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.
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ItemMechanisms of atrial fibrillation in man: importance of pulmonary veins and left atrial drivers( 2012)Atrial fibrillation is thought to involve an interaction between initiating factors, usually in the form of ectopic impulses from the pulmonary veins (PVs) and an abnormal atrial substrate capable of maintaining the arrhythmia. However, the underlying pathophysiology of atrial fibrillation remains poorly understood. The main aims of this thesis are to evaluate the mechanisms of pulmonary vein arrhythmogenesis and to determine the mechanisms of persistent atrial fibrillation in humans. Chapters 2 and 3 examine important aspects of pulmonary vein electrophysiology in the context of atrial fibrillation ablation. In Chapter 2, we use double and single lung transplant surgery as models of unilateral and bilateral pulmonary vein antral isolation akin to catheter based pulmonary vein isolation approaches to determine the impact of enduring PV isolation on the maintenance of sinus rhythm. We demonstrate in a large cohort of patients undergoing lung transplantation that double but not single lung transplantation is associated with a very low incidence (0.5%) of atrial fibrillation during long-term follow up. This study highlights the importance of enduring four-vein pulmonary vein isolation in the maintenance of sinus rhythm. In Chapter 3 we demonstrate that dissociated pulmonary vein potentials occurring at the time of acute pulmonary vein isolation are common and usually manifest as slow cycle length activity or isolated ectopic beats. We demonstrate that dissociated pulmonary vein potentials are not associated with worse ablation outcomes during long-term follow up. Chapter 4 examines the underlying electrophysiological properties of the pulmonary veins. By performing high-density epicardial mapping in patients undergoing open-heart surgery without a history of AF, we demonstrate that the PV-LA junction is the area with the most marked functional conduction delay, compared to the LA and the PV itself. We demonstrate areas of slowed and blocked conduction, fractionated electrograms at the PV-LA junction and observe circuitous activation patterns across this area during programmed extra stimulation. These findings suggest that functional conduction block at the PV-LA junction may facilitate reentry and may be an important mechanism of PV arrhythmogenesis. Complex fractionated atrial electrograms (CFAE) have emerged as targets for substrate-based ablation. This is based on the premise that they identify critical sites important in the perpetuation of AF. They can be defined by electrogram morphology or purely by atrial fibrillation cycle length (AFCL<120ms). In Chapter 5 we perform high-density epicardial mapping in patients with persistent AF and demonstrate that the prevalence of CFAE is highly dependent on the definition used. We show there is poor anatomical overlap between CFAE defined by multicomponent electrograms and CFAE defined by an AFCL <120ms. Sites of multicomponent electrograms were found adjacent to areas of high dominant frequency, consistent with optical mapping studies in animal models of AF. One of the fundamental uncertainties in our understanding of AF is whether or not persistent AF is due to random multiple wavelet reentry or focal drivers contained within the atria. Because of the spatiotemporal complexity of mapping AF in humans very little is known about the underlying wave dynamics of human persistent AF. In Chapter 6 we develop an AF mapping tool that allows us to visualise wave dynamics during continuous AF. We demonstrate that majority of activations in patients with persistent AF are characterised by passive wavefront activation or disorganised activity, consistent with the multiple wavelet hypothesis. Rotors as described in optical mapping studies in animals do exist in human persistent AF but are rare. Sites of high dominant frequency, CFAE and short cycle length are thought to identify putative drivers critical in the maintenance of persistent AF. These surrogate markers are often targeted during persistent AF ablation, however their underlying mechanisms remain unclear. In Chapter 7 we use the wavemapping tool to characterise activation patterns at sites of high dominant frequency, CFAE and short AFCL. We demonstrate that the majority of these sites are activated by passive wavefronts or disorganised activity and do not reliably identify putative drivers such as rotors or sustained focal sources. These findings have implications for substrate-based ablation.
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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.
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ItemMechanisms of atrial fibrillation in humans: contributions from triggers and substrate( 2011)Atrial fibrillation (AF) remains the most common clinical arrhythmia in humans, causing significant morbidity and mortality. Current understanding involves contributions from initiating triggers and remodelled atrial substrate, however the precise nature of these remains elusive. This thesis evaluates the nature of pulmonary vein (PV) triggers and atrial substrate that contribute towards AF mechanism and the potential for reversal of atrial remodelling. Chapters 2 and 3 are introductory chapters examining the relative importance of triggers (focal PV tachycardia) and atrial substrate (flutter following atrial septal defect (ASD) surgery) by studying the incidence of AF after catheter ablation (RFA). These studies demonstrate that although AF does not occur after elimination of PV triggers in patients without atrial substrate (PV tachycardia), it commonly occurs in patients with atrial substrate (ASD surgery). Chapters 4 and 5 examine the electrophysiologic substrate of the PVs. Chapter 4 demonstrates that the PVs of both paroxysmal (PAF) and persistent AF (PeAF) patients possess lower voltage, shorter muscle sleeves, slowed conduction, altered refractoriness and more complex electrograms compared to controls. Some of the substrate remodelling was more marked in PeAF than PAF patients. Chapter 5 demonstrates that ageing is associated with a reduction in PV voltage, conduction slowing and increased signal complexity without changes in refractoriness. Together, these chapters provide insights into the mechanisms responsible for PV arrhythmogenesis and the increasing prevalence of AF with age. Although complex fractionated electrograms (CFE) are commonly targeted as AF substrate, their significance remains controversial. Chapters 6 and 7 evaluate the significance of CFE in the coronary sinus (CS) and the relationship between CFE seen during AF and paced-rhythm. Chapter 6 demonstrates that both PAF and PeAF patients demonstrate a higher prevalence of CFE and short cycle length activation and slower conduction in the CS than control patients with induced AF. There was no difference in dominant frequency and CFE were also common in the control group. Chapter 7 demonstrates that low-voltage and the proportion of CFE were significantly greater during AF than paced-rhythm. CFE during AF did not correlate with abnormal atrial substrate in paced-rhythm. Together, these chapters highlight that CFE may not always reflect abnormal atrial substrate. Chapter 8 evaluates the left atrial substrate associated with AF and demonstrates that patients with AF have lower voltage, slowed conduction and increased complex signals compared with a control population. Most of these changes were more pronounced in the PeAF than PAF group, providing further insights into the progressive nature of AF. Chapter 9 evaluates the long-term effects of RFA for AF on remodelling of the right atrial substrate. Compared to a control population, there was lower voltage, slowed conduction, increased complex signals, prolonged refractoriness and left atrial dilatation in the AF group at baseline. At 10±13 months following successful ablation, the AF group demonstrated further voltage reduction, no improvement or worsening of conduction and further prolongation of refractoriness despite a reduction in left atrial size. These observations suggest that changes in atrial substrate associated with AF are not reversed by RFA.