Atrial fibrillation and obesity: characterization of electro-structural atrial substrate with sustained obesity and reversal upon weight reduction.

Abstract

Atrial fibrillation (AF) is the most prevalent arrhythmia affecting humans. The identification of risk factors for AF has ushered a risk factor based approach for management. Obesity is a highly prevalent and novel risk factor for AF with a potential for reversibility. The epidemiological link between obesity and AF has been established in population based studies; however the atrial substrate remains to be fully characterized. Furthermore, mechanism and degree of reversibility with weight reduction has not been described. This thesis evaluates the various aspects of endocardial and epicardial atrial remodeling with sustained obesity and the underlying mechanisms in an ovine model. It also examines the endocardial atrial remodeling with obesity in humans and its relationship with epicardial adipose tissue. In addition, the reversal of obesity related atrial substrate with weight reduction has been characterized in a sustained obesity ovine model. Chapter 2 examines the endocardial electrophysiological remodeling with sustained obesity in an ovine model. Sustained obesity was associated bi-atrial slow and heterogeneous atrial conduction with increased fractionation and greater vulnerability for AF. There is no significant alteration in endocardial atrial refractoriness. Although there was no difference in mean voltage there was increased voltage heterogeneity. Obesity was associated with overexpression of pro-fibrotic TGFβ1 and increased atrial fibrosis. Infiltration of the epicardial atrial musculature by the contiguous fat was seen and this could represent a unique substrate for AF in obesity. Chapter 3 describes the reversal of the obesity related atrial substrate with weight reduction in an ovine model. Sustained obesity was associated with bi-atrial epicardial slow and heterogeneous conduction, reduced atrial refractoriness (epicardial) and increased propensity for AF. This was associated with hemodynamic stress and diastolic dysfunction. Histologically obesity was associated with atrial fibrosis, inflammation and fatty infiltration. There was up-regulation of atrial TGFβ1 expression and Endothelin receptor B. The TGFβ1 expression correlated with electrophysiological changes and atrial fibrosis, and this relationship persisted even after adjusting for left atrial pressure. There was decreased expression of atrial gap junction protein Connexin43 expression. The changes observed with sustained obesity were reversed with moderate weight reduction. Chapter 4 describes the electrophysiological reverse remodeling with weight reduction in an ovine model. Weight reduction resulted in improvement in endocardial atrial conduction velocity and decrease in conduction heterogeneity. However, the atrial refractoriness from endocardial sites did not change with either obesity or weight reduction. This is in contrast to epicardial atrial refractoriness which shortened with sustained obesity and improved to control values with weight reduction. This endocardial- epicardial dissociation in atrial refractoriness may represent part of the unique substrate for AF in obesity. Chapter 5 describes the validation of atrial pericardial fat assessment on cardiac magnetic resonance imaging against the gold standard of autopsy. Chapter 6 describes the electroanatomic remodeling with obesity in humans and describes the association with atrial pericardial fat.