Submitted on August 28, 2006
Accepted on November 25, 2006
IKr and IKs Remodeling Differentially Affects QT Interval Prolongation and Dynamic Adaptation to Heart Rate Acceleration in Bradycardic Rabbits
Fumiaki Suto1, Wei Zhu2, Alice Chan1, and Gil Gross3*
1 Cardiovascular Research Programme, Hospital for Sick Children Research Institute, Toronto, Canada
2 Cardiovascular Research Programme, Hospital for Sick Children, Toronto, Canada; Cardiovascular Research Programme, Hospital for Sick Children Research Institute, Toronto, Canada
3 Cardiovascular Research Programme, Hospital for Sick Children Research Institute, Toronto, Canada; Cardiology Division, Hospital for Sick Children, 555 University Avenue, Toronto, M5G 1X8, Canada; Department of Pediatrics, University of Toronto, Toronto, Canada; Heart & Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, Canada
* To whom correspondence should be addressed. E-mail: ggross{at}sickkids.ca.
Objective: 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 (CHB) 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 physiologic-rate pacing.
Methods: At specified time points after CHB 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. IKr and IKs tail current densities were evaluated using whole cell patch clamp in isolated right ventricular myocytes.
Results: Steady-state QT interval prolongation at both 2 and 8 days was associated with moderate IKr reduction. IKs 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 physiologic-rate pacing.
Conclusions: In this bradycardic model, IKs downregulation (i) proceeds more gradually but more extensively than that of IKr, and (ii) 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 IKs, consistent with stress-related phenomena in known IKs-impaired states. Relative early sparing of IKs could explain delay in onset of lethal tachyarrhythmia predisposition in bradycardic electrical remodeling. Reversibility of remodeling supports the potential utility of preventive pacing intervention soon after bradycardia onset.
