Studies on the effects of colchicine on neutrophil biology in acute myocardial infarction

ST段抬高心肌梗死(STEMI)患者复发重大不良反应风险高 心血管事件(MACE)(三年时约为20%)。血管炎症在以下疾病中起关键作用 这种反复发作的MACE的发病机制中，中性粒细胞是最丰富的炎性细胞。中性粒细胞 黏附于炎症或损伤的内皮细胞，迁移到血管壁，释放蛋白水解酶，可以 导致斑块的侵蚀或破裂，激活炎症小体和白介素1β的合成，已知 心血管事件二级预防的治疗目标。中性粒细胞也会释放中性粒细胞 细胞外陷阱(Net)和微粒，两者都可以促进持续的炎症信号和 即使在中性粒细胞死亡后也会产生血栓。 秋水仙碱是一种安全的、耐受性良好的抗炎药，它优先在中性粒细胞中蓄积。 与其他炎性细胞相比。秋水仙碱抑制趋化作用、内皮细胞黏附和 中性粒细胞在内皮损伤或炎症部位的外渗；抑制炎症小体- 介导IL-1β的产生，并减少心脏稳定患者的炎症和MACE 疾病。然而，秋水仙碱对STEMI患者的影响尚不清楚。明显的协同效应 这项研究是一项对4000名接受经皮冠状动脉介入治疗的STEMI患者进行的秋水仙碱与安慰剂的多中心随机试验。 这项建议利用明确的协同研究来获取血液样本，用于中性粒细胞的鉴定。 这项建议的目的是1)评估秋水仙碱对中性粒细胞激活的影响，包括中性粒细胞- 驱动反应，如网络和微粒，2)检查临床和遗传因素 根据中性粒细胞活性标记物确定治疗反应的异质性，以及3)发生风险 基于中性粒细胞活性标志物的评分预测STEMI后3年以上MACE的发生 评估秋水仙碱对这一风险评分与MACE之间关系的影响。通过利用血液样本 来自STEMI后立即和3个月随访的明确协同研究参与者， 提案提供了对这一大型随机试验的结果提供机械性洞察的机会； 经济高效地增加科学价值，独立于明确的综合研究结果；潜在地促进 发现新的选择性靶点和治疗方案，以最小限度地减少心血管炎症 免疫抑制；并培养STEMI后的个性化药物治疗方法。最后，调查结果 这项研究也可能为其他心血管疾病的治疗策略打开一扇门 炎症和损伤(例如，外周动脉疾病、中风)和中性粒细胞 发挥关键作用(例如，脉管炎、伤口愈合)。

Patient with ST-segment elevation myocardial infarction (STEMI) have a high risk of recurrent major adverse cardiovascular events (MACE) (approximately 20% at three years). Vascular inflammation plays a key role in this pathogenesis of recurrent MACE, and neutrophils are the most abundant of inflammatory cells. Neutrophils adhere to inflamed or injured endothelium, migrate into the vessel wall, release proteolytic enzymes that can lead to erosion or rupture of plaque, and activate the inflammasome and synthesis of interleukin-1β, a known target for therapy for secondary prevention of cardiovascular events. Neutrophils also release neutrophil extracellular traps (NETs) and microparticles, both of which may promote sustained inflammatory signaling and thrombus generation even after neutrophil death. 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 interleukin-1β; and reduces inflammation and MACE in patients with stable heart disease. The effects of colchicine in patients with STEMI, however, is not known. The CLEAR SYNERGY study is a multicenter randomized trial of colchicine versus placebo in 4000 STEMI patients treated with PCI. This proposal leverages the CLEAR SYNERGY study to obtain blood samples for neutrophil characterization. The aims of this proposal are to 1) assess the effect of colchicine on neutrophil activation, including neutrophil- driven responses such as NETs and microparticles, 2) examine the clinical and genetic factors that may determine heterogeneity of treatment response based on neutrophil activity markers, and 3) develop a risk score based on markers of neutrophil activity to predict occurrence of MACE over 3 years after STEMI, and assess the impact of colchicine on the relation between this risk score and MACE. By utilizing blood specimens derived from CLEAR SYNERGY study participants immediately after STEMI and on 3-month follow-up, this proposal offers the opportunity to provide mechanistic insight into the findings of this large randomized trial; cost-effectively add scientific value independent of the CLEAR SYNTERGY study findings; potentially promote discovery of novel selective targets and therapeutic options to reduce cardiovascular inflammation with minimal immunosuppression; and foster a personalized medicine approach to therapy after STEMI. 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).