Medicine (RMH) - Theses
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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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ItemInsights into mechanisms and effects of omega-3 polyunsaturated fatty acid supplementation in human atrial fibrillation( 2012)Atrial fibrillation (AF) is the most common cardiac arrhythmia in humans, causing significant morbidity, mortality and health care expenditure. Anti-arrhythmic drugs are the cornerstone of AF management but are limited in their efficacy, side effects and potential for pro-arrhythmia. A concordance of in vivo and in vitro animal experimental studies have demonstrated that omega-3 polyunsaturated fatty acids (ω-3 PUFAs) in fish oils may have anti-arrhythmic and anti-fibrillatory effects. However, definitive demonstration of the efficacy of fish oils in human AF has remained elusive. This thesis systematically evaluates the mechanisms and effects of ω-3 PUFAs in human AF incorporating the vast body of pre-clinical information from animal experimental paradigms, information on ω-3 PUFA dosing, duration of supplementation, kinetics of membrane incorporation and the importance of form of administration. The thesis characterises the effects of ω-3 PUFAs on human atrial electrical and mechanical function and examines the efficacy of ω-3 PUFAs on clinical AF endpoints. Chapter 1 describes the current state of knowledge about AF mechanisms in the absence and presence of structural heart disease, mechanisms of action and efficacy of contemporary anti-arrhythmic and anti-remodeling drugs and the pre-clinical and clinical evidence for ω-3 PUFAs in cardiac arrhythmias. Chapter 2 assesses the use of AF inducibility as a metric for future experimental chapters and its appropriateness for use as a clinical endpoint after electrical isolation of the pulmonary veins for AF. This study demonstrates that in the absence of structural heart disease or clinical AF, inducible and sustained AF occurs at a similar frequency to that noted in patients with a history of AF. It highlights the criticality of the induction protocol, inducibility definitions and number of inductions on rates of AF inducibility and persistence. Chapter 3 and 4 are the first randomised human studies of their kind to examine the effects of long-term ω-3 PUFA supplementation (>30 days) on human atrial electrophysiology in the absence of confounders such as structural heart disease or a history of clinical AF or flutter (Chapter 3) and on pulmonary vein and left atrial electrophysiology in the presence of paroxysmal AF (Chapter 4). Both studies showed that long-term supplementation results in chronic incorporation of ω-3 PUFA in plasma phospholipids. This results in significant prolongation of right, left atrial and pulmonary venous refractoriness. Long-term oral ω-3 PUFAs had no effect on atrial or pulmonary venous conduction. Most importantly, both studies showed a significant reduction in vulnerability toward and persistence of AF, an effect attributed to refractory period prolongation. Together, these studies provide mechanistic insights into the anti-fibrillatory effects of long-term oral ω-3 PUFA exposure. Chapter 5 examines the effects of long-term ω-3 PUFA supplementation on human atrial mechanical function after reversion of persistent atrial arrhythmias to sinus rhythm. Reversion of persistent atrial arrhythmias to sinus rhythm is associated with transient depression of left atrial mechanical function, a phenomenon known as atrial mechanical stunning. Stunning is implicated in the heightened risk of thromboembolic complications such as stroke, failure of improvement in cardiac output and exercise tolerance, and increased risk of recurrence atrial arrhythmias. The main finding was that patients randomised to fish oils, compared to controls, had markedly reduced incidence of atrial mechanical stunning. This study provides insights into how fish oils can attenuate adverse atrial remodeling in response to persistent atrial arrhythmias. Chapter 6 is a randomised clinical trial examining the efficacy of long-term fish oils in the prevention of persistent AF recurrence post electrical cardioversion in a high risk population. Patients were randomised to control or fish oil groups; the latter was commenced >1 month prior to cardioversion and continued till return of AF or maximum of 1 year. The main finding was that fish oil patients had higher rates of pharmacological reversion, and a significantly lower risk of persistent AF recurrence compared to controls at 1 year. These effects were seen in the presence or absence of concurrent anti-arrhythmic drugs. This study shows the critically of long-duration, high dose supplementation to allow sufficient time for maximal myocardial incorporation and for the all expected electrophysiologic, anti-remodeling and anti-inflammatory mechanisms of ω-3 PUFA to take effect before assessment of clinical endpoints, an approach rarely used in previous clinical studies. Chapter 7 is a prospective randomised study examining if long-term ω-3 PUFA supplementation (6 or 12 months) reduces burden of paroxysmal atrial tachycardia/fibrillation (AT/AF) in a high risk population of elderly patients with sinus node dysfunction, implanted dual chamber pacemakers and a history of the same arrhythmias. The main findings were that whilst fish oils did not suppress AT/AF burden per se, they significantly attenuated temporal progression of AT/AF burden over time that was seen in controls over 18 months of follow up. There was no demonstrable effect on arrhythmia triggers, but significantly shorter episodes of AF were seen suggesting that the predominant effect of fish oils are on atrial substrate. This study demonstrates that long-term ω-3 PUFA supplementation reduces paroxysmal atrial arrhythmia burden likely mediated by effects on atrial structural remodeling. Chapter 8 is the first human study of its kind examining the effects of acute, intravenously delivered, high dose ω-3 PUFAs on human atrial electrophysiology. The main findings were that when given intravenously, fish oils are predominantly present as free ω-3 PUFAs, with little or no membrane incorporation. Free ω-3 PUFAs predominantly caused atrial conduction slowing with minimal effects on atrial refractoriness which was in contrast to the previous observations that incorporated ω-3 PUFAs had no effect on atrial conduction, but prolonged atrial refractoriness. Moreover, free ω-3 PUFA reduced AF inducibility and persistence, organised inducible AF into atrial flutter and significantly increased the inducibility of atrial flutter in patients with no clinical history of this arrhythmia. This study provides novel insights into the complex effects of incorporated versus free ω-3 PUFAs on atrial electrophysiology and provides evidence for a future clinical study examining the efficacy of high dose IV fish oil on acute AF termination.