Inflammatory Pathogenesis of Coronary Atherosclerosis in HIV

HIV冠状动脉粥样硬化的炎症发病机制

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：当今艾滋病毒阳性（HIV+）患者的冠状动脉疾病（CAD）燃烧越来越多。尽管已经假定感染增加与传统的危险因素相互作用以加速HIV+人的动脉粥样硬化，但感染本身在HIV+人中的CAD发病机理中的重要性尚不清楚。去年，NHLBI工作组确定了有关CAD发病机理的这一关键差距。在艾滋病毒的情况下，还可以定义抗炎方法改变艾滋病毒+人的CAD的作用（如果有的话）。抗炎策略与患有炎症性自身免疫性疾病的个体的心血管事件发生率较低有关，并且正在HIV+人群中出现，但目前未在实践中使用，因为缺乏既定且易于获得的炎症对冠状动脉症的效果的衡量量很容易获得，因为没有临床试验的策略是造成的，这是否导致了竞争性的策略。这样的过程之一是冠状动脉内皮功能障碍，它在CAD的发育，进展和临床表现中起着关键作用，并且是亚临床疾病的标志，这是心血管不良事件的独立预测指标，并且是医疗干预的潜在靶标。我们最近开发了基于MRI的非侵入性，基于MRI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的双盲，单中心机械试验，以检验以下假设：抗炎方法低剂量秋水仙碱（LDC）可改善HIV+亚临床CAD患者的局部CEF受损。这些研究将提供急需的机械洞察力，以了解减少抗炎策略的潜力，以减少冠状动脉内皮功能障碍的潜力，炎症生物局部预示着CEF的反应，CAD和CEF与表外心脂肪脂肪组织的关系，以及表达的伴侣促进症的副作用，以及对近距离疾病的副作用），以及对近距离的副作用），以及cod的促进症的相互作用）轻度解散的冠状动脉血管，提示局部抗炎作用。除了这一新颖的机械信息外，这些发现还将提供有关HIV+人民中发达国家的关键安全数据，以指导有关此临床上可用药物的大型多中心结果试验。（抽象的结尾）