Shear Stress and Endothelial Pathophysiology in Intracranial Atherosclerosis

项目总结/摘要 本提案的总体目标是确定低剪切应力（0 - 4 dyne/cm 2）的焦点区域 ICAD的下游或狭窄后段是动脉粥样硬化形成的标志物， 抗炎或抗血栓形成干预的治疗靶点。我们的核心假设是，后- 与致动脉粥样硬化内皮病理生理学相关的狭窄性低切应力提供了合理的基础， ICAD的精准医学我们在SAMMPRIS内这些区域的低剪切应力的初步数据 证实了与内皮病理生理学相关的切应力的潜在影响作用， 系统性动脉粥样硬化，但第一次扩展到脑循环。三个独立的 具体的目标利用了正在进行的、宝贵的合作和SAMMPRIS数据的无与伦比的质量 存档。加州大学洛杉矶分校的神经血管成像研究中心将进行前瞻性实验， 使用详细的解剖血流模型验证MCA ICAD CTA CFD上测量的局灶性低切应力 从相同的源图像创建，在4D MRA上测量共配准血流[SA-1]。这一步使 我们使用这些经过验证的流动模型来直接观察流动旋涡和邻近的颗粒上的低剪切应力 显微镜下图像测速[SA-1]。这些经验证的MCA血流模型可作为以下研究的支架： 内皮，其中可以研究细胞形态、VCAM-1的表达和血小板聚集[SA-2010]。 2]。这50处MCA病变中狭窄后低切应力（0 - 4 dyne/cm 2）的临床相关性将如下 通过与对侧同源节段的CTA CFD比较得到证实[SA-3]。协会 狭窄后低切应力的明确定义的潜在治疗目标将在以下方面进行检查 SAMMPRIS中的其他临床变量和后续神经学结局[SA-3]。这些观察结果 将在所有140名SAMMPRIS CTA CFD受试者中进行类似的研究，以调查 其他动脉病变部位的无创CTA CFD [SA-3]。所有图像后处理、CTA CFD、4D MRA、3D 内皮病理生理学的打印和生物测定将在加州大学洛杉矶分校进行，在那里我们有 开创了这种工作流程。WASID和SAMMPRIS试验领导层的合作和指导是一个 这一新方法的一个重要元素，以ICAD，采用统计专业知识，在埃默里大学的这些 具有里程碑意义的试验及其详细的成像和临床分析。我们广泛的前期工作反映了 在新的成像和生物学框架上的协作专业知识，加上丰富的经验， SAMMPRIS成像和临床数据集提供了有关致动脉粥样硬化低 剪切应力进入脑循环。

PROJECT SUMMARY/ABSTRACT The overall goal of this proposal is to establish that the focal region of low shear stress (0-4 dyne/cm2) immediately downstream or in the post-stenotic segment of ICAD is a marker of atherogenesis, providing a therapeutic target for anti-inflammatory or anti-thrombotic interventions. Our central hypothesis is that post- stenotic low shear stress associated with atherogenic endothelial pathophysiology provides a rational basis for precision medicine of ICAD. Our preliminary data on low shear stress in these regions within SAMMPRIS confirm the potential influential role of shear stress associated with endothelial pathophysiology recognized in systemic atherosclerosis, yet extended to the cerebral circulation for the first time. Our three independent specific aims leverage an ongoing, invaluable collaboration and the unmatched quality of the SAMMPRIS data archive. The Neurovascular Imaging Research Core at UCLA will conduct the prospective experiments to validate focal low shear stress measured on CTA CFD of MCA ICAD with detailed anatomical flow models created from the same source images, with co-registered flow measured on 4D MRA [SA-1]. This step enables us to use these validated flow models to directly observe flow vortices and adjacent low shear stress on particle image velocimetry under microscopy [SA-1]. These validated MCA flow models serve as a scaffold for endothelium, where the cell morphology, expression of VCAM-1 and platelet aggregation can be studied [SA- 2]. The clinical relevance of post-stenotic low shear stress (0-4 dyne/cm2) in these 50 MCA lesions will be corroborated via comparison with CTA CFD of the contralateral homologous segment [SA-3]. Associations of this clearly defined potential therapeutic target of post-stenotic low shear stress will be examined with respect to other clinical variables and subsequent neurological outcomes in SAMMPRIS [SA-3]. These observations will be similarly conducted across all 140 SAMMPRIS CTA CFD subjects to investigate the generalizability of non-invasive CTA CFD in other arterial lesion sites [SA-3]. All image post-processing, CTA CFD, 4D MRA, 3D printing and biological assays of endothelial pathophysiology will be conducted at UCLA, where we have pioneered this workflow. The collaboration and guidance of the WASID and SAMMPRIS trial leadership is an important element of this new approach to ICAD that employs the statistical expertise at Emory of these landmark trials and their detailed imaging and clinical analyses. Our extensive preliminary work reflecting collaborative expertise on a novel imaging and biological framework, coupled with intensive experience linking the SAMMPRIS imaging and clinical datasets, provide a logical extension of knowledge on atherogenic low shear stress into the cerebral circulation.