Hexarelin treatment preserves myocardial function and reduces cardiac fibrosis in a mouse model of acute myocardial infarction

Ischemic heart disease (IHD) is a leading cause of morbidity and mortality worldwide. Growth hormone secretagogues (GHS) have been shown to improve cardiac function in models of IHD. This study determined whether hexarelin (HEX), a synthetic GHS, preserves cardiac function and morphology in a mouse model of myocardial infarction (MI). MI was induced by ligation of the left descending coronary artery in C57BL/6J mice followed by vehicle (VEH; n=10) or HEX (0.3mg/kg/day; n=11) administration for 21days. MI-injured and sham mice (treated with VEH; n=6 or HEX; n=5) underwent magnetic resonance imaging for measurement of left ventricular (LV) function, mass and infarct size at 24h and 14days post-MI. MI-HEX mice displayed a significant improvement (P<0.05) in LV function compared with MI-VEH mice after 14days treatment. A significant decrease in LV mass, interstitial collagen and collagen concentration was demonstrated with chronic HEX treatment (for 21days), accompanied by a decrease in TGF-beta 1 expression, myofibroblast differentiation and an increase in collagen-degrading MMP-13 expression levels. Furthermore, heart rate variability analysis demonstrated that HEX treatment shifted the balance of autonomic nervous activity toward a parasympathetic predominance and sympathetic downregulation. This was combined with a HEX-dependent decrease in troponin-I, IL-1 beta and TNF-alpha levels suggestive of amelioration of cardiomyocyte injury. These results demonstrate that GHS may preserve ventricular function, reduce inflammation and favorably remodel the process of fibrotic healing in a mouse model of MI and hold the potential for translational application to patients suffering from MI.