Influence of an ACE inhibitor on frailty and cardiac function in old male C57BL/6 mice

Abstract

Background: Frailty is the accumulation of health deficits over the lifespan. Frailty results in increased risk of adverse outcomes including poor cardiovascular outcomes. Angiotensin converting enzyme (ACE) inhibitors improve exercise capacity in older adults without cardiovascular disease, and could be a potential frailty intervention. The aim of this study was to investigate whether chronic treatment with the ACE inhibitor enalapril would attenuate frailty in mice, and whether this occurs through changes to cardiac function. Methods: Male C57BL/6 mice (17 months) were fed enalapril containing chow (40 mg/kg/day; n=25) or control feed (n=13). After 6 weeks blood pressure (BP) was measured with a tail-cuff. Once the mice were 24 months old (7 months treatment), frailty was quantified with a validated mouse frailty index and in vivo cardiac function was measured using echocardiography. Results: Frailty index scores were significantly lower in the enalapril group than the control group after 7 months (0.24 ± 0.01 vs 0.29 ± 0.01, p<0.001). Enalapril treatment also resulted in lower systolic BP (85.0 ± 10.5 vs 98.1 ± 12.3 mmHg, p<0.01), with a trend towards decreased diastolic BP (65.4 ± 4.0 vs 75.8 ± 3.9 mmHg, p=0.08). Echocardiography showed changes to the left ventricle (LV) of the enalapril treated mice compared to control, including a thinner LV anterior wall in systole (1.38 ± 0.08 vs 1.60 ± 0.05 mm, p<0.05), smaller LV mass (127.2 ± 9.6 vs 180.7 ± 14.4 mg, p<0.01) and reduced stroke volume (36.5 ± 2.4 vs 48.5 ± 3.6 μl, p<0.01) and cardiac output (18.3 ± 1.2 vs 23.2 ± 1.7 ml/min, p<0.05). Conclusion: Enalapril treatment attenuated frailty in old male mice. As expected it also resulted in reduced blood pressure. Cardiac mechanisms contributing to the attenuation of frailty may include changes to the structure and function of the heart.