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Modelling the effects of chloroquine on KCNJ2-linked short QT syndrome.

ABSTRACT: A gain-of-function KCNJ2 D172N mutation in KCNJ2-encoded Kir2.1 channels underlies one form of short QT syndrome (SQT3), which is associated with increased susceptibility to arrhythmias and sudden death. Anti-malarial drug chloroquine was reported as an effective inhibitor of Kir2.1 channels. Using biophysically-detailed human ventricle computer models, this study assessed the effects of chloroquine on SQT3. The ten Tusscher et al. model of human ventricular cell action potential was modified to recapitulate functional changes in the inward rectifier K+ current (IK1) due to heterozygous and homozygous forms of the D172N mutation. Mutant formulations were incorporated into multi-scale models. The blocking effects of chloroquine on ionic currents were modelled using IC50 and Hill coefficient values from literatures. Effects of chloroquine on action potential duration (APD), effective refractory period (ERP) and pseudo-ECGs were quantified. It was shown that chloroquine caused a dose-dependent reduction in IK1, prolonged APD, and decreased the maximum voltage heterogeneity. Chloroquine prolonged QT interval and declined the T-wave amplitude. Although chloroquine reduced tissue's temporal vulnerability, it increased the minimum substrate size necessary for sustaining re-entry. The actions of chloroquine decreased arrhythmia risk, due to the reduced tissue vulnerability, prolonged ERP and wavelength of re-entrant excitation waves, which in combination prevented and terminated re-entry in the tissue models. In conclusion, the results of this study provide new evidence that the anti-arrhythmic effects of chloroquine on SQT3 and, by extension, to the possibility that chloroquine may be a potential therapeutic agent for SQT3 treatment.

SUBMITTER: Luo C

PROVIDER: S-EPMC5739752 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Modelling the effects of chloroquine on KCNJ2-linked short QT syndrome.

Luo Cunjin C Wang Kuanquan K Zhang Henggui H

Oncotarget 20171118 63

A gain-of-function KCNJ2 D172N mutation in KCNJ2-encoded Kir2.1 channels underlies one form of short QT syndrome (SQT3), which is associated with increased susceptibility to arrhythmias and sudden death. Anti-malarial drug chloroquine was reported as an effective inhibitor of Kir2.1 channels. Using biophysically-detailed human ventricle computer models, this study assessed the effects of chloroquine on SQT3. The ten Tusscher et al. model of human ventricular cell action potential w ...[more]

PMID: 29290967

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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 ? 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.

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Dataset Information

Modelling the effects of chloroquine on KCNJ2-linked short QT syndrome.

Publications

Modelling the effects of chloroquine on <i>KCNJ2</i>-linked short QT syndrome.

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