Pro-arrhythmogenic Effects of the V141M KCNQ1 Mutation in Short QT Syndrome and Its Potential Therapeutic Targets: Insights from Modeling.

Gain-of-function mutations in the pore-forming subunit of I channels, KCNQ1, lead to short QT syndrome (SQTS) and lethal arrhythmias. However, how mutant I channels cause SQTS and the possibility of I-specific pharmacological treatment remain unclear. V141M KCNQ1 is a SQTS associated mutation. We studied its effect on I gating properties and changes in the action potentials (AP) of human ventricular myocytes. oocytes were used to study the gating mechanisms of expressed V141M KCNQ1/KCNE1 channels. Computational models were used to simulate human APs in endocardial, mid-myocardial, and epicardial ventricular myocytes with and without β-adrenergic stimulation. V141M KCNQ1 caused a gain-of-function in I characterized by increased current density, faster activation, and slower deactivation leading to I accumulation. V141M KCNQ1 also caused a leftward shift of the conductance-voltage curve compared to wild type (WT) I (V = 33.6 ± 4.0 mV for WT, and 24.0 ± 1.3 mV for heterozygous V141M). A Markov model of heterozygous V141M mutant I was developed and incorporated into the O'Hara-Rudy model. Compared to the WT, AP simulations demonstrated marked rate-dependent shortening of AP duration (APD) for V141M, predicting a SQTS phenotype. Transmural electrical heterogeneity was enhanced in heterozygous V141M AP simulations, especially under β-adrenergic stimulation. Computational simulations identified specific I blockade as a beneficial pharmacologic target for reducing the transmural APD heterogeneity associated with V141M KCNQ1 mutation. V141M KCNQ1 mutation shortens ventricular APs and enhances transmural APD heterogeneity under β-adrenergic stimulation. Computational simulations identified I blockers as a potential antiarrhythmic drug of choice for SQTS.