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: 8915889
• 负责人: ROBERT G WEISS
• 金额: $ 62.58万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-10 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8915889
• 关键词: AIDS/HIV problem; Address; Adipose tissue; Anatomy; Angiography; Anti-Inflammatory Agents; Anti-Retroviral Agents; Anti-inflammatory; Arteries; 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 therapy; Health; Heart Diseases; Hematological Disease; Human; 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; Pathogenesis; Pathway interactions; Patients; Pericarditis; Peripheral; Pharmaceutical Preparations; Placebo Control; Placebos; Play; Population; Process; Randomized; Recruitment Activity; Recurrence; Research; Risk; Risk Factors; Role; Safety; Source; Testing; Time; Translating; United States National Institutes of Health; Vasomotor; X-Ray Computed Tomography; 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 patients 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 patients, the importane of inflammation per se in the pathogenesis of CAD in HIV patients 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 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 patients. Anti-inflammatory strategies have been 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. Inflammation contributes to the process of 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 patients 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 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 with a clinically available drug could be more rapidly translated to practice.

描述（由申请人提供）：如今，HIV 患者的冠状动脉疾病 (CAD) 负担日益增加。尽管人们推测炎症增加与传统危险因素相互作用，加速 HIV 患者的动脉粥样硬化，但炎症本身在 HIV 患者 CAD 发病机制中的重要性尚不清楚。去年，NHLBI“推进心脏、肺和血液疾病领域的艾滋病毒/艾滋病研究”工作组发现了关于 CAD 发病机制的这一重大知识空白，它不仅对我们了解艾滋病毒背景下的体内血管生物学很重要，而且对我们的研究也很重要。 定义抗炎方法在改变 HIV 患者 CAD 方面的作用（如果有的话）。抗炎策略与炎症性自身免疫性疾病患者较低的心血管事件发生率相关，并且在 HIV 人群中很有吸引力，但目前尚未在实践中使用，因为缺乏既定且容易获得的炎症对导致冠状动脉粥样硬化过程的影响的测量方法，而且还没有临床试验确定单独的抗炎策略是否会改变这些过程。炎症导致冠状动脉内皮功能障碍，在 CAD 的发生、进展和临床表现中发挥着关键作用，是亚临床疾病的标志物、不良心血管事件的独立预测因子以及医疗干预的潜在目标。我们最近开发了基于 MRI 的无创、可重复的方法来测量冠状动脉内皮功能 (CEF)。我们提出了一项安慰剂对照、双盲、单中心机制试验来检验以下假设： 抗炎方法，低剂量秋水仙碱 (LDC)，可改善患有亚临床 CAD 的 HIV 患者受损的局部 CEF。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，其中炎症生物标志物预示着CEF反应，CAD和CEF与心外膜脂肪组织（据称是炎症介质的局部旁分泌来源）的关系，以及异质CEF反应是否发生在较严重的疾病和较轻微的疾病中具有不同的影响 冠状血管，表明局部抗炎作用。除了这种新颖的机制信息之外，临床可用药物的发现可以更快地转化为实践。