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

既往有冠状动脉血运重建的患者发生严重心血管不良的风险很高 大手术后事件(MACE)，与未接受手术的患者相比，高达2倍以上 有冠状动脉血运重建史。黄曲霉毒素所致的促炎和高凝状态 手术以及液体转移和麻醉引起的血流动力学变化都很重要。 引发围手术期心肌缺血。的确，围手术期的全身炎症是 与围术期Mace风险增加近4倍有关。中性粒细胞，最多 大量的炎性细胞，黏附在炎症或损伤的内皮上，迁移到 血管壁，释放蛋白水解酶，可导致斑块的侵蚀或破裂。佩里- 可操作的细胞因子的产生也可以激活炎症小体，从而激活巨噬细胞- 白介素1β的介导性合成，已知的二级预防治疗靶点 MACE，特别是在C-反应蛋白(CRP)浓度较高的情况下。 秋水仙碱是一种安全、耐受性良好的抗炎药，优先在 中性粒细胞与其他炎性细胞相比。秋水仙碱抑制血管内皮细胞趋化作用 中性粒细胞在内皮细胞损伤或炎症部位黏附、渗出； 抑制炎症小体介导的巨噬细胞产生IL-1β；并减少 心血管疾病患者的炎症和MACE。秋水仙碱心血管 结果试验和小剂量秋水仙碱2号试验显示， 约4000名既往心肌梗死患者和约5000名既往心肌梗死患者服用秋水仙素 分别为稳定型冠状动脉疾病。我的VA CDA资助的秋水仙碱-PCI试验 首次证明在受伤前服用秋水仙碱会抑制 用C反应蛋白测定炎症反应。秋水仙碱对围术期不良反应的影响 既往接受过大手术的冠状动脉血运重建术患者，目前尚不清楚。 这项建议的目的是：1)评估秋水仙碱对围术期不良反应的影响。 既往冠心病患者对中高风险非心脏手术的反应 血管重建；2)表征全身炎症程度和围手术期的情况 中性粒细胞在这一人群中的分布；以及3)决定围产期疾病的临床和遗传预测因素。 手术MACE和检查决定治疗反应异质性的因素 人口。这项提案提供了使用秋水仙素来描述 炎症在术后炎症发展中的作用，以及潜在的检测 以最小系统费用减少围手术期不良事件的成本-效果分析 免疫抑制。该提案还旨在促进个性化医疗方法，以 围手术期应用炎症标志物和心脑血管优化 用药物遗传学确定预测患者围手术期MACE风险的因素 尽管使用秋水仙碱，因此可能需要替代抗炎或抗炎药物 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。 心血管炎症和损伤的其他环境中的策略(例如，外周动脉 疾病、中风)和中性粒细胞起关键作用的其他疾病状态(例如，脉管炎， 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).