Cardiac Fibrillation: Mechanisms and Therapy

描述（由申请人提供）：室颤（VF）是猝死的最常见原因，仅在美国每年就有超过30万例死亡。本项目的目标是通过在机制水平上了解VF的发病机制，制定一种合理的方法来治疗心脏性猝死（SCO）。这项建议是我们继续努力的结果，这项努力始于我们的SCOR， 1995年的心脏性猝死，通过将数学生物学与实验生物学相结合，在分子、细胞、组织和系统水平上整合信息来实现这一目标。该拟议计划项目的主题是动态波不稳定性（由电恢复、细胞内Cai循环、心脏记忆和扩散电流调节）与患病心脏中增加的电和结构组织异质性协同作用，以增加VF和SCO的风险，并且通过开发旨在减少动态波不稳定性的分子干预措施，可以预防VF和SCO。这四个项目和三个核心将使用实验方法解决这一主题，包括膜片钳，荧光染料光学映射，分子生物学，腺病毒基因转移，以及理论方法，包括数学建模，计算机模拟和非线性动力学。从分离的心肌细胞到完整的正常和患病心室，无论是在体内还是在计算机上，将通过该计划项目进行交互式研究，以全面评估控制波稳定性的动态因素，作为预防VF和SCO的治疗目标。

DESCRIPTION (provided by applicant): Ventricular fibrillation (VF) is the most common cause of sudden death, accounting for over 300,000 deaths annually in the US alone. The objective of this proposed Program Project is to develop a rational approach to the therapy of sudden cardiac death (SCO) through understanding the pathogenesis of VF at the mechanistic level. The proposal represents a continuation of our efforts, which began with our SCOR in Sudden Cardiac Death in 1995, to address this objective by combining mathematical biology with experimental biology to integrate information at the molecular, cellular, tissue and systems levels. The theme of this proposed Program Project is that dynamic wave instability (regulated by electrical restitution, intracellular Cai cycling, cardiac memory and diffusive currents) interacts synergistically with increased electrical and structural tissue heterogeneity in the diseased heart to increase the risk of VF and SCO, and that by developing molecular interventions designed to decrease dynamic wave instability, VF and SCO can be prevented. The four projects and three cores will address this theme using experimental approaches including patch clamping, optical mapping with fluorescent dyes, molecular biology, adenoviral gene transfer, and theoretical approaches including mathematical modeling, computer simulations and nonlinear dynamics. Studies ranging from isolated myocytes to intact normal and diseased ventricles, both in vivo and in silico, will be conducted interactively through this Program Project to evaluate comprehensively dynamic factors controlling wave stability as therapeutic targets for prevention of VF and SCO.