Impact of Colchicine on Peri-Operative Major Adverse Cardiovascular Events in Patients with Prior Coronary Revascularization

既往接受过冠状动脉血运重建的患者发生主要不良心血管事件的风险较高， 大手术后的MACE发生率是未接受大手术患者的2倍以上。 既往冠状动脉血运重建术。诱导的促炎和高凝状态 手术和由液体转移和麻醉引起的血流动力学变化都很重要 围手术期心肌缺血的诱因事实上，围手术期全身性炎症是 与围手术期MACE风险增加近4倍相关。中性粒细胞， 大量的炎性细胞粘附在发炎或损伤的内皮上，迁移到 血管壁，释放蛋白水解酶，可导致斑块侵蚀或破裂。围- 有效的细胞因子产生也可以激活炎性小体，从而激活巨噬细胞。 介导的白细胞介素（IL）-1 β的合成，这是一种已知的二级预防治疗靶点， MACE，特别是在高C反应蛋白（CRP）浓度的情况下。 秋水仙碱是一种安全、耐受性良好的抗炎药， 中性粒细胞与其他炎症细胞相比。秋水仙碱抑制趋化性，内皮细胞 内皮损伤或炎症部位中性粒细胞的粘附和外渗; 抑制巨噬细胞产生炎性小体介导的IL-1 β; 心血管疾病患者的炎症和MACE。秋水仙碱心血管 结果试验和低剂量秋水仙碱2试验证明， 在约4000例既往心肌梗死患者和约5000例 稳定型冠状动脉疾病。我的VA CDA资助的秋水仙碱-PCI试验 首次证明受伤前给予秋水仙碱可以抑制 通过CRP测量的炎症反应。秋水仙碱对围手术期主要不良心血管事件的影响 既往接受过大手术的冠状动脉血运重建患者的情况仍然未知。 本建议的目的是：1）评估秋水仙碱对围手术期MACE的影响， 既往有冠状动脉病变的患者对中度或高度风险非心脏手术的反应 血运重建; 2）表征全身炎症水平和围手术期特征 该人群中的嗜中性粒细胞;和3）确定慢性粒细胞白血病的临床和遗传预测因子， 手术MACE，并检查决定这种治疗反应异质性的因素。 人口这项提议提供了使用秋水仙碱来描述 炎症在术后炎症的发展，以及测试这可能 降低围手术期MACE的成本-效益治疗， 免疫抑制该提案还旨在促进个性化医疗方法， 基于使用炎症标志物的围手术期心血管优化， 药物遗传学，以确定预测围手术期MACE风险患者的因素 尽管使用了秋水仙碱，因此可能需要替代的抗炎或抗 血栓治疗最后，这项研究的发现也可能为新的治疗方法打开大门。 在心血管炎症和损伤的其他情况下的策略（例如，外周动脉 疾病，中风）和其中嗜中性粒细胞起关键作用的其它疾病状态（例如，血管炎， 伤口愈合）。

Patients with prior coronary revascularization have a high risk of major adverse cardiovascular events (MACE) after major surgery, up to more than 2-fold when compared to patients without prior coronary revascularization. The pro-inflammatory and hypercoagulable states induced by surgery and the hemodynamic changes caused by fluid shifts and anesthesia are all important triggers of perioperative myocardial ischemia. Indeed, peri-operative systemic inflammation is associated with a nearly 4-fold increase in the risk of perioperative MACE. Neutrophils, the most abundant of inflammatory cells, adhere to inflamed or injured endothelium, migrate into the vessel wall, release proteolytic enzymes that can lead to erosion or rupture of plaque. Peri- operative cytokine generation may also activate the inflammasome and, thereby, macrophage- mediated synthesis of interleukin (IL)-1β, a known target for therapy for secondary prevention of MACE, particularly in the setting of high C-reactive protein (CRP) concentration. Colchicine is a safe, well-tolerated anti-inflammatory agent that preferentially accumulates in neutrophils compared with other inflammatory cells. Colchicine inhibits chemotaxis, endothelial adhesion, and extravasation of neutrophils at sites of endothelial injury or inflammation; suppresses the inflammasome-mediated production of IL-1β by macrophages; and reduces inflammation and MACE in patients with cardiovascular disease. The Colchicine Cardiovascular Outcomes Trial and Low Dose Colchicine 2 Trial demonstrated a reduction in MACE with colchicine in about 4000 patients with prior myocardial infarction and about 5000 patients with stable coronary artery disease, respectively. My VA CDA-funded Colchicine-PCI trial demonstrated for the first time that administration of colchicine prior to injury dampens the inflammatory response measured by CRP. The effects of colchicine on peri-operative MACE in patients with prior coronary revascularization undergoing major surgery, remains unknown. The aims of this proposal are to 1) assess the effect of colchicine on peri-operative MACE in response to intermediate- or high-risk non-cardiac surgery in patients with prior coronary revascularization; 2) characterize the level of systemic inflammation and profile of peri-operative neutrophils in this population; and 3) determine the clinical and genetic predictors of peri- operative MACE and examine factors that determine heterogeneity of treatment response in this population. This proposal offers the opportunity to use colchicine to delineate the role of inflammation in the development of post-operative inflammation, as well as test this potentially cost-effective therapy in the reduction of peri-operative MACE with minimal systemic immunosuppression. The proposal also aims to foster a personalized medicine approach to peri-operative cardiovascular optimization based on use of inflammatory markers and pharmacogenetics to identify factors that predict patients who are at risk of peri-operative MACE despite the use of colchicine and may, therefore, require alternative anti-inflammatory or anti- thrombotic therapy. Finally, findings from this study may also open a door to novel therapeutic strategies in other settings of cardiovascular inflammation and injury (e.g., peripheral artery disease, stroke) and other disease states in which neutrophils play a pivotal role (e.g., vasculitis, wound healing).