Angiotensin receptor neprilysin inhibition provides superior cardioprotection compared to angiotensin converting enzyme inhibition after experimental myocardial infarction

Background: Angiotensin receptor neprilysin inhibitor (ARNi) enhances beneficial natriuretic peptides by inhibiting their breakdown through neprilysin. Although the first-in-class ARNi sacubitril/valsartan (LCZ696) reduced mortality and morbidity in heart failure (HF) with reduced ejection fraction (EF) compared to angiotensin converting enzyme inhibitor (ACEi), mechanistic data on ARNi are scarce. ARNi may be superior to ACEi in attenuating adverse cardiac remodeling and dysfunction post-myocardial infarction (MI). Methods: Rats randomized at 1 week post-MI were administered LCZ696 (60 mg/kg, N = 12), the ACEi perindopril (2 mg/kg, N = 11) or vehicle (corn oil, N = 13), orally for 4 weeks. Sham rats received vehicle (corn oil, N = 9). Echocardiography was assessed before and after treatment, prior to invasive hemodynamics using pressure-volume analysis. Hypertrophy and fibrosis was evaluated by histochemical staining, and analysis of myocardial gene and protein expression using real-time quantitative PCR and Western blot. Results: Compared to Sham, MI groups had large infarcts (>40%) and reduced left ventricular (LV) EF. LCZ696 improved LVEF and end systolic pressure-volume relationship compared to perindopril (P < 0.05). LCZ696 but not perindopril reduced lung weight and LV filling pressures post-MI. Reductions in cardiac hypertrophy and fibrosis were similar, however gene expression of hypertrophic markers, ANP and βMHC were reduced with LCZ696 versus perindopril. LCZ696 versus perindopril reduced myocardial TIMP2 gene expression with a trend (P = 0.067) to lowering collagen I. Conclusion: LCZ696 attenuated adverse cardiac remodeling and dysfunction and reduced pulmonary congestion and hypertrophic markers after MI compared to perindopril. This study supports clinical evaluation of ARNi versus ACEi in targeting post-MI cardiac dysfunction and remodeling.