FIBRILLATION DYNAMICS IN THE VIRTUAL HEART

室颤是导致心源性猝死的主要原因，电活动的特点是波形破裂和随后的兴奋波碎裂。最近几个小组的工作集中在这种破波的机制上。疾病增加了解剖结构的复杂性，这是破波的一个重要原因，但数学建模人员已经表明，动力因素在这个过程中也是关键的，独立于无序的解剖底物，并与其协同作用。这种向动力学的范式转变在治疗上很重要，因为动力因素与解剖学不同，可以通过药物或基因疗法来改变。该项目在大规模的、逼真的、计算机模型的心室传导中研究颤动的动力学机制。这些包含大约5000万个变量的模型已经被开发出来，并将在本提案中扩展到生理现实主义的水平，使它们具有临床相关性。几个机械假说将在这些“虚拟心脏”模型(正常和疾病)中得到检验，其中最重要的是 通过干预来提高波的稳定性，可以防止再入的诱导和分解为纤颤。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“不和谐交替”现象中。纤颤的机制，长期以来一直难以捉摸，现在可以用电子计算机来研究。在这样的模型中，详细的生理学知识基本上已经到位；只有这种大规模模拟的计算困难仍然是一个障碍。通过改进的数值方法和超级计算机的使用，这些问题已经被驯服了，因此这些模型现在可以用于研究纤颤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，以定义室颤和心脏性猝死的新疗法。

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.