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

主动脉瓣狭窄病理学研究中的先进无创成像

• 批准号: 10693935
• 负责人: Jonathan R Lindner
• 金额: $ 72.18万
• 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/10693935
• 关键词: ADAMTS; Acceleration; Acetylcysteine; Adhesions; Affect; Age; Age Years; Animal Model; Animals; Antioxidants; Aorta; 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; Ligands; Longitudinal Studies; Low-Density Lipoproteins; Mediating; Mediator; Medical; Methods; Modeling; Molecular Conformation; Mus; Operative Surgical Procedures; PDGFA gene; Pathway interactions; Patients; Pattern; Peptide Hydrolases; Phenotype; Plasma; Platelet-Derived Growth Factor; Population; Predictive Factor; Procedures; Process; Proliferating; Proteolysis; RANTES; Reactive Oxygen Species; Recombinants; Research; Resistance; Resources; 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; 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; pharmacologic; 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

总结 主动脉瓣狭窄（AS）是一种严重的疾病，影响2-4%的老年人，并负责美国医疗保健 每年超过60亿美元的支出主要用于瓣膜置换手术。通常，如 在严重或有症状之前通过非侵入性成像诊断。但目前还没有药物疗法 来减缓疾病的发展AS的病理生物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）转化。所述多 影响VIC的事件和信号通路是缺乏有效药物治疗的原因之一。使用 在体内主动脉根部的分子成像和综合超声心动图中，我们发现， 缺乏从内皮表面切割血管性血友病因子（VWF）多聚体的能力， 进行性AS和负荷相关的左心室肥大。这些动物的瓣叶显示 血小板和血小板细胞外囊泡的内皮粘附，以及维克增殖的典型模式 和转变。这些发现与血小板通过结合VWF参与AS的观点一致 并通过局部释放血小板衍生的生长因子、细胞因子和反应性细胞因子， 氧物种（ROS），其已知刺激维克转化。因此，抑制血小板 与VWF在瓣膜内皮表面的相互作用可以阻止许多平行信号的激活 导致AS的途径。我们的总体目标是将非侵入性成像与组织学相结合， 转录组学和血液标志物来表征AS的这种潜在可治疗机制。在目标1中，我们 通过对缺乏血小板粘附的小鼠进行纵向评估，提供了血小板粘附导致AS的明确证据。 ADAMTS 13蛋白酶从内皮表面切割剪切激活的VWF。我们将调查 是否缺失血小板GPIb β，VWF的反配体;以及用重组ADAMTS 13治疗。 由于血小板-内皮细胞粘附也会导致血管僵硬，因此将采用系统生物学方法来研究血小板-内皮细胞粘附。 与动脉顺应性、LV重构和LV负荷依赖性指数的无创成像一起使用 功能在目标2中，我们将测试是否有新的药理学方法，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。疗法 将包括（i）抑制VWF自结合的N-乙酰半胱氨酸，和（ii）Nox 2的乙酰香草酮抑制剂 其减少ROS的产生，并因此减少过量的内皮相关VWF。在目标3中，一个证明- 将在轻度或中度AS患者中进行概念前瞻性临床试验，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 和动脉不顺应性这些数据将与瓣膜剪切的新超声心动图特征相结合 基于已知的剪切依赖性的“开放”的其他隐蔽的VWF A1结构域的血小板GPIb蛋白， 血小板信号分子的结合和剪切相关转录组学控制