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 主动脉狭窄（AS）是一种严重的疾病，影响了较早的2-4％，并负责美国医疗保健 每年超过60亿美元的支出主要归因于阀门更换程序。经常是 在严重或有症状之前，通过非侵入性成像进行诊断。但是没有药理疗法 减慢疾病的进展。 AS的病理生物学涉及肌成纤维细胞和成骨细胞 介导基质重塑和钙化的瓣膜间质细胞（VIC）的转化。多数 影响VIC的事件和信号通路是缺乏有效医疗疗法的原因之一。使用 主动脉根和全面的超声心动图的体内分子成像，我们发现小鼠是 缺乏从内皮表面发育中清除von willebrand因子（VWF）多元中的能力 进行性AS和负荷相关的左心室肥大。这些动物的瓣膜传单证明 血小板和血小板外蔬菜的内皮粘附，以及典型的VIC增殖模式 和转型。这些发现与血小板通过约束vwf做出贡献的想法一致 并通过局部释放血小板衍生的生长因子，细胞因子和反应性来以苦难的方式作用 氧气（ROS）已知会刺激VIC转化。根据抑制血小板 在阀内皮表面与VWF的相互作用可以防止许多平行信号传导激活 促成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， 转录组学和血液标记以表征这种潜在可治疗的机制。在AIM 1中，我们将 提供明确的证据，表明血小板的粘膜促成小鼠的纵向评估 对于ADAMTS13蛋白酶，将剪切激活的VWF从内皮表面切割。我们将调查 是否删除血小板GPIB，VWF的反物；和重组ADAMTS13的治疗。 由于血小板 - 内皮粘合剂也有助于血管僵硬，因此系统生物学方法将是 与动脉依从性，LV重塑和LV负载依赖性指数的非侵入性成像一起使用 功能。在AIM 2中，我们将测试新颖的药物是否使用减少过量内皮的方法 相关的VWF多元素抑制了鼠模型中AS和LV重塑的开发。疗法 将包括（i）抑制VWF自我关联的N-乙酰半胱氨酸，以及（ii）NOX2的乙酰支持解器 这减少了ROS的产生，因此超过了与内皮相关的VWF。在AIM 3中，证明 - 概念概念的前瞻性临床试验将在轻度或中度的患者中进行，以确定是否 异常VWF蛋白水解和血小板衍生的信号传导因素的血液标志物预测迅速进行性为 和动脉不合规。这些数据将与阀剪切的新型超声心动图特征集成 基于血小板gpib的其他加密VWF A1域的“打开”的已知剪切依赖性 血小板信号分子的结合和剪切相关的转录组控制