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

Abstract

The short QT syndrome (SQTS) is a rare genetic disorder associated with arrhythmias and sudden cardiac death (SCD). The SQTI 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 SQTI and SQT3. The ten Tusscher et al. human ventricle model was modified to a Markov chain formulation of $I_{J}$<r and a Hodgkin-Huxley formulation of $I_{J}$<1 describing SQTI and SQT3 mutant conditions, respectively. Cell models were incorporated into heterogeneous one-dimensional (ID) transmural ventricular strand model to assess prolongation of the QT intervals. The blocking effects of CQ on $I_{J}$<1 and $I_{J}$<r were modelled by using Hill coefficient and IC50 from literatures. At the single cells, CQ prolonged the AP duration (APD) under both the SQTI and SQT3 conditions; at the multi-cell strand level, CQ prolonged the QT intervals and declined the T-wave amplitude under both conditions. This computational study provides novel insights into the efficacy of CQ in the setting of SQTI and SQT3 variants, and indicates that CQ is a useful drug in the treatment of SQTS.