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This Article Full Text Full Text (PDF) All Versions of this Article: 292/4/H1782    most recent 00932.2006v1 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 ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Suto, F. Articles by Gross, G. J. Search for Related Content PubMed PubMed Citation Articles by Suto, F. Articles by Gross, G. J.

I_Kr and I_Ks remodeling differentially affects QT interval prolongation and dynamic adaptation to heart rate acceleration in bradycardic rabbits

¹Physiology and Experimental Medicine Program, Hospital for Sick Children Research Institute; ²Cardiology Division, Hospital for Sick Children; and ³Department of Pediatrics and Heart and Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, Canada

Submitted 28 August 2006 ; accepted in final form 25 November 2006

Bradycardic ventricular electrical remodeling predisposes to lethal tachyarrhythmias. We investigated the early temporal sequence and reversibility of electrical remodeling in a rabbit complete heart block model subjected to bradycardic ventricular pacing for either 2 or 8 days, with a third group of animals undergoing 8 days of bradycardic pacing followed by 8 days of physiological-rate pacing. At specified time points after complete heart block induction and pacing initiation, steady-state QT interval measurements and variability as well as dynamic QT interval adaptation to abrupt heart rate acceleration were assessed in the absence and presence of isoproterenol. Rapidly (I_Kr) and slowly (I_Ks) activating delayed rectifier repolarizing K⁺ tail current densities were evaluated using whole cell patch clamp in isolated right ventricular myocytes. Steady-state QT interval prolongation at both 2 and 8 days was associated with moderate I_Kr reduction. I_Ks downregulation was apparent by day 2 but more profound at day 8. Dynamic QT interval adaptation was impaired under baseline conditions at day 8 but only during isoproterenol administration at day 2. Both in vivo and cellular manifestations of remodeling reverted toward control values after 8 days of physiological-rate pacing. In conclusion, in this bradycardic model, I_Ks downregulation 1) proceeds more gradually but more extensively than that of I_Kr and 2) is most prominently associated with impaired dynamic QT interval adaptation to heart rate acceleration. Isoproterenol blunts the dynamic QT interval response in animals with partially downregulated I_Ks, consistent with stress-related phenomena in known I_Ks-impaired states. Relative early sparing of I_Ks could explain the delay in the onset of lethal tachyarrhythmia predisposition in bradycardic electrical remodeling. Reversibility of remodeling supports the potential utility of preventive pacing intervention soon after bradycardia onset.

bradycardia; ion channels; repolarization; ventricular arrhythmias