Endothelial Activation and Microangiopathy in HIV-related Cardiovascular Disease

HIV 相关心血管疾病中的内皮激活和微血管病

• 批准号: 8984228
• 负责人: Susan Marie Graham
• 金额: $ 27.27万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-20 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8984228
• 关键词: Address; Adhesions; Adhesives; Age; Age-Years; American; Angiopoietin-1; Angiopoietin-2; Antioxidants; Atherosclerosis; Biological; Biological Markers; Biology; Blood; Blood Platelets; Blood Vessels; Blood coagulation; Cardiovascular Diseases; Cardiovascular system; Caring; Cessation of life; Chronic; Clinical; Coagulation Process; Collaborations; Complement; Cytoplasmic Granules; Data; Development; Disease; Disease Progression; E-Selectin; Endothelial Cells; Endothelium; Ensure; Epidemiologist; Event; Face; Factor VIII-Related Antigen; Goals; HIV; HIV Infections; HIV-1; Hemostatic Agents; Hemostatic function; Immune; Immunologic Surveillance; Impairment; Incidence; Individual; Inflammation; Inflammatory; Intercellular adhesion molecule 1; Intervention; Investigation; Lead; Life; Link; Morbidity - disease rate; Myocardial Infarction; Opportunistic Infections; Outcome; Participant; Pathogenesis; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Phenotype; Plasma; Play; Population Control; Population Study; Production; Proteins; Provider; Reactive Oxygen Species; Regimen; Relative (related person); Research; Research Personnel; Resources; Risk; Sampling; Specimen; System; Thrombosis; Time; Treatment Protocols; United States; Universities; Validation; Vascular Cell Adhesion Molecule-1; Virus Diseases; Vital Status; Washington; Work; adjudicate; adjudication; adverse outcome; antiretroviral therapy; cardiovascular disorder risk; case control; cohort; cytokine; density; design; endothelial dysfunction; experience; immune activation; improved; innovation; member; mortality; novel; novel therapeutics; patient population; premature; public health relevance; repository; sound; success; systems research; translational approach; treatment duration; von Willebrand Factor

 DESCRIPTION (provided by applicant): Now that antiretroviral therapy (ART) has greatly reduced morbidity and mortality from opportunistic infections, a major challenge HIV care providers and their patients face is an elevated risk of premature or accelerated cardiovascular disease, often resulting in premature death. A growing body of evidence suggests that endothelial activation accompanies HIV infection, whether treated or untreated. Evidence for endothelial activation includes increased blood concentrations of the proteins released by activated endothelial cells, including soluble vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion marker 1 (ICAM-1), E- selectin, and an elevated angiopoietin 2 (ANG-2): angiopoietin 1 (ANG-1) ratio. Endothelial activation also increases release of the adhesive protein von Willebrand factor from endothelial storage granules, promoting platelet adhesion to the vessel wall, resulting in accelerated atherosclerosis in large vessels and platelet occlusion i small vessels, leading to microinfarcts and a form of "microangiopathy." This application aims to use prospectively collected data and samples from the CFAR Network of Integrated Clinical Systems (CNICS) research network to determine whether biomarkers of endothelial activation (ANG2:ANG1 ratio, sVCAM-1) and coagulation (VWF antigen, active VWF) are elevated prior to development of MI among HIV-infected patients taking ART and to elucidate the mechanisms by which HIV-associated endothelial dysfunction and altered hemostasis/thrombosis lead to premature or accelerated cardiovascular disease in persons living with HIV infection. The project teams a clinical epidemiologist with >10 years of HIV research experience (co-PI Graham) with an expert on thrombosis and hemostasis (co-PI López), a translational researcher renowned for his work on biomarker discovery and validation (co-I Liles), and experienced investigators from the CNICS Consortium (co-I Crane and consultant Hunt). This multi-disciplinary team will use an innovative translational approach to investigate the importance of endothelial activation and hemostasis/thrombosis biomarkers in primary myocardial infarction among HIV-infected persons, using valuable stored repository samples. This study will leverage the rigorously adjudicated patient outcomes in the CNICS cohort through the use of an innovative case-control design that will match cases and controls on time since ART initiation and ART regimen, thereby minimizing medication effects. Existing collaborations and proximity of the investigators, combined with the world-class facilities and resources of the University of Washington and Puget Sound Blood Center, will ensure successful implementation of this project. This work is a vital precursor to the development of strategies aimed at reversing or minimizing atherosclerosis and its clinical consequences by targeting underlying inflammation, endothelial dysfunction, and altered hemostasis with medications or other treatment regimens.

 描述（由适用提供）：现在，抗逆转录病毒疗法（ART）大大降低了机会性感染的发病率和死亡率，HIV护理提供者及其患者面临的主要挑战是过早或加速心血管疾病的风险升高，通常导致过早死亡。越来越多的证据表明，内皮激活涉及HIV感染，无论是治疗还是未经治疗。内皮激活的证据包括活化内皮细胞释放的蛋白质的血液浓度升高，包括固体血管细胞粘附分子1（VCAM-1），细胞间粘附标记物1（ICAM-1），E-纤维素和血管生成素2（Angiopietin 2（-2）：Angiopietin 1（Angiopietin 1（Angiopietin 1）（Angiopietin 1（Angiopietin 1））。内皮激活还增加了内皮储存颗粒的粘合剂蛋白von Willebrand因子的释放，从而促进了血小板粘附到容器壁上，从而导致大容器中的动脉粥样硬化和小血管加速了动脉粥样硬化，导致了微型物质，并导致“微型物质”和“微型神经疗法”。该应用程序旨在使用来自CFAR综合临床系统（CNIC）研究网络的前瞻性收集的数据和样品，以确定内皮激活的生物标志物（ANG2：ANG2：ANG1比，SVCAM-1）和凝结（VWF抗原，主动VWF）是否在对MI升高的机制中升高HIV的患者是否会升高HIV的机制，以使HIV升高到HIV升高，从而确定MI升高到HIV的机制中。患有HIV感染的人的功能障碍和止血/血栓形成改变导致过早或加速心血管疾病。该项目与一名临床流行病学家与艾滋病毒研究经验（Co-Pi Graham）> 10年（Co-Pi Graham）与血栓形成和止血专家（Co-PiLópez），这是一位翻译成的研究人员，他因其在生物标志物发现和验证（Co-I Liles）的工作以及CNICS CONSORTIUM（CNICSICS CONSORTIUM）（CO-i Liles）的工作而闻名。这个多学科的团队将使用一种创新的翻译方法来研究HIV感染者在原发性心肌梗死中使用有价值的存储存储库样本中内皮激活和止血/血栓形成生物标志物的重要性。这项研究将通过使用创新的病例对照设计来利用CNICS队列中严格调整的患者结局，该设计将与ART Initiative and Art Archimen一起按时与案例和控制匹配，从而最大程度地减少药物效果。研究人员的现有合作和接近性，再加上华盛顿大学和普吉特海湾血液中心的世界一流的设施和资源，将确保成功实施该项目。工作是旨在通过靶向潜在的感染，内皮功能障碍以及用药物或其他治疗方案改变止血的策略发展策略及其临床后果的策略的重要先驱。