Short Term Memory and Discordant Alternans in the Heart

在这个项目中，PI将利用心脏动力学的非线性时空分析，确定短期记忆在心脏动作电位时程(APD)恢复和空间不协调交替(SDA)形成中的作用。PI将使用膜片钳和光学映射技术对分离的细胞和完整的兔心进行记录。在理论研究中，PI将使用唯象数学模型，以及使用最近开发的详细的离子兔心室细胞模型的2D数值模拟。这项拟议研究的第一个目标是证明短期记忆在心脏中的空间分布与交替和室颤(VF)的发生相关。该提案的第二个目标是建立心脏SDA形成机制的室间差异。利用分离的兔心的光学标测，PI将检验这一假设，即心脏左、右室SDA的形成主要通过不同的机制发生：陡峭的传导速度恢复和短期记忆。研究方案的第三个目标是评估短期记忆和陡峭传导速度恢复在SDA形成中的具体作用。PI将使用药理学方法进一步梳理出这些机制对心脏SDA形成的个体贡献。该项目将在多学科环境中培养研究生和本科生。该项目将对我们理解室颤的根本原因和先兆产生重大影响，室颤是人类死亡的主要原因之一。

In this project the PI will establish the role of short term memory in action potential duration (APD) restitution and the formation of spatially discordant alternans (SDA) in the heart using nonlinear spatio-temporal analysis of the heart's dynamics. The PI will use patch clamp and optical mapping techniques to perform recording from isolated cells and intact rabbit hearts. In the theoretical studies, the PI will use a phenomenological mathematical model, as well as 2D numerical simulations utilizing the recently developed detailed ionic rabbit ventricular cell model. The first objective of the proposed research is to demonstrate that the spatial distribution of short-term memory in the heart correlates with the onset of alternans and ventricular fibrillation (VF). The second objective of the proposal is to establish inter-ventricular differences in mechanisms of SDA formation in the heart. Using optical mapping of the isolated rabbit heart, the PI will test the hypothesis that the formation of SDA in the right and left ventricles of the heart occurs predominantly through different mechanisms: steep conduction velocity restitution and short term memory. The third objective of the research proposal is to assess the specific roles of short term memory and steep conduction velocity restitution in SDA formation. The PI will use a pharmacological approach to further tease out the individual contributions of these mechanisms to SDA formation in the heart. The project will train graduate and undergraduate students in a multidisciplinary environment. The project will have significant impact on our understanding of the fundamental causes and precursors of ventricular fibrillation, a major cause of death in humans.