Advanced Non-invasive Imaging in the Investigation of Aortic Stenosis Pathobiology

先进的无创成像在主动脉瓣狭窄病理学研究中的应用

• 批准号: 10522099
• 负责人: Jonathan R Lindner
• 金额: $ 69.65万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522099
• 关键词: Acetylcysteine; Adhesions; Affect; Age; Age-Years; Animal Model; Animals; Antioxidants; Aortic Valve Stenosis; Arteriogram; Atherosclerosis; Binding; Biology; Blood; Blood Platelets; Blood Vessels; Cardiac Death; Cell Proliferation; Clinical Trials; Country; Data; Dependence; Development; Disease; Disease Progression; Doppler Echocardiography; Doppler Ultrasound; Echocardiography; Elderly; Endothelial Cells; Endothelium; Evaluation; Event; Generations; Goals; Growth Factor; Guidelines; Health Expenditures; Heart; Heart Valves; Heart failure; Histologic; Histology; Human; Image; Inflammatory; Intervention; Investigation; Left; Left Ventricular Function; Left Ventricular Hypertrophy; Left Ventricular Mass; Left Ventricular Remodeling; Longitudinal Studies; Low-Density Lipoproteins; Mediating; Mediator of activation protein; Medical; Methods; Modeling; Molecular Conformation; Mus; Operative Surgical Procedures; PDGFA gene; Pathway interactions; Patients; Pattern; Peptide Hydrolases; Pharmacology; Phenotype; Plant Roots; Plasma; Platelet-Derived Growth Factor; Play; Population; Predictive Factor; Procedures; Process; Proteolysis; RANTES; Reactive Oxygen Species; Recombinants; Research; Resistance; Resources; Role; Sclerosis; Secondary to; Signal Pathway; Signal Transduction; Signaling Molecule; Surface; Systems Biology; Techniques; Testing; Tissues; Ventricular; Wild Type Mouse; acetovanillone; aggressive therapy; aortic valve; aortic valve replacement; base; blood pump; calcification; cell transformation; contrast enhanced; cytokine; electric impedance; extracellular vesicles; hemodynamics; high risk; hypertension treatment; in vivo; indexing; inhibitor; interstitial cell; molecular imaging; mouse model; non-compliance; non-invasive imaging; noninvasive diagnosis; novel; osteogenic; paracrine; prevent; prospective; recruit; therapeutic target; transcriptomics; ultrasound; valve replacement; von Willebrand Factor

SUMMARY Aortic stenosis (AS) is a serious condition that affects 2-4% of the elderly, and is responsible for U.S. healthcare expenditures of over $6 billion annually attributable mostly to valve replacement procedures. Frequently, AS is diagnosed by non-invasive imaging before it is severe or symptomatic. Yet there are no pharmacologic therapies to slow progression of disease. The pathobiology of AS involves the myofibroblastic and osteoblastic transformation of valvular interstitial cells (VICs) that mediate matrix remodeling and calcification. The plurality of events and signaling pathways that influence VICs is one reason for lack of effective medical therapy. Using in vivo molecular imaging of the aortic root and comprehensive echocardiography, we have found that mice that lack the ability to cleave von Willebrand Factor (VWF) multimers from the endothelial surface develop progressive AS and load-related left ventricular hypertrophy. Valve leaflets from these animals demonstrate endothelial adhesion of platelets and platelet extracellular vesicles, and also typical patterns of VIC proliferation and transformation. These findings are consistent with the idea that platelets contribute to AS by binding VWF and acting in a juxtracrine fashion through local release of platelet-derived growth factors, cytokines, and reactive oxygen species (ROS) which are known to stimulate VIC transformation. Accordingly, inhibiting platelet interaction with VWF at the valve endothelial surface could prevent the activation of many parallel signaling pathways that contribute to AS. Our overall goal is to integrate non-invasive imaging with histology, transcriptomics, and blood markers to characterize this potentially treatable mechanism for AS. In Aim 1, we will provide definitive evidence that platelet adhesion contributes to AS by longitudinal assessment of mice deficient for the ADAMTS13 protease that cleaves shear-activated VWF from the endothelial surface. We will investigate whether deletion of platelet GPIb, the counterligand for VWF; and treatment with recombinant ADAMTS13. Because platelet-endothelial adhesion also contributes to vascular stiffness, a systems-biology approach will be used with non-invasive imaging of arterial compliance, LV remodeling, and load-dependent indices of LV function. In Aim 2, we will test whether novel pharmacologic approaches that reduce excess endothelial- associated VWF multimers suppress the development of AS and LV remodeling in the murine models. Therapies will include (i) n-acetylcysteine which inhibits VWF self-association, and (ii) an acetovanillone inhibitor of Nox2 which reduces the generation of ROS and, consequently, excess endothelial-associated VWF. In Aim 3, a proof- of-concept prospective clinical trial will be performed in patients with mild or moderate AS to determine whether blood markers of abnormal VWF proteolysis and platelet-derived signaling factors predict rapidly progressive AS and arterial non-compliance. These data will be integrated with novel echocardiographic features of valve shear based on the known shear-dependency of “opening” of the otherwise cryptic VWF A1 domain for platelet GPIb binding and shear-related transcriptomic control of platelet signaling molecules

概括 主动脉瓣狭窄 (AS) 是一种严重疾病，影响 2-4% 的老年人，是美国医疗保健的重灾区 每年超过 60 亿美元的支出主要归因于瓣膜置换手术。 在病情严重或出现症状之前通过非侵入性成像进行诊断，但尚无药物治疗方法。 AS 的病理学涉及肌纤维母细胞和成骨细胞。 介导基质重塑和钙化的瓣膜间质细胞（VIC）的转化。 影响 VIC 的事件和信号通路的缺失是缺乏有效药物治疗的原因之一。 主动脉根部的体内分子成像和综合超声心动图，我们发现小鼠 缺乏从内皮表面裂解血管性血友病因子 (VWF) 多聚体的能力 这些动物表现出进行性 AS 和负荷相关的左心室肥大。 血小板和血小板细胞外囊泡的内皮粘附，以及 VIC 增殖的典型模式 这些发现与血小板通过结合 VWF 促进 AS 的观点一致。 通过局部释放血小板源性生长因子、细胞因子和反应性物质以近分泌方式发挥作用 已知会刺激 VIC 转化的氧物质 (ROS)，从而抑制血小板。 与瓣膜内皮表面的 VWF 相互作用可以阻止许多并行信号的激活 我们的总体目标是将非侵入性成像与组织学相结合， 在目标 1 中，我们将通过转录组学和血液标记来描述 AS 的这种潜在可治疗机制。 提供明确的证据表明血小板粘附有助于对 AS 缺陷小鼠进行纵向评估 我们将研究从内皮表面裂解剪切激活的 VWF 的 ADAMTS13 蛋白酶。 是否删除血小板 GPIb（VWF 的反配体）；以及用重组 ADAMTS13 进行治疗。 由于血小板-内皮粘附也会导致血管僵硬，因此系统生物学方法将是 与动脉顺应性、左心室重塑和左心室负荷依赖性指数的非侵入性成像一起使用 在目标 2 中，我们将测试是否有新的药理学方法可以减少过量的内皮细胞。 相关的 VWF 多聚体抑制小鼠模型中 AS 和 LV 重塑的发展。 将包括 (i) 抑制 VWF 自缔合的 n-乙酰半胱氨酸，以及 (ii) Nox2 的乙酰香草酮抑制剂 这减少了 ROS 的产生，从而减少了过量的内皮相关 VWF。在目标 3 中，这是一个证明- 将在轻度或中度 AS 患者中进行概念性前瞻性临床试验，以确定是否 异常 VWF 蛋白水解和血小板衍生信号因子的血液标志物可预测快速进展的 AS 这些数据将与瓣膜剪切的新颖超声心动图特征相结合。 基于已知的血小板 GPIb 神秘 VWF A1 结构域“打开”的剪切依赖性 血小板信号分子的结合和剪切相关转录组控制