Electrical remodeling in a transgenic mouse model of alpha1B-adrenergic receptor overexpression.

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, Ca(2+)-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.