VOLTAGE-CA DYNAMICS IN SIMPLIFIED TISSUE MODELS

心室颤动（VF）和心源性猝死的发生包括几个关键步骤，例如折返的启动、多折返波的退化以及心室颤动的维持。 issue heterogeneity has been traditionally considered as the major cause for these key steps leading to VF.然而，最近的研究表明，动态波不稳定性与预先存在的组织异质性协同作用，促进波破裂。动态波稳定性受多种因素调节，包括电恢复、细胞内 Ca (Cai) 循环、心脏记忆和电紧张电流。该项目的目标是使用简化模型的计算机模拟来开发理论，识别控制 VF 发展的关键参数，作为新型治疗策略的理论基础。 The central task of this project is to investigate how voltage, Cai, and tissue heterogeneity interact to regulate vulnerability to rentry and maintenace of VF.第一个目标是开发简化模型来研究蔡循环与膜电压耦合的非线性动力学，以了解心脏交替的动力学机制。第二个目标是在同质组织中使用生理详细的 AP 模型来确定电压-Cai 动力学促进空间不协调交替、不应性分散、波不稳定性和心律失常发生的生理机制。第三个目标是确定电压-Cai 动力学如何与组织异质性相互作用，以调节空间不一致的交替、不应性的分散、波不稳定性和心律失常发生。这个项目 将发展一般理论，然后在项目 1、3 和 4 中在更现实的环境中进行验证。该项目中的方法将使我们能够广泛探索参数空间并系统地研究 VF 启动和维持的机制，以确定开发新治疗策略所必需的关键参数。

The development of ventricular fibrillation (VF) and sudden cardiac death include several key steps, such as initiation of reentry, degeneration to multiple reentrant waves, and maintenance of VF. issue heterogeneity has been traditionally considered as the major cause for these key steps leading to VF. However, recent studies indicate that dynamic wave instability operates synergistically with pre-existing tissue heterogeneity to promote wavebreak. Dynamic wave stability is regulated by multiple factors, including electrical restitution, intracellular Ca (Cai) cycling, cardiac memory, and electrotonic currents. The goal of this project is to use computer simulations with simplified models to developed theories which identify the critical parameters controlling the development of VF, as the theoretical basis for novel therapeutic strategies. The central task of this project is to investigate how voltage, Cai, and tissue heterogeneity interact to regulate vulnerability to rentry and maintenace of VF. The first aim is to develop simplified models to investigate the nonlinear dynamics of Cai cycling coupled to membrane voltage, in order to understand dynamical mechanisms of cardiac alternans. The second aim is to use physiologically-detailed AP models in homogeneous tissues to determine the physiological mechanisms by which voltage-Cai dynamics promotes spatially discordant alternans, dispersion of refractoriness, wave instability and arrhythmogenesis. The third aim is to determine how voltage-Cai dynamics interacts with tissue heterogeneities to regulate spatially discordant alternans, dispersion of refractoriness, wave instability and arrhythmogenesis. This project will develop general theories which will then be validated in more realistic settings in Projects 1, 3, and 4. The approach in this project will allow us to extensively explore the parameter space and systematically investigate the mechanisms of VF initiation and maintenance to identify the critical parameters essential for developing novel therapeutic strategies.