LCZ696 Prevents Cardiac Rupture and Improves Survival After Acute MI in Mice
LCZ696 (sacubitril/valsartan) protects against cardiac rupture and improves survival after acute myocardial infarction (MI) in mice, according to results presented by Koichi Kaikita, MD, PhD, in a Hot Line session on August 28 at ESC Congress 2017 in Barcelona and simultaneously published in JACC: Basic to Translational Science.
Although the long-term benefits of LCZ696 in patients with heart failure (HF) with reduced ejection fraction are known, its short-term effects on cardiac dysfunction are unknown. The aims of this study were to examine the effects of LCZ696 on acute experimental MI in mice and clarify whether it has cardioprotective effects beyond renin-angiotensin-aldosterone system (RAAS) blockade.
A preliminary dose-ranging study with LCZ696 and enalapril was conducted first to determine non-antihypertensive doses. The mice were then anesthetized and the left anterior descending coronary artery was permanently ligated at the level of the left atrium to induce MI. Only mice with a percentage of fractional shortening <30 percent at 24 hours after MI were included to minimize variability in infarct size. The mice were randomized to oral LCZ696 (20 mg/kg/day; n = 75), enalapril (4 mg/kg/day; n = 79), or vehicle (n = 77). The maximum dose of each drug that did not lower baseline blood pressure was used. A group of sham-operated mice had the same surgery but without coronary ligation.
There were no differences in infarct size among the three treatment groups at post-operative day 1. The post-MI survival rate was significantly higher in the LCZ696 group compared with the enalapril (p < 0.01) and vehicle (p < 0.01) groups. The cause of death was left ventricular (LV) rupture in 94.8 percent of the mice. The rate of death caused by LV rupture was lower in the LCZ696 group compared with the enalapril (p < 0.05) and vehicle (p < 0.01) groups. The remaining deaths were due to HF.
No differences in fractional shortening, LV end-diastolic dimension, or LV end-systolic dimension were observed in any of the groups before and one day after MI. The percentage of fractional shortening improved significantly in the LCZ696 group compared with the vehicle group 14 days (mean difference 4.60; 95 percent confidence interval [CI], 0.03-9.18; p < 0.05) and 28 days (mean difference, 5.45; 95 percent CI, 0.78-10.1; p < 0.05) after MI, but did not improve significantly compared with enalapril.
Three days after MI, in the infarcted region, mRNA expression was significantly lower with LCZ696 vs. enalapril for interleukin (IL)-1β, IL-6 and matrix metalloproteinase (MMP)-9, and vs. vehicle for IL-1β, MMP-9 and tissue inhibitors of metalloproteinases (TIMP)-1. In the non-infarcted region, mRNA expression was significantly lower with LCZ696 vs. vehicle for atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Immunofluorescence imaging indicated that macrophages might be a main source of MMP-9 in the infarcted myocardium.
Three days after MI, the LCZ696 group had significantly lower levels of plasma aldosterone vs. vehicle and higher levels of plasma cyclic GMP (cGMP) vs. vehicle and enalapril. The aldosterone/cGMP ratio was significantly lower with LCZ696 vs. vehicle and enalapril.
The investigators concluded that LCZ696 improved the balance between the RAAS and natriuretic peptide systems, prevented cardiac rupture and improved survival after MI, likely due to suppression of proinflammatory cytokines and extracellular matrix degradation in macrophages. Thus, LCZ696 might be useful clinically to improve survival in the acute phase of MI.
Keywords: ESC Congress, ESC2017, Mice, Animals, Tissue Inhibitor of Metalloproteinase-1, Atrial Natriuretic Factor, Enalapril, Natriuretic Peptide, Brain, Aldosterone, Matrix Metalloproteinase 9, Interleukin-6, Interleukin 1 Receptor Antagonist Protein, Renin-Angiotensin System, Macrophages, Cytokines, Survival Rate, Cyclic GMP, Coronary Vessels, Ligation, Ligation, Stroke Volume, Blood Pressure, Cause of Death, Heart Rupture, Myocardium, Myocardium, Heart Failure, Myocardial Infarction, Heart Atria, Fluorescent Antibody Technique, Extracellular Matrix, RNA, Messenger
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