title: Na/Ca exchange in heart failure: contractile dysfunction and arrhythmogenesis.
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.
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, USA. spogwidz@uic.edu
authors.forename: Steven M
authors.initials: SM
authors.lastname: Pogwizd
authors.forename: Donald M
authors.initials: DM
authors.lastname: Bers
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism*; D004195:Disease Models, Animal; D006333:Heart Failure / Q000503:physiopathology*; D009200:Myocardial Contraction / Q000502:physiology*; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000502:physiology; D012964:Sodium / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000502:physiology*
chemical_list: D019831:Sodium-Calcium Exchanger; D012964:Sodium; D002118:Calcium