Abstract Body: Background: An effective pharmacological therapy yet exists to mitigate mitral regurgitation (MR) progression before surgical interventions. Angiotensin receptor-neprilysin inhibitor (ARNI) has shown benefits in patients with heart failure (HF) with reduced ejection fraction but whether it can reduce degenerative MR induced HF remains unknown.
Aim: To test the efficacy of ARNI in improving cardiac function in degenerative MR -induced HF.
Methods and Results: Using a novel rat model of degenerative MR, we found that in degenerative MR rats treated with ARNI, left ventricular function and atrial fibrillation (AF) inducibility significantly improved compared with those treated with valsartan only (fractional shortening 61.78±7.26% v.s. 55.07±6.63%). Also, the AF inducibility dropped from 83% to 25% in MR rats treated with ARNI than to 58.3% in those treated with valsartan. ARNI treatment demonstrated significant attenuation of fibrosis, apoptosis and expressions of endoplasmic reticulum (ER) stress and inflammatory-associated proteins in left ventricular tissues compared to valsartan. In a shear stress model, the treatment of ARNI on cardiomyocytes mitigated the flow triggered activities of both ER released calcium signaling and store-operated calcium entry. Parallelly, we prospectively included 65 patients with degenerative MR receiving valsartan or ARNI and followed Holter electrocardiography and echocardiography. Notably, compared with degenerative MR patients receiving valsartan, those prescribed with ARNI demonstrated significant improvement of AF burden and left ventricular function.
Conclusions: Degenerative MR-induced cardiovascular dysfunction including fibrosis and ER stress, were more effectively attenuated by ARNI treatment than by valsartan alone.