Metformin Improves Cardiac Metabolism and Function, and Prevents Left Ventricular Hypertrophy in Spontaneously Hypertensive Rats

BACKGROUND: In spontaneously hypertensive rats (SHR) we observed profound myocardial metabolic changes during early hypertension before development of cardiac dysfunction and left ventricular hypertrophy. In this study, we evaluated whether metformin improved myocardial metabolic abnormalities and simultaneously prevented contractile dysfunction and left ventricular hypertrophy in SHR. METHODS AND RESULTS: SHR and control Wistar–Kyoto rats were treated with metformin from 2 to 5 months of age, when SHR hearts exhibit metabolic abnormalities and develop cardiac dysfunction and left ventricular hypertrophy. We evaluated the effect of metformin on myocardial glucose uptake rates with dynamic 2‐[(18)F] fluoro‐2‐deoxy‐D‐glucose positron emission tomography. We used cardiac MRI in vivo to assess the effect of metformin on ejection fraction, left ventricular mass, and end‐diastolic wall thickness, and also analyzed metabolites, AMP‐activated protein kinase and mammalian target‐of‐rapamycin activities, and mean arterial blood pressure. Metformin‐treated SHR had lower mean arterial blood pressure but remained hypertensive. Cardiac glucose uptake rates, left ventricular mass/tibia length, wall thickness, and circulating free fatty acid levels decreased to normal, and ejection fraction improved in treated SHR. Hearts of treated SHR exhibited increased AMP‐activated protein kinase phosphorylation and reduced mammalian target‐of‐rapamycin activity. Cardiac metabolite profiling demonstrated that metformin decreased fatty acyl carnitines and markers of oxidative stress in SHR. CONCLUSIONS: Metformin reduced blood pressure, normalized myocardial glucose uptake, prevented left ventricular hypertrophy, and improved cardiac function in SHR. Metformin may exert its effects by normalizing myocardial AMPK and mammalian target‐of‐rapamycin activities, improving fatty acid oxidation, and reducing oxidative stress. Thus, metformin may be a new treatment to prevent or ameliorate chronic hypertension–induced left ventricular hypertrophy.