Transient Outward K+ Current Underlies Heterogeneity of Action Potential Duration and Early Afterdepolarization from Right Ventricle in Transgenic Rabbit Model of Long QT Type 1

Abstract

Introduction: Long QT syndrome type 1 (LQT1) is a congenital disease lacking slowly activating K+ channel (IKs), associated with polymorphic VT (pVT) and sudden cardiac death. Tissue heterogeneity has been proposed as an important factor to trigger and maintain pVT. We investigated ionic mechanisms that underlie regional differences in the formation of early afterdepolarization (EAD) using transgenic rabbit model of LQT1.Methods: The initiation of pVT under isoproterenol was mapped using optical mapping and myocytes isolated from RV and septum were studied using voltage clamp and confocal calcium imaging.Results: Optical mapping of LQT1 hearts showed pVT preferentially originating from right ventricle (RV) (16 of 18 pVTs), which was changed after perfusing transient outward K channel (Ito) blocker, 0.5 mM 4-aminopyridine (only 1 of 5 pVTs from RV, n=5 hearts). Myocytes isolated from RV demonstrated higher incidence of EADs under 50 nM isoproterenol (8 of 12 cells from RV vs. 2 of 11 cells from septum). Voltage clamp study highlighted regional differences of Ito (4.7 ± 0.5 in RV vs. 2.9 ± 0.7 pA/pF in septum at 0 mV) but other currents such as ICaL, IKr and RyR-mediated Ca2+ leak and SERCA-mediated Ca2+ uptake were same between RV and septum. Computer modeling study of rabbit action potential lacking IKs exhibit frequent EADs but reduction of Ito prevented EAD formation, verifying that Ito plays a major role in EAD formation by providing repolarizing currents during the plateau phase to maintain the membrane potential lower enough to re-activate ICa window current to form EADs.Conclusion: Regional differences of Ito in LQT1 rabbits underlie frequent pVTs originating mostly from RV myocytes with high incidence of EADs.