Abstract 13368: Angiotensin-Receptor Neprilysin-Inhibitor Reduces Adverse Cardiac Remodeling after Experimental Myocardial Infarction by Direct Effect on Cardiac Hypertrophy and Fibrosis
Purpose: Dual-acting angiotensin-receptor neprilysin (NEP) inhibitors (ARNi), a novel drug class blocking both the angiotensin-II (AngII) receptor and breakdown of natriuretic peptides by NEP, may be of benefit in patients with hypertension and heart failure. Direct effects of ARNi on cardiac cells have not been previously evaluated.
Methods: Initially, to establish effects on cardiac remodeling, adult rats were subjected to myocardial infarction (MI) by surgical ligation of the left anterior descending coronary artery (LAD). MI-rats were randomized to treatment with the ARNi LCZ696 (68 mg/kg body weight administered PO; MI-ARNi, n=11) or vehicle (MI-Vhc, n=6), commencing one week post-MI, with cardiac structure and function assessed at 5 weeks post-MI. To assess direct effects of ARNi on cardiac cells, we quantified AngII-stimulated (100nM) cardiomyocyte (CM) hypertrophy and cardiac fibroblast (CF) collagen accumulation by 3[H]leucine-incorporation over 60 h (CM) and 3[H]proline-incorporation over 48 h (CF), respectively. Cells were pretreated with increasing doses of valsartan (VAL) with or without NEP inhibitor LBQ657 (LBQ; 10μM).
Results: See table. MI-ARNi-treated rats had lower cardiac weights and improved cardiac structure and systolic function compared to MI-Vhc. In vitro, VAL showed robust dose-dependent inhibition on cardiac hypertrophy and fibrosis. Addition of LBQ further enhanced the inhibitory effects of VAL, and the highest combined VAL+LBQ dose completely abrogated AngII-mediated effects.
Conclusions: ARNi attenuated post-MI cardiac remodeling, contributed to by direct anti-fibrotic and anti-hypertrophic actions that appear superior to VAL alone.
- © 2013 by American Heart Association, Inc.