基于虚拟心脏电生理模型的短QT综合征发病机制解析及药物筛选研究

The short QT syndrome (SQTS) is an inherited disorder associated with abnormally abbreviated QT intervals on the clinical ECG and an increased incidence of cardiac arrhythmias and sudden cardiac death. In recent years, it has widespread attention about the underlying pro-arrhythmogenic effects of SQTS and possible pharmacological anti-arrhythmic treatment of SQTS. However, it is not realistic and unscientific to use animal models to achieve research goals. In this project, firstly, we plan to use the electrophysiological models of virtual heart, parallel computing, scientific computing and visualization technology to develop biophysically detailed mathematical models of mutant potassium channels associated with SQTS conditions, and to develop drug-in-action ensemble model and dose-dependent model. Secondly, we plan to develop multi-scale models of the heart from microcosmic myocardial cell to macroscopic cardiac tissue, and then to simulate and analyze the underlying mechanisms of arrhythmia associated with patients with SQTS induce by single and multiple gene mutations, and screen specific drugs for treating SQTS variants. In this project, the pathological and pharmacological studies of SQTS are provided from qualitative analysis to quantitative analysis. The research achievements will provide an initial theoretic base for pharmacological treatment of SQTS and anti-arrhythmic drug screening in general, which will be of great values in design new drugs for treating general cardiac arrhythmias.

短QT综合征（short QT syndrome，SQTS）是以临床心电图QT间期缩短为主要特征的一类遗传性心脏病，目前对于基因变异诱发SQTS及恶性心律失常的机制及其有效治疗方法的研究受到关注，但全部通过动物模型的手段来达到研究目的不现实也不科学。本项目利用虚拟心脏电生理模型、并行计算以及科学计算与可视化的相关理论和技术，依据基因不同位点变异、通道功能特性改变、药物影响通道电流等相关电生理实验数据，建立多尺度虚拟心脏的SQTS病理模型和药物作用集成模型以及药物剂量依赖性模型，并通过人机交互的方式仿真实验，从定量和定性两方面来解析SQTS基因单个位点、多个位点变异产生恶性心律失常的发病机制，筛选治疗SQTS不同分型的药物。该研究将为SQTS的临床诊治和药物筛选提供前期理论依据，建立的虚拟心脏模型和药物作用模型对于更好的理解普遍意义紊乱状态的心律失常和开展药物筛选也有很大价值。

本项目依据基因不同位点变异、通道功能特性改变、药物影响通道电流等相关电生理实验数据，建立多尺度虚拟心脏的SQTS病理模型和药物作用模型，并通过人机交互的方式仿真实验，解析SQTS基因变异产生心律失常的发病机制，筛选治疗SQTS不同分型的药物。主要内容有：1. 建立多尺度的SQTS病理模型，通过计算从定性和定量两方面解析基因变异致SQTS并诱发恶性心律失常的发病机制；2. 建立药物作用集成模型和药物剂量依赖性模型，提出治疗SQTS的药物作用预测新方法，并用于筛选治疗SQTS不同分型的特效药；3. 开发智能医疗诊断系统（IMDS）仿真平台，并将心脏智能诊断加到IMDS中。在此基础上研究IMDS如何被攻击和诊断记录篡改，并提出一系列安全防御策略来预防此类攻击。本研究为SQTS病人的临床治疗和抗心律失常药物筛选提供前期理论依据。