VOLTAGE-CA DYNAMICS IN SIMPLIFIED TISSUE MODELS

简化组织模型中的电压-CA 动力学

• 批准号: 7108466
• 负责人: ZHILIN QU
• 金额: $ 28.05万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-10 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7108466
• 关键词: action potentials; alternatives to animals in research; calcium; calcium flux; cardiac myocytes; computer simulation; disease /disorder model; disease /disorder prevention /control; electrical potential; heart electrical activity; intracellular transport; mathematical model; membrane potentials; model design /development; pathologic process; sudden cardiac death; ventricular fibrillation

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.

心室纤维化（VF）和心脏突然死亡的发展包括多个关键步骤，例如重新进入，对多个重新进入波的退化以及VF的维持。传统上，问题异质性被视为导致VF的这些关键步骤的主要原因。然而，最近的研究表明，动态波不稳定性与先前存在的组织异质性协同起作用，以促进波浪破裂。动态波稳定性由多种因素调节，包括电恢复，细胞​​内CA（CAI）循环，心脏记忆和电流电流。该项目的目的是使用具有简化模型的计算机模拟来开发理论，这些理论识别控制VF开发的关键参数，作为新型治疗策略的理论基础。该项目的核心任务是研究电压，CAI和组织异质性 互动以调节VF的租赁和维护的脆弱性。第一个目的是开发简化的模型，以研究与膜电压耦合的CAI循环的非线性动力学，以了解心脏替代品的动态机制。第二个目的是在均质组织中使用生理上详细的AP模型来确定电压-CAI动力学促进空间不一致的替代品，难治性，波浪不稳定性和心律失常发生的生理机制。第三个目的是确定电压-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替代品，耐火性，波浪不稳定性和心律失常发生。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启动和维护的机制，以确定开发新型治疗策略所必需的关键参数。