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Circulation Research. 2001;88:1159-1167
Published online before print May 24, 2001, doi: 10.1161/hh1101.091193
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(Circulation Research. 2001;88:1159.)
© 2001 American Heart Association, Inc.


Cellular Biology

Arrhythmogenesis and Contractile Dysfunction in Heart Failure

Roles of Sodium-Calcium Exchange, Inward Rectifier Potassium Current, and Residual ß-Adrenergic Responsiveness

Steven M. Pogwizd1, Klaus Schlotthauer1, Li Li, Weilong Yuan, Donald M. Bers

From the Department of Medicine (S.M.P.), University of Illinois, Chicago, Ill, and Department of Physiology and Cardiovascular Institute (K.S., L.L., W.Y., D.M.B.), Loyola University Chicago.

Correspondence to Donald M. Bers, PhD, Department of Physiology, Loyola University Chicago, 2160 S First Ave, Maywood, IL 60153. E-mail dbers{at}luc.edu

Abstract

Abstract—Ventricular arrhythmias and contractile dysfunction are the main causes of death in human heart failure (HF). In a rabbit HF model reproducing these same aspects of human HF, we demonstrate that a 2-fold functional upregulation of Na+-Ca2+ exchange (NaCaX) unloads sarcoplasmic reticulum (SR) Ca2+ stores, reducing Ca2+ transients and contractile function. Whereas ß-adrenergic receptors (ß-ARs) are progressively downregulated in HF, residual ß-AR responsiveness at this critical HF stage allows SR Ca2+ load to increase, causing spontaneous SR Ca2+ release and transient inward current carried by NaCaX. A given Ca2+ release produces greater arrhythmogenic inward current in HF (as a result of NaCaX upregulation), and {approx}50% less Ca2+ release is required to trigger an action potential in HF. The inward rectifier potassium current (IK1) is reduced by 49% in HF, and this allows greater depolarization for a given NaCaX current. Partially blocking IK1 in control cells with barium mimics the greater depolarization for a given current injection seen in HF. Thus, we present data to support a novel paradigm in which changes in NaCaX and IK1, and residual ß-AR responsiveness, conspire to greatly increase the propensity for triggered arrhythmias in HF. In addition, NaCaX upregulation appears to be a critical link between contractile dysfunction and arrhythmogenesis.


Key Words: heart failure • excitation-contraction coupling • Na+-Ca2+ exchange • Ca2+ transport • K+ currents




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