VOLTAGE-CA DYNAMICS IN SIMPLIFIED TISSUE MODELS

心室颤动（VF）和心源性猝死的发展包括几个关键步骤，如折返的开始，退化为多个折返波，以及VF的维持。问题异质性传统上被认为是导致VF的这些关键步骤的主要原因。然而，最近的研究表明，动态波的不稳定性与预先存在的组织异质性协同作用，以促进波破碎。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，以确定控制VF发展的关键参数，作为新治疗策略的理论基础。该项目的中心任务是研究电压、Cai和组织异质性 相互作用以调节VF的恢复和维持的脆弱性。第一个目标是建立简化模型来研究Cai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。第二个目的是使用生理学上详细的AP模型在均匀的组织，以确定的生理机制，电压蔡动力学促进空间不一致的交替，分散的不应性，波的不稳定性和embrymogenesis。第三个目的是确定电压-蔡动力学如何与组织异质性相互作用，以调节空间上不一致的交替，不应性的分散，波的不稳定性和mammogenesis。这个项目 将开发一般理论，然后在项目1，3和4中更现实的设置中进行验证。该项目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，以确定开发新的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.