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).

先前的冠状动脉血运重建患者患有主要广告心血管的风险很高 大手术后事件（狼牙棒），与没有的患者相比， 先前的冠状动脉血运重建。由 手术和由液体转移和麻醉引起的血液动力学变化都是重要的 周期性心肌缺血的触发因素。确实，围手术期的全身注射是 与周期性MACE的风险增加了近4倍。中性粒细胞，最多 最丰富的炎性细胞，遵守发炎或受伤的内皮，迁移到 血管壁，释放可能导致斑块侵蚀或破裂的蛋白水解酶。骨 手术细胞因子产生也可能激活炎症体，从而激活巨噬细胞 - 介导的白介素（IL）-1β的合成，这是次级预防治疗的已知靶标 狼牙棒，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，优先积累 与其他炎症细胞相比，中性粒细胞。秋水仙碱抑制趋化性，内皮 在内皮损伤或注射部位的中性粒细胞的粘附和渗出； 通过巨噬细胞抑制炎症体介导的IL-1β产生；并减少 心血管疾病患者的炎症和狼牙棒。秋水仙碱心血管 结局试验和低剂量秋水仙碱2试验显示，MACE的减少 大约4000名先前心肌梗塞患者的秋水仙碱，约5000例患者 稳定的冠状动脉疾病。我的VA CDA资助的Colchicine-PCI试验 首次证明秋水仙碱在受伤之前的给药会抑制 通过CRP测量的炎症反应。秋水仙碱对围手术期MACE的影响 接受大术进行大术的先前冠状动脉血运重建患者仍然未知。 该提议的目的是1）评估秋水仙碱对围手术期MACE的影响 对先前冠状动脉患者的中间或高风险非心脏手术的反应 血运重建； 2）表征全身感染的水平和围手术的特征 该人群中的中性粒细胞； 3）确定周期的临床和遗传预测因子 手术钉和检查决定治疗反应异质性的因素 人口。该建议提供了使用秋水仙碱来描述角色的机会 术后感染发展中的炎症，并测试了这一点 具有成本效益 免疫抑制。该提案还旨在培养一种个性化的医学方法 基于炎症标记的使用和围手术性心血管优化 药物遗传学以识别预测有围手术期MACE风险的患者的因素 尽管使用秋水仙碱，因此可能需要替代的抗炎或抗 血小板疗法。最后，这项研究的发现也可能打开新的治疗之门 心血管感染和损伤其他环境中的策略（例如，周围动脉 疾病，中风）和其他中性粒细胞发挥关键作用的疾病状态（例如，血管炎， 伤口愈合）。