Inflammation and Coronary Endothelial Function

描述(申请人提供)：尽管目前积极的指南驱动的治疗，冠状动脉疾病(CAD)患者仍然面临更高的心血管事件风险，可能是因为常规治疗没有充分解决与疾病有关的一些炎症途径。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，在更普通的CAD人群中很受欢迎，但目前并未在实践中使用，这是因为缺乏对炎症对导致冠状动脉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抗炎策略本身是否会改变这些过程。炎症参与了冠状动脉内皮细胞功能障碍的过程，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物，是不良心血管事件的独立预测因素，也是药物干预的潜在靶点。我们最近开发了基于MRI的非侵入性、可重复性的方法来测量CEF。我们提出了一项2x2的随机、安慰剂对照试验，以检验抗炎方法，即极低剂量甲氨蝶呤(VLDM)、低剂量秋水仙碱(LDC)和/或它们的组合，可以改善稳定性冠心病患者局部CEF受损的情况，这些患者的炎症标志物在常规心血管药物中增加。这些研究将为抗炎策略减少冠状动脉内皮细胞功能障碍的潜力提供新的、急需的机制洞察，这些炎症生物标志物预示着CEF反应，以及是否发生异质性的冠状动脉反应，在更严重的冠状动脉血管中具有不同的影响，提示局部抗炎作用。除了这种新的机制信息，这些临床可用药物的发现将指导下一代临床结果试验，并可以迅速转化为实践。

DESCRIPTION (provided by applicant): Despite aggressive current guideline-driven therapies, coronary artery disease (CAD) patients remain at increased risk of cardiovascular events, possibly because conventional treatments do not adequately address some of the inflammatory pathways implicated in the disease. Anti- inflammatory strategies have been associated with lower cardiovascular event rates in individuals with inflammatory autoimmune disease and are appealing in more general CAD 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, per se, 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 CEF. We propose a 2x2 blinded, placebo-controlled trial to test the hypothesis that anti-inflammatory approaches, namely very low dose methotrexate (VLDM), low dose colchicine (LDC) and/or their combination, improve impaired local CEF in stable CAD patients with increased markers of inflammation on conventional cardiovascular medications. 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, and whether a heterogeneous coronary 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 these clinically available drugs will guide the next generation of clinical outcome trials and can be rapidly translated to practice.