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: 10458052
• 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/10458052
• 关键词: Adult; Animal Genetics; Animal Model; Arrhythmia; Biomechanics; Budgets; Cardiac; Cardiac Myocytes; Cardiac development; Cardiomyopathies; Collaborations; Congenital Heart Defects; Custom; Development; Diagnosis; Diastole; Disease; ERBB2 gene; 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; Pharmacology; Phenotype; Prevalence; Resolution; Signal Transduction; Structure; System; Testing; Time; United States; Ventricular; Ventricular Dysfunction; Ventricular Function; Ventricular Remodeling; Zebrafish; automated segmentation; deep learning; erbB-2 Receptor; gene interaction; hemodynamics; high risk; in silico; indexing; insight; interdisciplinary approach; learning strategy; mechanotransduction; multidisciplinary; notch protein; preservation; receptor; shear stress; skeletal; 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 体光场与计算流体力学结合研究心肌 小梁形成和功能 致密化不全型心肌病（NCC）是一种肌内膜小梁形成疾病， 海绵状心肌NCC具有恶性心律失常、血栓栓塞事件和 与先天性心脏病或骨骼肌病相关的心室功能障碍。研究 左心室致密化不全与常染色体显性遗传性疾病相关， Notch通路与小梁形成缺陷和心室NCC有关。生物力学力是 与机械传导和心脏形态发生密切相关。在开发过程中， 心肌分化成外部致密区和内部小梁化区。Notch受体- 配体相互作用诱导EphrinB 2-Nrg-ErbB 2信号传导以启动小梁形成。我们的计算机模拟 分析（Alison Marsden，斯坦福大学）显示小梁中振荡剪切指数（OSI）升高 脊，导致粘性耗散增加，这与心室肌的变化有关。 收缩功能和重塑。然而，将心肌收缩与心内血流分离 动力学来阐明Notch介导的小梁组织以及随后的相关变化 局部血液动力学仍然是一个未满足的生物力学挑战。在这种情况下，我们假设， 血液动力学剪切力和心肌收缩力协调所需小梁组织， 保护心室结构和收缩效率。结合激光光片和光- 场的超分辨率和体积成像，我们同时捕捉心肌收缩 和心内血流动力学。与斯坦福大学心脏力学合作，我们整合了流体 结构相互作用（FSI）与超分辨率成像，以证明4-D内剪切应力， 小梁脊和槽作为可能的发育调节剂。为了验证我们的假设，我们 提出三个具体目标。在目标1中，我们将证明心内剪切应力激活 内分泌Delta-Notch信号传导促进小梁嵴形成。在目标2中，我们将 证明心室收缩激活心肌锯齿状缺口信号， 小梁沟形成。在目标3中，我们将证明骨小梁嵴的组合 并且沟形成导致最佳的局部血液动力学和心室能量学。的 先进的成像、流体结构相互作用和斑马鱼遗传学的整合是唯一合适的 揭示与动能耗散相关的小梁组织。我们的多学科方法 为非致密化心肌病的病理生理学提供了新的生物力学见解 对心室重构和功能的重要性。