NaCa Exchange in Heart Failure

Congestive heart failure (HF) is characterized by contractile dysfunction and a high incidence of sudden death from nonreentrant ventricular arrhythmias, both of which involve altered intracellular calcium handling. The focus of this article is on the critical role of the NaCa exchanger. We demonstrate that upregulation of NaCa exchanger unloads the sarcoplasmic reticulum (SR), leading to contractile dysfunction. At the same time, NaCa exchanger underlies the arrhythmogenic transient inward current (Iti) in HF. Preserved ?-adrenergic responsiveness in HF plays a crucial role in increasing SR Ca load, leading to SR Ca release and activation of Iti. In addition, decreased IK1(inward rectifier) current in HF destabilizes resting membrane potential (Em) and further enhances arrhythmogenesis mediated by the upregulated NaCa exchanger. We thus propose a new paradigm in which upregulated NaCa exchanger in HF plays a dual role in underlying both the contractile dysfunction and arrhythmogenesis in the failing heart. Therapeutic approaches to the treatment of HF will need to balance increasing SR Ca load with the arrhythmogenic effects of SR Ca overload that involve activation of Iticarried by NaCa exchanger.