THE ROLE OF ANATOMIC STRUCTURES IN VENTRICULAR FIBRILLATION

解剖结构在心室颤动中的作用

• 批准号: 8169367
• 负责人: Alan J Garfinkel
• 金额: $ 3.35万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8169367
• 关键词: Abnormal Cell; Anatomic Models; Anatomic structures; Anatomy; Anisotropy; Arrhythmia; Automobile Driving; Biological Models; Calcium; Cardiac; Cell model; Cells; Cicatrix; Communities; Computer Retrieval of Information on Scientific Projects Database; Computer software; Computing Methodologies; Coupled; Coupling; Databases; Development; Electrophysiology (science); Environment; Fibrosis; Funding; Generations; Grant; Hand; Heart; Heart failure; Heterogeneity; Infarction; Institution; Maintenance; Modeling; Myocardial; Normal Cell; Oryctolagus cuniculus; Pathology; Play; Property; Relative (related person); Research; Research Personnel; Resources; Role; Source; Structure; Testing; Thick; Tissues; United States National Institutes of Health; Ventricular; Ventricular Fibrillation; sudden cardiac death; tool; virtual

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. (A) OBJECTIVES In ventricular fibrillation (VF), the leading cause of sudden cardiac death, the wave of electrical activation breaks up into a multi-wave chaotic state. Our research has focused on the question: what are the causes of this wavebreak? The traditional view was that the wave was broken up by anatomic heterogeneity, such as the curved ventricular and septal walls with their varying thicknesses, and the systematically varying anisotropy that is seen as one proceeds transmurally across the myocardial walls. The objective of our earlier research was to answer the questions: how important are anatomical heterogeneities as opposed to purely dynamical instabilities in generating and sustaining fibrillation? How do they interact? We have now shown that while the anatomic factors above can play contributory roles, the decisive role is played by the dynamical stability of conduction, which is determined by the electrophysiologic properties of the cells and tissue. We now propose to extend this research to consider the anatomic and electrophysiologic changes that are seen in heart failure. Our Specific Aims are to study arrhythmias in heart failure, and especially to tease apart the contributions to arrhythmia generation made by abnormal anatomy, on the one hand, and abnormal cell electrophysiology, on the other. To study this, we will study the normal cell in the abnormal structural heart, the abnormal cell in the normal heart and then the two pathologies, cell and tissue, together. We will use the three-dimensional ventricular anatomic models and tools developed by the NBCR investigators, and by us in conjunction with NBCR researchers, to study these questions. Specific Aim 1: To use the rabbit Virtual Heart to test the effects on cardiac wave conduction produced by adding such pathological factors as fibrosis, infarct scars, and loss of cell-to-cell electrical coupling. Specific Aim 2: To use the NBCR modeling environment to study the effects of alterations in intracellular calcium handling on the genesis and maintenance of VF. The UCSD cell systems modeling environment, coupled to the geometry models, are the ideal platforms on which to test our hypotheses that altered intracellular calcium handling is a key to the genesis of fibrillation in heart failure. Specific Aim 3: To develop anatomically realistic models of several forms of heart failure in the rabbit, and use those models together with our cell models for normal and heart failure rabbit, to test the relative contributions of altered tissue structure vs. altered cell electrophysiology, in the genesis of arrhythmias in heart failure. The proposed collaborative research will provide a driving application for the new developments in software and computational methods in Specific Aims 1 of Core [4A.2B], and the resulting new anatomic and electrophysiological meshes and models will be shared with the community via the database to be developed in Specific Aim 2. It will serve as a platform for testing and developing new bidomain models and coupled ODE solvers in Specific Aim 2.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 （a）目标 在心室纤颤（VF）中，心脏猝死的主要原因，电活激活的波浪分化为多波动的混沌状态。我们的研究集中在一个问题上：这次波浪破坏的原因是什么？ 传统的观点是，波浪是由解剖异质性分解的，例如弯曲的心室和间隔壁，其厚度变化，并且系统地变化的各向异性被视为经传播遍布整个心肌壁。我们较早的研究的目的是回答以下问题：解剖异质性与纯粹动态不稳定性在产生和维持纤颤时的重要性有多重要？ 他们如何互动？ 现在，我们已经表明，尽管上述解剖因素可以发挥作用，但决定性作用是通过传导的动态稳定性发挥的，这取决于细胞和组织的电生理特性。 现在，我们建议扩展这项研究，以考虑心力衰竭中看到的解剖学和电生理学变化。 我们的具体目的是研究心力衰竭的心律不齐，尤其是嘲笑一方面对异常解剖学产生的心律不齐产生的贡献，另一方面是异常的细胞电生理学。为了研究这一点，我们将研究异常的结构心脏，正常心脏中异常细胞，然后研究两种病理，细胞和组织中的正常细胞。 我们将使用NBCR研究人员开发的三维心室解剖模型和工具，以及与NBCR研究人员一起研究这些问题。 特定目的1：使用兔虚拟心脏来测试通过添加诸如纤维化，梗塞疤痕和细胞对细胞电气耦合损失等病理因素产生的对心浪传导的影响。 特定目的2：使用NBCR建模环境来研究细胞内钙处理中改变对VF的起源和维持的影响。与几何模型相连的UCSD细胞系统建模环境是测试改变细胞内钙处理的假设的理想平台，是心力衰竭纤维化起源的关键。 特定目的3：为兔子中几种形式的心力衰竭建立解剖学现实模型，并将这些模型与我们的细胞模型一起用于正常和心力衰竭兔子，以测试组织结构改变的相对贡献与改变的细胞电生理学的相对贡献，在心律失常的发生在心脏失败中。 拟议的协作研究将为Core [4A.2B]的特定目的1中的软件和计算方法的新发展提供驾驶应用程序，由此产生的新的解剖学和电生理网络和模型将通过与社区共享的数据库，该数据库将在特定的目标2中开发，可用于测试和开发新的BIDOMAIN模型。