Novel mechanisms of Atrial Fibrillation
AuthorNalliah, Chrishan Joseph
Document TypePhD thesis
Access StatusThis item is embargoed and will be available on 2022-01-09.
© 2019 Chrishan Joseph Nalliah
This thesis has 3 distinct strands comprising of 5 separate studies, all of which evaluate novel mechanisms of atrial fibrillation (AF) in humans. The 3 strands include the impacts of sleep apnoea (OSA) (Chapters 2-4), epicardial adipose tissue (EAT) (Chapter 5) and the crista terminalis (CT) (Chapter 6) on AF mechanism. The first chapter summarizes multiple perspectives that examine the epidemiologic, mechanistic and therapeutic associations between AF and a variety of novel factors that include obstructive sleep apnoea (OSA), epicardial adipose tissue (EAT) and the unique contribution of the crista terminalis, and provide a framework for the subsequent 5 studies. While OSA has been observed to associate with AF, the composition of sleep and its relevance to AF remains poorly described. Chapter 2 evaluates the impact of the various parameters of sleep on the AF phenotype. Specifically, the impact of hypoxia on the atrial substrate is examined. These data suggest that hypoxic burden is an important factor for determining the progression of AF and provides new insights for the pathophysiologic relationship between these 2 common disorders. Chapters 3 and 4 examine the impacts of OSA and OSA management on the atrial substrate for AF. By utilizing high density mapping, chapter 3 describes the dose dependent relationship of OSA severity on the electroanatomic substrate for AF and its relationship with the AF phenotype. It observes that the strongest association between OSA and AF are observed in the paroxysmal AF cohort with severe OSA. Chapter 4 then evaluates the impacts of OSA management on reversal of atrial remodeling in OSA by utilizing a randomized controlled trial design. OSA management reverses atrial remodeling in AF. Together, these data suggest a tacit relationship between OSA and atrial remodeling, with potential for clinical reversal. Chapter 5 focuses on the impacts of EAT content on the atrial substrate in humans assessed using radiological, electrophysiologic, histologic and molecular techniques. The histologic and molecular aspects of this project were completed with the assistance of the Cardiac Phenomics Laboratory of Professor Lea Delbridge at the University of Melbourne. We observed that local EAT depots associate with local electrophysiologic, histologic and molecular changes, implying a mechanistic relationship between the 2 factors. Chapter 6 presents an epicardial high density mapping study evaluating the role of the crista terminalis (CT) for maintaining persistent AF. It assessed the electrophysiologic substrate in patients without AF and then describes the dynamics of atrial activation during persistent AF in a separate patient cohort. In addition to identifying local electrophysiologic anisotropy, this project observed increased prevalence of circuitous activation at the CT relative to other atrial regions that often associates with lines of transient block. These observations raise the proposition that the CT forms an important substrate for maintaining persistent AF. Chapter 7 concludes by summarizing the key findings of the studies and their clinical implications. Further, it paves the way for future work that might progress our understanding of AF, especially in light of new and novel mechanisms.
KeywordsAtrial fibrillation; mechanisms; arrhythmia; obstructive sleep apnoea; obesity; continuous positive airway pressure; epicardial adipose tissue; crista terminalis; risk factor modification; high density mapping; substrate; atrial remodeling; hypoxia
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- Medicine (RMH) - Theses