Inflammatory Pathogenesis of Coronary Atherosclerosis in HIV

 描述(由申请人提供)：艾滋病毒阳性(HIV+)的人今天经历了越来越多的冠状动脉疾病(CAD)负担。虽然已经假设炎症增加与传统的危险因素相互作用，加速了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工作组发现了关于CAD发病机制的这一关键差距，并解决了这一问题不仅对我们理解体内血管生物学具有重要意义 在艾滋病毒的背景下，这不仅是为了确定抗炎方法在改变艾滋病毒阳性患者的CAD方面的作用(如果有的话)。抗炎策略在炎症性自身免疫性疾病患者中与较低的心血管事件发生率相关，在HIV+人群中很受欢迎，但目前并未在实践中使用，因为缺乏对炎症对导致冠状动脉粥样硬化的过程的影响的既定且容易获得的衡量标准，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。其中一个过程是冠状动脉内皮功能障碍，它在冠心病的发生、发展和临床表现中起着关键作用，是亚临床疾病的标志，是不良心血管事件的独立预测因素，也是医学干预的潜在靶点。我们最近开发了基于MRI的无创性、可重复性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、单中心机械性试验，以检验抗炎方法小剂量秋水仙碱(LDC)改善HIV+亚临床CAD患者局部CEF受损的假设。这些研究将为抗炎策略减轻冠状动脉内皮功能障碍的潜力提供新的、亟需的机制洞察，这些炎症生物标志物预示着CEF反应，CAD和CEF与心外膜脂肪组织(据称是促炎介质的局部旁分泌来源)的关系，以及不同的CEF反应是否发生在比轻度病变更严重的冠状动脉中，提示局部抗炎作用。除了这一新的机制信息外，这些发现还将提供有关HIV+患者LDC的关键安全数据，以指导对这种临床可用药物进行的更大规模的多中心结果试验。(摘要结束)

 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)