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

Hsiang-Chun Lee,Chih-Chieh Chen,Yoram Rudy,Ching-Hsing Luo,Hongwu Liang,Jianmin Cui,Sheng-Hsiung Sheu

doi:10.1007/s40846-017-0257-x

Abstract

Gain-of-function mutations in the pore-forming subunit of IKs channels, KCNQ1, lead to short QT syndrome (SQTS) and lethal arrhythmias. However, how mutant IKs channels cause SQTS and the possibility of IKs-specific pharmacological treatment remain unclear. V141M KCNQ1 is a SQTS associated mutation. We studied its effect on IKs gating properties and changes in the action potentials (AP) of human ventricular myocytes. Xenopus 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 IKs characterized by increased current density, faster activation, and slower deactivation leading to IKs accumulation. V141M KCNQ1 also caused a leftward shift of the conductance-voltage curve compared to wild type (WT) IKs (V1/2 = 33.6 ± 4.0 mV for WT, and 24.0 ± 1.3 mV for heterozygous V141M). A Markov model of heterozygous V141M mutant IKs 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 IK1 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 IK1 blockers as a potential antiarrhythmic drug of choice for SQTS.

Highlights

Short QT Syndrome (SQTS) is an inherited channelopathy associated with marked shortening of QT intervals on the ECG and sudden cardiac death in individuals with structurally normal hearts [1,2,3,4]
We examined the effects of various anti-arrhythmic drugs on V141M KCNQ1-augmented transmural AP duration (APD) heterogeneity and identified a potential target for suppressing Transmural dispersion of repolarization (TDR) and reducing arrhythmic risk in SQT2
The KCNQ1/KCNE1 channels that were expressed in Xenopus oocytes were activated every 100 s from a holding potential of -100 mV with 3 s depolarizing pulses ranging from -100 to ?60 mV (Fig. 1a)

Summary

Introduction

Short QT Syndrome (SQTS) is an inherited channelopathy associated with marked shortening of QT intervals on the ECG and sudden cardiac death in individuals with structurally normal hearts [1,2,3,4]. In patients with SQTS, the QT interval is relatively normal at fast rates, but abnormally short at slow heart rates [14]. Transmural dispersion of repolarization (TDR) has been suggested to correlate to ventricular arrhythmias in an experimental SQTS model that was generated by application of an IK,ATP opener, pinacidil, and in patients with SQTS [15, 16]. Reducing TDR has been suggested as an important antiarrhythmic property of quinidine in a SQTS model [17] and in patients exhibiting the SQT1 variant [14]. In other forms of SQTS, data regarding pharmacological therapy remain too limited to permit specific suggestions or recommendations

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