FIBRILLATION DYNAMICS IN THE VIRTUAL HEART

虚拟心脏中的颤动动力学

• 批准号: 7108470
• 负责人: Alan J Garfinkel
• 金额: $ 35.23万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-10 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7108470
• 关键词: action potentials; alternatives to animals in research; biological models; calcium flux; computer simulation; electrophysiology; heart; heart electrical activity; heart function; laboratory rabbit; model design /development; pathologic process; sudden cardiac death; ventricular fibrillation

In ventricular fibrillation, the leading cause of sudden cardiac death, electrical activity is marked by wavebreak and subsequent fragmentation of the wave of excitation. Recent work by several groups has focused on the mechanisms of this wavebreak. Anatomical complexity, enhanced by disease, is an important cause of wavebreak, but mathematical modelers have shown that dynamical factors are also critical in this process, independently of, and synergistically with, a disordered anatomical substrate. This paradigm shift towards dynamics is important therapeutically because dynamical factors, unlike anatomy, can be modified by drugs or gene therapy. This Project studies the dynamical mechanisms of fibrillation, in large-scale, realistic, computer models of ventricular conduction. These models, containing roughly 50 million variables, have been developed, and will be extended in this proposal to a level of physiological realism that will make them clinically relevant. Several mechanistic hypotheses will be tested in these "Virtual Heart" models (normal and diseased), the most important of which is that by intervening to improve wave stability, the induction of reentry and its breakdown into fibrillation can be prevented. Specific therapeutic approaches will be explored, including modifying Ca channel kinetics and its interaction with intracellular Ca cycling, especially in the phenomenon of "discordant alternans." The mechanisms of fibrillation, long elusive, can now be studied in silico in models like these, The detailed physiological knowledge is largely already in place; only the computational difficulty of such large-scale simulations remained as an obstacle. These problems have been tamed, through improved numerical methods and the use of supercomputers, so that these models can now be used to study the mechanisms of fibrillation, and potential therapies. The simulations will be performed interactively with theoretical and experimental approaches used in the other projects to define novel therapies for ventricular fibrillation and sudden cardiac death.

在心室纤维化中，心脏猝死的主要原因是，电活动以波浪破裂和随后的激发波的碎裂为特征。几个小组的最新工作集中在这种波浪破裂的机制上。解剖学复杂性是通过疾病增强的，是波浪破裂的重要原因，但是数学建模者表明，在此过程中，动力学因素在此过程中也至关重要，独立于和与无序的解剖学基材协同作用。这种范式向动力学转移至关重要，因为与解剖学不同的动态因素可以通过药物或基因治疗来改变。该项目在大规模，逼真的，计算机的心室传导模型中研究了原纤维的动力学机制。这些模型已开发出大约5000万个变量，并将在该提案中将其扩展到一定程度的生理现实主义，这将使它们在临床上相关。这些“虚拟心脏”模型（正常和患病）将测试几种机械假设，其中最重要的是 通过介入以提高波浪稳定性，可以防止再入诱导及其对纤维化的衰减。将探索特定的治疗方法，包括修改CA通道动力学及其与细胞内CA循环的相互作用，尤其是在“不和谐替代品”现象中。现在可以在硅中研究纤颤的机制，即在这种模型中进行研究，详细的生理知识已经在很大程度上已经存在。只有这种大规模模拟的计算困难仍然是障碍。通过改进的数值方法和超级计算机的使用，这些问题被驯服了，因此现在可以使用这些模型来研究纤颤的机理和潜在的疗法。这些模拟将通过其他项目中用于定义心室纤颤和猝死的新型疗法的理论和实验方法进行交互性进行。