Abstract 540: Magnesium Improves Cardiac Diastolic Function by Modulating Mitochondria

Abstract

Rationale: A diet rich in saturated fat has been found to induce diabetes mellitus (DM) accompanied by myocardial mitochondrial dysfunction, insulin resistance, and magnesium (Mg) deficiency. The most prominent characteristic of diabetic cardiomyopathy is cardiac diastolic dysfunction (DD). Mg supplementation improves the heart rate variability and arterial elasticity in chronic heart failure. Recently, we have reported that mitochondrial reactive oxygen species (mitoROS) play a critical role in the progress of DD and diastolic heart failure. Therefore, we hypothesized that Mg supplementation would benefit diastolic function by improving mitochondrial function. Methods and Results: High fat diet (HFD)-induced diabetic mouse hearts showed cardiac DD with increased E/e’ (45±2 in DM mice vs. 32±2 in control mice), increased left ventricular diastolic volume (LVDV, 80±1 μL in DM vs. 61±4 μL in control), and increased incidence of DD (9 of 10 mice in DM vs 1 of 10 mice in control; P<0.05 for all). DM mice also showed decreased plasma Mg concentration (0.80±0.04 mmol/L in DM vs. 0.98±0.03 mmol/L in control, P<0.05). Ventricular cardiomyocytes isolated from DM mice exhibited decreased mitochondrial ATP production (75±11% of control), a 1.7±0.2-fold increase in mitoROS, significantly depolarized mitochondrial membrane potential, and mitochondrial Ca 2+ overload (3.7±1.3-fold; P<0.05 vs. control for all). Dietary Mg administration (50 mg/mL, ≈6-8 g/kg/day) for 6 weeks corrected all these parameters with increased plasma Mg concentration (1.5±0.1 mmol/L), improved cardiac diastolic function (E/e’ 37±1; LVDV 54±5 μL; LVPWT 0.77±0.02 mm; the incidence of DD, 2 of 10 mice; P<0.05 vs. DM for all). Mitochondrial function was improved significantly by Mg with increased ATP production, decreased mitoROS, repolarized mitochondrial membrane potential, and decreased mitochondrial Ca 2+ overload in DM mice. Conclusion: These results indicate that Mg supplementation improved mitochondrial function, reduced oxidative stress, and prevented diastolic dysfunction in DM.