Inflammatory Pathogenesis of Coronary Atherosclerosis in HIV

HIV冠状动脉粥样硬化的炎症发病机制

• 批准号: 8992823
• 负责人: ROBERT G WEISS
• 金额: $ 62.92万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8992823
• 关键词: AIDS/HIV problem; Address; Adipose tissue; Anatomy; Anti-Inflammatory Agents; Anti-inflammatory; Atherosclerosis; Autoimmune Diseases; Biological Markers; Biology; Blood Vessels; Caliber; Cardiovascular system; Catheterization; Cholesterol; Chronic Disease; Clinical; Clinical Trials; Colchicine; Coronary; Coronary Arteriosclerosis; Coronary Vessels; Coronary artery; Data; Development; Disease; Dose; Double-Blind Method; Evaluation; Event; Gout; Guidelines; HIV; HIV Seropositivity; HIV therapy; Health; Heart Diseases; Hematological Disease; Hypertension; Image; Immune; Immune response; Individual; Inflammation; Inflammation Mediators; Inflammatory; Intervention; Intervention Studies; Knowledge; Laboratories; Lung diseases; Magnetic Resonance Imaging; Measures; Medical; Methods; National Heart, Lung, and Blood Institute; Outcome; Pathogenesis; Pathway interactions; Patients; Pericarditis; Peripheral; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Placebo Control; Play; Population; Process; Randomized; Recruitment Activity; Recurrence; Research; Risk; Risk Factors; Role; Safety; Source; Testing; Time; United States National Institutes of Health; Vasomotor; abstracting; antiretroviral therapy; base; brachial artery; cardiovascular disorder risk; clinical practice; clinically relevant; cohort; conventional therapy; coronary computed tomography angiography; endothelial dysfunction; experience; imaging modality; immune function; improved; in vivo; insight; novel; paracrine; response; treatment strategy; working group

 DESCRIPTION (provided by applicant): HIV positive (HIV+) people today experience an increasing burden of coronary artery disease (CAD). Although it has been postulated that increased inflammation interacts with traditional risk factors to accelerate atherosclerosis in HIV+ people, the importance of inflammation per se in the pathogenesis of CAD in HIV+ people is not known. This critical gap in knowledge about CAD pathogenesis was identified by the NHLBI Working Group on "Advancing HIV/AIDS Research in Heart, Lung, and Blood Diseases" last year and addressing it is important not only for our understanding of in vivo vascular biology in the setting of HIV but also for defining the role, if any, for anti-inflammatory approaches in altering CAD in HIV+ people. Anti-inflammatory strategies are associated with lower cardiovascular event rates in individuals with inflammatory autoimmune disease and are appealing in HIV+ populations but are not currently used in practice because of the lack of an established and easily obtained measure of the effect of inflammation on the processes which result in coronary atherosclerosis and because no clinical trial has established whether an anti-inflammatory strategy alone alters these processes. One such process is coronary endothelial dysfunction, which plays a pivotal role in the development, progression, and clinical manifestations of CAD, and is a marker for sub-clinical disease, an independent predictor of adverse cardiovascular events, and a potential target for medical interventions. We recently developed noninvasive, reproducible MRI-based methods to measure coronary endothelial function (CEF). We propose a placebo-controlled, double blind, single-center mechanistic trial to test the hypothesis that the anti-inflammatory approach, low dose colchicine (LDC), improves impaired local CEF in HIV+ people with subclinical CAD. The studies will provide novel much-needed mechanistic insight into the potential of anti-inflammatory strategies to reduce coronary endothelial dysfunction, which inflammatory biomarkers herald the CEF response, the relationship of CAD and CEF with epicardial adipose tissue (a purported local paracrine source of pro-inflammatory mediators), and whether a heterogeneous CEF response occurs with differential effects in more severely than mildly diseased coronary vessels, suggesting local anti-inflammatory effects. In addition to this novel mechanistic information, the findings will provide critical safety data on LDC in HIV+ people to guide larger multicenter outcomes trials on this clinically available pharmaceutical. (End of Abstract)

 描述（由申请人提供）： 如今，HIV阳性（HIV+）人群的冠状动脉疾病（CAD）负担日益加重。虽然已经假设炎症增加与传统的危险因素相互作用，加速HIV+人群的动脉粥样硬化，但炎症本身在HIV+人群CAD发病机制中的重要性尚不清楚。去年，NHLBI工作组在“推进艾滋病在心脏、肺和血液疾病中的研究”中发现了关于CAD发病机制的知识方面的这一关键差距，解决这一问题不仅对我们理解体内血管生物学很重要， 在HIV的背景下，也用于定义抗炎方法在改变HIV+人群中CAD中的作用（如果有的话）。抗炎策略与患有炎性自身免疫性疾病的个体中较低的心血管事件发生率相关，并且在HIV+人群中具有吸引力，但目前尚未在实践中使用，因为缺乏炎症对导致冠状动脉粥样硬化的过程的影响的确定且容易获得的测量，并且因为没有临床试验确定抗-TNF-α是否是一种有效的抗-TNF-α药物。炎症策略单独改变这些过程。其中一个过程是冠状动脉内皮功能障碍，其在CAD的发生、进展和临床表现中起关键作用，并且是亚临床疾病的标志物、不良心血管事件的独立预测因子和医学干预的潜在靶点。我们最近开发了无创的，可重复的基于MRI的方法来测量冠状动脉内皮功能（CEF）。我们提出了一个安慰剂对照，双盲，单中心的机制试验，以测试的假设，抗炎的方法，低剂量秋水仙碱（LDC），改善受损的局部CEF在HIV+的人与亚临床CAD。这些研究将为抗炎策略减少冠状动脉内皮功能障碍的潜力提供新的急需的机制见解，炎症生物标志物预示着CEF反应，CAD和CEF与心外膜脂肪组织的关系（一种据称的促炎介质的局部旁分泌来源），以及在较严重的冠状动脉血管中是否发生异质性CEF反应，表明有局部抗炎作用。除了这种新的机制信息外，这些发现还将提供关于LDC在HIV+人群中的关键安全性数据，以指导这种临床可用药物的大型多中心结局试验。 (End摘要）