Substrate for atrial fibrillation in cardiomyopathies.

Abstract

Atrial Fibrillation is the most common heart rhythm disorder. However, our understanding of the underlying patho-physiological mechanisms of AF remains limited. Both hypertension and heart failure are known to play an important role as risk factors for AF. With the increase in the incidence and prevalence of both these conditions and the predicted atrial fibrillation epidemic, their underlying mechanistic associations require careful attention. This thesis focused on the evaluation of atrial remodeling in large animal models of these common substrates. Chapter 2 presents the detailed anatomical, histological and functional characterization of the cardiac changes in the ovine “one-kidney, one-clip” model of hypertension using state of the art cardiac magnetic resonance imaging. Chapter 3 presents the significant atrial electrical, structural and functional remodeling evident with short duration (mean of 7 weeks) of hypertension. Pivotal changes were seen in increased atrial interstitial fibrosis and the resultant conduction abnormalities. This highlighted the importance of early and aggressive therapy of hypertension which may prevent the development of an arrhythmogenic atrial substrate. Chapter 4 examines the time course of atrial remodeling during the development of hypertension over a period of 15 weeks. Anatomical and functional remodeling started early while structural changes in increased fibrosis occurred later in the remodeling process. The early changes were associated with increased atrial fibrillation inducibility while the late changes were associated with more prolonged induced atrial fibrillation episodes. This understanding of the time course of remodeling provided important insights, whereby a narrow window of opportunity exists for preventing more permanent structural changes that can sustain atrial fibrillation. This work also implicates the need to maintain good blood pressure levels in atrial fibrillation patients. In particular, recent evidence has shown that pre-hypertension is associated with increased incidence of atrial fibrillation. To date, experimental studies on atrial remodeling in heart failure had utilized one single animal model of rapid ventricular tachypacing induced heart failure. This model may not be representative of all types of cardiomyopathy in the heart failure syndrome since different underlying causes of heart failure have been shown to portend different prognostic value. Chapter 5 further evaluates atrial remodeling in heart failure using a recently characterized ovine model of non-reversible doxorubicin-induced non-ischemic cardiomyopathy. The main feature of atrial remodeling lies in the structural changes of atrial interstitial fibrosis with increased conduction heterogeneity which resulted in longer induced atrial fibrillation episodes. These findings suggest a consistent substrate for atrial fibrillation in different heart failure models indicating ‘remodeling of the same sort’. Chapter 6 presents the atrial effects of omega-3 fatty acids treatment in ovine heart failure. Omega-3 fatty acids prevented atrial enlargement, reduced atrial fibrosis and the related conduction abnormalities resulting in shorter atrial fibrillation episodes. Clinically, omega-3 fatty acids have been shown to provide additional albeit modest improvement in outcomes of heart failure patients above current evidence-based therapies. Therefore, omega-3 fatty acids may potentially provide a relatively affordable and non-toxic option to prevent adverse atrial remodeling and reduce atrial fibrillation burden in this subgroup of patients with heart failure.