LAUSR

BACKGROUND Synergistic interactions between neprilysin inhibition (NEPi) with sacubitril and angiotensin receptor type1 blockade (ARB) with valsartan have been implicated in improvement of left ventricular (LV) contractility, relaxation, exercise tolerance, and fibrosis in preexisting heart failure induced by aortic valve insufficiency (AVI). It is not known whether this pharmacologic synergy can prevent cardiovascular pathology in a similar AVI model. AIM To investigate pharmacology of sacubitril/valsartan in an experimental setting with therapy beginning immediately after creation of AVI. METHODS HF was induced through partial disruption of the aortic valve in rats. Therapy began 3 hours after valve disruption and lasted 8 weeks. Sacubitril/valsartan (68 mg/kg), valsartan (31 mg/kg), sacubitril (31 mg/kg), or vehicle were administered daily via oral gavage (N=8 in each group). Hemodynamic assessments were conducted using MillarTM technology, and an exercise tolerance test was conducted using a rodent treadmill. RESULTS Only sacubitril/valsartan increased total arterial compliance and ejection fraction (EF). Therapies with sacubitril/valsartan and valsartan similarly improved load dependent (dP/dtmax) and load independent indices (Ees) of LV contractility, and exercise tolerance while sacubitril did not. None of the therapies improved LV relaxation (dP/dtmin) while all reduced myocardial fibrosis. CONCLUSIONS 1) The synergistic interaction between NEPi and ARB in early therapy with sacubitril/valsartan leads to increased total arterial compliance and EF. 2) Improvement in indices of LV contractility, and exercise tolerance with sacubitril/valsartan is likely due to ARB effect of valsartan. 3) All three therapies provided antifibrotic effects, suggesting both ARB and NEPi are capable of reducing myocardial fibrosis.