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(申请人提供)：既然抗逆转录病毒疗法(ART)已经大大降低了机会性感染的发病率和死亡率，艾滋病毒护理提供者及其患者面临的一个主要挑战是过早或加速心血管疾病的风险增加，通常会导致过早死亡。越来越多的证据表明，内皮细胞的激活伴随着艾滋病毒感染，无论是治疗还是未经治疗。内皮激活的证据包括由激活的内皮细胞释放的蛋白质的血液浓度增加，包括可溶性血管细胞黏附分子1(VCAM-1)、细胞间黏附标记1(ICAM-1)、E-选择素以及血管生成素2(Ang-2)：血管生成素1(Ang-1)的比率升高。血管内皮细胞活化还会增加黏附蛋白von Willebrand因子从内皮储存颗粒中的释放，促进血小板与血管壁的黏附，导致大血管动脉粥样硬化加速和小血管血小板闭塞，导致微梗塞和一种形式的微血管病变。这项应用旨在利用从CFAR综合临床系统网络(CNICs)研究网络中前瞻性收集的数据和样本，确定在接受抗逆转录病毒治疗的HIV感染患者发生MI之前，内皮细胞激活(ANG2：Ang1比率，sVCAM-1)和凝血(VWF抗原，活性VWF)的生物标志物是否升高，并阐明HIV相关内皮功能障碍和止血/血栓改变导致HIV感染者过早或加速心血管疾病的机制。该项目的团队包括一位具有10年艾滋病毒研究经验的临床流行病学家(共同参与Pi Graham)、一位血栓形成和止血专家(共同参与Pi López)、一位以生物标记物发现和验证工作而闻名的翻译研究员(共同参与LILES)以及来自CNICs联盟的经验丰富的研究人员(联合参与Crane和咨询公司Hunt)。这个多学科团队将使用一种创新的翻译方法，使用宝贵的存储库样本，研究血管内皮细胞激活和止血/血栓生物标记物在艾滋病毒感染者中的原发性心肌梗死中的重要性。这项研究将利用CNICs队列中严格判断的患者结果，通过使用创新的病例对照设计，该设计将自ART启动和ART方案以来及时匹配病例和对照，从而将药物影响降至最低。现有的合作和调查人员的接近，再加上华盛顿大学和普吉特湾血液中心的世界级设施和资源，将确保这一项目的成功实施。这项工作是制定旨在通过靶向潜在炎症、内皮功能障碍和药物或其他治疗方案改变止血来逆转或最小化动脉粥样硬化及其临床后果的战略的重要先驱。