VOLTAGE-CA DYNAMICS IN SIMPLIFIED TISSUE MODELS

室颤(VF)和心脏性猝死的发生包括几个关键步骤，如启动折返性心动过速、退变为多个折返性波和维持室颤。传统上，问题的异质性被认为是导致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，促进了波形破裂。动态波形稳定性受多种因素的调节，包括电恢复、细胞内钙循环、心脏记忆和电紧张性电流。该项目的目标是使用计算机模拟和简化的模型来开发理论，以确定控制室颤发展的关键参数，作为新的治疗策略的理论基础。这个项目的中心任务是研究电压、cai和组织异质性 相互作用以调节对VF的租入和维护的脆弱性。第一个目的是建立简化的模型来研究膜电压耦合的CaI循环的非线性动力学，以了解心脏交替的动力学机制。第二个目的是在均匀组织中使用生理细节的AP模型来确定电压-CAI动力学促进空间不协调交替、不应期离散、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-蔡氏动力学如何与组织异质性相互作用，以调节空间不和谐交替、不应期离散、波不稳定性和心律失常的发生。这个项目 将发展一般理论，然后将在更现实的环境中验证项目1、3和4。该项目中的方法将使我们能够广泛探索参数空间，并系统地研究室颤的启动和维持机制，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.