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Am J Physiol Heart Circ Physiol 296: H704-H718, 2009. First published December 26, 2008; doi:10.1152/ajpheart.00337.2008
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Electrical remodeling in a transgenic mouse model of {alpha}1B-adrenergic receptor overexpression

Katy Rivard,1,2 Véronique Trépanier-Boulay,1,2 Hansjorg Rindt,1 and Céline Fiset1,2

1Research Center, Montreal Heart Institute, and 2Faculty of Pharmacy, Université de Montréal, Montréal, Québec, Canada

Submitted 31 March 2008 ; accepted in final form 19 December 2008

Cardiac-specific overexpression of wild-type {alpha}1B-adrenergic receptors ({alpha}1B-AR) in mice predisposes to dilated cardiomyopathy and sudden death. Although {alpha}-adrenergic stimulation is thought to contribute to induction of arrhythmias in heart failure, the electrophysiological consequences of chronic {alpha}1-adrenergic activation have not been clearly defined. Thus we characterized ventricular repolarization and monitored incidence of spontaneous arrhythmias in end-stage heart failure {alpha}1B-AR mice (9–12 mo) and younger {alpha}1B-AR mice (2–3 mo) that do not present signs of heart failure. Compared with aged-matched controls, the corrected QT interval was 34% longer in the 9- to 12-mo {alpha}1B-AR mice, and the action potential durations were also significantly prolonged in these mice. These changes were associated with a decrease in the density of the outward K+ currents, Ca2+-independent transient, ultrarapid delayed rectifier, and steady state (at +30 mV, reduction of 68, 64, and 41%, respectively), and underlying K+ channel expression. Electrocardiogram (ECG) recordings revealed that older {alpha}1B-AR mice exhibited spontaneous ventricular arrhythmias. The alterations in repolarization can contribute to these rhythm abnormalities and are likely caused by chronic {alpha}1B-AR activity. Additional data obtained in 2- to 3-mo {alpha}1B-AR mice clearly showed that electrical remodeling was already observed in younger transgenic animals. However, it appeared to be slightly less pronounced than in older mice. These results suggest that there are two waves of remodeling: one due to chronic {alpha}1B-AR activity, and a second due to heart failure. Taken together, these data provide strong evidence for a pathological role of chronic {alpha}1B-AR activity in the development of repolarization defects and ventricular arrhythmias.

mouse ventricle; arrhythmias; K+ currents


Address for reprint requests and other correspondence: C. Fiset, Research Center, Montreal Heart Institute, 5000 Bélanger, Montréal, Québec, Canada H1T 1C8 (e-mail: celine.fiset{at}icm-mhi.org)






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