Biophysics of Cardiac Rhythms

这一建议涉及三个主要方面的研究，以阐明心律失常的机制：(1)单通道门控机制，(2)心脏动作电位的重建，以及药物对动作电位传播的三种作用。一般的方法是对模型进行数学建模，并将模型与来自他人生理研究的实验数据相关联。具体地说，这项建议的第一部分从非马尔科夫威布尔动力学的角度讨论了心肌细胞中的离子通道活动。马尔科夫模型将与非马尔科夫模型进行比较，以确定它们的相对优点，并确定非马尔可夫威布尔模型是否可归类为“分维”模型。建议的第二部分是利用前人获得的动作电流的实验数据，建立心脏动作电位的最小统一模型，以研究房室化钙离子在自发搏动条件下的动态作用，并构建心脏动作电位的数学模型。这项建议的第三部分涉及阐明钙通道阻滞剂对动作电位传播的影响。为了实现这些目标，将使用Cray X-MP/48超级计算机模拟心脏脉冲的启动和传播，并研究离子通道属性的变化如何改变传播波的属性。先进的科学计算机的出现极大地扩展了使用数学建模作为研究生理过程的方法的可能性。尽管心脏动作电位的模型多年来一直令人感兴趣，但实验进展提供了新的信息，这些信息现在可以被合并到更复杂的模型中，这些模型反过来可能指向更精细的实验。这些方法的最终目标是彻底了解心脏节律活动背后的电现象。

This proposal addresses three major aspects of research to elucidate the mechanisms underlying cardiac rhythms: (1) single channel gating mechanisms, (2) reconstructing caridac action potentials, and three effects of pharmacological agents on the propagation of action potentials. The general approach is mathematical modeling and correlation of the models with experimental data derived from the physiological studies of others. Specifically, the first part of this proposal deals with the ionic channel activity in heart cells from the viewpoint of non-Markovian Weibull kinetics. Markovian models will be compared with non-Markovian models to determine their relative merits and to determine whether the non-Markovian Weibull model can be classified as a "fractal" model. The second part of the proposal deals with the construction of a minimal unified model for cardiac action potentials using experimental data on action currents obtained by others, so as to study the dynamic role of compartmentalized calcium ions under spontaneous beating conditions, and to construct a mathematical model for the cardiac action potential. The third part of this proposal deals with elucidation of the effect of calcium channel blockers on the action potential propagation. To acheive these objectives the cardiac impulse initiation and propagation will be simulated using the Cray X-MP/48 supercomputer and study how changes in the ionic channel properties would alter the properties of the propagating waves. The availability of advanced scientific computers has greatly expanded the possibility for using mathematical modeling as an approach to study physiological processes. Although models of the heart action potential have been of interest for many years, experimental advances have provided new information that can now be incorporated into more sophisticated models which, in turn, may point to more refined experiments. The ultimate goal of these approaches is to develop a thorough understanding of the electrical phenomena that underly the rythmic activity of the heart.