Medicine (RMH) - Theses
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ItemMechanisms Driving Persistent Atrial Fibrillation: Insights from Endocardial-Epicardial Dissociation and Regional High-Density Mapping of the Human Atrium( 2020)Atrial fibrillation (AF) is an extremely common clinical problem with increasing global prevalence. Besides its frequent association with stroke, heart failure and increased mortality, recent data have shown the significant quality of life impairment and psychological distress that results from this arrhythmia. The clinical spectrum of AF can manifest as brief episodic paroxysmal AF or as a sustained arrhythmia in persistent AF in patients with progressive atrial disease. Mechanistically, paroxysmal AF is often triggered by rapidly firing impulses that originate in the pulmonary veins, allowing catheter-mediated elimination of sources, with clinical success rates of 70–85%. However, in persistent AF, the mechanism that sustains the arrhythmia remains incompletely understood and is a topic of ongoing debate. Recent advances in cardiac mapping and computational methods have suggested localised drivers and non-pulmonary vein triggers particularly from the left atrial appendage but there is also accumulating evidence that the atrium frequently functions electrically as a 3-dimensional structure and there exists endocardial-epicardial dissociation in activation during AF. The aims of this thesis are three-fold: Firstly, we review the evidence for the current and expanding indications for catheter ablation in AF and highlight some of the novel tools and technological advancements that have emerged in the recent years for achieving durable pulmonary vein isolation (PVI). Secondly, we investigate the role of some of the novel mechanisms that potentially sustain persistent AF. We addressed this first by systematically reviewing the evidence for a computational mapping technique thought to identify localised sources and then performed a series of cardiac mapping studies in humans. These high-density mapping studies characterised atrial endocardial-epicardial electrical dissociation in the presence of structural heart disease and explored the mechanistic role of localised sources in the left atrium and the left atrial appendage (LAA) in persistent AF. Finally, given the emerging evidence for the mental health effects from AF, we discuss the rationale and methodology of a randomised controlled study comparing catheter ablation with medical therapy on psychological distress and neurocognitive function in patients with AF. Chapter 1 summarizes several aspects of AF including the epidemiology, our current understanding of the classic and novel mechanisms of AF the mechanistic role of risk factors and their implications in remodelling and atrial cardiomyopathy. Chapter 2 reviews the role of catheter ablation in AF and highlights the recent technological advancements. Catheter ablation is a safe and effective rhythm control strategy for symptomatic patients who failed medical therapy or who prefer not to take medications and there is emerging evidence for its role in mortality reduction in AF patients with heart failure. Pulmonary vein isolation is the cornerstone approach and both radiofrequency and cryoablation have similar efficacy. Mounting evidence demonstrates the importance of risk factor management for improving ablation outcomes. In the era of high-density cardiac mapping, FIRM (focal impulse and rotor modulation) emerged as a novel computational mapping technique to identify rotors and focal sources that could potentially be targeted during catheter ablation. Despite early promising results, many studies that followed showed mixed outcomes and indeed, some others showed a pro-arrhythmic consequence. Chapter 3 presents a systematic review and meta-analysis of 11 observational studies and demonstrates the wide variability in the medium-term outcomes of FIRM guided ablation and explores the significant heterogeneity between published studies. Chapters 4 and 5 examine the characteristics of endocardial-epicardial dissociation (EED) in patients with structural heart disease. We performed high-density simultaneous endocardial-epicardial phase mapping of the right atrium in patients undergoing cardiac surgery to study this. In Chapter 3 we report the for the first time, functional EED based on observations of synchronous activation during sinus rhythm and EED in activation timing and wavefront propagation during pacing drive and premature extra-stimulation providing compelling evidence for the functional nature of the atrial substrate. Chapter 4 presents data of phase mapping prolonged persistent AF recordings. The results provide novel evidence for endocardial-epicardial wave front mismatch in AF along with marked EED with temporal heterogeneity. In Chapter 6 we sought to characterise the preferential 3-dimensional nature of sinoatrial conduction in humans using simultaneous endocardial-epicardial mapping of the sinus node region. In intact hearts of patients with structural heart disease, data confirmed the presence of multiple differential endocardial and epicardial sino-atrial exits and hence the redundant structure of the pacemaker complex. This is consistent with data from optical mapping of ex-vivo human hearts and demonstrates that clinical sinus node dysfunction only occurs in the setting of advanced atrial structural remodelling. Recently, data from cohort studies and a randomised controlled trial have shown that LAA isolation improves ablation outcomes in patients undergoing redo ablation for persistent AF. However, there have been concerning reports that such empirical ablation is associated with a heightened risk of LAA thrombus, even in patients who are anticoagulated. Furthermore, data from mapping studies have also shown mixed results on the potential role of LAA as a driver in persistent AF. In Chapter 7 we examine the role of localised sources in the left atrium particularly in the LAA by performing regional high-density mapping of persistent AF. In addition to finding infrequent drivers in the left atrium, this project also showed paucity of triggers from the LAA providing further evidence of its passive role rather than an active driver in persistent AF. Besides physical symptoms that patients with AF experience, recent data has shown the enormity of mental health effects that AF can have that is often underappreciated by clinicians. More importantly, preliminary data from observational studies show the benefits of catheter ablation to improve mental health. Chapters 8 and 9 present the methodology and rationale of a multicentre, randomised controlled trial that assesses the impact of catheter ablation on psychological distress and neurocognitive function in patients with AF. The study has completed recruitment and successfully enrolled 100 participants across the Royal Melbourne and Alfred Hospitals and completion of analysis is expected by March 2022. Chapters 10 and 11 conclude by summarizing the key findings of the studies and their clinical implications. Further, it paves the way for future work that might progress our understanding of AF, especially in light of novel mechanisms
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ItemA multi-faceted approach to atrial fibrillation: from lifestyle factors to invasive therapies( 2019)Atrial fibrillation (AF) is a leading epidemic of cardiovascular disease in developed countries, owing to an ageing population and the Western lifestyle. In addition to effects on quality of life and economic burden on the health system, AF is associated with heart failure, stroke and a higher risk of mortality. The focus of AF management over the last decade has shifted from anticoagulation and rate control to a more a more holistic and multi-faceted approach. This encompasses attention to potentially modifiable lifestyle factors and adoption of novel invasive strategies such as catheter ablation to maintain rhythm control. The aim of this thesis is to explore these emerging strategies in AF management, with a focus on rhythm control. Initially, we assess the impact of lifestyle related factors on AF and cardiovascular disease. The emphasis initially is on the effects of habitual alcohol consumption on the atria and ventricles and the impact of abstinence in the AF population. We explore novel strategies for cardioversion of persistent AF, focussing on improving success rates in obese patients. Finally, we explore the evolution of catheter ablation as an increasingly utilized rhythm control strategy. Chapter 1 details our evolving understanding of AF pathogenesis, and the impact of common lifestyle factors on arrhythmogenesis, with a focus on alcohol, caffeine, diet and obesity. We then explore the evidence base for rhythm control strategies, including role of anti-arrhythmics, cardioversion and catheter ablation. Chapter 2 and 3 explore the impact of regular alcohol consumption on the atrium to determine whether there is an association with electrical and structural remodelling. Chapter 2 is a prospective observational study of 75 patients undergoing novel high-density electroanatomical mapping of their left atria at the time of AF ablation. We compare non-drinkers, mild drinkers and moderate drinkers to determine whether there are differences in voltage and conduction properties between the three groups. Chapter 3 is a prospective observational study of 160 AF patients comparing atrial size, mechanical and reservoir function based on degree of alcohol intake utilizing high-definition cardiac magnetic resonance imaging (CMR). We conclude that moderate-to-heavy levels of consumption are associated with adverse atrial remodelling, characterised by reduction in voltage, slowing of atrial conduction, atrial dilatation and impaired mechanical function suggestive of progressive fibrosis. Chapter 4 is a randomized controlled trial of 140 moderate habitual drinkers with a history of AF. We examine the impact of 6 months of abstinence on risk of AF recurrence, AF burden, symptom scores, blood pressure, weight and atrial structure / function. Key findings include reduction in AF recurrence rates, with small but significant reductions in systolic blood pressure and weight. This is the first randomized trial to demonstrate the benefits of abstinence from alcohol in the AF population. Chapter 5 examines the paradox between adverse effects of moderate alcohol consumption on the atrium and AF with widely reported benefits of light-to-moderate habitual alcohol consumption with respect to cardiovascular disease, heart failure and mortality. We undertook a cross-sectional study of 165 stable outpatients comprising of lifelong non-drinkers and regular drinkers. Participants underwent cardiac MRI T1 mapping, a novel imaging sequence that examines markers of ventricular fibrosis. Interestingly, light-to-moderate drinkers displayed lower markers of fibrosis. The clinical implications of this finding require further investigation. Chapter 6 focusses on novel and improved treatment strategies for persistent AF in obese patients. We undertook a randomized controlled trial of 125 obese patients undergoing cardioversion for AF (as well as an observational sub-study of morbidly obese patients). Key findings included higher success rates with the use of hand-held paddles, manual pressure augmentation and higher energies (up to 360 Joules biphasic). Chapter 7 also focuses on improving outcomes for cardioversion in persistent AF, looking at the strategy of early presentation for cardioversion in the emergency department. We report a retrospective cohort study of 150 patients and conclude that compared to (delayed) elective cardioversion, earlier restoration of sinus rhythm prevented adverse atrial remodelling, delaying onset of next AF recurrence and improving quality of life. Chapter 8 examines our evolving understanding of ablation strategies for persistent AF. Recent studies highlight that adjunctive substrate modification beyond pulmonary vein isolation (PVI) may not offer additional benefit and may in fact be pro-arrhythmic. We perform a meta-analysis of 14 studies reporting outcomes from PVI alone in this patient population. We conclude that with current technology, acceptable arrhythmia-free survival can be achieved without additional substrate modification. Chapters 9 and 10 report observational data from our institution with the aim of critically assessing key performance measures for catheter ablation of AF over time. Chapter 9 demonstrates a significant reduction in radiation exposure over time for both operator and patient, and examines the factors responsible. Chapter 10 focuses on procedural safety over time through the prism of increasing patient complexity, greater operator experience and technological advances over time. We conclude that at a high-volume centre, catheter ablation is an acceptable strategy that can be performed safely in a large majority of patients.
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ItemAtrial fibrillation and systolic heart failure: the role of myocardial fibrosis and catheter ablation( 2017)Atrial fibrillation and systolic dysfunction are both emerging epidemics in the developed world and both frequently co-exist. Each condition, both individually and in combination, are associated with significantly worsened morbidity and mortality. Both share pathophysiological mechanisms and may promote the progression of each other. Traditional pharmacological therapies for AF have limited efficacy, which is also the case in patients with concurrent systolic dysfunction. Catheter ablation has emerged as an effective treatment for AF with superior outcomes compared to pharmacological rhythm control, the current standard of care. An increasing body of evidence has shown that catheter ablation is feasible and effective in patients with systolic dysfunction. Nonetheless, identifying those patients with systolic impairment likely obtain the greatest benefit from catheter ablation remains a evolving challenge. Additionally, the electrophysiological and structural changes associated with the co-morbid AF and systolic dysfunction is yet to be fully elucidated. The central aim of this thesis is to comprehensively evaluate the role of catheter ablation as a treatment for systolic dysfunction. Following a comprehensive review of the relevant existing literature in this area in Chapter 1, Chapters 2, 3 and 4, of this thesis seek to clinically evaluate the effectiveness of catheter ablation in selected patients with systolic impairment and AF, with a particular focus on utilising advanced imaging techniques such as cardiac magnetic resonance imaging (CMR), as a tool to optimise patent selection, and evaluate treatment outcomes. Secondly in Chapters 5 to 8, this thesis seeks to characterise the electrophysiological and structural characteristics of patients with AF in the setting of systolic impairment and additionally to highlight the limitations and challenges of catheter ablation in persistent AF, with a focus on pulmonary vein electrical activity and the role of intra-procedural adenosine.
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ItemThe remodelled atrium: causes, and implications for curative ablation( 2012)Atrial fibrillation has been described as an evolving epidemic in the setting of an aging population. Ongoing research into the atrial substrate responsible for maintaining atrial fibrillation is fundamental to therapeutic advances. There have been considerable advances in ablation techniques aimed at treating and potentially curing atrial fibrillation. To date success has been achieved predominantly in patients with paroxysmal atrial fibrillation with structurally normal hearts where presumably the triggers are more important than the substrate. The developments of technology and ablation techniques are currently evolving more rapidly than an understanding of their impact on the remodeled atria. It remains unclear whether “sinus rhythm begets sinus rhythm” a key premise in AF ablation strategies. The aims of this thesis were to provide important original insights into both the electrical and structural remodeling responsible for atrial arrhythmias; and to the therapeutic implications for a procedure targeting this arrhythmia that is becoming increasingly performed in an expanding patient population. Hypertension is the most prevalent, independent and potentially modifiable risk factor for atrial fibrillation. In Chapter 2 conventional electrophysiologic studies were performed in patients with hypertension and no prior history of atrial fibrillation. The aim of this study was to gain insight into the underlying substrate before it is modified by the arrhythmia itself. This has been recognized as “atrial remodeling of a different sort”. In Chapter 3 we studied a population of patients with idiopathic pulmonary hypertension to study the atrial effects of pulmonary hypertension in the absence of the confounding effects of other disease states, such as obstructive sleep apnoea and chronic obstructive pulmonary disease. A better understanding of the atrial effects of pulmonary hypertension may help dissect out the relevant pathophysiologic factors responsible for the vulnerability to AF in these varied clinical conditions. In Chapter 4 the comparison of atrial substrate changes between patients with atrial fibrillation and atrial flutter are presented. Atrial fibrillation and atrial flutter are the most common sustained arrhythmias seen in clinical practice. Whilst there may be alternate expression of both AF and AFL in an individual patient, clinically one of these arrhythmias often predominates. Although it has been well recognized that both arrhythmias are associated with atrial substrate remodeling, to date there has been no direct comparison of atrial substrate changes in patients with AFL vs. AF. It has recently been recognized that atrial fibrillation is a risk factor for dementia in an aging population. However, the prevalence of neurocognitive abnormalities in a young low-risk population of AF patients is unknown. Chapter 5 describes the prevalence of neurocognitive abnormalities in patients with atrial fibrillation (paroxysmal and persistent atrial fibrillation); and an age-matched population of patients with supraventricular tachycardia, compared to normative controls. Our understanding of the efficacy and safety of catheter ablation is continuing to evolve as the procedure becomes more widespread and with longer follow up. Chapter 6 describes the change in neurocognitive outcomes after ablation for AF in patients with PAF and PeAF and in patients with ablation for supraventricular tachycardia, in comparison to patients with AF without ablation. The aetiology of neurocognitive abnormalities post AF ablation is likely to include cerebral microembolism. Chapter 7 describes the prevalence of cerebral microembolism occurring during AF ablation. Importantly, and a highly original finding, we report the composition of cerebral emboli (gaseous vs. solid) using a multi-frequency transcranial Doppler ultrasound. A significant part of this thesis details the formation of the atrial substrate that supports atrial fibrillation yet triggers from rapidly firing foci in the right and left atrium may be responsible for the initiation of focal atrial tachycardia. In Chapter 8, the incidence of tachycardia-induced cardiomyopathy among patients with focal atrial tachycardia is presented, with the electrophysiologic characteristics and the long-term clinical outcomes after successful catheter ablation. In summary this thesis provides insights into the atrial substrate responsible for arrhythmias that is critical in the development of further therapeutic advances. However, advances in therapy must include a comprehensive understanding of the safety profile. Further insights into these will lead to better clinical management and improvement in treatment strategies.