Validation of a preclinical model of heart failure with reduced ejection fraction by a dual angiotensin receptor-neprilysin inhibitor and an angiotensin-converting enzyme inhibitor

Abstract

Heart failure (HF) patients often suffer from several co-existing diseases and co-morbidities. Among them, hypertension and myocardial infarction (MI) are two of the most frequent causes of HF1. Thus, as expected, experimental induction of MI in Spontaneously Hypertensive Rats (SHR) provokes severe left ventricular dysfunction and is associated with signs of HF2. Therapeutic effects of Angiotensin-converting enzyme inhibitor (ACEi) and Angiotensin receptor-neprilysin inhibitor (ARNi) have been demonstrated in HF patients with reduced ejection fraction (HFrEF). The aim of the present study was to validate the translational value of the HF preclinical model SHR PMI using ARNi (Valsartan/Sacubitril, LCZ696) and ACEi (perindopril) treatments recommended by the ESC guidelines for HFrEF patients. Permanent MI (PMI) was induced by coronary ligation in SHR (8-week-old; N = 30) randomized in three groups: –placebo, LCZ696 (68 mg/kg/d); –Perindopril (1 mg/kg/d); –compared to a sham operated group ( N = 10). Three months post-MI, LV function was assessed by echocardiography and hemodynamic study. HF signs were assessed by LV end-diastolic pressure (LVEDP, mmHg), lung and right ventricle (RV) weights (mg). Two vehicle-treated SHR PMI died during the follow-up, no death was observed in LCZ696 or Perindopril treated groups. Post-MI, both ARNi or ACEi treatments had beneficial effects on the adverse LV remodeling and seemed to prevent the mortality and signs of HF (further studies required to confirm these results). In summary, the SHR PMI model has a good predictive value and can be used as preclinical model for the evaluation of new therapeutic strategy in HFrEF [1] , [2] .