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Am J Physiol Heart Circ Physiol (December 9, 2005). doi:10.1152/ajpheart.00097.2005
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Submitted on February 1, 2005
Accepted on November 9, 2005

Electrical Remodeling of Cardiac Myocytes from Mice with Heart Failure due to the Over-expression of Tumor Necrosis Factor {alpha}

Polina S Petkova-Kirova1, Erdal Gursoy2, Haider Mehdi2, Charles F McTiernan2, Barry London2, and Guy Salama1*

1 Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, PA, USA
2 Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA, USA

* To whom correspondence should be addressed. E-mail: gsalama{at}pitt.edu.

Mice that overexpress the inflammatory cytokine tumor necrosis factor-alpha in the heart (TNF mice) develop heart failure characterized by atrial and ventricular dilatation, decreased ejection fraction, atrial and ventricular arrhythmias and increased mortality (males>females). Abnormalities in Ca2+ handling, prolonged action potential (AP) duration (APD), calcium alternans, and reentrant atrial and ventricular arrhythmias were previously observed using optical mapping of perfused hearts from TNF mice. We therefore tested whether altered voltage-gated outward K+ and/or inward Ca2+ currents contribute to the altered AP characteristics and the increased vulnerability to arrhythmias. Whole-cell voltage clamp recordings of K+ currents from left ventricular myocytes of TNF mice revealed an ~50% decrease in the rapidly activating, rapidly inactivating transient outward K+ current Ito and in the rapidly activating, slowly inactivating delayed rectifier current IK,slow1, and ~25% decrease in the rapidly activating, slowly inactivating delayed rectifier current IK,slow2, and no significant change in the steady state current Iss compared to controls. Peak amplitudes and inactivation kinetics of the L-type Ca2+ current (ICa,L) were not altered. Western blot analyses revealed a reduction in the proteins underlying Kv4.2, Kv4.3, and Kv1.5. Thus, decreased K+ channel expression is largely responsible for the prolonged APD in the TNF mice and may, along with abnormalities in Ca2+ handling, contribute to arrhythmias.




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