Computer Modelling the Effects of Chloroquine on KCNJ2 D172N and E299V Mutations-linked Short QT Syndrome

Cunjin Luo1, Ying He2, Kuanquan Wang3, Henggui Zhang4
1University of Essex, 2De Montfort University, 3Harbin Institute of Technology, 4The University of Manchester


Background. The short QT syndrome (SQTS) is an inherited cardiac channelopathy characterised by an abnormally short QT interval and increased risk for arrhythmias and sudden cardiac death (SCD). The SQT3, SQTS variant, result from gain-of-function mutations (such as D172N, E299V) in the KCNJ2-encoded potassium current (IK1) channels. There have been some studies on the electrophysiological effects of the KCNJ2 D172N and E299V mutations on the heart and identified the possibility of arrhythmia caused by these mutations in SQT3 through the simulation study by using mathematical models. Previous studies showed that anti-malarial drug chloroquine has some efficacy in the potassium channel IK1 blocking. Therefore, this study used computer modelling to predict the potential effects of chloroquine for the treatment of the different mutant D172N and E299V-linked SQT3, and also predict whether or not the drug chloroquine is a generic agent for the treatment of SQTS.

Methods and Results. The ten Tusscher et al. human ventricle model of electrophysiology was modified to describe the SQT3 KCNJ2 D172N and E299V mutant conditions. single cell models were incorporated into heterogeneous one-dimensional (1D) transmural ventricular strand model to assess prolongation of the QT intervals, and two-dimensional ventricular sheet model to observe the electrophysiological properties of the electrical re-entrant waves during ventricular arrhythmias. The blocking effects of chloroquine on potassium currents were modelled by using Hill coefficient and IC50 from literatures. In the single cell simulations, chloroquine prolonged the action potential duration (APD) under both the SQT3 D172N and E299V conditions. In the multi-cell simulations, chloroquine prolonged the QT intervals and terminated the re-entrant waves under both the mutant conditions.

Conclusions. This study provides new evidence that chloroquine may be an effective and generic drug for the treatment of different mutant D172N and E299V -linked SQT3.