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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 （一） 目标 在心室颤动（VF）中，心脏性猝死的主要原因，电激活波分裂成多波混沌状态。我们的研究集中在这个问题上：这种波的原因是什么？ 传统的观点认为，波被解剖异质性所破坏，例如弯曲的室壁和间隔壁，它们的厚度不同，以及当一个波穿过心肌壁时所看到的系统变化的各向异性。我们早期研究的目的是回答以下问题：相对于纯粹的动力学不稳定性，解剖学不均匀性在产生和维持纤颤中有多重要？ 它们如何相互作用？ 我们现在已经表明，虽然上述解剖因素可以发挥贡献作用，但决定性作用是由传导的动力学稳定性发挥的，这是由细胞和组织的电生理特性决定的。 我们现在建议将这项研究扩展到心力衰竭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，特别是梳理出异常解剖结构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，我们将研究异常结构心脏中的正常细胞，正常心脏中的异常细胞，然后将两种病理，细胞和组织一起研究。 我们将使用由NBCR研究人员开发的三维心室解剖模型和工具，以及我们与NBCR研究人员合作开发的工具来研究这些问题。 具体目标1：利用兔虚拟心脏，测试加入纤维化、梗死瘢痕、细胞间电耦合丧失等病理因素对心电波传导的影响。 具体目标二：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，再加上几何模型，是一个理想的平台，在其上测试我们的假设，改变细胞内钙处理是一个关键的起源，在心力衰竭纤颤。 具体目标3：建立家兔几种形式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家兔细胞模型一起使用，以测试组织结构改变与细胞电生理改变在心力衰竭心律失常发生中的相对作用。 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，由此产生的新解剖和电生理网格和模型将通过特定目标2中开发的数据库与社区共享。它将作为测试和开发Specific Aim 2中新的bidomain模型和耦合ODE求解器的平台。