Cardiac Fibrillation: Mechanisms and Therapy

描述(申请人提供)：室颤(VF)是最常见的猝死原因，仅在美国每年就有超过30万人死亡。该计划的目标是通过从机制水平上了解室颤的发病机制，为心脏性猝死(SCO)的治疗开发一种合理的方法。这项建议代表了我们从#年开始的SCOR开始的努力的继续。 1995年，为了解决这一目标，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。这项拟议项目的主题是动态波不稳定性(受电恢复、细胞内钙循环、心脏记忆和扩散电流调节)与疾病心脏中增加的电和结构组织异质性协同作用，从而增加室颤和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包括膜片钳、荧光染料光学作图、分子生物学、腺病毒基因转移在内的实验方法以及包括数学建模、计算机模拟和非线性动力学在内的理论方法来解决这一主题。从分离的心肌细胞到完整的正常和病变的脑室，无论是在体内还是在硅胶中，都将通过该计划项目进行互动研究，以全面评估控制波形稳定性的动态因素，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.