Medicine (RMH) - Theses
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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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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.