Abstract 14582: Pro-Arrhythmogenic Effects of the KCNQ1-V141M Mutation in Short QT Syndrome and Its Potential Therapeutic Targets - Insights From Modeling
Background: Short QT syndrome (SQTS) posts elevated risks for lethal arrhythmias. The gain-of-function mutations of the pore-forming subunits of IKs channels, KCNQ1, have been shown associated with SQTS. However, how the mutant IKs causes SQTS and IKs-specific pharmacological treatment remain unclear.
Objective: KCNQ1-V141M is a SQTS associated mutation. We study the effect of V141M on IKs gating properties and consequent changes in action potentials (AP) in human ventricular myocytes.
Methods: Xenopus oocytes were used to study the function and gating mechanisms of expressed V141M IKs channel. Computational models of human ventricular myocytes were used to simulate APs in endocardial, midmyocardial, and epicardial ventricular myocytes with and without the presence of β-adrenergic stimulation.
Results: KCNQ1-V141M caused a gain-of-function in IKs channels characterized by increased current density, faster activation, and slower deactivation leading to IKs current accumulation. It also caused a leftward shift of the conductance-voltage curve compared to that of the wide type IKs (V1/2 = 33.6±4.0 mV for WT, 24.0±1.3 mV for heterozygous V141M, and 17.9±5.7 mV for homozygous V141M). A Markov model of heterozygous V141M-IKs was developed and incorporated into the O’Hara-Rudy (ORd) human ventricular cell model. AP simulations using the cell model demonstrated marked rate-dependent shortening of action potential duration predicting a short QT phenotype. Isoproterenol-challenged early afterdepolarizations (EADs) were noted in midmyocardial myocytes but not in either endo- or epicardial myocytes. Transmural electrical heterogeneity was enhanced in heterozygous V141M AP simulations especially under β-adrenergic stimulation. A series of simulations of the effects of anti-arrhythmic drugs on heterozygous V141M-IKs APs and the arrhythmogenecity will also be presented.
Conclusions: KCNQ1-V141M IKs shortens ventricular APs, is related to EADs and enhances transmural electrical heterogeneity under β-adrenergic stimulation. Computational simulations demonstrate cellular electrophysiological phenotype for SQTS and help evaluate potential targets for effective antiarrhythmic therapy.
- © 2013 by American Heart Association, Inc.