面向短QT综合征的药物作用建模与仿真研究

短QT综合征(short QT syndrome,SQTS)是以心电图QT间期、心室和心房不应期明显缩短为主要显性特征,并伴有晕厥、高发心源性猝死(sudden cardiac death,SCD)和恶性心律失常风险的一类遗传性心肌离子通道病.据目前资料信息,关于SQTS致病机理的报道比较多,而对SQTS药物治疗的报道罕见.为了揭示在SQTS下的药物作用,本文通过计算机仿真构建人体心室细胞和组织的药物作用模型,利用该模型,从亚细胞、细胞、组织三个尺度,模拟SQT1、SQT2和SQT3下的普罗帕酮药物作用过程,并仿真心电图的变化情况.仿真结果表明:在SQT1下普罗帕酮延长了动作电位时程(action potential duration,APD)和心电图QT间期,并降低T波幅值;相反,在SQT2和SQT3下普罗帕酮缩短了APD和QT间期.计算使用药物前后细胞间膜电压和APD空间离散度的变化,定量分析了普罗帕酮降低T波振幅的原因.总之,对SQT1,普罗帕酮有效;对SQT2和SQT3,普罗帕酮没有改变其致心律失常的危险.仿真结果为普罗帕酮用于临床治疗SQTS提供理论参考.

A Modelling and Simulation Study of Drug Effects on Short QT Syndrome

Abstract Short QT syndrome (SQTS), a new genetic channelopathy, is characterized by the abbreviated QT interval on ECG and abbreviated effective refractory period (ERP) of ventricles and atrium, associated with syncope and a higher risk of sudden cardiac death (SCD) due to malignant arrhythmias. To our knowledge, pro-arrhythmogenic effects of SQTS have been extensively characterized, but less is known about the pharmacology of SQTS. Therefore, we built a drug-blocking model to predict the effects of propafenone on SQTS. The biophysically detailed model of the human ventricular action potential (AP) was modified to incorporate the drug-blocking model and the potassium current formulations including SQT1, SQT2, and SQT3. The modified ventricular cell model was then integrated into one-dimensional strand tissue with transmural heterogeneities. Effects of propafenone on ventricular activities and pseudo-ECGs were simulated and quantified. The results showed that propafenone prolonged the action potential duration (APD) and QT interval in SQT1, and decreased the T-wave amplitude. However, it shortened the APD and QT interval in SQT2 and SQT3. Propafenone in SQT1 decreased the maximal transmural voltage heterogeneity and transmural heterogeneity of APD across the strand tissue, which contributed to the decreased T-wave amplitude. These findings provide new evidence of anti-arrhythmic effects of propafenone on SQT1 and pro-arrhythmic effects on SQT2 and SQT3.