Dataset Information

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

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.

SUBMITTER: Lee HC

PROVIDER: S-EPMC5714284 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Publications

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

Lee Hsiang-Chun HC Rudy Yoram Y Liang Hongwu H Chen Chih-Chieh CC Luo Ching-Hsing CH Sheu Sheng-Hsiung SH Cui Jianmin J

Journal of medical and biological engineering 20170705 5

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 ...[more]

PMID: 29213224

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Project description:Atrial fibrillation (AF) and sinus bradycardia have been reported in patients with short QT syndrome variant 2 (SQT2), which is underlain by gain-of-function mutations in KCNQ1 encoding the α subunit of channels carrying slow delayed rectifier potassium current, I Ks. However, the mechanism(s) underlying the increased atrial arrhythmogenesis and impaired cardiac pacemaking activity arising from increased I Ks remain unclear. Possible pharmacological interventions of AF in the SQT2 condition also remain to be elucidated. Using computational modelling, we assessed the functional impact of SQT2 mutations on human sinoatrial node (SAN) pacemaking, atrial repolarisation and arrhythmogenesis, and efficacy of the anti-arrhythmic drug quinidine. Markov chain formulations of I Ks describing two KCNQ1 mutations - V141M and V307L - were developed from voltage-clamp experimental data and then incorporated into contemporary action potential (AP) models of human atrial and SAN cells, the former of which were integrated into idealised and anatomically detailed tissue models. Both mutations shortened atrial AP duration (APD) through distinct I Ks 'gain-of-function' mechanisms, whereas SAN pacemaking rate was slowed markedly only by the V141M mutation. Differences in APD restitution steepness influenced re-entry dynamics in tissue - the V141M mutation promoted stationary and stable spiral waves whereas the V307L mutation promoted non-stationary and unstable re-entrant waves. Both mutations shortened tissue excitation wavelength through reduced effective refractory period but not conduction velocity, which served to increase the lifespan of re-entrant excitation in a 3D anatomical human atria model, as well as the dominant frequency (DF), which was higher for the V141M mutation. Quinidine was effective at terminating arrhythmic excitation waves associated with the V307L but not V141M mutation, and reduced the DF in a dose-dependent manner under both mutation conditions. This study provides mechanistic insights into different AF/bradycardia phenotypes in SQT2 and the efficacy of quinidine pharmacotherapy.

Dataset Information

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

Publications

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

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