Myocyte [Na⁺]_i Dysregulation in Heart Failure and Diabetic Cardiomyopathy

By controlling the function of various sarcolemmal and mitochondrial ion transporters, intracellular Na⁺ concentration ([Na⁺]_i) regulates Ca²⁺ cycling, electrical activity, the matching of energy supply and demand, and oxidative stress in cardiac myocytes. Thus, maintenance of myocyte Na⁺ homeostasis is vital for preserving the electrical and contractile activity of the heart. [Na⁺]_i is set by the balance between the passive Na⁺ entry through numerous pathways and the pumping of Na⁺ out of the cell by the Na⁺/K⁺-ATPase. This equilibrium is perturbed in heart failure, resulting in higher [Na⁺]_i. More recent studies have revealed that [Na⁺]_i is also increased in myocytes from diabetic hearts. Elevated [Na⁺]_i causes oxidative stress and augments the sarcoplasmic reticulum Ca²⁺ leak, thus amplifying the risk for arrhythmias and promoting heart dysfunction. This mini-review compares and contrasts the alterations in Na⁺ extrusion and/or Na⁺ uptake that underlie the [Na⁺]_i increase in heart failure and diabetes, with a particular emphasis on the emerging role of Na⁺ - glucose cotransporters in the diabetic heart.