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

秋水仙碱对既往冠状动脉血运重建患者围手术期主要不良心血管事件的影响

• 批准号: 10580501
• 负责人: Binita Shah
• 金额: --
• 依托单位: VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580501
• 关键词: ABCB1 gene; Acute; Adhesions; American Heart Association; Anesthesia procedures; Anti-Inflammatory Agents; Biological Markers; Blood Platelets; Blood Vessels; C-reactive protein; Cardiac Death; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Adhesion Molecules; Cells; Cessation of life; Chemotaxis; Chemotaxis Inhibition; Clinical; Code; Colchicine; Consensus; Coronary; Coronary Arteriosclerosis; Coronary artery; Data; Development; Disease; Dose; Double-Blind Method; Endothelium; Event; Extravasation; Fluid Shifts; Fostering; Funding; Generations; Genetic; Genetic Polymorphism; Heart; Heart Diseases; Heart Injuries; Heterogeneity; Hospitalization; Hospitals; Hour; Immune; Immunosuppression; Impairment; Incidence; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-1 beta; Interleukin-6; Interruption; Intervention Trial; Lipids; Macrophage; Measures; Mediating; Medical; Membrane Glycoproteins; Multi-Drug Resistance; Myocardial Infarction; Myocardial Ischemia; Operative Surgical Procedures; Outcome; Patients; Peptide Hydrolases; Perioperative; Peripheral; Peripheral arterial disease; Pharmaceutical Preparations; Pharmacogenetics; Phenotype; Placebos; Platelet aggregation; Play; Population; Postoperative Period; Predictive Factor; Production; Proteomics; Randomized; Research; Research Design; Risk; Risk Reduction; Role; Rupture; Safety; Secondary Prevention; Site; Stroke; Surface; Testing; Therapeutic Effect; Thrombophilia; Thrombosis; Time; United States; Vascularization; Vasculitis; Veterans; cardiovascular risk factor; clinical predictors; cost effective; cost effective treatment; cytokine; endothelial dysfunction; extracellular; gastrointestinal; genetic predictors; hemodynamics; high risk; improved; inflammatory marker; injured; insight; migration; myocardial injury; neutrophil; novel therapeutic intervention; operation; patient subsets; percutaneous coronary intervention; perioperative mortality; personalized medicine; randomized trial; resistance gene; responders and non-responders; response; systemic inflammatory response; targeted treatment; thrombotic; treatment response; uptake; vascular inflammation; vascular injury; wound healing

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).

既往接受过冠状动脉血运重建的患者发生重大心血管不良事件的风险很高 与未接受大手术的患者相比，大手术后发生的主要不良事件 (MACE) 高达 2 倍以上 先前的冠状动脉血运重建引起的促炎和高凝状态。 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 事实上，围手术期全身炎症是围手术期心肌缺血的诱因。 与围手术期 MACE 风险增加近 4 倍相关，其中中性粒细胞风险增加最多。 大量炎症细胞粘附在发炎或受损的内皮上，迁移到 血管壁，释放蛋白水解酶，导致斑块周围侵蚀或破裂。 有效的细胞因子生成也可能激活炎症小体，从而激活巨噬细胞 介导白细胞介素 (IL)-1β 的合成，这是二级预防治疗的已知靶标 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、耐受性良好的抗炎剂，优先积聚在 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； 抑制巨噬细胞炎症小体介导的 IL-1β 产生； 心血管疾病患者的炎症和 MACE。 结果试验和低剂量秋水仙碱 2 试验表明，MACE 减少 秋水仙碱用于约 4000 名既往心肌梗塞患者和约 5000 名患有心肌梗塞的患者 My VA CDA 资助的秋水仙碱-PCI 试验分别为稳定型冠状动脉疾病。 第一次在受伤前服用秋水仙碱可以抑制 通过 CRP 测量的炎症反应。秋水仙碱对围手术期 MACE 的影响。 既往接受过冠状动脉血运重建的患者接受大手术的情况仍然未知。 该提案的目的是 1) 评估秋水仙碱对围手术期 MACE 的影响 既往冠状动脉疾病患者对中危或高危非心脏手术的反应 血运重建；2) 描述全身炎症水平和围手术期情况 该人群中的中性粒细胞；3) 确定围周期的临床和遗传预测因子 手术 MACE 并检查决定治疗反应异质性的因素 该提案提供了使用秋水仙碱来描述其作用的机会。 术后炎症发展中的炎症，并对其进行潜在测试 具有成本效益的治疗方法，可减少围手术期 MACE，且全身性最小化 该提案还旨在促进个性化医疗方法。 基于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患者围手术期 MACE 风险的因素 尽管使用了秋水仙碱，因此可能需要替代的抗炎或抗- 最后，这项研究的结果也可能为治疗小说打开一扇大门。 其他心血管炎症和损伤情况下的策略（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（例如血管炎、 伤口愈合）。