BS-452682-4 EFFECTS OF CHRONIC ANGIOTENSIN CONVERTING ENZYME INHIBITION ON ATRIAL FUNCTION AND ARRHYTHMOGENESIS IN AGED AND FRAIL MICE

Abstract

Aging is associated atrial remodeling and increased susceptibility to atrial fibrillation (AF); however, aging-dependent changes can be variable. Frailty measures health status independent of chronological age, can be quantified using a frailty index (FI) and can account for heterogeneity in aging individuals. Angiotensin converting enzyme inhibition (ACEi) can impact frailty however its effects on AF and atrial remodeling are unknown. To determine the effects of chronic ACEi on atrial structure, function, and arrhythmogenesis in aged and frail mice. Wildtype mice were treated with the ACEi enalapril (20 mg/kg/day) or placebo for 6 months starting at 75 weeks of age. Mice aged 10-15 weeks were used as young controls. Mice were used in intracardiac electrophysiology, high resolution optical mapping, patch-clamping, and histology. ACEi reduced FI in aged mice (0.24 vs 0.36; n=27-31; P<0.05) without altering blood pressure. AF susceptibility was increased in aged vs young mice (100 vs 17%; n=6; P<0.05) and reduced in ACEi vs aged mice (43 vs 100%; n=6-7; P<0.05). P wave duration was reduced in ACEi vs aged mice (27.4 vs 32.5 ms; n=7; P<0.05), showed variability within age/treatment groups, and was correlated and graded by FI (R=0.91; n=20; P<0.05). Optical mapping revealed an age dependent reduction in atrial conduction velocity (CV; 35.3 vs 40.2 cm/s; n=6-9; P<0.05) while ACEi improved CV in aged mice (37.7 vs 35.3 cm/s; n=6-9; P=0.05). CV was also correlated with FI score (R=0.72; n=24; P<0.05). Patch-clamp studies in isolated left atrial (LA) myocytes identified a reduction in action potential upstroke velocity (Vmax; 150.8 vs 165.4 V/s; n=18-32; P<0.05) that was associated with a reduction in peak sodium current (INa; -38.3 vs -52.1 pA/pF; n=7-19; P<0.05) in aged vs young mice. INa was increased in ACEi vs aged (-47.2 vs -38.3 pA/pF; n=14–19; P=0.09) and not different (P=0.62) vs young mice. Importantly, Vmax (R=0.32; n=73; P<0.05) and INa (R=0.5; n=36; P < 0.05) were graded by FI. LA fibrosis was increased in aged mice vs young (10.8 vs 3.9%; n=5-8; P<0.05), reduced in ACEi vs aged mice (8.9 vs 10.8%; n=5-8; P<0.05), and strongly correlated with FI (R=0.89; n=19; P<0.05). ACEi reduced frailty in aging mice and attenuated age-related AF and atrial remodeling. Aging was associated with substantial variability within groups. Frailty was a strong predictor of changes atrial function in aging mice including after ACEi treatment, independent of chronological age.