基于多尺度心脏计算模型的Timothy综合征发病机制研究

Cardiovascular diseases are the world’s biggest killers. Although much progress has been made in medical technology for cardiac treatment, understanding mechanisms underlying heart function and the prevention and treatment of heart disease remain incomplete. To further study on these issues, potential mechanistic links between gene mutations and the Timothy syndrome (TS), ventricular tachycardia and ventricular/atrial fibrillation，which cannot be effectively explained by physiological experiments, our group takes advantage of computational simulation and hypothetical analysis to carry out this project “Research on the Pathogenesis of Timothy Syndrome Based on Multi-scale Computational Model of the Human Heart”. Firstly, a multi-scale computational model from subcellular proteins to surface electrocardiogram is established based on experimental data on the genetic variation of Timothy syndrome, changes in ion channel function, autonomic nervous regulation and clinical electrocardiogram; Secondly, we investigate the effects of gene mutations linked to Timothy syndrome on electrophysiological characteristics, such as action potential, excitation conduction ability, vulnerable window for unidirectional conduction block and simulated electrocardiogram; Finally, these potential mechanisms underlying Timothy syndrome and arrhythmias are explained. This study will provide a preliminary theoretical basis for clinical treatment and antiarrhythmic drug screening in patients with Timothy syndrome.

心脏病是严重威胁人类健康的第一杀手，虽然治疗技术取得了长足的发展，但是人们对心脏更深层次上的认识以及心脏病的预防和治疗远未达到理想水平。为了更深入研究目前靠生理实验手段无法有效解释的基因变异导致Timothy综合征(TS)并诱发室速、室/房颤发病机制的问题，本课题拟利用计算模型仿真和假设分析的优势，来开展“基于多尺度心脏计算模型的Timothy综合征发病机制研究”，首先基于TS基因变异、离子通道功能改变、自主神经调控作用和临床心电图等相关生理实验数据，建立从亚细胞到体表心电图的多尺度计算模型，然后通过模拟仿真结果来分析TS基因变异对细胞动作电位、兴奋传导能力、单向传导阻滞时间窗、心电图等电生理特征的影响，来研究和解释TS基因变异产生致命性心律失常的发病机制。本研究将为TS病人的临床治疗和抗心律失常药物筛选提供理论和技术支撑。

室/房颤的预防与治疗是一个值得关注的问题，而基因突变致心律失常机制一直是心脏病领域的研究热点之一。本项目着眼于基因突变引起的多尺度电生理动力学行为研究与抗心律失常药物疗效的评估研究。经过项目组成员三年的共同努力，取得了以下的结果：（1）建立了从离子通道、心肌细胞（心室、心房与窦房结）、1D 纤维、2D 组织和3D 心脏器官的多尺度模型，数值模拟仿真了亚细胞、细胞、纤维、组织切片和心脏器官的电传导过程，所得到的伪心电图与临床心电图心室波形一致，提供了研究心脏电生理的有力工具。（2）研究了基因突变对离子通道、细胞动作电位、组织电传导和心脏功能的影响，观察到了心室早期后去极、心室跨壁折返波、心房动作电位缩短、心房延迟后去极等心律失常现象，解释了不同基因突变情况下室/房颤的产生机制。（3）评估了现有临床药物治疗基因突变引起室/房颤的效果，确定了有效的抗房颤药物及其适用情况。所获得的研究成果为基因突变引起的室/房颤预防与治疗提供了理论依据和数值仿真参考，有助于人们理解在心脏系统中出现的复杂现象，并为消除室/房颤提供新思路。项目发表SCI论文16篇，发明专利2项，会议报告3个,项目负责人被提名为美国科学家荣誉学会会员(Sigma Xi).