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，如心室再入的起始、退变为多次心室再入波和心室再颤的维持。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，动态波不稳定性与预先存在的组织异质性协同作用，促进波破。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。本项目的目标是使用简化模型的计算机模拟来发展理论，以确定控制VF发展的关键参数，作为新的治疗策略的理论基础。本项目的中心任务是研究电压、Cai和组织异质性

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.