The combination of Sacubitril and Valsartan protects against cardiac rupture and improves survival after acute myocardial infarction in murine model
A study examined the effects of LCZ696 ( Sacubitril and Valsartan; Entresto ) on acute experimental myocardial infarction ( MI ) in mice and whether it has cardioprotective effects beyond renin-angiotensin-aldosterone system ( RAAS ) blockade.
Mice with a percentage of fractional shortening ( %FS ) less than 30% at 24 hours after myocardial infarction were randomized to oral LCZ696 ( 20 mg/kg/day; n = 75 ), Enalapril ( 4 mg/kg/day; n = 79 ) or vehicle ( n = 77 ).
At post-operative day one, no differences in infarct size were seen between groups. The post-MI survival rate was significantly higher with LCZ696 versus Enalapril ( p less than 0.01 ) and vehicle ( p less than 0.01 ).
In most mice ( 94.8% ), the cause of death was left ventricular rupture. With LCZ696, left ventricular rupture was lower versus Enalapril ( p less than 0.05 ) and vehicle ( p less than 0.01 ).
No differences in fractional shortening, left ventricular end-diastolic dimension or left ventricular end-systolic dimension were observed in any group before and one day after myocardial infarction.
The %FS improved significantly with LCZ696 compared with vehicle at 14 days and 28 days after myocardial infarction, but did not improve significantly compared with Enalapril.
LCZ696 has improved the balance between the RAAS and natriuretic peptide system, prevented cardiac rupture and improved survival after myocardial infarction, likely due to suppression of proinflammatory cytokines and extracellular matrix degradation in macrophages.
Three days after myocardial infarction, in the infarcted region, mRNA expression was significantly lower with LCZ696 versus Enalapril for interleukin (IL)-1b, IL-6 and matrix metalloproteinase (MMP)-9, and versus vehicle for IL-1b, MMP-9 and tissue inhibitors of metalloproteinases (TIMP)-1.
In the non-infarcted region, mRNA expression was significantly lower with LCZ696 versus 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.
With LCZ696, at three days post myocardial infarction, plasma aldosterone levels were significantly lower versus vehicle and plasma cyclic GMP ( cGMP ) levels were higher vs. vehicle and Enalapril. The aldosterone/cGMP ratio was significantly lower with LCZ696 versus vehicle and Enalapril.
According to the investigators, LCZ696 has improved the balance between the RAAS and natriuretic peptide system, has prevented cardiac rupture and has improved survival after myocardial infarction, likely due to suppression of proinflammatory cytokines and extracellular matrix degradation in macrophages.
As a result, LCZ696 might be useful clinically to improve survival in the acute phase of myocardial infarction. ( Xagena )
Ishii M, Kaikita K, Sato K, et al. JACC Basic Transl Sci 2017; Epub ahead of print