Abstract 12122: Absence of Rgs5 Prolongs Cardiac Repolarization and Predisposes to Ventricular Tachyarrhythmia in Mice
Objective The aim of this study was to elucidate the effects of regulator of G-protein signaling 5 (Rgs5), a negative regulator of G-protein-mediated signaling, on cardiac repolarization and arrhythmia in mice.
Methods and Results Wild-type (WT) and Rgs5-/- mice were subjected to in vivo, in vitro, and cellular electrophysiological experiments. Compared with WT group, Rgs5-/- mouse hearts showed significantly prolonged cardiac repolarization, including prolonged QTc interval (55.3±6.3ms vs 45.4±6.6ms, P<0.05) and 90% of action potential duration (APD90) in left ventricle (60.6±5.5ms vs 54.2±6.1ms, P<0.05). Consistent with these findings, measurement of K+currents in ventricular myocytes of Rgs5-/- mice revealed lower density of the outward voltage-dependent K+ currents than that in wild-type mice, including Ipeak, Ito, Ikur, andIss (P<0.05) (Fig.1A). Transcript and protein expression levels of Kv4.2, Kv4.3, Kv1.5, and Kv2.1 were also markedly downregulated in Rgs5-/- mouse ventricle (P<0.05) (Fig.1F). In arrhythmia induction, the inducibility of ventricular tachyarrhythmias (VAs) was facilitated by Rgs5-/- during program electrical stimuli (PES) (53.3%, 12/23) and burst pacing (39.1%, 9/23). And the incidence of sustained VAs were also increased in Rgs5-/- group (16.7%, 3.23), but none of them in WT mice. Importantly, the facilitated electrically induced VAs were associated with increased transmural dispersion of repolarization (TDR) (Rgs5-/-: 9.1±2.1, WT: 5.1±1.6, P<0.05) and spatial heterogeneity of Ipeak, Ito and IKur between the epicardium and endocardium in the Rgs5[[Unable to Display Character: -]]/- heart (P<0.05) (Fig.1D,E).
Conclusion The results strongly indicate that (i) Knockout of Rgs5 induced prolongation of the QT interval and the APD, which were due to the decreased K+ current density and reduced channel expression. (ii) The spatial heterogeneity of K+ current density increased the dispersion of APD and predisposed Rgs5-/- mice to electrically induced VAs.
- © 2012 by American Heart Association, Inc.