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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 中心，不一定是研究者的机构。 (一) 目标 在心室颤动（VF）（心源性猝死的主要原因）中，电激活波分解为多波混沌状态。我们的研究重点是这样一个问题：这次浪潮的原因是什么？ 传统观点认为，波被解剖结构的异质性所破坏，例如弯曲的心室壁和间隔壁的厚度不同，以及系统变化的各向异性（当一个人透壁穿过心肌壁时）。我们早期研究的目的是回答以下问题：在产生和维持颤动方面，与纯粹的动力学不稳定性相比，解剖异质性有多重要？ 他们如何互动？ 我们现在已经证明，虽然上述解剖因素可以发挥重要作用，但决定性作用是传导的动态稳定性，这是由细胞和组织的电生理特性决定的。 我们现在建议扩展这项研究，以考虑心力衰竭中出现的解剖学和电生理学变化。 我们的具体目标是研究心力衰竭中的心律失常，特别是梳理异常解剖学和异常细胞电生理学对心律失常产生的贡献。为了研究这一点，我们将研究结构异常心脏中的正常细胞、正常心脏中的异常细胞，然后一起研究细胞和组织这两种病理。 我们将使用 NBCR 研究人员以及我们与 NBCR 研究人员合作开发的三维心室解剖模型和工具来研究这些问题。 具体目的1：利用兔虚拟心脏来测试加入纤维化、梗塞疤痕、细胞间电耦合丧失等病理因素对心波传导的影响。 具体目标 2：使用 NBCR 建模环境研究细胞内钙处理的改变对 VF 发生和维持的影响。 UCSD 细胞系统建模环境与几何模型相结合，是检验我们假设的理想平台，即改变细胞内钙处理是心力衰竭中纤维性颤动发生的关键。 具体目标 3：开发几种兔子心力衰竭的解剖学真实模型，并将这些模型与我们的正常和心力衰竭兔子的细胞模型一起使用，以测试改变的组织结构与改变的细胞电生理学的相对贡献，心力衰竭心律失常的起源。 拟议的合作研究将为核心 [4A.2B] 的特定目标 1 中的软件和计算方法的新发展提供驱动应用，由此产生的新的解剖和电生理网格和模型将通过数据库与社区共享将在 Specific Aim 2 中开发。它将作为在 Specific Aim 2 中测试和开发新双域模型和耦合 ODE 求解器的平台。