Integrating Volumetric Light-Field with Computational Fluid Dynamics to Study Myocardial Trabeculation and Function

将体积光场与计算流体动力学相结合来研究心肌小梁和功能

• 批准号: 10626035
• 负责人: Tzung K Hsiai
• 金额: $ 49.17万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10626035
• 关键词: Adult; Animal Genetics; Animal Model; Arrhythmia; Biomechanics; Budgets; Cardiac; Cardiac Myocytes; Cardiomyopathies; Collaborations; Congenital Heart Defects; Custom; Development; Diagnosis; Diastole; Disease; ERBB2 gene; Echocardiography; Event; Failure; Functional disorder; Genetic; Genotype; Goals; Heart; Heart failure; Hereditary Disease; Image; Kinetics; Knowledge; Lasers; Left ventricular non-compaction; Ligands; Light; Link; Liquid substance; Malignant - descriptor; Mechanics; Mediating; Morphogenesis; Muscle Cells; Mutation; Myocardial; Myocardial Contraction; Myocardium; Myopathy; Non-compaction cardiomyopathy; Optics; Oxygen; Pathway interactions; Patients; Perfusion; Persons; Phenotype; Prevalence; Proliferating; Signal Transduction; Structure; System; Testing; Time; United States; Ventricular; Ventricular Dysfunction; Ventricular Function; Ventricular Remodeling; Viscosity; Zebrafish; automated segmentation; autosome; cardiogenesis; deep learning; erbB-2 Receptor; gene interaction; hemodynamics; high risk; in silico; indexing; insight; interdisciplinary approach; learning strategy; mechanotransduction; multidisciplinary; notch protein; pharmacologic; preservation; receptor; shear stress; skeletal; superresolution imaging; ultra high resolution; vector

ABSTRACT Integrating Volumetric Light-Field with Computational Fluid Dynamics to Study Myocardial Trabeculation and Function Non-compaction cardiomyopathy (NCC) is a disease of endomyocardial trabeculation or known as spongy myocardium. NCC carries a high risk of malignant arrhythmias, thromboembolic events, and ventricular dysfunction in association with congenital heart defects or skeletal myopathy. Studies have linked left ventricular non-compaction with autosomal dominant inherited disorders, and mutations in Notch pathways are implicated in defective trabeculation and ventricular NCC. Biomechanical force is intimately connected with mechanotransduction and cardiac morphogenesis. During development, the myocardium differentiates into an outer compact zone and an inner trabeculated zone. Notch receptor- ligand interaction induces EphrinB2-Nrg-ErbB2 signaling to initiate trabecular formation. Our in silico analysis (Alison Marsden, Stanford) revealed elevated oscillatory shear index (OSI) in trabecular ridges, leading to increased viscous dissipation, which was associated with changes in ventricular contractile function and remodeling. However, uncoupling myocardial contraction from intracardiac flow dynamics to elucidate Notch-mediated trabecular organization and subsequent associated changes in local hemodynamics remains an unmet biomechanical challenge. In this context, we hypothesize that hemodynamic shear and myocardial contractile forces coordinate trabecular organization needed to preserve the ventricular structure and contractile efficiency. In combination of laser light-sheet and light- field for super resolution and volumetric imaging, we simultaneously captured myocardial contraction and intracardiac flow dynamics. In collaboration with Stanford Cardiac Mechanics, we integrated fluid structure interaction (FSI) with super resolution imaging to demonstrate 4-D endocardial shear stress in the trabecular ridges and grooves as possible developmental modulator. To test our hypothesis, we propose three specific aims. In Aim 1, we will demonstrate that intracardiac shear stress activates endocardial Delta-Notch signaling to promote trabecular ridge formation. In Aim 2, we will demonstrate that ventricular contraction activates myocardial Jagged-Notch signaling to organize trabecular groove formation. In Aim 3, we will demonstrate that the combination of trabecular ridge and groove formation leads to optimal local hemodynamics and ventricular energetics. The integration of advanced imaging, fluid structure interaction, and zebrafish genetics is uniquely suitable to unveil trabecular organization in relation to kinetic energy dissipation. Our multi-disciplinary approach provides new biomechanical insights into non-compaction cardiomyopathy with pathophysiological significance to ventricular remodeling and function.

摘要 体积光场与计算流体力学相结合研究心肌 骨小梁形成与功能 非致密性心肌病(NCC)是一种心内膜心肌小梁疾病，或称为 海绵状心肌。NCC具有恶性心律失常、血栓栓塞症和 与先天性心脏病或骨骼肌病相关的心功能不全。研究表明， 与常染色体显性遗传病相关的左心室致密化不全，以及 切迹通路与小梁缺陷和脑室NCC有关。生物力学力是 与机械转导和心脏形态发生密切相关。在开发过程中， 心肌分化为外层致密区和内层小梁区。缺口受体- 配基相互作用诱导EPhinB2-NRG-ErbB2信号通路启动骨小梁形成。我们的硅胶 分析(艾莉森·马斯登，斯坦福大学)显示骨小梁振荡剪切指数(OSI)升高 脊状突起，导致粘性消散增加，这与脑室改变有关 收缩功能和重塑。然而，将心肌收缩与心内血流分离 阐明Notch介导的骨小梁组织及其相关变化的动力学 局部血流动力学仍然是一个尚未满足的生物力学挑战。在这种情况下，我们假设 血流动力学剪切力和心肌收缩力协调小梁组织所需的 保护心室结构和收缩效率。在激光光片和光的组合中- 用于超分辨率和体积成像的视野，我们同时捕捉到心肌收缩 和心内血流动力学。在与斯坦福心脏力学的合作下，我们将流体 结构相互作用(FSI)超分辨成像技术显示心内膜切应力的研究 小梁脊和小梁沟可能是发育的调节器。为了检验我们的假设，我们 提出三个具体目标。在目标1中，我们将演示心内切应力激活 心内膜Delta-Notch信号促进骨小梁形成。在目标2中，我们将 证明心室收缩激活心肌锯齿状切迹信号来组织 小梁沟的形成。在目标3中，我们将演示小梁脊的组合 而沟的形成导致局部血流动力学和心室能量的最佳变化。这个 先进的成像、流体结构相互作用和斑马鱼遗传学的集成是唯一合适的 揭示与动能耗散有关的骨小梁组织。我们的多学科方法 为非致密性心肌病的病理生理学提供了新的生物力学见解 对心脏重塑和功能的意义。