Inflammatory Pathogenesis of Coronary Atherosclerosis in HIV

描述（由申请人提供）：艾滋病毒患者今天经历冠状动脉疾病（CAD）的负担越来越重。虽然已经假设炎症增加与传统的危险因素相互作用加速了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、肺和血液疾病中的艾滋病毒/艾滋病研究”工作组发现了这一关于CAD发病机制的关键知识缺口，这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

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.