Inflammatory Pathogenesis of Coronary Atherosclerosis in HIV

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。尽管已经假设炎症增加与传统危险因素相互作用以加速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工作组在“推进艾滋病毒/艾滋病在心脏、肺和血液疾病中的研究”上确定了关于CAD发病机制的知识的这一关键差距，这不仅对我们理解艾滋病毒背景下的体内血管生物学很重要，而且对我们理解艾滋病毒背景下的体内血管生物学也很重要。 以确定抗炎方法在改变HIV患者CAD中的作用。抗炎策略已经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群体中具有吸引力，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的抗-TNF-α是否有效。炎症策略单独改变这些过程。炎症导致冠状动脉内皮功能障碍的过程，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， 抗炎方法，低剂量秋水仙碱（LDC），改善亚临床CAD的HIV患者受损的局部CEF。这些研究将为减轻冠状动脉内皮功能障碍的抗炎策略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与心外膜脂肪组织的关系（一种据称的炎症介质的局部旁分泌来源），以及是否在比轻度病变更严重的冠状动脉血管中发生异质性CEF反应，表明有局部抗炎作用。除了这种新的机制信息，临床可用药物的发现可以更快地转化为实践。

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.