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.

在室颤中，心源性猝死的主要原因，电活动以波中断和随后的兴奋波碎片为标志。几个小组最近的工作集中在这种波的机制上。由于疾病而增强的解剖学复杂性是波裂的重要原因，但数学建模者已经表明，动力学因素在这一过程中也是至关重要的，独立于无序的解剖学基底，并与之协同作用。这种向动力学的范式转变在治疗上是重要的，因为动力学因素与解剖学不同，可以通过药物或基因治疗来改变。本计画以心室传导的大规模、真实的电脑模型来研究心室颤动的动力学机制。这些模型包含大约5000万个变量，已经开发出来，并将在本提案中扩展到生理现实主义的水平，使其与临床相关。将在这些“虚拟心脏”模型（正常和患病）中测试几种机制假设，其中最重要的是， 通过干预以提高波的稳定性，可以防止折返的诱导及其分解成纤颤。将探索具体的治疗方法，包括改变钙通道动力学及其与细胞内钙循环的相互作用，特别是在“不协调交替”现象中。“纤维性颤动的机制，长期难以捉摸，现在可以在像这样的模型中进行计算机研究，详细的生理知识在很大程度上已经到位;只有这种大规模模拟的计算难度仍然是一个障碍。通过改进的数值方法和使用超级计算机，这些问题已经得到解决，因此这些模型现在可以用于研究纤维性颤动的机制和潜在的治疗方法。这些模拟将与其他项目中使用的理论和实验方法交互进行，以确定心室颤动和心脏性猝死的新疗法。