Medicine (RMH) - Theses
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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.