Effects of voluntary exercise and administration of renin angiotensin inhibitor on cardiac function in inherited dilated cardiomyopathy model.

Abstract

Dilated cardiomyopathy (DCM) is one of major causes of heart failure (HF) especially in Asia. Although exercise is regarded as one of therapies for HF, the effects of exercise on patients with DCM have not been established. A knock-in mouse model of human inherited DCM, TNNT2 ΔK210, shows similar characteristics to DCM patients. We have showed that one of angiotensin receptor blockers (ARB) is effective on cardiac function and electrical remodeling. We also have found that voluntary exercise improves cardiac function in homozygote model mice (DCM mice). In this study, we examined combination therapy of ARB and exersise in DCM mice. The DCM mice showed enlarged heart and frequent sudden death with t1/2 of ∼70 days. Male DCM mice were divided into 4 groups based on the administration of ARB and voluntary exercise: without drug or exercise (CON), oral administration of ARB (ARB), daily exercise (EXE), and combined ARB and exercise (COMB). The EXE and COMB groups started wheel running at 1 month of age. Cardiac function was measured with echocardiography and electrocardiogram at 2.5 months of age. After sacrifice, weights of body, heart, lung, and lower extremity muscles were measured. Gene expressions of HF- and arrhythmia-related genes in myocardium were quantified by qPCR analysis. There was no significant difference in driving performance between EXE and COMB (EXE: 7.0 ± 1.6 km/day (n = 8), COMB: 6.3 ± 2.2 km/day (n = 7)). On echocardiography, the ejection fraction was significantly improved in only COMB (CON: 21.7 ± 6.1% (n = 6), ARB: 26.9 ± 5.1% (n = 6), EXE: 27.2 ± 4.5% (n = 5), COMB: 31.9 ± 3.6% (n = 6)). On the other hand, the heart weight/body weight ratio decreased in the ARB and the COMB groups. Our results suggest that the combination of ARBs and exercise may have a greater effect on cardiac function in DCM mice.