INSIGHTS INTO THE BASIS FOR ATRIAL ELECTROPHYSIOLOGICAL REMODELLING AND ARRHYTHMOGENESIS IN HYPERTENSIVE HEART DISEASE, AGEING, AND FRAILTY

Abstract

Atrial fibrillation (AF) is a major complication in heart disease and is linked to alterations in Angiotensin II (Ang II) signalling; however, the effects of Ang II on atrial electrophysiology is poorly understood. Natriuretic peptides (NPs) are a family of cardioprotective hormones that elicit their effects by binding to NP receptors denoted NPR-A, NPR-B, and NPR-C; however, their role in atrial arrhythmias and heart disease is poorly understood. In addition, the prevalence of cardiovascular disease increases with age; however, individuals age at different rates such that overall health status varies from fit to frail. Accordingly, the goals of this thesis were to characterize the effects of Ang II treatment on atrial electrophysiology and determine the role of NPR-C in modulating disease progression. The last goal of this thesis was to determine the effects of age and frailty on cardiac function in vivo. Ang II treated wildtype mice had an increased susceptibility to AF. Patch-clamp studies revealed Ang II treatment was associated with distinct patterns of electrical remodelling in right and left atrial myocytes. Ang II treatment in NPR-C-/- mice resulted in a more severe disease phenotype. Electrical remodelling was not different in right atrial myocytes and worsened in left atrial myocytes from Ang II treated NPR-C-/- vs. NPR-C+/+ mice. Strikingly, mice co-treated with Ang II and cANF (a selective NPR-C agonist) had improvements in in vivo atrial function and a reduced susceptibility to AF. Electrical remodelling was normalized in Ang II with cANF treated right, but not left, atrial myocytes. There is a decline in SAN and atrial function with chronological age. By quantifying frailty (overall health status), this thesis demonstrates SAN and atrial function are correlated with frailty. Collectively, these findings demonstrate Ang II treatment is associated with distinct patterns of electrical remodelling in atrial myocytes and NPR-C plays a critical role in atrial disease progression. In fact, enhanced NPR-C signalling can be used as a therapeutic target for the treatment and prevention of AF. Frailty can be used as a powerful tool to predict SAN and atrial function, and should be considered when treating patients with cardiac disease.