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+ (Nai+), which can dramatically influence the transfer rates and distribution of Ca2+ among the intracellular compartments of the myocyte. Since Nai+ 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 Nai+ on cell function is complex, requiring an integrative view of cardiomyocyte physiology. Here, we discuss how abnormal Nai+ 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.

Section editors:Rahul Kakkar and Richard T. Lee – Harvard Medical School, Brigham and Women's Hospital, Cambridge, MA, USA