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