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

Abstract

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-[¹⁸F] 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.

Keywords: cardiac MRI; cardiac hypertrophy; dynamic FDG PET; metformin; spontaneously hypertensive rats.

Figure 1. Metformin treatment reduced blood pressure and normalized in vivo glucose uptake rates in SHR hearts.

A, MAP in WKY rats (n=6), SHR (n=6), and SHR treated with metformin (300 mg/kg per day) for 3 months (SHR+M) (n=6). B, In vivo FDG PET images normalized to (SUV). C, Glucose uptake rates (Ki) computed from in vivo dynamic FDG PET images. All data are shown as mean±SE. FDG PET, fluorodeoxyglucose positron emission tomography; MAP, mean arterial pressure; SHR, spontaneously hypertensive rats; SUV, standardized uptake value; WKY, Wistar–Kyoto.

Figure 2. Metformin treatment improved cardiac function and normalized cardiac structure in SHR in vivo.

A, Short‐axis CMR images at ED and ES. B, EF, (C) LVM normalized to tibia length (TL), and (D) EDWT measured by CMR for WKY (n=6), SHR (n=6), and SHR treated with metformin (300 mg/kg per day) for 3 months (SHR+M) (n=6). All data are shown as means±SE. CMR indicates cardiac MRI; ED indicates end‐diastole; EF, ejection fraction; EDWT, end‐diastolic wall thickness; ES, end‐systolic; LVM, left ventricular mass; M, metformin; SHR, spontaneously hypertensive rats; WKY, Wistar–Kyoto.

Figure 3. Effects of metformin treatment on cardiac AMPK and ACC phosphorylation and mTOR activity, and on cardiac and circulating metabolites in SHR.

A, Immunoblots for p‐AMPK and (B) signal intensities for p‐AMPK and AMPK normalized to GAPDH and p‐AMPK/AMPK ratios determined. C, Immunoblots for p‐ACC and (D) signal intensities for p‐ACC and ACC normalized to GAPDH and p‐ACC/ACC ratios determined. E, Immunoblots for p‐p70S6K, a marker for mTOR activity, and (F) signal intensities for p‐p70S6K and p70S6K normalized to GAPDH and p‐p70S6K/p70S6K ratios determined. G, FFA in circulation. A through G, Data for WKY (n=6), SHR (n=6), and SHR treated with metformin (300 mg/kg per day) for 3 months (SHR+M [n=6]). H, Changes in cardiac fatty acyl carnitines (left) and lipid oxidation and peroxidation products (right) in SHR treated with metformin (100 mg/kg per day) (n=10) for 1 month from 1 to 2 months of age when compared with untreated WKY (n=10) and SHR (n=9). Data for biochemicals in raw area counts were rescaled to set medians equal to 1 and plotted. Data for untreated SHR and WKY were reported in our earlier study⁵ and are shown here for comparison with treated SHR. Data for WKY vs SHR, SHR vs SHR+M, and WKY vs SHR+M were statistically significantly different at P<0.05 except for the ones marked NS (WKY vs SHR+M). All data are shown as mean±SE. ACC indicates acetyl‐CoA carboxylase; FFA, free fatty acids; M, metformin; mTOR, mammalian target of rapamycin; SHR, spontaneously hypertensive rats; WKY, Wistar–Kyoto.