Computational Analysis of the Action of Chloroquine on Short QT Syndrome Variant 1 and Variant 3 in Human Ventricles

Cunjin Luo, Tong Liu, Henggui Zhang

Abstract: The short QT syndrome (SQTS) is a rare genetic disorder associated with arrhythmias and sudden cardiac death (SCD). The SQT1 and SQT3, SQTS variants, result from gain-of-function mutations (N588K and D172N, respectively) in the KCNH2-encoded and KCNJ2-encoded potassium channels, in which treatment with potassium channel blocking agents has demonstrated some efficacy. This study used in silico modelling to gain mechanistic insights into the actions of anti-malarial drug chloroquine (CQ) in the setting of SQT1 and SQT3. Methods and Results: The ten Tusscher et al. human ventricle model was modified to a Markov chain formulation of IKr and a Hodgkin-Huxley formulation of IK1 describing SQT1 and SQT3 mutant conditions, respectively. Cell models were incorporated into heterogeneous one-dimensional (1D) transmural ventricular strand model to assess prolongation of the QT intervals. The blocking effects of CQ on IK1 and IKr were modelled by using Hill coefficient and IC50 from literatures. At the single cells, CQ prolonged the AP duration (APD) under both the SQT1 and SQT3 conditions; at the multi-cell strand level, CQ prolonged the QT intervals and declined the T-wave amplitude under both conditions. Conclusions: This computational study provides novel insights into the efficacy of CQ in the setting of SQT1 and SQT3 variants, and indicates that CQ is a useful drug in the treatment of SQTS.