The Angiotensin-Receptor Neprilysin Inhibitor LCZ696 Attenuates Cardiac Remodeling and Dysfunction After Myocardial Infarction by Reducing Cardiac Fibrosis and Hypertrophy von Lueder et al: ARNi Attenuates Cardiac Fibrosis and Hypertrophy

Background—Angiotensin-receptor neprilysin inhibitors (ARNi), beyond blocking angiotensin II (AngII)-signalling, augment natriuretic peptides by inhibiting their breakdown by neprilysin (NEP). The myocardial effects of ARNi have been little studied until recently. We hypothesized that LCZ696 attenuates left ventricular (LV) remodeling after experimental myocardial infarction (MI), and that this may be contributed to by inhibition of hypertrophy and fibrosis in cardiac cells. Methods and Results—One week after MI, adult male Sprague-Dawley rats were randomized to treatment for four weeks with LCZ696 (68 mg/kg body weight PO; MI-ARNi, n=11) or vehicle (MI-Vhc, n=6). Five weeks after MI, MI-ARNi versus MI-Vhc demonstrated lower LV end-diastolic diameter (LVEDD, by echocardiography; 9.7±0.2 vs 10.5±0.3 mm), higher LV ejection fraction (LVEF, 60±2 vs 47±5%), diastolic wall strain (0.23±0.02 vs 0.13±0.02), and circular strain (CS, -9.8±0.5 vs -7.3±0.5%; all P<0.05). LV pressure-volume loops confirmed improved LV function. Despite similar infarct size, MIARNi versus MI-Vhc had lower cardiac weights (P<0.01), and markedly reduced fibrosis in peri-infarct and remote myocardium. AngII-stimulated incorporation of 3[H]leucine in cardiac myocytes and 3[H]proline in cardiac fibroblast was used to evaluate hypertrophy and fibrosis, respectively. The NEP inhibitor component of LCZ696, LBQ657, inhibited hypertrophy but not fibrosis. The ARB component of LCZ696, valsartan (VAL) inhibited both hypertrophy and fibrosis. Dual VAL+LBQ augmented the inhibitory effects of VAL and the highest doses completely abrogated AngII-mediated effects. Conclusions—LCZ696 attenuated cardiac remodeling and dysfunction post-MI. This may be contributed to by superior inhibition of LCZ696 on cardiac fibrosis and cardiac hypertrophy than either stand-alone NEPi or ARB.