Chronic angiotensin-converting enzyme inhibition attenuates frailty and protects against atrial fibrillation in aging mice

Abstract

BackgroundAging 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 with a frailty index (FI). ObjectiveThis study aimed to determine the effects of angiotensin-converting enzyme (ACE) inhibition on AF and atrial remodeling in aging and frail mice. MethodsAging mice were treated with the ACE inhibitor enalapril for 6 months beginning at 16.5 months of age and frailty was quantified. AF susceptibility and atrial structure and function were assessed by 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. ResultsEnalapril 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 whereas atrial fibrosis was increased in aging mice. Action potential Vmax, INa, and fibrosis were improved by enalapril and also correlated with FI scores. ConclusionACE inhibition with enalapril attenuates frailty and reduces AF susceptibility in aging mice by preventing atrial electrical and structural remodeling.