Luo Cunjin, Wang Kuanquan, Liu Tong, Zhang Henggui
Annu Int Conf IEEE Eng Med Biol Soc. 2018 Jul;2018:5462-5465. doi: 10.1109/EMBC.2018.8513572.
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 IC 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.
短QT综合征（SQTS）是一种罕见的遗传性疾病，与心律失常和心源性猝死（SCD）相关。SQTI和SQT3这两种SQTS变体分别是由KCNH2编码和KCNJ2编码的钾通道中的功能获得性突变（分别为N588K和D172N）引起的，其中钾通道阻滞剂治疗已显示出一定疗效。本研究使用计算机模拟来深入了解抗疟药物氯喹（CQ）在SQTI和SQT3情况下的作用机制。
将Ten Tusscher等人的人体心室模型分别修改为描述SQTI和SQT3突变条件的$I_{J}$<r的马尔可夫链公式和$I_{J}$<1的霍奇金-赫胥黎公式。将细胞模型纳入异质一维（ID）跨壁心室肌束模型以评估QT间期的延长。通过使用文献中的希尔系数和IC对CQ对$I_{J}$<1和$I_{J}$<r的阻断作用进行建模。在单细胞水平，CQ在SQTI和SQT3条件下均延长了动作电位时程（APD）；在多细胞肌束水平，CQ在两种条件下均延长了QT间期并降低了T波振幅。
这项计算研究为CQ在SQTI和SQT3变体情况下的疗效提供了新的见解，并表明CQ是治疗SQTS的一种有效药物。
