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

Abstract

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 (0.3 mg/kg/day; n = 11) administration for 21 days. 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 24 h and 14 days post‐MI. MI‐HEX mice displayed a significant improvement (P < 0.05) in LV function compared with MI‐VEH mice after 14 days treatment. A significant decrease in LV mass, interstitial collagen and collagen concentration was demonstrated with chronic HEX treatment (for 21 days), accompanied by a decrease in TGF‐β1 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‐1β and TNF‐α 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.