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.

心室颤动是心源性猝死的主要原因，其电活动的特征是波断和随后的兴奋波碎裂。最近几个小组的工作集中在这种波破的机制上。疾病加剧的解剖复杂性是波破的重要原因，但数学建模者已经表明，在这一过程中，动力学因素也至关重要，既独立于混乱的解剖基底，又与之协同作用。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。本项目研究颤的动力学机制，在大规模，现实，计算机模型的心室传导。这些模型，包含大约5000万个变量，已经被开发出来，并将在本提案中扩展到生理现实主义的水平，这将使它们具有临床相关性。在这些“虚拟心脏”模型（正常和患病）中，将测试几个机制假设，其中最重要的是