SACUBITRIL-VALSARTAN AMELIORATES MITOCHONDRIAL FUNCTION IN A MURINE MODEL OF ISOPROTERENOL-INDUCED LEFT VENTRICULAR DYSFUNCTION

Background Sacubitril/valsartan, a first-in-class angiotensin receptor neprilysin inhibitor, has proven to promote left ventricular (LV) reverse remodelling in patients with heart failure (HF) with reduced ejection fraction. However, its molecular and tissue effects have not been fully elucidated yet, due to the paucity of preclinical studies, mostly based on ischaemic models. Aim To evaluate the effects of sacubitril/valsartan on LV remodelling and cardiac mitochondrial function in a murine model of non-ischaemic LV dysfunction. Methods Adult male transgenic mice with cardiac-specific hyperaldosteronism (AS mice) received subcutaneous isoproterenol injection (300 mg/kg BID over two days), to induce LV systolic dysfunction. Mice were then randomized to a 2-week treatment with saline (0,2 mL BID) (ISO-AS n=15), valsartan (26 mg/kg in 0,2 mL of saline) (ISO+V n=12) or sacubitril/valsartan (57 mg/kg in 0,2 mL of saline) (ISO+S/V n=12). Echocardiography was performed at baseline, day 7, 15 and 21 of treatment. Mice were sacrificed at day 21, and histological and immunochemical assays were performed. A control group (Ctrl-AS n=8), not receiving isoproterenol nor pharmacological treatment, was obtained. Results Treatment with sacubitril/valsartan, but not with valsartan, induced a significant improvement of LV ejection fraction (p=0.009 vs ISO-AS) and fractional shortening (p= 0.032 vs ISO-AS) after 2-week treatment. In both ISO+V and ISO+S/V groups, a trend toward reduction of the extent of myocardial fibrosis was detected at histological analysis, confirmed by the lower cardiac collagen 1/3 expression ratio (p= 0.074). ISO+V and ISO+S/V groups showed a significant recovery of mitochondrial morphology and inner membrane function meant for oxidative phosphorylation. Additionally, both treatments reverted the alterations of the expression of genes involved in mitochondrial distribution, transport of organic/inorganic compounds, myocardial cell death, and response to the superoxide. Conclusion In a murine model of non-ischaemic HF, sacubitril/valsartan proved to have beneficial effects on LV remodelling and on cardiac energetics by improving mitochondrial activity.