Abstract 24021: Sacubitril/Valsartan Attenuates Fibrosis and Improves Left Ventricular Function in a Rabbit Model of HFrEF

Abstract

Background: Sacubitril/Valsartan (SAC/VAL), a drug combining a neprilysin inhibitor and an angiotensin receptor blocker, was shown to reduce myocardial infarct size and left ventricular (LV) dysfunction in preclinical models of myocardial infarction (MI). In the PARADIGM-HF trial, SAC/VAL prevented the clinical progression of patients with heart failure (HF) more effectively than enalapril. Whether SAC/VAL attenuates cardiac fibrosis and improves LV function in a rabbit model of MI-induced HF with reduced ejection fraction (rEF) is unknown. Methods: Anesthetized adult male NZW rabbits (~2.5kg) underwent left thoracotomy and the left anterior descending (LAD) coronary artery was identified and occluded for 45 min followed by reperfusion. Weekly echocardiography was performed to confirm reduced EF (~40%), which was uniformly achieved at 5 weeks post MI. Subsequently, rabbits were randomized to orally receive placebo (volume-matched water, BID), SAC/VAL (10 mg/kg, BID) or VAL (9.1mg/kg/day) starting on week 6. At 10 weeks post MI, rabbits were sacrificed and hearts were harvested, fixed with 10% formalin and embedded in paraffin to assess myocardial fibrosis (Picrosirius red staining). Operators performing echocardiography, Picrosirius red staining and analysis were blinded to treatment allocation. Results: Two weeks after treatment initiation, a significant improvement in LVEF was observed in the SAC/VAL group compared to both placebo and VAL, a benefit that lasted throughout the entire study (Fig. A). The functional improvement observed was associated with a significant reduction in LV scar size compared to placebo at week 10 (Fig. B). However, when compared to VAL, the decrease in scar size did not reach statistical significance despite a clear trend. Conclusion: Our results suggest that SAC/VAL may offer superior benefits compared to equivalent dose of stand-alone VAL in attenuating LV scar size and improving LVEF in a rabbit model of ischemic HFrEF.