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.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 (A)目标 在室颤(VF)中，电激活波分裂成多波混沌状态，是导致心源性猝死的主要原因。我们的研究集中在这样一个问题上：造成这种破波的原因是什么？ 传统的观点认为，波是通过解剖的异质性来分解的，例如不同厚度的弯曲的室壁和隔壁，以及系统变化的各向异性，这种各向异性被认为是通过心肌壁进行的。我们早期研究的目的是回答这样的问题：相对于纯粹的动力学不稳定性，解剖学上的异质性在产生和维持纤颤方面有多重要？他们是如何互动的？ 我们现在已经证明，虽然上述解剖因素可以起到贡献作用，但起决定性作用的是传导的动态稳定性，这是由细胞和组织的电生理属性决定的。 我们现在建议扩展这项研究，以考虑在心力衰竭中所见的解剖和电生理变化。我们的具体目标是研究心力衰竭中的心律失常，特别是梳理出异常解剖结构和异常细胞电生理对心律失常发生的贡献。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，然后将细胞和组织这两种病理组织放在一起研究。 我们将使用NBCR研究人员开发的三维脑室解剖模型和工具，以及我们与NBCR研究人员共同开发的工具来研究这些问题。 具体目的1：利用兔虚拟心脏，测试加入纤维化、梗死性瘢痕、细胞间电耦合丧失等病理因素对心电波传导的影响。 具体目的2：利用NBCR模拟环境研究细胞内钙离子处理的改变对室颤发生和维持的影响。UCSD细胞系统建模环境，再加上几何模型，是检验我们的假设的理想平台，该假设改变了细胞内钙处理是心力衰竭中纤颤发生的关键。 具体目标3：在兔体内建立几种形式的心力衰竭的解剖学模型，并将这些模型与我们的正常和心力衰竭兔的细胞模型一起使用，以测试组织结构改变和细胞电生理学改变在心力衰竭心律失常发生中的相对贡献。 拟议的合作研究将为核心[4A.2B]的特定目标1在软件和计算方法方面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在特定目标2开发的数据库与社区共享。它将作为测试和开发新的双域模型和特定目标2的耦合常数解算器的平台。