Circulation Research. 2001;88:1159-1167
Published online before print May 24, 2001, doi: 10.1161/hh1101.091193
Published online before print May 24, 2001, doi: 10.1161/hh1101.091193
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© 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
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 
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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