Inflammation and Coronary Endothelial Function

描述（由申请人提供）：尽管目前指南驱动的治疗具有积极性，但冠状动脉疾病（CAD）患者的心血管事件风险仍然增加，这可能是因为常规治疗无法充分解决与疾病相关的一些炎症途径。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，并且在更一般的CAD群体中具有吸引力，但是目前没有在实践中使用，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的和容易获得的测量，并且因为没有临床试验已经确定抗炎策略，改变了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。我们最近开发了非侵入性的，可重复的基于MRI的方法来测量CEF。我们提出了一项2 × 2盲法、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/或其组合）改善常规心血管药物治疗炎症标志物增加的稳定型CAD患者受损局部CEF的假设。这些研究将为抗炎策略减少冠状动脉内皮功能障碍的潜力提供新的急需的机制性见解，其中炎症生物标志物预示着CEF反应，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冠状动脉反应并具有差异效应，表明局部抗炎作用。除了这些新的机制信息，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.