Chronic Angiotensin Converting Enzyme Inhibition Attenuates Frailty and Protects Against Atrial Fibrillation in Aging Mice

Background Aging is a major risk factor for atrial fibrillation (AF); however, not all individuals age at the same rate. Frailty, which is a measure of susceptibility to adverse health outcomes, can be quantified using a frailty index (FI). Objective To determine the effects of angiotensin converting enzyme (ACE) inhibitors on AF and atrial remodeling in aging and frail mice. Methods Aging mice were treated with the ACE inhibitor enalapril for 6 months beginning at 16.5 months of age and frailty was quantified. AF susceptibility as well as atrial structure and function were assessed using intracardiac electrophysiology in anesthetized mice, high-resolution optical mapping in intact atrial preparations, patch-clamping in isolated atrial myocytes, and histology and molecular biology in atrial tissues. Results Enalapril attenuated frailty in aging mice with larger effects in females. AF susceptibility was increased in aging mice, but attenuated by enalapril. AF susceptibility and duration also increased as a function of FI score. P wave duration was increased and atrial conduction velocity was reduced in aging mice and improved after enalapril treatment. Furthermore, P wave duration and atrial conduction velocity were strongly correlated with FI score. Atrial action potential upstroke velocity (Vmax) and Na+ current (INa) were reduced while atrial fibrosis was increased in aging mice. Action potential Vmax, INa, and fibrosis were improved by enalapril and also correlated with FI scores. Conclusions ACE inhibition with enalapril attenuates frailty and reduces AF susceptibility in aging mice by attenuating atrial electrical and structural remodeling.