Abstract
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
Na/Ca exchanger. We demonstrate that upregulation of Na/Ca exchanger
unloads the sarcoplasmic reticulum (SR), leading to contractile dysfunction.
At the same time, Na/Ca exchanger underlies the arrhythmogenic transient
inward current (I(ti)) in HF. Preserved beta-adrenergic responsiveness
in HF plays a crucial role in increasing SR Ca load, leading to SR
Ca release and activation of I(ti). In addition, decreased I(K1)
(inward rectifier) current in HF destabilizes resting membrane potential
(E(m)) and further enhances arrhythmogenesis mediated by the upregulated
Na/Ca exchanger. We thus propose a new paradigm in which upregulated
Na/Ca 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 I(ti) carried by Na/Ca exchanger.
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