who remain symptomatic despite antiarrhythmic drug treatment. We investigated the relation between documented atrial fibrillation recurrences and QoL in patients after PVI.

MethodsOne hundred and six PVIs were performed in 99 patients. Follow-up was mainly per-formed at referring hospitals. Short Form 36 (SF-36) QoL questionnaires were completed before and 1 year after PVI. Electrocardiographic recordings from the first postproce-dural year were retrospectively collected, 3 months blanking excluded. Atrial fibrillation recurrence was defined as any recurrence of atrial arrhythmia documented on ECG or 24-h-Holter.

ResultsBefore PVI, patients had lower QoL than the general Dutch population in 7/8 SF-36 ques-tionnaire subscales (sumQoL 419.4±161 vs. 617.9, P<0.001). Atrial fibrillation recurred in 52 (49%) patients. In these patients, four subscales increased following PVI (physical functioning P<0.001, role physical P=0.006, bodily pain P=0.011 and social functioning P=0.047). SumQoL remained lower than the general Dutch population (546.7±157, P=0.003). In patients without documented recurrences, QoL improved to a level similar to that of the general Dutch population (602.9±148; P=0.46). The number of electrocar-diographic recordings was lower in the group without documented recurrences (2.5±1.8 vs. 3.8±1.7, P=0.002).

ConclusionIn patients without documentation of atrial fibrillation, QoL increased up to the level of the general population after PVI, but it remained lower in patients with recurrences. In the latter group more ECGs were done, suggesting that QoL relates particularly to symptomatic episodes. Improvement of QoL is therefore an important attribute of PVI.

6

Atrial fibrillation recurrences and quality of life 121

IntRoductIon

Atrial fibrillation is the most commonly encountered cardiac arrhythmia. It is associated with an increased morbidity and mortality.1 Currently, rate and rhythm control strategies are applied to manage the patient’s symptoms and to prevent complications, such as thromboembolic events and tachycardiomyopathy. An indication for invasive treatment (i.e. catheter ablation or surgery) exists in patients who remain symptomatic despite having tried at least one antiarrhythmic drug (AAD).2,3 Thus, the indication for invasive treatment depends on complaints/ symptoms, instead of the reduction or elimination of episodes of atrial fibrillation.

Catheter ablation for atrial fibrillation has been reported to suppress atrial fibrillation in 57–71% of cases after one or more procedures and a mean of 14 months’ follow-up in a meta-analysis of previously published studies.4 Atrial fibrillation suppression is related to the type of atrial fibrillation, patient selection, center experience, number of prior ablations and ablation technique.4

Atrial fibrillation recurrence after pulmonary vein isolation (PVI) can be symptomatic, as well as asymptomatic; therefore, the rate of recurrences may be underestimated when relying on patients’ complaints or when limited rhythm monitoring is available. The more rigorous the electrocardiographic follow-up, the higher the expected recurrence rate. Indeed, contemporary catheter ablation studies demonstrate a more modest free-dom of atrial fibrillation rate than reported previously, both with continuous monitoring (46% freedom of atrial fibrillation)5 as with intermittent rhythm monitoring (45–48%).6,7

The recent Discerning the Incidence of Symptomatic and Asymptomatic Episodes (DISCERN) atrial fibrillation study, employing a continuous monitoring strategy of atrial fibrillation recurrences, showed that only 46% of patients were free of atrial fibrillation after 1 year. Importantly, of the patients with recurrences, only 12% of the patients had asymptomatic episodes exclusively, whereas most patients had symptomatic episodes.5 The question arises what the clinical implications of the absence of atrial fibrillation during follow-up after PVI are, and therefore, whether the absence of atrial fibrillation is a clinically relevant parameter. This is important because symptoms are the mainstay of the indication for this invasive and potentially harmful procedure, and not atrial fibrillation elimination. Indeed, atrial fibrillation is associated with an increased stroke rate, risk of heart failure and morbidity.1,8 However, it is unclear whether prognosis nor-malizes after the treatment of atrial fibrillation and solid data to support that are lacking. The mere presence of asymptomatic atrial fibrillation after PVI may therefore be futile in terms of patient management as the absence of atrial fibrillation has no implication for antithrombotic therapy according to recent insights.9

122 Chapter 6

In a real-life clinical setting, we studied the relation between atrial fibrillation recur-rences and quality of life (QoL). We studied QoL directly before and 1 year after PVI in consecutive patients undergoing PVI for paroxysmal and persistent atrial fibrillation.

Methods

All consecutive patients undergoing catheter ablation for the treatment of atrial fibrillation in the center between 1 January 2008 and 31 December 2010 were screened. A waiver of consent has been obtained from the medical ethics committee. Prior to the ablation procedure, all patients had recent, that is less than 1-year-old, electrocar-diographically documented symptomatic episodes of paroxysmal or persistent atrial fibrillation and were refractory or intolerant to at least one class I or III AAD.2 Patients with reversible causes of atrial fibrillation, thyroid disease in particular, were excluded.

Ablation procedureDuring the study period, three different approaches toward PVI were employed. Circum-ferential PVI as described by Pappone et al.10, PVI using the Bard Mesh Ablator Catheter (MESH) ablator technique11, which was later discontinued because of low efficacy12, or Lasso controlled circumferential wide-area left atrial catheter ablation (WACA).13

Follow-upPatients were seen in the outpatient clinic of our center at 3 months following the cath-eter ablation. After this visit, follow-up took place either at our center or at the referring hospitals. Therefore, there was no standardized protocol with regard to discontinuation of AADs after ablation. Demographic and clinical data were collected through a medical chart review and through consultations with the referring physicians. We collected all available ECG and 24-h-Holter data obtained during the first year following the pro-cedure. The presence of atrial fibrillation, atrial flutter (AFL) and atrial tachycardia was documented. If multiple ECGs were done during a single visit (e.g. for electrical cardio-version), or in the absence of any atrial arrhythmia, the first ECG with the documented arrhythmia was used for rhythm outcome analysis.

Clinical outcomeAtrial fibrillation recurrences were defined according to the Heart Rhythm Society/Euro-pean Heart Rhythm Association/European Cardiac Arrhythmia Society expert consensus statement as any episode of atrial fibrillation/AFL or atrial tachycardia documented on ECG or Holter registration after a blanking period of 3 months, but within 1 year after the ablation procedure.3 The assumption was made that detected arrhythmias on a standard

6


ECG reflected episodes of more than 30s duration, as required by the consensus state-ment. The presence of atrial fibrillation/AFL/atrial tachycardia documentation on ECG or Holter within 1 year after the procedure was defined as procedural failure, whereas the absence of such documentation was assumed to indicate procedural success.

Quality of lifePatients were asked to complete an SF-36 QoL questionnaire before and12 months after the catheter ablation procedure. Patients who failed to return the 12-month question-naire were approached and encouraged to complete the questionnaire retrospectively.

The SF-36 questionnaire was used to determine the impact of atrial fibrillation and catheter ablation on QoL. The SF-36 is a multipurpose health survey, consisting of 36 questions. It yields an eight-scale profile of functional health and well-being scores including physical function , role physical, bodily pain, general health, vitality, social functioning, role emotional and mental health. The scores are standardized from 0 to 100. Total QoL (sumQoL) was calculated by summing up the eight different subscales to express a ‘general’ measurement of well-being. The scores were compared with a dataset displaying the QoL in the general healthy Dutch population.14

Physical component summary (PCS) and mental component summary (MCS) mea-sures were determined based on normative data from a Dutch population.14 PCS and MCS summary scores were calculated as the linear combination of the eight standard-ized [mean=0, standard deviation (SD)=1] sub-scores. Each summary score was then transformed by multiplying by 10 and adding 50 in order to be compared with scores from the Dutch population with mean 50 and SD 10.15

Statistical analysis Continuous values are expressed as mean (±SD). Categorical variables are expressed as numbers and percentages of patients. Nonparametric tests (Wilcoxon signed-rank test, χ2 test or one-way analysis of variance test)were used to detect significant differences between groups. One sample t-test was used to detect dif-ference with the reference group. A probability value <0.05 was considered statistically significant. Bonferroni correction was used in post-hoc testing.

The score of each subscale of the SF-36 was calculated as the mean of the items. Statistical analysis was performed using IBM SPSS Statistics v20.

Results

Two hundred and forty-four invasive procedures (i.e. surgical or catheter ablation) for atrial fibrillation were performed between January 2008 and December 2010. One hundred and seventy-eight catheter ablation procedures were carried out in 164 pa-tients who were approached to fill out the SF-36 QoL questionnaire before and 1 year

124 Chapter 6

after the procedure. Sixty-nine questionnaires from 67 patients were not returned after 12 months and from three procedures no documentation of follow-up was available. Complete QoL data were available from 106 procedures performed in 99 patients (55 Pappone, 25 WACA and 22 MESH). Additional lesions (inferior line, roofline, MV annulus) were applied in 22 procedures.

Eighty-two (77%) procedures were first PVI procedures. The remaining 24 procedures were redo-procedures after one or more previous procedures, of which seven were per-formed within the 3-year time frame of this study. Three patients experienced peripro-cedural complications. Two procedures were aborted without complete isolation of the pulmonary veins. One patient had short lasting ST-elevations in the inferior ECG leads, however, without coronary disease as evidenced by a normal coronary angiogram. Two of these patients did not have atrial fibrillation recurrence after PVI.

Patient characteristics are shown in Table 1. Mean age was 55 years (range 23–76) and 75% of the procedures was performed in male patients (n=79). Ninety-two percent (n=97) of the procedures was performed for paroxysmal atrial fibrillation and 8% (n=9) for persistent atrial fibrillation. All differences in baseline characteristics between the groups of patients with and without recurrences after PVI were nonsignificant.

Electrocardiographic follow-upAfter 1-year follow-up, a mean of 4.4 (±2.2) rhythm registrations per patient were avail-able, mostly 12-lead electrocardiograms. Thirty percent of the total amount of rhythm registrations in the study population was performed within the first 3 months after the procedure and were excluded from the analyses of rhythm outcome, because of the blanking period. A mean of 3.1 (±1.8) rhythm registrations per patient was used for determination of outcome. Patients with recurrences had significantly more rhythm registrations than patients without documented recurrences (3.8±1.7 vs. 2.5±1.8, P<0.001). Forty-nine percent (n=52) of the patients had registrations of recurrences of any atrial tachyarrhythmia during 12 months’ follow-up, with a mean time to recurrence of 180 (±74) days. We observed atrial fibrillation in 48 patients (92%), atrial tachycardia in three patients (6%) and right AFL in one patient (2%). All nine patients with persis-tent atrial fibrillation had recurrences within 12 months following the procedure. From the patients with recurrences 41 (79%) of registration of atrial fibrillation were initially documented on ECG and 11 (21%) during 24-h Holter monitoring. Recurrences were similar in men and women (n=43, 54% vs. n=9, 33%, P=0.058). Also, no difference existed between the different ablation strategies (Circumferential vs. WACA vs. MESH; 47 vs. 44 vs. 55%, P=0.692) or in age groups (divided in quartiles; age 0–52 years 42% vs. 52–56 years 59% vs. 56–61 years 43% vs. 61–76 years 52%, P=0.795). Subsequently, there was no difference in subgroups separated by CHA2DS2-VASc score (0; 46% vs. 1; 50% vs. 2 or higher; 55%, P=0.490). Forty-two percent (n=30) of the patients who did not return the

6


QoL questionnaire experienced a recurrence of atrial fibrillation during the first year of follow-up (P=0.3, vs. patients with complete QoL data).

Follow-up medicationComplete AAD history was available in 86 patients. Sixty percent (n=56) of the patients were on AADs after 1 year. Thirty-six patients (45%) used b-blockers during follow-up.


Baseline Characteristics n=99

Patients, n 99

Catheter ablation procedures, n 106

Age (years) 55.4±8.9 (23-76)

Male, n (%) 79 (75)

CHA2DS2VASc-score (mean). 0.8 (0-4)



Age ≥ 75, n (%) 1 (1)





Age ≥ 65, n (%) 10 (9)


CHA2DS2VASc-score = 1, n (%)CHA2DS2VASc-score ≥ 2, n (%)

36 (34)20 (19)


Type AF

Paroxysmal, n (%) 97 (91.5)

Persistent, n (%) 9 (8.5)

Anti-arrhythmic drugs,

Class IA, n (%) 1 (1)

Class IC, n (%) 41 (39)

Class II, n (%) 42 (40)

Class III, n (%) 48 (45)

Class IV, n (%) 11 (10)

Digoxin, n (%) 9 (9)

Anticoagulants (before PVI procedure),

Coumarins, n (%) 78 (74)

Antiplatelets, n (%) 13 (12)

AF: atrial fibrillation, PVI: pulmonary vein isolation, TIA: transient ischemic attack

126 Chapter 6

From the patients with atrial fibrillation recurrence 32% (n=15) used b-blockers vs. 41% (n=21) of patients with atrial fibrillation recurrence (P=0.3). Twenty-seven patients (32%) used a class I AAD and 20 patients (23%) a class III AAD. Some patients used a combina-tion of these medications. Sixty-nine percent of the patients (n=33) who were using class I or class III AAD at 1-year follow-up experienced recurrences of atrial fibrillation. The AAD use was equally distributed among patients with and without atrial fibrillation recurrence. Fifty-three percent (n=56) were on anticoagulant therapy after 12 months, partially because a CHA2DS2VASc-score at least 1, partially because of a potential redo procedure.

Quality of lifeAt baseline QoL was significantly lower in seven of eight SF-36 health survey subscales of patients with atrial fibrillation compared with the mean scores on SF-36 subscales in the general Dutch population (Table 2). The groups with and without atrial fibrillation recurrences had similar QoL at baseline.

The radar charts in Figure 1 show QoL on the eight subscales in patients with and without atrial fibrillation recurrence. The grey-shaded area between the curves displays the improvement of QoL after 12 months, with the scores of the general Dutch popu-lation as a reference. QoL improved significantly in patients without atrial fibrillation recurrence in seven of eight SF-36 subscales after 12 months. General health did not improve in these patients. In patients with atrial fibrillation recurrences QoL improved in four of the eight subscales (physical function, RP, bodily pain and social functioning, Table 2) describing the physical components. The four mental components remained unchanged after the ablation procedure in these patients.

Figure 1 shows that sumQoL significantly improved in both patient groups, but re-mained significantly diminished in patients with atrial fibrillation recurrence compared with the general Dutch population (P=0.002). In patients without atrial fibrillation recur-rence sumQoL was not different from the general Dutch population 12 months after catheter ablation.

The MCS improved in patients without atrial fibrillation recurrences, whereas PCS improved in both patient groups (Figure 2).

There was no significant difference in QoL subscales in patients with previous or primary PVI before or after the procedure. However, in the group of 54 patients without recurrences, patients with a previous PVI procedure (n=11) reported no significant in-crease in any of the eight SF-36 subscales, whereas patients with primary PVI (n=43) QoL increased in seven of eight subscales. In patients with atrial fibrillation recurrence QoL improved in three of eight subscales after previous PVI (n=13). However, patients with primary PVI improved in only one of eight subscales in this group.

6


Tabl

e 2.

QO

L ba

selin

e/12

mon

ths

QoL

Subs

cale

sN

o Re

curr

ence

AF

Recu

rren

ceM

ean

Dut

ch

Scor

es

No

Recu

rren

ceA

F Re

curr

ence

Base

line

12 m

onth

sBa

selin

e12

mon

ths

Mea

n D

utch

Sc

ores

vs.

Base

line

p-va

lue

Mea

n D

utch

sc

ores

vs.

12 m

onth

s

p-va

lue

Mea

n D

utch

sc

ores

vs.

Base

line

p-va

lue

Mea

n D

utch

sc

ores

vs.

12 m

onth

s

p-va

lue

Mea

n (±

SD)

Mea

n (±

SD)

p-va

lue

Mea

n (±

SD)

Mea

n (±

SD)

p-va

lue

PF69

.6 (±

24.1

)82

.8 (±

19.0

)<0

.001

65.7

(±21

.9)

75.4

(±22

.5)

<0.0

0183

.2<0

.001

0.87

1<0

.001

0.01

7

RP35

.6 (±

43.6

)64

.4 (±

42.8

)<0

.001

36.5

(±41

.6)

58.2

(±44

.5)

0.00

676

.6<0

.001

0.04

<0.0

010.

004

BP73

.2 (±

25.7

)82

.4 (±

23.6

)0.

0174

.2 (±

24.4

)82

.6 (±

21.6

)0.

011

75.0

0.60

90.

026

0.81

20.

014

SF63

.0 (±

28.4

)81

.9 (±

21.4

)<0

.001

66.6

(±23

.4)

72.6

(±25

.2)

0.04

784

.2<0

.001

0.44

2<0

.001

0.00

2

MH

73.8

(±19

.5)

79.1

(±15

.4)

0.01

870

.4 (±

18.3

)71

.5 (±

20.8

)0.

274

76.9

0.25

10.

297

0.01

30.

067

RE67

.9 (±

41.9

)81

.5 (±

32.8

)0.

034

68.6

(±42

.0)

74.4

(±42

.1)

0.31

082

.50.

013

0.82

00.

021

0.16

9

VT51

.8 (±

24.2

)66

.2 (±

19.7

)<0

.001

52.2

(±19

.7)

55.5

(±22

.1)

0.15

768

.6<0

.001

0.37

6<0

.001

<0.0

01

GH

58.5

(±21

.2)

64.7

(±21

.4)

0.07

055

.1 (±

22.4

)56

.5 (±

21.1

)0.

587

70.9

<0.0

010.

037

<0.0

01<0

.001

PCS

43.4

(±10

.2)

49.0

(±9.

2)<0

.001

42.7

(±9.

4)47

.0 (±

10.3

)0.

001

MCS

44.7

(±11

.7)

49.6

(±9.

7)0.

005

44.9

(±11

.1)

45.4

(±12

.1)

0.48

9

Sum

QoL

493.

4 (±

170.

9)60

2.9

(±14

7.9)

<0.0

0548

9.4

(±15

1.4)

546.

7 (±

156.

8)0.

003

QoL

: Qua

lity

of L

ife, A

F: a

tria

l fibr

illat

ion;

PF:

Phy

scia

l Fun

ctio

ning

, RP:

Rol

e Ph

ysic

al, B

P: B

odily

Pai

n, S

F: S

ocia

l Fun

ctio

ning

. MH

; Men

tal H

ealth

, RE:

Rol

e Em

otio

nal,

VT:

Vita

lity,

GH

; Gen

eral

Hea

lth, P

CS: P

hysi

cal C

ompo

nent

Sum

mar

y, M

CS: M

enta

l Com

pone

nt S

umm

ary

128 Chapter 6

Figure 1.Quality of life before and after pulmonary vein isolationRadar chart with eight different subscales (range 0-100) from the SF-36 quality of life (QoL) questionnaire represented on the axis. (A) QoL pre-PVI and post-PVI in patients without AF recurrences during the first 12 months after the procedure. (B) QoL pre-PVI and post-PVI in patients with registration of AF recurrences. The mean scores from a general Dutch population cohort are plotted in grey with dotted line. The shaded area between the curves represents the increase in QoL after 12 months. The subscales in which there is a significant increase (p<0.05) after 12 months are displayed in bold. The area between the dotted line and the shaded area represents the difference with the general Dutch population 12 months after ablation. (C) SumQoL (sum of the eight subscales) before and after PVI. Pre-PVI, the combined study population and the general Dutch population are plotted. Post-PVI, the study population is divided in patients with and without recurrences, showing that patients without recurrences have a sumQoL similar to the general population, while sumQoL in patients with recurrences remains significantly decreased. BP, bodily pain; GH, general health; MH, mental health; PF, physical functioning; PVI, pulmonary vein isolation; RE; role emo-tional; RP, role physical; SF, social functioning; VT, vitality.

6


Patients who used b-blockers before the procedure had significantly lower scores on physical functioning at that moment(62.2±25.4vs.71.9±20.3inpatientswithoutbblockers, P=0.031). The same applied to the physical functioning score of patients who used b-blockers after PVI (68.9±23.9 vs. 85.0±17.5, P=0.001). There was no difference in the other seven subscales in these patients.

There was no significant difference between men and women, and no relation with age, on any of the eight QoL subscales before and after PVI.

Before PVI, QoL was similar in patients with CHA2DS2VASc scores 0, 1 or at least 2. How-ever, patients with CHA2DS2VASc scores at least 2 had significantly lower sumQoL than patients with a CHA2DS2VASc score 0 after PVI(483±176 vs. 606±145, P=0.007),particularly for physical function, bodily pain and general health (63.0±25.4 vs. 83.8±17.7 P<0.001, 68.7±28.8 vs. 85.7±19.4, P=0.011 and 48.8±19.0 vs. 66.8±20.5, P=0.004).

dIscussIon

In this study we investigated the QoL in patients who underwent PVI to treat paroxysmal or persistent atrial fibrillation. PVI is becoming increasingly used as a rhythm control strategy in patients with symptomatic atrial fibrillation, but remains an expensive treat-ment. This is even more so because a substantial number of patients who have under-gone PVI are not free of further treatment and redo-procedures may be necessary in these patients. Previous studies have shown that just around 57% of the PVI procedures

Figure 2.Mental component summary and physical component summary.The mental component summary (MCS) and physical component summary (MCS) before and 12 months after PVI for patients with and without AF recurrence. The asterisk (*) marks significance. The dotted line represents the MCS and PCS of the general Dutch population with a mean of 50 and SD 10. SD, standard deviation.

130 Chapter 6

are successful, defined as freedom of atrial fibrillation after 1 year, without the use of AADs.4 However, the indication for PVI is symptomatic atrial fibrillation. Furthermore, the frequency of complications is reported to be around 6% and seems to be rising since the execution of PVI procedures has moved from high-volume centers to more inexperi-enced centers.16 Therefore, the selection of patients undergoing PVI or a redo-procedure is of clinical importance and the QoL of the individual patient after an intervention that covers this potential, non-life-threatening disease may be of higher importance than the mechanical success of the treatment itself.

For that reason, this study focused on the QoL in patients after PVI, especially in patients with the presence of atrial fibrillation recurrences on electrocardiographic recordings performed during regular follow-up visits and not on the absolute absence of atrial arrhythmias itself. The latter would be impossible without continuous rhythm monitoring. However, continuous rhythm monitoring is not currently used in daily prac-tice yet, especially not in non-academic centers, and therefore the data presented in this article may reflect a more real-world follow-upsetting for the general patient population that underwent PVI and were referred back to their physicians in smaller hospitals. Re-cently, Van Brabandt et al.17 described a comparable method to determine failure after catheter ablation. In their observational study the investigators focused more on failure of catheter ablation, by studying the number of drug prescriptions, electrical cardiover-sions and redo-procedures, rather than on success rates, and showed an atrial fibrillation recurrence rate of 59.8%.

As of today, data demonstrating a normalization of prognosis after the treatment of atrial fibrillation, with regard to morbidity and mortality, are lacking. Therefore, emphasis on QoL is clinically relevant. QoL was already reported to improve after catheter abla-tion18,19, whereas a sub study of the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial showed no improvement of QoL after pharmacological treatment. As previously reported by Mantovan et al.20, QoL after atrial fibrillation abla-tion improved in all patients, regardless of procedural outcome. In this study we report that patients with recurrence of atrial fibrillation, that is detected during follow-up visits or during a visit to the cardiac care unit, because of atrial fibrillation symptoms, show less increase in QoL than patients who do not report atrial fibrillation recurrence. Also QoL in these patients remains diminished compared with the general Dutch population. This patient group may therefore have an indication for further treatment of atrial fibrillation. In patients with atrial fibrillation recurrence we observed improvement in the physical component subscales, but not in the mental components, which may be explained by patients’ disappointment after failure of the procedure or by persisting symptoms of the arrhythmia. Alternatively, the improvement in the physical components may be the result of lower atrial fibrillation burden in these patients.

6


Following redo-procedures patients had no further improvement of QoL. This may be affected by the

expectations or bad experiences of patients undergoing a second procedure influencing QoL. Alternatively, patients who need a redo-procedure frequently have a more advanced arrhythmogenic substrate, which is supported by our finding that all patients with persistent atrial fibrillation had recurrences and likely qualify for a redo-procedure.

The finding that patients with documented atrial fibrillation recurrence had more electrocardiographic recordings might point at the notion that these patients were more symptomatic and therefore presented themselves more often to their physician. Hence, the relation we describe between atrial fibrillation recurrence and diminished QoL may be particularly true for symptomatic atrial fibrillation and may be less clear for asymptomatic recurrences, which could have passed by undetected.

Patients with asymptomatic atrial fibrillation, however, could not be selected with the method applied in this study. Therefore, the number of recurrences reported here may well be an underestimation. Recently, it was shown in the DISCERN study5 that 12% of atrial fibrillation recurrences, detected after catheter ablation in patients with an implanted continuous monitoring device, were asymptomatic. Also, the Assessing Arrhythmia Burden after Catheter Ablation of Atrial Fibrillation Using an Implantable Loop Recorder: The ABACUS study21 demonstrated, by comparing continuous monitor-ing with conventional monitoring, that more intensive monitoring results in a higher detection of atrial arrhythmias. However, from our study, we may conclude that the patient group without documented atrial fibrillation recurrence also has an improved QoL. These patients, despite the chance of having asymptomatic atrial fibrillation, have no indication for further invasive treatment of atrial fibrillation.

AAD therapy was continued in more than half of the study population, in the group of patients both with documented atrial fibrillation recurrence (71%) and without atrial fibrillation recurrence (35%). During follow-up patients used fewer AADs class I and class III than before catheter ablation (respectively 42 vs. 27%, and 45 vs. 36%); however, beta-blockers were used more often after catheter ablation (40 vs. 45%). The AAD use was equally distributed in patients with and without atrial fibrillation recurrences. Rate control strategies, usually with beta-blockers, have previously been associated with positive impact on QoL in patients with persistent atrial fibrillation.22 However, since the use of beta-blockers after catheter ablation was equally distributed between the groups in our study, this effect may be neutralized when comparing these groups. On the contrary, patients who used beta-blockers, either before or after PVI, had a significantly lower score on physical functioning, but not on the other seven subscales of the SF-36 questionnaire. Therefore, although it is not likely that the use of beta-blockers affected the QoL difference between the groups, it did affect the QoL of the patients using them.

132 Chapter 6

Rhythm control, with electrical cardioversion, AADs and anti-coagulants was not associ-ated with a change in QoL.

Indeed, one of the rationales behind detecting asymptomatic atrial fibrillation episodes could be the antithrombotic regimen in patients after catheter ablation. A common thought is that with the elimination of atrial fibrillation, not only AAD therapy becomes redundant but also antithrombotic drugs are no longer needed. Reynolds et al.23 showed, in a nonrandomized study, that patients who underwent atrial fibrillation ablation had a significantly lower rate of stroke and transient ischemic attack than patients who were treated with AADs. However, the AFFIRM study showed that pa-tients free of atrial fibrillation recurrences had an identical stroke risk to patients with recurrences.24 Also, patients without documented atrial fibrillation but with increased CHA2DS2VASc scores have an increased ischemic stroke risk.25 Moreover, the ASSERT study25 showed that stroke risk increased significantly with asymptomatic, device detected atrial fibrillation episodes as short as 6min. Therefore, and in agreement with the guidelines, anti-thrombotic therapy in patients with a history of atrial fibrillation should, in our opinion, be based on the presence (or absence) of stroke risk factors, us-ing the CHA2DS2VASc score, rather than on the presumed presence or absence of atrial fibrillation after catheter ablation. Thus, it is important to realize that catheter ablation has no consequences for antithrombotic therapy independently of the outcome. Atrial fibrillation patients with a high stroke risk (CHA2DS2VASc ≥1) should receive oral anti-thrombotic therapy, pre-ablation and post-ablation.2

Study limitations The current study has several limitations. The follow-up protocol was not standardized, as clinical data of our study population were collected retrospectively via charts from the referring hospitals, and therefore carry the burden of all retrospec-tive studies. It is not certain whether these patients were seen on a regular basis in other hospitals during the follow-up period. QoL was collected prospectively. Patients who did not complete questionnaires were excluded from this study, as were patients without follow-up data. This low response rate, possibly contributing to selection bias, is a well-known problem with postprocedural questionnaires. However, several arguments indicate that our study population represents a true life cohort of catheter ablation patients. First, a recurrence rate of 49% was seen in the remaining study population, congruent with previous efficacy studies on PVI procedures. Secondly, the percentage of recurrence was similar between responders and non-responders. Furthermore, this was not a prospective randomized controlled trial for which patients had to provide written informed consent and QoL was filled out at baseline by all patients. Patients who did not return the 1-year QoL questionnaire may well have refused signing such informed consent. These notions underscore the suggestion that the study population reflects a random selection of the complete PVI population in our center.

6


conclusIon

Quality of life is diminished in patients with atrial fibrillation and improves significantly after catheter ablation. However, QoL in patients with documentation of atrial fibrillation recurrence after ablation remains lower than that of the general population. These patients also have more electrocardiographic recordings during 12 months follow-up, suggesting more symptomatic episodes. QoL of patients without atrial fibrillation recur-rence did not differ from the general population anymore, even though these patients may have had asymptomatic episodes of atrial fibrillation.

Our study supports the notion that a successful PVI is an excellent treatment for improving QoL and reducing the symptoms of atrial fibrillation, which may be the most important goals of this therapy, as presumed absence of atrial fibrillation does not impact anticoagulation requirements.

134 Chapter 6

RefeRences 1. Benjamin EJ, Wolf PA, D’Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation

on the risk of death: the Framingham Heart Study. Circulation 1998;98:946-52. 2. Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the Task

Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Europace 2010;12:1360-420.



5. Verma A, Champagne J, Sapp J, et al. Discerning the incidence of symptomatic and asymptomatic episodes of atrial fibrillation before and after catheter ablation (DISCERN AF): a prospective, mul-ticenter study. JAMA Intern Med 2013;173:149-56.

6. de Groot JR. Reconnecting to the endpoint of atrial fibrillation ablation: should we mind the gaps? Europace 2013;15:157-8.

7. Bansch D, Bittkau J, Schneider R, et al. Circumferential pulmonary vein isolation: wait or stop early after initial successful pulmonary vein isolation? Europace 2013;15:183-8.

8. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22:983-8.

9. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the manage-ment 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. Europace 2012;14:1385-413.

10. Pappone C, Rosanio S, Oreto G, et al. Circumferential radiofrequency ablation of pulmonary vein ostia: A new anatomic approach for curing atrial fibrillation. Circulation 2000;102:2619-28.

11. Arruda MS, He DS, Friedman P, et al. A novel mesh electrode catheter for mapping and radio-frequency delivery at the left atrium-pulmonary vein junction: a single-catheter approach to pulmonary vein antrum isolation. Journal of cardiovascular electrophysiology 2007;18:206-11.

12. Koch L, Haeusler KG, Herm J, et al. Mesh ablator vs. cryoballoon pulmonary vein ablation of symp-tomatic paroxysmal atrial fibrillation: results of the MACPAF study. Europace 2012;14:1441-9.

13. Ouyang F, Bansch 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.

14. Aaronson NK, Muller M, Cohen PD, et al. Translation, validation, and norming of the Dutch lan-guage version of the SF-36 Health Survey in community and chronic disease populations. J Clin Epidemiol 1998;51:1055-68.

15. Ware JE, Jr., Kosinski M, Bayliss MS, McHorney CA, Rogers WH, Raczek A. Comparison of methods for the scoring and statistical analysis of SF-36 health profile and summary measures: summary of results from the Medical Outcomes Study. Med Care 1995;33:AS264-79.

16. Deshmukh A, Patel NJ, Pant S, et al. In-hospital complications associated with catheter ablation of atrial fibrillation in the United States between 2000 and 2010: analysis of 93 801 procedures. Circulation 2013;128:2104-12.

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17. Van Brabandt H, Neyt M, Devos C. Effectiveness of catheter ablation of atrial fibrillation in Belgian practice: a cohort analysis on administrative data. Europace 2013;15:663-8.

18. Weerasooriya R, Jais P, Hocini M, et al. Effect of catheter ablation on quality of life of patients with paroxysmal atrial fibrillation. Heart rhythm 2005;2:619-23.


20. Mantovan R, Macle L, De Martino G, et al. Relationship of quality of life with procedural success of atrial fibrillation (AF) ablation and postablation AF burden: substudy of the STAR AF randomized trial. Can J Cardiol 2013;29:1211-7.

21. Kapa S, Epstein AE, Callans DJ, et al. Assessing arrhythmia burden after catheter ablation of atrial fibrillation using an implantable loop recorder: the ABACUS study. Journal of cardiovascular electrophysiology 2013;24:875-81.

22. Hagens VE, Ranchor AV, Van Sonderen E, et al. Effect of rate or rhythm control on quality of life in persistent atrial fibrillation. Results from the Rate Control Versus Electrical Cardioversion (RACE) Study. Journal of the American College of Cardiology 2004;43:241-7.

23. Reynolds MR, Walczak J, White SA, Cohen DJ, Wilber DJ. Improvements in symptoms and quality of life in patients with paroxysmal atrial fibrillation treated with radiofrequency catheter ablation versus antiarrhythmic drugs. Circ Cardiovasc Qual Outcomes 2010;3:615-23.

24. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. The New England journal of medicine 2002;347:1825-33.

25. Hohnloser SH, Capucci A, Fain E, et al. ASymptomatic atrial fibrillation and Stroke Evaluation in pacemaker patients and the atrial fibrillation Reduction atrial pacing Trial (ASSERT). Am Heart J 2006;152:442-7.

Chapter 7Quality of Life Improves After Thoracoscopic Surgical Ablation of Advanced Atrial Fibrillation: Results of the Atrial Fibrillation Ablation and Autonomic Modulation via Thoracoscopic Surgery (AFACT) Study

Antoine H. G. Driessen *Wouter R. Berger *

Mark F. A. BierhuizenFemke R. Piersma

Nicoline W. E. van den BergJolien Neefs

Sébastien P. J. KrulWim Jan P. van Boven

Joris R. de Groot


J Thorac Cardiovasc Surg. 2018; 155:972-980.

138 Chapter 7

AbstRAct

ObjectiveWe evaluated health-related quality of life at 12 months after thoracoscopic surgical ablation in patients enrolled in the Atrial Fibrillation Ablation and Autonomic Modula-tion via Thoracoscopic Surgery (AFACT) study. The AFACT study assessed the efficacy and safety of ganglion plexus ablation in patients with symptomatic advanced atrial fibrillation undergoing thoracoscopic surgical ablation.

MethodsPatients (n = 240) underwent thoracoscopic pulmonary vein isolation with additional ablation lines in patients with persistent atrial fibrillation. Subjects were randomized to additional ganglion plexus ablation or control. Short Form 36 quality of life question-naires were collected at baseline and at 6 and 12 months of follow-up.

ResultsA total of 201 patients were eligible for quality of life analysis (age 59 ± 8 years, 72% were men, 68% had an enlarged left atrium, 57% had persistent atrial fibrillation). Patients improved in physical and mental health at 6 months (both P<.01) and 12 months (both P<.01) relative to baseline, with no difference between the ganglion plexus (n = 101) and control (n = 100) groups. Short Form 36 sub scores in patients with 1 or no atrial fibrilla-tion recurrences were similar to those in the general Dutch population after 12 months. Patients with multiple atrial fibrillation recurrences (30%) improved in mental (P<.01), but not physical health, and 6 of 8 Short Form 36 subscales remained below those of the general Dutch population. Patients with irreversible, but not with reversible procedural complications had persistently diminished quality of life scores at 12 months.

ConclusionsThoracoscopic surgery for advanced atrial fibrillation results in improvement in quality of life, regardless of additional ganglion plexus ablation. Quality of life in patients with no or 1 atrial fibrillation recurrence increased to the level of the general Dutch population, whereas in patients with multiple atrial fibrillation recurrences quality of life remained lower. Irreversible but not reversible procedural complications were associated with persistently lower quality of life.

7

Quality of life after thoracoscopic ablation of advanced AF 139

IntRoductIon

Atrial fibrillation (AF) is the most common cardiac arrhythmia, estimated to affect 33.5 million people worldwide. Its prevalence is increasing, as a result of the ageing popula-tion and the improved survival of chronic cardiovascular disease.1,2 Health related qual-ity of life (QoL) in AF patients is generally lower than the population norms.3 Rhythm control with catheter or surgical ablation is recommended for patients remaining symptomatic despite a trial with antiarrhythmic drugs (AAD), and invasive AF treatment may improve QoL.4 Following catheter ablation, QoL has been reported to improve, regardless of procedural success. It has been demonstrated that a substantial reduction in AF burden results in a significant improvement of QoL, whereas QoL changes less in patients with more AF recurrences.5-7 Similar to catheter ablation, thoracoscopic surgery for AF is performed to achieve freedom of AF and may further even reduce risk factors for stroke and heart failure.8 However, improvement of the patient’s symptoms remains central in the indication for invasive AF management.4 Thoracoscopic surgery for AF has been associated with high efficacy rates. It has been suggested that its higher efficacy goes at the cost of more procedural complications compared to catheter ablation, and therefore potentially negatively affects QoL.9 However, prospective data on QoL in pa-tients undergoing thoracoscopic surgery for AF is lacking. The Atrial Fibrillation ablation and AutonomiC Modulation via Thoracoscopic Surgery (AFACT) study demonstrated no efficacy of additional ganglion plexus (GP) ablation in patients with advanced AF under-going thoracoscopic AF surgery, but an increased incidence of complications compared to the control group.10 The aim of this prespecified sub study of AFACT was to determine the change in QoL following thoracoscopic AF ablation in relation to additional GP abla-tion, freedom of AF recurrence and procedural complications.

Methods

Study DesignThe AFACT study compared efficacy and safety of additional GP ablation to no additional GP ablation in patients with advanced paroxysmal or persistent AF undergoing thora-coscopic surgery for AF. The study was registered at clinicaltrials.gov (NCT01091389) and approved by the IRB of the Academic Medical Center. All patients provided written informed consent. The methods and main clinical findings have been published.10,11 In brief, the study included patients with advanced AF, that is, mostly persistent AF, with enlarged left atria or previously failed catheter ablation, refractory or intolerant to at least one anti-arrhythmic drug, undergoing thoracoscopic surgical ablation. All patients (n=240) were subjected to thoracoscopic pulmonary vein isolation (≥6 RF applications

140 Chapter 7

to the pulmonary vein antrum with the AtriCure IsolatorR Synergy™ bipolar RF ablation clamp). In patients with persistent AF additional left atrial lines were ablated conforming to the Dallas lesion set.12 Patients were randomized to either additional ablation of the four major ganglionic plexi and Marshall’s ligament (n=117) or no additional GP ablation (control group, n=123).

Clinical follow-upPatients were followed-up every three months with ECG and 24-hour Holter performed at every follow-up visit for one year. Patients were encouraged to obtain additional rhythm recording when symptomatic. AF recurrences were defined as any episode of AF, atrial tachycardia or atrial flutter documented on ECG or 24-hour Holter lasting >30 seconds. A blanking period of three months after the procedure was instituted during which AF recurrences were not considered a clinical endpoint.8 All AAD were discontinued three months after the procedure, unless the patient remained to have AF. Procedural complications were defined as major when causing (prolongation of ) hospital admission within 30 days.10 Of those, events were defined as irreversible when injury was permanent (i.e. pacemaker implantation, stroke or phrenic paralysis) or when the thoracoscopic procedure could not be completed.10

Health-Related Quality of Life FormAssessment of change in QoL was a pre-specified analysis of the AFACT study and SF-36 QoL questionnaires were filled out before randomization, and at 6 and 12 months follow-up. The SF-36 QoL questionnaire is a validated generic questionnaire to measure physical and mental health in individuals. It consists of 36 questions, grouped into eight scales, namely physical functioning (PF), role physical (RP), bodily pain (BP), social functioning (SF), mental health (MH), role emotional (RE), vitality (VT) and general health perception (GH). The eight scales are summarized in two dimensions, physical and mental component summary (PCS and MCS), normalized to an overall population mean±SD of 50±10. The eight scales and two summary dimensions are transformed to a scale from 0 to 100, where 100 is the best possible health, as described by Ware et al..13 The scores from a dataset displaying the QoL in the general Dutch population was used as a reference.14

Statistical AnalysisStatistical analyses were performed using SPSS version 23.0 and R for Windows version 3.1.1. Continuous data is reported as mean±SD and categorical data as number of sub-jects and proportions. As there were no differences in any of the SF-36 subscales, the treatment arms of AFACT were combined for the current analysis.

7


The baseline characteristics were compared using the Chi-square test for categorical data and Student’s unpaired t-test for normally distributed data or the Mann-Whitney U-test for non-normally distributed data. Normal distribution was tested with the Kol-mogorov- Smirnov test. Student’s unpaired t-test was used to compare the mean scores in SF-36 subscales between groups. To compare data from the SF-36 questionnaire with the reference population, a one-sample t-test was used. For comparing QoL on the eight subscales and two summary dimensions after thoracoscopic ablation relative to base-line the paired sample t-test was used. For univariable and multivariable analysis, simple linear regression and stepwise multivariable regression were used to study predictors for the change in MCS and PCS scores after 12 months. Graphic analyses of the residuals indicated that the assumptions of linear regression were met. All variables with p<0.01 in univariable analysis were entered in the multivariable regression. A p-value of <0.05 was considered significant.

Results

Study PopulationOf the 240 patients included in the AFACT study, 13 patients were not included in the present analysis: 4 patients died, 2 procedures were aborted and 7 patients were lost to follow-up. An additional 26 patients did not complete the SF-36 questionnaires either at baseline or at 6 or 12 months follow-up (9 in the GP group and 17 in the controls). For the present study, 201 patients with complete SF-36 questionnaires at baseline, 6 and 12 months (101 in the GP group and 100 in the control group) were analysed. Mean age was 59±8 years, 72% were men, mean left atrial volume index was 39.0±11.6ml/m2, and 114 (57%) patients had persistent AF. Baseline characteristics are displayed in Table 1.

Health Related Quality of LifeThere were no differences in QoL with respect to any of the eight SF subscales, nor on PCS or MCS between the GP ablation group and no GP ablation group at baseline, 6 months or 12 months (Figure 1, Table 2). Patients with advanced AF scored significantly lower than the general Dutch population before the ablation procedure in seven of the eight scales in SF-36, with the exception of bodily pain. PCS and MCS were 44.6±9.4 and 45.0±10.9 respectively. Table 3 shows that scores in all 7 subscales were significantly higher after 12 months in the full cohort. This increase was reached after 6 months and persisted up to 12 month. Subsequently, PCS and MCS were significantly higher after 6 and 12 months (p<0.001 and p<0.001 respectively).

142 Chapter 7


All(n=201)

No GP(n=100)

GP(n=101)

p-value

BaselineAge (years), mean±SD (range) 59.6±7.8

(39-73)60.0±7.4(39-72)

58.2±8.2(39-73)

0.10

Male, n (%) 145 (72) 72 (72) 73 (72) 1.00Type AF,Paroxysmal, n (%) 87 (43) 48 (48) 39 (39) 0.18Persistent, n (%) 114 (57) 52 (52) 62 (61) 0.18AF Duration (years), median [IQR] 4 [2-8] 5 [2-10] 4 [2-6] 0.25Congestive heart failure, n (%) 7 (4) 2 (2) 5 (5) 0.25Hypertension, n (%) 87 (43) 45 (45) 42 (42) 0.63Age ≥ 75, n (%) 0 (0) 0 (0) 0 (0) 1.00Diabetes, n (%) 13 (7) 7 (7) 6 (6) 0.76Stroke/TIA/Embolus, n (%) 16 (8) 8 (8) 8 (8) 0.98Vascular disease, n (%) 18 (9) 11 (11) 7 (7) 0.31Female gender, n (%) 56 (28) 28 (28) 28 (28) 0.84Age ≥ 65, n (%) 56 (28) 32 (32) 24 (24) 0.19CHA2DS2VASc-score, 0, n (%) 56 (28) 26 (26) 30 (30) 0.64 1, n (%) 66 (33) 31 (31) 35 (35) 0.66 ≥ 2, n (%) 79 (39) 43 (43) 36 (36) 0.31Previous catheter PVI, n (%) 51 (25) 26 (26) 25 (25) 0.84Previous PCI, n (%) 22 (11) 12 (12) 10 (10) 0.63Myocardial Infarction, n (%) 9 (5) 6 (6) 3 (3) 0.30BMI (kg/m2), mean±SD 27.1±3.8 26.9±3.3 27.3±4.3 0.47Echocardiographic parameters, Left Atrial Volume (ml), mean±SD 81.1±23.2 81.7±23.3 80.4±23.2 0.69 Left Atrial Volume Index (ml/m2), mean±SD 39.0±10.6 39.6±10.7 38.4±10.6 0.44 Left Atrial Diameter (mm), mean±SD 42.2±5.4 42.4±4.9 41.9±5.8 0.47 Left Ventricular Ejection Fraction (%),mean±SD 50.6±9.7 51.4±8.9 49.8±10.3 0.23Anti-arrhythmic drugs, Class IA, n (%) 4 (2) 2 (2) 2 (2) 1.00 Class IC, n (%) 69 (35) 35 (35) 34 (34) 0.84 Class II, n (%) 122 (49) 43 (43) 66 (56) 0.08 Class III, n (%) 79 (39) 40 (40) 39 (39) 0.59 Class IV, n (%) 27 (13) 16 (16) 11 (11) 0.84 Digoxin, n (%) 23 (11) 11 (11) 12 (12) 0.84Anticoagulants, Acenocoumarol, n (%) 153 (76) 71 (71) 82 (82) 0.90 Fenprocoumon, n (%) 21 (10) 13 (13) 8 (8) 0.24 NOAC, n(%) 26 (14) 16 (16) 10 (10) 0.20 Antiplatelets, n (%) 13 (7) 6 (6) 7 (7) 0.79

AF, atrial fibrillation; PVI, pulmonary vein isolation; PCI, percutaneous coronary intervention; TIA, transientischemic attack; BMI, Body Mass Index; MRI, Magnetic Resonance Imaging; AAD, Anti-arrhythmic drugs, NOAC: Non Vitamine K Oral Anticoagulants; SF-36, Short Form-36; QoL, Quality of Life;

7


ns ns ns

p<0.001 ns

0

20

40

60

80

PCS−score

Baseline 12 m6 m

ns ns ns

p<0.001 ns

0

20

40

60

80

MCS−score

Baseline 12 m6 m

Figure 1.Physical and mental component summariesPCS (A) and MCS (B) scores at baseline and 6 and 12 months after thoracoscopic ablation are shown for the GP ablation (blue) and control (white) arms of the study. PCS, physical component summary; MCS, mental component summary.

A B


All(n=201)

No GP(n=100)

GP(n=101)

p-value

SF-36 QoL Questionnaire, PCS, mean±SD 44.4±9.5 44.3±9.9 44.6±9.1 0.81 MCS, mean±SD 44.6±11.0 43.5±10.6 45.7±11.3 0.15 Physical Functioning, mean±SD 66.5±25.6 67.3±25.8 65.7±25.5 0.66 Role Physical, mean±SD 37.2±42.7 36.4±42.15 38.0±43.4 0.79 Bodily Pain, mean±SD 81.7±21.9 79.5±22.5 83.7±21.1 0.17 Social Functioning, mean±SD 67.4±24.7 64.8±23.5 70.0±25.7 0.13 Mental Health, mean±SD 72.0±17.6 70.9±16.8 73.5±18.3 0.30 Role Emotional, mean±SD 71.9±41.6 68.7±43.0 75.0±40.0 0.29 Vitality, mean±SD 49.1±21.2 48.2±21.9 50.0±20.6 0.54 General Health Perception, mean±SD 60.9±19.2 59.7±19.7 62.2±18.7 0.37

SF-36, Short Form-36; QoL, Quality of Life; PCS, Physical Component Summary; MCS, Mental Component Summary

144 Chapter 7

7


Table 3. Mean changes from baseline to 6 and 12 month of follow-up

6 months change vs baseline p-value

12 months change vs baseline p-value

Entire cohort, n 201 201

PCS 4.0 (2.6 to 5.4) <0.001 4.0 (2.7 to 5.4) <0.001

Physical functioning 13.3 (10.1 to 16.4) <0.001 13.7 (10.4 to 17.0) <0.001

Role physical 27.1 (20.0 to 34.3) <0.001 31.5 (24.2 to 38.8) <0.001

Bodily pain 0.6 (-2.5 to 3.6) 0.721 -1.4 (-4.6 to 1.9) 0.41

General health perceptions 5.5 (2.6 to 8.3) <0.001 5.2 (2.6 to 7.8) <0.001

MCS 5.0 (3.5 to 6.5) <0.001 5.3 (3.8 to 6.8) <0.001

Social functioning 14.2 (10.9 to 17.4) <0.001 13.3 (10.1 to 16.6) <0.001

Mental health 7.1 (5.1 to 9.2) <0.001 7.1 (5.0 to 9.1) <0.001

Role emotional 8.8 (2.2 to 15.3) 0.010 11.3 (5.1 to 17.5) <0.001

Vitality 14.8 (12.1 to 17.5) <0.001 15.6 (12.9 to 18.4) <0.001

No AF recurrence group, n 141 141

PCS 5.4 (3.8 to 7.0) <0.001 5.8 (4.3 to 7.4) <0.001

Physical functioning 15.3 (11.6 to 19.0) <0.001 16.9 (13.1 to 20.8) <0.001

Role physical 35.6 (27.1 to 44.1) <0.001 38.0 (29.4 to 46.7) <0.001

Bodily pain 0.6 (3.1 to 4.3) 0.752 -0.1 (-3.7 to 3.6) 0.976

General health perceptions 8.3 (4.9 to 11.7) <0.001 8.8 (5.7 to 11.8) <0.001

MCS 4.9 (3.2 to 6.7) <0.001 5.3 (3.5 to 7.0) <0.001

Social functioning 15.9 (11.9 to 19.8) <0.001 15.9 (12.0 to 19.7) <0.001

Mental health 7.1 (4.6 to 9.6) <0.001 8.1 (5.6 to 10.5) <0.001

Role emotional 7.1 (-0.3 to 14.6) 0.061 9.7 (2.2 to 17.3) 0.012

Vitality 16.8 (13.8 to 19.9) <0.001 17.8 (14.5 to 21.0) <0.001

AF Recurrence group, n 60 60

PCS 0.7 (-1.8 to 3.3) 0.567 -0.4 (-2.7 to 1.9) 0.719

Physical functioning 8.6 (2.6 to 14.6) 0.006 6.1 (0.0 to 12.2) 0.051

Role physical 7.2 (-4.9 to 19.0) 0.226 15.9 (2.5 to 29.4) 0.021

Bodily pain -0.5 (-5.1 to 6.0) 0.869 -4.5 (-11.2 to 2.2) 0.189

General health perceptions -1.1 (-6.2 to 4.0) 0.674 -3.2 (-7.9 to 1.5) 0.182

MCS 5.2 (2.3 to 8.2) 0.001 5.3 (2.4 to 8.2) 0.001

Social functioning 10.2 (4.4 to 16.0) 0.001 7.3 (1.4 to 13.2) 0.016

Mental health 7.3 (3.6 to 10.9) <0.001 4.9 (-0.9 to 8.8) 0.017

Role emotional 12.6 (1.2 to 26.5) 0.072 14.9 (4.3 to 25.9) 0.008

Vitality 10.1 (4.5 to 15.8) 0.001 10.7 (5.7 to 15.6) <0.001

Data are presented as mean (95% CI). AF, Atrial Fibrillation; PCS, Physical Component Summary; MCS, Men-tal Component Summary

144 Chapter 7

7


Tabl

e 4.

Cha

nge

in P

hysi

cal C

ompo

nent

Sum

mar

y an

d M

enta

l Com

pone

nt S

umm

ary

No

GP

(n=1

01)

GP

(n=1

00)

p

No

AF

Recu

rren

ce(n

=141

)A

F Re

curr

ence

(n=6

0)p

No

Maj

or A

E(n

=170

)M

ajor

AE

(n=3

1)p

Reve

rsib

le A

E(n

=36)

Irre

vers

ible

AE

(n=1

0)p

Base

line

PCS

44.3

±9.9

44.6

±9.1

0.81

444

.8±9

.743

.6±8

.80.

415

44.8

±9.4

42.6

±9.7

0.23

443

.2±9

.341

.7±1

0.4

0.67

MCS

43.5

±10.

645

.7±1

1.3

0.15

145

.4±1

0.2

42.7

±12.

60.

112

44.4

±11.

045

.8±1

0.9

0.53

444

.5±1

1.0

49.6

±10.

80.

20

6 m

onth

s

PCS

47.5

±9.7

49.6

±9.0

0.12

850

.3±8

.944

.6±9

.5<0

.001

49.1

±9.0

45.3

±11.

10.

039

46.6

±9.3

43.9

±13.

00.

48

MCS

48.6

±9.7

50.7

±8.8

0.10

650

.5±8

.847

.7±1

0.1

0.05

049

.7±9

.049

.3±1

0.8

0.83

149

.3±1

0.7

52.6

±8.3

0.39

12 m

onth

s

PCS

48.2

±9.1

49.3

±9.8

0.43

651

.0±8

.343

.6±1

0.0

<0.0

0149

.3±8

.945

.8±1

1.7

0.06

246

.2±1

0.5

42.9

±11.

10.

40

MCS

49.4

±9.1

51.1

±9.1

0.18

151

.2±8

.448

.0±1

0.3

0.02

350

.8±8

.747

.6±1

0.7

0.08

350

.2±9

.647

.3±1

2.5

0.45

Dat

a ar

e pr

esen

ted

as m

ean±

SD. G

P, G

angl

ion

Plex

us a

blat

ion;

AF,

Atr

ial F

ibril

latio

n; A

E, A

dver

se E

vent

; PCS

, Phy

sica

l Com

pone

nt S

umm

ary;

MCS

, Men

tal C

ompo

nent

Su

mm

ary

146 Chapter 7

Adverse EventsThe complications during the course of the study have previously been published, and major procedural complications occurred more often in patients undergoing GP abla-tion (10). In the present analysis, 31 patients (15%) had major procedural complications and 16 patients (8%) had minor complications. Ten major complications (5%) were ir-reversible. Table 4 shows that there was no difference in any of the SF-36 subscales or on PCS and MCS at baseline in patients with compared to patients without any major procedural complications. Figure 2A shows that patients with irreversible procedural complications (most often consisting of pacemaker implantation) did not demonstrate improvement on MCS and subscales, compared to the patients without complications. Patients with reversible periprocedural events or bleeding, eventually improved to the same extent as patients without (Figure 2B). Consequently, there were no significant differences on the combined scores or any of the sub scores between patients with and without reversible complications at 12 months.

Table 5. Univariable and multivariable predictors of change in PCS and MCS scores at 12 months after thoracoscopic surgical ablation

Change in PCS after 12 months

Change in MCS after 12 months

Univariable Multivariable Univariable Multivariable

B p B p B p B p

Age (years) -0.097 0.245 0.003 0.979

Gender (female) 0.103 0.945 -0.027 0.988

Type AF (persistent) -0.384 0.775 -0.866 0.581

AF duration (years) -0.098 0.448 -0.030 0.840

History of PVI (yes) -2.436 0.114 -0.089 0.961

CHA2DS2-VASc -0.424 0.422 0.833 0.175

BMI -0.196 0.267 0.287 0.163

AF Recurrences at 6 months FU (yes) -5.049 0.004 -1.312 0.550 -3.429 0.095 -1.288 0.424

AF Recurrences at 12 months FU (yes) -6.037 <0.001 -5.373 0.001 -1.318 0.434

Anti-arrhythmic drugs at 6 months FU (yes) -5.841 0.002 -3.408 0.068 -1.834 0.404

Anti-arrhythmic drugs at 12 months FU (yes) -0.004 0.681 -0.005 0.659

Major Adverse Events (yes) -1.574 0.384 -4.147 0.049 -3.23 0.049

GP ablation (yes) 1.175 0.376 -0.201 0.897

QoL at baseline -0.485 <0.001 -0.536 <0.001 -0.651 <0.001 -0.616 <0.001

PCS, Physical Component Summary; MCS, Mental Component Summary; AF, atrial fibrillation; PVI, pulmo-nary vein isolation; CHA2DS2VASc, congestive heart failure [C], hypertension [H], age > 75 years (2 points) [A2], diabetes [D], previous stroke (2 points) [S2], vascular disease [V], age 65-74 years [A], female sex [Sc]; BMI, body mass index; AAD, Antiarrhythmic drug; GP, ganglion plexus; QoL, quality of life.

7


Absence of AFOf the total study population, 141 patients (70%) discontinued AAD and did not experi-ence AF recurrence during one year of follow-up. Irrespective of AF absence, 83% of patients (n=167) were not using AAD at 12 months follow-up.

At baseline, no significant differences were observed in any of the SF-36 subscales and PCS and MCS between patients who would experience AF recurrence versus those without AF recurrence. As expected, and consistent with the finding in the entire cohort, BP was similar in AF patients at baseline as in the general Dutch population. Table 3 summarizes the change in SF 36 subscales during follow-up in patients with and without AF recurrences. Thirty-three patients (16%) had an AF recurrence before they completed the 6 months follow-up SF-36 questionnaire.

These patients did not show improvement on any of the eight subscales, whereas patients without recurrence at 6 months showed significant improvement on 7/8 sub-scales, except on BP and in PCS and MCS (PCS: p<0.001, MCS: p<0.001) at 6 months.

Figure 2.Radar chart with the SF-36-scoresThe octagonal axes for each SF-36 subscale read excentric from central (30) to peripheral (100). The dif-ferent conditions within 1 subscale can be read from the individual axes, whereas the surface of the en-tire graph indicates the aggregate QoL. QoL at baseline (red), 6 months follow-up (blue), and 12 months follow-up (green) are shown for (A) patients with irreversible complications and (B) patients with reversible complication during the procedure or 12 months follow-up. Dutch population means are denoted by the dashed orange lines. RE, role emotional; VT, vitality; PF, physical functioning; RP, role functioning; BP; bodily pain; GH, general health; SF, social functioning; MH, mental health.

A B

148 Chapter 7

After 12 months, patients with AF recurrences had lower scores on 6/8 subscales than those without AF recurrences with exception of BP and RE. Similarly, PCS and MCS were significantly lower in patients with AF recurrences, compared to patients without AF recurrence (p=0.001 and p=0.023 respectively).

In the AF recurrence group PCS did not significantly change compared to baseline (p=0.567), but MCS did increase after 12 months (p=0.001). QoL-scores remained decreased in PF, RP, SF, VT and GH in these patients (Figure 3). Twenty-seven (13%) patients had no recurrence at 6 months but at least one recurrence at 12 months follow-up. In those patients, PCS was significantly lower than in patients without AF at both 6 (p=0.021) and 12 months (p=0.001). MCS was equal compared to the non-recurrence group at 6 months (p=0.332), but was significantly decreased at 12 months follow-up (p=0.032).

Role of the number of documented AF recurrencesTo evaluate the effect of the AF burden, we compared the change in SF-36 scores in patients with one AF recurrence (n=19), versus those with multiple AF recurrences (n=41). There were no significant differences in any of the subscales or in PCS and MCS at baseline. Furthermore, baseline QoL subscale scores were not different from the patients without AF recurrences. Figure 4 summarizes that patients with only one AF recurrence improved on the SF-36 subscales, similar to the group with no AF recurrence, whereas in patients with multiple AF recurrences SF-36 subscales did not change after

Figure 3. Radar charts with SF-36 scores.Radar charts with the SF-36 scores at baseline (red), 6 months follow-up (blue), and 12 months follow-up (green) is shown for (A) patients without AF recurrence, (B) patients with 1 AF recurrence, (C) and patients with more than 1 AF recurrence. Dutch population means are denoted by the dashed orange lines. RE, role emotional; VT, vitality; PF, physical functioning; RP, role physical; BP, bodily pain; GH, general health; SF, social functioning; MH, mental health.

A B

7


the procedure and remained significantly lower than that of the general Dutch popula-tion.

Predictors of change in Quality of LifeTable 5 displays the univariable and multivariable predictors of change in MCS and PCS scores after 12 months relative to baseline. In multivariable analysis, AF recurrence within 12 months (p=0.001) and PCS at baseline (p<0.001) remained independent predictors of decreased PCS. For MCS, only the experience of having a major proce-dural complications (p=0.049) and MCS-score at baseline (p<0.001) were predictors of decrease at 12 months in univariable analysis. In multivariable analysis, these factors remained independent predictors of decreased MCS.

dIscussIon

In this predefined sub analysis of the AFACT study we demonstrate that QoL significantly increases after thoracoscopic surgery in all patients with advanced AF, both with and without GP ablation. We show that QoL improves in the entire cohort following thora-coscopic surgery. The most important determinant of absence of QoL improvement was

Figure 4. Improvement of QoL in relation to recurrences of AF.A radar chart with the SF-36 scores of patients with more than 1 AF recurrence (red), 1 AF recurrence (blue), and no AF recurrences (green) is shown at 12 months follow-up after thoracoscopic AF surgery. Dutch population means are denoted by the dashed orange lines. RE, Role emotional; VT, vitality; PF, physical functioning; RP, role physical; BP, bodily pain; GH, general health; SF, social functioning; MH, mental health; AF, atrial fibrillation.

A B

150 Chapter 7

AF recurrence. Patients with AF recurrences had a lower QoL than those without. Also, patients with a recurrence after >6 months showed a decreased at 12 month QoL com-pared to 6 months. One single AF recurrence appears to only temporarily decrease QoL, as in those patients there was no difference in the SF-36 subscales or in the domains compared to patients without AF after 12 months. Multiple AF recurrences, however, were associated with a significantly decreased QoL. Baseline QoL, AF recurrence and procedural complications independently predicted a lower QoL. This observation sug-gests that AF recurrence and the burden of recurrences, rather than the characteristics or invasiveness of the surgical procedure drive the change in QoL. Also that a baseline low QoL, is associated with limited improvement after surgery. These data support the use of AF symptoms, as advocated in the guidelines, as an indication for invasive therapy.8,15 Patients with complications of the procedure had no increase of the SF-36 subscales. However, in patients in whom the procedural complications appeared reversible, the lack of QoL increase was temporary, as these patients had a similar QoL as patients with-out complications at 12 months. Hence, the higher number of reversible complications after surgical ablation compared to catheter ablation, as reported by Boersma et al.9, appears not to affect QoL during follow-up in patients with advanced AF included in the AFACT study.10 Conversely, in patients with irreversible complications, pacemaker implantation in particular, QoL remained at the same decreased level as compared to before the procedure. The AFACT study reported more irreversible adverse effects in patients with GP ablation.10

Potentially, omitting GP ablation may decrease the number of irreversible complica-tions and consequently increase QoL after thoracoscopic surgery for AF.

Quality of Life after AF ablationImprovement of AF related symptoms is the primary objective of invasive treatment strategies for AF. However, improvement of QoL (beyond AF related symptoms) is the most important objective of the patient undergoing the treatment. Subsequently, the results of QoL questionnaires may influence the cost-effectiveness of AF ablation and therefore affect the choice of therapy in patients with AF refractory to AAD.

Previous studies on QoL after catheter ablation demonstrated significant improve-ment after ablation, particularly in patients without AF recurrence.16-18 Studies that com-pared catheter ablation to antiarrhythmic drug therapy reported that QoL scores were significantly higher in patients who underwent catheter ablation than in patients with AAD treatment.19-21 Small, non-randomized studies have reported an improvement of QoL after thoracoscopic surgery for AF, similar to the change in QoL that was observed after catheter ablation.22,23 These observations are in line with the current study in pa-tients with advanced AF undergoing a thoracoscopic procedure, which is more invasive than a catheter procedure. The absolute change in the different SF-36 scales in our study

7


was larger than in the QoL sub study of the SAFE-T study, investigating restoration of sinus rhythm with antiarrhythmic drugs, but a minimal clinically important difference in SF-36 scales has not been defined for AF.24 Our results imply that the recurrence of arrhythmia and not the perceived invasiveness of the procedure drives the change in QoL. In this prespecified sub analysis of the AFACT study, we demonstrate that in the overall population of patients undergoing thoracoscopic surgical ablation for AF, there is a significant increase in SF-36 assessed QoL at 6 months after ablation, which remains after 12 months after the procedure. A relatively constant and remaining increase in QoL after various cardiac surgery procedures has been described.25 We further show that the rhythm outcome of the procedure influences the gain in QoL. Patients without recur-rence improved significantly more than patients with AF recurrences. The latter showed an increase in mental health status after the procedure, but not in physical health. AF recurrence was defined as at least one episode of symptomatic or asymptomatic AF recorded on ECG or on 24-hour Holter, lasting more than 30 seconds. As this is an all-or-non definition, it does not take into account how symptoms relate to the burden of AF. We here show that patients in whom a single AF recurrence is documented during one year of follow-up, improve in QoL similar to patients without AF recurrences. However, multiple AF recurrences is associated with absence of QoL improvement. We found no QoL difference with regard to gender.26

Previous studies investigated the impact of the AF burden or symptom burden on QoL after catheter ablation. Similar to the results after thoracoscopic surgery presented here, patients with a high burden of AF show no improvement or even a decrease of QoL after catheter ablation. Furthermore, patients with demonstrated AF recurrences, but with a low AF burden, showed significant QoL improvement after ablation.27 Also, it has been shown that patients with symptomatic AF before ablation may experience asymptomatic episodes after the procedure.28 Evidently, asymptomatic AF recurrences are unlikely to affect QoL.

Study LimitationsAFACT was designed to evaluate the efficacy of GP ablation on AF outcome in patients undergoing thoracoscopic surgery for AF. Although the study was not designed, nor powered for specific changes in QoL, changes in the overall QoL as measured by the SF-36 questionnaire were a prespecified endpoint. The main driver of QoL outcome in this analysis was AF recurrences, although one of the multivariable predictors of lack of QoL increase was a preexisting low PCS or MCS. It cannot be excluded that patients were more likely to report improved QoL, because all underwent a procedure. However, the difference in reported outcome between patients with and without AF recurrences or irreversible complications argues against that. It should be noted that, although we followed up patients more rigorously than the guidelines require,8 periodic Holter

152 Chapter 7

monitoring may underestimate the true incidence of AF recurrences. However, as as-ymptomatic AF recurrences are not expected to affect general QoL, this likely did not affect our conclusions. The current analysis was restricted to one year of follow-up. Is cannot be excluded that during a longer follow-up period different results are achieved, in particular with respect to patients with (irreversible) procedural complications.

conclusIon

Patients with symptomatic advanced AF undergoing thoracoscopic surgery for AF had a substantial improvement in quality of life, regardless of additional GP ablation.

AF recurrences were the most important determinant for lack of QoL improvement. QoL in patients without or with a single AF recurrence increased to values similar to the Dutch reference population. Patients with multiple AF recurrences had no increase in QoL and remained at the low baseline level. Irreversible, but not reversible, complica-tions of the procedure were associated with lack of QoL improvement.

7


RefeRences 1. Chugh SS, Havmoeller R, Narayanan K, et al. Worldwide epidemiology of atrial fibrillation: a Global

Burden of Disease 2010 Study. Circulation 2014;129:837-47. 2. Naccarelli GV, Varker H, Lin J, Schulman KL. Increasing prevalence of atrial fibrillation and flutter

in the United States. Am J Cardiol 2009;104:1534-9. 3. Hagens VE, Ranchor AV, Van Sonderen E, et al. Effect of rate or rhythm control on quality of life in

persistent atrial fibrillation. Results from the Rate Control Versus Electrical Cardioversion (RACE) Study. Journal of the American College of Cardiology 2004;43:241-7.

4. Kirchhof P, Breithardt G, Bax J, et al. A roadmap to improve the quality of atrial fibrillation manage-ment: proceedings from the fifth Atrial Fibrillation Network/European Heart Rhythm Association consensus conference. Europace 2016;18:37-50.


6. Fichtner S, Deisenhofer I, Kindsmuller S, et al. Prospective assessment of short- and long-term quality of life after ablation for atrial fibrillation. Journal of cardiovascular electrophysiology 2012;23:121-7.

7. Erdogan A, Carlsson J, Neumann T, et al. Quality-of-life in patients with paroxysmal atrial fibrillation after catheter ablation: results of long-term follow-up. Pacing Clin Electrophysiol 2003;26:678-84.






13. Ware JE, Kosinski M, Keller SD. SF-36 Physical and Mental Health Summary Scales: A User’s Manual. Boston, MA: The Health Institute, New Engeland Medical Center 1994.

14. Aaronson NK, Muller M, Cohen PD, et al. Translation, validation, and norming of the Dutch lan-guage version of the SF-36 Health Survey in community and chronic disease populations. J Clin Epidemiol 1998;51:1055-68.

15. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrilla-tion developed in collaboration with EACTS. European heart journal 2016;37:2893-962.

16. Reynolds MR, Walczak J, White SA, Cohen DJ, Wilber DJ. Improvements in symptoms and quality of life in patients with paroxysmal atrial fibrillation treated with radiofrequency catheter ablation versus antiarrhythmic drugs. Circ Cardiovasc Qual Outcomes 2010;3:615-23.

17. Walfridsson H, Walfridsson U, Nielsen JC, et al. Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation: results on health-related quality of life and symptom burden. The MANTRA-PAF trial. Europace 2015;17:215-21.

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18. Berger WR, Krul SP, van der Pol JA, et al. Documented atrial fibrillation recurrences after pulmo-nary vein isolation are associated with diminished quality of life. J Cardiovasc Med (Hagerstown) 2016;17:201-8.

19. Wilber DJ, Pappone C, Neuzil P, et al. Comparison of antiarrhythmic drug therapy and radiofre-quency catheter ablation in patients with paroxysmal atrial fibrillation: a randomized controlled trial. JAMA 2010;303:333-40.

20. Jais P, Cauchemez B, Macle L, et al. Catheter ablation versus antiarrhythmic drugs for atrial fibril-lation: the A4 study. Circulation 2008;118:2498-505.

21. Wazni OM, Marrouche NF, Martin DO, et al. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a randomized trial. JAMA 2005;293:2634-40.

22. Pruitt JC, Lazzara RR, Dworkin GH, Badhwar V, Kuma C, Ebra G. Totally endoscopic ablation of lone atrial fibrillation: initial clinical experience. Ann Thorac Surg 2006;81:1325-30; discussion 30-1.

23. Kasirajan V, Spradlin EA, Mormando TE, et al. Minimally invasive surgery using bipolar ra-diofrequency energy is effective treatment for refractory atrial fibrillation. Ann Thorac Surg 2012;93:1456-61.

24. Singh SN, Tang XC, Singh BN, et al. Quality of life and exercise performance in patients in sinus rhythm versus persistent atrial fibrillation: a Veterans Affairs Cooperative Studies Program Sub-study. Journal of the American College of Cardiology 2006;48:721-30.

25. Grady KL, Lee R, Subacius H, et al. Improvements in health-related quality of life before and after isolated cardiac operations. Ann Thorac Surg 2011;91:777-83.

26. Shah SV, Kruse J, Andrei AC, et al. Gender differences in outcomes after surgical ablation of atrial fibrillation. The Journal of thoracic and cardiovascular surgery 2016;151:391-8 e2.

27. Mantovan R, Macle L, De Martino G, et al. Relationship of quality of life with procedural success of atrial fibrillation (AF) ablation and postablation AF burden: substudy of the STAR AF randomized trial. Can J Cardiol 2013;29:1211-7.

28. Verma A, Champagne J, Sapp J, et al. Discerning the incidence of symptomatic and asymptomatic episodes of atrial fibrillation before and after catheter ablation (DISCERN AF): a prospective, mul-ticenter study. JAMA Intern Med 2013;173:149-56.

Part IIIDeterminants of the substrate of advanced atrial fibrillation: the

role of atrial fibrosis

Chapter 8Atrial Fibrosis and Conduction Slowing in the Left Atrial Appendage of Patients Undergoing Thoracoscopic Surgical Pulmonary Vein Isolation for Atrial Fibrillation

Sébastien P.J. KrulWouter R. Berger

Nicoline W. SmitShirley C.M. van Amersfoorth

Antoine H.G. DriessenWim Jan van Boven

Jan W.T. FioletAntoni C.G. van Ginneken

Allard C. van der WalJacques M.T. de Bakker

Ruben CoronelJoris R. de Groot

Circ Arrhythm Electrophysiol. 2015 Apr;8(2):288-95

160 Chapter 8

AbstRAct

BackgroundAtrial fibrosis is an important component of the arrhythmogenic substrate in patients with atrial fibrillation (AF). We studied the effect of interstitial fibrosis on conduction velocity (CV) in the left atrial appendage of patients with AF.

Methods and ResultsThirty-five left atrial appendages were obtained during AF surgery. Preparations were superfused and stimulated at 100 beats per minute. Activation was recorded with opti-cal mapping. Longitudinal CV (CVL), transverse CV (CVT), and activation times (>2 mm distance) were measured. Interstitial collagen was quantified and graded qualitatively. The presence of fibroblasts and myofibroblasts was assessed immunohistochemically. Mean CVL was 0.55±0.22 m/s, mean CVT was 0.25±0.15 m/s, and the mean activation time was 9.31±5.45 ms. The amount of fibrosis was unrelated to CV or patient character-istics. CVL was higher in left atrial appendages with thick compared with thin interstitial collagen strands (0.77±0.22 versus 0.48±0.19 m/s; P=0.012), which were more frequently present in persistent patients with AF. CVT was not significantly different (P=0.47), but activation time was 14.93±4.12 versus 7.95±4.12 ms in patients with thick versus thin interstitial collagen strands, respectively (P=0.004). Fibroblasts were abundantly present and were associated with the presence of thick interstitial collagen strands (P=0.008). Myofibroblasts were not detected in the left atrial appendage.

ConclusionsIn patients with AF, thick interstitial collagen strands are associated with higher CVL and increased activation time. Our observations demonstrate that the severity and structure of local interstitial fibrosis is associated with atrial conduction abnormalities, presenting an arrhythmogenic substrate for atrial re-entry.

8

Atrial fibrosis and conduction in patients with AF 161

IntRoductIon

In patients with atrial fibrillation (AF), an increased amount of fibrosis is found in the atria.1,2 Atrial fibrosis is an important component of the arrhythmogenic substrate in patients with AF.3 Fibrosis can be arrhythmogenic by increasing the extracellular matrix collagen content, separating atrial myocytes, and increasing the length of activation pathways, or by direct fibroblast–cardiomyocyte coupling resulting in an increased passive electric load to the cardiomyocytes.4,5 In particular, myofibroblasts differentiated fibroblasts that develop during pathological stimuli contribute to the pathological fibrotic remodeling and couple directly with cardiomyocytes have been described.6,7 The changes in fibrosis formation and (myo)fibroblast–cardiomyocyte interaction can facilitate re-entry after a premature beat emanating from the pulmonary veins. The effect of the quantity and the structural organization of fibrosis on atrial conduction abnormalities in man is unknown. Animal experiments show an increase in the heterogeneity of conduction as a result of increased interstitial fibrosis.8,9 We studied the amount and organization of interstitial fibrosis and investigated the effect of interstitial fibrosis on conduction characteristics in the left atrial appendages (LAAs) from patients with AF.

Methods

Thoracoscopic Surgery Thirty-five LAAs were obtained from patients with AF during thoracoscopic surgery, as described before.10 The patient characteristics are shown in Table. The study was in accordance with the declaration of Helsinki and approved by the Institutional Review Board. All patients gave written informed consent. The LAAs were removed using an endoscopic stapling device (Endo Gia stapler, Tyco Healthcare Group). The tissue samples were transported to the optical mapping setup in 100-mL cooled superfusion fluid (Na+, 155.5 mmol/L; K+, 4.7 mmol/L; Ca2+, 1.45 mmol/L; Mg2+, 0.6 mmol/L; Cl−, 136.6 mmol/L; HCO3−, 27 mmol/L; PO43−, 0.4 mmol/L; glucose, 11.1 mmol/L; and heparin, 1000 IE).

Optical MappingPreparations were submerged in a tissue bath. The superfusion fluid was kept at a tem-perature of 36.5°C to 37.5°C and oxygenized with a mixture of 95% O2 and 5% CO2 to maintain a pH of 7.4. All LAAs were stimulated at 100 beats per minute at twice diastolic threshold with a pulse width of 2 ms using an epicardial electrode. In 6 LAA prepara-tions, short-coupled premature stimuli were applied and optical mapping recordings were made of the shortest conducting S1–S2 interval. The preparation was equilibrated for ≥30 minutes. Di-4ANEPPS (Tebu Bio) was used as a membrane potential-sensitive

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fluorescent dye. A contraction uncoupler 2 to 10 mmol/L 2-3-butanedione monoxime (DAM; Sigma-Aldrich, B0753) was added if motion artifacts precluded recording of fluo-rescent action potentials (n=7). A MiCAM Ultima camera (SciMedia USA Ltd) was used to record epicardial images of an area of 1 cm2 with a resolution of 100×100 pixels and a sample time of 0.5 ms. Images were stored using MiCAM Ultima Experiment Manager. A custom-made analysis program based on MATLAB R2006b (The MathWorks, Inc) was used to construct epicardial activation maps. The occurrence of motion artifacts pre-cluded analysis of the repolarization of the LAA.

Measurement of Conduction VelocityLocal activation times (ATs) were determined from the steepest upstrokes of the optical action potential at each pixel. Activation maps were constructed from local ATs. To as-sess conduction velocity (CV), a line was drawn in the activation map in the direction of the activation wavefront (Figure 1). Subsequently, ATs were plotted against the distance from the stimulation site. This relation allowed for identification of the latency close to the stimulation site and breakthrough of multiple wave fronts at larger distance of the stimulation site. CV was calculated from the slope of the linear portion of the relation between distance to the stimulation site and AT. Local longitudinal CV (CVL) and local transverse CV (CVT) were calculated from the line starting at the point of earliest acti-vation along, which activation spread most rapidly, and the line perpendicular to that respectively, assuming that this represented fiber direction. In addition, to assess the influence of fibrotic barriers on gross transverse conduction delay in the LAA, the AT was measured along an arbitrarily chosen 2-mm line on the activation maps perpendicular to the fiber direction at the site of greatest transverse conduction slowing (Figure 1).

Collagen Quantification and OrganizationAfter optical mapping, the LAAs were frozen at −80°C with liquid nitrogen. Slides were prepared from the recording area of the LAA. Picrosirius red staining was performed for visualization and quantification of interstitial collagen in 32 LAAs. Three to 5 photographs from each section of randomly selected areas were taken of nonoverlapping fields at ×10 magnification. The percentage of interstitial collagen of the total tissue (collagen and cardiomyocytes) was determined, after manual exclusion of epicardial, endocardial and perivascular fibrosis.11,12 Two independent observers (blinded to the origin of the sections) assessed the width of interstitial collagen strands (ICS) qualitatively (Figure 2). The width of the ICS was assessed and qualified as predominantly containing either thin (±<0.01 mm) or thick fibrotic strands (±≥0.01 mm).

8


Fibroblast HistologyFibroblasts were identified with antivimentin antibody (1:2000, DAKO, M0725) and an indirect peroxidase (3-amino-9-ethylcarbazole peroxidase) was used as the substrate in 27 LAAs. Sections were faintly counterstained with additional hematoxylin staining and 3 to 5 photographs of different, randomly selected areas were taken of nonoverlapping fields at ×20 magnification. The density of fibroblasts in the tissue was semiquantitatively

Figure 1.(A) Illustration of an activation map with a line drawn in direction of the activation wavefront. In the graph (B) the activation times (ATs) are plotted against the distance from the stimulus site. The latency (L) and potential breakthrough (Br) of multiple wave fronts are identified. The slope of the linear portion of the relation between distance and AT (a) is used to calculate the conduction velocity (CV). (C) Typical example of an activation map (1 cm2) of left atrial appendage (LAA). The isochronal lines are 2 ms apart and color scale is in ms; red represents the earliest and purple the latest activation. The graph (D) shows the ATs along the solid and striped lines in the activation map, which are drawn perpendicular to the isochronal lines for longitudinal and transverse conduction, respectively. CVL indicates longitudinal CV; CVT, transverse CV; and S, stimulation.

A B

C D

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assessed optically by 2 independent observers, blinded for section origins, based on the density of fibroblasts scattered throughout the tissue area (excluding microvessels). Two groups were identified (intermediate, ±<30% of tissue area and many, ±>30% of tis-sue area). All immunohistochemical staining included the use of positive and negative controls with omission of the primary antibody and stained using the same techniques.

Myofibroblast Histologyα–smooth muscle actin (α-SMA) antibody’s (1:800, Sigma, A2547) was used for stain-ing of myofibroblasts in 27 LAAs. Because α-SMA stains pericytes and vascular smooth muscle tissue as well, an antiCD31 antibody staining (1:500, DAKO, M0823) was per-formed to stain endothelial cells. Cell nuclei were stained with Sytox green (1:1000, Molecular Probes, S-7020). The combination of costaining of α-SMA and CD31 indicates microvasculature. Isolated α-SMA positive cells in the interstitium were considered to be myofibroblasts. Three to 5 photographs of different areas were taken of nonoverlapping fields at ×20 and ×40 magnification in each LAA to identify interstitial myofibroblasts. All immunohistochemical staining included the use of positive and negative controls with omission of the primary antibody and stained using the same techniques.

StatisticsData are presented as mean±SD for normally distributed continuous variables or me-dian and empirical limits for non-normally distributed variables. Categorical variables are presented in numbers with percentages. Differences were determined using an independent Student t test for normally distributed data or a Mann–Whitney U test for non-normally distributed data. To assess correlation in normally distributed data, the Pearson was used and in case of nonparametric data Spearmans was used. P<0.05 was

Figure 2.(A) Example of the picrosirius red staining of a left atrial appendage (LAA) with thick interstitial collagen fibers (ICS). The red color represents collagen and the yellow/orange staining represents cardiomyocytes. (B) An LAA with thin ICS.

A B

8


considered significant. Statistical analyses were performed using IBM SPSS Statistics version 20.

Results

Conduction VelocityMean CVL was 0.55±0.22 m/s and mean CVT was 0.25±0.15 m/s. Median anisotropy was 3.1 (1.05–13.4). CVL and CVT were not significantly different in patients with paroxysmal or persistent AF (CVL: P=0.25 and CVT: P=0.51). Other patient characteristics were not associated with CVL or CVT. In particular, the use of sodium channel blocking drugs flecainide and amiodarone were not related to CVL (P=0.94) or CVT (P=0.14). Mean AT was 9.31±5.45 ms. AT was not different between patients with paroxysmal or persistent AF (P=0.15). Patient characteristics, including the use of sodium channel blocking drugs flecainide and amiodarone were not associated with AT (P=0.76). A total of 7 LAAs required DAM to reduce motion artefacts. CVL (P=0.47), CVT (P=0.28), and AT (P=0.62) between the LAAs exposed to DAM and other LAAs were similar.

In the 6 LAAs with premature stimulation (shortest S1–S2 interval; mean 250 ms [200–260 ms]), CVL was 0.44 m/s [0.33–0.56 m/s] at baseline and 0.30 m/s [0.15–0.40 m/s; P=0.046] at shortest S1–S2 interval. CVT was 0.24 m/s (0.46– 0.06 m/s) at baseline and 0.16 m/s (0.05–0.25 m/s; P=0.12) at shortest S1–S2 interval. AT increased significantly from 4.73 ms (3.33–6.90 ms) to 8.08 ms (4.35–13.33 ms; P=0.028). Activation maps of the shortest captured S1–S2 interval showed prolonged ATs and clear lines of conduction block, that were absent during stimulation at basic cycle length.

Figure 3 shows 2 representative activation maps from the same LAA. In this LAA, the CVL was 0.46 m/s and CVT was 0.27 m/s at baseline. Note that at the short-coupled pre-mature stimuli the activation pattern shows a zig-zag pattern, calculated CVL was 0.15 m/s and CVT was 0.13 m/s, whereas the apparent CV along line C is 0.06 m/s. However, if we follow the activation wavefront (line D), circumventing the area of conduction block, apparent CV along the activation wavefront is 0.23 m/s.

Interstitial FibrosisIn 4 LAAs, severe artefacts precluded the semiquantitative analysis of interstitial colla-gen. In the remaining 28, the collagen content was 16.8±7.5%. There was no significant difference in the percentage of collagen between patients with paroxysmal and persis-tent AF (P=0.22). CVL and CVT were not associated with the amount of collagen (CVL: P=0.098 and CVT: P=0.91). However, a larger degree of transverse conduction delay was observed in patients with a high amount of collagen (AT: P=0.015). Other clinical charac-

166 Chapter 8

teristics of the patients, including left atrial size were not associated with the interstitial collagen content.

After qualitative assessment, 24 LAAs contained mainly thin ICS, whereas 8 LAAs had a mainly thick ICS. Thick strands were more often found in patients with a high degree of interstitial collagen content (mean 14.0% versus 21.1%; P=0.027). In addition, 7 of the 8 patients with thick ICS had persistent AF. CVL was higher in patients with thick ICS of 0.77±0.22 m/s compared with thin ICS of 0.48±0.19 m/s (P=0.012). CVT was not signifi-cantly different between samples with thick ICS and thin ICS (0.24±0.14 m/s compared with 0.22±0.16 m/s; P=0.47; Figure 4). However, AT was significantly higher in patients with thick ICS compared with patients with thin ICS (14.93±6.93 versus 7.95±4.12 ms; P=0.004).

Figure 3.Effect of a short coupled extrastimulus on conduction. (A) activation map (1 cm2) of the left atrial appendage (LAA) during pacing at 600 ms, isochrones at 2 ms. (B) Activation map of a short coupled extrastimulus of 250 ms. Over the red line crossing a line of block, ap-parent conduction velocity (CV) is 0.06 m/s. The black line shows the true direction of the activation wave-front, circumventing the line of block, with an appar-ent CV of 0.23 m/s. (C) Associated optical tracings of action potentials under the red line in (B). The maxi-mum dv/dt (activation times) are marked with circles, which show conduction block along the line.

A B

C

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Table 1. Patients characteristics

LAA(n=35)

Age, mean ± SD, years 58±9

Male, n (%) 20 (57)

Years of AF, mean ± SD, years 7±7

Type AF



CHA2DS2-VASc, median, limits 2 (0-4)

0-1 16 (46)

≥2 19 (54)

Medication

Flecainide, n (%) 11 (31)

Beta-blockers, n (%) 19 (54)

Sotalol, n (%) 7 (20)

Amiodarone, n (%) 3 (9)

Calcium-antagonists, n (%) 7 (20)

Echocardiographic atrial volume index, mean ± SD, mL/m2* 41±13

*Atrial volume indexed for the body surface area of the patient determined <6 months before surgery.AF: atrial fibrillation, SD: standard deviation.

Figure 4.Influence of the quantity and quality of fibrosis on conduction velocity (CV) and activation time (AT). (A) No correlation between the amount of fibrosis and longitudinal CV (CVL) and transverse CV (CVT), but correla-tion with AT (P=0.015). (B) Qualitative analysisreveals that a higher CVL is observed in samples with thick interstitial collagen fibers (ICSs) between cardiomyocytes (P=0.012). No influence of width of interstitial fibrosis is found on CVT. A longer AT is observed in the patients with thick ICS (P=0.004).

A B

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Fibroblast HistologyFibroblasts were abundantly present (intermediate, n=10 and many, n=17). A high den-sity of fibroblasts was associated with a high CVL as shown in Figure 5 (intermediate, 0.44±0.11 m/s versus many, 0.71±0.24 m/s; P=0.007). No differences were observed in CVT (intermediate, 0.21±0.09 m/s versus many, 0.30±0.20 m/s; P=0.66) and AT (interme-diate, 9.67±3.95 ms versus many, 10.64±6.68 ms; P=0.90). Furthermore, all the specimens with thick ICS also had many fibroblasts (P=0.008).

Myofibroblast HistologyThe combination of α-SMA and CD31 staining revealed a significant amount of intersti-tial atrial microvasculature, composed of CD31 positive smooth muscle cells bordered by a rim of α-SMA positive pericytes. Myofibroblasts could not be identified in the LAA (n=27) because no isolated α-SMA positive interstitial cells were present (Figure 6).

Figure 5.(A) Section of a left atrial appendage is shown with intermediate fibroblast stain-ing. (B) Section with a high number of fi-broblasts. (C) High number of fibroblasts was associated with a higher longitudi-nal CV (CVL; P=0.007), whereas no differ-ence is found in transverse CV (CVT). CV indicates conduction velocity.

100µm 100µm

A B

C

8


dIscussIon

This study shows that the structural local components of fibrosis, specifically the col-lagenous interstitial matrix, played an important role in modulating CVL and CVT in LAAs obtained from patients undergoing antiarrhythmic surgery for AF. Patients with persistent AF or high degree of interstitial collagen had predominantly thick ICS. This was associated with increased CVL, whereas local CVT was not affected. In spite of increased CVL, more transverse activation delay was present in these preparations and areas of activation block occurred, leading to zig-zag conduction. More pronounced slowing of conduction was observed after short-coupled stimuli. They also induced lines of conduction block, which were absent under baseline stimulation. Fibroblasts were abundantly present in the human LAA, and was associated with thick ICS and a high CVL. No myofibroblasts were detected in the LAAs.

The Role of Fibrosis in the Arrhythmogenic Substrate of AFThe patients undergoing thoracoscopic surgery for AF had a mean amount of 16.8% fi-brosis. In a study investigating patients with AF with or without mitral valve disease 7.6% fibrosis was reported in the LAAs of patients with lone AF and 10.7% in patients with mitral valve disease using similar methods of fibrosis quantification.1 The patients in our study are patients with highly symptomatic AF with an indication for surgical treatment.

Figure 6.High contrast pictures of the combined fluorescence of Sytox Green (cell nuclei, blue), CD31 (endothelial cells, red), and α-SMA (α–smooth muscle actin; myofibroblasts, pericytes and vascular smooth muscle tis-sue, green) at ×20 (A) and ×40 (B) magnification. Contrast is increased to visualize the background staining of the cardiomyocytes with CD31 (red) and α-SMA (green). Both the transverse and the longitudinal myo-cardial fibers are visible. The yellow and red\ green costaining reveals the microvasculature. No isolated α-SMA staining, indicating the presence of myofibroblasts, could be found.

A B

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The high amount of fibrosis in our patients might be explained by large atria, older age, and a greater predominance of persistent AF compared with earlier studies. However, no single patient characteristic was associated with the amount of fibrosis in the LAA in our data. In our patients, the organization of interstitial collagen rather than the amount was associated with conduction changes.9 The contribution of fibrosis to the arrhythmogenic mechanism has been extensively studied in monolayers of cultured myocytes, animal models, and in human ventricular myocardium.4,9,13,14 In our experiments, we observed the induction of activation delay, caused by propagation of the activation front around inexcitable barriers of collagen. In these LAAs, CV was only modestly affected, possibly because of increased transverse fiber separation.4,15 This may result in a heterogeneity of conduction, such as the occurrence of unidirectional conduction block and re-entry, facilitating both the induction and the maintenance of AF.16 At baseline, pacing some LAAs showed a high anisotropy and activation delay. High anisotropy might facilitate the development of AF because of ectopic foci.17 In the presence of short-coupled premature stimuli, such as during AF, lines of conduction block developed, and the activation wavefront propagated around this area of block (Figure 3).

CV is also determined by excitability and coupling, mediated by the voltage-gated sodium channels and connexins, respectively.18 Therefore, we cannot fully exclude that changes in CV between patients might be related to changed function or expression of the voltage-gated sodium channels and (lateralization of ) connexins.2,18 However, a severe reduction in functional gap junction, as well as a reduced voltage gated sodium channels would result in a reduced CV, whereas we observed an increase in CVL and a unaffected CVT. These findings illustrate the local arrhythmogenic effect of fibrosis in the pathophysiology of AF, but our data do not permit conclusions about the question whether fibrosis is a result or the cause of AF.19

The Role of Fibroblasts in the Substrate of AFA high density of fibroblasts in the LAA was associated with thick ICS, suggesting a local increase of extracellular matrix deposition. The increased extracellular matrix results in a separation between cardiomyocytes and subsequently in an increase in CVL.14 In in-silico models, fibroblasts have been described to act as passive electric load and to depolarize cardiomyocyte resting membrane potential through gap junctional coupling with myocytes.7 However, only the myofibroblast, a differentiated form of the fibroblast, connects to cardiomyocytes in in-vitro cell layer models.5,20 This connection can result in discontinuous slow conduction and induces spontaneous electric activity.21 Our observations argue against such a mechanism in the patients that we studied because CVL was increased in the presence of a high density of fibroblasts, which is not expected if reduced direct coupling is present. Alternatively, fibroblasts might exert their influ-ences on CV by a paracrine mechanism. In cell-cultures, a significant paracrine effect was

8


found on CV, resulting in reduced CV.22 However, our data showed an increase in CVL in the presence of many fibroblasts, thus it is unlikely that the paracrine influences on CV have a major role in these patients.

The Role of Myofibroblasts in the Substrate of AFIn response to pathological stimuli, fibroblasts differentiate into myofibroblasts.23 In our selected population of patients with symptomatic AF and enlarged atria undergoing thoracoscopic surgery for AF, no myofibroblasts were detected in the LAAs. However, myofibroblasts might play a more prominent role in other, more acute, causes of AF (eg, valvular AF, AF after ischemia, and experimental models)24,25 or in the earlier phases of AF. There, the myofibroblasts might contribute to an increase in extracellular matrix and subsequently differentiate to inactive fibrocytes in a later phase of the disease.

Clinical ImplicationsThe major finding of our study is that in patients with AF, an arrhythmogenic substrate for atrial re-entry is present, caused by the deposition of collagen. It may be conceivable that thick collagen strands anchor rotors that sustain human AF. Identification of the patients with severely affected fibrotic atria might help to guide therapeutic decision-making. Recent studies using noninvasive characterization of the fibrotic phenotype using MRI have shown an inverse relation between the success of catheter ablation for AF and the amount of fibrosis present in the atrium.26 Although present imaging techniques allow the detection of large areas of fibrosis, future developments might increase the resolution and enable the detection of smaller fibrotic strands.

Fibrosis consists of a dynamic substrate of fibroblasts and extracellular matrix in which collagen turnover is between 3% and 5% per day.27 A reduction in extracellular matrix se-cretion by fibroblasts or the prevention of the formation or migration of myofibroblasts, could possibly reduce or alter the deposition of collagen and could be a potential target of upstream therapy. Studies already have already demonstrated a moderate effect of upstream therapy in the setting of primary prevention.28 However, it is unclear whether secondary prevention can induce reverse remodeling and dissolve this arrhythmogenic substrate.29

lIMItAtIons

Because of the nature of surgery, we could obtain only LAAs, but no left atrial samples without cardioplegia for the electrophysiological experiments. Also, we were not able to obtain tissue from healthy control patients. It is unclear whether the LAA myocytes are different from the rest of the atrium. The distribution and amount of interstitial collagen

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in the LAA probably reflects the fibrotic changes in the left atrium, although no study has investigated the distribution of fibrotic remodeling throughout the entire human atrium. However, a similar amount of (increased) fibrosis was observed at different parts of the left atrium in patients with AF.30

Our model of the LAA provides a unique opportunity to study the atrial substrate in patients with AF. All patients underwent the procedure under general anesthesia and remained on antiarrhythmic drugs. These drugs could have influenced the electrophysi-ological findings in the LAA. However, no relation of the antiarrhythmic drugs with CV, especially sodium channel blocking drugs was observed. After administration of DAM to the superfusion medium, a certain degree of motion artifact remained. Although DAM can influence the electrophysiological properties of the LAA, the LAA samples that received DAM were limited (n=7), were evenly distributed among the groups and did not deviate from results of samples without DAM. Because of motion artifacts induced by LAA contraction, determination of action potential characteristics other than the upstroke (ie, repolarization) could not be reliably performed.

conclusIons

In patients undergoing thoracoscopic surgery for AF, the structural local interstitial components of fibrosis modulate conduction in the LAA. Patients with persistent AF had more thick interstitial fibrotic strands, which was associated with an increased longitu-dinal CV, consistent with a separation of myocardial fibers. Local transverse conduction was not affected by these fibrotic strands, but activation delay was present because of areas of activation block. Slowing of conduction and increased areas of conduction block were observed after short-coupled stimuli, but were absent under baseline stimulation. Fibroblasts were abundantly present in the human LAA and were associated with thick interstitial fibrotic strands and increased longitudinal conduction. However, myofibro-blasts were absent in the human LAAs. Our observations demonstrate that the severity and structure of local interstitial fibrosis is associated with atrial conduction abnormali-ties, presenting an arrhythmogenic substrate for atrial re-entry.

AcknowledgMents

We thank N. van Geloven, PhD, for her help with the statistical analysis of our data; P. Teeling, J.B.G. Mulder, and P.H.M. Ploegmakers for the work on the LAA sections; and A.A.M. Wilde, MD, PhD, for his critical review of our article.

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12. Rasband WS. ImageJ. 2013. 13. Spach MS, Dolber PC. Relating extracellular potentials and their derivatives to anisotropic

propagation at a microscopic level in human cardiac muscle. Evidence for electrical uncoupling of side-to-side fiber connections with increasing age. Circ Res 1986;58:356-71.

14. Spach MS, Boineau JP. Microfibrosis produces electrical load variations due to loss of side-to-side cell connections: a major mechanism of structural heart disease arrhythmias. Pacing Clin Electrophysiol 1997;20:397-413.

15. Koura T, Hara M, Takeuchi S, et al. Anisotropic conduction properties in canine atria analyzed by high-resolution optical mapping: preferential direction of conduction block changes from longitudinal to transverse with increasing age. Circulation 2002;105:2092-8.

16. Wu TJ, Ong JJ, Hwang C, et al. Characteristics of wave fronts during ventricular fibrillation in hu-man hearts with dilated cardiomyopathy: role of increased fibrosis in the generation of reentry. J Am Coll Cardiol 1998;32:187-96.

17. Wang YG, Kumar R, Wagner MB, et al. Electrical interactions between a real ventricular cell and an anisotropic two-dimensional sheet of model cells. Am J Physiol Heart Circ Physiol 2000;278:H452-60.

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18. Nattel S, Maguy A, Le Bouter S, Yeh YH. Arrhythmogenic ion-channel remodeling in the heart: heart failure, myocardial infarction, and atrial fibrillation. Physiol Rev 2007;87:425-56.

19. Schotten U, Verheule S, Kirchhof P, Goette A. Pathophysiological mechanisms of atrial fibrillation: a translational appraisal. Physiol Rev 2011;91:265-325.

20. Rohr S. Arrhythmogenic implications of fibroblast-myocyte interactions. Circ Arrhythm Electro-physiol 2012;5:442-52.

21. Miragoli M, Salvarani N, Rohr S. Myofibroblasts induce ectopic activity in cardiac tissue. Circ Res 2007;101:755-8.

22. Pedrotty DM, Klinger RY, Kirkton RD, Bursac N. Cardiac fibroblast paracrine factors alter im-pulse conduction and ion channel expression of neonatal rat cardiomyocytes. Cardiovasc Res 2009;83:688-97.

23. Vasquez C, Mohandas P, Louie KL, Benamer N, Bapat AC, Morley GE. Enhanced fibroblast-myocyte interactions in response to cardiac injury. Circ Res 2010;107:1011-20.

24. Park JH, Pak HN, Lee S, Park HK, Seo JW, Chang BC. The clinical significance of the atrial subendo-cardial smooth muscle layer and cardiac myofibroblasts in human atrial tissue with valvular atrial fibrillation. Cardiovasc Pathol 2013;22:58-64.

25. Burstein B, Libby E, Calderone A, Nattel S. Differential behaviors of atrial versus ventricular fibroblasts: a potential role for platelet-derived growth factor in atrial-ventricular remodeling differences. Circulation 2008;117:1630-41.

26. 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.

27. Laurent GJ. Dynamic state of collagen: pathways of collagen degradation in vivo and their pos-sible role in regulation of collagen mass. Am J Physiol 1987;252:C1-9.

28. Savelieva I, Kakouros N, Kourliouros A, Camm AJ. Upstream therapies for management of atrial fibrillation: review of clinical evidence and implications for European Society of Cardiology guide-lines. Part I: primary prevention. Europace 2011;13:308-28.

29. Savelieva I, Kakouros N, Kourliouros A, Camm AJ. Upstream therapies for management of atrial fibrillation: review of clinical evidence and implications for European Society of Cardiology guide-lines. Part II: secondary prevention. Europace 2011;13:610-25.

30. Platonov PG, Ivanov V, Ho SY, Mitrofanova L. Left atrial posterior wall thickness in patients with and without atrial fibrillation: data from 298 consecutive autopsies. J Cardiovasc Electrophysiol 2008;19:689-92.

Chapter 9The Change in Circulating Galectin-3 Predicts Absence of Atrial Fibrillation after Thoracoscopic Surgical Ablation

Wouter R. BergerBenoît Jagu

Nicoline W.E. van den BergDean R.P.P. Chan Pin Yin

Jan P. van StraalenOnno J. de Boer

Antoine H.G. DriessenJolien Neefs

Sébastien P.J. KrulWim Jan P. van BovenAllard C. van der Wal

Joris R. de Groot

Europace. 2018, 20:764-771.

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AbstRAct

AimsGalectin-3 (Gal-3) is an important mediator of cardiac fibrosis, particularly in heart fail-ure. Increased Gal-3 concentration (Gal-3), associated with increased risk of developing atrial fibrillation (AF), may reflect atrial fibrotic remodeling underlying AF progression. We aimed to investigate whether the change in serum Gal-3 reflects alterations of the ar-rhythmogenic atrial substrate following thoracoscopic AF surgery, and predicts absence of AF.

Methods and resultsConsecutive patients undergoing thoracoscopic AF surgery were included. Left atrial appendages (LAAs) and serum were collected during surgery and serum again 6months thereafter. Gal-3 was determined in tissue and serum. Interstitial collagen in the LAA was quantified using Picrosirius red staining. Ninety-eight patients (76% male, mean age 60±9 years) underwent thoracoscopic surgery for advanced AF. Patients with increased Gal-3 after ablation compared to baseline had a higher recurrence rate compared to patients with decreased or unchanged Gal-3 (HR 2.91, P=0.014). These patients more frequently had persistent AF, longer AF duration and thick atrial collagen strands (P=0.049). At baseline, Gal-3 was similar between patients with and without AF recur-rence: 14.8±3.9 mg/ L vs. 13.7±3.7 mg/L, respectively in serum (P=0.16); 94.5±19.4 mg/L vs. 93.3±30.8mg/L, respectively in atrial myocardium (P=0.83). There was no correlation between serum Gal-3 and left atrial Gal-3 (P=0.20), nor between serum Gal-3 and the percentage of fibrosis in LAA (P=0.18).

ConclusionThe change of circulating Gal-3, rather than its baseline value, predicts AF recurrence after thoracoscopic ablation. Patients in whom Gal-3 increases after ablation have a high recurrence rate reflecting ongoing profibrotic signalling, irrespective of arrhythmia continuation.

9

Galectin-3 in atrial fibrillation 179

IntRoductIon

Atrial fibrillation (AF) is the most common cardiac arrhythmia in man with a projected increase in prevalence in the years to come.1 Atrial fibrillation is a progressive disease and causes both electrical and structural remodeling. The latter has been shown partially to depend on fibrosis formation in the left atrium.2 In patients with advanced AF, that is, usually with enlarged left atria, history of pulmonary vein isolation (PVI) and persistent AF, atrial fibrosis is assumed to importantly contribute to the arrhythmogenic substrate of AF.3

Non-invasive quantification of atrial fibrosis may be of help in selecting patients for (invasive) rhythm control. Determining the amount of fibrosis in the atria in a clinical setting, however, remains challenging. Detecting and quantifying atrial fibrosis is pos-sible with delayed-enhancement magnetic resonance imaging (MRI), and relates to AF ablation outcome, but is time-consuming, complex and difficult to reproduce.4

Galectin-3 (Gal-3) is a soluble beta-galactoside binding lectin and has been shown to be an important mediator of cardiac fibrosis.5 Increased secretion of Gal-3, produced by macrophages and fibroblasts, stimulates the release of TGF-beta and promotes cardiac fibroblast proliferation, collagen deposition and ventricular dysfunction.6 Gal-3 was demonstrated to have prognostic value for mortality both in the general population as in patients with chronic heart failure.7 However, Gal-3 might also reflect ongoing atrial fibrosis and prognosis after ablation in patients with AF.8 For instance, an association of high circulating Gal-3 concentration (Gal-3) with increased risk of developing AF9 and increased Gal-3 in patients with persistent AF compared to paroxysmal AF has been reported.10

Currently, both the statistical and biological relation between circulating Gal-3 and its concentration in atrial tissue are unknown. We studied Gal-3 in serum and left atrial tis-sue in patients undergoing thoracoscopic surgery for AF, as well as the change in serum Gal-3 during follow-up. We studied if the baseline value of Gal-3, or rather the change in Gal-3 upon elimination of AF via thoracoscopic AF surgery reflects the profibrotic processes that drive the arrhythmogenic substrate. This implies that elimination of AF, as determinant of fibrosis formation, would separate those patients in whom Gal-3 is determined by AF (who would benefit from elimination of AF) from those in whom dif-ferent processes drive Gal-3 (who would have more AF recurrences).

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Methods

Study populationNinety-eight consecutive patients with symptomatic, advanced AF (paroxysmal or persistent) who were refractory or intolerant for at least one class I or III antiarrhythmic drug and underwent thoracoscopic surgical ablation for AF were included in this study.

Paroxysmal AF was defined as self-terminating episodes of AF, during up to 7 days. Atrial fibrillation was classified as persistent AF when episodes lasted longer than 7 days, up to one year, in accordance with current ESC guidelines.11 In all patients transthoracic echocardiography (TTE), non-gated magnetic resonance imaging (MRI), ECG and 24-h holter monitoring were performed before surgical ablation. The study was approved by the institutional Medical Ethics Committee and was conducted in accordance with the declaration of Helsinki.

Thoracoscopic surgical ablationThoracoscopic surgical ablation was performed in all patients as described previously.12

Seventy-four patients reported here were also included in the AFACT study, a random-ized trial comparing additional GP ablation to no GP ablation in patients undergoing thoracoscopic surgical ablation.13

In all patients, pulmonary veins were isolated using a bipolar radiofrequency clamp (Atricure Inc.). In a group of patients (n = 60), the four main ganglionic plexi (GP) were ablated based on anatomical landmarks and in 38 patients the GPs were left untouched, according to randomization in AFACT.13

In patients with persistent AF, additional left atrial ablation lines were performed conforming to the Dallas lesion set,14 consisting of a superior line connecting right and left antral pulmonary vein isolation islands and a left fibrous trigone line, connecting the superior line to the left fibrous trigone at the level of the aortic annulus, and serving as a mitral isthmus line. All additional lines were tested for bidirectional block.12 In all patients the left atrial appendage was removed using an endoscopic stapling device.

Follow-upAll patients were followed in the outpatient clinic every 3 months for two years after surgical ablation in accordance with the HRS/EHRA/ECAS Expert Consensus Statement.15 During every follow-up visit electrocardiography (ECG) and 24-h holter monitoring were performed. Patients were encouraged to visit a physician when symptomatic. Atrial fibrillation recurrences were defined as any atrial tachyarrhythmia lasting > 30 s docu-mented on ECG or 24-h holter monitoring.

9


Concentration of galectin-3 in bloodPeripheral blood samples were taken from patients before the surgical procedure and after 6 months of follow-up. Blood samples were collected in ethylenediaminetetra acetic acid (EDTA)-containing tubes, immediately processed and frozen at −80C for later measurement of Gal-3.

The Gal-3 was analysed using an enzyme-linked immunosorbent assay kit (BG Medicin Inc., Waltham, Massachusetts USA), based on a manual sandwich ELISA method using microtiterplates. The tests were performed according to the recommendations of the manufacturer.

NT proBNP was performed on a COBAS C8000 Modular Analyser (Roche Diagnostics GmbH, Mannheim, Germany) based on an automated sandwich ELISA method using two monoclonal antibodies. Reagents were obtained from Roche Diagnostics GmbH, Mannheim, Germany. Patients that had an AF recurrence that occurred before their follow-up blood was collected, were excluded from the analysis on change of Gal-3 upon thoracoscopic AF ablation and AF recurrence.

Concentration of galectin-3 in left atrial tissueLeft atrial appendages were snap frozen in liquid nitrogen directly upon removal in the operating room. Parts were fixed in formalin and embedded in paraffin wax upon removal in the operating room. Freshly frozen left atrial appendage tissue from all patients was thawed, rinsed in phosphate-buffered saline fluid to remove excess of blood, weighted and minced in small pieces. The tissue was homogenized in ice-cold lysis buffer contain-ing: 50 mM Tris-HCl pH = 7,4, NaCl 150 mM, 1 mM EDTA 1% NP-40, sodium deoxycholate 0.5%, SDS 0.1%. Extemporaneously, lysis buffer was supplemented with NaF (50 mM), phenylmethylsulfonyl fluoride (1 mM), NaV04 (1 mM) and protease inhibitor cocktail (Roche). Tissues were homogenized with MAGNALyser (Roche). Lysates were incubated for 30 min at 4 °C on orbital shaker, and centrifuged for 15 min at 10 500 rpm at 4 °C. Supernatants were collected, aliquoted and stored at −80 °C. Total protein concentration was determined by BCA protein assay method (Thermo Scientific Pierce BCA Protein Assay Kit). Galectin-3 levels from LAA tissue were measured using enzyme-linked im-munosorbent assay (BG Medicine Inc., Waltham, Massachusetts USA) and normalized for total protein concentration. All assays were performed in duplicate.

Collagen quantification and organization in left atrial tissueSlides were prepared from paraffin embedded left atrial samples and stained with Picro-sirius red for visualization and quantification of interstitial collagen. Slides were digitized at 20x magnification using iScan HT scanner (Ventana, AZ, USA) and from each slide 20 photographs of randomly selected, non-overlapping fields were used for analyses. The percentage of collagen of the total tissue (collagen and cardiomyocytes) was deter-

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mined, after manual exclusion of epicardial, endocardial, and perivascular fibrosis, using an automated image analysis with Image J software.16

The width of interstitial collagen strands was assessed qualitatively. The strands were qualified as either thin ( ± <0.01 mm) or thick fibrotic strands ( ± >0.01 mm), as previously described.3

Statistical analysisContinuous variables are presented as mean ±standard deviation (SD) when normally distributed, as median [interquartile range] for non-normally distributed data and as pro-portions for categorical variables. Comparison of continuous variables was performed using the unpaired Student’s t-test and of categorical variables using the Pearson χ2 test. To correlate serum Gal-3 with Gal-3 in tissue a Pearson correlation was used. Linear regression was used to investigate the relationship between clinical variables with base-line serum and left atrial Gal-3 as dependent variable in a univariable analysis. Logistic regression was used to investigate the relation of clinical variables with increase of Gal-3 after thoracoscopic AF surgery. Multivariable analyses included variables with a p-value <0.1 found on univariable analysis and were performed to identify independent predic-tors. To determine AF recurrence rate, event-free survival was plotted and estimated by Kaplan–Meier curves and Cox regression analyses was performed for subgroup analyses. A P-value <0.05 was considered statistically significant. Statistical analyses were per-formed using SPSS (version 23, SPSS Inc, Chicago, IL, USA).

Results

Study populationBaseline characteristics of the study population are summarized in Table 1. Mean age of the patients was 59.8 ± 8.6 years (range 40–75), and 74 (76%) were male. Forty-four (45%) patients had paroxysmal and 54 (55%) persistent AF. Patients with persistent AF had significantly higher serum levels of NT-proBNP (115.5 [IQR 88.5–216] vs. 426 [IQR 206–920.3], P < 0.001) and larger left atrial volume index (LAVI) than patients with paroxysmal AF (35.5 ± 10.7 mL/m2 vs. 40.8 ± 12.3 mL/m2, P = 0.029). Mean serum Gal-3 was 14.1 ± 3.8 µg/L (14.2 ± 4.2 µg/L in paroxysmal AF and 14.1 ± 3.6 µg/L in persistent AF, P = 0.97). There was no significant correlation between serum Gal-3 at baseline and age, gender, type of AF, duration of AF or LAVI. Hypertension was the only independent fac-tor associated with baseline serum Gal-3 after correcting for multiple clinical parameters (P = 0.01).

9


Change of serum galectin-3 following thoracoscopic ablation for atrial fibrillation and atrial fibrillation recurrenceAfter a mean follow-up of 20.7 ± 4.7 (range 6.6–27.7) months, 61 patients (62%) had no recurrence of AF and discontinued the use of anti-arrhythmic drugs. Seventy-seven percent (n = 34) of patients with paroxysmal and 50% (n = 27) of patients with persistent AF were free of AF and AAD after a single thoracoscopic procedure.

Galectin-3 concentration at follow-up was significantly higher in patients with AF recurrence (15.4 µg/L vs. 13.2 µg/L, P = 0.002) after a median of 210 [IQR 184–234] days follow-up. The mean difference in serum Gal-3 at follow-up compared to baseline was 0.5 µg/L in patients with AF recurrence vs. a decrease of 0.6 µg/L in patients without AF

Table 1. - Baseline characteristics

n = 98

Baseline Characteristics

Age(years), mean (sd), (range) 59.8±8.6 (40-75)

Male, n (%) 74 (76)

Type AF



AF duration (years), median [IQR] 3 [2-7]


LA volume index (ml/m2), meand (sd) 38.5 (11.8)

LV Ejection Fraction (%), mean (sd) 50.2 (10.3)

Body mass index (kg/m2), mean (sd) 27.3 (3.7)

CHA2DS2VASc-score

0 29 (30)

1 27 (28)

≥ 2 32 (42)







Age ≥ 65, n (%) 30 (31)

AF, atrial fibrillation; LA, left atrial; LV, left ventricular; PVI, pulmonary vein isolation; TIA, transient ischemic attack

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recurrence. Fifteen patients had recurrence of AF after the blanking period, but before the follow-up blood samples were collected. As we studied AF elimination as a driver of Gal-3 change, these patients were excluded for further analysis of procedural outcome.

Patients with Gal-3 above the median of 14 µg/L during follow-up, indeed had more frequent AF recurrence than patients with Gal-3 ≤ 14 µg/L (hazard ratio (HR) 2.71 (95%CI 1.14–6.47), P = 0.019) (Figure 1). Patients with Gal-3 >14 µg/L at follow-up were more often females, were older and had higher CHA2DS2-VASC-scores. Serum NT-proBNP concentration during follow-up was significantly higher in patients with Gal-3 >14 µg/L (P = 0.005) and LVEF was significantly lower (P = 0.040).

Patients with increased serum Gal-3 (n = 47) after ablation in relation to baseline had a higher AF recurrence rate than those in whom Gal-3 decreased or was unchanged (HR 2.91 (95%CI 1.19–7.15, log rank P = 0.014) (Figure 2). The significant difference between AF recurrence in patients with increased serum Gal-3 vs. those in whom Gal-3 decreased, remained when the patients with early AF recurrence (after blanking and before blood sampling at 6 months) were included (HR 1.93, 95%CI 1.00–3.72, P = 0.045). The mean difference in serum Gal-3 between baseline and follow-up was 2.5 ± 1.6 µg/L in patients with increased Gal-3 and 2.2 ± 3.2 µg/L in patients with decreased or unchanged Gal-3. Univariable predictors of increasing Gal-3 after ablation were females aged above 65 years (P = 0.046), AF type (P = 0.032) and thick left atrial fibrosis strands (P = 0.030). After correcting for females (>65 years), AF type, AF duration and AF recurrences, only thick LA fibrosis strands remained an independent predictor for increase in circulating Gal-3 after ablation compared to baseline (Table 2).

0 5 10 15 20 25

0

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renc

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)

Galectin−3 < 14µg/L at 6 months follow−up (n=49)Galectin−3 > 14µg/L at 6 months follow−up (n=34)

Log Rank p=0.019

Figure 1.Freedom of AF recurrence in patients that underwent thoracoscopic surgical ablation stratified for serum Galectin-3 concentration at 6 months follow-up.

9


There was a significant decrease in serum NT-proBNP levels during follow-up com-pared to baseline in patient without AF recurrence (194 ng/L [IQR 99–503]–126 ng/L [IQR 97–220], P = 0.011), but not in patients with AF recurrence.

0 5 10 15 20 25

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100


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F R

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)

Gal−3 decreased or unchanged (n=47)Gal−3 increased (n=36)

Log Rank p=0.014

Figure 2.Freedom of AF recurrence in patients that underwent thoracoscopic surgical ablation stratified for the change of serum Galectin-3 concentration after the procedure.

Table 2. Univariable and multivariable analysis of predictors of change in serum Galectin-3 after ablation.

Univariable Multivariable

Clinical variables Odds Ratio (95% CI) p-value Odds Ratio (95% CI) p-value

Age (years) 0.97 (0.95-1.05) 0.914

Gender (Female) 1.86 (0.67-5.24) 0.245

Female >65 years (yes) 4.19 (1.11-20.40) 0.046 2.47 (0.43-16.04) 0.315

AF Type (Persistent AF) 3.01 (1.25-7.88) 0.032 1.76 (0.55-5.65) 0.341

AF Duration (years) 1.08 (1.00-1.20) 0.056 1.08 (0.99-1.21) 0.103

Hypertension (yes) 0.64 (0.26-1.55) 0.319

Left Atrial Volume Index (ml/m2)

0.99 (0.96-1.03) 0.725

LV Ejection Fraction (%) 0.97 (0.93-1.01) 0.415

CHA2DS2-VASc-score 1.03 (0.72-1.49) 0.849

BMI (kg/m2) 1.04 (0.92-1.16) 0.503

NT-proBNP (ng/l) 1.00 (1.00-1.00) 0.431

LA Fibrosis (%) 1.02 (0.88-1.16) 0.829

LA Fibrosis Strands (thick) 3.56 (1.23-10.73) 0.030 3.63 (1.11-12.60) 0.035

AF Recurrence (yes) 4.08 (1.48-12.18) 0.017 1.66 (0.41-6.71) 0.473

AF, atrial fibrillation; LV, left ventricular; BMI, Body Mass Index

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Baseline galectin-3 and NT-proBNP in relation to atrial fibrillation recurrenceThere was no association between baseline Gal-3 or NT-proBNP levels and AF recur-rence. Median serum Gal-3 at baseline was 14.0 µg/L. Baseline serum Gal-3 in patients with and without AF recurrence was 14.8 ± 3.9 µg/L vs. 13.7 ± 3.7 µg/L, respectively, P = 0.162. There was no significant difference in AF recurrence during the follow-up pe-riod in patients with baseline serum Gal-3 ≤ 14.0µg/L compared to patients with serum Gal-3 > 14.0 µg/L (39% vs. 37% AF recurrence, respectively) (Figure 3A). NT-proBNP was 194 ng/L [IQR 99–503 vs. 309 ng/L [IQR 124–787] in patients without and with recur-rences, respectively (P = 0.08).

Galectin-3 concentrations in left atrial tissueWe observed no significant difference in Gal-3 protein levels in the left atrial append-age, adjusted for total protein levels, between patients with or without AF recurrence (94.5 ± 19.4 µg/L vs. 93.3 ± 30.8 µg/L respectively, P = 0.826) nor in patients with paroxys-mal and persistent AF patients (96.0 ± 24.6 µg/L vs. 92.0 ± 28.4 µg/L respectively, P = 0.48). Similarly, there was no significant correlation between tissue Gal-3 and age, duration of AF or LAVI. Serum [NT-proBNP] did not correlate with tissue Gal-3, but showed a trend for association after correcting for age and left ventricular ejection fraction (P = 0.06). In Pearson correlation analysis, baseline serum Gal-3 was not correlated with Gal-3 in left atrial tissue (r = 0.13, P = 0.198) (Figure 4).

0 5 10 15 20 25

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Galectin−3 < 14µg/L at baseline (n=54)Galectin−3 > 14µg/L at baseline (n=44)

Log Rank p=0.854

Figure 3(A) Kaplan-Meier of AF recurrence stratified for baseline Galectin-3 concentration and (B) Baseline Galec-tin-3 concentration in serum of patients with versus without AF recurrence.

A B

9


Fibrosis in atrial tissueThe percentage fibrous tissue content in the left atrial appendage was 8.0 ± 3.8% (7.7 ± 3.4% in paroxysmal AF and 8.2 ± 4.2% in persistent AF, P = 0.965). Within individual tissue samples, the standard deviations (SDs) of percentage fibrous tissue content were on average 2.3%. The percentage of fibrous tissue content was not correlated with the Gal-3 in atrial tissue adjusted for total protein (P = 0.929), nor with baseline serum Gal-3(P = 0.182).

The percentage of fibrous tissue content was higher in patients with predominantly thick collagen strands (11.2 ± 4.3% vs. 6.4 ± 2.2% in thin collagen strands, P < 0.001). There was no significant difference in left atrial Gal-3 in LAA with thick vs. thin colla-gen strands (88.6 ± 31.8 µg/L vs. 93.0 ± 19.1 µg/L, P = 0.342). Baseline serum Gal-3 was lower in patients with thick strands (12.3 ± 2.7 µg/L) compared to those with thin strands (14.9 ± 4.4 µg/L, P = 0.010). The organization of collagen was not associated with freedom of AF after thoracoscopic surgery (P = 0.315), nor with type of AF (P = 0.223). There was no difference in serum Gal-3 at follow-up between thick and thin collagen strands in left atrial myocardium (14.1 ± 4.1 µg/L vs. 13.1 ± 3.1 µg/L, respectively, P = 0.220). However, in those patients in whom serum Gal-3 increased after ablation, more thick collagen strands (52%) were encountered than in patients with unchanged or decreased serum Gal-3 after ablation (23%, P = 0.020). A typical example of LAA with thick and thin strands is displayed in Figure 5.

p=0.198

0

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150

200

250

300

0 5 10 15 20 25Baseline Serum Galectin−3 (µg/L)

Left

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alec

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Figure 4.Correlation of Galectin-3 in left atrial tissue and Galectin-3 in serum at baseline.

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dIscussIon

Galectin-3 is a marker for cardiac fibrosis and may be implicated in the fibrotic substrate of AF. We studied if the baseline value of Gal-3, or the change in Gal-3 upon elimination of AF, reflects the arrhythmogenic substrate and has prognostic implications. We found that Gal-3 in serum and left atrial tissue was similar in patients with paroxysmal and persistent AF. Similarly, Gal-3 in serum before ablation did not reflect that in atrial tis-sue. Gal-3 in atrial tissue in turn, did not correlate with fibrous tissue content in the left atrial appendage of the same patient. However, the change in Gal-3 after thoracoscopic surgery for AF (and subsequent absence of AF for more than 3 months) was clinically relevant. An increase in Gal-3 after ablation was associated with more AF recurrences during a 2 year follow-up period.

This finding suggests that we studied two types of patients; those in whom the serum Gal-3 is determined by AF itself, and those in whom Gal-3 reflects a process that may cause AF. In the first, after eliminating AF, Gal-3 decreased and AF did not recur within up to two years after ablation. However, in patients in whom Gal-3 increased compared to baseline, the elimination of AF did not affect Gal-3 and these patients showed to have a higher rate of AF recurrence. Note that this analysis was confined to patients who did not have an AF recurrence yet at the time of blood drawing. Interestingly, left ven-tricular ejection fraction and left atrial volume index were not different in these patients

A

B

Baseline Serum Galectin-3 (µg/l) 12.0 11.0

Left Atrial Galectin-3 (µg/l) 109.8 59.5

Fibrous Tissue Content (%) 6.0 18.6

Collagen Strands thin thick

Figure 5.Typical example of Picrosirius red staining in histological slides of left atrial tissue with (A) thin collagen strands and (B) thick collagen strands. The red colour represents collagen and the yellow colour represents cardiomyocytes.

9


compared to patients without increasing Gal-3 suggesting that the increase in Gal-3 was not caused by heart failure, but may be the result of another, remote process in the body. Patients with increased Gal-3 compared to baseline more often were females aged above 65 years and more often had persistent AF and long AF duration. Our results imply that in patients with Gal-3 increase over time, despite the presence of an indica-tion for invasive treatment, the outcome of ablation is poor. Potentially, this is because the profibrotic driver, resembled in serum Gal-3, has not changed upon elimination of AF, and therefore the arrhythmogenic substrate remains or even continues to develop.

Galectin-3 is not cardiac specific and is upregulated in various human disease entities, such as in diseases of the liver or kidneys. Therefore, Gal-3 in the blood in patients with AF may not per se reflect pathophysiological changes in the atria. This suggestion is sup-ported by our finding that hypertension was independently associated with serum Gal-3 at baseline. Kornej et al.17 also showed an association between Gal-3 and CHA2DS2-VASc score. We did not confirm this in our study, but the study by Kornej emphasizes that increasing Gal-3 after ablation may be the result of remote processes and that Gal-3 might not be causally related to the fibrotic substrate of AF.

The potential role of Gal-3 as marker for the progression of AF was adapted from studies investigating the role of Gal-3 in heart failure. Gal-3 was demonstrated to be upregulated in the decompensated hearts of animal models with heart failure.6 Sub-sequent studies showed an evident relation between Gal-3 and failing human heart in ventricular tissue and also in the serum of HF patients.5 Therefore, Gal-3, in combination with other markers, such as NT-proBNP, is proposed as a biomarker for decompensated heart failure.18

We found that serum Gal-3 measured before the procedure did not predict outcome after thoracoscopic AF surgery. This finding was also shown in patients undergoing catheter ablation17, whereas, to the contrary, Wu et al.19 did show a predictive value of Gal-3 in patients with persistent AF undergoing invasive treatment. They showed in a multivariate analysis that Gal-3 was an independent predictor of AF recurrence, particularly when combined with left atrial diameter. However, this was an analysis uncorrected for hypertension, BMI or CHA2DS2-VASc score, factors that have showed to be associated with the level of serum Gal-3.17 Also in the study of Takemoto et al.8 Gal-3 at baseline was demonstrated to be a predictor of AF recurrence after catheter ablation. That study also showed a difference in Gal-3 between patients with paroxysmal and persistent AF, which was also demonstrated by Gurses et al.10 Potentially, the patients in the study of Takemoto and Gurses, particularly the patients with paroxysmal AF, had less fibrotically remodelled atria, and therefore the role of Gal-3 may be different than in the cohort described. Indeed, a higher serum Gal-3 in our study population may explain the discrepancy between these findings. Note that we only included AF patients and that a control group of patients without AF was not included.

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Ho et al.9 showed an association between increased Gal-3 and an increased risk of developing AF over the subsequent 10 years. This association was no longer significant after correction for traditional AF risk factors. Therefore, the investigators suggested that Gal-3 is a dependent variable in the risk prediction of AF. Consequent to the findings demonstrated in our study, Kornej et al.17 did not show a difference in Gal-3 between patients with paroxysmal and persistent AF.

From this point of view, the role of Gal-3 as a potential marker for structural remodeling, in particular remodeling based on profibrotic changes in the atria, is interesting. Gursus et al.10 showed a difference in Gal-3 between patients with paroxysmal and persistent AF, which was suggested to reflect a more fibrotic atrial substrate of AF in the latter patients. However, the relation between Gal-3 and AF remains unclear and findings are inconsistent. No experimental or animal studies have been performed that prove the association between Gal-3 and atrial remodeling. In this study, we therefore quantified Gal-3 and fibrosis in the left atrial appendage of AF patients to investigate whether Gal-3 in serum indeed reflect the process of structural remodeling. We show that Gal-3 in left atrial tissue was not correlated with the percentage of fibrous tissue content in the same tissue. There was some variation in the amount of fibrous tissue content within each subject; the SD was on average 2.3%. Furthermore, serum Gal-3 did not correlate with the amount of fibrous tissue content in atrial tissue and there was no relation between Gal-3 in serum and in atrial tissue of the same patients. These findings suggest that Gal-3 in the serum at baseline do not reflect atrial Gal-3 or a fibrotic process in the atria. This contrasts with ventricular remodeling in patients with heart failure, in whom Gal-3 is a marker of the progression of the disease, potentially because ventricular myocardium has a larger mass than atrial myocardium.

In this study, there was no significant difference in the amount of fibrosis between patients with paroxysmal and persistent AF, potentially as a result of a mixed population with advanced AF. Conversely, we found that NT-proBNP levels in serum and echo-cardiographic left atrial volumes were significantly higher in patients with persistent AF, indicating more progressed remodeling in patients with persistent AF. Since LAVI was higher in patients with persistent AF, absolute amount of fibrosis might be higher in these patients despite a similar percentage of collagen compared to patients with paroxysmal AF.

Fibrosis is an important component of the arrhythmogenic substrate of AF and pa-tients with AF have an increased amount of fibrosis,20 however, the exact role of fibrosis in the progression of AF remains unclear. Krul et al.3 previously showed that the presence of thick fibrotic strands in atrial tissue, rather than the actual amount of collagen, may anchor re-entrant activation and thereby contributes to the arrhythmogenic substrate in AF. There was no association between thick and thin collagen strands and Gal-3 at baseline, but thick collagen strands were more often present in patients with serum

9


Gal-3 increase after ablation, suggesting a relation between profibrotic processes in the atrium and serum Gal-3, independent from the atrial tissue content of Gal-3.

These results stress the notion that the change in Gal-3, rather than its baseline value, reflects the change in the arrhythmogenic substrate and that the latter is of prognostic importance. Our results suggest that in patients in whom AF itself determines profi-brotic atrial remodeling, elimination of the AF triggers (as with thoracoscopic surgery for AF) also beneficially affects the fibrotic substrate (or its driver), evident from decreasing circulating Gal-3 and a high rate of AF absence. In patients, however, in whom Gal-3 is driven by extra-atrial processes among which hypertension, ageing and female gender, eliminating AF does not result in a decrease of serum Gal-3. To the contrary, an increas-ing Gal-3 after ablation in those patients is associated with high AF recurrence rates.

Strengths and limitationsThis study cohort consists of patients with advanced AF, despite paroxysmal or persis-tent episodes, with frequently severely enlarged left atria, long AF duration or previous catheter ablations. The inclusion of patients with less advanced AF may show a different relation between Gal-3 and outcome. Also, we obviously did not obtain atrial tissue, or serum, from healthy control patients and were not able to collect atrial tissue during follow-up.

Furthermore, it is unknown whether the amount and distribution of collagen in the left atrial appendage is representative for the entire left atrium. However, this study is the first to correlate circulating Gal-3 with Gal-3 in tissue and with actual fibrosis in the same patient.

conclusIon

In patients with advanced AF, the change of circulating Gal-3, rather than its baseline value, reflects the change in the arrhythmogenic substrate and predicts the outcome of thoracoscopic AF ablation. This is despite the absence of correlation between base-line serum and left atrial tissue Gal-3 content. Our study suggests that there is a group of patients in whom circulating Gal-3 content is driven by ongoing AF, and in whom elimination of AF results in a decrease in Gal-3. On the contrary, there is a different group in whom ablation of AF does not result in Gal-3 decrease, with a far worse prognosis with respect to AF recurrence. In this latter group, that consists of patients that more frequently were females aged over 65 years, had persistent AF and longer AF duration, the change in Galectin-3 merely drives AF, but is not caused by it.

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RefeRences 1. Naccarelli GV, Varker H, Lin J, Schulman KL. Increasing prevalence of atrial fibrillation and flutter

in the United States. Am J Cardiol 2009;104:1534-9. 2. Schotten U, Verheule S, Kirchhof P, Goette A. Pathophysiological mechanisms of atrial fibrillation:

a translational appraisal. Physiol Rev 2011;91:265-325. 3. Krul SP, Berger WR, Smit NW, et al. Atrial fibrosis and conduction slowing in the left atrial append-

age of patients undergoing thoracoscopic surgical pulmonary vein isolation for atrial fibrillation. Circ Arrhythm Electrophysiol 2015;8:288-95.

4. 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.

5. de Boer RA, Yu L, van Veldhuisen DJ. Galectin-3 in cardiac remodeling and heart failure. Curr Heart Fail Rep 2010;7:1-8.

6. Sharma UC, Pokharel S, van Brakel TJ, et al. Galectin-3 marks activated macrophages in failure-prone hypertrophied hearts and contributes to cardiac dysfunction. Circulation 2004;110:3121-8.

7. Ho JE, Liu C, Lyass A, et al. Galectin-3, a marker of cardiac fibrosis, predicts incident heart failure in the community. J Am Coll Cardiol 2012;60:1249-56.

8. Takemoto Y, Ramirez RJ, Yokokawa M, et al. Galectin-3 Regulates Atrial Fibrillation Remodeling and Predicts Catheter Ablation Outcomes. JACC Basic Transl Sci 2016;1:143-54.

9. Ho JE, Yin X, Levy D, et al. Galectin 3 and incident atrial fibrillation in the community. Am Heart J 2014;167:729-34 e1.

10. Gurses KM, Yalcin MU, Kocyigit D, et al. Effects of persistent atrial fibrillation on serum galectin-3 levels. Am J Cardiol 2015;115:647-51.

11. Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Europace 2010;12:1360-420.


13. Driessen AHG, Berger WR, Krul SPJ, et al. Ganglion Plexus Ablation in Advanced Atrial Fibrillation: The AFACT Study. J Am Coll Cardiol 2016;68:1155-65.



16. Hadi AM, Mouchaers KT, Schalij I, et al. Rapid quantification of myocardial fibrosis: a new macro-based automated analysis. Cell Oncol (Dordr) 2011;34:343-54.

17. Kornej J, Schmidl J, Ueberham L, et al. Galectin-3 in patients with atrial fibrillation undergoing radiofrequency catheter ablation. PLoS One 2015;10:e0123574.

18. van Kimmenade RR, Januzzi JL, Jr., Ellinor PT, et al. Utility of amino-terminal pro-brain natriuretic peptide, galectin-3, and apelin for the evaluation of patients with acute heart failure. J Am Coll Cardiol 2006;48:1217-24.

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19. Wu XY, Li SN, Wen SN, et al. Plasma galectin-3 predicts clinical outcomes after catheter ablation in persistent atrial fibrillation patients without structural heart disease. Europace 2015;17:1541-7.

20. Geuzebroek GS, van Amersfoorth SC, Hoogendijk MG, et al. Increased amount of atrial fibrosis in patients with atrial fibrillation secondary to mitral valve disease. J Thorac Cardiovasc Surg 2012;144:327-33.

Chapter 10Summary and Future Perspectives

196 Chapter 10

suMMARy

Atrial fibrillation (AF) is a complex arrhythmia and imposes a great burden on society with high healthcare costs that will grow in the future as prevalence of AF substantially increases with age. Understanding the pathophysiological mechanisms and optimizing therapeutic in the management of this arrhythmia is of increasing importance. The aim of this thesis was to study thoracoscopic surgery of AF, including the role of autonomic modulation, and its impact on quality of life. Subsequently, we investigate the role of atrial fibrosis as a determinant of the substrate of advanced AF.

Invasive treatment strategies for the treatment of patients with advanced atrial fibrillationIn chapter 2 we provide a contemporary systematic overview on efficacy and safety of catheter and minimally-invasive surgical ablation for patients with persistent AF. We know that the efficacy of catheter ablation is higher in patients with paroxysmal AF versus persistent AF.1 There is no consensus on the optimal treatment strategy for persistent AF patients. In this review, which included all treatment arms of randomized controlled trials available, we show that freedom of AF after 12 months was higher after minimally-invasive surgery (67%) compared to catheter ablation (51%), while minimally-invasive surgery is associated with numerically more adverse events. Heterogeneity was high between studies and treatment strategies, particularly in catheter ablation studies, making it difficult to implicate this data in clinical practice, but emphasizes the need for consistent reporting of outcome and complications after AF ablation, as advocated by the HRS/EHRA/ECAS consensus statement.2 Furthermore, it is important to note that both treatment strategies could not be compared directly, as only two RCTs were included directly comparing both treatments in patients with paroxysmal and persistent AF and the number of persistent AF patients in these studies was low. However, the results of these RCTs, showing that minimally-invasive surgery appears to be more effi-cacious in restoring sinus rhythm, were consistent with the data described in this review.

Chapter 3 describes the AFACT trial, which is the first randomized controlled trial investigating the role of additional ganglionated plexus (GP) ablation in thoracoscopic surgery of AF. This study shows that in patients with advanced AF, of whom 68% had enlarged left atria, GP ablation has no detectable effect on AF recurrence. GP ablation was associated with more major adverse events (19% versus 8%), particularly bleeding and sinus node dysfunction, leading to more pacemaker implantations. Furthermore, re-currences of atrial tachyarrhythmias were more often atrial tachycardias in patients who underwent additional GP ablation. In contrast to the study by Katritsis and colleagues3, which demonstrated fewer recurrences after endocardial GP ablation in patients with

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Summary and future perspectives 197

paroxysmal AF, we conclude that GP ablation has no beneficial effect and should there-fore not be performed routinely in patients with advanced AF.

In chapter 4, we describe the results of the AFACT trial after intermediate follow-up. Two years after thoracoscopic surgery, freedom of any atrial tachyarrhythmia did not differ significantly between patients who underwent GP ablation versus the control group. The majority of patients (78%) did not use anti-arrhythmic drugs after two years. Whereas all patients were highly symptomatic before the procedure, merely 11% of the patients remained to have frequent (>3 recurrences per year), symptomatic recurrences after treatment. While we did not perform continuous monitoring in this study, poten-tially underestimating the actual AF burden, we advocate that reporting the AF burden is clinically more meaningful than only reporting a Kaplan-Meier curve, since the main indication for invasive treatment of AF is reducing AF-related symptoms.

Most studies on invasive treatment of AF report efficacy at one year follow-up, while we know from catheter ablation studies that success rates after longer follow-up are poor and often redo-procedures are needed. In chapter 5, we assess freedom of AF recurrences at 5 years in the first 66 patients who underwent thoracoscopic surgery for advanced paroxysmal or persistent AF in the Academic Medical Center. After a single procedure, there was complete absence of AF in 50% of these patients (67% in parox-ysmal AF and 33% in persistent AF patients), without the use of anti-arrhythmic drugs. Only 9% had frequent AF recurrences, defined as >3 recurrences per year, or permanent AF. Eighty-eight percent of the patients returned for a follow-up visit at 5 years and 88% of those patients were in sinus rhythm, while 77% were not using anti-arrhythmic drugs.

Quality of life after invasive treatment of patients with atrial fibrillationQuality of life (QoL) is reduced in patients with AF compared to the general popula-tion.4 Treatment strategies for AF are aimed at reducing symptoms and improving QoL, moreover since current guidelines recommend continuation of anticoagulants based on risk of thrombo-embolic events, rather than on absence of AF. In the previous chapters we show that AF ablation is associated with fewer episodes of AF. In chapters 6 and 7 we study whether this translates to an improvement of QoL.

In chapter 6 we investigate the relation between the number of documented atrial fibrillation recurrences and QoL in patients who underwent catheter pulmonary vein isolation. We demonstrate that patients had a decreased QoL compared to the general Dutch population before they underwent catheter ablation. After the procedure, QoL increased up to the level of the general population in patients who did not experience any AF recurrence during follow-up. However, in patients with AF recurrence, QoL remained lower. Since we only detected an AF recurrence when patients presented themselves to their physician with symptoms, we conclude that the relation between

198 Chapter 10

AF recurrence and QoL may be particularly true for symptomatic AF, but may be less clear for asymptomatic AF.

Chapter 7 describes a predefined sub analysis of the AFACT trial, in which we ob-tained QoL questionnaires before thoracoscopic surgery and subsequently at 6- and 12-months follow-up. We demonstrate an improvement of QoL in the entire study cohort after the procedure, regardless of GP ablation. Patients with AF recurrences had lower QoL during follow-up than patients without AF recurrence. One single episode of AF appeared to only decrease QoL temporarily as we demonstrate a decreased QoL in these patients at 6 months, while in the same patients QoL was improved at 12 months follow-up. After one year, QoL in patients with one or no AF recurrences was similar to the general Dutch population, while patients with more than one AF recurrence showed no increase in QoL. Also, irreversible complications of thoracoscopic surgery, such as pacemaker implantations, were associated with no improvement of QoL, but in patients in whom complications could be resolved QoL was similar to those without procedural complications.

Determinants of the substrate of advanced atrial fibrillation: the role of atrial fibrosisOver the past years many research has been performed into the mechanisms that initiate and sustain AF. Atrial fibrosis is an important component of the arrhythmogenic substrate of AF.5 In addition, studies show that the amount of atrial fibrosis is increased in patients with AF.6,7 It is unclear whether atrial fibrosis is the result of structural remodeling caused by AF or a manifestation of a myocardial process that leads to the development of the arrhythmia. Experimental studies have shown that proliferation of fibroblasts, increased production of extracellular matrix and differentiation into myofibroblasts may have an arrhythmogenic effect by changing the architecture of the fibrotic myocardial tissue and affecting intracellular conduction, leading to development of structural and functional block.8 The effect of the quantity and the structural organization of fibrosis on atrial conduction abnormalities in man are unknown. In chapter 8 we investigate the amount and organization of interstitial fibrosis in 35 left atrial appendages (LAA) of patients with AF and study the effect of interstitial fibrosis on conduction characteristics. We show that structural local components of fibrosis have an important role in modulating the longitudinal and transversal conduction velocity (CV) in the LAA. Thick collagen strands, which were more frequently present in patients with persistent AF, were associated with higher longitudinal CV compared to thin strands, while transversal CV was not affected. Activation delay was present and areas of activation block occurred, leading to a zig-zag conduction. Fibroblasts were present in the LAA and were associated with thick collagen strands, however, myofibroblasts were not detected. From these results, we conclude that the organization of interstitial fibrosis, rather than the amount of fibrosis, causes

10


conduction changes in the LAA of AF patients, providing an arrhythmogenic substrate for AF.

Galectin-3 has been showed to be an important mediator of cardiac fibrosis and high concentrations of Gal-3 are associated with increased risk of developing AF.9,10 It might therefore be a potential marker for AF. In chapter 9 we demonstrate that, in patients who underwent thoracoscopic AF ablation, there was no association between Gal-3 and thick or thin collagen strands. However, thick collagen strands were more often present in patients with an increase of Gal-3 after thoracoscopic AF ablation. Furthermore, an increase of Gal-3 after AF ablation was associated with AF recurrence, suggesting a rela-tion between profibrotic processes in the atrium and serum Gal-3, independent from the atrial tissue content of Gal-3. These results stress the notion that the change in Gal-3, rather than its baseline value, reflects the change in the arrhythmic substrate and that the latter is of prognostic importance.

futuRe peRspectIves

Atrial fibrillation is a multifactorial disease and underlying pathophysiology is complex. The treatment of patients with AF is challenging, but treatment strategies are evolving and ablation strategies have shown to be excellent treatment options for AF patients. However, given the rising epidemic of AF, primary and secondary prevention strategies are urgently needed and will be the most important challenge in the future. An increas-ing focus is placed on the role of lifestyle and risk factor modification in primary preven-tion of AF. For example, bariatric surgery in patients without AF has shown to reduce the long-term risk of incident AF.11 Other forms of risk factor modification targeting physical inactivity, alcohol consumption or sleep apnea may be beneficial in the prevention of AF and further studies are needed to give more insight. Furthermore, the same risk fac-tors are found to be independent predictors of AF recurrence after ablation.12 In fact, Australian research showed that, in patients suffering from AF, a weight reduction of 10% can reduce symptoms, but also reduce further progression of AF.13 These patients require less treatment and have better outcomes. The same research group showed that intensive weight and risk factor management has a dose-dependent effect on long-term freedom of AF that is comparable to freedom of AF after AF ablation.14 These findings emphasize the importance of lifestyle management in the treatment of AF, which may reduce the need for AF ablation.

Ablation strategies have been proven effective for the treatment of paroxysmal AF, but the results in patients with non-paroxysmal AF are less consistent. Over the last decades, ablation strategies are continuously evolving, although the optimal ablation strategy remains unclear. The STAR AF II study showed us that ablation of complex frac-

200 Chapter 10

tionated atrial electrograms (CFAEs) or linear ablations were not beneficial in persistent AF patients and that PVI alone was sufficient.15 In this study, radiofrequency energy (RF) was used to isolate the pulmonary veins. Cryoballoon (CB) ablation is an alternative approach to RF ablation with the benefit of single-shot application to the PV antrum likely to make the ablation procedure easier as compared to RF ablation. The FIRE & ICE study demonstrated superiority of CB ablation over RF in patients with paroxysmal AF.16 Recently, new evidence is emerging, showing promising results of CB ablation in patients with persistent AF, with success rates close to 70%.17 This technique seems promising, but prospective randomized controlled trials are needed to define the role of CB ablation.

Alternatively, thoracoscopic AF ablation is a successful and safe treatment for patients with advanced AF, as shown in the studies in this thesis. Three randomized trials reported better outcomes after thoracoscopic ablation compared to catheter ablation, however, these studies contained mostly patients with paroxysmal AF or with previous catheter.18-20 It appears that success rates after thoracoscopic ablation are higher in patients with persistent AF than after catheter ablation. Since many different procedural strategies are currently employed and monitoring during follow-up is often not consistent, it is difficult to compare these treatment modalities. To date, there has been no prospective randomized controlled trial directly comparing the two treatment strategies in this spe-cific group of patients. Recently, the APPROACH AF trial has started in the Amsterdam University Medical Centers. This is a multicenter randomized trial including patients with persistent AF, who are randomly assigned to undergo either catheter pulmonary vein isolation or thoracoscopic pulmonary vein isolation. Hopefully, this trial will give more direction in choosing the optimal treatment strategy for persistent AF patients.

Thoracoscopic ablation is a relatively novel procedure that is not yet performed on a widely basis, therefore, standardization of the procedure is important for future development. Also, standardized monitoring during follow-up in ablation studies, as recommended in the latest guidelines, are essential to compare efficacy and safety with established techniques.

Following the results of the AFACT study, which are presented in this thesis, we would discourage epicardial GP ablation during thoracoscopic ablation as GP ablation has no beneficial effects on freedom of AF recurrence, while it increases procedural complica-tions.21 Interestingly, recent studies demonstrated novel approaches of neuromodula-tion by injecting botulinum or lidocaine in the fat pads of patients with AF, aiming to modify the GPs without the off-target effects of radiofrequency ablation.22-25 Although results are inconsistent, these studies nourish the concept that modulation of the GPs remains a potential component in the development of a targeted therapeutic strategy for AF.

10


The next step in optimizing invasive treatment of AF is a better selection of patients that will benefit from AF ablation. Biomarkers can have an important role as risk predic-tors or prognostic tools in cardiovascular diseases. While biomarkers are commonly used in the management of myocardial infarction and heart failure, the use of biomarkers has not yet been established in the diagnostic process and treatment of AF. However, these markers can help to further understand the history of AF and underlying histological or electrophysiological changes. An interesting new class of biomarkers that has been suggested, are circulating microRNAs (miRNA). miRNAs are short, non-coding RNAs that regulate gene expression and may be involved in the pathophysiology of AF.26 There-fore, miRNAs could provide insight into AF pathophysiology, but can also become novel targets for therapy. Further studies are required to investigate the potential of these miRNAs in the management of AF.

The ability to identify subgroups of patients that can benefit from a specific treatment strategy might provide more individualized therapeutic opportunities, improve prog-nostication and provide preventive opportunities in patients with AF. Further studies should aim to combine the use of imaging, biomarkers, electrophysiological data and clinical characteristics to establish a clinical classification based on the underlying pathophysiological mechanism.

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RefeRences 1. Calkins H, Reynolds MR, Spector P, et al. Treatment of atrial fibrillation with antiarrhythmic drugs

or radiofrequency ablation: two systematic literature reviews and meta-analyses. Circulation Ar-rhythmia and electrophysiology 2009;2:349-61.

2. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: Executive summary. Europace 2018;20:157-208.


4. Dorian P, Jung W, Newman D, et al. The impairment of health-related quality of life in patients with intermittent atrial fibrillation: implications for the assessment of investigational therapy. J Am Coll Cardiol 2000;36:1303-9.



7. Shirani J, Alaeddini J. Structural remodeling of the left atrial appendage in patients with chronic non-valvular atrial fibrillation: Implications for thrombus formation, systemic embolism, and as-sessment by transesophageal echocardiography. Cardiovasc Pathol 2000;9:95-101.

8. de Jong S, van Veen TA, van Rijen HV, de Bakker JM. Fibrosis and cardiac arrhythmias. J Cardiovasc Pharmacol 2011;57:630-8.

9. de Boer RA, Voors AA, Muntendam P, van Gilst WH, van Veldhuisen DJ. Galectin-3: a novel media-tor of heart failure development and progression. Eur J Heart Fail 2009;11:811-7.


11. Jamaly S, Carlsson L, Peltonen M, Jacobson P, Sjostrom L, Karason K. Bariatric Surgery and the Risk of New-Onset Atrial Fibrillation in Swedish Obese Subjects. J Am Coll Cardiol 2016;68:2497-504.

12. Jacobs V, May HT, Bair TL, et al. The impact of risk score (CHADS2 versus CHA2DS2-VASc) on long-term outcomes after atrial fibrillation ablation. Heart Rhythm 2015;12:681-6.

13. Middeldorp ME, Pathak RK, Meredith M, et al. PREVEntion and regReSsive Effect of weight-loss and risk factor modification on Atrial Fibrillation: the REVERSE-AF study. Europace 2018;20:1929-35.

14. Pathak RK, Middeldorp ME, Meredith M, et al. Long-Term Effect of Goal-Directed Weight Manage-ment in an Atrial Fibrillation Cohort: A Long-Term Follow-Up Study (LEGACY). J Am Coll Cardiol 2015;65:2159-69.

15. Verma A, Macle L, Sanders P. Catheter Ablation for Persistent Atrial Fibrillation. N Engl J Med 2015;373:878-9.

16. Kuck KH, Brugada J, Furnkranz A, et al. Cryoballoon or Radiofrequency Ablation for Paroxysmal Atrial Fibrillation. N Engl J Med 2016;374:2235-45.

17. Omran H, Gutleben KJ, Molatta S, et al. Second generation cryoballoon ablation for persistent atrial fibrillation: an updated meta-analysis. Clin Res Cardiol 2018;107:182-92.


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19. Adiyaman A, Buist TJ, Beukema RJ, et al. Randomized Controlled Trial of Surgical Versus Cath-eter Ablation for Paroxysmal and Early Persistent Atrial Fibrillation. Circ Arrhythm Electrophysiol 2018;11:e006182.

20. Pokushalov E, Romanov A, De Melis M, et al. Progression of atrial fibrillation after a failed initial ablation procedure in patients with paroxysmal atrial fibrillation: a randomized comparison of drug therapy versus reablation. Circ Arrhythm Electrophysiol 2013;6:754-60.


22. Romanov A, Pokushalov E, Ponomarev D, et al. Long-term suppression of atrial fibrillation by botulinum toxin injection into epicardial fat pads in patients undergoing cardiac surgery: Three-year follow-up of a randomized study. Heart Rhythm 2019;16:172-7.

23. Waldron NH, Cooter M, Haney JC, et al. Temporary autonomic modulation with botulinum toxin type A to reduce atrial fibrillation after cardiac surgery. Heart Rhythm 2019;16:178-84.

24. Lee S, Khrestian A, Waldo AL, Khrestian CM, Markowitz A, Sahadevan J. Effect of Lidocaine Injec-tion of Ganglionated Plexi in a Canine Model and Patients With Persistent and Long-Standing Persistent Atrial Fibrillation. J Am Heart Assoc 2019;8:e011401.

25. de Groot JR. Botulinum toxin injection in the autonomic ganglion plexi to prevent postoperative atrial fibrillation: More than a cosmetic treatment. Heart rhythm 2019;16:185-6.

26. van den Berg NWE, Kawasaki M, Berger WR, et al. MicroRNAs in Atrial Fibrillation: from Expression Signatures to Functional Implications. Cardiovasc Drugs Ther 2017;31:345-65.

Chapter 11Samenvatting en Toekomstperspectieven

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sAMenvAttIng

Atriumfibrilleren (AF) is een complexe ritmestoornis en zorgt voor hoge lasten voor onze samenleving door hoge zorgkosten, die waarschijnlijk alleen maar zullen groeien, aangezien de prevalentie van AF zal stijgen door de vergrijzing. Voor de behandeling van deze ritmestoornis is van toenemend belang om de pathofysiologische mechanis-men te begrijpen en om de behandelmogelijkheden te optimaliseren. Het doel van dit proefschrift was het onderzoeken van de thoracoscopische behandeling van AF, in het bijzonder de rol van autonome modulatie, en de impact van deze behandeling op de kwaliteit van leven. Daarnaast onderzoeken we de rol van atriale fibrose als bepaling van het substraat van gevorderd AF.

Invasieve behandelstrategieën voor de behandeling van patiënten met gevorderd atriumfibrillerenIn hoofdstuk 2 geven we een actueel systematisch overzicht van de effectiviteit en veiligheid van zowel katheter als minimaal-invasieve chirurgische ablatie voor de behandeling van patiënten met persisterend AF. Van eerdere studies weten we dat de effectiviteit van katheter ablatie hoger is bij patiënten met paroxysmaal AF vergeleken met persisterend AF.1 Er is geen consensus over de optimale behandelstrategie voor patiënten met persisterend AF. In dit review, waarin alle studie-armen van de geran-domiseerde studies die beschikbaar waren, zijn meegenomen, laten we zien dat de afwezigheid van recidieven van AF na 12 maanden hoger is na minimaal-invasieve chirurgie (67%) in vergelijking met katheter ablatie (51%), hoewel minimaal-invasieve chirurgie is geassocieerd met numeriek meer bijwerkingen.

De heterogeniteit tussen de studies en tussen de verschillende behandelstrategieën was hoog, voornamelijk in de katheter ablatie studies, waardoor het lastig is om deze data in de kliniek te implementeren, maar onderstreept wel de behoefte aan consistente rapportage van uitkomsten en complicaties na AF ablatie, zoals ook door het HRS/EHRA/ECAS consensus statement wordt geadviseerd.2 Daarnaast is het belangrijk om op te merken dat beide behandelstrategieën niet direct konden worden vergeleken, omdat er slechts twee gerandomiseerde studies geïncludeerd zijn in het review die een directe vergelijking van beide behandelingen bestudeerden en omdat het aantal patiënten met persisterend AF in deze studies laag was. Echter, de resultaten van deze studies, die laten zien dat minimaal-invasieve chirurgie meer effectief lijkt in het herstellen van sinusritme, zijn consistent met de data beschreven in ons review.

Hoofdstuk 3 beschrijft de AFACT studie, de eerste gerandomiseerde studie waarbij de rol van ganglion plexus (GP) ablatie als aanvulling op thoracoscopische chirurgie wordt bestudeerd. Deze studie toont aan dat in patiënten met gevorderd AF, waarvan 68% vergrote linker atria had, aanvullende GP ablatie geen aantoonbaar effect heeft op het

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Samenvatting en toekomstperspectieven 207

voorkomen van AF recidieven. GP ablatie was geassocieerd met meer belangrijke com-plicaties (19% versus 8%), vooral bloedingen en sinusknoop dysfunctie, waardoor ook meer pacemaker implantaties. Daarnaast zijn recidieven van atriale ritmestoornissen vaker atriale tachycardiën bij patiënten die GP ablatie hebben ondergaan. In tegenstel-ling tot de studie van Katritsis3, die aantoonde dat er minder recidieven optraden na endocardiale GP ablatie bij patiënten met parxysmaal AF, concluderen wij dat GP ablatie geen positief effect heeft en dat deze behandeling daarom niet standaard moet worden uitgevoerd in patiënten met gevorderd AF.

In hoofdstuk 4 beschrijven we de resultaten van de AFACT studie na een intermediaire follow-up duur. Twee jaar na thoracoscopische chirurgie was er geen significant verschil in afwezigheid van atriale ritmestoornissen bij patiënten die GP ablatie ondergingen, vergeleken met de controle groep. De meerderheid van de patiënten (78%) gebruikte geen antiaritmische medicatie na 2 jaar follow-up. Terwijl alle patiënten nog zeer symp-tomatisch waren voor de procedure, bleef slechts 11% van de patiënten regelmatig (>3 recidieven per jaar) symptomatische recidieven houden na de behandeling. Hoewel we geen gebruik hebben gemaakt van continue monitoring in de studie, waardoor de werkelijke ‘AF burden’ mogelijk onderschat wordt, suggereren wij dat het rapporteren van de ‘AF burden’ klinisch meer relevant is dan slechts de rapportage van een Kaplan-Meier curve, aangezien de belangrijkste indicatie voor invasieve behandeling van AF het verminderen van AF-gerelateerde symptomen is.

De meeste studies die de invasieve behandeling van AF onderzoeken, beschrijven effectiviteit na één jaar follow-up, terwijl we weten van katheter ablatie studies dat de succespercentages op lange termijn erg slecht zijn en dat vaak redo-procedures nodig zijn. In hoofdstuk 5 bekeken wij de afwezigheid van AF recidieven na 5 jaar follow-up in de eerste 67 patiënten die thoracoscopische chirurgie voor gevorderd paroxysmaal of persisterend AF ondergingen in het Academisch Medisch Centrum. Na één enkele procedure was er bij 50% van de patiënten afwezigheid van AF (67% in paroxysmaal AF en 33% in persisterend AF patiënten), zonder dat antiaritmische medicatie werd gebruikt. Slechts 9% had frequente recidieven van AF, gedefinieerd als >3 recidieven per jaar of permanent AF. Achtentachtig procent van de patiënten kwam terug voor een 5 jaar follow-up bezoek and 88% van die patiënten had op dat moment sinusritme, terwijl 77% geen antiaritmische medicatie gebruikte.

Kwaliteit van leven na invasieve behandeling van patiënten met atriumfibrillerenDe kwaliteit van leven (QoL) is lager in patiënten met AF vergeleken met de algemene populatie.4 Behandelmogelijkheden van AF zijn erop gericht op symptoom reductie en verbetering van QoL, voornamelijk omdat de huidige richtlijnen aanraden om antistolling te continueren aan de hand van trombose risico, onafhankelijk van de

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afwezigheid van AF. In de voorgaande hoofdstukken laten we zien dat AF ablatie geas-socieerd is met minder episodes van AF. In d hoofdstukken 6 en 7 bestuderen we of ook wordt vertaald naar een verbetering van QoL.

In hoofdstuk 6 onderzoeken we de relatie tussen het aantal gedocumenteerde recidi-even van AF en QoL in patiënten die een katheter ablatie hebben ondergaan. We tonen aan dat patiënten voorafgaand aan de katheter ablatie een verminderde QoL hadden. Na de procedure verbeterd de QoL tot hetzelfde niveau als de algemene populatie bij patiënten die geen recidief AF hebben gehad tijdens de follow-up. Echter, bij patiënten met een recidief bleef de QoL laag. Aangezien wij alleen AF recidieven hebben gedetect-eerd wanneer patiënten zich hadden gemeld bij hun arts met symptomen, concluderen wij dat de relatie tussen recidief AF en QoL voornamelijk geldt voor symptomatisch AF, maar dat dit minder duidelijk is voor asymptomatisch AF.

Hoofdstuk 7 beschrijft een vooraf gedefinieerde sub analyse van de AFACT studie, waarbij we QoL vragenlijsten hebben verzameld voordat patiënten thoracoscopische chirurgie ondergingen en op 6 en 12 maanden follow-up. We tonen een verbetering van QoL na de procedure in het totale cohort aan, onafhankelijk van GP ablatie. Patiënten met AF recidieven hadden een lagere QoL tijdens de follow-up vergeleken met patiënt-en zonder recidief. Eén enkel recidief AF lijkt de QoL slechts tijdelijk te verminderen, aangezien deze zelfde patiënten een verbeterde QoL lieten zien na 12 maanden follow-up. Na één jaar was de QoL in patiënten met slechts één of geen AF recidieven gelijk aan die van de algemene populatie, terwijl patiënten met meer dan één recidief AF geen verbetering in QoL lieten zien. Daarnaast waren irreversibele complicaties van thora-coscopische chirurgie, zoals pacemaker implantaties, geassocieerd met een gebrek aan verbetering van QoL, maar in patiënten waarbij complicaties worden opgelost, was de QoL gelijk aan patiënten zonder complicaties.

Determinanten van het substraat van gevorderd atriumfibrilleren: de rol van atriale fibroseEr is de laatste jaren veel onderzoek verricht naar de mechanismen die AF initiëren en in stand houden. Atriale fibrose is een belangrijke component van het aritmogene sub-straat van AF5. Als aanvulling daarop laten studies zien dat de hoeveelheid atriale fibrose verhoogd is in patiënten met AF6,7. Het is onduidelijk of atriale fibrose het resultaat is van structurele remodelering, die door AF veroorzaakt wordt, of dat het een manifes-tatie is van een myocardiaal proces dat leidt tot de ontwikkeling van de ritmestoornis. Experimentele studies hebben aangetoond dat proliferatie van fibroblasten, verhoogde productie van extracellulaire matrix en differentiatie in myofibroblasten een aritmo-geen effect kunnen hebben doordat dit de architectuur van het fibrotische myocard weefsel verandert, waardoor de intracellulaire geleiding wordt beïnvloed, leidend tot het ontstaan van een structureel en functioneel blok.8 Het effect van de hoeveelheid

11


en de structurele organisatie van fibrose op atriale geleidingsafwijkingen in de mens is onbekend. In hoofdstuk 8 onderzoeken we hoeveelheid en structuur van interstitiële fibrose in 35 linker hartoren van patiënten met AF en bestuderen we de invloed van interstitieel fibrose op geleidingskarakteristieken. We zien dat structurele lokale com-ponenten van fibrose een belangrijke rol spelen in het moduleren van de longitudinale en transversale geleidingssnelheid in het hartoor. Dikke collageen strengen worden vaker aangetroffen bij patiënten met persisterend AF en zijn geassocieerd met een hogere longitudinale geleidingssnelheid vergeleken met dunne strengen, terwijl de transversale geleidingssnelheid onveranderd is. Hierbij werden vertraging van activatie en gebieden van activatie blokkade gezien, leidend tot zogenaamde “zig-zag” geleiding. Fibroblasten waren aanwezig in het linker hartoor en waren geassocieerd met dikke collageen strengen, echter myofibroblasten werden niet gezien. Aan de hand van deze resultaten concluderen wij dat eerder de organisatie van interstitiële fibrose, dan de ho-eveelheid fibrose, zorgt voor geleidingsveranderingen in het hartoor van AF patiënten, waardoor een aritmogeen substraat voor AF ontstaat.

Het is gebleken dat Galectine-3 (Gal-3) een belangrijke rol speelt bij cardiale fibrose en hoge concentraties van Gal-3 zijn geassocieerd met een verhoogd risico op het ontwik-kelen van AF.9,10 Gal-3 is daarom een potentiële marker voor AF. In hoofdstuk 9 laten we zien dat in patiënten die thoracoscopische AF ablatie hebben ondergaan, er geen as-sociatie bestaat tussen Gal-3 en dikke of dunne collageen strengen in het linker hartoor. Echter, dikke collageen strengen waren vaker aanwezig bij patiënten die een verhoging van het Gal-3 level in het bloed hadden na thoracoscopische ablatie. Daarnaast is een verhoging van Gal-3 na AF ablatie geassocieerd met het optreden van recidieven van AF, wat suggereert dat er een relatie bestaat tussen profibrotische processen in het atrium en Gal-3 in het bloed, onafhankelijk van het de hoeveelheid Gal-3 in het atriale weefsel. De resultaten onderstrepen de bevinding dat eerder de verandering van Gal-3, meer dan de waarde op baseline, een verandering in het aritmogene substraat reflecteren en dat dit van prognostisch belang is.

ToekomstperspectievenAtriumfibrilleren is een multifactoriële ziekte en het onderliggende pathofysiologische mechanisme is complex. De behandeling van AF is lastig, maar behandelstrategieën ontwikkelen zich sterk en ablatie strategieën hebben aangetoond een uitstekende therapeutische optie te zijn voor patiënten met AF. Echter, gezien de toenemende epidemie van AF, zijn dringend primaire en secondaire preventie maatregelen nodig en dit zal dan ook de grootste uitdaging zijn in de toekomst. Er is steeds meer focus op de rol van het aanpassen van leefstijl en risicofactoren voor primaire preventie van AF. Zo is bijvoorbeeld aangetoond dat bariatrische chirurgie het risico op de lange termijn op het ontstaan van AF verminderd.11 Andere voor het modificeren van risicofactoren, die

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gericht zijn op verminderde fysieke activiteit, alcoholgebruik of slaap apneu kunnen een gunstige werking hebben in het voorkomen van AF. Nieuwe studies zijn nodig om hier meer duidelijkheid over te geven. Daarnaast zijn de hiervoor genoemde risicofactoren ook onafhankelijke voorspellers van AF recidieven na ablatie.12 Australisch onderzoek heeft zelfs aangetoond in patiënten met AF dat een gewichtsreductie van 10% het aantal symptomen kan verminderen, maar ook de progressie van AF vermindert.13 Deze patiënten hebben minder behandeling nodig en hebben betere uitkomsten. Dezelfde onderzoeksgroep liet ook zien dat een intensieve behandeling van gewicht en risico-factoren een dosis-afhankelijk effect heeft op de afwezigheid van AF op lange termijn, overeenkomend met het effect op afwezigheid van AF na ablatie.14 Deze bevindingen benadrukken het belang van leefstijl aanpassingen bij de behandeling van AF, waardoor mogelijk minder AF ablaties nodig zijn.

Ablatie technieken zijn bewezen effectief bij de behandeling van patiënten met paroxysmaal AF, echter deze resultaten zijn minder consistent bij patiënten met niet-paroxysmaal AF. In de laatste decades hebben ablatie strategieën zich ontwikkeld, maar de optimale strategie is nog steeds niet gevonden. De STAR AF II studie liet zien dat de ablatie van ‘complex fractionated atrial electrograms (CFAEs)’ of het plaatsen van lineaire ablatie lijnen geen voordeel hadden bij patiënten met persisterend AF en dat alleen de isolatie van de pulmonaal venen voldoende is.15 In deze studie werd radio-frequente energie (RF) gebruikt voor pulmonaal vene isolatie. Cryoballon (CB) ablatie is een alternatieve benadering en heeft het voordeel dat slechts één toediening in het antrum van de pulmonaal vene nodig is, waardoor d ablatie procedure makkelijker is dan RF ablatie. De FIRE & ICE studie liet een superioriteit zien van CB ablatie ten opzichte van RF ablatie bij patiënten met paroxysmaal AF.16 Recent is er nieuw bewijs opgeko-men met hoopvolle resultaten voor CB ablatie in patiënten met persisterend AF, met succespercentages rond de 70%.17 De techniek lijkt veelbelovend, maar prospectieve gerandomiseerde studies zijn nodig om de rol van CB ablatie te bevestigen.

Als een alternatief is thoracoscopische AF ablatie een succesvolle en veilige optie voor de behandeling van patiënten met gevorderd AF, zoals studies in dit proefschrift laten zien. Er bestaan drie gerandomiseerde studies die betere uitkomsten laten zien na thoracoscopische ablatie in vergelijking met katheter ablatie.18-20 Het lijkt dat succesper-centages hoger zij na thoracoscopische ablatie dan katheter ablatie bij patiënten met persisterend AF. Echter, er worden tegenwoordig veel verschillende technieken gebruikt en ritme-monitoring tijdens follow-up is vaak niet consistent is, waardoor het lastig is om verschillende modaliteiten te vergelijken. Tot nu toe zijn er geen prospectieve gerandomiseerde studies geweest die deze twee behandelstrategieëndirect vergeleken in deze specifieke patiëntengroep. Recent is in het Amsterdam UMC de APPROACH AF studie gestart. Dit is een multicenter, gerandomiseerde studie waarin patiënten met persisterend AF worden geïncludeerd die worden gerandomiseerd naar katheter pul-

11


monaal vene isolatie of thoracoscopische pulmonaal vene isolatie, zonder additionele ablatie in beide armen. Hopelijk gaat deze studie meer richting geven in de keuze voor de optimale behandelstrategie voor patiënten met persisterend AF.

Thoracoscopische ablatie is een relatief nieuw techniek die nog niet wijd verspreid wordt toegepast. Daarom is standaardisatie van de procedure van groot belang voor de toekomstige ontwikkeling van deze techniek. Daarnaast is een gestandaardiseerde ritme-monitoring tijdens follow-up essentieel in ablatie studies om effectiviteit en veiligheid te kunnen vergelijken, zoals ook wordt aanbevolen in de meest recente richtlijnen.

Naar aanleiding van de resultaten van de AFACT studie, gepresenteerd in dit proef-schrift, zouden wij ontraden om epicardiale GP ablatie te verrichten tijdens thoracosco-pische ablatie, aangezien GP ablatie geen voordeel geeft ten aanzien van afwezigheid van AF recidieven, terwijl het aantal complicaties als gevolg van de procedure wel verhoogd zijn.21 Interessant is dat er recente studies zijn die nieuwe manieren van neu-romodulatie beschrijven, zoals het injecteren van botulinum of lidocaïne in de atriale vet deposities van patiënten met AF met als doel het modificeren van de GPs, zonder het schadelijke “off-target” effect van radiofrequente ablatie.22-25 Hoewel de resultaten niet consistent zijn, voedden deze studies wel het concept dat modulatie van het autonome zenuwstelstel een potentiële component is in de ontwikkeling van gerichte therapeu-tische strategieën voor AF.

De volgende stap in het optimaliseren van de invasieve behandeling van AF is het beter selecteren van patiënten die voordeel kunnen hebben van AF ablatie. Biomarkers kunnen een belangrijke rol hebben als voorspellers of prognostische instrumenten bij cardiovasculaire aandoeningen. Hoewel biomarkers veelvuldig worden gebruikt bij de behandeling van het myocard infarct of hartfalen, is het gebruik van biomakers nog niet vastgesteld bij het diagnostisch en therapeutische proces van AF. Toch zouden deze markers kunnen helpen om de geschiedenis van AF en onderliggende histologische of elektrofysiologische veranderingen beter te begrijpen en detecteren. Een interessante nieuwe categorie van biomarkers zij circulerende microRNAs (miRNA). miRNAs zijn korte, niet coderende RNAs die gen expressie regeluren en die mogelijk betrokken zijn bij de pathofysiologie van AF.26 miRNAs kunnen daarom mogelijk inzicht geven in deze pathofysiologie, maar kunnen ook nieuwe targets zijn voor behandeling van AF. Er zijn meer studies nodig om de potentiële rol van deze miRNAs in de behandeling van AF verder te onderzoeken.

De mogelijkheid om subgroepen van patiënten te identificeren die voordeel hebben van specifieke behandelstrategieën kan zorgen voor meer geïndividualiseerde thera-peutische mogelijkheden, het stellen van prognoses verbeteren en kan zorgen voor preventieve mogelijkheden bij patiënten met AF.

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Toekomstige studies moeten trachten om de informatie van beeldvorming, het gebruik van biomarkers, elektrofysiologische metingen en klinische karakteristieken te combineren om een klinische classificatie te ontwikkelen gebaseerd op het onder-liggende pathofysiologische mechanisme van AF.

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RefeRentIes 1. Calkins H, Reynolds MR, Spector P, et al. Treatment of atrial fibrillation with antiarrhythmic drugs

or radiofrequency ablation: two systematic literature reviews and meta-analyses. Circulation Ar-rhythmia and electrophysiology 2009;2:349-61.

2. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: Executive summary. Europace 2018;20:157-208.

3. 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.

4. Dorian P, Jung W, Newman D, et al. The impairment of health-related quality of life in patients with intermittent atrial fibrillation: implications for the assessment of investigational therapy. J Am Coll Cardiol 2000;36:1303-9.



7. Shirani J, Alaeddini J. Structural remodeling of the left atrial appendage in patients with chronic non-valvular atrial fibrillation: Implications for thrombus formation, systemic embolism, and as-sessment by transesophageal echocardiography. Cardiovasc Pathol 2000;9:95-101.

8. de Jong S, van Veen TA, van Rijen HV, de Bakker JM. Fibrosis and cardiac arrhythmias. J Cardiovasc Pharmacol 2011;57:630-8.

9. de Boer RA, Voors AA, Muntendam P, van Gilst WH, van Veldhuisen DJ. Galectin-3: a novel media-tor of heart failure development and progression. Eur J Heart Fail 2009;11:811-7.


11. Jamaly S, Carlsson L, Peltonen M, Jacobson P, Sjostrom L, Karason K. Bariatric Surgery and the Risk of New-Onset Atrial Fibrillation in Swedish Obese Subjects. J Am Coll Cardiol 2016;68:2497-504.

12. Jacobs V, May HT, Bair TL, et al. The impact of risk score (CHADS2 versus CHA2DS2-VASc) on long-term outcomes after atrial fibrillation ablation. Heart Rhythm 2015;12:681-6.

13. Middeldorp ME, Pathak RK, Meredith M, et al. PREVEntion and regReSsive Effect of weight-loss and risk factor modification on Atrial Fibrillation: the REVERSE-AF study. Europace 2018;20:1929-35.

14. Pathak RK, Middeldorp ME, Meredith M, et al. Long-Term Effect of Goal-Directed Weight Manage-ment in an Atrial Fibrillation Cohort: A Long-Term Follow-Up Study (LEGACY). J Am Coll Cardiol 2015;65:2159-69.


16. Kuck KH, Brugada J, Furnkranz A, et al. Cryoballoon or Radiofrequency Ablation for Paroxysmal Atrial Fibrillation. N Engl J Med 2016;374:2235-45.

17. Omran H, Gutleben KJ, Molatta S, et al. Second generation cryoballoon ablation for persistent atrial fibrillation: an updated meta-analysis. Clin Res Cardiol 2018;107:182-92.


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19. Adiyaman A, Buist TJ, Beukema RJ, et al. Randomized Controlled Trial of Surgical Versus Cath-eter Ablation for Paroxysmal and Early Persistent Atrial Fibrillation. Circ Arrhythm Electrophysiol 2018;11:e006182.

20. Pokushalov E, Romanov A, De Melis M, et al. Progression of atrial fibrillation after a failed initial ablation procedure in patients with paroxysmal atrial fibrillation: a randomized comparison of drug therapy versus reablation. Circ Arrhythm Electrophysiol 2013;6:754-60.


22. Romanov A, Pokushalov E, Ponomarev D, et al. Long-term suppression of atrial fibrillation by botulinum toxin injection into epicardial fat pads in patients undergoing cardiac surgery: Three-year follow-up of a randomized study. Heart Rhythm 2019;16:172-7.

23. Waldron NH, Cooter M, Haney JC, et al. Temporary autonomic modulation with botulinum toxin type A to reduce atrial fibrillation after cardiac surgery. Heart Rhythm 2019;16:178-84.

24. Lee S, Khrestian A, Waldo AL, Khrestian CM, Markowitz A, Sahadevan J. Effect of Lidocaine Injec-tion of Ganglionated Plexi in a Canine Model and Patients With Persistent and Long-Standing Persistent Atrial Fibrillation. J Am Heart Assoc 2019;8:e011401.

25. de Groot JR. Botulinum toxin injection in the autonomic ganglion plexi to prevent postoperative atrial fibrillation: More than a cosmetic treatment. Heart rhythm 2019;16:185-6.

26. van den Berg NWE, Kawasaki M, Berger WR, et al. MicroRNAs in Atrial Fibrillation: from Expression Signatures to Functional Implications. Cardiovasc Drugs Ther 2017;31:345-65.

Appendices

Appendices

A

List of publications 219

lIst of publIcAtIons

Publications included in this thesisPart I.2019 Berger WR*, Meulendijks EM*, Limpens J, van den Berg NW, Neefs J, Driessen AH, Krul SP, van

Boven WJ, de Groot JR. Persistent Atrial Fibrillation: A systematic review and meta-analysis of invasive strategies. Int J Cardiol. 2019 Mar 1;278:137-143

2016 Driessen AH*, Berger WR*, Krul SP, van den Berg NW, Neefs J, Piersma FR, Chan Pin Yin DR, de Jong JS, van Boven WJ, de Groot JR

Ganglion Plexus Ablation in Advanced Atrial Fibrillation: The AFACT Study. J Am Coll Cardiol. 2016 Sep 13;68(11):1155-65

2019 Berger WR*, Neefs J*, van den Berg NW, Krul SP, van Praag EM, Piersma FR, de Jong JS, van Boven WJ, Driessen AH, de Groot JR

Additional Ganglion Plexus Ablation during Thoracoscopic Ablation of Advanced Atrial Fibrilla-tion. Intermediate Follow-up of the AFACT study.

JACC Clin Electrophysiol. 2019 Mar;5(3):343-353

2017 Driessen AH*, Berger WR*, Chan Pin Yin DR, Piersma FR, Neefs J, van den Berg NW, Krul SP, van Boven WJ, de Groot JR

Electrophysiologically Guided Thoracoscopic Surgery for Advanced Atrial Fibrillation: Five-year Follow-up.

J Am Coll Cardiol. 2017 Apr 4;69(13):1753-1754

Part II.2016 Berger WR, Krul SP, van der Pol JA, van Dessel PF, Conrath CE, Wilde AA, de Groot JR. Documented atrial fibrillation recurrences after pulmonary vein isolation are associated with

diminished quality of life. J Cardiovasc Med. 2016 Mar;17(3):201-8.

2018 Driessen AH*, Berger WR*, Bierhuizen MF, Piersma FR, van den Berg NW, Neefs J, Krul SP, van Boven WJ, de Groot JR

Quality of Life improves after Thoracoscopic Surgical Ablation of Advanced Atrial Fibrillation. Results of the AFACT study.

J Thorac Cardiovasc Surg. 2018 Mar;155(3):972-980.

Part III.2015 Krul SP, Berger WR, Smit NW, van Amersfoorth SC, Driessen AH, van Boven WJ, Fiolet JW, van

Ginneken AC, van der Wal AC, de Bakker JM, Coronel R, de Groot JR. Atrial Fibrosis and Conduction Slowing in the Left Atrial Appendage of Patients Undergoing

Thoracoscopic Surgical Pulmonary Vein Isolation for Atrial Fibrillation. Circ Arrhythm Electrophysiol. 2015 Apr;8(2):288-95

2018 Berger WR, Jagu B, van den Berg NW, Chan Pin Yin DR, van Straalen JP, de Boer OJ, Driessen AH, Neefs J, Krul SP, van Boven WJ, van der Wall AC, de Groot JR

The Change in Circulating Galectin-3 Predicts Absence of Atrial Fibrillation after Thoracoscopic Surgical Ablation.

Europace. 2018 May 1;20(5):764-771.

220 Appendices

Publications not included in this thesis2019 Bayer JD, Krul SP, Boukens BJ, Roney CH, Driessen AH, Berger WR, van den Berg NW, Vigmond EJ,

Coronel R, de Groot JR Acetylcholine delays atrial activation to facilitate atrial fibrillation. Front. Physiol. 2019 Sep (Epub)

2018 Mol D, Berger WR, Khan M, de Ruiter GS, Kimman GP, de Jong JS, de Groot JR Additional diagnostic value of mini electrodes in an 8-mm tip cavotricuspid isthmus ablation. J Atr Fibrillation. 2018 Oct 31;11(3):2082

2018 Khan M, Hendriks AA, Yap SC, Berger WR, de Ruiter GS, Szili-Torok T Damage to the left internal mammary artery during anterior epicardial access for ventricular

tachycardia ablation - case series Heart Rhythm Case Rep. 2018 Aug 14;4(11):534-537

2018 Veldkamp MW, Geuzebroek GS, Baartscheer A, Verkerk AO, Schumacher CA, Suarex GG, Berger WR, Wolswinkel R, van Amersfoorth SC, Driessen AH, Belterman CN, van Ginneken AC, de Groot JR, de Bakker JM, Remme CA, Boukens BJ, Coronel R

Cardiac Neurkinin-3 Receptor Stimulation Prolongs Atrial But Not Ventricular Refractoriness: A Novel, Potentially Anti-Arrhythmic Pathway.

Nat Commun. 2018 Oct 19;9(1):4357

2018 van den Berg NW, Chan Pin Yin DR, Berger WR, Neefs J, de Bruin-Bon R, Marquering H, Slaar A, Planken N, de Groot JR

Comparison of non-triggered Magnetic Resonance Imaging and Echocardiography for the As-sessment of Left Atrial Volume and Morphology

Cardiovasc Ultrasound. 2018 Sep 18;16(1):17.

2018 Brouwer TF, Kalkman DN, Vehmeijer JT, Berger WR, Knops RE, de Winter RJ, Peters RJ, van den Born BJ

Intensive blood pressure lowering in patients with and without type II Diabetes Mellitus: a pooled analysis from two randomized trials.

Diabetes Care. 2018 Jun;41(6):1142-1148.

2017 van den Berg NW, Neefs J, Berger WR, Baalman SW, Meulendijks EM, Kawasaki M, Kemper EM, Piersma FR, Veldkamp MW, Wesselink R, Krul SP, de Groot JR

Can we spice up our Christmas Dinner? Busting the myth of the ‘Chinese Restaurant Syndrome’. Neth Heart J. 2017 Dec;25(12):664-668.

2017 Kalkman DN, Brouwer TF, Vehmeijer JT, Berger WR, Knops RE, de Winter RJ, Peters RJ, van den Born BJ

The J-curve in patients randomly assigned to different systolic blood pressure targets - an experi-mental approach to an observational paradigm.

Circulation. 2017 Dec 5;136(23):2220-2229.

A

List of publications 221

2017 van den Berg NW, Kawasaki M, Berger WR, Neefs J, Meulendijks E, Tijsen AJ, de Groot JR MicroRNAs in Atrial Fibrillation: from Expression Signatures to Functional Implications. Cardiovasc Drugs Ther. 2017 Jun;31(3):345-365.

2017 Brouwer TF, Smeding LN, Berger WR, Driessen AH, de Groot JR, Wilde AA, Knops RE Assessment of the extravascular implantable defibrillator: feasibility of substernal ventricular

pacing. J Cardiovasc Electrophysiol. 2017 Jun;28(6):674-676

2017 Neefs J, van den Berg NW, Limpens J, Berger WR, Boekholdt SM, Sanders P, de Groot JR Aldosteron Pathway Blockade to Prevent Atrial Fibrillation: a Systematic Review and Meta-

analysis. Int J Cardiol. 2017 Mar 15;231:155-161.

2015 Krul SP, Berger WR, Veldkamp MW, Driessen AH, Wilde AA, Deneke T, de Bakker JM, Coronel R, de Groot JR

Treatment of atrial and ventricular arrhythmias through autonomic modulation. JACC Clinical Electrophysiology 2015, December 2015:496 – 508

2014 Krul SPJ, Meijborg VMF, Berger WR, Linnenbank AC, Driessen AHG, van Boven WJ, Wilde AAM, de Bakker JM, Coronel R, de Groot JR

Disparate response of high-frequency ganglionic plexus stimulation on sinus node function and atrial propagation in patients with atrial fibrillation.

Heart Rhythm 2014 Oct;11(10):1743-51

2013 de Groot JR, Berger WR, Krul SP, van Boven WJ, Salzberg SP, Driessen AH Electrophysiological Evaluation of Thoracoscopic Pulmonary Vein Isolation. J Atr Fibrillation 2013;6 (3):93-101

2013 Berger WR, Knops RE, de Groot JR. Internal cardioversion of persistent atrial fibrillation in implantable cardioverter defibrillator

patients: the juice is not worth the squeeze. Neth Heart J. 2013 Dec;21(12);545-7.

2013 Krul SP, Berger WR, Driessen AH, Wilde AA, de Groot JR Frequentie- en ritmecontrole bij boezemfibrilleren. Ned Tijdschr Geneeskd.2013;157:A5701

2011 Berger WR, Gow RM, Kamberi S, Cheung M, Smith KR, Davis AM. The QT and corrected QT interval in recovery after exercise in children. Circ Arrhythm Electrophysiol 2011 Aug;4(4):448-55

222 Appendices

contRIbutIng AuthoRs

Shirley C. van AmersfoorthAmsterdam University Medical Centers, Amsterdam, The Netherlands

Jacques M. de BakkerInteruniversity Cardiology Institute of the Netherlands, Utrecht, Netherlands

Nicoline W.E. van den BergAmsterdam University Medical Centers, Amsterdam, The Netherlands

Mark F. BierhuizenAmsterdam University Medical Centers, Amsterdam, The Netherlands

Onno J. de BoerAmsterdam University Medical Centers, Amsterdam, The Netherlands

Wim-Jan P. van BovenAmsterdam University Medical Centers, Amsterdam, The Netherlands

Dean R.P.P. Chan Pin YinSt. Antonius Hospital, Nieuwegein, Netherlands

Ruben CoronelAmsterdam University Medical Centers, Amsterdam, The Netherlands

Chantal E. ConrathAmsterdam University Medical Centers, Amsterdam, The Netherlands

Pascal F.H.M. van DesselMedisch Spectrum Twente, Enschede, Netherlands

Antoine H.G. DriessenAmsterdam University Medical Centers, Amsterdam, The Netherlands

Jan W. FioletAmsterdam University Medical Centers, Amsterdam, The Netherlands

Antoni C.G. van GinnekenAmsterdam University Medical Centers, Amsterdam, The Netherlands

Joris R. de GrootAmsterdam University Medical Centers, Amsterdam, The Netherlands

Benoit JaguInstitute of Thorax, University of Nantes, Nantes, France

A

Contributing authors 223

Sébastien P.J. KrulAmsterdam University Medical Centers, Amsterdam, The Netherlands

Jacqueline LimpensAmsterdam University Medical Centers, Amsterdam, The Netherlands

Eva M. MeulendijksAmsterdam University Medical Centers, Amsterdam, The Netherlands

Jolien NeefsAmsterdam University Medical Centers, Amsterdam, The Netherlands

Femke R. PiersmaAmsterdam University Medical Centers, Amsterdam, The Netherlands

Joy A. van der PolAmsterdam University Medical Centers, Amsterdam, The Netherlands

Elise M. van PraagAmsterdam University Medical Centers, Amsterdam, The Netherlands

Nicoline W. SmitAmsterdam University Medical Centers, Amsterdam, The Netherlands

Jan P. van StraalenAmsterdam University Medical Centers, Amsterdam, The Netherlands

Allard C. van der WalAmsterdam University Medical Centers, Amsterdam, The Netherlands

Arthur A.M. WildeAmsterdam University Medical Centers, Amsterdam, The Netherlands

224 Appendices

poRtfolIo

PhD Student: W.R. BergerPhD Period: June 2012 – September 2019Supervisors: Prof. dr. J.R. de Groot and Prof. mr. dr. B.A.J.M. de Mol

PhD TrainingYear ECTS

General courses

Basic course legislation and organization for clinical researchers (BROK) 2012 1.0

The AMC World of Science 2012 0.7

Practical biostatistics 2012 1.1

Clinical data management 2013 0.5

Entrepeneurship in health and life sciences 2013 1.5

Searching for a systematic review 2014 0.1

Clinical epidemiology: Systematic reviews 2014 0.7

Computing in R 2015 0.4

Specific courses

CVOI course: Masterclass: How to get your paper published 2014 0.4

St. Jude course: EP curriculum 2014 0.4

St. Jude course: Elektrofysiologie advanced 2014 0.4

Presentations and conferences

Heart Rhythm Society (HRS), Denver, USA 2013 0.4

European Society of Cardiology (ESC), Amsterdam, Netherlands 2013 0.4

Netherlands Heart Rhythm Association (NHRA), Ermelo, Netherlands 2013 0.4

Hybrid AF ablation, crossing borders, Maastricht, Netherlands 2013 0.4

European Society of Cardiology (ESC), Barcelona, Spain 2014 0.4

Netherlands Heart Rhythm Association (NHRA), Ermelo, Netherlands (Oral presentation) 2014 0.8

Hybrid AF ablation, crossing borders, Maastricht, Netherlands 2014 0.4

European Society of Cardiology (ESC), London, UK (Poster presentation) 2015 1.5

NVVC congres, Papendal, Netherlands (Oral presentation) 2015 0.8

NVVC congres, Noordwijk, Netherlands (Oral presentation) 2016 0.8

Heart Rhythm Society (HRS), San Fransisco, USA (Poster presentation) 2016 1.5

European Society of Cardiology (ESC), Rome, Italy (Poster presentation) 2016 1.5

NVVC congres, Papendal, Netherlands (Oral presentation) 2016 0.8

European Society of Cardiology (ESC), Barcelona, Spain (Poster presentation) 2017 1.5

European Heart Rhythm Association (EHRA), Barcelona, Spain (Moderated poster presentation)

2018 1.5

A

Portfolio 225

PhD TrainingYear ECTS

NVVC congres, Noordwijk, Netherlands (Oral presentation) 2018 0.8

European Society of Cardiology (ESC), München, Germany 2018 0.4

NVVC congres, Papendal, Netherlands 2018 0.4

NVVC congres, Noordwijk, Netherlands 2019 0.4

Internistendagen, Maastricht, Netherlands (oral presentation) 2019 0.8

European Society of Cardiology (ESC), Paris, France 2019 0.4

Teachingyear ECTS

Lecturing

Lecturer electrophysiology workshop for medical students AMC-UvA 2012-2016 2.0

Lecturer electrocardiography for advanced nursing courses 2013-2017 2.0

Supervision

1 medical student for master thesis2 medical students for bachelor thesis

20142014-2015

1.03.0

3 medical students for extra-curricular research projects 2014-2016 3.0

Other

Board member APROVE 2013-2016 3.0

Board member Juniorkamer NVVC 2018-2019 1.0

Awards and prizes

Heart Rhythm Society (HRS) Travel Scholarship 2016

European Heart Rhythm Association (EHRA) Congress Grant 2018

NVVC congres Best oral presentation (session: rhythm/devices) 2018

226 Appendices

dAnkwooRd

Zoals de meesten weten, ben ik over het algemeen een man van weinig woorden (liever daden), maar toch wil ik in dit dankwoord een aantal belangrijke personen noemen aan wie ik veel heb gehad in die zeven jaren dat ik aan dit proefschrift heb gewerkt. Er zijn daarnaast nog vele anderen die er, direct of indirect, voor hebben gezorgd dat dit proefschrift nu voor u ligt. Uiteraard ben ik ook hen zeer dankbaar.

In de eerste plaats wil ik alle patiënten bedanken die hebben deelgenomen aan de onderzoeken die in dit proefschrift worden beschreven. Zonder hen waren al deze onderzoeken niet mogelijk geweest.

Mijn promotor, Professor dr. J.R. de Groot. Beste Joris, ik wil nog maar eens onderstrepen dat jouw toewijding tot de wetenschap ongeëvenaard is. Misschien dat we niet altijd op dezelfde lijn zaten, maar ik heb echt ontzettend veel van je geleerd in deze periode. Ik ken niemand die telkens weer zo secuur een manuscript beoordeeld en precies de vinger op de zere plek weet te leggen, maar daar dan ook altijd weer een oplossing voor weet. Ik vind het ontzettend mooi dat wij dit proefschrift samen tot een geheel hebben gebracht en ik ben heel erg trots dat ik bij heb mogen dragen aan jouw weg naar het hoogleraarschap en de indrukwekkende onderzoekslijn die je hebt gecreëerd.

Beste Bas de Mol en beste Arthur Wilde, ik ben jullie erg dankbaar dat jullie mij de mo-gelijkheid gaven om een promotietraject in het AMC te beginnen.

Associate professor Andrew Davis. Dear Andrew, I am extremely grateful for the time we worked together during my research project at the Royal Children’s Hospital in Mel-bourne in 2008. I will not forget your warm welcome and your never ending enthusiasm was so contagious that it formed the basis for my decision to do a PhD and become a cardiologist. I want to thank you for that and I hope to see you again at a conference or, maybe even better, in Melbourne.

Ik wil graag de leden van mijn promotiecommissie, prof. Boersma, prof. Pinto, prof. Henriques, prof. Mariani, dr. de Jong en dr. Götte, bedanken voor hun bereidheid om mijn proefschrift te beoordelen en zitting te nemen in deze promotiecommissie. In het bijzonder wil ik Jonas de Jong bedanken voor zijn bijdrage aan mijn proefschrift, maar ook voor het gastvrije ontvangst in het OLVG. Ik vind het erg leuk dat er ook in het OLVG mogelijkheden zijn om betrokken te zijn bij het onderzoek naar de behandeling van atriumfibrilleren en hoop hier in de toekomst nog meer aan bij te kunnen dragen.

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Dankwoord 227

Beste Antoine en Wim Jan, veel dank voor jullie onuitputtelijke geduld tijdens de mo-menten dat jullie weer een operatie stil moesten leggen als ik weer met een bak met ijs aankwam of zo nodig weer een aantal metingen moest doen. De samenwerking heb ik altijd als zeer fijn ervaren en jullie zijn onmisbaar geweest bij het tot stand komen van dit proefschrift.

Ook zonder Sébastien en Femke was dit proefschrift er niet geweest. Sebas, jij hebt mij als een geweldige mentor ontvangen in de groep en ik heb erg veel van je geleerd. En Femke, ik vond het super gezellig om al die tijd met jou samen te werken.

Mijn opvolgers, Jolien, Nicoline, Eva en Robin. Een deel zelf inmiddels alweer bijna klaar. Wat een sterk team heeft Joris om zich heen gebouwd. Dank voor jullie bijdrage aan dit proefschrift en dank ook dat jullie mij betrokken hielden bij het onderzoek terwijl ik in dat andere ziekenhuis in Amsterdam aan het werk was.

Judith, Louise, Madelon, mijn moeders op onze kamer. Maar gelukkig waren jullie nog geen moeders toen ik begon met mijn promotietraject. Wat hebben wij lekker veel geklaagd, maar ook zoveel mooie momenten gehad, zowel tijdens werk, maar ook op alle congressen, promotieborrels en andere feestjes. Hopelijk worden we in te toekomst weer eens directe collega’s.

Maar ook de andere kamergenoten van F3-241, Anne-Floor, Tom, Jim en Veronique en Suzanne, heel veel dank voor de talloze koffies, wetenschappelijk hoogstaande, maar vooral ook heel veel slappe discussies die we hebben gehad. Het was een erg mooie tijd met jullie op de kamer.

Veel dank ook aan alle (oud-) arts-onderzoekers van de afdeling cardiologie in het AMC voor de fantastische skireizen, ontelbare borrels, congressen en weekendjes in Friesland.

Daarnaast wil ik de belangrijkste mensen van het AMC Hartcentrum, namelijk de secre-taresses Margreet, Regina, Anita en Lieve heel erg bedanken voor al hun ondersteuning. En ook researchverpleegkundige Ineke Radder, ik vond het heel fijn om met jou samen te werken.

Beste Reinoud, een zetje in de goede richting kan nooit kwaad. Dank daarvoor.

228 Appendices

Dank ook aan de (oud-) bestuursleden van APROVE voor de mooie tijd dat we bezig waren met interessante projecten, organisatie van leuke events, maar vooral het vele uitgebreide eten en ‘vergaderen’.

Drs. T. Slagboom en Dr. J.P. Herrman, Beste Ton en Jean Paul, mijn opleiders in het OLVG, ik wil jullie hartelijk danken dat jullie mij de mogelijkheid hebben geboden om mijn grote droom om cardioloog te worden waar te maken.

Daardoor ben ik ook onderdeel geworden van een fantastische groep cardiologie-assistenten, en daar horen Judith en Daniel natuurlijk ook gewoon bij. Wat een mooi team hebben we in het OLVG. Keihard werken, daarna afblussen in de Buko of op een festival of gewoon even een weekje naar Curaçao, het kan allemaal met jullie. En dan steken er drie collega’s met kop en schouder bovenuit: Laura, Sander en Robin, ik vind het geweldig om de gehele opleiding tegelijk met jullie te doorlopen.

Dank ook aan de collega’s AIOS en stafleden van de Interne Geneeskunde OLVG voor het warme bad waar ik tijdens mijn vooropleiding in terecht ben gekomen. Het zijn twee hele leerzame, maar vooral ook gezellige jaartjes geweest.

En dan zijn er in de laatste jaren gelukkig nog genoeg, net zo belangrijke, momenten geweest dat ik even niet met mijn onderzoek bezig was. Daartoe behoren onder andere de mooie feestjes en festivals met de nog altijd groeiende partycrew onder bezielende leiding van Veer, Flip en Sjakie. Ook de vakanties in Oostenrijk met een, inmiddels ietwat burgerlijke, maar daardoor niet minder gezellige wintersportgroep zorgden voor de noodzakelijke afleiding.

Maar veruit de meeste mooie momenten beleef ik al 15 jaar met mijn jaarclubgenoten van JC Steal. Jongens, waanzinnig dat we dit al zo’n tijd volhouden met z’n allen, waar op de wereld iedereen ook woont. Daar gaan we wat mij betreft nog wel een aantal jaartjes mee door.

Oké, ook dank aan de boys van FT, hopelijk heb ik binnenkort weer wat vaker tijd voor een biertje.

In het bijzonder wil ik nog Hugo bedanken. Sinds de kleuterschool beste vrienden, eerst onafscheidelijk, nu lukt het nauwelijks om één keer in het jaar af te spreken. Maar on-danks dat we elkaar weinig zien, blijf jij de eerste persoon die ik bel als er iets belangrijks is en is elk moment dat we elkaar zien weer als vanouds. Beter een verre vriend, dan een goede buur.

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Dankwoord 229

Mijn paranimfen, Florine Berger en Volkert Poulie Wilkens. Lieve Floor, van mijn drie zusjes heb jij mijn promotie van het dichts bij mee kunnen maken tijdens een congres in Rome waar wij beiden waren. Leuk dat ik me toen direct als grote broer mocht gedragen. Misschien wel de slimste van de familie, maar ook veruit de meest eigenwijze. Al kan dat soms tegen je werken, je weet daarom als geen ander wat je wilt en krijgt dat ook altijd voor elkaar. Daar heb ik heel veel bewondering voor. Ik ben heel blij dat jij naast mij staat tijdens de verdediging.

Beste Volkert, clubgenoot en huisgenoot tijdens een groot deel van mijn promotie. Net als veel anderen had jij geen idee waar ik mee bezig was, maar toch probeerde jij interesse te tonen in mijn onderzoek. Helaas vergat je het ook ieder keer weer, maar dat laat wel zien hoe betrokken jij altijd bent. Maar het meest heb je met toch geholpen door regelmatig NIET met mijn proefschrift bezig te zijn. Ik vind het bijzonder wat voor goede vrienden wij in die tijd zijn geworden en vind het daarom erg mooi dat je tijdens de verdediging naast mij staat. En al worden we steeds iets meer volwassen, van die momenten dat we even niet met werk bezig zijn, blijven altijd belangrijk.

Lieve schoonfamilie, Ton, Nynke, Laura en Mascha, ook al ben ik geen groot fan van hon-den, ik vind het iedere keer weer heel gezellig in Apeldoorn en voel me altijd thuis bij jullie. Beste Pim, veel dank voor je betrokkenheid en interesse in dit proefschrift.

Lieve Daan, nu ook in opleiding tot specialist, wat bewonder ik jouw doorzettingsver-mogen. Lieve Lot, ik vind het zo knap dat jij als enige van de familie hebt gekozen voor iets heel anders dan het bekende medische wereldje, sorry dat dit proefschrift dan weer alleen maar over medische dingen gaat. Elk jaar gaan wij weer met z’n allen op vakantie en dat zijn de momenten, op een kleine onenigheid hier en daar na, de meest ontspan-nen momenten die er zijn en ik hoop dan ook dat we dat zullen blijven doen. Wat ben ik trots op mijn drie kleine zusjes, maar dat weet ook iedereen die een keer op mijn telefoon kijkt.

Lieve pap en mam, mijn dank aan jullie kan ik hier niet in een paar zinnen omschrijven. Heel veel dank voor jullie liefde, hulp, tips, interesse, geduld en nog veel meer. Dank voor alles. Dit proefschrift is voor jullie

Lieve Joëlle, jij bent de reden dat ik zonder enige twijfel JA zou antwoorden als ik zou worden gevraagd of ik dit allemaal opnieuw zou doen. Ze zeggen wel dat een proef-schrift altijd iets bijzonders oplevert. Maar dat het zo bijzonder en leuk en fijn zou zijn, had ik nooit durven dromen. Nu we allebei ons ‘eigen kindje’ af hebben, hebben we straks nog iets veel mooiers van ons samen. En ik heb heel veel zin in die tijd samen!

230 Appendices

CURRICULUM VITAE

Wouter Rudolph Berger was born in Rotterdam on October 10th, 1986. After finishing secondary school at the Erasmiaans Gymnasium in 2004, he moved to Groningen to study Medicine at the Rijksuniversiteit Groningen. During his study he went to Mel-bourne, Australia for six months to conduct a research project at the department of paediatric cardiology in the Royal Melbourne Children’s Hospital under the enthusiastic supervision of Andrew Davis, for which he received a Dekker student grant from the Netherlands Heart Foundation. This is where he developed his interest in research. Dur-ing the last phase of his study, he did one year of clinical rotations at Isala Klinieken in Zwolle and subsequently, a senior internship at the Academic Medical Center (AMC) in Amsterdam. In April 2012 he obtained his medical degree and in June 2012 he started working as a PhD-student at the department of Cardiology in the AMC under the super-vision of Prof. Joris de Groot and Prof. Bas de Mol. Complementary to his work as a PhD-student he was a board member of APROVE, an association for AMC PhD candidates and worked as a teacher at the Amstel Academy. In 2017, he continued his medical career, working shortly as a resident not-in-training, before starting his training as a cardiologist at OLVG Oost under the supervision of Drs. Ton Slagboom and Dr. Jean-Paul Herrman. As part of his training he is currently working at the department of Internal Medicine under the supervision of Dr. Yves Smets, after which will he continue his training in cardiology at OLVG Oost. He is a board member of the Juniorkamer, representing the interests of cardiologists in training in the Netherlands. He lives together with Joëlle in Amsterdam.

[0144] Omslag:Naam Wouter Berger FC Formaat: 170 x 240 mmRugdikte: 11,6 mm

Boekenlegger: 60 x 230 mmDatum:19-11-2019


Wouter Berger

Markers of atrial rem

odeling and invasive treatment of atrial fibrillation

Wouter Berger

UITNODIGINGVoor de openbare verdediging

van het proefschrift:

Markers of atrial remodeling and

invasive treatment of atrial fibrillation

doorWouter R. Berger

Rooseveltlaan 246-21078 NZ [email protected]

Donderdag 9 januari 2020 om 14:00 uur

in de Agnietenkapel Universiteit van AmsterdamOudezijds Voorburgwal 231

te Amsterdam

Aansluitend bent u van harte uitgenodigd voor de receptie in het

nabijgelegen café:De Brakke Grond

Nes 43, Amsterdam

PARANIMFEN

Florine Berger [email protected]

Volkert Poulie [email protected]

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