LAUSR

Introduction: Hypomagnesemia is common in patients with diabetes, hypertension, and heart failure. A low circulating Mg level is associated with increased cardiovascular mortality, and conversely, dietary magnesium (Mg) intake is associated with a decreased risk of developing heart failure. In this study, we investigated whether Mg deficiency alone contributed to cardiomyopathy. Methods: C57BL/6J mice were fed with a low-Mg diet (low-Mg, 15-30 mg/kg Mg) or a normal Mg diet (nl-Mg, 600 mg/kg Mg) for 6 weeks. To test reversibility, half of the low-Mg mice were fed then with normal diet for another 6 weeks. Results: Mg deficiency increased mortality. The survival rate after 6-week low-Mg diet was 0 for female and 64.6% for male. Surviving male mice showed significantly decreased serum Mg (0.9±0.1 vs. 2.8±0.1 mg/dL for nl-Mg) and a reciprocal increase in serum Ca, K and Na. Mg deficiency was associated with a decreased ejection fraction (EF%, 39.8±1.9% vs. 52.0±1.7% of nl-Mg), diastolic dysfunction (E/e’: 21.1±1.1 vs. 15.4±0.4 of nl-Mg), and prolonged QTc intervals (55.1±0.8 vs. 46.0±1.2 ms of nl-Mg). At the cellular level, ATP, Ca transient amplitude, resting sarcomere length, and sarcomere shortening were all decreased significantly in low-Mg hearts. These changes were accompanied by significantly increased mitochondrial ROS production. Reintroduction of Mg normalized electrolytes, EF% (52.1±1.4%), E/e’ (15.3±0.7), QTc (49.4±1.7 ms) and cellular changes. SERCA2 was decreased, and oxidation of RyR2 and cardiac myosin binding protein C were increased in low-Mg hearts, all of which were reversed by Mg repletion. In vivo mitoTEMPO treatment on low-Mg mice (1 mg/kg/day IP injection for 2 weeks) improved the diastolic function (E/e’=16.7±2.0) and increased cellular ATP levels. Conclusion: Mg deficiency causes reversible diastolic and systolic cardiomyopathy associated with mitochondrial dysfunction. This cardiomyopathy may explain the relationship of hypomagnesemia and worsening heart failure. Mg intake reverses these changes, reinforcing the known correlation of increased Mg intake and reduced heart failure symptoms. In deficiency states, Mg supplementation may represent a novel treatment for both diastolic and systolic heart failure.