The role of Na dysregulation in cardiac disease and how it impacts electrophysiology

Ca²⁺ is well known as the central player in cardiac cell physiology, mediating Ca²⁺ activation of myosin ATPase and contraction, the stimulation of Ca²⁺-activated signaling pathways and modulation of mitochondrial energy production. Abnormalities of Ca²⁺ handling are a well-studied mechanism of decompensation in heart failure. Less appreciated is the role of cytosolic Na⁺ (Na_i⁺), which can dramatically influence the transfer rates and distribution of Ca²⁺ among the intracellular compartments of the myocyte. Since Na_i⁺ can vary widely under different physiological and pathological conditions, and its effects depend on multiple ion gradients and membrane electrical potentials, unraveling the global influence of Na_i⁺ on cell function is complex, requiring an integrative view of cardiomyocyte physiology. Here, we discuss how abnormal Na_i⁺ regulation not only influences the cytosolic Ca²⁺ transient and the cellular action potential but also alters mitochondrial Ca²⁺ uptake and the balance of energy supply and demand of the cardiomyocyte, which may contribute to oxidative stress and cardiac decompensation. The implications for sudden cardiac death and the potential for novel therapeutic interventions are discussed.