基于3D电-力耦合人心室模型的生物起搏器机制研究

Biological pacemaker is a novel technique that has many advantages to typical electronic pacemakers in controlling heart rhythm for patients that requires an implanted cardiac pacemaker. Recently it has attracted widely interests in scientific and industrial communities. However, there are still some challenges (such as stable and long-lasting pacing, potential pro-arrhythmic effects) requiring to be addressed before clinical applications of biological pacemakers. In order to address these challenges, we propose a research project entitled “Investigation of the pacemaking mechanism of biological pacemaker based on 3D electrical-mechanical ventricular computational model”. The objectives of this research are: (i) to develop a 3D electrical-mechanical computer model for the human heart that integrates detailed extant experimental data on electrophysiology of the heart and stem-cell biology at multi-physical scales, ranging from sub-cellular, cellular, tissue to whole organ levels; (ii) to use nonlinear dynamics theory and methods to analyze these models in order to elucidate the mechanism underlying the genesis and maintenance of stable pacemaking activities of biological pacemaker cells; (iii) to investigate the effects of self-organization, cell-to-cell electrical coupling in generating of spontaneous and synchronized pacemaking activity in large groups of biological pacemaking cells in cardiac tissue; and (iv) at 3D whole heart level to investigate the effects of the location and size of the bio-pacemaker on the electrical and mechanical dynamics of the heart, therefore the functions of the heart in pumping the blood. The output of this project will provide a solid theoretical basis for designing effective and stable biological pacemakers for clinical applications.

生物起搏器作为一种既有心脏起搏功能又能够克服电子起搏器缺点的新技术，已经引起学术界和企业界的广泛关注，但其离临床应用还有诸多重大问题亟需解决。为了解决实验手段在生物起搏器的起搏机制、对心脏电传导与收缩功能的影响等关键科学问题上的研究局限性，本课题拟在前期虚拟生理心脏模型研究工作基础上，利用计算模型模拟和假设分析的优势，开展“基于3D电-力耦合人心室模型的生物起搏器机制研究”。本研究将基于基因变异诱导的心室细胞产生自律性的实验数据，建立“起搏”心室细胞计算模型并以此模型为基础建立3D电-力耦合人的心室模型。利用计算模型与非线性理论分析，研究“起搏”心室细胞起搏机制和起搏稳定性，“起搏”心室细胞同步起搏机制和其驱动心脏的能力，“起搏”心室细胞落巢位置对心脏电传导和心脏收缩产生的影响等关键科学问题。本研究将为生物起搏器的实验研究和最终临床应用提供详实的理论依据和指导。

起搏功能障碍已成为威胁人类健康的一种重大疾病，严重时可能导致心律失常、晕厥，甚至死亡。由于其引起并发症的风险较低，而且能够对生理情绪做出反应，生物起搏器有望替代电子起搏器，进行心脏起搏障碍治疗。迄今为止，生物起搏器已成功应用于大型哺乳动物，但其应用于临床治疗人类心脏病，仍有很长的路要走。使用生物起搏器的计算模型有望加速此进程。通过计算机模型，可以定性、定量地模拟起搏基因过表达对心室细胞自发起搏行为的诱导作用。针对舒张间期过长的问题提出优化的起搏细胞模型。并构建了能够体现物种差异的生物起搏器细胞模型，基于该模型探讨起搏电流特性对起搏细胞构建的影响。然后研究IK1电流和If电流协同作用对诱导非自律细胞自发起搏的影响。并构建3D生物起搏器模型，研究“起搏”心室细胞落巢位置对心脏电传导和心脏收缩产生的影响。