Background and Aim. Despite significant advances in the treatment of heart failure (HF) following acute myocardial infarction (AMI), prognosis remains poor, and many patients suffer from lifelong symptoms. The development of the angiotensin/neprilysin inhibitor (ARNI) sacubitril/valsartan represents an important milestone in the treatment of HFrEF. However, the PARADISE-MI trial did not show superiority of sacubitril/valsartan to reduce the primary endpoint in a contemporary enriched AMI population, compared with ramipril. Induction of angiogenic responses to promote vascular development is a promising treatment approach to restore oxygen and nutrient delivery after MI and to slow the development of HF. Here, we investigate the value of sacubitril/valsartan treatment after myocardial infarction to induce angiogenesis for cardioprotection in a preclinical mouse model.

Methods and Results. In mice subjected to LAD ligation, sacubitril/valsartan treatment resulted in a significantly improved overall survival, augmented cardiac function, and reduced infarct size compared to DMSO controls. This functional improvement was accompanied by enhanced expression of the pro-angiogenic Vegfr2, Notch1 and Dll4 in heart tissue, which translated in higher CD31 counts in histological slices of sacubitril/valsartan-treated mice when compared to controls. In primary HUVEC cultures subjected to hypoxia/reoxygenation (H/R), sacubitril/valsartan induced endothelial cell proliferation, sprouting capacity and pro-angiogenic signaling superior to sole valsartan, sacubitrilat or ramiprilat treatment via induction of NOTCH1-driven VEGFR2 expression and phosphorylation.

Conclusion. Our preclinical model suggests that sacubitril/valsartan is highly efficient for improving post-infarction cardiac function and survival. Despite the results of the PARADISE-MI trial, sacubitril/valsartan induces cardioprotection after experimental MI by stimulating NOTCH1/DLL4/VEGFR2 signaling in endothelial cells for de novo angiogenesis.