Homoarginine Supplementation Prevents Left Ventricular Dilatation and Preserves Systolic Function in a Model of Coronary Artery Disease

Abstract

Background Homoarginine (hArg) has been shown to be cardioprotective in a model of ischemic heart failure; however, the mechanism remains unknown. hArg can inhibit tissue‐nonspecific alkaline phosphatase (TNAP), an enzyme that promotes vascular calcification. We hypothesized that hArg will exert beneficial effects by reducing calcification in a mouse model of coronary artery disease associated with TNAP overexpression and hypercholesterolemia. Methods and Results TNAP was overexpressed in the endothelium in mice homozygous for a low‐density lipoprotein receptor mutation (wicked high cholesterol [WHC] allele). WHC and WHC–endothelial TNAP mice received placebo or hArg supplementation (14 mg/L in drinking water) starting at 6 weeks of age simultaneously with an atherogenic diet. Outcomes were compared between the groups after 4 to 5 weeks on treatment. Experiments were performed in males, which presented a study limitation. As expected, WHC–endothelial TNAP mice on the placebo had increased mortality (median survival 27 days, P<0.0001), increased coronary calcium and lipids (P<0.01), increased left ventricular end‐diastolic diameter (P<0.0001), reduced ejection fraction (P<0.05), and increased myocardial fibrosis (P<0.0001) compared with WHC mice. Contrary to our hypothesis, hArg neither inhibited TNAP activity in vivo nor reduced coronary artery calcification and atherosclerosis in WHC–endothelial TNAP mice; however, compared with the placebo, hArg prevented left ventricular dilatation (P<0.01), preserved ejection fraction (P<0.05), and reduced myocardial fibrosis (P<0.001). Conclusions The beneficial effect of hArg supplementation in the setting of calcified coronary artery disease is likely due to its direct protective actions on the myocardial response to the ischemic injury and not to the inhibition of TNAP activity and calcification.

Keywords

• cardiac remodeling
• coronary artery disease
• coronary calcium
• homoarginine