Comparative effectiveness of the new calpain inhibitor NPO-2270 versus enalapril in pressure overload-induced heart failure

Abstract Background Studies performed in multiple preclinical models support the contribution of Ca2+-dependent cysteine proteases calpains to ventricular remodelling and heart failure (HF). However, pharmacological calpain inhibition has not yet been tested patients with HF mainly due limitations available inhibitors. Purpose To determine effect NPO-2270 (NPO), a new ketoamide derivative inhibitor, mouse model pressure-overload compare its effectiveness that enalapril. Methods C57BL6 mice were subjected transverse aortic constriction (TAC) for 4 weeks. Mice randomised receive orally administered NPO or enalapril at dose 10 mg/kg/day once day, vehicle, starting day 7 after TAC surgery. The combination both drugs 1 surgery additional mice. Echocardiographic data, markers hypertrophy, fibrosis, activity cleavage substrates measured different time points. Results increased calpain-1 -2 expression activity. Administration prevented progression hypertrophy interstitial fibrosis induced by no statistically significant differences between two treatments. ongoing dysfunction was less severe group than (27% LVEF reduction control group, 6% 16% TAC, P=0.024 groups). combined treatment administration from first superior alone days TAC. These correlated better preservation cadherin-based cell adhesion complex treated NPO-2270. No adverse effects associated long-term observed sham group. Conclusions inhibitor prevents development similar efficacy but cardiac more effectively pressure overload when given equivalent doses. Funding Acknowledgement Type funding sources: Public grant(s) – National budget only. Main source(s): Instituto de Salud Carlos III Spanish Ministry Health