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

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