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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ItemMechanisms and consequences of atrial fibrillation: insights into the electrical mechanisms sustaining atrial fibrillation, the drivers of underlying atrial remodeling, and the factors governing symptom severity and quality of life( 2015)Atrial fibrillation (AF) exists on a clinical spectrum from paroxysmal to persistent and eventually permanent AF. Progression through this spectrum is well described, but is not universal. Mechanistically, paroxysmal AF is driven by fast electrical triggers most commonly located in the myocardial sleeves of the pulmonary veins, whilst persistent AF is dependent on perpetuating electrical mechanisms rooted in an abnormal atrial substrate. The nature of these mechanisms remains a subject of debate, with recent evidence pointing towards rotors, a form of functional reentry, providing a driving source for human persistent AF. Various studies have ascribed quite different properties to these rotors. More severe abnormalities in the electroanatomic properties of the left atrium (LA) have been demonstrated in persistent than in paroxysmal AF, and improvement in such properties has been described after catheter ablation of AF, but there is little data describing the rate of deterioration in LA properties with ongoing AF, or the key drivers of change. Finally, it is recognized that AF is frequently associated with significant quality of life impairment, but there is a wide spectrum of clinical severity and the factors governing this variation are incompletely understood. Chapters 2 and 3 of this thesis examine the atrial substrate. The extent of remodeling of the LA is a key determinant of the success of catheter ablation, and so non-invasive techniques with which to assess remodeling are keenly sought. In chapter 2, the association between the extent of LA electroanatomic remodeling and the fibrillatory cycle length derived from lead V1 of the surface electrocardiogram during AF is characterized. It is demonstrated that a longer AF cycle length in lead V1 is associated with more advanced LA remodeling, specifically slower atrial conduction and more extensive electrogram fractionation. Given that gender-based differences in clinical behaviour of multiple cardiac arrhythmias are well described, the presence of systematic gender-based differences in the pulmonary vein and atrial substrate is examined in chapter 3. No such between-gender differences were observed, either in those with or without a history of AF, and with a similar prevalence of AF-related comorbidities seen in both male and female groups. Chapters 4, 5 and 6 move to an exploration of the electrical mechanisms underlying AF, through detailed epicardial mapping studies of the LA and its junction with the pulmonary vein (PV-LA junction). Chronic stretch is fundamental to atrial remodeling in human AF, and conditions associated with acute stretch are recognized triggers for episodes of AF. In chapter 4 the response of the PV-LA junction to acute stretch was characterized, with the observation that acute stretch results in conduction slowing across the PV-LA junction and a greater degree of signal complexity, providing conditions suitable for reentry. Chapters 5 and 6 involved epicardial mapping in patients with longstanding persistent AF, with the aim of determining the spatiotemporal stability of the AF cycle length and of atrial activation patterns, including the stability of any demonstrated rotors, over a 10 minute period. This is a time period much in excess of that over which detailed mapping has previously ben performed. It was observed that atrial activation patterns are spatiotemporally stable over this time scale, with clear anatomic determinism, and that in the great majority of patients transient rotors can be demonstrated. These appear to last only a median of 3 cycles, usually develop due to perpendicular wavefront-wavetail interaction, and are commonly anchored on a region of short cycle electrical activity. Such activity, however, is highly non-specific for rotor localization, more often being the result of passive wavefront collision. The frequency of atrial activation appears much more variable over 10 minutes, but there was clear inter-dependence between left and right atrial cycle lengths during mapping of anatomically disparate regions, and within each region the relative distribution of locations with faster and slower activation frequencies was highly conserved. These observations, indicating significant underlying spatiotemporal organization, are consistent with the presence of focal drivers such as rotors governing global atrial activation. Chapter 7 returns to the issue of atrial remodeling, with the aim of defining the magnitude and the predictors of change in the extent of LA electroanatomic remodeling over 12 months of high burden AF. Using measures of atrial myocardial deformation characteristics derived from strain imaging to of the atrial wall and P-wave characteristics as non-invasive biomarkers of remodeling, ongoing high burden AF was found to be associated with measurable progression in the extent of LA remodeling even over a 12 month period, whilst after AF ablation in a similar cohort results there was significant reversal of existing remodeling. These data may have implications for timing of ablative intervention. Finally, chapter 8 addresses the key determinants of AF symptom severity and quality of life. It is demonstrated that a high proportion of patients with AF experience significant psychological distress and even thoughts of self-harm. Clinical variables including age, body mass index and the burden of AF influence the perceived severity of the AF syndrome, with key differences between patients with intermittent and continuous forms of AF. The influence of organic cardiac variables, however, is subsumed by the dominant influence of personality style, with a predisposition to perceive life events as stressful and a chronic tendency to anxiety and negativity particularly powerful. Effective rhythm control through AF ablation was found to lead to marked improvements in AF symptom severity, quality of life and levels of psychological distress, suggesting that psychological distress is a consequence of the arrhythmia itself interacting with a vulnerable personality style.