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

Cunjin Luo, Kuanquan Wang, Henggui Zhang

    Research output: Contribution to journalArticlepeer-review

    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.

    Original languageEnglish
    Pages (from-to)106511-106526
    Number of pages16
    JournalOncotarget
    Volume8
    Issue number63
    Early online date18 Nov 2017
    DOIs
    Publication statusPublished - 2017

    Keywords

    • Arrhythmia
    • Chloroquine (CQ)
    • Computer modelling
    • Inward rectifier
    • Short QT syndrome (SQTS)

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