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This Article Full Text Full Text (PDF) All Versions of this Article: 290/5/H2098    most recent 00097.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (10) Citing Articles via Google Scholar Google Scholar Articles by Petkova-Kirova, P. S. Articles by Salama, G. Search for Related Content PubMed PubMed Citation Articles by Petkova-Kirova, P. S. Articles by Salama, G.

Electrical remodeling of cardiac myocytes from mice with heart failure due to the overexpression of tumor necrosis factor-

¹Department of Cell Biology and Physiology and ²Cardiovascular Institute, University of Pittsburgh, Pittsburgh, Pennsylvania

Submitted 1 February 2005 ; accepted in final form 9 November 2005

Mice that overexpress the inflammatory cytokine tumor necrosis factor- 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 duration (APD), calcium alternans, and reentrant atrial and ventricular arrhythmias were previously observed with the use of 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 action potential 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 I_to and in the rapidly activating, slowly inactivating delayed rectifier current I_K,slow1, an 25% decrease in the rapidly activating, slowly inactivating delayed rectifier current I_K,slow2, and no significant change in the steady-state current I_ss compared with controls. Peak amplitudes and inactivation kinetics of the L-type Ca²⁺ current I_Ca,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.

ion currents; ion channel expression; electrophysiology; cytokines

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