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.