Jason Arya Varzaly MBBS Centre for Heart Rhythm Disorders, The … · 2018-08-30 · Centre for...

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The Surgical Management of Atrial Fibrillation

Jason Arya Varzaly

MBBS

Centre for Heart Rhythm Disorders, The School of Medicine, University of Adelaide

April, 2017

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Table of Contents

Chapter 1 Introduction

1.1. Burden of Atrial Fibrillation

1.1.1. Risk Factors of AF

1.1.2. Consequences of AF

1.1.3. Economic Burden of AF

1.2. Mechanisms of Atrial Fibrillation

1.2.1. Multiple Wavelets

1.2.2. Focal Triggers

1.2.3. Anatomical Structures as Sources of Foci

1.2.4. Cardiac Autonomic Nervous System

1.2.5. Endocardial to Epicardial Connections

1.2.6. Rotors

1.3. Management options available

1.3.1. Risk Factor Modification

1.3.2. Anticoagulation

1.3.3. Rate Control

1.3.4. Rhythm Control

1.3.4.1. Catheter Ablation

1.4. Role of surgery

1.5. Available technologies

1.6. Previous Meta-Analyses

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Meta-Analysis and Literature Review

Chapter 2 Surgical Ablation of Atrial Fibrillation Concomitant to

Mitral Valvular Repair or Replacement – Analysis of

Valvular Disease and Intervention, Ablation Method, Safety

and Success in Sinus Rhythm Maintenance

2.1. Introduction

2.2. Methods

2.2.1. Definitions

2.2.2. Statistical Analysis

2.3. Results

2.3.1. Study & Patient Characteristics

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2.3.2. Mitral and Concurrent Valvulopathy

2.3.3. Surgical Ablation Procedures

2.3.3.1. Approach and Technique

2.3.3.2. Lesion Set

2.3.3.3. Operative Parameters

2.3.4. Post-Procedure Follow-up

2.3.5. Recurrent Arrhythmia

2.3.6. Antiarrhythmic Drug Use

2.3.7. Outcomes

2.3.8. Procedural Complications

2.3.9. Subgroup Analysis

2.3.9.1. Lesion Set

2.3.9.2. Energy Source

2.3.9.3. LAA Exclusion

2.3.9.4. Randomised Controlled Data

2.4. Discussion

2.4.1. Valvular Disease, Surgery and AF

2.4.2. Surgical Ablation Technique

2.4.3. Complications

2.4.4. Clinical Implications

2.4.5. Study Limitations

2.5. Conclusions

2.6. Figure and Tables

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Chapter 3 Surgical Ablation of Atrial Fibrillation with Concurrent

Cardiac Surgery – Assessment of the Safety and Efficacy of

Ablation procedures during any other Cardiac Surgical

Intervention

3.1. Introduction

3.2. Methods

3.2.1. Definitions


3.3. Results


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3.3.2. Concurrent Cardiac Surgical Procedures



3.3.3.2. Lesion Set


3.3.4. Post Procedure Follow-up

3.3.5. Definitions of Recurrent Arrhythmia


3.3.7. Outcomes


3.3.9. Sub-Group Analysis

3.3.9.1. Baseline Characteristics

3.3.9.2. Lesion Set Comparison

3.3.9.3. Energy Source Comparison


3.3.9.5. Randomised Control Trial Data

3.4. Discussion

3.4.1. Concomitant Cardiac Surgery and AF

3.4.2. Comparison to Studies of Concomitant Mitral Valve

Procedures




3.5. Conclusions

3.6. Figures and Tables

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Chapter 4 Isolated Surgical Ablation for Atrial Fibrillation – The

Methodology, Safety and Success in Sinus Rhythm

Maintenance of Sole Cardiac Surgical Procedures

4.1. Introduction

4.2. Methods

4.2.1. Definition


4.3. Results

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IV



4.3.2.1. Surgical Access


4.3.2.3. Lesion Set


4.3.2.5. Procedural Endpoints


4.3.4. Outcomes

4.3.5. Sub-group Analysis

4.3.5.1. Lesion Set



4.3.5.4. Procedural Complications

4.4. Discussion

4.4.1. Catheter vs Surgical Ablation for Isolated AF

4.4.2. The LAA Dilemma

4.4.3. Clinical Implications: Developing Superior Results


4.5. Conclusions

4.6. Figures and Tables

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Chapter 5 Hybrid Ablation (Surgical and Electrophysiological) of

Atrial Fibrillation – The Methodology, Safety and Success of

Sinus Rhythm Maintenance

5.1. Introduction

5.2. Methods

5.2.1. Definitions


5.3. Results



5.3.2.1. Surgical Approach

5.3.2.2. Energy Utilised

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5.3.2.3. LAA Management and Additional

Approaches

5.3.2.4. Endpoints

5.3.3. Catheter-base Electrophysiological Procedures

5.3.3.1. Timing after Surgery

5.3.3.2. Endocardial Procedure Type


5.3.3.4. Procedural Time

5.3.4. Post-Procedural Follow-up

5.3.5. Outcomes

5.3.5.1. Univariate Predictors of Outcome

5.3.5.2. Sequential vs Staged

5.3.5.3. Block Analysis


5.3.5.5. Surgical Lesion Set

5.3.5.6. Energy Type

5.3.5.7. Device Type

5.3.5.8. Left Atrial Appendage

5.3.5.9. Ganglionated Plexi Ablation

5.3.5.10. AAD Management


5.3.6.1. Sub-Group Analysis of Complications

5.4. Discussion

5.4.1. Outcomes and Complications of Hybrid Ablation

5.4.2. Lessons from Early Experiences



5.5. Conclusions

5.6. Figure and Tables

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Chapter 6 The Contact Force Effect of Bipolar Radio-Frequency

Clamps on Lesion Formation in the Surgical Management of

Atrial Fibrillation

6.1. Introduction

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6.2. Methods

6.2.1. Pressure Assessment

6.2.1.1. Surgical Equipment

6.2.1.2. Tissue Selection

6.2.1.3. Clamp Pressure Assessment Methodology

6.2.1.4. Contact Force

6.2.1.5. Pressure Film and Analysis

6.2.2. Ablation Lesion Analysis

6.2.2.1. Experimental Preparation


6.2.2.3. Ablation and Evaluation of Transmurality


6.3. Results

6.3.1. Pressure Analysis

6.3.2. Lesion Analysis

6.3.3. Total RF Time and Impedance

6.3.4. Lesion Depth

6.3.5. Fat Presence and Effect

6.3.6. Transmurality

6.4. Discussion

6.4.1. Major Findings

6.4.2. Importance of Contact Force

6.4.3. Number of Burns

6.4.4. The Interaction of Fat

6.4.5. Impedance as a Measure of Ablation Endpoint


6.5. Conclusion

6.6. Figures

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Chapter 7 Conclusions and Discussion 170

Chapter 8 Future Directions 174

Chapter 9 References

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VII

ABSTRACT

Atrial fibrillation (AF) is the most common atrial arrhythmia with an increasing prevalence

identified worldwide. Symptomatic episodes have resulted in increasing hospitalisations such

that this is now one of the dominant cardiovascular reasons for hospital admission in Australia.

Beyond this, AF predisposes to heart failure, stroke and increasing cognitive decline. While

medical therapy is available for the treatment of this condition the use of medication has not

always proven sufficient for its management leading to the development of catheter and

surgical ablation therapies. However, while surgical ablation procedures are widely utilised,

the true efficacy of these approaches has not been well understood due to the wide variety of

methodologies, concomitant procedures, technologies utilised and follow-up implemented.

This thesis evaluates the current state of surgical ablation for AF.

Chapter 1 provides an overview of the burden of AF on our community, the

mechanisms of arrhythmia, a summary of medical and catheter based therapies and an in-depth

analysis of how surgical therapies for atrial fibrillation were developed and the current

approaches to surgical ablation with the current technologies available for use. Chapters 2

through 5 examine the efficacy and safety of the surgical ablation of AF when performed

concurrent to mitral valve disease intervention, concomitant cardiac surgery in general, as a

standalone procedure and as part of an emerging technique of hybrid ablation (joint surgical

and cardiology electrophysiology) procedure. This evaluation has been performed through

systematic literature review and meta-analyses identifying that surgical ablations procedures

offer good medium term results in sinus rhythm maintenance (SRM) on and off antiarrhythmic

drugs(AAD) achieving 79.6% SRM concurrent to mitral valve intervention, 79.6% on AAD

and 65.3% off AAD concurrent to general cardiac surgical procedures, 85.3% on and 65.5%

off AAD as a standalone procedure, and 79.4% on AAD and 70.7% off AAD when performed

as a hybrid ablation procedure. The complication rates were low across all series, with the

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lowest complication rates associated with the hybrid procedure. Chapter 6 then presents the

results of a series of experiments analysing the properties of surgical bipolar RF clamps and

how ablation lesions are formed, with the identification that the efficacy of these surgical

ablative tools is subject to the effects of contact force for the delivery of transmural lesions,

increased numbers of ablation increase the likelihood of a transmural lesion irrespective of the

device indicating transmurality, the presence of fat significantly attenuates the ability to deliver

of a transmural lesion and these effects are amplified with increased thickness of the tissue

being ablated. The observations of this thesis thus provide insight into the optimal conditions

under which the surgical ablation of AF may obtain the best results in sinus rhythm

maintenance.

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Declaration of Authorship

I certify that this work contains no material which has been accepted for the award of any other

degree or diploma in my name in any university or other tertiary institution and, to the best of

my knowledge and belief, contains no material previously published or written by another

person, except where due reference has been made in the text. In addition, I certify that no part

of this work will, in the future, be used in a submission in my name for any other degree or

diploma in any university or other tertiary institution without the prior approval of the

University of Adelaide and where applicable, any partner institution responsible for the joint

award of this degree.

I give consent to this copy of my thesis, when deposited in the University Library, being

made available for loan and photocopying, subject to the provisions of the Copyright Act 1968.

I also give permission for the digital version of my thesis to be made available on the

web, via the University's digital research repository, the Library Search and also through web

search engines, unless permission has been granted by the University to restrict access for a

period of time.

Jason Arya Varzaly

27-04-2017

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ACKNOWLEDGEMENT

I would like to thank Professor Prashanthan Sanders, Mr Michael Worthington and Dr Dennis

Lau for their mentorship, encouragement, direction and friendship throughout my candidature

period. I have been grateful for the opportunity to work under the supervision of such esteemed

clinical scientists and I will carry forward the skills and knowledge I have acquired throughout

this journey onwards through all my future endeavours. I am truly appreciative for all your

support allowing me to explore the world of medical research and make this thesis possible.

My further thanks to the research group of the Centre of Heart Rhythm Disorders who

have been my colleagues and friends along this pathway. Foremost a special thanks to Mr

Darius Chapman whose friendship, teamwork, assistance and ingenuity through so many

experiments, and much hard work, has made so much possible throughout these exciting times

of science and discovery. I would also like to thank Drs Rajiv Mahajan, Anthony Brooks and

Adrian Elliott for their help throughout my candidature in analysis, review and statistics of my

work, even in the tightest of times frames.

I am also grateful for the perpetual support of the Cardiothoracic Surgery Department

of the Royal Adelaide Department for encouraging me to undertake this pathway of research

and supporting me along it over the years.

Further, I would like to thank the assistance of the team at the Preclinical, Imaging and

Research Laboratory of the South Australian Health and Medical Research Institute for

accommodating me throughout my experiments.

I would like to acknowledge the assistance of the Dr Jennie Louise and Ms Suzanne

Edwards of the Biostatistics Department of the University of Adelaide for their statistical

assistance throughout my candidature.

Most importantly I would like to thank my family. The most special of thanks to my

parents Afsaneh and Laird Varzaly whose limitless love, support, encouragement, guidance

and inspiration throughout my life has not only guided me through the toughest of times, but

has given me strength to forge forward and always have the belief to know that anything is

possible. To my sister, Jenifer Varzaly whose love and friendship have been constant in my

life as you have inspired me to work harder through your ongoing achievments, to my brother-

in-law Thomas Mulraney for the friendship and support he has offered for as long as I have

known him and to Amy Reid who continues to encourage and support me in all my life’s

pursuits. Through all your support this thesis was made possible.

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PRESENTATIONS TO LEARNED SOCIETIES

1) Awards and Grants

a) Nimmo Prize for Medical Research – Royal Adelaide Hospital – 2016

Awarded for “The Pressure Effect of Surgical Clamps on Ablation for Atrial

Fibrillation”

b) Young Achiever Award – Australia New Zealand Society of Cardio Thoracic

Surgeons (ANZSCTS) – 2015

Awarded for “The Pressure Effect of Bipolar RF Clamps on Ablation for Atrial

Fibrillation”

c) Mentorship and Travel Grant – American Heart Association – 2014

Awarded for “Hybrid approach for ablation of Atrial Fibrillation – a Meta-Analysis

and review of the literature”

Mentor: Prof Ralph Damiano Jr

2) Presentations:

a) The Pressure Effect of Bipolar RF Clamps on Ablation for Atrial Fibrillation

JA Varzaly, D Chapman, DH Lau, F Viana, J Edwards, RG Stuklis, P Sanders and M

Worthington

Presentation at the 2015 Australia New Zealand Society of Cardio Thoracic Surgeons

scientific meeting

b) The Pressure Effect of Bipolar Radio-Frequency Clamps for Treatment of Atrial

Fibrillation

JA Varzaly, D Chapman, DH Lau, F Viana, J Edwards, RG Stuklis, P Sanders and M

Worthington

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Presentation at the 2015 European Association of Cardio Thoracic Surgeons annual

meeting

c) Surgical Contact Force Effect in Creating RF Lesions in the Isolated and Hybrid

Ablation of Atrial Fibrillation

JA Varzaly, DH Lau, D Chapman, F Viana, J Edwards, RG Stuklis, M Worthington

and P Sanders

Presentation at Heart Rhythm Society 2016

d) The Efficacy of Joint Catheter and Surgical Ablation for Atrial Fibrillation – a

Review of the Literature and Meta-Analysis

JA Varzaly, DH Lau, D Chapman, F Viana, J Edwards, RG Stuklis, M Worthington

and P Sanders

Presentation at Asia Pacific Heart Rhythm Society 2015

e) Feasibility, Efficacy and Safety of isolated Surgical Ablation for Atrial

Fibrillation: A Systematic Review

JA Varzaly, DH Lau, D Chapman, R Mahajan, F Viana, J Edwards, RG Stuklis, M

Worthington and P Sanders

Presentation at Asia Pacific Heart Rhythm Society 2015

f) Surgical ablation of Isolated atrial fibrillation – a systematic review of the

literature

JA Varzaly, DH Lau, D Chapman, R Mahajan, F Viana, J Edwards, RG Stuklis, M

Worthington and P Sanders

Presentation at Heart Rhythm Society 2015

g) Hybrid approach for ablation of Atrial Fibrillation – a Meta-Analysis and review

of the literature

JA Varzaly, DH Lau, D Chapman, AG Brooks, J Edwards, RG Stuklis, M Worthington

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and P Sanders

Presentation at American Heart Association 2014

h) Surgical ablation of “lone” atrial fibrillation – a systematic review of the

literature

JA Varzaly, A Brooks, J Edwards, RG Stuklis, P Sanders and M Worthington

Presentation at Australia New Zealand Society of Cardio Thoracic Surgeons 2013

i) Hybrid approach for ablation of Atrial Fibrillation – a systematic review of the

literature

JA Varzaly, AG Brooks, DH Lau, J Edwards, RG Stuklis, P Sanders and M

Worthington

Presentation at Australia New Zealand Society of Cardio Thoracic Surgeons 2013

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Chapter 1

INTRODUCTION

1.1. THE BURDEN OF ATRIAL FIBRILLATION

Atrial Fibrillation (AF) is the most common atrial arrhythmia affecting 0.4% of the general

population with population based studies have estimated the lifetime risk of developing AF is

1 in 4, for both men and women, aged over 40 years of age.(1,2) Further long term analyses of

patients revealed that the incidence of AF has been increasing over time. An observational

study looking at a population over 50 years between the 10 year periods of 1958 to 1967 and

1998 to 2007 demonstrated that the age-adjusted prevalence of AF quadrupled from 20.4 to

96.2 cases per 1000 person-years in men and from 13.7 to 49.4 cases per 1000 person-years in

women.(3) In studies assessing community based trends in AF it has been estimated that by

2050 the number of people with AF will reach 12.1 million in the USA, however, when

corrected for the increasing incidence seen in the last 20 years this estimate rises to 15.9

million.(4) Indeed these estimates in the United States may be dwarfed by predictions in the

Asia-Pacific region, where accurate data still remains elusive.(5)

1.1.1. RISK FACTORS AND AF

The development of AF has been linked to structural heart disease with mitral valvopathy

identified as being associated with the development of AF in 30% to 40% of medically

managed patients in early studies.(6,7) Subsequent studies have confirmed the finding of a

high prevalence of AF in mitral valve disease, but have further identified that after the onset of

AF the incidence of cardiac morbidity and mortality increased.(8)

The growing burden of this disease, out of keeping from currently known risk factors,

has led the search for novel risk factors and new treatment targets for known risk factors.

Established risk factors for AF include increasing age, hypertension, congestive heart failure,

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myocardial infarction, and valvular heart disease.(9-12) Increasingly recognised new risk

factors include obesity, sleep apnoea, physical inactivity, endurance sports, aortic stiffness and

a genetic predisposition.(13-17)

1.1.2. CONSEQUENCES OF AF

The significance of the increasing burden of AF in the community stems from the identification

that it is associated with risk of thromboembolic stroke and loss of atrial systole with resultant

negative impact on ventricular function.(18-20) Studies analysing the link of AF to

thromboembolic stroke have identified that AF increases the risk of stroke fivefold,

independent of heart failure and coronary artery disease, and this effect was amplified to

seventeen fold in patients with rheumatic heart disease.(19,20)

The association of AF and heart failure has been established with the presence of heart

failure increasing the risk for developing AF 4.5 to 6 fold,(9,10) and associations have been

made to suggest that AF itself can result in heart failure through atrial and ventricular mediated

tachycardia driving cardiomyopathy.(18,21)

From a broader perspective AF has been associated with decreased quality of life and

increased incidence dementia, memory impairment and cognitive impairment, even in the

absence of an overt stroke.(22-26) The cumulative effect of these consequences of AF is an

increased risk of mortality estimated to be increased by 1.5 to 1.9 fold beyond the general

population.(9,10,19-21,27,28)

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1.1.3. ECONOMIC BURDEN OF AF

Further to the rising prevalence of AF it has significant monetary cost implications as the

number of hospitalisations related to AF increase in Australia(29) and the use catheter ablation

therapies for the control of this arrhythmia have been increasing exponentially.(30) Studies on

the economic burden of AF have reported increasing expenditures being required by health

systems to combat the increasing burden of this disease through general practitioner

consultations, referrals, drug prescriptions and hospital admissions, all of which have been

increasing over time.(29,31) In a report prepared for the National Stroke Foundation by

PricewaterhouseCoopers in June of 2010 it was estimated that the costs annual costs to the

Australian economy were at least $1.25 billion per annum in 2008-2009 owing to medical costs

of $874 million in addition to the long term care for those with this disability and the loss of

productive output to the community.(32)

1.2. MECHANISMS OF ATRIAL FIBRILLATION

The mechanisms of AF have drawn significant focus of study over many years with major

hypotheses about how it is initiated and triggered being documented.

1.2.1. Multiple Wavelet Hypothesis

The initial predominant theory of the mechanism of AF was based on multiple wavelets

of irregular electrical activity occurring simultaneously and propagating throughout the

atria in such wise that multiple wavelets would co-exist, divide around areas of

refractory tissues and result in further wavelet propagation.(33) This initial work based

on computer simulation was then confirmed by further experimental work by mapping

activation wavefronts in pacing induced AF in a canine model.(34) This model

suggested that a critical number of wavelets were required to co-exist for AF to develop,

and this condition was favoured by slowed conduction, shortened refractory periods

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and increased atrial mass. This phenomenon was subsequently mapped and described

in humans by Cox et al. leading to the early development of surgical procedures for the

control of AF.(35) His landmark work in the field of the surgical management of AF

postulated that surgical lines of conduction block could be “Cut and Sewn” into the

atrial tissue itself to interrupt the propagating wavefront of these wavelets and thus

terminate AF.(36) This work formed the basis for the Maze procedure which

demonstrated the clinical observation that chronic AF could be treated in patients by

compartmentalising the atria into small enough regions that were then unable to sustain

macro re-entrant circuits for the propagation of AF.(36,37)

While the multiple wavelets theory suggests the process of AF is a random and

chaotic one, other studies suggest that AF could be maintained by single or multiple re-

entrant sources within the Left Atrium (LA) alone. In a canine model with increasing

concentrations of acetylcholine; multiple re-entrant circuits converted to a single,

relatively stable circuit that resulted in fibrillation.(38) Based on these findings it was

postulated that such sources of high frequency waves from within the LA may act as

drivers for AF, and this was then supported through further animal studies.(39,40)

Alternatively, it was postulated that these findings could be equally explained by the

multiple anatomic structures that form the LA resulting in greater wavelet fractionation

thus leading to higher frequency waves and AF.(41) Perhaps the most interesting

demonstration of the left atrial source of driving AF was seen in the surgical isolation

of the LA resulting in right atrial sinus rhythm and persisting left atrial AF.(42)

1.2.2. Focal Triggers

The importance of atrial ectopy acting as a trigger for the development of AF was a

significant finding, only eclipsed by the finding that ablation of these areas can result

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in the termination of AF.(43-45) As this understanding was furthered multiple areas of

sites of atrial ectopy have been identified including the ligament of Marshall, the

coronary sinus, the crista terminalis and the superior vena cava.(43,45,46) However,

the area attracting the most interest for containing the vast majority of atrial ectopic

sites is the pulmonary veins, which had been previously been identified as structures

composed of cardiac tissue, and not simply blood vessels.(43,47)

1.2.3. Anatomical Structures as Sources of Foci

Both the right and left atria contain sites from which originate foci of automaticity

which in turn give rise to atrial tachycardia, and it has been recognised these sites are

in close relationship to anatomical structures such as the crista terminalis, the tricuspid

annulus, the interatrial septum, the coronary sinus, the ligament of Marshall, the

superior vena cava, the right or left atrial appendage, the mitral annulus and the

pulmonary veins.(47-54)

The pulmonary veins have become clinically apparent as one of the major sites of

not only atrial ectopy, but atrial tachycardia and AF as well.(45,50,53,55) This is due

in part to the sleeving of the atrial tissue into the pulmonary vein for ~1-3cm being

thickest most proximally to the LA itself.(56,57) Further, the cardiac myocytes that are

found along these sleeves of pulmonary vein tissue are predisposed to

arrhythmogenesis by discrete ion channel and action potential properties inherent

within them.(58,59) However, despite these properties, the pulmonary vein isolation

(PVI) has primarily proven effective only in paroxysmal AF, but not in persistent forms

of AF.(60-62) In studies utilising mapping technology coupled with high-frequency

amplitude analysis to localise the dominant sites of activation it has been shown that in

paroxysmal AF patients the pulmonary veins contain the highest frequency sites

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allowing termination of AF in up to 87% of patients through ablation, but in persistent

AF additional sites outside the pulmonary veins were seen.(63,64)

1.2.4. Cardiac Autonomic Nervous System

The atria possess autonomic input from the central nervous system through pre-

ganglionic nerve fibres as well as through the intrinsic cardiac autonomic nervous

system.(65) These intrinsic cardiac autonomic nervous system clusters, termed

ganlionated plexi(GP) are located in epicardial fat pads as well as the ligament of

Marshall and have been linked with the initiation of AF, thus making them a target for

therapeutic intervention.(66) It has been identified that stimulation of these GP

produces repetitive, short bursts of activity in the spatially associated pulmonary veins

initiating AF through parasympathetic and sympathetic activity.(67,68) Thus PVI

ablation may also disrupt the GP nerves reducing the firing of focal sites within the

pulmonary veins.(69)

It has also been observed that GP exist near areas of complex fractionated atrial

electrograms(CFAE) have been identified.(70) Though some studies have indicated

that a stepwise fashion in ablation with the incorporation of CFAE ablation may

decrease the inducibility of AF, other mapping studies have investigated areas of CFAE

for spatial and temporal stability, making it a dynamic target for AF elimination.(71-

74)

1.2.5. Endocardial to Epicardial Connections

Deeper analyses have been performed to examine the substrate of AF to better

understand the sub-optimal outcomes achieved in the more persistent forms of this

arrhythmia. Such analyses have focused on developing a further understanding of the

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sustaining mechanism of AF on a substrate level. One such body of work is focusing

on the role of both the dissociation and connections between the endocardial and

epicardial surfaces of the atria in contributing to the complexity of the substrate of

AF.(75,76) While initially mapped in animal studies, subsequent human studies have

identified that the breakthrough of fibrillatory waves from the epicardial surface to the

enocardial surface of the atria which may account for the focal activation waves

observed in persistent forms of AF.(77)

1.2.6. Rotors

Animal studies by the Jalife group have consistently visualised the presence of

rotors.(78-82) The phenomenon of electrical rotors has also been described as a

localised, unstable source of AF in mapping studies and has also formed targets for

ablation therapies with results suggestive of offering improved outcomes.(83,84)

Recently there have been several studies that have evaluated the possibility of such a

phenomenon in humans.(85,86) Sanders et al undertook a retrospective study

evaluating the relationship between sites of high dominant frequency and the impact of

ablation.(63) Indeed they were able to demonstrate that during ablation at sites

harbouring high dominant frequency sites (presumed to represent the rotor) there was

slowing and termination of AF. This was further evaluated in a prospective study of

ablation guided by mapping high dominant frequency sites by Atienza and colleagues

but demonstrated only modest results.(87) Narayan and colleagues used basket catheter

mapping to performed phase analysis and demonstrated the presence of rotors in most

individuals with ablation at these sites resulting in significant outcomes with

ablation.(88) In contrast, Haissaguerre et al. used body surface mapping and have

demonstrated the presence of short lived rotors.(89) Similarly, the Kalman group have

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shown that with epicardial mapping of the atria there was rotors observed in a small

number of patients.(90) Although the existence of such a phenomenon remains debated,

their possible role in the maintenance of AF is intriguing and may have implications on

future therapeutic ventures.

The development of AF requires areas not only the aforementioned areas of focal activity to

act as triggers, but also changes in the atrial tissue to act as substrate for the perpetuation of the

arrhythmia.(91) Atrial re-entry is an important concept in the development of AF as it sets-up

a potential substrate AF, with the atrial wavelength key to the number of re-entry circuits that

a given mass of atrial tissue can sustain.(92) Through this finding it has been identified that

increased LA size reduces the ability for ablation strategies to return the patient to sinus

rhythm.(93) Further, the nature of the anatomic structures within the atria, such as the crista

terminalis, triangle of Koch, coronary sinus and pulmonary veins, have also been implicated in

the development of re-entry.(94-97) There is also an increasing body of evidence focusing on

how the development of atrial fibrosis results in atrial electro-structural remodelling

supporting the potentiation of AF on a substrate level.(98,99)

1.3. MANAGEMENT OF ATRIAL FIBRILLATION

The management of AF has been summarised in the 2016 European Society of Cardiology

Guidelines for the Management of AF developed in collaboration with the European

Association of Cardio-Thoracic Surgery. There are now recognised 4 pillars to the management

of AF comprising; 1) Risk Factor Modification, 2) Anticoagulation, 3) Rate Control and 4)

Rhythm Control.(100)

1.3.1. Risk Factor Modification

The impact of risk factor modification in the management of AF has been a new

development of significant impact as it was identified through such intervention alone

9

the burden and severity of AF can be reduced.(101) Initial work in the animal model

established that risk factors, such as obesity, significantly impact the atria to establish

substrate for its development.(102) Most importantly, the landmark observations were

then made that lifestyle adjustment and aggressive risk factors modification in patients

suffering from AF are not only able to improve outcomes directly, but are also able to

improve outcomes of other rhythm control strategies, such as catheter ablation.(103-

106) The ability of such integrated forms of care for patients with AF has been

demonstrated to have such an effect on the quality of life of patients with AF that it

now is integral to the successful management of the patient with AF.(107,108)

1.3.2. Anticoagulation

Presently, scoring systems are being utilised to determine the type of anticoagulation

most suited to a certain patient as stratified by stroke risk such as CHA2DS2-VASc

which is guiding clinical practice to stratify patients that do not need antiplatelet or

anticoagulant treatment, those that should be considered and those that require

it.(100,109,110) The need for anticoagulation for prevention of thromboembolic

strokes in the setting of AF has been established with the mainstay therapy being the

use of Vitamin K antagonists (warfarin) which has seen a reduction in the risk of stroke

in patients with AF by two-thirds over aspirin alone.(111) However, the use of warfarin

has come at the cost of increased risk of major bleeding events.(112) This has led to the

interest in alternative drugs for use in stroke prevention in patients with AF. These

alternative drugs have been termed novel oral anti-coagulant (NOAC) medications and

are being examined closer for their therapeutic use with the potential for lower rates of

stroke or systemic thromboembolism while reducing the risk of major bleeding

events.(113-116) At present it has been seen that Warfarin or NOACs offer a superior

10

result to aspirin in stroke prevention while not having an increased risk of bleeding to

aspirin.(117,118) Though of note only warfarin has evidence to suggest the safety of

use in patients with rheumatic mitral valve disease or those with mechanical heart

valves.(119) The alternative method to pharmacological management is the mechanical

closure of the left atrial appendage with one such device (Watchman) having been

compared to warfarin therapy and having shown non-inferiority for stroke

prevention.(120,121) The surgical exclusion of the LAA concomitant to cardiac surgery

is an alternative method which has been employed, but only limited data is available at

present with a large randomised trial underway.(122-124)

1.3.3. Rate Control

Several well-constructed studies have looked to assess the differences in outcome

obtained through rate or rhythm control.(125-131) Overall there was no difference in

outcome when comparing the strategies of rate and rhythm control, the rhythm control

strategy was associated with significant adverse events owing to the pharmacological

profiles of the AAD, but analysis of the patients who actually maintained sinus rhythm

shows a survival advantage.(132,133) Consideration of this suggests that if there were

a way to maintain sinus rhythm without the adverse events associated with AAD there

may be a benefit. Of further note, when similar trials have been conducted on patients

who developed AF post cardiac surgery the same relationship of no superior difference

in rhythm to rate control was upheld.(134) Importantly of note in all these studies the

need for anticoagulation was not ameliorated.(127,134)

11

1.3.5. Rhythm Control

The use of AAD compared to placebo has doubled the rate of SRM.(135,136) And

while no significant improvement in mortality or cardiovascular complications has been

demonstrated through the use of AAD, it still provides a pathway for the reduction of

the symptoms of AF.(137) In consideration of this, catheter ablation therapy has been

shown to be superior to AAD in controlling AF, the symptoms of AF and improving

left ventricular function.(138-140)

1.3.5.1. Catheter ablation

Whilst several studies have shown no difference in the outcomes of rate or rhythm

control,(125,134) in practice, several patients remain highly symptomatic and have

required more invasive approaches to rhythm control. Catheter ablation is an

increasingly utilised effectively in highly symptomatic patients. Indeed, several

randomised controlled studies have consistently demonstrated that ablation therapy is

superior to medical therapy alone.(141,142)

The goal of catheter ablation is the treatment of symptomatic AF through the

creation of cardiac lesions which block the propagation of arrhythmic wavefronts of

conduction and alter the atrial substrate to eliminate the triggers of AF.(143,144)

Multiple energy sources are available for the creation such lesions with the most

common technologies being radio-frequency (RF) and cryoablation.(145,146) The use

of RF energy effects the creation of a lesion through the delivery of alternating

electrical current which is dissipated as heat in the cardiac myocytes, which in turn

causes coagulative necrosis that evolves into non-conducting myocardial scar.(147)

Further iterations of RF technology have recognised that lesion size and depth is

proportional to the contact and force of the catheter delivering the

12

technology.(148,149) This in turn has given rise to contact force sensing catheters with

results suggestive of improved efficacy at sinus rhythm maintenance at follow-up of

ablation procedures.(150,151) Cryothermal lesions are delivered through the creation

of an endothermic reaction at the catheter interface which in turn cools the cells,

creating intracellular ice crystals that disrupt the cellular membrane and eventually

result in scar formation.(152,153) Other devices such as ultrasound and laser based

ablation systems are continuing to be investigated with various results.(154,155)

With the identification of the site of triggers for AF commonly being within the

pulmonary veins the early catheter ablation interventions focused on elimination of

these focal triggers themselves.(43,44) However, this was limited not only by initial

difficulties with reproducibly identifying the trigger sites, but also subsequent

complications with pulmonary vein stenosis, thus the target for catheter ablation

evolved to segmental pulmonary vein isolation and then on to wider antral ablation

techniques.(156-158) PVI has been proven an effective treatment in paroxysmal AF,

but with high rates of recurrence seen in persistent forms of AF further ablation

approaches have been investigated to improve outcomes.(60,61) Additional

approaches have included the use of further linear ablation lines of block akin to the

lesions of the Maze procedure,(159,160) the identification and elimination of non-

pulmonary vein activation sites,(161,162) the mapping and elimination of areas of

CFAE(163,164) and the ablation of GP targets.(69,165) These additional interventions

are being investigated for their role in the treatment of persistent AF patients with

reports suggesting improved rates of sinus rhythm maintenance compared to PVI

alone.(166-169) However, in a subsequent large, multi-centre randomised control trial

assessing the addition of the linear ablation and CFAE ablation to PVI in persistent AF

patients has found no improvement in the rate of SR maintenance.(170) With the

13

progressive advances in catheter ablation technique and technology there remain

several inherent limitations to the current catheter approach which include the accurate

evaluation of transmurality, the creation of contiguous lesions, the potential for

collateral injury, and the accepted need for multiple procedures.(151,171-174)

Regardless, the long-term results in SR maintenance of catheter ablation has been an

area of great study with meta-analyses performed in the area. An analysis performed

on the results of the randomised control trials assessing catheter ablation efficacy

identified a 76.8% success rate of freedom of recurrence of tachyarrhythmia.(175)

Further, a meta-analysis not confined to randomised control trials reported a single

procedure success of 53% and multiple procedure success approaching 80% at ≥3

years of follow up.(176)

1.4. ROLE OF SURGERY

The first surgically described procedures for the surgical management of AF date back to 1980

in which Williams et al described the Left Atrial Isolation Procedure in which patients with AF

had the LA surgical electrically isolated from the rest of the heart.(177) While this left the rest

of the heart in sinus rhythm, as it was driven by the SA node, it did not terminate the AF of the

LA, thus the risk of thromboembolism was not ameliorated.(36) Following this work the

Corridor Procedure was then described in 1985 by Guiraudon et al in which a corridor of atrial

tissue was isolated from the remaining atrial tissue to allow the SA node to drive ventricular

contraction via the AV node at regular rate without the chaotic interference of AF.(178) While

this was successful to drive the ventricles, it once more left the atria fibrillating, thus retaining

the thromboembolic risk, and further resulting in haemodynamic compromise from the

asynchronous activity of the atria from the ventricles.(36) The landmark study of Cox et al in

1991 in which he first described his Maze technique for the elimination of AF through the

14

development of lines of conduction block to disrupt the propagation of macro re-entrant circuits

within the atria formed the foundation for the ideal surgical procedure in the management of

AF.(35,36,179,180) The first iteration of this procedure, now known as the Maze I, was based

on the principle of the interruption of all the potential pathways of macro re-entrant circuits

that had been identified through mapping studies, while still maintain the ability of a wave

front of conduction to propagate from the SA node to the AV node.(35,36) While the procedure

was reported to be successful in regards to elimination of AF, the follow-up of the first 32

patients undergoing this procedure identified a frequent association of an attenuated response

of the SA node to exercise as well as LA dysfunction.(181) This finding was thought likely to

be related to an incision directly anterior the location of the SA node and the Maze II procedure

was then formulated to eliminate this incision. However, the alteration of lesion sets proposed

and investigated found the newer Maze II lesion set had further increased technical difficulty,

requiring the SVC to be completely transected in order to allow adequate access for completion

of the lesion set.(181,182) The Maze III lesion set was subsequently described in 1995 in which

the left atrial incision was shifted posteriorly and facilitated reduced technical difficulty and

functional improvements in the procedure.(181,182) The Maze III procedure then formed the

gold standard for the surgical treatment of AF with excellent results reported at 5.4 years

follow-up of 83% SRM off AAD and 97% SRM with AAD. However, despite these results

there was not wide uptake of the procedure and it was postulated this was due to a combination

of perceived technical difficulty, requirement for cardiopulmonary bypass, invasiveness and

associated significant morbidity, particularly that of pacemaker requirement and left atrial

dysfunction.(183-186) In order to maintain the clinical results being obtained in SRM the

adoption of alternative energy course for the creation of lines of conduction block was

investigated. The Maze IV procedure was described in 2004 by Gaynor et al in which a bipolar

RF surgical clamp was utilised for the creation of ablation lesions to replace the traditional cut

15

and sewn lines.(187) This procedure has had a wider uptake with results as high as achieving

84% SRM off AAD and 90% SRM with AAD at 2 years follow-up.(188,189) Though the Maze

procedures were considered invasive in nature with the use a median sternotomy and

cardiopulmonary bypass, they were able to be conducted not only as a standalone procedure,

but also concurrent to the treatment of mitral valve repair and other cardiac procedures to which

AF commonly coexists.(190-193) Further studies on surgical populations of patients have also

demonstrated the strong link between mitral valvular disease and AF with 40% to 60% of

patients presenting for mitral valve surgery suffering from this arrhythmia.(9,194,195) Thus

the ability to treat this arrhythmia at the time of mitral valve surgery identifies a population of

significant need. Importantly, in the setting of valvular heart disease, AF confers a much higher

risk of stroke than patients with valvular heart disease who do not have AF.(196)Following the

establishment of the Maze IV procedure the form of evolution has been down minimising the

invasiveness of the procedure as a median sternotomy had been required. In 2004 Ad et al

described the ability to perform a Maze III lesion set from an anterolateral mini-thoracotomy

instead of the standard median sternotomy with subsequent confirmation of maintaining good

results at 36 months of 92% SRM and 80% SRM off AAD.(197,198) Continuing to further

minimise the invasiveness of surgical procedures for AF a range of thoracoscopic “key hole”

procedures, with or without robotic assistance began to be described.(199-203) The most recent

of such procedures report the reproduction of the Maze lesion set thoracoscopically through

the creation of 5-boxes of ablation, without the need for cardiopulmonary bypass, achieving

SRM off AAD of 95.6% at 13 months.(204-206) The long term results of this approach are still

pending. Finally, a new hybrid procedure is evolving in which both a cardiac

electrophysiologist and cardiac surgeon undertake a joint procedure for treatment of AF.(207)

The early results of this procedure are encouraging as a potential procedure to combine the

strengths of surgical ablation, through the use direct epicardial access allowing direct

16

visualisation of the heart for ablation, and the strengths of catheter ablation, with endocardial

access allowing direct mapping of triggers, conduction and block.(208,209) Most recently, the

Society of Thoracic Surgeons has released an update of their clinical practice guidelines

focused on the surgical ablation of AF providing the most updated recommendations in which

they assigned Class I recommendations to the ablation of AF concurrent to mitral valve

operations without added risk (Level A), concurrent to aortic valve, CABG and a combination

(Level B), however, they only assigned Class II recommendations to stand alone ablation

(Level B) and left atrial appendage management at the time of surgery for AF or other cardiac

surgery to ameliorate thromboembolic risk (Level C).(210)

1.5. AVAILABLE TECHNOLOGIES

Since the evolution of the Maze procedure beyond the cut and sewn lesions to alternative

energy sources an increasing interest in available technologies has arisen. The current

technologies implemented in the surgical field for the creation of such lesions are RF and

Cryothermy, the tissue injury mechanisms of which of have been described earlier.

RF is available in unipolar and bipolar forms. Bipolar RF clamps are available from

Atricure (West Chester, OH, USA) in the form of 2 curved, parallel jaws that clamp together

in a sliding fashion.(211) They offer 3 such varieties at present named Synergy OLL2/OSL2

at 53mm and 65mm jaw length, EML2/EMR2 at 60mm jaw length each facing alternate curves

of left and right, and EMT1 at 64mm jaw length with an adjustable jaw angle; all of which are

non-irrigated.(212-214) Each jaw of the clamp houses a pair of electrodes running the length

of the jaw through which RF energy is delivered to create an RF lesion.(212) All Atricure

bipolar clamp devices are non-irrigated, the jaws are rigid and are suitable for epicardial use or

a combination of endo/epicardial use with a jaw on each surface of the atrial tissue.(212-214)

Medtronic (Minneapolis, MN, USA) offers the alternative bipolar RF clamps available on the

17

market with Cardioblate LP/BP2 and the Gemini, both of which clamps closed in a scissor type

fashion from a proximal hinge.(215-218) These devices house an RF electrode on each jaw

underneath an irrigated pad and these devices are also suitable for epicardial use or a

combination of endo/epicardial use with a jaw on each surface of the atrial tissue. The LP/BP2

are designed for open access procedures with adjustable necks and adjustable articulation of

the jaw clamp with the neck to allow for increased flexibility of angle.(216,217) The most

recent of these devices allows for the jaws themselves to be malleable and shaped by the

surgeon to deliver the best fit for the patient specific anatomy. The Gemini system offers a

thoracoscopic alternative of this device with a longer neck for improved access.(218) Both

Atricure and Medtronic have their own RF generators for use with their products, with visual

displays indicating energy delivery and ablation status.(219,220) The Medtronic device is

specifically reported to supply “Audible tones and touch screen messages notify user of

ablation status, transmurality, and other critical information”.(220)

A series of ablation pens are available through both Atricure (West Chester, OH, USA)

and Medtronic (Minneapolis, MN, USA) and are suitable for epicardial or endocardial use. The

Atricure devices are primarily bipolar in nature with 2 electrodes on the same surface of the

pen (in a rail fashion) generating RF between these 2 electrodes.(211) Three such pens are

available in 3 forms; Coolrail Linear at 30mm electrode length, Isolator Linear at 20mm

electrode length and Isolator Transpolar Pen with short tip electrodes.(221-223) The Medtronic

devices are 2 unipolar type pens; the Cardioblate irrigated pen and the Cardioblate MAPS pen

device.(224,225) The Atricure Isolator Linear, Transpolar Pen and the Medtronic MAPS all

have the ability to stimulate, pace and sense, in addition to ablation.(222,223,225)

The most recent RF device companies have recently been acquired by Atricure (West

Chester, OH, USA) and are now featured within their product line; the COBRA devices and

the EPi-Sense Coagulation Device, both of which are designed for epicardial use, utilise suction

18

technology to maintain tissue contact and are internally cooled as opposed to externally

irrigated.(211) The COBRA range of devices (previously produced by Estech, San Ramon,

CA, USA) are designed for thoracoscopic access utilising a series of longitudinal electrodes

housed in a soft casing designed to be placed epicardially on the atrial surface of the heart. The

devices come in 50mm length and 150mm length, with the most recent iterations of these

devices have upgraded from purely unipolar energy delivery to a combination of poles able to

be activate in order to achieve a transmural lesion.(226) The EPi-Sense devices are a series of

unipolar devices designed for minimally invasive access via laparoscopy to gain access to the

pericardium through the diaphragm. These devices house a series of 4 electrodes across 3 cm

array of the distal end of the device.(227)

Surgical Cryothermy devices are also produced by Atricure (West Chester, OH, USA)

and Medtronic (Minneapolis, MN, USA). The Atricure Cryo devices are 3 in number (CRYO2,

CRYO3 and CRYOF) all in the form of a single, malleable shaft probes which utilise Nitrous

Oxide as their cooling agent.(228) They represent a series of probes that have been developed

progressively and require less force to shape with the newest model of the CRYOF.(228) The

Medtronic Cryo devices include 2 single malleable shaft devices (7cm and 10cm lengths

available) and 1 clamp device, all of which utilise Argon gas as their cooling

agent.(215,229,230)

Other forms of ablation devices have been trialled with Micro-Wave technology,(231-

234) Laser ablation(235-237) and High-intensity focused ultrasound.(238-240) However, most

of these devices have not been able to create consistently reproducible lesions and are not

currently commercially on offer for clinical use.(153,241)

It is worth considering some of the already understood limitations of RF and Cryo

energy in creating lesions of conduction block. Firstly, all aforementioned technologies have

the ability to cause collateral damage; reports of damage to the oesophagus in animal

19

studies,(242,243) with unipolar RF reports of injury documented in human trials.(244) Even

though Cryo technology is reported to be preservative of the fibrous skeleton of the heart,

experimental studies have demonstrated variable amounts of hyperplasia of coronary arteries

exposed to this energy source.(153,245-248) Secondly, no device has been documented to

demonstrate 100% transmurality; Cryo lesions have varied in efficacy of animal studies from

25% to 100% transmurality of tested lesions with results negatively impacted by beating heart

procedures caused by blood acting as a heat sink on the endocardial surface;(242,249) Unipolar

RF lesions have also seen low reports of transmural lesions ranging from 7% to 92% efficacy

owing it’s wide variability to the effect of epicardial fat, tissue thickness, use on a beating heart

model and the development of char on the electrode;(250-252) Bipolar RF clamps have been

shown to be the most reliable and quickest at achieving transmurality, even in the beating heart

model, but studies cannot confirm consistent 100% achievement of transmurality.(153,253-

255) Third, ablation times reported as necessary for achievement of conduction block have a

wide variance from as quick as 5-10 seconds with a bipolar RF clamp to 3 minutes of

application for Cryo.(153,253)

1.6. PREVIOUS META-ANALYSES

Multiple meta-analyses are currently published on the topic of surgical ablation of atrial

fibrillation; however, a large proportion of the published studies included within these meta-

analyses were of small sample size and not well controlled series.(256-261) This has led to

clouding of the data in this field

To rationalise the current state of the field of the surgical ablation of atrial fibrillation

this thesis will undertake a high-quality analysis of the literature. To ensure the articles selected

are representative by only including studies containing at least 100 patients. Further, through

assessment of previous published analyses within this area it has become apparent that distinct

20

groups of surgical patients and procedures are contained within the broad context of surgical

ablation. The first group to be addressed in Chapter 2 are patients solely undergoing mitral

valve surgery concurrent to surgical ablation, as these patients represent a specific cohort of

surgical patients with cardiac valvular disease that affects the atrial substrate. In Chapter 3 we

analyse studies in which patients presenting for cardiac surgery, with concurrent AF, undergoes

ablation – this is a unique cohort that is separate from the isolated pathology of mitral disease

as it includes patients with AF potentially unrelated to any cardiac valvular pathology. Further,

this group is of particular interest as many patients present for cardiac surgery without mitral

valve pathology, but with AF nonetheless, and thus the decision of how to best manage such

general cardiac surgical patients is a separate and pertinent issue. In Chapter 4 we address

patients with isolated AF in the absence of any other cardiac surgical pathology as not only is

the substrate for AF potentially different, but these patients would not undergo surgery for any

other reason and thus the threshold for undertaking ablation may be different from concurrent

cardiac surgical ablation procedures. The final meta-analysis of Chapter 5 is an assessment of

hybrid ablation for AF in which both a cardiac surgical procedure and cardiac

electrophysiological procedure are performed on a single patient to deliver the best results.

21

Chapter 2

Surgical ablation of atrial fibrillation concomitant to mitral valvular repair or

replacement – analysis of valvular disease and intervention, ablation method, safety and

success in sinus rhythm maintenance

2.1. INTRODUCTION

Atrial Fibrillation (AF) is the most common atrial arrhythmia with a 1 in 4 lifetime risk of

developing AF for both men and women aged over 40 years.(1,2) Significant risk factors for

development of AF include increasing age, hypertension, congestive heart failure, myocardial

infarction and valvular heart disease.(9,10) In particular, mitral valvular disease has a strong

association with AF and it has been identified in 40% to 60% of patients presenting for mitral

valve surgery.(9,194,195) Importantly, in the setting of valvular heart disease, AF confers a

much higher risk of stroke.(196)

The Cox-Maze procedure has defined the gold standard for the surgical management of

AF in which lines of conduction block were cut and sewn into the atria achieving sinus rhythm

maintenance (SRM) at 5.4 years follow-up, of 83% off anti-arrhythmic drugs (AAD) and 97%

with AAD.(186) The Cox-Maze IV procedure is the latest iteration of this in which lines of

conduction block were created using RF, achieving 84% SRM off AAD and 90% SRM with

AAD at 2 years follow-up.(188,189) This procedure is commonly undertaken in conjunction

with other cardiac surgical procedures to treat the AF concurrently; however, a relative paucity

of level 1 evidence exists and as such high-level recommendations for when to employ this

strategy has been lacking in the HRS/EHRA/ECAS Expert Consensus Statement on Catheter

and Surgical Ablation for AF.(262)

Here, we undertook a systematic review of the literature and meta-analysis to evaluate

the efficacy and safety of surgical ablation, concurrent to mitral valve repair or replacement, at

22

maintaining sinus rhythm in patients with AF. We hypothesised that AF ablation concurrent to

mitral valve surgery is a safe and effective intervention.

2.2. METHODS

This study was registered with the PROSPERO International prospective register of systematic

reviews website (Registration Number CRD42017058123). The MOOSE Guidelines for Meta-

Analyses and Systematic Reviews of Observational Studies were utilised as a guide for this

study. A systematic review of electronic databases including Pubmed, Embase and Cochrane

Database of Systematic Reviews was carried out using search terms of “[(Atrial

Fibrillation[MeSH Terms] OR Atrial Fibrillation OR AF[Ti] OR Cox OR Maze OR Mini-

maze) AND (Unipolar [All fields] OR Bipolar[All fields] OR Radiofrequency OR Ablation

technique*[All Fields] OR Cryoabla*[All Fields] OR Cryomaze OR Cryo-maze OR

Cryosurgery[MeSH Terms] OR Cryosurg*[All Fields]) AND (Surgery[All Fields] OR

Surgical procedures, operative[MeSH Terms])]”. The search was conducted from January 1991

to March 2016. The results were imported into Endnote reference database for further review.

These searches were supplemented by reviewing the bibliographies of published studies and

reviews. Studies were accepted if they conducted a surgical ablation procedure for the

treatment of AF and reported outcomes on SRM. Studies that did not perform ablation

concurrent to mitral valve intervention or that had primarily other concurrent cardiac surgical

procedures (coronary artery bypass grafting, etc) and sample size <100 patients were excluded.

Citations related to animal studies and those published in journals in languages other than

English were not included. After exclusions, the publications were analysed for the following

outcomes: SRM on and off anti-arrhythmic drugs (AAD), block success if assessed, mortality,

pericardial effusion/tamponade, significant bleeding, atrio-esophageal fistula, conversion to

open procedure if minimally invasive, stroke, length of stay, permanent pacemaker (PPM)

23

requirement and 30-day mortality. Figure 2.1 shows breakdown of the search, number of

studies retrieved and review process of citations. At the completion of the review process 16

studies remained for analysis.

2.2.1. Definitions

For the purposes of this study, surgical ablation procedures concurrent to mitral valve surgery

were defined as a surgical procedure, of any incision approach, in which a series of lesions

were placed in the heart (Cut and Sew/Radiofrequency/Cryothermy/Micro-Wave) for the

management of AF, with concomitant mitral valve repair or replacement. Additional, cardiac

valve procedures, coronary artery bypass or any other cardiac surgery procedure are

permissible if performed concurrent to mitral valve intervention. AF ablation procedures were

broadly categorised into Bi-Atrial Maze, Left Atrial Maze and Pulmonary Vein Isolation.

Surgical exclusion of the LAA appendage is part of the Maze procedure and has been included

as part of ablation procedures.

The classification of AF was made according to HRS/EHRA/ECAS Expert Consensus

Statement on Catheter and Surgical Ablation for AF, with any study patients that were

described as in permanent AF reclassified to long-standing persistent (LSP) AF.(262)


Meta-analysis was performed using Stata/SE version 14. Means were weighted and standard

deviation of continuous variables or proportion and Exact binomial lower and upper confidence

limits of categorical variables were pooled across studies and analyzed using a random effects

meta-analysis model. This type of model was chosen to partially compensate for any inherent

heterogeneity. Linear regressions were performed to investigate associations between

outcomes of sinus rhythm maintenance and complications in each paper versus ablation

24

method, lesions set utilized, exclusion of LAA and use of RCT, weighting for number of

patients who completed follow-up. Assumptions of a linear model were upheld throughout.

Statistical significance was assigned to P value <0.05.

2.3. RESULTS


The 16 included studies (Table 2.1) were published between 2002 and 2015 and consisted of

13 case series studies (11 retrospective and 2 prospective) and 3 randomized control trials.

(193,263-277) Fourteen of these studies were single center and 2 were multi-center studies.

Overall, the total cohort contained 3313 patients with a mean sample size of 207 patients

(Range: 103-340). The composition of patients was 14.9% paroxysmal, 19.4% persistent and

59.1% long standing persistent. One study did not delineate the AF type of their patients leaving

6.6% of the cohort unspecified.(273) The average AF duration was 45.5 months (Range: 30.3-

108), though 2 studies reported median length of AF(193,268) and 3 studies did not report a

pre-operative length of AF.(264,270,274) The mean patient age was 58.4 years (Range: 45-

69.7), with a mean left atrial (LA) diameter of 5.6cm (Range: 4.6-6.1) and mean left ventricular

ejection fraction (LVEF) 56.2% (Range: 47-61.3). Though, 1 study did not report LA

diameter(193) and 3 studies did not report on LVEF.(266,269,273) Beyond these factors there

was incomplete reporting of previous ablation, pre-operative anti-arrhythmic drug (AAD) use,

warfarin use, or other risk factors for AF development (Hypertension, COPD, diabetes, BMI,

etc). The mean follow-up duration across the studies was 27 months (Range: 10.1-46.1), though

of note 1 study provided follow-up length in median.(270)

25

2.3.2. Mitral and Concurrent Valvulopathy

The various forms of mitral valve pathology were grouped into rheumatic, degenerative or

others (infective, ischemic, cardiomyopathy, congenital, mixed, etc). Four studies did not

report on the valvular pathology of their patients.(266,269,272,273) Of those studies that

reported the valve pathology, rheumatic valvular disease accounted for 1748 (72%),

degenerative valvular disease 561 (23%) and others in 125 (5%). Analysis of surgical

procedure undertaken identified the rate of mitral valve repair was 31.6% and the rate of

replacement was 56.7%, with 11.7% undefined due to 1 study not providing a breakdown of

mitral valve procedure.(273) Concomitant valvular procedures included aortic valve

intervention in 687 (20.7%) patients and tricuspid valve intervention in 1247 (37.6%) patients.

Concomitant non-valvular procedures were performed in 430 (13%) of patients of which

coronary artery bypass grafting was the most common procedure.



The surgical access, lesion set, energy source and operative characteristic are presented in the

Table 2.2. In mixed ablation cohorts (where some patients had Bi-Atrial Maze and others PVI)

the minimum basic lesions that all patients had performed were documented in the “Included

Lesions” section of the Table 2.2. A generalised diagrammatic representation of lesions

employed is displayed in the Figure 2.2. Surgical access was obtained by sternotomy in all

studies except the studies by Gillinov et al (which utilised either sternotomy or

thoracotomy)(193) and the study by Jeanmart et al (which utilised thoracotomy alone).(269)

The methodology of creating a lesion varied among the studies and was usually created by a

combination of approaches. This point becomes particularly of note as the studies included

26

performed their lesions through a combination of endocardial and epicardial energy delivery

or only endocardial – in either case an atriotomy is required resulting in an effective “Cut and

Sew” (C&S) lesion being placed, even if not with intent of this to be a lesion to terminate

arrhythmia. In general, there were 3 studies that used a combination of C&S, radio-frequency

(RF) and cryothermy (Cryo),(193,268,270) 8 studies that used a combination of C&S and

RF,(264,265,267,269,272,274-276) 4 studies that utilised a combination of C&S and

Cryo,(263,266,273,277) and 1 study that utilised a combination of C&S, Cryo and Micro-Wave

(MW).(271)

The RF devices used to create lesions were Mono-Polar RF in 5

studies(267,269,270,272,276) with the range of devices being Cardioblate (Medtronic,

Minneapolis, MN, USA),(269,270,272,274) ThermaLine (Boston Scientific, Marlborough,

MA, USA),(267) Cobra (Boston Scientific, Marlborough, MA, USA – at the time study was

published),(267) a custom made probe,(276) and a combination of the above utilised over the

length of the study.(267) Bi-Polar RF devices were utilised in 6

studies(264,265,268,270,274,275) which consisted of Synergy (Atricure, West Chester, OH,

USA),(264,265,268,274,275) and Cardioblate Bipolar (Medtronic, Minneapolis, MN,

USA).(270) The cryo devices utilised varied over the studies consisting of either Frigitronics

(Cooper Surgical, Shelton, CN, USA),(263,266,268,271,273) SurgiFrost (CryoCath

Technology, Pointe-Claire, Canda),(277) a 140 Cryo Unit (Spembly Medical, Andover,

UK).(270) The micro-wave device utilised was FLEX (Afx Inc, Fremont, CA, USA).(271)

There was one study that did not specify energy source.(193)

2.3.3.2. Lesion Set

There was also variability of lesion sets used throughout all studies. These have been broadly

classified as follows for reporting: Bi-Atrial Maze (BAM); Left Atrial Maze (LAM); and

27

Pulmonary Vein Isolation (PVI) (Figure 2.2). A BAM lesion set was used in 11

studies(193,263-266,268,270,271,273,275,276) with 3 of those studies not exclusively using

BAM on their patients and having a number of patients with either LAM or PVI lesion

sets.(193,268,276) In the mixed cohort study by Gillinov et al. a combination of PVI (n=31;

RF:28, 3:Cryo), PVI + Left Atrial Connecting Lesion (n=80; Both RF and cryo all), CM (n=41;

Cut and sew + cryo: CMII in 6 and CMIII in 35) was utilised in their patients with no difference

in ablation cohorts freedom from AF.(268) In the next mixed cohort study of Gillinov et al a

combination of PVI (n=67) and BAM (n=66) was utilised with no difference in freedom from

AF in either group.(193) In the mixed cohort study of Wang et al the breakdown was LAM

(n=70) and BAM (n=70) with no difference in terms of AF recurrence between the

groups.(276) Three studies used a LAM lesion set exclusively(269,272,274) and 2 studies used

PVI with the study of Geidel et al an additional line across the posterior LA joining the PV

lesions.(267,277)

The Left Atrial Appendage (LAA) was excluded in all but 2 studies(269,273) with

exclusion methods consisting of oversewing/suture exclusion, (264,265,267,270,275)

excision,(263) either method allowed in 2 studies,(266,274) and method not

specified.(193,268,271-273,276) Additional intervention undertaken related to arrhythmia

control included left atrial reduction in 2 studies,(270,275) and division of the Ligament of

Marshall in 3 studies.(264,265,276)

The practice of Direct Current Cardioversion (DCC) was variable across the studies

with it utilized in 10 studies(263,265-267,269,272-276) and not specified in the remaining

studies.(193,264,268,270,271) In those studies that utilized DCC; 1 study reported immediate

use,(263) 8 studies utilized DCC on a proportion of their patients during the hospital stay as

required,(266,267,269,272-276) and 1 study reported use in the first 3 to 6 months post-op as

required.(265)

28


The operative time indices of cardio-pulmonary bypass (CPB) time and aortic cross clamp time

were reported in 11 studies with the meta-analysed CPB time being 138 minutes (Median: 148,

95% CI: 115-162) and average cross clamp time of 96 minutes (95% CI: 78-114). One study

reported total operative time of 192±27 minutes.(267)


The mean follow-up duration across the studies was 27 months (95% CI: 18.5-35.4). Table 2.3

details the follow-up frequency and methodology. All studies reported follow-up as a mean,

except 1 study which reported as median.(270) The 2 primary methods of follow-up rhythm

assessment were ECG and Holter monitoring. ECG was utilised in all studies except the study

by Gillinov et al.(193) Seven studies reported specific time periods of follow-up ranging from

3 monthly to 1 year.(263,265,266,271,273,275,276) Ten studies utilised a form of Holter

monitor or continuous telemetry for their follow-up;(193,263,266,267,270,272,275,276) the

length of monitoring was a 3 day Holter monitor in 1 study,(193) a 2 day holter in 1 study,(275)

1 day in 4 studies,(267,270,272,276) and not specified in the remaining 2 studies.(263,266).

Further, in 3 studies the use of Holter monitoring was only employed if AF was suspected, and

not routinely.(266,272,275)

2.3.5. Recurrent Arrhythmia

There was insufficient reporting on the results of specific AF subgroups

(Paroxysmal/Persistent/Long Standing Persistent) at follow-up to comment on sub-group

outcomes. The way the studies defined a recurrence of AF was also variable; 3 studies used a

documented of AF/Atrial Flutter/Atrial Tachycardia lasting >30 seconds,(193,264,265,276) 1

29

study also used documented AF/Atrial Flutter/Atrial Tachycardia though did not define length

of episode required,(268) 1 study defined as any recurrent AF/Atrial Flutter/Atrial Tachycardia

after a 3 month blanking period,(271) 2 studies defined maintenance of SR, instead of AF, as

a supraventricular rhythm with P-waves present on ECG,(272,273) and the remaining studies

did not provide a specific definition.(263,266,267,269,271,274,275,277)


The post-operative use of AAD was also variable in practice; 11 studies utilised amiodarone

as their primary choice,(263-265,268,270-272,274-277) 3 studies did not provide any

statement on AAD use,(193,268,269) 1 study stated Amiodarone and Sotalol were never

used,(273) and 1 study stated AAD was used only if post-operative arrhythmia developed, but

did not comment on the one selected.(266) Of those that utilised Amiodarone post-operatively;

5 commenced an intra-venous form initially followed by an oral regime for 3 to 6 months,(263-

265,267,274) 4 only used the oral form of amiodarone for 3 to 6 months,(270,272,275,276)

and 2 studies did not commence it routinely, but used it as their first line option if any recurrent

of AF developed.(271)

2.3.7. Outcomes

The mean SRM across the studies was 79.9% (95% CI: 78.4-81.3; Figure 2.3). Only 1 study

reported the use of AAD at the time of follow-up, but did not specify the number of patients in

SR and on AAD.(193) Warfarin use at final follow-up was only described in 3 studies with a

total rate 49.3%.(267,269,272) The need for re-intervention by catheter ablation in the follow-

up period was only reported in 1 study and was required for 2 out of 133 patients.(193)

30


The complications recorded from across the studies is displayed in the Table 2.4 and Forest

Plots of complications in Figure 2.4. The weighted mean complication rate across the studies

was 6.9% (95% CI: 5.8-8.0;), which composed the following complications (Figure 2.5):

mortality of 0.92% (95% CI: 0.5-1.4;); CVA/TIA of 0.31% (95% CI: 0-0.6;);

bleeding/tamponade requiring intervention or return to the operating theatre of 0.24% (95%

CI: -0.1-0.5;); pulmonary embolus of 0.02% (95% CI: -0.2-0.3); and requirement for permanent

pacemaker of 1.2% (95% CI: 0.7-1.6;). There were no reported cases of atrio-esophageal

fistula.

Further analysis of mortality across the studies found the most common reported cause

to by multi-organ dysfunction in 7 patients, followed by heart failure in 4 patients, myocardial

infarction in 3 patients, cerebral haemorrhage in 2 patients, CVA/neurological cause in 1

patient, infection/sepsis in 1 patient and pulmonary embolus in 1 patient. One study only

provided a mortality cause breakdown of “cardiac” vs “non-cardiac”,(267) another study

provided their mortality caused grouped together with a comparator cohort so was not suitable

for further analysis(275) and 4 studies did not list causes of death.(193,268,271,277)

The meta-analysed mean length of stay was 10.7 (95% CI: 4.0-17.4) days with only 3

studies reporting a mean length of stay.(193,267,269)

2.3.10. Subgroup Analysis

2.3.10.1. Lesion Set

The categorised lesion sets for analysis comprised 1881 (62%) patients in the BAM group, 486

(16%) in the LAM group, 271 (9%) patients in the PVI group and 398 (13%) patients in the

combination group with patients not restricted to 1 specific lesion set group. Lesion set was

shown to be a significant univariate predictor of SRM across the included studies (p<0.001).

31

The SRM of the BAM group was 84% (95% CI: 78.7-88.9), of the LAM group was 64% (95%

CI: 54.0-74.0), of the PVI group 75% (95% CI: 61.8-88.7) and of the Combination group 66%

(95% CI: 54.5-76.7) (Figure 2.6A). Comparison of these groups found the BAM group superior

to the LAM (p<0.001) and superior to the combination group (p<0.01), but no statistical

difference to the PVI group (p=0.25). There were no significant differences between LAM,

combination and PVI groups.

Complication rates related to lesion set are shown in Figure 2.6B. Interestingly, both

the BAM group and the LAM group were statistically superior to the PVI group in terms of

reduced mortality (BAM vs PVI: 1.5% [95% CI: 1.1-1.9] vs 3.0% [95% CI: 1.8-4.1], p=0.02;

LAM vs PVI: 1.0% [95% CI: 0.2-1.9] vs 3.0% [95% CI: 1.8-4.1], p<0.01). Further sub-group

analysis demonstrated a significantly lower rate of PPM placement when comparing BAM to

LAM and BAM to Combination groups (BAM vs LAM: 2.2% [95% CI: 0.0-4.7] vs 7.8% [95%

CI: 2.4-12.8], p=0.048; BAM vs Comb: 2.2% [95% CI: 0.0-4.7] vs 11% [95% CI: 5.6-16.6],

p<0.01). In total complication rate analysis, the BAM group showed a statistical significant

superiority to the Combination group (6.6% [95% CI: 2.6-10.6] vs 16.8% [95% CI: 8.1-25.5],

p=0.04). There were no other statistical differences between any of the groups regarding

mortality, CVA, bleeding, PPM or total complication rates in the remaining sub-group analyses

between ablation groups.


The categorised lesion sets for analysis comprised C&S/RF/Cryo in 477 (16%) patients,

C&S/RF in 1464 (48%), C&S/Cryo in 765 (25%) patients and C&S/MW/Cryo in 330 (11%)

patients. The rate of SRM achieved with each energy source was 79.9% (95% CI: 66.7-93.1)

with C&S/RF/Cryo, 72.8% (95% CI: 65.2-80.3) with C&S/RF, 80.7% (95% CI: 70.2-91.1)

with C&S/Cryo in 765 (25%) patients and 87.6% (95% CI: 71.7-103.5) C&S/MW/Cryo in 330

32

(11%) patients. There was no statistically significant difference between any combination of

energy source used and SRM, mortality rate or total complication rates.


The number of patients who underwent LAA exclusion were 2717 (89.5%) and the number

who did not were 319. There was no statistically significant difference between the groups in

terms of SRM, but a statistically significant difference between mortality rate was identified

with a reduction shown when the LAA was not excluded (LAA Excluded vs NOT: 1.7±0.3%

vs 0.3±0.1%, p=0.02). No other differences in complication rates were statistically significant

between these groups.

2.3.11. Randomized-Controlled Data

Analysis was performed to compare the Randomised Control Trials (RCT) to the Case Series

of the total cohort. The RCTs demonstrated a SRM of 70.8% (95% CI: 57.7-83.9) compared to

the Case Series cohort of 79% (95% CI: 72.8-85.1) which was not statistically significant.

Further, there was no statistical difference in the mortality or complication rates of either group.

2.4. DISCUSSION

Atrial fibrillation occurring in the context of valvular heart disease is common. Surgical

ablation for the treatment of AF at the time of concurrent mitral valve surgery is an opportune

therapeutic procedure. However, the level of evidence for such an approach and safety of

concurrent surgery are issues that are frequently raised. This systematic review and meta-

analysis on the efficacy and safety of these procedures demonstrates the following information:

1. The ablation of AF concurrent to mitral valve surgery is an effective procedure for

maintaining SR with the BAM lesion set appearing to offer a superior result compared

to procedures confined to the left atrium.

33

2. The overall total complication rate was low at 6.9%. This number was included the

PPM requirement rate of 1.2%.

3. The mean follow-up across this series was 27 months with a SRM of 79.6% achieved

displaying good medium term results for ablation concurrent to mitral valve surgery.

4. The exclusion of the LAA in this population does not appear to reduce stroke risk or

offer a statistically significant difference in rhythm control. Interestingly, the exclusion

of the LAA may confer a high mortality rate, so consideration should be given when

including this intervention.

Although this review has highlighted the considerable variability in the methods of follow up

and reporting of the data in these studies, a substantial proportion of the population had

persistent AF at baseline which was not present at follow up. In addition, this group represent

the most advanced substrate in which there has been limited success with catheter ablation

techniques. In this context, the current data provides evidence for the feasibility of intervention

in this group to rhythm control.(278)

2.4.1. Valvular Disease, Surgery and AF

The incidence of AF concurrent to mitral valve disease is significant and the association of this

with increased risk of stroke has been demonstrated.(9,194-196) As such, in symptomatic

patients, if there is an opportunity to reduce the risk of AF it should be strongly considered.

Previous large analyses conducted utilising the Society of Thoracic Surgeons database with a

cohort on 58,370 isolated mitral valve operations described a median CPB time of 112 minutes,

a median aortic cross-clamp time of 82 minutes with major complications of permanent stroke

was 1.31% and operative mortality rate of 2.45%.(279) The length of these median indices

measured in this meta-analysis are indeed longer by more than 30 minutes for CPB time and

20 minutes for aortic cross-clamp time. However, importantly, the complications rates of CVA

34

and mortality are both significantly reduced in this analysis when compared to previously

published data on the natural history, which may suggest a protective effect for the patient in

returning them to SR post mitral valve surgery.

The most recent guidelines produced by the STS on the surgical management of AF

provided their highest recommendation (Class A, Level 1) to the concurrent ablation of AF to

mitral valve surgery with no increase in morbidity or mortality.(210) The findings of this meta-

analysis are consistent with these guidelines, although, it must be recognised that there still

remains a paucity of level 1 evidence in this area.


The optimal technique for the surgical ablation of AF is a complex consideration. This analysis

has demonstrated no statistically significant difference in lesion energy source selection in

obtaining SRM at follow-up. The goal must remain to obtain a transmural lesion, regardless of

energy source. The optimal lesion set to apply appears to favour BAM in this analysis with a

statistically significant superior result obtained in SRM when compared to studies only

performing LAM ablation or studies that included a multiple of lesion sets, and a statistically

significant superior result in mortality rate compared to PVI. The question of optimal ablation

technique is one of careful consideration and would warrant future focused studies to answer

this question.

2.4.3. Complications

Catheter ablation of AF is a safe and effective treatment for AF typically employed in the

absence of structural heart disease. A recent systematic literature review on the complications

of catheter ablation extracted data of 83,236 patients undergoing catheter ablation found a 2.9%

total complication rate, a mortality rate of 0.06%, CVA/TIA rate of 0.6%, pericardial

35

tamponade rate of 1.0% and phrenic nerve injury of 0.4%. Though it comes with the additional

complications of atria-oesophageal fistula of 0.08% and valve damage of 0.2%.(280) When

these are compared to the complication rates of this analysis, it is likely that the surgical cohort

represents a sicker cohort of patients to require surgery in the first place, and this is then coupled

with a larger procedure to treat their heart disease in totality (mitral valvulopathy in addition to

AF).


Patients presenting for mitral valve intervention with concurrent AF should be considered for

the addition of a concurrent ablation procedure. The rate of SRM achievable is significant, and

regardless of the energy source preference of the surgeon, a bi-atrial lesion set will offer the

best results without a significant increase in patient morbidity. Previous studies analysing the

30-day mortality rate of general patients undergoing mitral valve repair or replacement

identified a range rate of 2.2% to 10.4%, with more recent studies finding lower rates of

mortality.(281-284) In consideration of this, no increase in mortality rate is seen with the

addition of an ablation procedure.


The composition of the included studies identifies a relative paucity of level 1 evidence

identified within this area. Further, there exists significant heterogeneity in terms of surgical

procedure and follow-up method and intervals among these included studies, and this should

be considered in interpreting the results. There is also variability in the quality of studies with

discrepancies in recording of baseline variables, consistency of ablation method and follow-

up. These variations serve to not only highlight the features of the highest quality studies, but

also the need for standardisation of reporting within the field. Additionally, as with any meta-

36

analysis there may be confounding variables, measured and unmeasured, which may impact

the results of this analysis. Finally, we are unable to provide more extensive analysis on long

term results of patients off AADs and in AF subtypes given the lack of patient level data

available. Nonetheless, these identified limitations serve to highlight key areas of attention in

future studies.

2.5. CONCLUSIONS

Surgical ablation procedures for the management of AF carried out concurrent to mitral valve

intervention have good results in terms of sinus rhythm maintenance at medium-term follow-

up with no additive mortality effect. The best results have been seen with more extensive lesion

sets (bi-atrial) regardless of energy source utilised. However, it must be noted that there is

significant variability in study follow up length and method. Further prospective studies with

structured follow-up could confirm these results and help delineate procedural success for

specific patient AF subtype populations presenting for mitral valve surgery.

37

2.6. FIGURES AND TABLES

Figure 2.1: Search Strategy

38

Figure 2.2 – Lesion Sets

Depicts the common lesions performed for AF ablation in the given studies. The Blue and

Green represent PVI and Box lesions respectively (considered together), the addition of Red

represents a Left Atrial Maze lesion set (PVI/Box + Left Atrial Appendage Line + Exclusion

+ Mitral Line), with the further addition of Purple to the afore mentioned representing a Bi-

Atrial Lesion Set (Superior Vena Cava Line + Inferior Vena Cava Line + Right Atrial

Appendage Line + Tricuspid Line).

39

Figure 2.3 – Sinus Rhythm Maintenance Forest Plot

40

Figure 2.4 –Complication Forest Plots

41

Figure 2.5 – Mean Complication Rates

The mean complication rates of mortality, CVA, RTOT and PPM requirements are shown

here with error bars representing the 95% CI. Tabulated from meta-analysis forest plot

findings.

42

Figure 2.5 – Lesion Set Comparisons

A) The comparative SRM rates achieved based on lesion set with statistically significant

differences highlighted. B) Comparative complication rates based on lesion set.

47

Chapter 3

Surgical Ablation of Atrial Fibrillation with Concurrent Cardiac Surgery – Assessment

of the Safety and Efficacy of Ablation procedures during any other Cardiac Surgical

Intervention

3.1. INTRODUCTION

Atrial Fibrillation (AF) is the most common atrial arrhythmia effecting the general population

with the major risk factors for development being the common risk factors of those patients

presenting for cardiac surgery of advanced age, hypertension, congestive cardiac failure,

myocardial infarction and cardiac valulopathy.(1,2,9,10) Studies analysing the outcome of

patients undergoing cardiac surgery in the form of Coronary Artery Bypass Grafting (CABG)

and heart valve disease have identified a negative impact on in hospital complications and long

term outcomes when preoperative AF is present.(285-289) Thus in those patients with a

mixture of structural heart disease and coronary artery disease concomitant to AF the

elimination of AF may offer a protective effect against in hospital complications and long term

patient outcomes.

Historically, the Cox-Maze procedure has provided the best results for the surgical

elimination of AF achieving sinus rhythm maintenance results of 89% sinus rhythm

maintenance (SRM) with the use of antiarrhythmic drugs (AAD) and 78% SRM without AAD

at 5.4 years follow-up.(188,189) This procedure is commonly undertaken in conjunction with

potentially any other cardiac surgical procedures to treat AF concurrently; however, there has

been a relative paucity of level 1 evidence and as such high-level recommendations for whether

to employ this strategy concurrent to other cardiac surgical procedures has been lacking in the

HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation for

AF.(262)

48

The majority of literature published on the surgical ablation of AF has not been

restrictive of inclusion criteria for other cardiac procedures carried out concomitantly,

consequently, the largest series are formed of mixed cohorts of patients that have undergone

surgical ablation concurrent to either coronary artery bypass grafting, valvular intervention of

any cardiac valve or a mixture of these procedures.(190,191) This presents a highly

heterogenous cohort of patients undergoing surgical ablation of AF that is of interest as it is

representative of the common patients presenting for cardiac surgery that may also be identified

to have AF incidentally. We have elected to analyse this cohort as a separate group,

independent of surgical ablation carried out concurrent to purely mitral valve intervention or

surgical ablation as a standalone procedure as this cohort not only represents a population with

a highly variable risk profile, but this cohort also does not reflect one sole mechanism for the

development of AF, as what may be seen in the ablation of AF concurrent to mitral valve

intervention.(290) Rather, it presents a cohort of patients requiring cardiac surgery that

incidentally have AF and now are provided with an opportunity for interventional treatment

while their primary cardiac pathology is being treated.

Here, we undertook a systematic review of the literature and meta-analysis to evaluate

the efficacy and safety of surgical ablation, concurrent to any cardiac surgical procedure, but

excluding studies of purely mitral valve surgical procedures or standalone cardiac surgical

ablation procedures. We hypothesised that AF ablation concurrent to other cardiac surgical

procedures is a safe and effective intervention.

3.2. METHODS




49








to March 2017. The results were imported into Endnote reference database for further review.

These searches were supplemented by reviewing the bibliographies of published studies and


treatment of AF and reported outcomes on sinus rhythm maintenance (SRM). Studies that

performed ablation concurrent to only mitral valve intervention were excluded as this was felt

to represent a separate population cohort of AF. The following studies were excluded: (i)

sample size <100 patients; did not consistently report on rhythm outcome; highly

heterogeneous intervention arms with multiple ablation strategies in the one paper; those with

an absence of data on lesion set utilisation; animal studies; and those published in journals in

languages other than English. If citations had multiple ablation arms for analysis that were

>100 patients each they were divided and both kept for analysis. If the individual arms were

statistically different and <100 patients they were excluded and if they were not statistically

different they were combined and included as a single cohort for analysis. If multiples citations

were identified from the same author and/or institute with patients captured from the same

period the most complete data set article was accepted and the other articles were discarded. If

studies contained multiple ablation strategies the predominate or most basic lesion set was

chosen for study categorisation. Selected publications were analysed for the following

outcomes: SRM on and off anti-arrhythmic drugs (AAD), block success if assessed, mortality,

50

pericardial effusion/tamponade, significant bleeding, atrio-oesophageal (AO) fistula,

conversion to open procedure if minimally invasive, stroke, length of stay, PPM requirement

and 30-day mortality. Figure 3.1 shows the number of studies retrieved and review process of

citations. At the completion of the review process 29 studies remained which supplied 31 data

sets for analysis.

3.2.1. Definitions

For the purposes of this study, surgical ablation procedures concurrent to cardiac surgical

procedures were defined as any adult cardiac surgical procedure, of any incision approach, in

which a series of lesions were placed in the heart (Cut and

Sew/Radiofrequency/Cryothermy/Micro-Wave/Combination) for the management of AF.

Additional procedures recorded included any specific cardiac valve procedures, coronary artery

bypass or any other cardiac surgery procedure. Lone procedures for AF were excluded if they

represented the entire cohort, but were permissible if they represented only a subsection of the

study cohort that is otherwise composed of patients have undergone other cardiac surgical

procedures. AF ablation procedures were broadly categorised into Bi-Atrial Maze, Left Atrial

Maze and Pulmonary Vein Isolation. Surgical exclusion of the LAA appendage is part of the

Maze procedure and has been included as part of ablation procedures.



described as being in permanent AF reclassified to long-standing persistent.(262)


Meta-analysis was performed using R (Version 3.3.0). Mean and standard deviation of

continuous variables or proportion and Exact binomial lower and upper confidence limits of

51

categorical variables were pooled across studies and analysed using a random effects meta-

analysis model. This type of model compensated for any inherent heterogeneity. Mixed model

meta-regression techniques were performed to investigate associations between outcomes of

sinus rhythm maintenance and complications in each paper versus ablation method, lesions set

utilised, exclusion of LAA and use of RCT, weighting for number of patients who completed

follow-up. Assumptions of a linear model were upheld throughout. Statistical significance was

assigned to P value <0.05.

3.3. RESULTS


The 31 included studies supplied 33 cohorts for analysis (Table 3.1). These studies were

published between 2002 and 2015 that consisted of 25 case series studies (15 retrospective and

10 prospective), 3 cohort comparator studies and 2 randomized control trials.(188,190-

192,291-317) Twenty-five of these studies were single center and 4 were multicenter studies.

Overall, the total cohort contained 6791 patients with a mean sample size of 206

patients (Range: 100-576). The pooled cohort consisted of 27% paroxysmal, 20% persistent,

45% longstanding persistent AF. Two studies did not delineate the AF subtype of their patients

leaving 8% of patients in the total cohort unspecified.(305,315) The average AF duration was

46.3 months (Range: 12-98), though 4 studies reported length of AF in

median(190,296,299,312) and 5 studies did not report a length of pre-op

AF.(295,301,303,308,311)

The mean patient age was 64.2 years (Range: 38-73.1), with a mean left atrial (LA)

diameter of 5.3 cm (Range: 4.3-7.3) and mean left ventricular ejection fraction (LVEF) 54.9%

52

(Range: 48-60.1). Of note, 1 study reported age in median,(312) 7 studies did not report mean

LA diameter(295,297,301,303,304,311,312) and 13 studies did not report

LVEF.(192,292,295,297,303,304,307-313). The incidence of pre-operative catheter ablation,

pre-operative use of anti-arrhythmic drugs (AAD) and warfarin were inconsistently reported.

Baseline risk factors for development of AF were not consistently reported across the studies

(Table 3.2).

The mean follow-up duration across the studies was 22.1 months (Range: 6-48), with 2

studies reporting a median duration.(294,296)

3.3.2. Concurrent cardiac surgical procedures

The reporting of concurrent cardiac surgical procedures was not uniform across the studies as

overlap of procedures was not routinely documented. The most common concurrent procedure

performed in addition to AF ablation was mitral valve repair or replacement in 3625 patients

(53.4%), followed by tricuspid valve procedures in 1125 patients (16.6%), coronary artery

bypass grafting (CABG) in 1197 patients (17.6%), aortic valve procedures in 975 patients

(14.4%) and other non-valve or CABG procedures in 517 patients (7.6%) (Table 3.3). Further,

the reported incidence of combined CABG and valvular procedures was 902 patients (13.3%),

isolated valve procedures in 3100 patients (45.7%) and isolated AF ablation in 595 patients

(8.8%).



The surgical access, lesion set, energy source and other operative characteristics are presented

in Table 3.4. In mixed ablation cohorts (where some patients had Bi-Atrial Maze and others

Pulmonary Vein Isolation) the minimum basic lesions that all patients had performed were

53

documented in the “Included Lesions” section of the Table 3.4. A generalised diagrammatic

representation of lesions employed is displayed in Figure 2.2. Across the studies surgical access

was obtained through sternotomy. Though of note the study by Ad et al reported thoracotomy

access in 219 patients,(190) the study by Damiano et al had 10% of patients with access via

thoracotomy(188), Guden et al reported a minimally invasive procedure in 43 patients without

further specification,(301) the study by Henn et all reported 44 patients undergoing a mini-

thoracotomy(191) and the study by Yanagawa et al reported thoracotomy access in 40

patients.(317) The methodology of creating lesions of conduction block varied across the

studies with the majority utilising an atriotomy to gain access to the inside of the heart, which

is effectively a “Cut and Sew” (C&S) lesion. Beyond this most studies then utilised a separate

device to create the remaining lesion set. As such, all energy sources utilised in a study are

tabulated with the primary method of creating most lesions shown underlined in Table 3.4. In

general terms, the studies could be categorised as primarily Radio-Frequency(RF) for 34% of

the patients,(192,291,292,294,295,298,301,302,305,308,310,313,315) Cryothermy in 15% of

the patients,(293,296,303,306,307,316,317) RF or Microwave in 3% of the patients,(300) C&S

in 12% of the patients(312) and a combination of C&S,RF and Cryo in 36% of the

patients.(188,190,191,299,304,309,311,314)

Devices used to created lesions in studies varied; Bipolar RF devices used included the

Isolator Synergy devices (Atricure, West Chester, OH, USA) in 8 studies,(188,190,295,297-

299,304,313,314) and the Cardioblate devices (Medtronic, Minneapolis, MN, USA) in 8

studies.(188,190,192,292,293,295,311,315) Monopolar RF devices utilised included

Thermaline (Boston Scientific, San Jose, CA, USA) in 3 studies,(291,302,310) Cobra (Boston

Scientific, San Jose, CA, USA) in 2 studies,(291,298) Cardioblate Monpolar Device

(Medtronic, Minneapolis, MN, USA) in 4 studies(188,192,292,300) and a custom made RF

device (Osypka GmbH, Grenzach-Wyhlen, Germany) in 3 studies(292,305,308). A non-stated

54

RF device was utilised in 5 studies.(191,291,294,301,309) The cryo devices used across the

studies included the ATS system (Medtronic, Minneapolis, MN, USA) in 6

studies,(190,293,296,303,316,317) Frigitronics (Cooper Surgical, Shelton, CN, USA) in 1

study,(299) 142 Cyro Unit (Spembly Medical, Andover, Hampshire, UK) in 1 study,(306)

Cryo1 (Atricure, West Chester, OH, USA) in 1 study(190) and cryo device not specified in 4

studies.(191,295,307,314) Micro-wave was utilised in 1 study with the Flex 4 device (Guidant

Corp, Santa Clara, CA, USA).(300)

In closer study analysis the study by Budera et al used cryo with 97% of the patients

and RF with the remaining 3% and was classified as a cryo study(293) and the study by

Grubitzsch et al utilised RF energy in 102 patients and MW in 110 patients.(300) Of note, the

study of Doty et al was broken into 2 cohorts of C&S BAM and RF BAM for inclusion.(295)

3.3.3.2. Lesion Set

Variability of lesion sets also existed across the studies and were broadly categorised into Bi-

Atrial Maze (BAM), Left Atrial Maze (LAM) and Pulmonary Vein Isolation (PVI) for analysis.

The common lesion sets are diagrammatically represented in Figure 2.2.

Primary lesion set utilisation consisted of a BAM lesion set in 15 studies comprising

59% of the total cohort,(188,190-192,292,295-297,304,306,308,312,315-317) the LAM lesion

set in 10 studies comprising 21% of the total

cohort,(291,293,294,300,301,303,307,311,312,315) the PVI lesion set in 5 studies comprising

19% of the total cohort(298,299,302,305,313) and 1 study had a cohort of patients who

underwent any of the 3 basic lesion sets to comprise 2% of the total cohort.(309)

Of note the study by Deneke at al utilised either the LAM in 66 patients or the BAM in

64 patients with no difference in outcome between the groups,(294) the RF cohort by Doty et

al had a BAM in 125 patients and a PVI in 32 patients,(295) the study by Gaynor et al had 3

55

variants of a BAM consisting of a Cox-Maze I in 33 patients, Cox-Maze II in 16 patients, Cox-

Maze III in 197 patients and a Cox-Maze IV in 30 patients,(297) Guden et al reported a BAM

in 48 patients and a LAM in 57 patients,(301) Martinez-Comendador et al reported a LAM in

89 patients and BAM in 66 patients(303) and Sternik et al reported a LAM in 142 patients and

BAM in 50 patients.(311) In addition, the study by Wang et al was broken into 2 cohorts for

analysis of LAM and BAM.(315)

Additional ablation lines beyond the basic categorising lesion set included Ligament of

Marshall ablation in 2 studies,(291,315) PVI joining line in 3 studies,(298,302,305) Mitral line

in 1 study(310) and RA isthmus line with or without floor or roof lines in 1 study.(299)

The Left Atrial Appendage (LAA) was excluded in all but 2 studies.(300,305) The

method was by resection in 12 studies,(188,292-295,297,304,309-311,315,317) oversewn in 8

studies,(291,296,298,303,306-308,316), either oversewn or resected in 3 studies,(299,301,315)

stapled in 1 study,(313) either oversewn, resected or stapled in 1 study(192) and not stated in

4 studies.(190,191,302,314)

The use of Direct Current Cardioversion (DCC) was variable among studies with it

being used post-op if necessary in 11 studies,(292,298,300,303,305,307-309,311,312,314) as

part of the procedure either routinely or if required in 4 studies,(192,302,309,314) if there was

an early recurrence without time frame being listed in 1 study,(315) not performed in 1

study(301) and not stated in the remaining 16 studies.(188,190,191,291,293-

297,299,304,306,310,313,316,317)


The operative time indices reported included cardio-pulmonary bypass (CPB) time, aortic cross

clamp time and total procedure time. The mean CPB time was 141 minutes (Range: 113-188),

the mean aortic cross clamp time was 88 minutes (Range: 69-119) and the mean total

56

procedural time was 220 minutes (Range: 167-294). Of note, 8 studies did not provide any time

indices for analysis.(190,295,301,307-309,313,316)


The mean follow-up duration across the studies was 22.1 months (Range: 6-48) with Table 3.5

detailing follow-up frequency and methodology. All studies reported follow-up duration as a

mean with only 2 studies reporting as a median.(294,296) The primary methods of follow-up

across all studies was ECG and Holter monitor; 7 day Holter monitor was the highest level of

monitoring utilised in 3 studies,(296,313,316) a 1d Holter (or Holter length not specified) was

utilised in 15 studies,(188,190-192,291,293,294,301-303,305,306,311,315,317) 3 studies

utilised a Holter monitor if possible or symptomatic, but not routinely,(297,307,314) but

otherwise those studies reverted to ECG follow-up which then comprised 11

studies.(292,295,297-299,307-310,312,314)

There was not routine delineation of follow-up to specific groups of paroxysmal,

persistent or long standing persistent to comment on the outcomes of these sub-groups.

3.3.5. Definitions of Recurrent Arrhythmia

The adopted definition for recurrence of arrhythmia was variable among the studies with the

most common definition being the recurrence of AF, atrial flutter or atrial tachycardia lasting

longer than 30 seconds on follow-up monitoring in 11 studies,(188,190-

192,293,294,296,300,313,316,317) 1 study defined as any occurrence of AF or atrial flutter on

ECG without specifying time period or length,(299) 1 study defined as any occurrence of AF

or atrial flutter after 6 months,(297) 1 study conversely defined SR as the presence of p-

waves(305) and the remaining 17 studies did not provide a definition.(291,292,295,298,301-

304,306-312,314,315)

57


The post-operative use of AAD had varying practice among the studies; 8 studies routinely

used Amiodarone or Sotalol post-operatively and continued for a period after

surgery,(291,293,298,301,304,312-315) 10 studies utilised Amiodarone or Sotalol post-

operatively if there was a recurrence of AF,(292,296,303,305,308-311,314,316) 4 studies listed

the use of a Class I or III AAD without specifying beyond,(188,191,192,299) 1 study listed the

use of either the patients pre-operative beta blocker or commencement of amiodarone or

sotalol,(300) 1 study listed the use of AAD as not routine(306) and the remaining 5 studies did

not specify.(190,294,295,297,307)

3.3.7. Outcomes

The mean SRM across all included studies was 79.6% (95% CI: 76.2-82.5) and the mean SRM

off AAD was 65.3% (95% CI: 57.4-72.5) (Figure 3.2 and 3.3). Of note, 9 studies did not supply

data on the number of patients in SRM without AAD.(295,298,301-303,305,307,312,315)


The complications recorded across the studies is presented in Table 3.6, the complication rates

Forest Plots in Figure 3.4 and comparative rates in Figure 3.5. The mean total complication

rate was 15.1% (95% CI: 11.7-19.3), which comprised mean mortality rate of 4.3% (95% CI:

3.4-5.4), mean CVA rate of 1.8% (95% CI: 1.3-2.5), mean rate of return to the operating theatre

(RTOT) for bleeding of 4.3% (95% CI: 3-6.1), mean rate of post-operative permanent pace

maker (PPM) requirement of 5.4% (95% CI: 3.8-7.5), and mean rate of atrio-esophageal(AO)

fistula of 0.5% (95% CI: 0.3-0.9). There was no incidence reported of phrenic nerve injury. Of

note, the study by Ad et al did not report number of complications.(190)

58

Analysis of mortality found 191 deaths reported across all studies with breakdown

analysis of cause demonstrating cardiac to be most common with 35 cases (18%), followed by

multi-organ dysfunction with 22, sepsis in 10 cases, respiratory failure in 5 cases, CVA in 2

cases, AO fistula in 2 cases, PE in 2 cases, renal failure in 1 case and gastro-intestinal

complication in 1 case. The majority were unknown, not stated or not reported with 109 cases.

The mean length of stay was 11.2 days (Range: 6-14) with 9 studies reporting mean

length of stay(191,192,291,293,300,302,303,306,316) and 7 studies reporting median length

of stay.(188,296,297,304,311,314,317)


3.3.9.1. Baseline Characteristics

Univariate analysis was performed across the studies examining their relationship to SRM with

age and paroxysmal AF status being statistically significant. For every 1 year increase in

baseline patient age there was a 0.6% decline in SRM (p=0.02) and for every 1% in increase

in the percentage of patients in a given study having paroxysmal AF there was a 0.2% increase

in SRM (p=0.02). The pre-operative duration of AF, LA diameter, percentage of mitral valve

intervention, year of study publication and follow-up duration were not shown to be statistically

significant predictors of SRM.

Further univariate analysis was then performed to determine predictors of

complications and it was identified that every 1% increase in the proportion of patients

undergoing mitral valve surgery was associated with a 0.2% decline in complication rate

(p=0.02). In other words, patients not undergoing mitral valve surgery in this cohort were more

likely to experience a complication. Analysis of age, AF duration, follow-up duration,

percentage of paroxysmal AF patients, LA diameter, publication year or CPB time were not

predictive of increased complication rate.

59

3.3.9.2. Lesion Set Comparison

The categorised lesion sets for analysis comprised BAM in 3996 patients (59% of total cohort),

LAM in 1400 patients (21% of total cohort), PVI in 1275 patients (19% of total cohort) and a

combination study of 120 patients (1% of total cohort). Comparison of lesion sets did not

identify any significant difference in terms of SRM with or without AAD achieved at final

follow-up (Figure 3.6). Further, there was no significant difference in terms of any individual

complication or total complication rates.

3.3.9.3. Energy Source Comparison

The categorised energy sources for comparison comprised RF as the primary modality in 2293

patients (34% of total cohort), cryo in 1030 patients (15% of total cohort), RF/MW in 212

patients (3% of total cohort), C&S in 831 patients (12% of total cohort) and a combination of

C&S, RF and Cryo in 2425 patients (36% of total cohort).

The effect of energy source on SRM on and off AAD is shown in Figure 3.7, with

analysis of SRM demonstrating that the studies utilising a combination of ablation modalities

in their operations or those utilising C&S to be superior to the use of RF(Combo: 85.6% [95%

CI: 80.3-89.7] vs RF: 75.4% [95% CI: 70.7-79.6], p=0.007; C&S: 87.3% [95% CI: 73.8-94.4]

vs RF: 75.4% [95% CI: 70.7-79.6], p=0.03), and the combination approach was also shown to

be superior to the use of Cryo(Combo: 85.6% [95% CI: 80.3-89.7] vs Cryo: 76.5% [95% CI:

68.5-83.1], p=0.04). However, no statistically significant difference was found in SRM off

AAD between any approach, nor in any of the rates of complication.

60


The LAA was excluded in 6345 patients (93%) and not excluded in the remaining 446 patients

(7%). Comparison revealed no significant difference in SRM with or without AAD, and no

significant difference in rate of CVA or any other complications. However, the rate of mortality

was lower in the LAA exclusion group (LAA Excl: 4% [95% CI: 3.2-5] vs LAA Not Excl:

10.3% [95% CI: 7.2-14.5], p=0.001) and the overall rate of complications was lower in the

LAA exclusion group(LAA Excl: 14.2% [95% CI: 11-18.2] vs LAA Not Excl: 33.3% [95%

CI: 10.2-68.9]. p=0.04).

3.3.10. Randomised Control Trial Data

Analysis was performed to compare the Randomised Control Trials to the Case Series studies

of the total cohort. This revealed no statistically significant difference between the groups in

terms of SRM or total complications.

3.4. DISCUSSION

Atrial fibrillation is commonly present in patients presenting for cardiac surgery and this

presents a unique opportunity for the potential treatment of their arrhythmia. The treating

physician must then consider if the efficacy and safety of an additional procedure for the

management of AF is justified to outweigh the negative effects of on-going AF for the patient.

This systematic review and meta-analysis demonstrates the following information:

1. The ablation of AF concurrent to general cardiac surgical procedures is an effective

treatment for maintaining SR with mean follow-up across the series of 22.1 months

demonstrating SRM of 79.6% (95% CI: 76.2-82.5) and SRM off AAD of 65.3% (95%

CI: 57.4-72.5).

61

2. No statistically significant difference exists in results obtained with BAM, LAM or PVI

lesion set, however, the use of C&S for creating lesions or a combination of modalities

is associated with superior outcomes in SRM on AAD.

3. Younger patient age and paroxysmal AF are associated with superior results in terms

of SRM.

4. The overall total complication rate was low at 15.1% (95% CI:11.7-19.3) with mortality

rate 4.3% (95% CI:3.4-5.4), CVA rate of 1.8% (95% CI:1.3-2.5), RTOT of 4.3% (95%

CI:3-6.1), PPM of 5.4% (95% CI:3.8-7.5) and AO fistula of 0.5% (95% CI:0.3-0.9).

5. Ablations which incorporate exclusion of the LAA and those performed concurrent to

mitral valve intervention offer reduced risk of complications.

6. There is notable variability in follow-up methodology, with ECG and 1 day Holter

monitoring being the most utilised methods.

3.4.1. Concomitant Cardiac Surgery and AF

It has previously been established that the presence of preoperative AF in cardiac surgery

patients is associated with worse long term outcomes.(285-289) Thus, in patients presenting

for cardiac surgery, a concomitant intervention capable of returning the patient to sinus rhythm

may offer long term benefits to patients if it does not significantly increase the risk of the

planned surgery. The Society of Thoracic Surgeons reported in 2016 the results of CABG,

AVR, MVR, AVR + CABG and MVR + CABG reported over 201,553 operations throughout

the 2014 calendar year with in-hospital mortality ranging across these procedures from 1.7%

to 9.2%, permanent stroke ranging from 1.1% to 3.8% and reoperation ranging from 2.3%

to7.5% with the higher complication rates seen in CABG+MVR procedures.(290) While this

analysis does not represent a matched cohort of patients for comparison the mean complication

rates of mortality 4.3% (95% CI: 3.4-5.4), CVA/TIA 1.8% (95% CI: 1.3-2.5) and RTOT 4.3%

62

(95% CI: 3-6.1) identified here are not representative of a higher complication rate. As such,

the addition of an ablation procedure to common cardiac surgical procedures may improve

longer term results for patients through maintaining SRM while not incurring additive risk.

However, this inference would need further study to be evaluated.

Interestingly, a similar sub-group of patients has been evaluated in the recent guidelines

of the STS focused on the practice of the surgical ablation of AF in which they evaluated the

outcomes of ablation providing recommendations on ablation concurrent to AVR, CABG or

the combination AVR+CABG.(210) They provided a Class I, Level B recommendation in this

setting for the addition of concurrent ablation in consideration that it did not increase mortality

or morbidity. These same guidelines evaluated separately the ablation of AF concurrent to

mitral valve surgery arriving at Class I, Level A recommendations for the addition of ablation

in also seeing no additional mortality or major morbidity risk.(210) Both findings are in

keeping with results produced by this meta-analysis looking at an effective cohort that spans

both of these guideline recommendations. However, there is a difference in the level of

evidence identified in this meta-analysis with a paucity of level 1 evidence and those suggested

in the guidelines. Further, the guidelines were only able to assign Class II, Level C

recommendations to intervention performed on the LAA at the time of ablation, which has been

identified as a protective factor in this meta-analysis reducing the risk of mortality.(210) This

may warrant further analysis in future prospective trials such as are currently underway.(122)

3.4.2. Comparison to Studies of Concomitant Mitral Valve Procedures

This cohort provides an interesting comparator group to those analysed in Chapter 2 that was

comprised of studies with 100% mitral valve intervention. The cohort in this Chapter by

comparison is a sundry group of patients which have been undergone ablation concurrent to a

63

variety of other interventions; however, this still offers a population of interest as many patients

presenting to the cardiac surgeon with AF will not only have a single pathology in the mitral

valve for treatment, but potentially multiples pathologies in the form of other valves and

ischaemic heart disease. Thus, the surgeon is faced with a far more complex task of providing

a risk profile for a wider combination cohort of patients that may benefit from the elimination

of AF. Comparison of the results of this Chapter to Chapter 2 have revealed the following

information:

1. There is no significant difference in the SRM obtained in either cohort (p=NS)

2. The total number of complications trended towards significance, but did not reach

significant (6.9% [95% CI: 5.8-8.0] vs 15.1% [95% CI: 11.7-19.3], p=0.058)

3. The mortality rate in patients undergoing ablation concurrent to mitral valve

intervention was significantly lower than those in this mixed cohort of patients (0.92%

[95% CI: 0.5-1.4] vs 4.3% [95% CI: 3.4-5.4], p=0.001).

The STS database report described a notable increase of mortality when CABG is added to

mitral valve surgery with the in-hospital mortality going from 4.2% to 9.2% with mitral valve

replacement and from 1.0% to 4.3% in the mitral valve repair cohort.(290) This comparative

analysis has identified an increase in mortality factor in keeping with the mitral valve repair

cohort of the STS report, though of interest the repair rate in the mitral valve repair rate in

Chapter 2 was only 31.6% with a replacement rate of 56.7% and 11.7% undefined. Thus, the

significant increase in mortality and trend towards increased complications identified in this

series with procedures of increasing complexity is in keeping with larger database cohorts and

the addition of AF ablation does not indicate an increase in complication rate compared to the

reports of large cross sectional studies.(290)

64


This meta-analysis has identified no statistically significant difference in lesion set but suggests

a trend towards BAM being most efficacious. The ablation methodologies of C&S and

combination approaches were both found to offer superior results in SRM compared to RF and

the combination approach was found to be superior to Cryo.

The most balanced approach would be to offer ablation for any patient with a history

of AF – particularly the younger patients with paroxysmal AF and mitral valve disease. The

ideal ablation lesion set is not apparent from this analysis, however, a more extensive lesion

set, such as with a BAM trends towards offering the best results. The most ideal ablation

methodology suggested from this analysis would be C&S or a combination approach, but the

ultimate goal of any approach is the creation of contiguous lines of conduction block and this

should be the guiding principle of the proceduralist. The LAA should be excluded as part of

the procedure.


The addition of AF ablation to any cardiac surgical procedure should be considered in patients

presenting with a history of AF. While the complication rates are not insignificant in this series,

when compared to the STS data of a similar mixed cohort of patients the rates of the major

complications of mortality, stroke and returning to theatre for bleeding fall within the range

reported.(290) Utilising this as a comparison cohort represents the most comprehensive

published cohort of patients undergoing cardiac surgery and thus a robust comparator. As such,

this represents a cohort of patients of inherently higher risk presenting for cardiac surgery with

incidental AF that have the opportunity to undergo concurrent ablation in the context that it has

been identified that pre-operative AF when left untreated is associated with higher

complication rates and worse long term outcomes.(285-289) Encouragingly though the rate of

65

SRM achieved at mean follow-up 22 months was 79.6% representing a large reduction in the

burden of AF of this population, which has the potential translate to improved long term

survival in patients presenting with AF. However, such an assertion would need to be

confirmed by large prospective studies.


The composition of included studies in this analysis represents a highly heterogenous cohort

of patients that are not specific to valvular intervention or coronary artery bypass intervention,

as such, they likely represent multiple mechanisms behind the development of AF within the

any given study. There is also variability in the quality of studies in this area with discrepancies

in recording of baseline variables, consistency of ablation method, lesion set and follow-up.

These variations serve to not only highlight the features present within the highest quality

studies, but also the need for standardisation of reporting within the field. Further, the included

studies identify a relative paucity of level 1 evidence within the literature of this area.

Additionally, as with any meta-analysis there may be confounding variables, measured and

unmeasured, which may impact the results of this analysis. Further, significant heterogeneity

exists in the literature in terms of surgical ablation procedure, follow-up length and

methodology, and this should be considered in interpreting the results. To manage the

significant literature heterogeneity with RCTs with <100 patients only those that did not have

statistically significant outcome measures were retained – this however does not retain

statistically significant control arms for comparison analysis. Finally, we are unable to provide

more extensive analysis on long term results of patient subtypes of AF given the lack of patient

level data available. Nonetheless, these identified limitations serve to highlight key areas of

attention for future studies.

66

3.5. CONCLUSIONS

Surgical ablation procedures for the management of AF carried out concomitant to other

cardiac surgical procedures are effective at maintaining SR on and off AAD at medium term

follow-up with relatively low complication rates compared to mixed cohorts of cardiac surgical

patients not undergoing ablation. The best results in SRM are obtained in younger patients with

paroxysmal AF and lower complication rates are seen when performed concomitant to mitral

valve intervention and with the exclusion of the LAA. However, it should be noted that this is

a highly heterogeneous cohort of patients at baseline with a wide variability in study follow-up

method and length. Further prospective studies with structured delineation of the wide variety

of cardiac surgical procedures that may be performed concurrent to ablation with a structured

follow-up methodology could confirm these results and help delineate the most ideal cardiac

surgical populations for the concomitant ablation of AF.

67


Figure 3.1

68


Forest plot for sinus rhythm maintenance achieved across the studies

69

Figure 3.3 – Sinus Rhythm Maintenance without AAD Forest Plot

Forest plot for sinus rhythm maintenance achieved without anti-arrhythmic drugs

70

Figure 3.4 – Complication Rates Forest Plots

71

Figure 3.5 – Mean Complication Rates

Mean complication rates from meta-analysis with error bars representing 95% CI

72

Figure 3.6 – Lesion Set Comparison

Comparison of lesion sets utilised across the studies

73

Figure 3.7 – Energy Source Comparison

Comparison of energy sources for ablation

80

Chapter 4

Isolated Surgical Ablation for Atrial Fibrillation – The Methodology, Safety and

Success in Sinus Rhythm Maintenance of Sole Cardiac Surgical Procedures

4.1. INTRODUCTION

The management of symptomatic atrial fibrillation (AF) remains a question of ongoing

importance with increasing hospitalizations placing significant burden on the healthcare

system.(29) Whilst several studies have shown no difference in the outcomes of rate or rhythm

control,(125,134) in practice, several patients remain highly symptomatic and have required

approaches to rhythm control. Catheter ablation is an increasingly utilised effectively in highly

symptomatic patients. Indeed, several randomised controlled studies have consistently

demonstrated that ablation therapy is superior to medical therapy alone.(141,142) However,

there remain several inherent limitations to the current catheter approach which include the

accurate evaluation of transmurality, the creation of contiguous lesions, the potential for

collateral injury, and the accepted need for multiple procedures.(151,171-174) In this setting,

there is interest in developing more definitive techniques. A meta-analysis of catheter ablation

procedures for AF has demonstrated that at long-term follow-up of more than three years,

single procedural success has been estimated at 53% and with multiple ablation procedures

(average 1.5), this figure is approaching 80% (176).

The gold standard for the surgical management of AF has been the Maze procedure

since first being described in 1991 by Cox et al.(36) This procedure has evolved since its

inception with the latest iterations of this procedure delivering 84% freedom from AF off AAD

and 90% freedom from AF with AAD at 2 years follow-up (188,189). Most commonly, this

procedure is undertaken in conjunction with other cardiac surgical procedures; however, the

experience with this procedure as a stand-alone surgical ablation for AF is limited (262).

81

Here we review the current literature to provide the current state of play with the use of

stand-alone AF ablation by undertaking a systematic literature review to evaluate the efficacy

and safety of the isolated surgical approach at maintaining sinus rhythm in patients with AF.

4.2. METHODS

A systematic review of electronic databases including Pubmed, Embase and Cochrane







to April 2017. The results were imported into Endnote reference database for further review.

These searches were supplemented by reviewing the bibliographies or published studies and


treatment of AF and reported outcomes on sinus rhythm maintenance (SRM). Studies that

performed other concurrent cardiac surgical procedures (valve repair or replacement, coronary

artery bypass grafting, etc) and sample size <100 patients were excluded. In addition, studies

that reported techniques of hybrid ablation were excluded (see definition below). Citations

related to animal studies and those published in journals in languages other than English were

not included. Selected publications were analysed for the following outcomes: SRM on and off

anti-arrhythmic drugs (AAD), block success if assessed, mortality, pericardial

effusion/tamponade, significant bleeding, atrio-oesophageal (AO) fistula, conversion to open

procedure if minimally invasive, stroke, length of stay, PPM requirement and 30-day mortality.

This study was registered with the PROSPERO international prospective register of

82

systematic reviews website (Registration Number CRD42017058255). The MOOSE

Guidelines for Meta-Analyses and Systematic Reviews of Observational Studies were utilised

as a guide for this study.

4.2.1. Definition

For the purposes of this study, isolated surgical ablation procedure was defined as a surgical

procedure, of any incision approach, for the sole management of AF, without concomitant

cardiac valve, coronary artery bypass or any other cardiac surgery procedure. Surgical

exclusion of the LAA appendage is part of the Maze procedure and has been included as part

of ablation procedures. Hybrid or convergent procedures in which an Electrophysiologist

undertaking catheter mapping and ablation study have also been excluded.


Meta-analysis was performed using Stata/SE version 14. Means were weighted and standard

deviation of continuous variables or proportion and Exact binomial lower and upper confidence

limits of categorical variables were pooled across studies and analyzed using a random effects

meta-analysis model. This type of model was chosen to partially compensate for any inherent

heterogeneity. Linear regressions were performed to investigate associations between


method, lesions set utilized, exclusion of LAA and use of RCT, weighting for number of


Statistical significance was assigned to P value <0.05. All confidence intervals reported

represented 95% Confidence Intervals (CI).

83

4.3. RESULTS


Figure 4.1 shows the number of studies retrieved and review process of citations. At the

completion of the review process 9 studies remained for analysis. The 9 included studies (Table

4.1) were all non-randomised, case series published between 2003 and

2013.(186,198,202,206,318-322) The overall cohort size was 1082 patients with an average

study sample size of 120 patients. Three studies were multi-centre(318-320) with the remaining

being single centre, and two studies provided a comparator group for analysis (Concomitant

cardiac surgical procedures in addition to a Maze).(186,322)

Overall, the patient cohort comprised 32.3% paroxysmal, 22.7% persistent and 35.4%

long-standing persistent, with 9.6% unspecified. It should be noted that one study did not

present a breakdown of AF subtype.(321) The mean AF duration was 5.7 years (Range: 4.9-

9.6), although 2 studies reported median AF duration,(198,320) and 2 studies did not report a

pre-operative AF duration.(319,321) The mean patient age was 60.4 years (Range: 51.3-67.5),

the mean LA diameter was 4.7cm (Range: 4.3-5.2) and the mean left ventricular ejection

fraction was 53.6% (Range: 50-55). However, three studies did not report any

echocardiographic patient parameters.(186,202,321)

There was incomplete to no reporting of AF risk factors across the studies (Table 4.2).

Two studies reported the incidence of hypertension and diabetes,(318,321) two studies reported

NYHA class,(318,322) one study reported the incidence of hypercholesterolemia, COPD,

smoking and CVA/TIA(318) and one study reported the mean CHADS2 score of their cohort

and BMI.(320)

The mean follow-up duration was 17.4 months (Range: 6.8-64.8) utilising ECG (1),

Holter (2) or a combination of both (6) at variable time points. Of note, 3 of the studies provided

84

time interval follow-up periods instead of mean and in these cases the longest follow-up period

with >50% of the cohort was selected as the follow-up period.(198,206,322)


4.3.2.1. Surgical Access

The surgical access, lesion set, energy source and operative characteristic are presented in the

Table 4.3. Procedural descriptions were provided in all studies. Surgical access was by

sternotomy in 2 of the studies,(186,322) mini-thoracotomy in 5 studies(198,318-321) and

Video Assisted Thoracoscopy (VAT) in 2 studies.(202,206)


Energy source varied amongst the studies with 5 studies utilising Radio-Frequency (RF) to

create the lesion set,(206,318-321) “Cut and Sew” in 1 study,(186) Cryo in 1 study,(198)

Micro-Wave (MW) in 1 study(202) and a combination of modalities (RF/Cut and Sew/Cryo)

in 1 study.(322) Of further note, all the RF devices used were bipolar in nature (they developed

a lesion through heating tissue between 2 electrodes) through either a bipolar clamp (in which

2 opposing jaws housed the electrodes of the device) or a bipolar rail (in which the 2 electrodes

were mounted on a device at a fixed distance and the device applied epicardially). Within the

studies that utilised RF, 2 studies used a bipolar clamp to create the lesions,(318,319) 1 study

used only a bipolar rail device(321) and 2 studies utilised a combination of clamp and rail

devices.(206,320) The RF Devices were manufactured by Medtronic (Minneapolis, MN) in 1

study,(318) Atricure (Cincinnati, OH) in 3 studies(206,320,322) and Estech (San Ramon, CA)

in 1 study.(321) The Cryo devices were produced by Medtronic (Minneapolis, MN) in 1

study(198) and Cooper Surgical (Trumbull, CT) in 1 study.(322) The MW device was

manufactured by Guidant (Indianapolis, IN).(202)

85

4.3.2.3. Lesion Set

The two major base lesion sets performed in the studies were either a Maze type lesion set or

Pulmonary Vein Isolation (PVI)/Box lesion set (Isolation of posterior left atrium including

pulmonary veins. A maze type lesion set was defined as any study that defined their procedure

as a “Maze” – in these studies bi-atrial lesions were performed with some variability in the

specific lesions placed. General examples of the lesion sets are displayed diagrammatically in

the Figure 2.2. In total there were 4 studies that utilised a Maze lesion set(186,198,206,322)

and 5 that utilised a PVI/Box lesion set.(202,318-321)

In consideration of the Maze classified procedures, the study by Ad et al described their

lesion set using a diagram – this displayed a box lesion encircling all the pulmonary veins, a

Left Atrial Appendage (LAA) line, a Mitral Valve Line (MVL), a line to the Superior Vena

Cava (SVC), a line to the Inferior Vena Cava (IVC), a line to the Tricuspid Valve Line (TVL)

and one towards the Right Atrial Appendage (RAA).(198) The study by Prasad et al did not

specifically described the procedural lines placed, beyond describing it as the “full Cox Maze

III” with the majority of these procedures performed by Dr James Cox himself.(186) The study

by Saint et al referenced a further study by Gaynor et al for procedural description – this

description interpreted from a diagram entailed bilateral PVI, floor line joining the inferior

aspect of the PVI, LAA line, MVL, SVC line, IVC line, TVL and RAA line.(187,322) The

study by Sirak et al utilised a unique “5 box” lesion set in order to recreate much of the same

lines as the traditional Maze procedure in thoracoscopic fashion – these boxes incorporated

bilateral PVI, roof line, floor line, coronary sinus line, anterior mitral trigone line, LAA line

and SVC line.(206)

In consideration of the PVI/Box lesion studies, additional lines may have been placed

in the PVI/Box studies and consisted of: Ligament of Marshall ablation in 2 studies;(318,319)

86

Roof and floor lines in 1 study;(320) and the addition of a line to the LAA, right atrial

appendage and superior and inferior vena caval lines in 1 study.(202)


The LAA was excluded in all but 1 study,(321) with the method being stapler excision in 3

studies,(202,318,319) clipped in 1 study,(206) oversewn in 1 study,(198) a combination of

stapling, excision and clipping in 1 study(320) and 2 studies did not state the method of

exclusion.(186,322) In the study by Edgerton et al the LAA was excluded in 89% of cases, in

the study by Kasirajan et al it was excluded in 95% of cases and in the study by Pruitt et al it

was excluded in 85% of cases.(202,319,320) The operative time, cross clamp time and

cardiopulmonary bypass time across the studies were inconsistently reported.


Three studies reported procedural duration with a mean of 172.2 minutes (Range:82-253)

(202,318,321) and two studies reported the use of cardiopulmonary bypass and cross clamp

times with respective means of 149 minutes (Range:135-163) and 66.5 minutes (Range:40-93).

The endpoint of the surgical procedure was bidirectional block across lesions in 3

studies(202,206,318), exit block in 2 studies,(321,322) entrance block combined with no vagal

response on pacing stimulation in 1 study(319) and not stated in 3 studies.(186,198,320) The

study by Pruitt et al with the endpoint of bidirectional block described a low rate of success in

achieving this endpoint, but did not provide a figure for the incidence of success.(202) Three

studies reported the use of Direct Current Cardioversion (DCC); with the study by Beyer et al

utilising DCC at the end of the procedure if the patient was still in AF (47/100 patients).(318)

In the study by Kasirajan et al it was utilised (8/118 patients) either immediately post-

operatively or 3 months later.(320) In the study by Saint et al DCC was performed on patients

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in AF at the time of surgery as part of the procedure.(322) Only the study by Beyer et al reported

the number of patients who achieved Sinus Rhythm (SR) by the completion of the procedure,

which was 86/100.(318)

4.3.3. Post-Procedure Follow-up

The mean follow-up duration was 17.4 months (Range: 6.8-64.8). Table 4.4 details follow-up

frequency and methodology. In studies where specific time points of follow-up were provided

instead of mean, the latest follow-up with >50% of the cohort was selected for analysis. In the

study by Edgerton et al the follow-up period was presented in days and this was converted into

months for statistical analysis in this review.(319) In the study by Edgerton et al the patients

received either a 1 day Holter monitor or long-term monitoring (defined as a 14 to 21-day event

monitor) at 6 months follow-up, but the number of patients in each category was not

specified.(319) In the study by Pruitt et al no specific time follow–up period was documented

but the majority of patients were between 12 and 36 months at last follow-up. In the study by

Kasirajan et al the specific time points of planned follow-up was not stated.(320) The follow-

up methodology was performed utilising ECG (1), Holter (2) or a combination of both (6). The

use of ECG was documented in 7 studies,(186,198,202,318,319,321,322) 1 day Holter monitor

in 7 studies,(198,202,318-322) 7 day Holter monitor in 3 studies,(198,202,206) Long Term

Monitoring (defined as the use of either a 14 to 21 or 30 day event monitor) in 2

studies(319,320) and Permanent Pacemaker (PPM) interrogation in 4 studies.(206,318-320)

Closer analysis of the studies utilising Holter monitor identified that either a 1 day or 7 day

Holter was performed at 6,12 and 24 months in the study by Ad et al,(198) a 1 day Holter at

the 6 month mark in the study by Edgerton et al,(319) a 1 day Holter monitor at 6,12 and 24

months in the study by Kasirajan et al,(320) a 1 day Holter monitor at 3 months, 6 months and

6 monthly thereafter in the study by Nasso et al,(321) a 1 day or 7 day Holter monitor in the

88

study by Pruitt et al,(202) a 1 day Holter monitor in the study by Saint et al,(322) and 7 day

Holter monitoring at 3,6,13 and 24 months in the study by Sirak et al.(206) Only 2 studies

provided information on success rate of maintaining SR in the different classifications of AF

(Paroxysmal/Persistent/Long Standing Persistent).(318,319)

Definition of recurrent arrhythmia was not uniform across the studies with 4 studies

utilising an atrial arrhythmia of >30 seconds duration,(198,206,320,322) 1 study stated to be

using the “HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation

of AF”(319) and the remaining 4 studies did not specifically define recurrent

arrhythmia.(186,202,318,321)

4.3.4. Outcomes

Overall SRM at final follow-up from this meta-analysis with and without AAD respectively

was 83.3% (95% CI: 75.2-91.5) and 65.5% (95% CI: 50.6-80.3; Figures 4.2 and 4.3). Analysis

of the 2 studies which provided success in AF types supplies a cohort of 214 patients with

88.9% SRM of 99 paroxysmal patients, 75.4% SRM of 61 persistent patients and 63% SRM

of 54 long-standing persistent. Within the study by Pruitt et al 10 patients went on to have a

formal Maze procedure after their initial procedure PVI and these patients were excluded from

the follow-up analysis.(202) Further, in the study by Kasirajan et al 6 patients went on to have

a catheter ablation procedure in the follow-up period to treat AF or atrial tachycardia within

the 3 month blanking period and they were considered failure of treatment in the articles

analysis.(320) Analysis of post-operative AAD usage found that it was not utilised uniformly

across the studies and the AAD utilised was also varied. Regarding AAD choice; the study by

Edgerton et al documented use of Amiodarone, Sotalol, Flecainamide or Digoxin at

discharge,(319) the study by Nasso et al utilised Amiodarone or Flecainamide at

discharge,(321) the study by Pruitt et al utilised Amiodarone(202) and the study by Saint et al

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utilised Class I/III AADs.(322) Kasirajan et al aiming to discontinue AAD use by 6 months

with ideally 2 months free of AAD prior to the 6 month follow-up.(320) Nasso et al used AAD

in all and would discontinue if the patient was in SR at both 3 and 6 month follow-up

visits.(321) Saint et al used AAD in all and would discontinue it at 2 months post-procedure if

the patient was in SR.(322) The remaining 6 studies did not specify an AAD usage

protocol.(186,198,202,206,318,319)


4.3.5.1. Lesion Set

The 2 primary base lesion sets employed across the studies were a Maze type lesion set or a

PVI/Box lesion set. The Maze type lesion set was associated with a higher rate of SRM both

off and on AAD than PVI/Box lesion sets reaching 79.2% (95% CI: 64.7-93.6) vs 54.1% (95%

CI: 42.2-67.1; p<0.01) and 93.8% (95% CI: 81.2-106.3) vs 73.8% (95% CI: 62.6-85.1; p=0.02)

respectively (Figure 4.4).


The energy source utilised to create lesions of cardiac conduction block had a wide variance

across the studies and comparison between these in shown in Figure 4.5A. The use of Cut and

Sew, RF or the use of a combination of modalities were superior to the use of MW for achieving

SRM (p<0.05) and the use of Cut and Sew, RF, Cryo or a combination of modalities were

superior to the use of MW for achieving SRM with AAD (p<0.001). The use of Cut and Sew

to create lines of conduction block was associated with a 79.6% (95% CI: 71.7-87.5) rate of

SRM off AAD and 95.9% (95% CI: 85.5-106.3) with AAD. The use of RF to create lesions

was associated with SRM of 67.1% (95% CI: 54.7-79.5) and 84.5% (95% CI: 79-90) with

AAD. The use of Cryo to create lesions was associated with SRM of 65.2% (95% CI: 57.3-73)

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and 92.4% (95% CI: 82-104.8) with AAD. The use of MW energy to create lesions was

associated with SRM of 30.7% (95% CI: 22.8-38.6) and 42.1% (95% CI: 31.6-52.5) with AAD.

The use of a combination of all of these modalities in a procedure achieved a SRM of 76.2%

(95% CI: 68.4-84.1) and 91.1% (95% CI:80.7-101.5) with AAD.

Further analysis of RF devices conducted to compare rail and clamp devices (Figure

4.5B) shows that the joint use of clamp and rail devices in a single procedure was superior to

clamp alone (p<0.001) and clamp alone was superior to the use of rail alone (p<0.001) in SRM.

There was no statistical difference between RF modalities in SRM with AAD use. The SRM

of joint clamp and rail use was associated with SR off AAD of 87.6% (95% CI: 82.1-93.2) and

87.6% (95% CI: 80.3-95) with AAD, the use of clamp devices alone was associated with SR

off AAD of 60% (95% CI: 54.4-65.6) and 79% (95% CI: 71.7-86.4) with AAD, and the use of

rail devices alone was associated with SR off AAD of 40.2% (95% CI: 6.6-73.8) and 89.2%

(95% CI: 78.8-99.6) with AAD.


Studies that excluded the LAA were compared to the study which did not for analysis of effect

on rhythm and incidence of stroke (Figure 4.6). There was no statistical difference in rhythm

outcomes on or off AAD but there was a statistically significant reduction in stroke risk with

exclusion of the LAA (0.7% [95% CI: 0.4-1.1] vs 2.0% [95% CI: 0.9-3], p=0.028).


The procedural complications reported in the studies are outlined in Table 4.5 and complication

rates Forest Plots in Figure 4.7. The overall complication rate was 7.4% (95% CI: 0.8-14) with

a 0.5% (95% CI: 0-2) mortality rate, 0.9% (95% CI: 0-2) CVA rate, 1% (95% CI: 0-3.4) rate

of conversion to an open procedure from a minimally invasive one, 0.6% (95% CI: 0-3.1) rate

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of bleeding requiring return to operating theatre, 0.3% (95% CI: 0-3) rate of pleural or

pericardial effusion, a 3.2% (95% CI: 0-9.2) rate of PPM requirement, 0.2% (95% CI: 0-1) of

post-operative pulmonary embolus and a 1.4% (CI:0-8) rate of phrenic nerve injury. There

were no reports of atrio-oesophageal fistula in any of the studies. The mean length of hospital

stay was 4.3 days (CI:1.9-6.6), though of note 2 studies reported median instead of mean length

of stay (186,320) and 1 study did not report length of stay (321). The 0.5% mortality rate

consisted of a total of 5 deaths from the time of procedure to within the first 30 days following.

The causes consisted of 1 case of an avulsed LAA, 1 from an unknown cause (inconclusive

autopsy), 1 case of multi-organ failure from delayed cardiac tamponade, 1 case of acute

respiratory failure secondary to amiodarone toxicity and cause not specified in 1 case

(186,319,322). No statistically significant difference existed in complication rates between

procedures though a trend towards significance existed with PPM requirement (Figure 4.8).

4.4. DISCUSSION

Isolated surgical procedures for the treatment of AF are aimed to restore patients to SR in the

absence of structural heart disease. This systematic review and meta-analysis on the efficacy

and safety of these procedures demonstrates the following information:

1. Good medium to long term results in SRM are achievable, particularly with use of

AAD;

2. Higher success rates are seen with earlier stages of disease (paroxysmal > persistent >

long-lasting persistent AF cohorts);

3. Utilisation of a more extensive lesion set delivers superior results in SRM with or

without AAD;

4. Lesion sets developed through “Cut and Sew”, RF or a combination of modalities in a

single procedure are the most effective;

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5. There is a difference in RF modalities in terms of efficacy in achieving SRM without

AAD. In this analysis using a combination of RF clamp and rail devices was most

effective, though this may reflect a more extensive lesion set employed. The use of RF

clamp alone was superior to rail alone in achieving SRM off AAD;

6. Exclusion of LAA during procedure does not provide a difference in rhythm control,

but it is protective of future CVA event;

7. An overall complication rate of 7.4% (95% CI: 0.9-14) has been noted and is driven

largely by a significant PPM requirement of 3.2% (95% CI: 0-9.2).

Importantly, this review is based on non-randomised, case series with only 2 studies providing

a comparator cohort for analysis. Of note, this analysis has highlighted a significant lack of

level 1, randomised control trials in this area. Nevertheless, the current review demonstrating

the safety and efficacy of the approach suggests that such an approach could be considered in

selected individuals and warrants further evaluation.

4.4.1. Catheter vs Surgical Ablation for Isolated AF

Patients with symptomatic AF that have failed medical therapy should be considered for

ablation to treat their arrhythmia.(262) Catheter ablation techniques have rapidly and continue

to evolve. Indeed, studies have consistently demonstrated the superiority of catheter ablation

over medical therapy for rhythm control. Not only has the evidence base for the use of catheter

ablation has expanded but there have now been several randomized controlled studies that have

evaluated a variety of techniques.(323-325) Nevertheless, there remain several inherent

limitations to the current catheter approach which include the accurate evaluation of

transmurality, the creation of contiguous lesions, the potential for collateral injury, procedural

93

duration, and the accepted need for multiple procedures. It is in this context that one could

consider the optimal method for ablation of AF and the potential to use a surgical technique.

Compared to a contemporary meta-analysis on catheter ablation of AF, which has

identified a single procedure SRM success of 53% and multiple procedure success of ~80% at

≥3 years of follow up of (176), this systematic review and meta-analysis has identified a

procedural success of 65% without AAD and 83% with AAD, which offers results superior to

a single catheter procedure and similar to multiple catheter procedures with the addition of

AAD use. However, this is delivered at the cost of higher procedural complication rate,

primarily that of increased PPM requirement.

The FAST Trial sought to answer this question through a randomised clinical trial

comparing catheter ablation and minimally invasive surgical ablation across 2 centres over a

12-month period. The enrolled patient cohort comprised 124 patients with AAD refractory AF

with left atrial dilatation and hypertension (42 patients [33%]) or failed previous catheter

ablation (82 patients [67%]). This trial included patients of both paroxysmal and persistent AF

with 63 patients randomised to catheter ablation and 61 patients to surgical ablation. At final

analysis it had identified superior results with surgical ablation in terms of SRM (65.6% vs

36.5%), but was once again at the cost of higher complication rate (34.4% vs 15.9%).(326)

There are however several questions that remain using such a technique with the best

results being achieved using a more extensive procedure, the need for an open-chest procedure,

the in hospital and recovery time for the individual and the longer-term maintenance of these

results. Nevertheless, this review suggests that further evaluation of the use of a surgical

approach is warranted.

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4.4.3. The LAA Dilemma

The role of the LAA in arrhythmia and stroke risk is one of on-going scrutiny and interest.

There are increasing modalities of how to handle the LAA (excision, ligation, stapler excision,

clip) the most apt term to describe the fundamental intervention is LAA exclusion as in all

cases it is removed from the circulating blood volume. The LAAOS trial identified that not all

methods were equal in eliminating the LAA with stapling being superior to over-sewing, but it

was not able to determine a protective role in stroke prevention through its elimination.(123)

Further, recent studies have suggested that incomplete exclusion of the LAA is a predictor of

stroke or systemic embolization.(327) Within the most recent guidelines produced by the STS

examining the issue of the LAA at the time of surgery it was felt a reasonable intervention to

perform for the reduction in thromboembolic events; however, this recommendation only

reached Class IIA, Level C evidence.(210) The results of our analysis are consistent with these

aforementioned studies and guidelines, with primary method of exclusion being stapling,

suggesting a protective effect against CVA and as such should be considered at the time of

surgery.

4.4.4. Clinical Implications: Developing Superior Results

The most recent guidelines produced by the Society of Thoracic Surgeons focusing on the

clinical practice of surgical ablation for AF identified the standalone surgical procedure as a

reasonable intervention to undertake for symptomatic AF refractory to AAD or catheter

ablation, assigning Class IIA, Level B evidence.(210) Interestingly, they suggested the use of

the Cox Maze procedure over PVI as reasonable, assigning the same level of evidence.(210) In

consideration of these recommendations and the results identified in this meta-analysis the

most reasonable approach would be to only undertake such procedures where appropriate

experience and expertise are available to achieve the most efficacious and safe results.

95

This review has identified three important technical considerations for the clinician

embarking upon this treatment strategy for their patient. First, undertaking a more extensive

lesion set, such as a Maze procedure, is more likely to deliver increased rates of success in long

term maintenance of SR and therefore if this should always be considered when planning

surgery. Second, these results suggest that not all methods of creating lines of conduction block

are of equal efficacy and the incorporation of Cut and Sew or RF seems to deliver the best

results. Assessment of conduction block at either the time of surgery or post procedurally with

an electrophysiologist may help overcome this technology limitation. Third, exclusion of the

LAA is associated with protection against CVA and as such should routinely be excluded at

the time of operation. In these considerations, the isolated surgical procedure for treatment of

AF should be considered as part of the armamentarium for clinicians treating medically

refractory, symptomatic AF.


There exists significant heterogeneity in terms of surgical procedure and follow-up method and

intervals among these included studies, and this should be considered in interpreting the results.

There is variability in the quality of studies with discrepancies in recording of baseline

variables, patient characteristics, consistency of ablation method and follow-up. These

variations serve to highlight the features of the highest quality studies and also the need for

standardisation of reporting within the field. Further, the composition of these studies is all

non-randomised, patient cohort studies. Additionally, as with any meta-analysis there may be

confounding variables, measured and unmeasured, which may impact the results of this

analysis. Finally, we are unable to provide more extensive analysis on patient AF subtype given

the lack of patient level data available. Nonetheless, these identified limitations serve to

highlight key areas of attention in future studies.

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4.5. CONCLUSION

Stand-alone surgical procedures carried out for the treatment of AF have good results in sinus

rhythm maintenance with moderate results in freedom from AAD at medium term follow up.

The greatest results have been seen with more invasive procedures which typically have a more

aggressive ablation or electrical isolation strategy. However, it must be recognised that there is

significant variability in study follow up length and method due to the generally retrospective

nature of these studies. Further prospective randomised studies, with structured follow up are

required to confirm these results and help delineate specific procedure success for specific

patient populations based on AF type.

97


Figure 4.1 –Search Strategy

98

Figure 4.2 –Sinus Rhythm Maintenance Forest Plot

99


100

Figure 4.4 – Lesion Set Comparison

The lesion set comparison highlights the difference in SR on and off AAD of Maze vs

PVI/Box. Error bars represent 95% confidence interval.

101

Figure 4.5 – Energy Sources Comparison for Sinus Rhythm Maintenance

A) The rates of SR on and off AAD is shown for different energy sources. No statistically

significant difference was detected between lesions sources. B) Comparison made between

the different forms of RF ablation device types. Only statistically significant differences are

shown – the SR off AAD achieved between all comparisons. Error bars represent 95%

confidence interval.

102

Figure 4.6 – LAA Exclusion Comparison

The LAA excluded comparison highlights the difference in SR on and off AAD with CVA

rate. Only significant p-values are depicted with error bars representing 95% confidence

interval.

103

Figure 4.7 – Complications Rates Forest Plots

104

Figure 4.7 – Complications Comparison

110

Chapter 5

Hybrid Ablation (Surgical and Electrophysiological) of Atrial Fibrillation – The

Methodology, Safety and Success of Sinus Rhythm Maintenance

5.1. INTRODUCTION

Symptomatic atrial fibrillation (AF) remains a significant public health burden with increasing

hospitalizations.(29) In symptomatic patients, ablation has consistently been demonstrated to

be superior to medical therapy.(139,141)

Although multiple catheter-based procedures may be required for sinus rhythm

maintenance, a recent meta-analysis has demonstrated that this is an effective and durable long-

term therapeutic option.(176) Specifically, at long-term follow-up of more than three years,

single procedural success has been estimated at 53% and with multiple ablation procedures

(average 1.5), this figure is approaching 80%.(176) In comparison, surgical Cox- Maze

procedures have also documented sinus rhythm maintenance results of up to 96% with the Cox-

Maze III and 91% for the Cox-Maze IV, with respective results off anti-arrhythmic drugs

(AAD) of up to 83% and 78% respectively at up to 5.4 years follow-up.(186,188,189,322)

These apparent superior results may be due to the ability to obtain direct or videoscopic

visualization, better stabilization of the cardiac tissue substrate at the time of surgery and

confirmation of lesion transmurality, particularly when the lesions are cut and sewn in.

However, the greater invasiveness of the Cox Maze procedures is also accompanied by greater

peri-operative morbidity and potential major complications including death, bleeding and

stroke.(186,189)

More recently, a new hybrid approach for AF comprising initial surgical epicardial

ablation with concurrent or sequential endocardial catheter based ablation has emerged. This

strategy seeks to combine the strengths and minimise the drawbacks of the individual

111

approaches by balancing invasiveness and duration of ablation procedure with improved

delivery of ablative lesions sets followed by endocardial electrophysiological evaluation and

additional consolidative ablation if required. Initial studies have shown promising results of

sinus rhythm maintenance.(208) Here, we undertook a systematic literature review to evaluate

the efficacy and safety of this approach at maintaining sinus rhythm in patients with AF.

5.2. METHODS










Surgical procedures, operative[MeSH Terms])]” and “[(Atrial Fibrillation[MeSH Terms] OR

Atrial Fibrillation OR AF[Ti] OR Cox OR Maze OR Mini-maze) AND (Unipolar [All fields]

OR Bipolar[All fields] OR Radiofrequency OR Ablation technique*[All Fields] OR

Cryoabla*[All Fields] OR Cryomaze OR Cryo-maze OR Cryosurgery[MeSH Terms] OR

Cryosurg*[All Fields]) AND (Surgery[All Fields] OR Surgical procedures, operative[MeSH

Terms])]”. The search was conducted from January 1991 to March 2017. The results were

imported into Endnote reference database for further review. These searches were

supplemented by reviewing the bibliographies of published studies and reviews. Studies were

accepted if they conducted a surgical ablation procedure for the treatment of AF and reported

112

outcomes on SRM. Studies were accepted if they conducted a hybrid (joint surgical and

electrophysiology procedure) ablation procedure for the treatment of AF and reported

outcomes on sinus rhythm maintenance (SRM). Studies with different definitions of hybrid

(catheter ablation + AAD use, cryo + radiofrequency, two types of surgical ablation, etc) and

sample size <15 were excluded. Citations related to animal studies and those published in

journals in languages other than English were not included. After exclusions, the publications

were analysed for the following outcomes: SRM on and off anti-arrhythmic drugs (AAD),

block success if assessed, mortality, pericardial effusion/tamponade, significant bleeding,

atrio-esophageal (AO) fistula, conversion to open procedure if minimally invasive, stroke,

length of stay, permanent pacemaker (PPM) requirement and 30-day mortality. Figure 5.1

shows breakdown of the search, number of studies retrieved and review process of citations.

At the completion of the review process 22 studies remained for analysis.

5.2.1. Definitions

For the purposes of this study hybrid surgical ablation were defined as a combined surgical and

electrophysiological endocardial catheter-based approach for the sole management of AF.

Typically, a surgically conducted ablation is followed by catheter-based study either during the

same procedure or in the coming months. The aim is to confirm the integrity of the surgically

placed ablation lines with endocardial mapping, consolidate these ablation lesions sets as

required and perform additional substrate-based ablation. Surgical incision may be of

sternotomy, thoracotomy, video-assisted thoracoscopy (VAT) or sub-xiphoid/laparoscopic

trans-diaphragmatic approach. Surgical lesions were defined as any series of lesions placed on

the heart (Cut and Sew/Radiofrequency/Cryothermy/Micro-Wave) for the management of AF.

Additional, cardiac valve procedures, coronary artery bypass or any other cardiac surgery

procedure are permissible if performed concurrent to AF ablation. AF ablation procedures were

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broadly categorised into Maze, Box and Pulmonary Vein Isolation. Surgical exclusion of the

LAA appendage has been included as part of ablation procedures for analysis.



described as being in permanent AF reclassified to long-standing persistent (LSP) AF.(262)


Data was collected by the investigators and all statistical calculations were checked and further

analysis performed by an independent statistician. Meta-analysis was performed using R

version 3.2. Mean and standard deviation of continuous variables and Exact binomial lower

and upper confidence limits of categorical variables were pooled across studies and analysed

using a random effects meta-analysis model. Random effects meta-analysis of single

proportions was performed using the Freeman-Turkey Double arcsine transformation. Mixed

model meta-regression models were implemented to investigate associations between


method, lesions set utilised, exclusion of LAA and use of RCT, weighting for number of


Statistical significance was assigned to P value <0.05.

5.3. RESULTS


The 22 included studies (Table 5.1) were published between 2010 and 2017 and were all single

centre, non-randomised studies with 17 case studies (7 prospective, 6 retrospective, 4 not

stated) and 5 case series studies with a comparator group (3 prospective, 1 retrospective, 1 not

stated).(207,208,328-347) The studies that had comparator groups comprised Cut and sew

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Cox-Maze (342), lone catheter ablation (331,338,343) and isolated surgical thoracoscopic

ablation (341). The total cohort contained 925 patients with a mean cohort size of 42 patients

(Range: 15-101) comprised of 103 paroxysmal (11%), 351 persistent (38%) and 471 long

standing persistent (51%) in terms of AF type. The mean length of AF was 5.1 years (Range:

2.42-8) with 3 studies reporting a median length. (337,342,346)

The mean patients age was 60.5 years (Range: 53.7-63.8), with mean LAD of 4.91cm

(Range: 4.3-5.3) and mean LVEF of 54.8% (Range: 47-59.3). Of note 3 studies did not report

LAD,(331,338,342) 1 study reported median LAD(345) and 3 studies did not report

LVEF(336,337,341) with 1 study providing median LVEF.(345)

The rate of AF related comorbidities reported across the total cohort included 59.3%

hypertension (Range: 0-83), 12.1% diabetes (Range: 0-31%), average BMI of 29 (Range: 26.8-

32.8) and 18.5% having had a prior failed catheter ablation (Range: 0-76). Of note 4 studies

did not report on rate of hypertension,(333,336,344,345) 7 studies did not report on rate of

diabetes,(207,333,336,339,340,344,345) 5 studies did not report average

BMI(208,333,336,343,345) with 2 reporting number of patients in the obese range,(328,334)

and only 9 studies reporting the rate of prior catheter ablation.(207,329,330,334,337,338,340-

342,347)

The mean follow-up duration achieved across the studies was 19 months (Range: 6-

128.4) Of note, 5 of the studies provided only time interval follow-up periods and in these cases

the longest follow-up period with >50% of the cohort included was selected as the follow-up

period.(331,334-336,340)

115



The surgical access site, surgical lesion set, energy source and other basic operative

characteristics are detailed in Table 5.2 and Figure 5.2. Both surgical access and ablation lesion

sets varied amongst the studies with one study necessitating interpretation of lesion set from

their published diagram.(335) Surgical access was via unilateral or bilateral VATS

(videoscopic assisted thoracoscopic surgery) in 13 studies, (207,208,328-330,337-341,343-

345) sub-xiphoid/trans-diaphragmatic laparoscopy in 6 studies, (331,334-336,346,347)

sternotomy in 2 studies (332,333) and mini-thoracotomy.(342) The fundamental ablation lesion

sets included pulmonary vein isolation (PVI) for 11 studies, (207,333-337,339,341-343,346)

box isolation that encompasses isolation of all pulmonary veins and the posterior left atrium in

10 studies (208,328-331,338,340,344,345,347) or a Maze procedure in 1 study.(332)

Additional lesions included roof line,(207,333-337,339,341,343,346) floor line,

(334,337,339,341) mitral isthmus line, (207,330,333,334,336,337,339,341,343) ganglionated

plexi ablation,(208,329,335,339-343,345-347) ligament of Marshall

ablation,(329,331,332,334-337,339,343,345-347) between the right inferior pulmonary vein

and inferior vena cava,(207,334-336,346) superior vena cava,(207,330,343,345) inferior vena

cava,(207,345) bicaval line,(207,330) between the right inferior pulmonary vein and Thebesian

valve,(336) oblique sinus,(336) Waterson’s groove line(334,336) and complete posterior wall

ablation.(347)

5.3.3.2. Energy Utilized

Twenty studies utilized Radio-Frequency (RF) for surgical ablation energy

source(207,208,328-331,334-347) while two used cryothermy (332,333). Devices for surgical

ablation varied among the studies which utilised RF; 3 utilizing the monopolar Cobra Adhere

116

XL device(Estech, San Ramon, CA, USA),(208,328,340), 1 utilising the bipolar Cobra Fusion

150(Estech, San Ramon, CA, USA)(344), 9 the Atricure Synergy bipolar ablation system

clamp with or without bipolar ablation rail device (Coolrail)(Atricure, West Chester, OH,

USA),(207,329,330,337-339,341,343,345) 6 the nContact ablation system (nContact Surgical,

Morrisville, NC, USA),(331,334-336,346-348) and 1 primarily the Medtronic Gemini-X

ablation system (10% of the cases with the Atricure system)(Medtronic, Minneapolis, MN,

USA).(342) Of the 2 studies utilising cryo; 1 used the Frigitronics cryothermy system

(Frigitronics, Cooper Surgical, Shelton, Connecticut),(333) and 1 the CryoFlex Medtonic

system (Medtronic, Minneapolis, MN, USA).(332) Figure 5.2 shows the RF devices used in

these studies.

In consideration of energy applications 11 studies reported on amount of energy

delivered per lesion (9 RF studies and 1 cryo). Regarding the RF studies; 2 studies reported 4

to 6 applications of RF,(207,330) 2 studies reported >5 applications,(329,339) 3 studies

reported 3,(337,341,342) 1 study reported 3-7 applications,(343) 1 study reported >2

applications(208) and 1 study reported >1 minute time of application.(345) The cryo study

which provided data on application length reported 2 minutes of cryo time per lesion.(332)

5.3.3.3. LAA Management and Additional Approaches

The LAA was surgically managed in 11 of the studies; it was stapled off in 5

studies,(207,337,338,342,343) clipped off in 3 studies,(329,330,339) a combination of stapled

or clipped in 2 studies(341,345) and method not stated in 1 study.(332) Among the studies that

surgically excluded the LAA the number of patients within each study that had this intervention

ranged from 27% to 100%.

Additional procedures included; removal of the fat along Waterson’s groove to

facilitate disruption of the ganglionic plexi In the study of Muneretto et al,(208) the addition

117

of concomitant surgery consisting of valve replacement in 19 patients, CABG in 7 patients and

combination of these procedures of 8 patients in the study of Eisenberger et al(332) and 1

patient underwent a concurrent minimally invasive mitral valve repair in the study by Kiser et

al.(336) In the study by Pison et al, the lesions were placed in a stepwise fashion with additional

lines only added when further testing with isoprenaline was able to demonstrate inducible

sustained AF (207). The commonly employed lesions are diagrammed in Figure 5.2.

5.3.3.4. Endpoints

The end point of the surgical procedure was conduction block in 12 studies

(208,328,329,334,335,337,339,341-345) with 5 of those being endocardial block confirmation

by the electrophysiologist,(208,328,334,343,344) completion of the planned lesion set in 9

studies(207,330-333,338,340,346,347) and visual confirmation of contiguity of ablation lines

in 1 study.(336) The mean procedure time was 218.2 minutes (Range: 85-450.1) with 10 studies

reporting total procedural time,(207,328,330,331,335,337,338,340,341,343) 6 studies

reporting their surgical procedure time(208,329,336,339,344,347) and 6 studies not reporting

total or surgical procedural time.(332-334,342,345,346)

5.3.4. Catheter-based Electrophysiological Procedures

5.3.4.1. Timing after Surgery

Nine studies undertook immediate follow on to endocardial catheter-based ablation in a hybrid

theatre,(207,330,331,334,336-338,340,341) while nine studies utilized a staged approach with

a variable interval period ranging from 4 to 167 days before the endocardial

procedure,(208,328,329,332,333,339,342-344) and 4 studies utilising a combination of both

sequential and staged approaches (Table 5.3).(335,345-347) Of note, Lee et al only performed

catheter-based procedure in patients with recurrent AF more than 3 months after the initial

118

surgical procedure.(342) In this study, only 23 out of the cohort of 25 underwent further

electrophysiological study and ablation, with 2 patients declining further intervention given

symptomatic improvement (342). Further, the study of Gersak et al had 5 patients that declined

the endocardial ablation stage of the procedure (335).

5.3.4.2. Endocardial Procedure Type

Seventeen studies utilised RF energy for catheter ablation; 6 studies reported use of irrigated

Thermocool [Biosense Webster, CA, USA],(329,332,335,339,345,346) 2 reported use

Thermocool with no comment on being irrigated,(340,341) 2 reported utilising irrigated

Navistar Thermocool [Biosense Webster, CA, USA],(330,347) 2 Thermocool Navistar with no

comment on being irrigated,(328,333) 2 reported use of SmartTouch [Biosense Webster, CA,

USA],(338,344) 1 a combination of either irrigated Navistar Thermocool or non-

cooled/irrigated Blazer II [Boston Scientific, MA, USA],(334) 1 a combination of an irrigated

RF catheter from either Biosense or Boston, but without specification of catheter model (343)

and 1 study used a combination of RF Thermocool (no comment on irrigated) and cryo-balloon

technology(Arctic Front, Arctic Front, Cryocath, Montreal, Quebec)(207). Five studies did not

state the device employed for catheter procedure.(208,331,336,337,342)

Fourteen studies reported the use of mapping with 12 studies using the Carto system (Biosense

Webster, CA, USA),(208,328-330,332,333,336,338,339,344,345,347) 2 studies utilised either

Carto or Ensite NavX (St Jude Medical, Austin, TX, USA) (334,343), and 8 studies did not

specify a mapping method.(207,331,335,337,340-342,346)

Catheter ablation strategy differed among the studies apart from all studies ensuring the

pulmonary veins were isolated (Table 5.3). Eleven studies added a cavo-tricuspid isthmus line

as required,(207,329,330,334,336,338-341,344,345) 6 studies added a mitral line as

required,(329,330,340,342,345,346) 4 studies added a coronary sinus line as

119

required,(331,334,343,347) 3 studies added a roof line,(335,342,346) 4 studies performed an

additional ablation line of the SVC with or without IVC(335,341,343,346) and 1 study

performed GP ablation.(344) In addition, 6 studies procedures carried out Complex

Fractionated Atrial Electrogram (CFAE) ablation and this was utilised on a case by case basis

if SR was not able to be obtained.(330,331,334,338,343,345) Four studies did not perform

additional lines of ablation other than consolidating the surgically placed lines as required.

(208,328,332,333,337) Two studies did not provide a specific written description of catheter

ablation lines, necessitating interpretation from diagrams in the respective studies (335,348).


At the beginning of the procedure, 16 studies reported checking for conduction block with

variable results in gap free lesions (Range: 0-91.1%).(207,208,328-333,338-345) Post

procedural block confirmation was described in all studies with 11 studies reporting

specifically to what extent they were successful.(328-330,332-335,339-341,344) The

remaining studies listed achieving block as the end point of the procedure, but did not specify

how successful they were.(207,208,331,336-338,342,343,345-347) Lee et al only tested for

conduction block if the patients were still in AF, and this occurred in seven (29%) patients with

a further 2 being offered catheter ablation, but declined (342). Further testing with AF induction

was performed with 4 studies using pacing manoeuvres (208,328,339,342) and 4 others using

isoproterenol challenge (207,336,341,343). In the study by Kiser et al, if SR not achieved at

end of EP procedure DC cardioversion was performed and mapping of triggers using Isuprel

was performed (336). In the study by Mahapatra et al at the end of ablation procedure

isoproterenol was administered at increasing quantities every 2 minutes or until MAP

<60mmHg. If atrial flutter induced it was mapped and ablated. If the patient returned to SR at

this point PV isolation and block confirmed. Then isoproterenol was administered again and

120

further targeted ablation of triggers carried out. If the patient was then in AF a multipolar

catheter was used to check PV isolation and CFAE performed. After 30 minutes if SR was still

not obtained DC cardioversion was performed (343). In the studies by Pison et al and La Meir

et al, if after the completion of PV isolation, the patient reverted to SR, coronary sinus pacing

was carried out in an attempt to induce AF. If AF could not be induced with pacing,

isoproterenol was infused and linear lesions applied if AF became inducible with this

(207,341). Only 5 studies reported rhythm status of their patients at the end of the procedure

(207,328,334,336,344).

5.3.4.4. Procedural Time

The procedural time for the catheter-based component was not uniformly reported with 13

studies not reporting any procedural time indices.(207,328,333-335,337,339-342,345-347)

Seven studies reported time of fluoroscopy use with mean of 18.3 minutes (Range: 7.3-

36.2)(329-332,338,343,344) and 5 studies providing length of procedure with mean 112.3

minutes (Range: 18-216).(208,329,332,336,344) The study by Gaita et al reported that no

fluoroscopy was used (333).

5.3.5. Post-Procedural Follow-up

Follow-up methodology consisted primarily of the use of implantable loop recorders for 5

studies,(208,328,335,345,346) Holter monitoring (1 or 7 day) in 16 studies(207,329-334,336-

341,343,344,347) and 12 lead ECG in 1 study.(342) However, the follow-up frequency was

variable as detailed in Table 5.4. The overall mean follow-up duration for all studies was 19

months (Range: 6-128.4) after initial surgical procedure with follow-up completed by 93.3%

of the total cohort. Definition of recurrent arrhythmia varied across studies with 13 defining

AF recurrence as any atrial tachyarrhthmia lasting >30 seconds,(207,329-332,334,337-

121

339,341,343,345,347) 3 studies as the total burden of AF on a monthly basis being greater than

0.5%(208,328,346) and not defined in 6 studies.(333,335,336,340,342,344)

5.3.6. Outcomes

Overall Sinus Rhythm Maintenance(SRM) at final follow-up from this meta-analysis was

79.4% (95% CI: 72.4-85.7) and 70.7%(95% CI: 62.2-78.7) without AAD (Figure 5.3 and 5.4).

Of note SRM off AAD was not reported in 2 studies.(328,334)

5.3.6.1. Univariate Predictors of Outcome

Univariate analysis was conducted across the variables of age, AF type, LA diameter, AF

duration and follow-up length with none shown to be statistically significant in predicting

SRM.

5.3.6.2. Sequential vs Staged

There was no significant difference in SRM with or without AAD in comparison of the studies

utilising a staged procedure, sequential procedure or a combination of both approaches (SR

with AAD: Staged 85.3% [95% CI: 77.1-92.1], Sequential 75.5% [95% CI: 61.6-87.2] and

Combined 74.6% [95% CI: 59.6-87.2]) (SR without AAD: Staged 75.9% [95% CI: 64.4-85.9],

Sequential 70.4% [95% CI: 51.9-86.2] and Combined 60.4% [95% CI: 51.1-69.3]).

5.3.6.3. Block Analysis

Analysis was performed comparing those studies that confirmed 100% block by the end of the

EP study to those that achieved <100% block with no statistically significant difference

identified. (SRM with AAD: Block 100%: 87.6% [95% CI: 78.4-94.7], Block<100%: 73.1%

[95% CI: 60.2-84.4]) (SRM without AAD: Block 100%: 81.5% [95% CI: 72.9-88.8],

Block<100%: 62% [95% CI: 39.4-82.3]) (Figure 5.5).

122


Comparison of surgical approach comparing laparoscopic trans-diaphragmatic approach, mini-

thoracotomy, sternotomy and VATS showed no significant difference in SR with or without

AAD.

5.3.6.5. Surgical Lesion Set

No significant difference was found between Box, PVI or Maze in terms of SR with or without

AAD (SR with AAD: Box: 77.9% [95% CI: 66.2-87.8], PVI: 79.3% [95% CI: 69.7-87.6],

Maze: 91.4% [95% CI: 79.4-98.9]) (SR without AAD: Box: 63.3% [95% CI: 50.4-75.2], PVI:

76% [95% CI: 63.6-86.6], Maze: 85.7% [95% CI: 71.9-95.7]).

5.3.6.6. Energy Type

No significant differences existed between Bipolar RF, Unipolar RF or Cryo in terms of SR

with or without AAD (SR with AAD: Bipolar RF: 84% [95% CI: 75-91.4], Unipolar RF: 72.9%

[95% CI: 58.9-85], Cryo: 77.9% [95% CI: 42.7-99.2] and Combo: 86.5% [95% CI: 73.6-95.8])

(SR without AAD: Bipolar RF: 78.1% [95% CI: 67.8-87], Unipolar RF: 56.8% [95% CI: 40.5-

72.5], Cryo: 68.6% [95% CI: 29.4-96.9] and Combo: 82.1% [95% CI: 57.3-97.9]).

5.3.6.7. Device Type

No significant difference was identified between devices in terms of SR with AAD; however,

the use of the Atricure Synergy system was superior to the nContact system in SRM without

AAD (Atricure: 82% [95% CI: 72.5-90] vs nContact: 68.6% [95% CI: 29.4-96.9],p=0.01)

(Figure 5.5).

123

Further, analysis of the catheters utilised for ablation found no statistically significant

difference in outcome between irrigated, non-irrigated and contact force sensing catheters in

terms of SRM on or off AAD.

5.3.6.8. Left Atrial Appendage

No significant difference in SR with AAD existed between the groups who excluded the LAA

as opposed to those who did not, but a superior result in SR without AAD was found with the

LAA exclusion group (79.5% [95% CI: 71.2-86.8] vs 55.8% [95% CI: 41.4-69.8], p<0.001)

(Figure 5.5).

5.3.6.9. Ganglionated Plexi Ablation

No significant difference in SR with or without AAD was identified between the studies that

ablated the ganglionated plexi and those that did not.

5.3.7. AAD management

Analysis of post-operative AAD usage found 6 studies initiated an AAD post-operatively,

without stating which specific drug, and left AAD direction to the discretion of the referring

physician,(208,333,334,336,340,341) 6 studies utilised amiodarone as their post-operative

AAD of choice with varying protocols,(335,339,343,344,346,347) 4 studies initiated the

patients pre-operative AAD as soon as possible,(207,330,331,338) 2 studies discharged

patients without any AAD post-operatively,(329,332) 1 study continued whichever AAD the

patient was on throughout the admission(337) and 3 studies did not state an AAD

protocol.(328,342,345)

124


Table 5.5 outlines the various procedural complications from the 22 included studies with

complication rates forest plots in Figure 5.6. Ten studies reported mean post-operative length

of stay providing a total mean of 5 days (Range: 3.4-7.6).(207,208,328-330,334,339,342-344)

Of note 5 studies reported a median length of stay(331,337,340,341,345) and 7 studies did not

report on hospital length of stay.(332,333,335,336,339,346,347) The mean total complication

rate across the studies was 6.5% (95% CI: 3.4-10.2) comprising of a mean mortality rate of

0.2% (95% CI: 0-0.9), mean stroke rate of 0.3% (95% CI: 0-1.1), mean return to OT for

bleeding (RTOT) of 1.6% (95% CI: 0.6-3.0), post op PPM rate of ~0% (95% CI: 0-0.5),

conversion to sternotomy rate of 0.3% (95% CI: 0-1.1), mean incidence of AO fistula of ~0%

(95% CI: 0-0.5) and phrenic nerve injury either temporary or permanent of 0.3% (95% CI: 0-

1.1). Mortality was considered in the first 30 days of either surgical or catheter procedure in

which time frame there were 8 deaths; 3 were secondary to AO fistula, 1 secondary to bleeding

and cardiac tamponade, 1 sudden cardiac death, 1 secondary to CVA and the remaining 2 not

determined. One of the cases of death recorded as secondary to AO fistula resulted in the death

at 33 days, but this was still recorded in the mortality rate of this analysis due to the time frame

remaining pertinent to the complication rate.(335) In total, there was 4 AO fistulae reported

across the series with 3 mortalities resultant and 1 being repaired surgically, though this patient

died 8 months later from a cerebrovascular event. Of note all AO fistula occurred in studies

that utilised mono-polar RF. There was not routine reporting of post-operative pain in any study

though the study by Kumar et al reported 1 patient representing with recurrent chest pain after

a few weeks(338) and the study by Pison et al reported 1 patient representing with pain from a

VATS working port.(207) The study by Gehi et al reported a significant improvement in the

Canadian Cardiovascular Society Severity of AF [CCS-SAF] as being significantly improved

125

to their final follow-up of 12 months,(334) but no other study reported on this or resumption

of normal activity.

5.3.9.1. Sub-Group Analysis of Complications

Comparison across the studies did not reveal any statistically significant predictors of

major complications.

5.4. DISCUSSION

Hybrid (joint surgical and catheter-based) ablation for AF is an emerging technique purporting

to improve rhythm control outcomes in patients with this debilitating arrhythmia. This

systematic review and meta-analysis on the standalone hybrid ablation approach in an overall

cohort of 925 (89% non-paroxysmal AF) subjects demonstrates the following new information:

1. Favourable overall mean sinus rhythm maintenance of 79% and 71% with and without

AAD at mean follow-up of 19 months;

2. Ensuring lesion completeness at the end of the endocardial procedure with electrical

testing for bi-directional block is indicative of better outcomes though this observation

did not reach statistical significance;

3. No difference in rhythm outcome on whether the catheter ablation was conducted

immediately following or staged for a later date;

4. The use of the Atricure Synergy bipolar RF ablation system was associated with

superior outcomes in terms of SRM off AAD when compared to the use of the nContact

unipolar RF ablation system;

5. The best results in terms of SR without AAD are achieved when the LAA is excluded;

6. Comparable risk profile to that described with the initial use of catheter ablation alone

with a complication rate of approximately 6.5%;

126

Whilst in its infancy, the approach to potentially improve the longer-term durability of ablation

results and reduce the need for multiple procedures, is of potential importance. A recent study

based on a US administrative data set has suggested that a 1% reduction in repeat procedures

is associated with a $30M/year saving to the health care system.(349) The current data

demonstrates the safety and efficacy of the approach when compared to catheter ablation alone

and suggests that the technique warrants further evaluation.

5.4.1. Outcomes and Complications of Hybrid Ablation

The mean overall sinus rhythm maintenance with AAD of 79% and without AAD of 71% at

mean 19-month follow-up with the standalone hybrid ablation approach in largely non-

paroxysmal AF patients (89% of overall cohort) appears to be favourable in comparison to

other established approaches although the heterogeneity of the included studies must also be

taken into consideration. Recent meta-analysis of the outcome of catheter ablation approach

has demonstrated sinus rhythm maintenance at 2-year follow-up to be 60% after single ablation

procedure and 80% following multiple procedures.(176) Further, single procedural catheter

ablation outcome for those with non-paroxysmal AF was only 42% at 2-year follow-up (176).

The success rates for standalone surgical Cox-Maze procedure for AF were reported to range

from 79 to 99% from earlier series although the follow-up methods were highly variable with

most studies relying on rhythm status or symptoms at last follow-up visit and not utilizing

extended monitoring.(312) However, contemporary reports of the standalone Cox-Maze

approach with stricter follow-up regimens have demonstrated sinus rhythm maintenance off

AAD of 76 to 82% at 1 to 2 year follow-up from patient cohorts with 50 to 70% having non-

paroxysmal form of AF.(188,189,322)

127

In comparison to 2 catheter ablation procedures the hybrid procedure offers the

advantage of a surgical epicardial ablation placing broad, continuous lesions to isolate the

pulmonary veins in a relatively quick time frame. This can be done, in addition to placing a

number of additional lines and LAA exclusion, in between 80 to 200 minutes. Therefore, a

hybrid ablation approach provides a surgically placed broad, epicardial lesion substrate at the

beginning of the EP procedure, which allows mapping to focus on block confirmation and

targeted endocardial ablation to ensure lesion contiguity and electrical isolation. Additionally,

this combined approach can see reduced procedure times, with the study by Muneretto et al

completing the surgical procedure with a mean time of 80±7minutes, mean EP procedural time

of 18±2 minutes and an additional 25±4 minutes if additional ablation was required beyond

confirming block.(208) Such times suggest faster procedures are possible with this approach

compared to a multiple catheter ablations. Therefore, the hybrid ablation approach appears to

be superior to single catheter ablation procedure and comparable to multiple catheter ablation

procedures and surgical Cox-Maze procedure.

The overall rate of complications with the standalone hybrid approach from this review

was 6.5%. That no specific major complication had a statistically significant association with

energy source, device, lesion set or procedure type is most likely reflective of the overall low

number of complications causing the comparisons to be underpowered. However, it is worth

noting that all incidence of AO fistula occurred with use of nContact unipolar RF device, which

suggests an area for further study. In consideration of comparison of the complication rates of

the hybrid procedure to other interventions for AF recent systematic review on complications

from catheter-based AF ablation procedures indicated a decline over recent years of major

complications to 2.6%.(280) Data from the worldwide surveys have also demonstrated a

decline in major complication rates from 6% between 1995-2012 to 4.5% between 2003-

2006.(350,351) In addition, a recently published retrospective cohort analysis from the

128

Californian Medicare beneficiaries undergoing catheter ablation for AF between 2007-2009

has shown a major procedural complication rate of 4.1%.(352) The major complication rate for

standalone surgical Cox-Maze procedure for AF has been reported at 7.1% although the rate is

much lower with the latest iteration of the Cox-Maze IV procedure at 2 to 4%.(189,322)

Therefore, the hybrid approach appears to be comparable to other established treatment

modalities with similar major complication rates. Interestingly, both the hybrid and Cox-Maze

approaches have been shown to result in a significant proportion of patients needing permanent

pacing post-procedurally at 1.5% and 7-9% respectively, a complication not usually seen with

catheter-based ablation procedures.(189,322) Further, patients undergoing the hybrid approach

seem to require a shorter hospital stay of 5 days as compared to the Cox-Maze procedure at 7-

8 days,(189,322) although this remains substantially longer than in the current catheter based

approaches. The hybrid ablation approach appears to provide the ‘best of both worlds’ with

less invasiveness than the Cox-Maze procedures and seemingly comparable outcomes to

catheter-based approach that often requires multiple procedures.

5.4.2. Lessons from Early Experiences

The move to a hybrid procedure from a surgical standpoint represents the potential for a less

invasive surgical procedure, than that of the tradition Cox-Maze procedure, while potentially

offering equivalent results. The traditional Cox-Maze procedure is typically done through a

median sternotomy and requires cardiopulmonary bypass to complete, thus increasing the

invasiveness of the procedure through incision coupled with the sequelae of a cardiopulmonary

bypass run. While advances in surgical techniques have been progressing the evolution of the

Cox-Maze procedure to be completed via mini-thoracotomy or equivalent lesions through

VATS approach,(198,206) the hybrid procedure adds an additional dimension through

assessment of the endocardium.

129

This review identified three important technical considerations with this novel

standalone hybrid ablation technique. First, ensuring bi-directional conduction block as the

procedural endpoint following endocardial ablation is indicative of a superior rate of sinus

rhythm maintenance off AAD of 81.5% when 100% block was achieved as to 66.5% in those

with less than 100% confirmation of conduction block at 19-month follow-up. While this

observation did not reach statistical significance, it suggests a strong trend towards significance

which may be realised in the observations of future prospective studies. This observation is not

surprising, as experience from catheter-based ablation procedures has shown that recovery of

pulmonary vein conduction was associated with early recurrence of atrial arrhythmia

(353,354). The hybrid approach allows for the seeming advantage of direct visualization of the

lesion sets to achieve more durable ablation. Given our findings above, efforts should be made

to ensure the endpoint of complete isolation is obtained, to justify the greater invasiveness of

the hybrid procedure. Second, this review has not been able to identify a statistically significant

difference in outcome when the hybrid procedure is performed sequentially in the same setting

as opposed to the staged approach with follow on catheter based ablation after an interval of

weeks to months. There are potential advantages offered in each procedure type. Sequential

procedures offer the potential for immediate identification of lesion gaps which can be treated

at that time and thereby provide the ability for substrate remodelling to take place without

delay. Staged procedures offer the potential for complete lesion formation and regression of

oedema to aid identification of lesion gaps once any oedema has regressed, and further, such

procedures do not necessitate a hybrid theatre to be available. Further work is needed to

delineate the differences in the two approaches. Third, the use of the Atricure bipolar RF system

offered superior results in SRM off AAD at final follow-up, being statistically significant when

compared to the nContact unipolar RF system. Further of note to this point is that in this series

all atrio-esophageal fistulae occurred with the use of the nContact unipolar RF devices

130

suggesting that the use of bipolar RF devices may be protective against this serious

complication.


The standalone hybrid ablation approach for AF appears promising with this systemic review

and meta-analysis demonstrating favourable outcomes without significant additional

procedural related complications. This novel technique may fill the gap in our current

armamentarium of ablating patients with more persistent form of AF given that the optimal

catheter ablation approach for this subgroup of patients remains unclear (355). The

invasiveness and complexity of the Cox-Maze III procedure might have limited its uptake

despite excellent sinus rhythm maintenance results (186). In contrast, the hybrid ablation

procedure is less invasive, does not require cardiopulmonary bypass and allows for shorter

hospitalization. As with all novel techniques, there remains room for improvement with further

reduction in complication rates following greater experience, improvement in ablation devices

and ablation techniques. This hybrid ablation approach can be potentially extended to AF

patients undergoing concomitant valvular or coronary artery bypass graft surgery in place of a

traditional Cox-Maze procedure, to reduce cardiopulmonary bypass time and associated

complications. Recently, novel risk factors for AF have been identified and aggressive

targeting of risk factors for AF has been shown to reduce AF burden and recurrence following

catheter ablation (15,101,356,357). Incorporation of these strategies should not be neglected in

patients undergoing invasive ablation procedures.


We are unable to detail the specific hybrid ablation outcomes according to types of AF

(paroxysmal vs. non-paroxysmal) given the lack of available patient level data. We recognize

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the limitations of the individual included studies may affect the robustness of this review and

meta-analysis. First, the average number of subjects in most studies is low. Second, all the

available studies on hybrid ablation were non-randomized, single-centre cohort series. Third,

there is significant heterogeneity of the hybrid ablation approach with variable epicardial and

endocardial lesion sets, different ablation devices used and surgical access employed. Fourth,

as with any meta-analysis there may be confounding variables, measured and unmeasured,

which may impact the results of this analysis. Fifth, there is also variability in the quality of

studies with variations in recording of baseline variables, consistency of both epicardial and

endocardial ablation method and follow-up. These variations serve to not only highlight the

features of the highest quality studies, but also the need for standardisation of reporting within

this field to determine the true efficacy of this evolving technique. Last, there is a lack of

reporting standard in the included studies with variable follow-up methodology and time

points. Nevertheless, these limitations serve to highlight areas of focus for future studies.

5.5. CONCLUSIONS

The standalone hybrid ablation procedure for AF shows favourable outcome without increased

complication rates as compared to more established catheter-based or surgical approach. Early

results suggest a potential role for this novel strategy in selected AF patients given the

suboptimal results of catheter-based approach in those with more persistent form of the

arrhythmia. Further studies are needed to determine the optimal hybrid ablation technique and

longer-term outcome results.

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Figure 5.1

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Figure 5.2 – Surgical Lesions and Devices

(Left) Figure depicting the commonly placed surgical lines of Pulmonary Vein Isolation

(Blue), Box lesion (Green), Roof Line (Purple), Mitral Line (Yellow), Right inferior

pulmonary vein to Right Atrium Line (Orange), Left Atrial Appendage Exclusion (Red).

(Right) The Radio-Frequency Devices utilised in the studies: A) Medtronic Gemini, B)

Atricure Synergy, C) nContant system, D) Estech Cobra

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Sinus rhythm maintenance achieved across studies in terms of mean and 95% Confidence

Interval

135


Sinus rhythm maintenance without Anti-Arrhythmic Drugs (AAD) achieved across studies in

terms of mean and 95% Confidence Interval.

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Figure 5.5 – Sinus Rhythm Subgroup Analysis

Procedural success in obtaining sinus rhythm maintenance at final follow-up related to device

utilised, LAA exclusion and block confirmation at the end of the EP procedure.

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Figure 5.6 – Complication Rates Forest Plots

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Chapter 6

The Contact Force Effect of Bipolar Radio-Frequency Clamps on Lesion Formation in

the Surgical Management of Atrial Fibrillation

6.1. INTRODUCTION

The surgical treatment of atrial fibrillation (AF) has grown in popularity since the development

of the Cox-Maze procedure in 1987 where lines were cut and sewn in the atria to create scars

that inhibit electrical conduction.(36) As technology advanced the technique was modified to

utilise modern energy sources such as cryothermy and radiofrequency (RF) to create lesions of

conduction block, by developing myocardial cell damage which evolves into non-conducting

myocardial scar, with greater efficiency and ease.(187,192) The mainstay tool of the

contemporary Cox-Maze IV procedure is the bipolar RF clamp which delivers RF energy

through opposing jaws of a clamp.(153) This technique has been shown to be effective for the

treatment of AF; however, the cut-and-sew technique has been shown to be superior to RF

ablation, despite advances in ablation technology.(358)

Recent studies of RF catheter technology have shown that RF lesion size is related to

contact force.(148,359-361) Further studies have also demonstrated that higher contact force

is associated with superior rhythm control at follow-up.(362,363) Additionally, studies

analysing the lesions formed during surgical ablation procedures for AF have found the

presence of gaps in ablation lines made with RF.(364,365) This in turn has led to the

development of hybrid procedures for the treatment of AF to optimise results by following

surgical ablation by an electrophysiology study to assess contiguity of ablation lines and

complete them as necessary delivering excellent results.(207,341)

In consideration of these findings, we hypothesized that the jaws of the bipolar RF

clamps used in AF surgery may yield varying force profiles over different thickness of tissue,

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which may in turn effect subsequent RF lesions. An analysis of two commonly used bipolar

RF clamps with different systems of jaw apposition (hinged and parallel) was undertaken to

determine contact and force profiles of these clamps, and the impact on the likelihood of

achieving transmurality during ablation.

6.2. METHODS

6.2.1. Pressure Assessment

6.2.1.1. Surgical Equipment

There are presently 2 types of bipolar RF clamps with jaws that possess different articulation

designs and therefore close in 2 different manners. The “hinged” have jaws that approximate

from a hinge at the proximal portion of the jaw, and the “parallel” have jaws that approximate

along a straight axis. Two different styles of bipolar RF clamps were identified with these

different jaw apposition mechanisms (Hinged: Cardioblate LP, Medtronic, Minneapolis, MN,

USA and Parallel: Synergy, Atricure, West Chester, OH, USA; Figure 6.1). The hinged clamp

is 70mm in length and at the fulcrum of the jaw is 67.5mm wide which tapers to 3.5mm wide

after 1cm and remains that width to the tip. The parallel jaw is 60mm in length and 4.0mm

wide along the length. Both clamps possess locking mechanisms to keep the jaws closed once

applied and both clamps were fully closed as per their design when utilised.

It is important to note that the hinged clamp is an irrigated clamp whereas the parallel

clamp is non-irrigated. As both clamps were subjected to the same battery of tests it is unlikely

that this feature in isolation should have a significant interaction that would affect the validity

of comparing them in for contact force. Irrigation technology in RF lesions may be protective

against the build-up of char or debris on the probe itself but it does not seem to overcome the

effect of decreased contact.

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Bovine skeletal muscle was used as biological tissue model. Initial testing was performed on

atrial tissue extracts but due to the uneven surface of such tissue and the focus of analysis being

pressure assessment skeletal muscle was selected as an analogue that was able to have

properties of thickness controlled along the entire length of tissue sample. Thickness was

controlled in muscle preparations to have three samples for testing at each thickness from 1mm

to 8mm.

6.2.1.3. Clamp Pressure Assessment Methodology

Ablation clamps were loaded with the muscle sample and a pressure sensitive film sample, and

the clamp jaws were then closed in a standard fashion until the locking mechanism engaged.

Each sample was clamped for 40 seconds, then released and the pressure film removed for

analysis. This procedure was repeated three times for each millimetre tissue thickness between

1mm and 8mm. New tissue samples and pressure films are used for each test.

6.2.1.4. Contact Force

Catheter ablation technology utilising RF creates lesions to eliminate the triggers of AF and

block the propagation of AF wave fronts.(145) To optimise the creation of such lesions catheter

technology evolved to incorporate cooled-tip catheters, irrigated catheters, adjustable power

delivery and contact force sensing catheters.

It has been described that the contact force during catheter ablation for AF correlates

with clinical outcomes and when lesions are placed with an average contact force of >20g

superior rhythm control results are obtained.(362) Catheter contact force is traditionally

expressed in grams, but as this figure is simply a weight, a conversion was required to calculate

actual contact force in g/mm2 (Calculation: 7Fr Catheter diameter is 2.333mm. Assuming a half

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spherical shape the surface area is 2πr2. This gram pressure is then divided by this area

calculation). Figure 6.2 displays the contact force of a 7Fr Catheter in g/mm2 of 10g, 20g, 30g,

40g, 50g, 60g and 70g as well as the mean contact force of the hinged and parallel clamps at

each 1cm increment from tissue thickness 1mm-8mm. A colour chart has been applied to these

tables such that weights of ≤10g are displayed in white to denote areas with contact force which

would be associated with rhythm control failure in catheter studies, 20g to 70g in shades of

blue to denote areas of expected superior rhythm control and >70g in red to denote pressure

that would be considered exceptionally high in catheter studies.

6.2.1.5. Pressure film and analysis

A pressure sensitive film (4LW Prescale, Fujifilm) was used to assess the pressure profile of

the clamps on the biological tissue model samples. The film develops an image with colour

intensity correlating to pressure. These film images were then digitally scanned and the length

of the image was divided into 10mm strips for pressure calculation of each portion of the jaw.

The method of pressure film use and analysis is displayed in Figure 6.3.

6.2.2. Ablation Lesion Analysis

6.2.2.1. Experimental Preparation

A total of 6 Merino Cross Wethers were studied. All procedures were conducted in accordance

with the guidelines outlined in the “Position of the American Heart Association on Research

Animal Use” adopted on November 11, 1984, by the American Heart Association. Approval

for the performance of the study was provided by the Animal Ethics Committees of the South

Australian Health and Medical Research Institute and the University of Adelaide, Adelaide,

Australia

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Assessment was initially performed on ventricular muscle to determine its suitability for use

with determining a pressure effect with ablation; however, it was found that it was not uniform

over the length of a given clamp due to papillary muscles and trabeculae carneae, and only 1

sample per muscle thickness could be obtained in each sheep. As the experimental question to

be answered was regarding a pressure effect a uniform muscle was required for analysis. Cuts

of skeletal muscle were thus selected over cardiac muscle as they could be controlled for

thickness, are uniform over the length (no trabeculations) and, are therefore, ideal for pressure

testing experiments which require an even surface to minimise confounding effects. As cell

types of skeletal and cardiac muscle are both striated in nature the effect RF has on each should

be the same, and further, each clamp was submitted to the same test design and therefore

remains valid in this experimental model. Ovine pectoral muscle was thus selected for

experimentation as it provides a broad, flat sheet of muscle with area for multiple, similar

thickness tissue samples to be utilised.

6.2.2.3. Ablation and Evaluation of Transmurality

Intact ovine pectoral muscle flap was used as in-vivo tissue model for ablation assessment.

Right and left pectoral muscle flaps were exposed surgically on 6 anaesthetised animals. Each

flap was created to allow for 6 parallel ablation lesion with a margin of ~20mm between lesion.

Thus, each animal provided 12 lesions and 1 clamp style was used per animal, providing a total

of 36 ablation lesions per clamp for study. The ablation clamp was positioned with the proximal

edge of the clamp against the muscle flap edge prior to engaging the locking mechanism

(Figure 6.4). RF energy was applied according to manufacturer guidelines. A single burn was

defined as delivery of RF energy to the tissue until the energy source generator indicated that

a lesion was created (displayed as ‘transmural’ indicator light/label on generator display as

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determined by the manufacturer). In the case of the hinged clamp, irrigation was tested prior to

the delivery of all burns energy in accordance with manufacturer guidelines. Following each

lesion, the ablation clamp jaws were wiped clean of char and blood prior to further ablation.

To determine the effect of multiple applications of RF energy on lesion formation, either one,

two or three applications of RF was applied to a single area of muscle tissue. This was repeated

such that for each muscle flap, there were two samples of one burn, two samples of two burns

and two samples of three burns of RF energy. Each clamp was measured and marked with 1cm

lines along the clamp such that when the jaw was closed the tissue itself was able to be marked

at each 1cm segment correlating correctly to the conditions of the clamp when the lesion was

created. Following lesion creation, whole muscle flaps were excised and sectioned in 10mm

increments (along the aforementioned marks) for histological analysis.

Tissue samples were soaked in 1% Triphenyl-Tetrazolium Chloride (TTC) for 30

minutes and were then placed into Formaldehyde for tissue fixation. Lesion assessment was

then carried out digitally. TTC is a vital stain such that it stains viable tissue red and non-viable

tissue is left white, allowing for visual assessment. A camera was used to acquire images of the

tissue samples at a resolution of 3264x1840 pixels. All measurements on digital images were

calibrated for size by including a ruler in the image and all measurements scaled accordingly.

Digital images were analysed using commercially available tools in Photoshop CC2014

(Adobe Systems, San Jose, CA, USA). For each 10mm section-image, analysis was performed

to quantify; tissue thickness, presence of overlying fat, thickness of fat, lesion depth and

transmurality. All images were verified by 2 investigators.


All continuous variables reported as mean ± SD. Statistical analyses were performed using

SAS v9.3 (Cary, NC, US) and Stata v13 (College Station, TX: StataCorp). Differences

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between clamp styles were investigated using linear regression (for continuous outcomes) or

logistic regression (for binary or categorical outcomes). An interaction term (clamp style by

distance) was included to test for modification of the effect of clamp style (hinged vs parallel)

by distance (proximal vs distal), or vice versa; separate estimates were derived for (a) the

difference between proximal and distal for each clamp style, and (b) the difference between

hinged and parallel clamp for each distance. Generalised Estimating Equations (or random

effects where required) were used to account for clustering due to sheep and side (left/right).

In the case of burn thickness, the linear regression model also included an offset term for total

lesion thickness, while percentage burn thickness was investigated via several methods

(standard linear regression, Tobit regression, and ordinal logistic regression with outcome

grouped into 6 categories) due to a high proportion of values at the upper bound of 100%. In

the case of pressure, log transformation was applied due to a skewed distribution, with

estimates back-transformed to the original scale. Additional models were also fitted to

investigate the effect of thickness (and potential interaction with distance) for each clamp style.

Transmurality, as a binary outcome, was investigated using logistic regression; additional

models were fitted to investigate the effect of epicardial fat (considered as both a continuous

and a binary outcome) on transmurality for each clamp type. Statistical significance was taken

as P<0.05.

6.3. RESULTS

6.3.1. Pressure Analysis

Three muscle samples were tested for each 1mm thickness yielding 24 pressure profile

samples per clamp for pressure assessment.

The hinged clamp is 70mm in length and the parallel clamp is 60mm in length (Figure

6.1). The cross-sectional area of each segment of the hinged clamp is 35mm2 with the most

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proximal segment (0-10mm) having a slightly larger area of 67.5mm2. The cross-sectional area

of each segment of the parallel clamp is 40mm2.

The mean pressure exerted (g/mm2) of every 10mm segment of each clamp style (from

proximal to distal) at increasing tissue thickness (from 1-8mm) is plotted for analysis in Figure

6.5. The range of mean pressures exerted on the tissue by the hinged clamp was 0.12 to

25.05g/mm2 and by the parallel clamp was 1.96 to 10.89g/mm2.

Analysis was then conducted to compare the proximal and distal portions of each jaw

(The initial 2cm of each jaw compared to the distal 2cm of each jaw). Due to the skewed

distribution of data the statistical analysis was conducted on median value. Figure 6.6 depicts

the pressure comparisons of each clamp comparing the proximal 2cm and distal 2cm. The

parallel clamp demonstrates no statistical difference in pressure exerted between the proximal

and distal clamp segments for all tissue thickness tested except 4mm. The hinged clamp

demonstrates a statistically significant pressure drop off between proximal and distal clamp

segments for all tissue thicknesses tested. If all tissue thicknesses between 1mm and 8mm are

analysed together the hinged clamp demonstrates a statistically significant pressure drop off

(p<0.0001) and the parallel clamp does not demonstrate and statistically significant pressure

change (p=0.6).

6.3.2. Lesion Analysis

Data was extracted and analysed from every 1cm segment of muscle tissue along the burn. An

example of tissue segments for 1 burn, 2 burns and 3 burns for each clamp style is presented in

Figure 6.7. The mean thickness of muscle was 13.5mm.

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6.3.2.2. Total RF Time and Impedance

The time in seconds of RF energy delivered for each burn was recorded for both clamp styles.

In lesions created using 2 and 3 RF energy delivery cycles, the individual RF times were

recorded and summed to provide total RF time for analysis. Statistical analysis was then

conducted to see if a correlation existed between total burn time of each lesion and

transmurality. With the parallel clamp for every 1 second increase in burn time the odds of

creating a transmural lesion increased by 7% (p<0.001); however, no statistically significant

association between burn time and transmurality existed for the hinged clamp (p=0.6).

Impedance results differed between the 2 clamp styles. The hinged clamp console

possessed a digital display which provided a specific figure of impedance and as such the value

at the commencement of RF delivery as well as the value and the completion of RF delivery

could be recorded. At the completion of each burn the device would display transmural. The

parallel clamp did not provide a digital figure read out, but only a graph which tracked

impedance until it plateaued below a set level, at which point the device would indicate

transmurality. As such only the peak level interpreted from the graph was recorded. Due to the

different nature of impedance recordings direct comparison between clamp styles is not

possible, but analysis of the association of impedance figures with transmurality of each clamp

was conducted.

For the parallel clamp, the peak or maximum impedance was associated with

transmurality, such that for every unit of conductance increase the odds of transmurality

increased by 9.5% (p=0.0002). However, this association was not statistically significant for

peak conductance reached on the 2nd or 3rd RF deliveries.

For the hinged clamp no statistically significant association between the transmurality

and the initial impedance, the final impedance or the magnitude of change between the initial

and final impedance existed, except with the start impedance of the 2nd RF delivery, which

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found that for every unit increase in start impedance the odds of transmurality decreased by

2% (p=0.018).

6.3.2.3. Lesion Depth

Lesion depth was measured at 10mm increments along the length of the burn for each clamp

style at 1, 2 and 3 burns. The lesion depth was then divided by the measured tissue thickness

at the specific burn increment (to standardise burn depth for each data point) and is then

expressed as a percentage. Figure 6.8 demonstrates the mean lesion depth percentage for both

hinged and parallel clamps with application of 1, 2 and 3 burns. The mean burn depth for 1

burn of energy delivery for the parallel clamp was 62.9% (95% CI: 49.0-76.9%) and in the

hinged clamp was 40.6% (95% CI: 27.9-53.4%; p=0.02). The mean burn depth for 2 burns of

energy delivery for the parallel clamp was 77.2% (95% CI: 62.6-91.8%) and in the hinged

clamp was 52.3% (95% CI: 39.2- 65.5%; p=0.01). The mean burn depth for 3 burns of energy

delivery for the parallel clamp was 99.6% (95% CI: 84.3-114.9%) and in the hinged clamp was

74.0% (95% CI: 60.1-87.9%; p=0.02).

Analysis was then undertaken to compare burn depth at the proximal and distal

segments of each clamp (Figure 6.9). Burn depth was analysed using a linear regression model

with an offset for total lesion thickness; an interaction term between clamp style and segment

was included to derive separate estimates of (a) difference between clamp style for each

segment, and (b) difference between segments for each clamp style. For the hinged clamp the

proximal 2cm segment estimated mean burn depth was 10.2mm (95% CI: 9.1–11.4mm) and

the distal 2cm estimated mean burn depth was 8.0mm (95% CI: 7.1–9.0mm). For the parallel

clamp the proximal 2cm segment had an estimated mean burn depth of 11.7mm (95% CI: 10.2-

13.2mm) and in the distal 2cm 10.2mm (95% CI: 9.1–11.2mm).

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Tests of the differences between these estimated burn depths showed that the difference

between proximal and distal segments in the hinged clamp was statistically significant

(p=0.002), whereas the difference between proximal and distal segments in the parallel clamp

was not statistically significant (p=0.07). Secondly, the proximal segment comparison across

clamp style revealed no statistically significant difference (p=0.1) whereas comparison of the

distal segments of each clamp identified a statistically significant difference in burn depth

(p=0.003).

6.3.3. Fat Presence and Effect

Analysis was performed to assess odds of transmurality in relation to the presence and

thickness of overlying fat between the clamp and the muscle (Figure 6.10). It was found that

for every 1mm increase in fat tissue thickness the odds of being transmural decreased with both

clamps; parallel clamp by 13% (p=0.002), hinged clamp by 15% (p=0.001) and overall by 11%

(p=0.006). Further, in analysis of larger amounts of fat in between the clamp and the tissue it

was identified that in the presence of 15mm of fat the odds of transmurality with a parallel

clamp decreases from 0.85 to 0.41 representing a 51.6% decrease and with a hinged clamp

decreases from 0.59 to 0.1 representing a 82.5% decrease.

6.3.4. Transmurality

The overall odds ratio of 1, 2 or 3 burns being transmural with either clamp is depicted on a

forest plot for analysis (Figure 6.11). This graph demonstrates that the odds of transmurality

are greater with a parallel clamp for 1, 2 or 3 burns (p=0.03, p=0.003, p=0.002, respectively).

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DISCUSSION

6.3.5. Major Findings

This study provides new information characterizing the ablation profile of bipolar RF surgical

ablation clamps. It demonstrates that:

1) The hinged clamp loses tissue contact force at the tips of the jaw (away from the hinge

of jaw closure);

2) Increasing the number of burns delivered, by either bipolar clamp device, increases the

likelihood of true transmurality - regardless of indications provided by the devices;

3) When ablating tissue with overlying fat the likelihood of transmurality is significantly

reduced; and

4) Reduced contact force reduces lesion depth and likelihood of transmurality.

These findings have significant implications to achieving transmural and contiguous lesions,

both important elements for the success of ablation.

6.3.6. Importance of Contact Force

It has been demonstrated that increased contact force results in increased lesion depth as

exemplified in the comparison of proximal and distal segments of lesion depth of each clamp.

The parallel clamp did not demonstrate a statistically significant difference between the

proximal and distal segments in terms of lesion depth, but it trended towards a decrease lesion

depth. Further inspection of the clamp revealed that is constructed from a more inherent flexible

material which likely renders a small decrease in contact force at the distal tip, which may

explain the down trend noticed. This suggests that, regardless of which clamp is utilised for AF

surgery, when ablating across thicker structures such as the pulmonary veins, ablating from 2

directions should negate this effect (ie. position the clamp around the pulmonary veins from

both the superior and inferior directions for separate burn delivery).

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As can be readily seen with the hinged jaw type, regardless of tissue thickness, there is

significantly lower pressure distally in the clamp when compared to a parallel jaw type which

delivers a more uniform pressure across all tissue thicknesses. It has previously been reported

that the posterior left atrial wall thickness is 4.1±0.7mm with a range of 2.5mm to 5.3mm.(366)

If we consider this when planning epicardial pulmonary vein isolation the thickness of tissue

that would be ablated could range from 5mm to 10.6mm in thickness (with epicardial fat in

addition to the measurement) and therefore, maintaining contact force with such ablations is of

paramount importance to deliver a truly transmural lesion.

The use of a parallel clamp as associated with increased lesion depth and increased

likelihood of delivering a transmural lesion with 1, 2 or 3 burns.

6.3.7. Number of Burns

For either clamp style an increasing number of burns is associated with a higher likelihood of

transmurality. Determining the number of burns required clinically to develop a transmural

lesion is of the utmost importance in successful surgery for the ablation of AF. While up to 3

burns did not deliver transmurality all the time, the parallel clamp was very close to achieving

this. This study only went up to 3 burns over a given area so anything beyond this number of

burns would only be extrapolation, but with the parallel clamp it would seem likely that with 4

or more burns over a single area transmurality along the length of the lesion should be obtained.

6.3.8. The Interaction of Fat

The presence of fat intervening between the clamp and muscle tissue is a common occurrence

in the clinical setting and, as such, it is important to understand the effect on the RF lesion

created when this takes place. This analysis has revealed significant effect on lesion

transmurality from even 1mm of intervening fat in a bipolar clamp and this effect is important

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to consider. Firstly, when utilising a bipolar clamp to generate RF lesions selecting an area with

minimal fat or clearing the intervening epicardial fat becomes of great importance to guarantee

a transmural lesion. Second, when utilising non-clamp style device (such a bipolar rail device

or unipolar device) to generate an RF lesion the area of selection and the ability to clear any

overlying fat becomes of paramount importance as not only is the contact force difficult to

maintain uniformly with the tissue, but the entire delivery of RF energy must pass through the

attenuating effect of the intervening fat to then create a transmural lesion. Finally, it is still

unclear if simply increasing the number of burns delivered over an area of fat overcomes the

decreased odds of transmurality or if fat clearance is indeed required.

6.3.9. Impedance as a Measure of Ablation Endpoint

Increasing amounts of RF burn time are associated with increased likelihood of transmurality

with the parallel clamp, however, not for the hinged clamp. The loss of this association with

the hinged clamp may be more reflective of the physical design suffering from loss of distal

pressure. As with decreased contact the RF energy is unable to bridge the physical gap between

the jaw and the tissue resulting in decreased lesion depth and this is a barrier which is simply

not able to be overcome by burning longer.

Analysis of impedance is complex as the algorithm utilised by either device in

calculating transmurality has not been provided. It would be expected that as the RF energy

excites the molecules within the cell and the resultant energetic movement of molecules would

generate heat and thereby causing thermal damage and lysis of the cell. As such, with increased

cellular death the intracellular ions would be released and allow current to flow more freely

across the lesion area. Thus, with as a lesion approaches transmurality the impedance should

drop.

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Interestingly, for the most part impedance did not have a statistically significant

association with transmurality outside of 2 instances. First, increased peak impedance with the

first RF delivery of a lesion with the parallel clamp was associated with increased likelihood

of transmurality. Second, increased initial impedance with the second RF delivery of a lesion

with the hinged clamp was associated with a decreased likelihood of transmurality.

Importantly, there is no obvious association of impedance changes with transmurality. While

we do not know the algorithm used for transmurality determination with either device, it should

also be noted that with up to 3 burns with the device displaying ‘transmural’ the histological

staining of these burns lesions demonstrates that this label is not accurate. This supports the

hypothesis that impedance may not be completely accurate in transmurality determination. The

impedance measures in the hinged clamp are likely hindered by the design as when thick tissue

is clamped there is loss of tissue contact distally in between the jaws. As such, the RF electrode

would be interfacing with air instead of tissue and this would invariably have a higher

impedance which would negatively impact any algorithm in determining transmurality. In

addition, in the clinical setting only relying on impedance changes when delivering RF energy

may not be the best guide to determine lesion transmurality. Therefore, this is an area which

would benefit from further analysis in futures studies.


The ability to generate consistently transmural lesions is a key feature of the appropriate tool

for the surgical ablation of AF. This study aids the clinician in providing information of how

surgical tools function to create lesions and should be utilised in the selection and use of bipolar

RF clamps.

Obesity is frequently linked to the development of AF and is associated with increased

pericardial fat. As the presence of fat reduces the efficacy of bipolar clamps to deliver a

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transmural lesion it is highly important that epicardial fat located at the site of a burn is cleared

prior to delivering energy to increase the likelihood of transmurality.

The use of impedance alone may not be the best measure of transmurality. Utilisation

of conduction testing at the time of procedure may be a useful adjunct for transmurality

assessment.

6.4. CONCLUSION

Parallel and hinged design bipolar RF clamps have different pressure profiles and resultant RF

lesions. The use of a parallel clamp as associated with increased lesion depth and increased

likelihood of delivering a transmural lesion with 1, 2 or 3 burns. The presence of fat

significantly decreases the likelihood of obtaining transmurality in bipolar RF clamps. Ablation

lesions along thick tissues, such as may be experienced with epicardial pulmonary vein

isolation, may not be transmural along the entire length of the burn despite the device indicating

that the lesion is transmural. These findings have implications for all surgical ablation

procedures carried out with bipolar RF clamps and should be considered when selecting

ablation device, number of burns, location and clearance of epicardial fat.

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6.5. FIGURES

Figure 6.1 – Bipolar Ablation Clamps and Corresponding Footprints

The Parallel (Left) and Hinged (Right) closure style bipolar RF clamps are shown with their

corresponding foot prints below. The hinged clamp has a proximal increased width for the

first 10mm.

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Figure 6.2 – Pressure Tables

Pressure tables of Hinged Jaw, Parallel Jaw and 7 Fr Catheter for comparison. Pressure of

10g or less is represented in white shading, 20g to 70g in deepening shades of blue and

greater than 70g is represented in red.

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Figure 6.3 – Methods - Pressure Analysis

Methodology sequence of Pressure Analysis: A) Muscle is clamped between clamp jaws with

pressure sensitive film, B) Pressure Film is scanned as a raw image, C) Film image converted

to greyscale for intensity standardisation, D) Image is divided into 1cm segments for

segmented analysis and E) The image is then digitally sampled against the pressure film

reference table for analysis.

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Figure 6.4 – Methods - Experimental Ablation Diagram

The clamp is engaged over the pectoral muscle and ablation delivered. The superior burn line

of the diagram represents where a single burn was delivered with incision marks placed at the

superior edge to denote the segments. The clamp is shown over the next segment down where

2 burns will be applied to the same area. The next burn in the pattern will be 3, and this series

will repeat itself once more.

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Figure 6.5 – Clamp Pressure Profiles

Clamp Pressure Profiling with A representing the Hinged Clamp pressure profile and B

representing the Parallel Clamp pressure profile. The x-axis of each graph displays the

distance from proximal to distal along the clamp, the y-axis displays the thickness of muscle

on which the clamp was applied and the z-axis represents the pressure exerted.

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Figure 6.6 – Proximal and Distal Clamp Segment Pressure Comparisons

A comparison of exerted pressures of the Proximal (First 2cm) and Distal (Last 2cm) portions

of each clamp at increasing tissue thickness (1mm to 8mm). Error bars indicate 95%

confidence interval [The Upper Confidence Intervals of 7mm and 8mm for the Hinged Clamp

are 39.58mm and 48.38mm respectively] (* indicates a non-significant p-value)

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Figure 6.7 – Burn Lesion Samples and

Examples of lesion specimens from 1 burn, 2 burns and 3 burns for each clamp style are

shown. The lesions have been sectioned at 1cm increments and stained with Triphenyl-

Tretrazolium Chloride (TTC) which stains viable tissue red and is not taken up by dead cells.

166

Figure 6.8 Mean Burn Lesion Depth

Mean burn depth standardised to tissue thickness for 1 burn, 2 burns and 3 burns of energy

delivery across all samples. Comparator p-values are presented for the difference between

parallel and hinged clamps.

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Figure 6.9 – Burn Lesion Analysis

Burn depth analysis of the proximal and distal segments of each clamp in comparison. Linear

regression model estimates of burn depth (mm) are plotted. The p-values in black denote the

represented burn segments with comparison across clamp type. The coloured p-values are

matched with clamp style showing comparison between segments of the clamp. Error bars

represent a 95% confidence interval.

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Figure 6.10 – Odds of Transmurality in Relation to Depth of Fat

Each data point represents a single burn segment for each clamp style expressed in terms of

odds of obtaining transmurality and the depth of fat at that point of the burn. Odds based off

of measurement of overlying fat for every segment of ablated tissue.

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Figure 6.11 – Odds of Transmurality Forest Plot

Forest plot depicting the odds of transmurality. Increased likelihood of obtaining

transmurality with a hinged clamp is represented on the left side of the graph and increased

likelihood with a parallel clamp on the right. The estimate point for 1 burn, 2 burns and 3

burns lies to the right with highly significant p-values and the 95% CI completely to the right

of the graph.

170

Chapter 7

Conclusion and Discussion

This thesis presents current perspectives on the nature of the surgical management of AF. In

the introductory chapter an overview of the impact that AF is currently having on the general

population and the burden this has placed on patients and health care systems is presented.

Mechanisms for how this arrhythmia develops are then addressed followed by the paradigm

for medical management presently available. The development of the therapy of catheter

ablation is then addressed incorporating the rational, technique and results that are currently

being achieved. Finally, the history of the surgical ablation of AF is analysed, culminating in

the present state of this surgical procedure with an analysis of the current technologies available

for carrying out this technique. While surgical treatment of AF has evolved, this has largely

been in small series and with variable experiences.

In this context, Chapters 2 through 5 then perform an in-depth analysis of the current

literature on the surgical ablation of AF through meta-analyses covering four distinct

populations of surgical ablation procedures; 1) those performed concomitant to mitral valve

repair or replacement, 2) those performed concurrent to mixed cardiac surgical procedures, 3)

those performed as a standalone procedure or 4) those performed as part of a joint procedure

with a cardiac electrophysiologist in the hybrid ablation for AF. These chapters summarise the

efficacy of the surgical ablation of AF as follows:

• When carried out concurrent to mitral valve repair or replacement the surgical ablation

of AF achieves SRM of 79.6% at mean follow-up of 27 months. The rhythm follow-up

was carried out primarily with ECG with only half of the studies utilising Holter

monitoring. The best results are obtained with a Bi-Atrial Maze procedure in this

cohort, with a low total complication rate of 6.9% driven by a post-op PPM requirement

of 1.2%. The mortality rate was low at 0.9% and the stroke rate of 0.3%.

171

• When carried out concomitant to general cardiac surgical procedures, such as coronary

artery bypass grafting or any valvular intervention, the surgical ablation of AF achieves

SRM of 79.6% and SRM off AAD of 65.3% at mean follow-up of 22 months. The

rhythm follow-up consisted primarily of ECG with a further two thirds of the studies

utilising Holter monitoring for follow-up. No lesion set proved statistically superior,

but the best results are obtained in younger patients with paroxysmal AF. The overall

total complication rate was low for this cohort of higher complexity concomitant

procedures at 15.1% with mortality rate of 4.3%, CVA rate of 1.8%, PPM rate of 5.4%

and atria-oesophageal fistula rate of 0.5%. When these procedures were carried out

concurrent to mitral valve intervention and they excluded the left atrial appendage the

complication rate was lowest.

• When carried out as a standalone procedure the surgical ablation of AF achieves SRM

of 83.3% and SRM off AAD of 65.5% at mean follow-up of 17 months. The primary

method of follow-up was the use of single day Holter monitors with half of the studies

utilising a longer form of assessment with seven day Holter monitor. The best results

are achieved with a Bi-Atrial Maze procedure and the creation of this lesion set through

a Cut and Sew technique, the use of RF or the incorporation of multiple ablative

modalities were the most successful. The overall complication rate was low at 7.4%,

which was largely driven by a PPM rate of 3.2%. The exclusion of the left atrial

appendage corresponded with a lower risk of stroke.

• When performed jointly with a cardiac electrophysiologist the hybrid ablation

procedure achieves SRM of 79.4% and 70.7% off AAD at mean follow-up of 19

months. The primary method of rhythm assessment was a seven day Holter monitor

with a further one third utilising loop recorder technology. The best results were

achieved through the surgical use of a bipolar RF clamp and the exclusion of the left

172

atrial appendage. Ensuring lesion completeness at the end of the endocardial procedure

with electrical testing for block was indicative of better outcomes. The overall

complication rate was low at 6.5% being driven by post-operative bleeding requiring

return to the operating theatre in 1.6% of patients.

As the surgical ablation of AF has evolved the use of alternative ablative strategies to cut and

sewn lesions it has seen the rise in many technologies to achieve the delivery of a safe and

effective transmural lesion, but even the most efficacious devices as seen in bipolar RF clamps

have not been able to achieve 100% reliably transmural lesions.(153) In analysis of this point

we undertook a series of experiments to develop an increased understanding of RF lesion

formation with surgical bipolar RF clamps. In particular, are they subject to effects of contact

force as has been identified in catheter ablation.(151) Chapter 6 thus elucidates how different

mechanisms of clamp have different pressure profiles which result in a variable degrees of

contact force being transmitted through the clamp to the tissue which is to be ablated, an effect

which is amplified at greater tissue thickness. This hypothesis thus confirmed was taken

through to animal experimentation where it was then demonstrated how contact force directly

correlates with the ability of surgical clamps to deliver a transmural lesion along the entire

length of the clamp, regardless of the device indicating to that the lesion is transmural. The use

of a clamp with parallel jaws that close evenly on tissue is associated with a higher likelihood

of delivering a transmural lesion than those with a hinged jaw. Through the delivery of

increasing numbers of burns the likelihood of transmurality increases, however, the presence

of intervening fat between the clamp and the ablated tissue is associated with a significant

decrease in the ability to deliver a transmural lesion, an effect that increases with every

millimetre of fat intervening. These results thus describe potentially why bipolar RF clamps

for the surgical ablation of AF have not attained 100% reliable efficacy, and most importantly,

these results are instructive to the surgeon using these devices for the surgical ablation of AF

173

as to how to ensure the best results. Firstly, the area of the heart planned for ablation must be

cleared of any intervening epicardial fat to optimise lesion creation efficacy and likelihood of

transmurality. Secondly, clamp selection as it relates to the mechanism of jaw closure is of

paramount importance for the delivery of a truly transmural lesion across the length of the jaw.

Thirdly, increasing the number of burns delivered to an area increases the likelihood of

obtaining a transmural lesion, irrespective of the device indicating transmurality to the

operator.

In summary, this thesis provides not only an overview for the current state of the

surgical ablation of AF, but also offers new understandings on how to optimise the efficacy of

these ablative strategies for the elimination of AF.

174

Chapter 8

Future Direction

The analyses conducted over the course of this thesis have provided important understandings

into the optimal management strategies for the surgical ablation of AF. However, many

questions remain to be answered in this arena of study. Firstly, a common thread across all the

meta-analyses we conducted in this area revealed a paucity of level 1 randomised control trial

evidence with a large variability in both ablation technique and follow-up methodology. To

understand what the best lesion set is, to confirm the most efficacious way to apply this lesion

set and to determine what the ultimate efficacy of the surgical ablation of AF is a large,

prospective RCT will need to be conducted. Secondly, an evolving body of evidence is

emerging in which superior results in the elimination of AF are being obtained through the

aggressive control of risk factors in patients with AF.(106) In the vast majority of studies

analysing the results of surgical ablation of AF the risk factors of the patients have not even

been documented for consideration, so if the surgical arena mimics that of catheter ablation an

increased level of surgical ablation efficacy may be able to obtained with the same risk factor

management. This is certainly an area that will warrant further study in future. Thirdly, as the

current ablation technology available for the surgical management of AF is imperfect at this

present time as, we do not possess an ablation source capable of delivering 100% reliably

transmural lesions beyond cut and sew. Until such a device is developed the remaining

questions of optimal lesion set, technique of delivery and impact of concomitant procedures

will be confounded by the overarching issue of uncertainty that a true lesion of conduction

block has been created to abolish AF. In relation to this point the role of assessing conduction

block in cardiac surgical ablation procedures also requires further investigation as to the impact

this provides on long term results in sinus rhythm maintenance. The testing of block in the

surgical arena also has implications in technique, as when ablation is performed concomitant

175

to other cardiac surgical procedures cardiopulmonary bypass is necessitated and cardioplegia

would acutely inhibit the ability to determine electrical block. Finally, as the field of cardiac

electrophysiology advances achieving strong results in sinus rhythm maintenance through

catheter ablation, the results of the surgical ablation of AF must be compared to this to

determine the ideal ablative therapies for patients with AF. The goal must be to deliver the best

long term results in sinus rhythm maintenance and lowest complication rates across the range

of patients with AF; from those undergoing concomitant cardiac surgery to those with a lone

arrhythmia. Through such analysis in future we will be able to form the ideal treatment

paradigm for patients suffering from AF in the modern era of medicine.

176

Chapter 9

References

1. Fuster V, Ryden LE, Asinger RW et al. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: executive summary. A Report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation): developed in Collaboration With the North American Society of Pacing and Electrophysiology. J Am Coll Cardiol 2001;38:1231-66.

2. Lloyd-Jones DM, Wang TJ, Leip EP et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation 2004;110:1042-6.

3. Schnabel RB, Yin X, Gona P et al. 50 year trends in atrial fibrillation prevalence, incidence, risk factors, and mortality in the Framingham Heart Study: a cohort study. Lancet 2015;386:154-62.

4. Miyasaka Y, Barnes ME, Gersh BJ et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation 2006;114:119-25.

5. Tse HF, Wang YJ, Ahmed Ai-Abdullah M et al. Stroke prevention in atrial fibrillation--an Asian stroke perspective. Heart Rhythm 2013;10:1082-8.

6. Diker E, Aydogdu S, Ozdemir M et al. Prevalence and predictors of atrial fibrillation in rheumatic valvular heart disease. Am J Cardiol 1996;77:96-8.

7. Rowe JC, Bland EF, Sprague HB, White PD. The course of mitral stenosis without surgery: ten- and twenty-year perspectives. Ann Intern Med 1960;52:741-9.

8. Grigioni F, Avierinos JF, Ling LH et al. Atrial fibrillation complicating the course of degenerative mitral regurgitation: determinants and long-term outcome. J Am Coll Cardiol 2002;40:84-92.

9. Benjamin EJ, Levy D, Vaziri SM, D'Agostino RB, Belanger AJ, Wolf PA. Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study. JAMA : the journal of the American Medical Association 1994;271:840-4.

10. Kannel WB, Abbott RD, Savage DD, McNamara PM. Epidemiologic features of chronic atrial fibrillation: the Framingham study. The New England journal of medicine 1982;306:1018-22.

11. Wang TJ, Parise H, Levy D et al. Obesity and the risk of new-onset atrial fibrillation. JAMA : the journal of the American Medical Association 2004;292:2471-7.

12. 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 Factors in Atrial Fibrillation (ATRIA) Study. JAMA : the journal of the American Medical Association 2001;285:2370-5.

13. Vizzardi E, Sciatti E, Bonadei I, D'Aloia A, Curnis A, Metra M. Obstructive sleep apnoea-hypopnoea and arrhythmias: new updates. Journal of cardiovascular medicine (Hagerstown, Md) 2014.

14. Huxley RR, Misialek JR, Agarwal SK et al. Physical activity, obesity, weight change, and risk of atrial fibrillation: the Atherosclerosis Risk in Communities study. Circulation Arrhythmia and electrophysiology 2014;7:620-5.

15. Lau DH, Middeldorp ME, Brooks AG et al. Aortic stiffness in lone atrial fibrillation: a novel risk factor for arrhythmia recurrence. PloS one 2013;8:e76776.

16. Olshansky B, Sullivan R. Increased prevalence of atrial fibrillation in the endurance athlete: potential mechanisms and sport specificity. The Physician and sportsmedicine 2014;42:45-51.

177

17. Roberts JD, Gollob MH. A contemporary review on the genetic basis of atrial fibrillation. Methodist DeBakey cardiovascular journal 2014;10:18-24.

18. Grogan M, Smith HC, Gersh BJ, Wood DL. Left ventricular dysfunction due to atrial fibrillation in patients initially believed to have idiopathic dilated cardiomyopathy. Am J Cardiol 1992;69:1570-3.

19. Wolf PA, Dawber TR, Thomas HE, Jr., Kannel WB. Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: the Framingham study. Neurology 1978;28:973-7.

20. Wolf PA, Kannel WB, McGee DL, Meeks SL, Bharucha NE, McNamara PM. Duration of atrial fibrillation and imminence of stroke: the Framingham study. Stroke 1983;14:664-7.

21. Lin C, Edwards C, Armstrong GP et al. Prevalence and prognostic significance of left ventricular dysfunction in patients presenting acutely with atrial fibrillation. Clinical Medicine Insights Cardiology 2010;4:23-9.

22. Ott A, Breteler MM, de Bruyne MC, van Harskamp F, Grobbee DE, Hofman A. Atrial fibrillation and dementia in a population-based study. The Rotterdam Study. Stroke 1997;28:316-21.

23. Knecht S, Oelschlager C, Duning T et al. Atrial fibrillation in stroke-free patients is associated with memory impairment and hippocampal atrophy. Eur Heart J 2008;29:2125-32.

24. Ball J, Carrington MJ, Stewart S. Mild cognitive impairment in high-risk patients with chronic atrial fibrillation: a forgotten component of clinical management? Heart 2013;99:542-7.

25. Marzona I, O'Donnell M, Teo K et al. Increased risk of cognitive and functional decline in patients with atrial fibrillation: results of the ONTARGET and TRANSCEND studies. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne 2012;184:E329-36.

26. Thrall G, Lane D, Carroll D, Lip GY. Quality of life in patients with atrial fibrillation: a systematic review. The American journal of medicine 2006;119:448.e1-19.

27. Stewart S, Hart CL, Hole DJ, McMurray JJ. A population-based study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley study. The American journal of medicine 2002;113:359-64.

28. Wang TJ, Larson MG, Levy D et al. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study. Circulation 2003;107:2920-5.

29. Wong CX, Brooks AG, Leong DP, Roberts-Thomson KC, Sanders P. The increasing burden of atrial fibrillation compared with heart failure and myocardial infarction: a 15-year study of all hospitalizations in Australia. Arch Intern Med 2012;172:739-41.

30. Kalman JM, Sanders P, Brieger DB et al. National Heart Foundation of Australia consensus statement on catheter ablation as a therapy for atrial fibrillation. The Medical journal of Australia 2013;198:27-8.

31. Stewart S, Murphy NF, Walker A, McGuire A, McMurray JJ. Cost of an emerging epidemic: an economic analysis of atrial fibrillation in the UK. Heart 2004;90:286-92.

32. PricewaterhouseCoopers. The Economic Costs of Atrial Fibrillation in Australia. 2010. 33. Moe GK, Rheinboldt WC, Abildskov JA. A COMPUTER MODEL OF ATRIAL FIBRILLATION. Am

Heart J 1964;67:200-20. 34. Allessie MA LW, Bonke F, Hollen J. Experimental evaluation of Moe's multiple wavelet

hypothesis of atrial fibrillation. Cardiac arrhythmias 1985. 35. Cox JL, Canavan TE, Schuessler RB et al. The surgical treatment of atrial fibrillation. II.

Intraoperative electrophysiologic mapping and description of the electrophysiologic basis of atrial flutter and atrial fibrillation. The Journal of thoracic and cardiovascular surgery 1991;101:406-26.

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

178

37. Cox JL, Boineau JP, Schuessler RB, Kater KM, Lappas DG. Five-year experience with the maze procedure for atrial fibrillation. The Annals of thoracic surgery 1993;56:814-823; discussion 823-4.

38. Schuessler RB, Grayson TM, Bromberg BI, Cox JL, Boineau JP. Cholinergically mediated tachyarrhythmias induced by a single extrastimulus in the isolated canine right atrium. Circulation research 1992;71:1254-67.

39. Mansour M, Mandapati R, Berenfeld O, Chen J, Samie FH, Jalife J. Left-to-right gradient of atrial frequencies during acute atrial fibrillation in the isolated sheep heart. Circulation 2001;103:2631-6.

40. Morillo CA, Klein GJ, Jones DL, Guiraudon CM. Chronic rapid atrial pacing. Structural, functional, and electrophysiological characteristics of a new model of sustained atrial fibrillation. Circulation 1995;91:1588-95.

41. Jalife J, Berenfeld O, Mansour M. Mother rotors and fibrillatory conduction: a mechanism of atrial fibrillation. Cardiovascular research 2002;54:204-16.

42. Nitta T, Lee R, Watanabe H et al. Radial approach: a new concept in surgical treatment for atrial fibrillation. II. Electrophysiologic effects and atrial contribution to ventricular filling. The Annals of thoracic surgery 1999;67:36-50.

43. 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.

44. Haissaguerre M, Marcus FI, Fischer B, Clementy J. Radiofrequency catheter ablation in unusual mechanisms of atrial fibrillation: report of three cases. J Cardiovasc Electrophysiol 1994;5:743-51.

45. Jais P, Haissaguerre M, Shah DC et al. A focal source of atrial fibrillation treated by discrete radiofrequency ablation. Circulation 1997;95:572-6.

46. Hwang C, Wu TJ, Doshi RN, Peter CT, Chen PS. Vein of marshall cannulation for the analysis of electrical activity in patients with focal atrial fibrillation. Circulation 2000;101:1503-5.

47. Nathan H, Eliakim M. The junction between the left atrium and the pulmonary veins. An anatomic study of human hearts. Circulation 1966;34:412-22.

48. Chen CC, Tai CT, Chiang CE et al. Atrial tachycardias originating from the atrial septum: electrophysiologic characteristics and radiofrequency ablation. J Cardiovasc Electrophysiol 2000;11:744-9.

49. Hoffmann E, Reithmann C, Nimmermann P et al. Clinical experience with electroanatomic mapping of ectopic atrial tachycardia. Pacing and clinical electrophysiology : PACE 2002;25:49-56.

50. Kay GN, Chong F, Epstein AE, Dailey SM, Plumb VJ. Radiofrequency ablation for treatment of primary atrial tachycardias. J Am Coll Cardiol 1993;21:901-9.

51. Morton JB, Sanders P, Das A, Vohra JK, Sparks PB, Kalman JM. Focal atrial tachycardia arising from the tricuspid annulus: electrophysiologic and electrocardiographic characteristics. J Cardiovasc Electrophysiol 2001;12:653-9.

52. Natale A, Breeding L, Tomassoni G et al. Ablation of right and left ectopic atrial tachycardias using a three-dimensional nonfluoroscopic mapping system. Am J Cardiol 1998;82:989-92.

53. Tracy CM, Swartz JF, Fletcher RD et al. Radiofrequency catheter ablation of ectopic atrial tachycardia using paced activation sequence mapping. J Am Coll Cardiol 1993;21:910-7.

54. Volkmer M, Antz M, Hebe J, Kuck KH. Focal atrial tachycardia originating from the musculature of the coronary sinus. J Cardiovasc Electrophysiol 2002;13:68-71.

55. Chen SA, Hsieh MH, Tai CT et al. Initiation of atrial fibrillation by ectopic beats originating from the pulmonary veins: electrophysiological characteristics, pharmacological responses, and effects of radiofrequency ablation. Circulation 1999;100:1879-86.

179

56. Ho SY, Sanchez-Quintana D, Cabrera JA, Anderson RH. Anatomy of the left atrium: implications for radiofrequency ablation of atrial fibrillation. J Cardiovasc Electrophysiol 1999;10:1525-33.

57. Weiss C, Gocht A, Willems S, Hoffmann M, Risius T, Meinertz T. Impact of the distribution and structure of myocardium in the pulmonary veins for radiofrequency ablation of atrial fibrillation. Pacing and clinical electrophysiology : PACE 2002;25:1352-6.

58. Chen YC, Pan NH, Cheng CC, Higa S, Chen YJ, Chen SA. Heterogeneous expression of potassium currents and pacemaker currents potentially regulates arrhythmogenesis of pulmonary vein cardiomyocytes. J Cardiovasc Electrophysiol 2009;20:1039-45.

59. Ehrlich JR, Cha TJ, Zhang L et al. Cellular electrophysiology of canine pulmonary vein cardiomyocytes: action potential and ionic current properties. The Journal of physiology 2003;551:801-13.

60. Nilsson B, Chen X, Pehrson S, Kober L, Hilden J, Svendsen JH. Recurrence of pulmonary vein conduction 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.

61. Oral H, Knight BP, Tada H et al. Pulmonary vein isolation for paroxysmal and persistent atrial fibrillation. Circulation 2002;105:1077-81.

62. 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;14:661-667.

63. Sanders P, Berenfeld O, Hocini M et al. Spectral analysis identifies sites of high-frequency activity maintaining atrial fibrillation in humans. Circulation 2005;112:789-97.

64. Lin YJ, Tsao HM, Chang SL et al. Role of high dominant frequency sites in nonparoxysmal atrial fibrillation patients: insights from high-density frequency and fractionation mapping. Heart Rhythm 2010;7:1255-62.

65. Pauza DH, Skripka V, Pauziene N, Stropus R. Morphology, distribution, and variability of the epicardiac neural ganglionated subplexuses in the human heart. The Anatomical record 2000;259:353-82.

66. Sakamoto S, Fujii M, Watanabe Y et al. Exploration of theoretical ganglionated plexi ablation technique in atrial fibrillation surgery. The Annals of thoracic surgery 2014;98:1598-604.

67. 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.

68. Scherlag BJ, Yamanashi W, Patel U, Lazzara R, Jackman WM. Autonomically induced conversion of pulmonary vein focal firing into atrial fibrillation. J Am Coll Cardiol 2005;45:1878-86.

69. 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 and clinical electrophysiology : PACE 2010;33:1231-8.

70. Scherlag BJ, Hou YL, Lin J et al. An acute model for atrial fibrillation arising from a peripheral atrial site: evidence for primary and secondary triggers. J Cardiovasc Electrophysiol 2008;19:519-27.

71. Lau DH, Maesen B, Zeemering S, Verheule S, Crijns HJ, Schotten U. Stability of complex fractionated atrial electrograms: a systematic review. J Cardiovasc Electrophysiol 2012;23:980-7.

72. O'Neill MD, Jais P, Takahashi Y et al. The stepwise ablation approach for chronic atrial fibrillation--evidence for a cumulative effect. Journal of interventional cardiac electrophysiology : an international journal of arrhythmias and pacing 2006;16:153-67.

73. Stiles MK, Brooks AG, Kuklik P et al. High-density mapping of atrial fibrillation in humans: relationship between high-frequency activation and electrogram fractionation. J Cardiovasc Electrophysiol 2008;19:1245-53.

180

74. Verma A, Wulffhart Z, Beardsall M, Whaley B, Hill C, Khaykin Y. Spatial and temporal stability of complex fractionated electrograms in patients with persistent atrial fibrillation over longer time periods: relationship to local electrogram cycle length. Heart Rhythm 2008;5:1127-33.

75. Verheule S, Tuyls E, van Hunnik A, Kuiper M, Schotten U, Allessie M. Fibrillatory conduction in the atrial free walls of goats in persistent and permanent atrial fibrillation. Circulation Arrhythmia and electrophysiology 2010;3:590-9.

76. Eckstein J, Zeemering S, Linz D et al. Transmural conduction is the predominant mechanism of breakthrough during atrial fibrillation: evidence from simultaneous endo-epicardial high-density activation mapping. Circulation Arrhythmia and electrophysiology 2013;6:334-41.

77. de Groot NM, Houben RP, Smeets JL et al. Electropathological substrate of longstanding persistent atrial fibrillation in patients with structural heart disease: epicardial breakthrough. Circulation 2010;122:1674-82.

78. Chen J, Mandapati R, Berenfeld O, Skanes AC, Gray RA, Jalife J. Dynamics of wavelets and their role in atrial fibrillation in the isolated sheep heart. Cardiovascular research 2000;48:220-32.

79. Filgueiras-Rama D, Price NF, Martins RP et al. Long-term frequency gradients during persistent atrial fibrillation in sheep are associated with stable sources in the left atrium. Circulation Arrhythmia and electrophysiology 2012;5:1160-7.

80. Kalifa J, Tanaka K, Zaitsev AV et al. Mechanisms of wave fractionation at boundaries of high-frequency excitation in the posterior left atrium of the isolated sheep heart during atrial fibrillation. Circulation 2006;113:626-33.

81. Mandapati R, Skanes A, Chen J, Berenfeld O, Jalife J. Stable microreentrant sources as a mechanism of atrial fibrillation in the isolated sheep heart. Circulation 2000;101:194-9.

82. Skanes AC, Mandapati R, Berenfeld O, Davidenko JM, Jalife J. Spatiotemporal periodicity during atrial fibrillation in the isolated sheep heart. Circulation 1998;98:1236-48.

83. Haissaguerre M, Hocini M, Denis A et al. Driver domains in persistent atrial fibrillation. Circulation 2014;130:530-8.

84. Narayan SM, Krummen DE, Shivkumar K, Clopton P, Rappel WJ, Miller JM. Treatment of atrial fibrillation 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.

85. Rodrigo M, Guillem MS, Climent AM et al. Body surface localization of left and right atrial high-frequency rotors in atrial fibrillation patients: a clinical-computational study. Heart Rhythm 2014;11:1584-91.

86. Jones AR, Krummen DE, Narayan SM. Non-invasive identification of stable rotors and focal sources for human atrial fibrillation: mechanistic classification of atrial fibrillation from the electrocardiogram. Europace 2013;15:1249-58.

87. 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 randomized multicenter RADAR-AF trial. J Am Coll Cardiol 2014;64:2455-67.

88. Narayan SM, Krummen DE, Rappel WJ. Clinical mapping approach to diagnose electrical rotors and focal impulse sources for human atrial fibrillation. J Cardiovasc Electrophysiol 2012;23:447-54.

89. Haissaguerre M, Hocini M, Shah AJ et al. Noninvasive panoramic mapping of human atrial fibrillation mechanisms: a feasibility report. J Cardiovasc Electrophysiol 2013;24:711-7.

90. Lee G, Kumar S, Teh A et al. Epicardial wave mapping in human long-lasting persistent atrial fibrillation: transient rotational circuits, complex wavefronts, and disorganized activity. Eur Heart J 2014;35:86-97.

91. Allessie MA, Boyden PA, Camm AJ et al. Pathophysiology and prevention of atrial fibrillation. Circulation 2001;103:769-77.

181

92. Rensma PL, Allessie MA, Lammers WJ, Bonke FI, Schalij MJ. Length of excitation wave and susceptibility to reentrant atrial arrhythmias in normal conscious dogs. Circulation research 1988;62:395-410.

93. Henry WL, Morganroth J, Pearlman AS et al. Relation between echocardiographically determined left atrial size and atrial fibrillation. Circulation 1976;53:273-9.

94. Olgin JE, Kalman JM, Fitzpatrick AP, Lesh MD. Role of right atrial endocardial structures as barriers to conduction during human type I atrial flutter. Activation and entrainment mapping guided by intracardiac echocardiography. Circulation 1995;92:1839-48.

95. Jais P, Shah DC, Haissaguerre M et al. Mapping and ablation of left atrial flutters. Circulation 2000;101:2928-34.

96. Papageorgiou P, Monahan K, Boyle NG et al. Site-dependent intra-atrial conduction delay. Relationship to initiation of atrial fibrillation. Circulation 1996;94:384-9.

97. Sun Y, Arruda M, Otomo K et al. Coronary sinus-ventricular accessory connections producing posteroseptal and left posterior accessory pathways: incidence and electrophysiological identification. Circulation 2002;106:1362-7.

98. Burstein B, Nattel S. Atrial fibrosis: mechanisms and clinical relevance in atrial fibrillation. J Am Coll Cardiol 2008;51:802-9.

99. Abed HS, Samuel CS, Lau DH et al. Obesity results in progressive atrial structural and electrical remodeling: implications for atrial fibrillation. Heart Rhythm 2013;10:90-100.

100. Kirchhof P, Benussi S, Kotecha D et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Europace 2016;18:1609-1678.

101. Abed HS, Wittert GA, Leong DP et al. Effect of weight reduction and cardiometabolic risk factor management on symptom burden and severity in patients with atrial fibrillation: a randomized clinical trial. JAMA : the journal of the American Medical Association 2013;310:2050-60.

102. Mahajan R, Lau DH, Brooks AG et al. Electrophysiological, Electroanatomical, and Structural Remodeling of the Atria as Consequences of Sustained Obesity. J Am Coll Cardiol 2015;66:1-11.

103. Gallagher C, Hendriks JM, Mahajan R et al. Lifestyle management to prevent and treat atrial fibrillation. Expert review of cardiovascular therapy 2016;14:799-809.

104. Malmo V, Nes BM, Amundsen BH et al. Aerobic Interval Training Reduces the Burden of Atrial Fibrillation in the Short Term: A Randomized Trial. Circulation 2016;133:466-73.

105. Pathak RK, Middeldorp ME, Meredith M et al. Long-Term Effect of Goal-Directed Weight Management in an Atrial Fibrillation Cohort: A Long-Term Follow-Up Study (LEGACY). J Am Coll Cardiol 2015;65:2159-69.

106. Pathak RK, Middeldorp ME, Lau DH et al. Aggressive risk factor reduction study for atrial fibrillation and implications for the outcome of ablation: the ARREST-AF cohort study. J Am Coll Cardiol 2014;64:2222-31.

107. Carter L, Gardner M, Magee K et al. An Integrated Management Approach to Atrial Fibrillation. Journal of the American Heart Association 2016;5.

108. Hendriks JM, de Wit R, Crijns HJ et al. Nurse-led care vs. usual care for patients with atrial fibrillation: results of a randomized trial of integrated chronic care vs. routine clinical care in ambulatory patients with atrial fibrillation. Eur Heart J 2012;33:2692-9.

109. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest 2010;137:263-72.

110. Lip GY, Al-Khatib SM, Cosio FG et al. Contemporary management of atrial fibrillation: what can clinical registries tell us about stroke prevention and current therapeutic approaches? Journal of the American Heart Association 2014;3.

111. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study. Lancet 1994;343:687-91.

182

112. Oral anticoagulation in patients after cerebral ischemia of arterial origin and risk of intracranial hemorrhage. Stroke 2003;34:e45-6.

113. Connolly S, Pogue J, Hart R et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006;367:1903-12.

114. Granger CB, Alexander JH, McMurray JJ et al. Apixaban versus warfarin in patients with atrial fibrillation. The New England journal of medicine 2011;365:981-92.

115. Lopes RD, Al-Khatib SM, Wallentin L et al. Efficacy and safety of apixaban compared with warfarin according to patient risk of stroke and of bleeding in atrial fibrillation: a secondary analysis of a randomised controlled trial. Lancet 2012;380:1749-58.

116. Lip GY, Lim HS. Atrial fibrillation and stroke prevention. Lancet neurology 2007;6:981-93. 117. Mant J, Hobbs FD, Fletcher K et al. Warfarin versus aspirin for stroke prevention in an elderly

community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet 2007;370:493-503.

118. Diener HC, Eikelboom J, Connolly SJ et al. Apixaban versus aspirin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a predefined subgroup analysis from AVERROES, a randomised trial. Lancet neurology 2012;11:225-31.

119. Eikelboom JW, Connolly SJ, Brueckmann M et al. Dabigatran versus warfarin in patients with mechanical heart valves. The New England journal of medicine 2013;369:1206-14.

120. Holmes DR, Reddy VY, Turi ZG et al. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial. Lancet 2009;374:534-42.

121. Reddy VY, Sievert H, Halperin J et al. Percutaneous left atrial appendage closure vs warfarin for atrial fibrillation: a randomized clinical trial. JAMA : the journal of the American Medical Association 2014;312:1988-98.

122. Whitlock R, Healey J, Vincent J et al. Rationale and design of the Left Atrial Appendage Occlusion Study (LAAOS) III. Annals of cardiothoracic surgery 2014;3:45-54.

123. Healey JS, Crystal E, Lamy A et al. Left Atrial Appendage Occlusion Study (LAAOS): results of a randomized controlled pilot study of left atrial appendage occlusion during coronary bypass surgery in patients at risk for stroke. Am Heart J 2005;150:288-93.

124. Whitlock RP, Vincent J, Blackall MH et al. Left Atrial Appendage Occlusion Study II (LAAOS II). The Canadian journal of cardiology 2013;29:1443-7.

125. Olshansky B, Rosenfeld LE, Warner AL et al. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study: approaches to control rate in atrial fibrillation. J Am Coll Cardiol 2004;43:1201-8.

126. Saksena S, Slee A, Waldo AL et al. Cardiovascular outcomes in the AFFIRM Trial (Atrial Fibrillation Follow-Up Investigation of Rhythm Management). An assessment of individual antiarrhythmic drug therapies compared with rate control with propensity score-matched analyses. J Am Coll Cardiol 2011;58:1975-85.

127. 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.

128. Carlsson J, Miketic S, Windeler J et al. Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation: the Strategies of Treatment of Atrial Fibrillation (STAF) study. J Am Coll Cardiol 2003;41:1690-6.

129. Hohnloser SH, Kuck KH, Lilienthal J. Rhythm or rate control in atrial fibrillation--Pharmacological Intervention in Atrial Fibrillation (PIAF): a randomised trial. Lancet 2000;356:1789-94.

130. Ogawa S, Yamashita T, Yamazaki T et al. Optimal treatment strategy for patients with paroxysmal atrial fibrillation: J-RHYTHM Study. Circulation journal : official journal of the Japanese Circulation Society 2009;73:242-8.

183

131. Shelton RJ, Clark AL, Goode K et al. A randomised, controlled study of rate versus rhythm control in patients with chronic atrial fibrillation and heart failure: (CAFE-II Study). Heart 2009;95:924-30.

132. Caldeira D, David C, Sampaio C. Rate versus rhythm control in atrial fibrillation and clinical outcomes: updated systematic review and meta-analysis of randomized controlled trials. Archives of cardiovascular diseases 2012;105:226-38.

133. de Denus S, Sanoski CA, Carlsson J, Opolski G, Spinler SA. Rate vs rhythm control in patients with atrial fibrillation: a meta-analysis. Arch Intern Med 2005;165:258-62.

134. Gillinov AM, Bagiella E, Moskowitz AJ et al. Rate Control versus Rhythm Control for Atrial Fibrillation after Cardiac Surgery. The New England journal of medicine 2016;374:1911-21.

135. Lafuente-Lafuente C, Longas-Tejero MA, Bergmann JF, Belmin J. Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation. Cochrane database of systematic reviews (Online) 2012:Cd005049.

136. Roy D, Talajic M, Nattel S et al. Rhythm control versus rate control for atrial fibrillation and heart failure. The New England journal of medicine 2008;358:2667-77.

137. Al-Khatib SM, Allen LaPointe NM, Chatterjee R et al. Rate- and rhythm-control therapies in patients with atrial fibrillation: a systematic review. Ann Intern Med 2014;160:760-73.

138. Cosedis Nielsen J, Mortensen LS, Hansen PS. Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation. The New England journal of medicine 2013;368:478-9.

139. Wilber DJ, Pappone C, Neuzil P et al. Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial fibrillation: a randomized controlled trial. JAMA : the journal of the American Medical Association 2010;303:333-40.

140. Anselmino M, Matta M, D'Ascenzo F et al. Catheter ablation of atrial fibrillation in patients with left ventricular systolic dysfunction: a systematic review and meta-analysis. Circulation Arrhythmia and electrophysiology 2014;7:1011-8.

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

142. Wilber DJ, Pappone C, Neuzil P et al. Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial fibrillation: a randomized controlled trial. JAMA : the journal of the American Medical Association 2010;303:333-40.

143. Kobza R, Kottkamp H, Dorszewski A et al. Stable secondary arrhythmias late after intraoperative radiofrequency ablation of atrial fibrillation: incidence, mechanism, and treatment. J Cardiovasc Electrophysiol 2004;15:1246-9.

144. Ouyang F, Ernst S, Chun J et al. Electrophysiological findings during ablation of persistent atrial fibrillation with electroanatomic mapping and double Lasso catheter technique. Circulation 2005;112:3038-48.

145. Calkins H, Kuck KH, Cappato R et al. 2012 HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design. Europace 2012;14:528-606.

146. Kuck KH, Brugada J, Furnkranz A et al. Cryoballoon or Radiofrequency Ablation for Paroxysmal Atrial Fibrillation. The New England journal of medicine 2016;374:2235-45.

147. Nath S, DiMarco JP, Haines DE. Basic aspects of radiofrequency catheter ablation. J Cardiovasc Electrophysiol 1994;5:863-76.

148. Wong MC, Edwards G, Spence SJ et al. Characterization of catheter-tissue contact force during epicardial radiofrequency ablation in an ovine model. Circulation Arrhythmia and electrophysiology 2013;6:1222-8.

149. Holmes D, Fish JM, Byrd IA et al. Contact sensing provides a highly accurate means to titrate radiofrequency ablation lesion depth. J Cardiovasc Electrophysiol 2011;22:684-90.

184

150. Natale A, Reddy VY, Monir G et al. Paroxysmal AF catheter ablation with a contact force sensing catheter: results of the prospective, multicenter SMART-AF trial. J Am Coll Cardiol 2014;64:647-56.

151. Reddy VY, Dukkipati SR, Neuzil P et al. Randomized, Controlled Trial of the Safety and Effectiveness of a Contact Force-Sensing Irrigated Catheter for Ablation of Paroxysmal Atrial Fibrillation: Results of the TactiCath Contact Force Ablation Catheter Study for Atrial Fibrillation (TOCCASTAR) Study. Circulation 2015;132:907-15.

152. Holman WL, Ikeshita M, Douglas JM, Jr., Smith PK, Lofland GK, Cox JL. Ventricular cryosurgery: short-term effects on intramural electrophysiology. The Annals of thoracic surgery 1983;35:386-93.

153. Melby SJ, Schuessler RB, Damiano RJ, Jr. Ablation technology for the surgical treatment of atrial fibrillation. ASAIO journal (American Society for Artificial Internal Organs : 1992) 2013;59:461-8.

154. Meininger GR, Calkins H, Lickfett L et al. Initial experience with a novel focused ultrasound ablation system for ring ablation outside the pulmonary vein. Journal of interventional cardiac electrophysiology : an international journal of arrhythmias and pacing 2003;8:141-8.

155. Doll N, Suwalski P, Aupperle H et al. Endocardial laser ablation for the treatment of atrial fibrillation in an acute sheep model. J Card Surg 2008;23:198-203.

156. Robbins IM, Colvin EV, Doyle TP et al. Pulmonary vein stenosis after catheter ablation of atrial fibrillation. Circulation 1998;98:1769-75.

157. Haissaguerre M, Jais P, Shah DC et al. Electrophysiological end point for catheter ablation of atrial fibrillation initiated from multiple pulmonary venous foci. Circulation 2000;101:1409-17.

158. 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.

159. 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.

160. Jais P, Hocini M, Hsu LF et al. Technique and results of linear ablation at the mitral isthmus. Circulation 2004;110:2996-3002.

161. 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.

162. Tsai CF, Tai CT, Hsieh MH et al. Initiation of atrial fibrillation by ectopic beats originating from the superior vena cava: electrophysiological characteristics and results of radiofrequency ablation. Circulation 2000;102:67-74.

163. Nademanee K, McKenzie J, Kosar E et al. A new approach for catheter ablation of atrial fibrillation: mapping of the electrophysiologic substrate. J Am Coll Cardiol 2004;43:2044-53.

164. Oral H, Chugh A, Good E et al. Radiofrequency catheter ablation of chronic atrial fibrillation guided by complex electrograms. Circulation 2007;115:2606-12.

165. Scherlag BJ, Nakagawa H, Jackman WM et al. Electrical stimulation to identify neural elements on the heart: their role in atrial fibrillation. Journal of interventional cardiac electrophysiology : an international journal of arrhythmias and pacing 2005;13 Suppl 1:37-42.

166. Hocini M, Jais P, Sanders P et al. Techniques, evaluation, and consequences of linear block at the left atrial roof in paroxysmal atrial fibrillation: a prospective randomized study. Circulation 2005;112:3688-96.

167. Sauer WH, Alonso C, Zado E et al. Atrioventricular nodal reentrant tachycardia in patients referred for atrial fibrillation ablation: response to ablation that incorporates slow-pathway modification. Circulation 2006;114:191-5.

185

168. Haissaguerre M, Hocini M, Sanders P et al. Catheter ablation of long-lasting persistent atrial fibrillation: clinical outcome and mechanisms of subsequent arrhythmias. J Cardiovasc Electrophysiol 2005;16:1138-47.

169. Takahashi Y, O'Neill MD, Hocini M et al. Effects of stepwise ablation of chronic atrial fibrillation on atrial electrical and mechanical properties. J Am Coll Cardiol 2007;49:1306-14.

170. 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.

171. Arujuna A, Karim R, Caulfield D et al. Acute pulmonary vein isolation is achieved by a combination of reversible and irreversible atrial injury after catheter ablation: evidence from magnetic resonance imaging. Circulation Arrhythmia and electrophysiology 2012;5:691-700.

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

173. Tzou WS, Marchlinski FE, Zado ES et al. Long-term outcome after successful catheter ablation of atrial fibrillation. Circulation Arrhythmia and electrophysiology 2010;3:237-42.

174. Weerasooriya R, Khairy P, Litalien J et al. Catheter ablation for atrial fibrillation: are results maintained at 5 years of follow-up? J Am Coll Cardiol 2011;57:160-6.

175. Bonanno C, Paccanaro M, La Vecchia L, Ometto R, Fontanelli A. Efficacy and safety of catheter ablation versus antiarrhythmic drugs for atrial fibrillation: a meta-analysis of randomized trials. Journal of cardiovascular medicine (Hagerstown, Md) 2010;11:408-18.

176. Ganesan AN, Shipp NJ, Brooks AG et al. Long-term outcomes of catheter ablation of atrial fibrillation: a systematic review and meta-analysis. Journal of the American Heart Association 2013;2:e004549.

177. Williams JM, Ungerleider RM, Lofland GK, Cox JL. Left atrial isolation: new technique for the treatment of supraventricular arrhythmias. The Journal of thoracic and cardiovascular surgery 1980;80:373-80.

178. Guiraudon G, Campbell CS, Jones DL, McLellan JL, MacDonald JL. Combined sino-atrial node atrio-ventricular node isolation: a surgical alternative to His bundle ablation in patients with atrial fibrillation [Abstract]. Circulation 1985;72.

179. Cox JL. The surgical treatment of atrial fibrillation. IV. Surgical technique. The Journal of thoracic and cardiovascular surgery 1991;101:584-92.

180. Cox JL, Boineau JP, Schuessler RB et al. Operations for atrial fibrillation. Clin Cardiol 1991;14:827-34.

181. Cox JL, Boineau JP, Schuessler RB, Jaquiss RD, Lappas DG. Modification of the maze procedure for atrial flutter and atrial fibrillation. I. Rationale and surgical results. The Journal of thoracic and cardiovascular surgery 1995;110:473-84.

182. Cox JL, Jaquiss RD, Schuessler RB, Boineau JP. Modification of the maze procedure for atrial flutter and atrial fibrillation. II. Surgical technique of the maze III procedure. The Journal of thoracic and cardiovascular surgery 1995;110:485-95.

183. Lonnerholm S, Blomstrom P, Nilsson L, Blomstrom-Lundqvist C. Atrial size and transport function after the Maze III procedure for paroxysmal atrial fibrillation. The Annals of thoracic surgery 2002;73:107-11.

184. Schaff HV, Dearani JA, Daly RC, Orszulak TA, Danielson GK. Cox-Maze procedure for atrial fibrillation: Mayo Clinic experience. Semin Thorac Cardiovasc Surg 2000;12:30-7.

185. Feinberg MS, Waggoner AD, Kater KM, Cox JL, Lindsay BD, Perez JE. Restoration of atrial function after the maze procedure for patients with atrial fibrillation. Assessment by Doppler echocardiography. Circulation 1994;90:Ii285-92.

186. 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.

186

187. Gaynor SL, Diodato MD, Prasad SM et al. A prospective, single-center clinical trial of a modified Cox maze procedure with bipolar radiofrequency ablation. The Journal of thoracic and cardiovascular surgery 2004;128:535-42.

188. Damiano RJ, Jr., Schwartz FH, Bailey MS et al. The Cox maze IV procedure: predictors of late recurrence. The Journal of thoracic and cardiovascular surgery 2011;141:113-21.

189. 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.

190. Ad N, Holmes SD, Shuman DJ, Pritchard G. Impact of Atrial Fibrillation Duration on the Success of First-Time Concomitant Cox Maze Procedures. The Annals of thoracic surgery 2015;100:1613-8; discussion 1618-9.

191. 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, 1178.e1-2.

192. Damiano RJ, Jr., Badhwar V, Acker MA et al. The CURE-AF trial: a prospective, multicenter trial of irrigated radiofrequency ablation for the treatment of persistent atrial fibrillation during concomitant cardiac surgery. Heart Rhythm 2014;11:39-45.

193. 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.

194. Brodell GK, Cosgrove D, Schiavone W, Underwood DA, Loop FD. Cardiac rhythm and conduction disturbances in patients undergoing mitral valve surgery. Cleveland Clinic journal of medicine 1991;58:397-9.

195. Chua YL, Schaff HV, Orszulak TA, Morris JJ. Outcome of mitral valve repair in patients with preoperative atrial fibrillation. Should the maze procedure be combined with mitral valvuloplasty? The Journal of thoracic and cardiovascular surgery 1994;107:408-15.

196. Petty GW, Khandheria BK, Whisnant JP, Sicks JD, O'Fallon WM, Wiebers DO. Predictors of cerebrovascular events and death among patients with valvular heart disease: A population-based study. Stroke 2000;31:2628-35.

197. Ad N, Cox JL. The Maze procedure for the treatment of atrial fibrillation: a minimally invasive approach. J Card Surg 2004;19:196-200.

198. Ad N, Henry L, Friehling T, Wish M, Holmes SD. Minimally invasive stand-alone Cox-maze procedure for patients with nonparoxysmal atrial fibrillation. The Annals of thoracic surgery 2013;96:792-8; discussion 798-9.

199. Balkhy HH, Chapman PD, Arnsdorf SE. Minimally invasive atrial fibrillation ablation combined with a new technique for thoracoscopic stapling of the left atrial appendage: case report. The heart surgery forum 2004;7:353-5.

200. Gillinov AM, Mihaljevic T. Thoracoscopic epicardial radiofrequency ablation for atrial fibrillation: commentary. Heart 2009;95:1110-1.

201. Pruitt JC, Lazzara RR, Dworkin GH, Badhwar V, Kuma C, Ebra G. Totally endoscopic ablation of lone atrial fibrillation: initial clinical experience. The Annals of thoracic surgery 2006;81:1325-30; discussion 1330-1.

202. Pruitt JC, Lazzara RR, Ebra G. Minimally invasive surgical ablation of atrial fibrillation: the thoracoscopic box lesion approach. Journal of interventional cardiac electrophysiology : an international journal of arrhythmias and pacing 2007;20:83-7.

203. 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. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 2010;38:356-60.

204. Sirak J, Jones D, Schwartzman D. The five-box thoracoscopic maze procedure. The Annals of thoracic surgery 2010;90:986-9.

187

205. Sirak J, Jones D, Sun B, Sai-Sudhakar C, Crestanello J, Firstenberg M. Toward a definitive, totally thoracoscopic procedure for atrial fibrillation. The Annals of thoracic surgery 2008;86:1960-4.

206. Sirak JH, Schwartzman D. Interim results of the 5-box thoracoscopic maze procedure. The Annals of thoracic surgery 2012;94:1880-4.

207. Pison L, La Meir M, van Opstal J, Blaauw Y, Maessen J, Crijns HJ. Hybrid thoracoscopic surgical and transvenous catheter ablation of atrial fibrillation. J Am Coll Cardiol 2012;60:54-61.

208. Muneretto C, Bisleri G, Bontempi L, Curnis A. Durable staged hybrid ablation with thoracoscopic and percutaneous approach for treatment of long-standing atrial fibrillation: a 30-month assessment with continuous monitoring. The Journal of thoracic and cardiovascular surgery 2012;144:1460-5; discussion 1465.

209. Pison L, Gelsomino S, Luca F et al. Effectiveness and safety of simultaneous hybrid thoracoscopic and endocardial catheter ablation of lone atrial fibrillation. Annals of cardiothoracic surgery 2014;3:38-44.

210. Badhwar V, Rankin JS, Damiano RJ, Jr. et al. The Society of Thoracic Surgeons 2017 Clinical Practice Guidelines for the Surgical Treatment of Atrial Fibrillation. The Annals of thoracic surgery 2017;103:329-341.

211. Atricure. RF Ablation, Pacing and Sensing. 2017. 212. Atricure. Isolator Synergy Clamps. 2017. 213. Atricure. Isolator Synergy Clamps - EML2,EMR2. 2017. 214. Atricure. Isolator Synergy Access Clamp. 2017. 215. Medtronic. ABLATION PRODUCTS – SURGICAL. 2017. 216. Medtronic. Cardioblate BP2. 2017. 217. Medtronic. Cardioblate LP. 2017. 218. Medtronic. Cardioblate Gemini. 2017. 219. Atricure. Ablation Sensing Unit & Switch Matrix. 2017. 220. Medtronic. Cardioblate 68000. 2017. 221. Atricure. Coolrail Linear Pen. 2017. 222. Atricure. Isolator Linear Pen. 2017. 223. Atricure. Isolator Transpolar Pen. 2017. 224. Medtronic. Cardioblate Surgical Pen. 2017. 225. Medtronic. Cardioblate MAPS. 2017. 226. Atricure. COBRA Fusion 150 and 50 Ablation System. 2017. 227. Atricure. EPi-Sense Coagulation Device. 2017. 228. Atricure. Cryo. 2017. 229. Medtronic. Cardioblate CryoFlex. 2017. 230. Medtronic. Cardioblate CryoFlex Clamp. 2017. 231. Lee SK, Choo SJ, Kim KS, Lee JW. Epicardial microwave application in chronic atrial fibrillation

surgery. Journal of Korean medical science 2005;20:727-31. 232. MacDonald DRW, Maruthappu M, Nagendran M. How effective is microwave ablation for

atrial fibrillation during concomitant cardiac surgery? Interactive Cardiovascular and Thoracic Surgery 2012;15:122-127.

233. Manasse E, Medici D, Ghiselli S, Ornaghi D, Gallotti R. Left main coronary arterial lesion after microwave epicardial ablation. The Annals of thoracic surgery 2003;76:276-7.

234. Molloy TA. Midterm clinical experience with microwave surgical ablation of atrial fibrillation. The Annals of thoracic surgery 2005;79:2115-8.

235. Bokeriia LA, Borisov KV, Revishvili A et al. [Surgical treatment of supraventricular tachyarrhythmias using laser]. Grudnaia i serdechno-sosudistaia khirurgiia / Ministerstvo zdravookhraneniia SSSR [i] Vsesoiuznoe nauchnoe obshchestvo khirurgov 1992:23-30.

188

236. Dorschler K, Muller G. The role of laser in cardiac surgery. The Thoracic and cardiovascular surgeon 1999;47 Suppl 3:385-7.

237. Schade A, Krug J, Szollosi AG, El Tarahony M, Deneke T. Pulmonary vein isolation with a novel endoscopic ablation system using laser energy. Expert review of cardiovascular therapy 2012;10:995-1000.

238. Metzner A, Chun KR, Neven K et al. Long-term clinical outcome following pulmonary vein isolation with high-intensity focused ultrasound balloon catheters in patients with paroxysmal atrial fibrillation. Europace 2010;12:188-93.

239. Mitnovetski S, Almeida AA, Goldstein J, Pick AW, Smith JA. Epicardial high-intensity focused ultrasound cardiac ablation for surgical treatment of atrial fibrillation. Heart, lung & circulation 2009;18:28-31.

240. Neven K, Metzner A, Schmidt B, Ouyang F, Kuck KH. Two-year clinical follow-up after pulmonary vein isolation using high-intensity focused ultrasound (HIFU) and an esophageal temperature-guided safety algorithm. Heart Rhythm 2012;9:407-13.

241. Melby SJ, Zierer A, Bailey MS et al. A new era in the surgical treatment of atrial fibrillation: the impact of ablation technology and lesion set on procedural efficacy. Ann Surg 2006;244:583-92.

242. Doll N, Kornherr P, Aupperle H et al. Epicardial treatment of atrial fibrillation using cryoablation in an acute off-pump sheep model. The Thoracic and cardiovascular surgeon 2003;51:267-73.

243. Aupperle H, Doll N, Walther T et al. Ablation of atrial fibrillation and esophageal injury: effects of energy source and ablation technique. The Journal of thoracic and cardiovascular surgery 2005;130:1549-54.

244. Gillinov AM, Pettersson G, Rice TW. Esophageal injury during radiofrequency ablation for atrial fibrillation. The Journal of thoracic and cardiovascular surgery 2001;122:1239-40.

245. Holman WL, Ikeshita M, Ungerleider RM, Smith PK, Ideker RE, Cox JL. Cryosurgery for cardiac arrhythmias: acute and chronic effects on coronary arteries. Am J Cardiol 1983;51:149-55.

246. Iida S, Misaki T, Iwa T. The histological effects of cryocoagulation on the myocardium and coronary arteries. The Japanese journal of surgery 1989;19:319-25.

247. Mikat EM, Hackel DB, Harrison L, Gallagher JJ, Wallace AG. Reaction of the myocardium and coronary arteries to cryosurgery. Laboratory investigation; a journal of technical methods and pathology 1977;37:632-41.

248. Misaki T, Allwork SP, Bentall HH. Longterm effects of cryosurgery in the sheep heart. Cardiovascular research 1983;17:61-9.

249. Guiraudon GM, Jones DL, Skanes AC et al. En bloc exclusion of the pulmonary vein region in the pig using off pump, beating, intra-cardiac surgery: a pilot study of minimally invasive surgery for atrial fibrillation. The Annals of thoracic surgery 2005;80:1417-23.

250. Bugge E, Nicholson IA, Thomas SP. Comparison of bipolar and unipolar radiofrequency ablation in an in vivo experimental model. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 2005;28:76-80; discussion 80-2.

251. Miyagi Y, Ishii Y, Nitta T, Ochi M, Shimizu K. Electrophysiological and histological assessment of transmurality after epicardial ablation using unipolar radiofrequency energy. J Card Surg 2009;24:34-40.

252. Thomas SP, Guy DJ, Boyd AC, Eipper VE, Ross DL, Chard RB. Comparison of epicardial and endocardial linear ablation using handheld probes. The Annals of thoracic surgery 2003;75:543-8.

253. Gaynor SL, Ishii Y, Diodato MD et al. Successful performance of Cox-Maze procedure on beating heart using bipolar radiofrequency ablation: a feasibility study in animals. The Annals of thoracic surgery 2004;78:1671-7.

189

254. Melby SJ, Gaynor SL, Lubahn JG et al. Efficacy and safety of right and left atrial ablations on the beating heart with irrigated bipolar radiofrequency energy: a long-term animal study. The Journal of thoracic and cardiovascular surgery 2006;132:853-60.

255. Voeller RK, Zierer A, Lall SC, Sakamoto S, Schuessler RB, Damiano RJ, Jr. Efficacy of a novel bipolar radiofrequency ablation device on the beating heart for atrial fibrillation ablation: a long-term porcine study. The Journal of thoracic and cardiovascular surgery 2010;140:203-8.

256. Huffman MD, Karmali KN, Berendsen MA et al. Concomitant atrial fibrillation surgery for people undergoing cardiac surgery. Cochrane database of systematic reviews (Online) 2016:CD011814.

257. Je HG, Shuman DJ, Ad N. A systematic review of minimally invasive surgical treatment for atrial fibrillation: a comparison of the Cox-Maze procedure, beating-heart epicardial ablation, and the hybrid procedure on safety and efficacy. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 2015;48:531-40; discussion 540-1.

258. Phan K, Xie A, La Meir M, Black D, Yan TD. Surgical ablation for treatment of atrial fibrillation in cardiac surgery: a cumulative meta-analysis of randomised controlled trials. Heart 2014;100:722-30.

259. 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.

260. Cheng DC, Ad N, Martin J et al. Surgical ablation for atrial fibrillation in cardiac surgery: a meta-analysis and systematic review. Innovations (Philadelphia, Pa) 2010;5:84-96.

261. Kong MH, Lopes RD, Piccini JP, Hasselblad V, Bahnson TD, Al-Khatib SM. Surgical Maze procedure as a treatment for atrial fibrillation: a meta-analysis of randomized controlled trials. Cardiovascular therapeutics 2010;28:311-26.

262. Calkins H, Kuck KH, Cappato R et al. 2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design: a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation. Developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC) and the European Cardiac Arrhythmia Society (ECAS); and in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), the Asia Pacific Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons (STS). Endorsed by the governing bodies of the American College of Cardiology Foundation, the American Heart Association, the European Cardiac Arrhythmia Society, the European Heart Rhythm Association, the Society of Thoracic Surgeons, the Asia Pacific Heart Rhythm Society, and the Heart Rhythm Society. Heart Rhythm 2012;9:632-696 e21.

263. Baek MJ, Na CY, Oh SS et al. Surgical treatment of chronic atrial fibrillation combined with rheumatic mitral valve disease: Effects of the cryo-maze procedure and predictors for late recurrence. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 2006;30:728-36.

264. Chen L, Xiao Y, Ma R et al. Bipolar radiofrequency ablation is useful for treating atrial fibrillation combined with heart valve diseases. BMC surgery 2014;14:32.

265. Dong L, Fu B, Teng X, Yuan HS, Zhao SL, Ren L. Clinical analysis of concomitant valve replacement and bipolar radiofrequency ablation in 191 patients. The Journal of thoracic and cardiovascular surgery 2013;145:1013-7.

266. Funatsu T, Kobayashi J, Nakajima H, Iba Y, Shimahara Y, Yagihara T. Long-term results and reliability of cryothermic ablation based maze procedure for atrial fibrillation concomitant with mitral valve surgery. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 2009;36:267-71; discussion 271.

190

267. Geidel S, Lass M, Ostermeyer J. Seven-year experience with ablation of permanent atrial fibrillation concomitant to mitral valve surgery in 152 patients. The heart surgery forum 2008;11:E175-80.

268. Gillinov AM, Bakaeen F, McCarthy PM et al. Surgery for paroxysmal atrial fibrillation in the setting of mitral valve disease: a role for pulmonary vein isolation? The Annals of thoracic surgery 2006;81:19-26; discussion 27-8.

269. Jeanmart H, Casselman F, Beelen R et al. Modified maze during endoscopic mitral valve surgery: the OLV Clinic experience. The Annals of thoracic surgery 2006;82:1765-9.

270. Kasemsarn C, Lerdsomboon P, Sungkahaphong V, Chotivatanapong T. Left atrial reduction in modified maze procedure with concomitant mitral surgery. Asian cardiovascular & thoracic annals 2014;22:421-9.

271. Kim JB, Cho WC, Jung SH, Chung CH, Choo SJ, Lee JW. Alternative energy sources for surgical treatment of atrial fibrillation in patients undergoing mitral valve surgery: microwave ablation vs cryoablation. Journal of Korean medical science 2010;25:1467-72.

272. Maltais S, Forcillo J, Bouchard D et al. Long-term results following concomitant radiofrequency modified maze ablation for atrial fibrillation. J Card Surg 2010;25:608-13.

273. Nakajima H, Kobayashi J, Bando K et al. The effect of cryo-maze procedure on early and intermediate term outcome in mitral valve disease: case matched study. Circulation 2002;106:I46-I50.

274. Nardi P, Mve Mvondo C, Scafuri A et al. Left atrial radiofrequency ablation associated with valve surgery: midterm outcomes. The Thoracic and cardiovascular surgeon 2013;61:392-7.

275. Wang W, Buehler D, Martland AM, Feng XD, Wang YJ. Left atrial wall tension directly affects the restoration of sinus rhythm after Maze procedure. European Journal of Cardio-thoracic Surgery 2011;40:77-82.

276. Wang X, Wang X, Song Y, Hu S, Wang W. Efficiency of radiofrequency ablation for surgical treatment of chronic atrial fibrillation in rheumatic valvular disease. Int J Cardiol 2014;174:497-502.

277. Rahmanian PB, Filsoufi F, Salzberg S, Coppolino A, Castillo JG, Adams DH. Surgical treatment of atrial fibrillation using cryothermy in patients undergoing mitral valve surgery. Interact Cardiovasc Thorac Surg 2008;7:990-5.

278. John B, Stiles MK, Kuklik P et al. Electrical remodelling of the left and right atria due to rheumatic mitral stenosis. Eur Heart J 2008;29:2234-43.

279. Gammie JS, Sheng S, Griffith BP et al. Trends in mitral valve surgery in the United States: results from the Society of Thoracic Surgeons Adult Cardiac Surgery Database. The Annals of thoracic surgery 2009;87:1431-7; discussion 1437-9.

280. Gupta A, Perera T, Ganesan A et al. Complications of catheter ablation of atrial fibrillation: a systematic review. Circulation Arrhythmia and electrophysiology 2013;6:1082-8.

281. Albeyoglu SC, Filizcan U, Sargin M et al. Determinants of hospital mortality after repeat mitral valve surgery for rheumatic mitral valve disease. The Thoracic and cardiovascular surgeon 2006;54:244-9.

282. Kaartama T, Heikkinen L, Vento A. An evaluation of mitral valve procedures using the European system for cardiac operative risk evaluation. Scandinavian journal of surgery : SJS : official organ for the Finnish Surgical Society and the Scandinavian Surgical Society 2008;97:254-8.

283. Stahle E, Kvidal P, Nystrom SO, Bergstrom R. Long-term relative survival after primary heart valve replacement. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 1997;11:81-91.

284. Vassileva CM, Mishkel G, McNeely C et al. Long-term survival of patients undergoing mitral valve repair and replacement: a longitudinal analysis of Medicare fee-for-service beneficiaries. Circulation 2013;127:1870-6.

191

285. Anghel D, Anghel R, Corciova F, Enache M, Tinica G. Preoperative arrhythmias such as atrial fibrillation: cardiovascular surgery risk factor. BioMed research international 2014;2014:584918.

286. Ngaage DL, Schaff HV, Mullany CJ et al. Does preoperative atrial fibrillation influence early and late outcomes of coronary artery bypass grafting? The Journal of thoracic and cardiovascular surgery 2007;133:182-9.

287. Quader MA, McCarthy PM, Gillinov AM et al. Does preoperative atrial fibrillation reduce survival after coronary artery bypass grafting? The Annals of thoracic surgery 2004;77:1514-22; discussion 1522-4.

288. Rogers CA, Angelini GD, Culliford LA, Capoun R, Ascione R. Coronary surgery in patients with preexisting chronic atrial fibrillation: early and midterm clinical outcome. The Annals of thoracic surgery 2006;81:1676-82.

289. Russell EA, Walsh WF, Tran L et al. The burden and implications of preoperative atrial fibrillation in Australian heart valve surgery patients. Int J Cardiol 2017;227:100-105.

290. Jacobs JP, Shahian DM, Prager RL et al. The Society of Thoracic Surgeons National Database 2016 Annual Report. The Annals of thoracic surgery 2016;102:1790-1797.

291. Benussi S, Nascimbene S, Agricola E et al. Surgical ablation of atrial fibrillation using the epicardial radiofrequency approach: mid-term results and risk analysis. The Annals of thoracic surgery 2002;74:1050-6; discussion 1057.

292. Beukema WP, Sie HT, Misier AR, Delnoy PP, Wellens HJ, Elvan A. Intermediate to long-term results of radiofrequency modified Maze procedure as an adjunct to open-heart surgery. The Annals of thoracic surgery 2008;86:1409-14.

293. Budera P, Straka Z, Osmancik P et al. Comparison of cardiac surgery with left atrial surgical ablation 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;33:2644-2652.

294. Deneke T, Khargi K, Voss D et al. Long-term sinus rhythm stability after intraoperative ablation of permanent atrial fibrillation. Pacing and clinical electrophysiology : PACE 2009;32:653-9.

295. Doty JR, Doty DB, Jones KW et al. Comparison of standard Maze III and radiofrequency Maze operations for treatment of atrial fibrillation. The Journal of thoracic and cardiovascular surgery 2007;133:1037-44.

296. Gammie JS, Didolkar P, Krowsoski LS et al. Intermediate-term outcomes of surgical atrial fibrillation correction with the CryoMaze procedure. The Annals of thoracic surgery 2009;87:1452-8; discussion 1458-9.

297. Gaynor SL, Schuessler RB, Bailey MS et al. Surgical treatment of atrial fibrillation: predictors of late recurrence. The Journal of thoracic and cardiovascular surgery 2005;129:104-11.

298. Geidel S, Krause K, Boczor S et al. Ablation surgery in patients with persistent atrial fibrillation: an 8-year clinical experience. The Journal of thoracic and cardiovascular surgery 2011;141:377-82.

299. Gillinov AM, McCarthy PM, Blackstone EH et al. Surgical ablation of atrial fibrillation with bipolar radiofrequency as the primary modality. The Journal of thoracic and cardiovascular surgery 2005;129:1322-9.

300. Grubitzsch H, Dushe S, Beholz S, Dohmen PM, Konertz W. Surgical Ablation of Atrial Fibrillation in Patients With Congestive Heart Failure. Journal of Cardiac Failure 2007;13:509-516.

301. Guden M, Akpinar B, Caynak B et al. Left versus bi-atrial intraoperative saline-irrigated radiofrequency modified maze procedure for atrial fibrillation. Cardiac electrophysiology review 2003;7:252-8.

302. Mantovan R, Raviele A, Buja G et al. Left atrial radiofrequency ablation during cardiac surgery in patients with atrial fibrillation. J Cardiovasc Electrophysiol 2003;14:1289-95.

192

303. Martinez-Comendador J, Castano M, Mosquera I et al. Cryoablation of atrial fibrillation in cardiac surgery: Outcomes and myocardial injury biomarkers. Journal of Cardiothoracic and Vascular Anesthesia 2011;25:1030-1035.

304. Melby SJ, Kaiser SP, Bailey MS et al. Surgical treatment of atrial fibrillation with bipolar radiofrequency ablation: Mid-term results in one hundred consecutive patients. Journal of Cardiovascular Surgery 2006;47:705-710.

305. Mohr FW, Fabricius AM, Falk V et al. Curative treatment of atrial fibrillation with intraoperative radiofrequency ablation: short-term and midterm results. The Journal of thoracic and cardiovascular surgery 2002;123:919-27.

306. Nakamura T, Izutani H, Sawa Y. Mid-term outcomes of the modified Cox-maze procedure for elderly patients: a risk analysis for failure. Interact Cardiovasc Thorac Surg 2011;12:924-8.

307. Sakamoto Y, Takakura H, Onoguchi K et al. Cryosurgical left-sided maze procedure in patients with valvular heart disease: medium-term results. Annals of thoracic and cardiovascular surgery : official journal of the Association of Thoracic and Cardiovascular Surgeons of Asia 2011;17:148-52.

308. Sie HT, Beukema WP, Elvan A, Ramdat Misier AR. Long-term results of irrigated radiofrequency modified maze procedure in 200 patients with concomitant cardiac surgery: six years experience. The Annals of thoracic surgery 2004;77:512-6; discussion 516-7.

309. Srivastava V, Kumar S, Javali S et al. Efficacy of three different ablative procedures to treat atrial fibrillation in patients with valvular heart disease: a randomised trial. Heart, lung & circulation 2008;17:232-40.

310. Starck C, Botha CA, Roser D, Paula J, Rein JG, Hemmer W. Results of a modified left atrial maze procedure as a combined procedure. The Thoracic and cardiovascular surgeon 2003;51:147-53.

311. Sternik L, Luria D, Glikson M, Malachy A, First M, Raanani E. Efficacy of surgical ablation of atrial fibrillation in patients with rheumatic heart disease. The Annals of thoracic surgery 2010;89:1437-42.

312. Stulak JM, Sundt TM, 3rd, Dearani JA, Daly RC, Orsulak TA, Schaff HV. Ten-year experience with the Cox-maze procedure for atrial fibrillation: how do we define success? The Annals of thoracic surgery 2007;83:1319-24.

313. Veasey RA, Segal OR, Large JK et al. The efficacy of intraoperative atrial radiofrequency ablation for atrial fibrillation during concomitant cardiac surgery-the Surgical Atrial Fibrillation Suppression (SAFS) Study. Journal of interventional cardiac electrophysiology : an international journal of arrhythmias and pacing 2011;32:29-35.

314. Voeller RK, Bailey MS, Zierer A et al. Isolating the entire posterior left atrium improves surgical outcomes after the Cox maze procedure. The Journal of thoracic and cardiovascular surgery 2008;135:870-7.

315. Wang J, Meng X, Li H, Cui Y, Han J, Xu C. Prospective randomized comparison of left atrial and biatrial radiofrequency ablation in the treatment of atrial fibrillation. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 2009;35:116-22.

316. Watkins AC, Young CA, Ghoreishi M et al. Prospective assessment of the CryoMaze procedure with continuous outpatient telemetry in 136 patients. The Annals of thoracic surgery 2014;97:1191-8; discussion 1198.

317. Yanagawa B, Holmes SD, Henry L, Hunt S, Ad N. Outcome of concomitant cox-maze III procedure using an argon-based cryosurgical system: A single-center experience with 250 patients. Annals of Thoracic Surgery 2013;95:1633-1639.

318. Beyer E, Lee R, Lam BK. Point: Minimally invasive bipolar radiofrequency ablation of lone atrial fibrillation: early multicenter results. The Journal of thoracic and cardiovascular surgery 2009;137:521-6.

193

319. Edgerton JR, McClelland JH, Duke D et al. Minimally invasive surgical ablation of atrial fibrillation: Six-month results. Journal of Thoracic and Cardiovascular Surgery 2009;138:109-114.

320. Kasirajan V, Spradlin EA, Mormando TE et al. Minimally invasive surgery using bipolar radiofrequency energy is effective treatment for refractory atrial fibrillation. The Annals of thoracic surgery 2012;93:1456-61.

321. Nasso G, Bonifazi R, Del Prete A et al. Long-term results of ablation for isolated atrial fibrillation through a right minithoracotomy: toward a rational revision of treatment protocols. The Journal of thoracic and cardiovascular surgery 2011;142:e41-6.

322. Saint LL, Bailey MS, Prasad S et al. Cox-Maze IV results for patients with lone atrial fibrillation versus concomitant mitral disease. The Annals of thoracic surgery 2012;93:789-94; discussion 794-5.

323. 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.

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

325. Verma A, Sanders P, Champagne J et al. Selective complex fractionated atrial electrograms targeting for atrial fibrillation study (SELECT AF): a multicenter, randomized trial. Circulation Arrhythmia and electrophysiology 2014;7:55-62.

326. 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.

327. Aryana A, Singh SK, Singh SM et al. Association between incomplete surgical ligation of left atrial appendage and stroke and systemic embolization. Heart Rhythm 2015;12:1431-7.

328. Bisleri G, Rosati F, Bontempi L, Curnis A, Muneretto C. Hybrid approach for the treatment of long-standing persistent atrial fibrillation: electrophysiological findings and clinical results. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 2013.

329. Bulava A, Mokracek A, Hanis J, Kurfirst V, Eisenberger M, Pesl L. Sequential hybrid procedure for persistent atrial fibrillation. Journal of the American Heart Association 2015;4:e001754.

330. de Asmundis C, Chierchia GB, Mugnai G et al. Midterm clinical outcomes of concomitant thoracoscopic epicardial and transcatheter endocardial ablation for persistent and long-standing persistent atrial fibrillation: a single-centre experience. Europace 2017;19:58-65.

331. Edgerton Z, Perini AP, Horton R et al. Hybrid Procedure (Endo/Epicardial) versus Standard Manual Ablation in Patients Undergoing Ablation of Longstanding Persistent Atrial Fibrillation: Results from a Single Center. J Cardiovasc Electrophysiol 2016;27:524-30.

332. Eisenberger M, Bulava A, Mokracek A, Hanis J, Kurfirst V, Dusek L. Sequential Hybrid Surgical CryoMaze and Transvenous Catheter Ablation of Atrial Fibrillation. Pacing and clinical electrophysiology : PACE 2015.

333. Gaita F, Ebrille E, Scaglione M et al. Very long-term results of surgical and transcatheter ablation of long-standing persistent atrial fibrillation. The Annals of thoracic surgery 2013;96:1273-8.

334. Gehi AK, Mounsey JP, Pursell I et al. Hybrid epicardial-endocardial ablation using a pericardioscopic technique for the treatment of atrial fibrillation. Heart Rhythm 2013;10:22-8.

335. Gersak B, Pernat A, Robic B, Sinkovec M. Low rate of atrial fibrillation recurrence verified by implantable loop recorder monitoring following a convergent epicardial and endocardial ablation of atrial fibrillation. Journal of Cardiovascular Electrophysiology 2012;23:1059-1066.

336. Kiser AC, Landers M, Horton R, Hume A, Natale A, Gersak B. The convergent procedure: a multidisciplinary atrial fibrillation treatment. The heart surgery forum 2010;13:E317-21.

194

337. 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.

338. Kumar N, Pison L, Lozekoot P et al. The symbiosis of contact force catheter use for hybrid ablation for atrial fibrillation. Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation 2015;23:438-46.

339. Kurfirst V, Mokracek A, Bulava A, Canadyova J, Hanis J, Pesl L. Two-staged hybrid treatment of persistent atrial fibrillation: short-term single-centre results. Interact Cardiovasc Thorac Surg 2014;18:451-6.

340. La Meir M, Gelsomino S, Lorusso R et al. The hybrid approach for the surgical treatment of lone atrial fibrillation: one-year results employing a monopolar radiofrequency source. Journal of cardiothoracic surgery 2012;7:71.

341. La Meir M, Gelsomino S, Luca F et al. Minimally invasive surgical treatment of lone atrial fibrillation: early results of hybrid versus standard minimally invasive approach employing radiofrequency sources. Int J Cardiol 2013;167:1469-75.

342. Lee R, McCarthy PM, Passman RS et al. Surgical treatment for isolated atrial fibrillation: minimally invasive vs. classic cut and sew maze. Innovations (Philadelphia, Pa) 2011;6:373-7.

343. Mahapatra S, LaPar DJ, Kamath S et al. Initial experience of sequential surgical epicardial-catheter endocardial ablation for persistent and long-standing persistent atrial fibrillation with long-term follow-up. The Annals of thoracic surgery 2011;91:1890-8.

344. Osmancik P, Budera P, Zdarska J, Herman D, Petr R, Straka Z. Electrophysiological findings after surgical thoracoscopic atrial fibrillation ablation. Heart Rhythm 2016;13:1246-52.

345. Richardson TD, Shoemaker MB, Whalen SP, Hoff SJ, Ellis CR. Staged versus Simultaneous Thoracoscopic Hybrid Ablation for Persistent Atrial Fibrillation Does Not Affect Time to Recurrence of Atrial Arrhythmia. J Cardiovasc Electrophysiol 2016;27:428-34.

346. Toplisek J, Pernat A, Ruzic N et al. Improvement of Atrial and Ventricular Remodeling with Low Atrial Fibrillation Burden after Hybrid Ablation of Persistent Atrial Fibrillation. Pacing and clinical electrophysiology : PACE 2016;39:216-24.

347. Zembala M, Filipiak K, Kowalski O et al. Staged hybrid ablation for persistent and longstanding persistent atrial fibrillation effectively restores sinus rhythm in long-term observation. Archives of medical science : AMS 2017;13:109-117.

348. Zembala M, Filipiak K, Kowalski O et al. Minimally invasive hybrid ablation procedure for the treatment of persistent atrial fibrillation: one year results. Kardiol Pol 2012;70:819-28.

349. Mansour M, Karst E, Heist EK et al. The Impact of First Procedure Success Rate on the Economics of Atrial Fibrillation Ablation. JACC: Clinical Electrophysiology 2017;3:129-138.

350. Cappato R, Calkins H, Chen SA et al. Up-dated Worldwide Survey on the Methods, Efficacy and Safety of Catheter Ablation for Human Atrial Fibrillation. Circ Arrhythm Electrophysiol 2009.

351. Cappato R, Calkins H, Chen SA et al. Worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circulation 2005;111:1100-5.

352. Piccini JP, Sinner MF, Greiner MA et al. Outcomes of Medicare beneficiaries undergoing catheter ablation for atrial fibrillation. Circulation 2012;126:2200-7.

353. Ouyang F, Antz M, Ernst S et al. Recovered pulmonary vein conduction as a dominant factor for recurrent atrial tachyarrhythmias after complete circular isolation of the pulmonary veins: lessons from double Lasso technique. Circulation 2005;111:127-135.

354. Lemola K, Hall B, Cheung P et al. Mechanisms of recurrent atrial fibrillation after pulmonary vein isolation by segmental ostial ablation. Heart Rhythm 2004;1:197-202.

355. Brooks AG, Stiles MK, Laborderie J et al. Outcomes of long-standing persistent atrial fibrillation ablation: a systematic review. Heart Rhythm 2010;7:835-46.

195

356. Wong CX, Abed HS, Molaee P et al. Pericardial fat is associated with atrial fibrillation severity and ablation outcome. Journal of the American College of Cardiology 2011;57:1745-51.

357. Pathak RK, Middeldorp ME, Lau DH et al. Aggressive Risk factor REduction STudy for Atrial Fibrillation (ARREST-AF Cohort Study): implications for the outcome of ablation. J Am Coll Cardiol 2014;In Press.

358. Stulak JM, Dearani JA, Sundt TM, 3rd et al. Superiority of cut-and-sew technique for the Cox maze procedure: comparison with radiofrequency ablation. The Journal of thoracic and cardiovascular surgery 2007;133:1022-7.

359. Shah DC, Lambert H, Nakagawa H, Langenkamp A, Aeby N, Leo G. Area under the real-time contact force curve (force-time integral) predicts radiofrequency lesion size in an in vitro contractile model. J Cardiovasc Electrophysiol 2010;21:1038-43.

360. Thiagalingam A, D'Avila A, Foley L et al. Importance of catheter contact force during irrigated radiofrequency ablation: evaluation in a porcine ex vivo model using a force-sensing catheter. J Cardiovasc Electrophysiol 2010;21:806-11.

361. Yokoyama K, Nakagawa H, Shah DC et al. Novel contact force sensor incorporated in irrigated radiofrequency ablation catheter predicts lesion size and incidence of steam pop and thrombus. Circulation Arrhythmia and electrophysiology 2008;1:354-62.

362. Reddy VY, Shah D, Kautzner J et al. The relationship between contact force and clinical outcome during radiofrequency catheter ablation of atrial fibrillation in the TOCCATA study. Heart Rhythm 2012;9:1789-95.

363. Kautzner J, Neuzil P, Lambert H et al. EFFICAS II: optimization of catheter contact force improves outcome of pulmonary vein isolation for paroxysmal atrial fibrillation. Europace 2015;17:1229-35.

364. Kasirajan V, Sayeed S, Filler E, Knarik A, Koneru JN, Ellenbogen KA. Histopathology of Bipolar Radiofrequency Ablation in the Human Atrium. The Annals of thoracic surgery 2016;101:638-43.

365. Takahashi K, Miyauchi Y, Hayashi M et al. Mechanisms of postoperative atrial tachycardia following biatrial surgical ablation of atrial fibrillation in relation to the surgical lesion sets. Heart Rhythm 2016;13:1059-65.

366. Ho SY, Cabrera JA, Sanchez-Quintana D. Left atrial anatomy revisited. Circulation Arrhythmia and electrophysiology 2012;5:220-8.

Jason Arya Varzaly MBBS Centre for Heart Rhythm Disorders, The … · 2018-08-30 · Centre for...

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