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

秋水仙碱对急性心肌梗死中性粒细胞生物学影响的研究

• 批准号: 10352394
• 负责人: Binita Shah
• 金额: $ 41.94万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10352394
• 关键词: ABCB1 gene; Acute myocardial infarction; Adhesions; Alleles; Ancillary Study; Anti-Inflammatory Agents; Biology; Blood Vessels; Blood specimen; C-reactive protein; Cardiac Death; Cardiovascular system; Cause of Death; Cells; Cessation of life; Chemotaxis; Clinical; Codon Nucleotides; Colchicine; Derivation procedure; Disease; Distal; Endothelium; Enrollment; Event; Extravasation; Fostering; Funding; Gene Expression; Generations; Genetic Polymorphism; Gout; Health; Heart Diseases; Heterogeneity; Hour; Immunosuppression; Inflammasome; Inflammation; Inflammatory; Injury; Institutes; Interleukin-1 beta; L-Selectin; LCN2 gene; Lead; Leukocyte Elastase; Leukocytes; Mediating; Medical Genetics; Membrane Glycoproteins; Microcirculatory Bed; Multi-Drug Resistance; Myocardial; Myocardial Infarction; Myocardial Ischemia; Neutrophil Activation; Outcome Study; Participant; Pathogenesis; Patients; Peptide Hydrolases; Peripheral arterial disease; Pharmaceutical Preparations; Pharmacogenetics; Placebos; Plasma; Play; Predictive Factor; Production; Pump; Randomized; Recurrence; Research; Research Design; Residual state; Risk; Role; Rupture; Secondary Prevention; Signal Transduction; Site; Spironolactone; Stroke; Testing; Therapeutic Effect; Thrombin; Thrombosis; Thrombus; Vasculitis; activity marker; adjudicate; arm; base; cell type; cost; cost effective; design; extracellular; follow-up; high risk; injured; insight; neutrophil; novel; novel therapeutic intervention; percutaneous coronary intervention; personalized medicine; primary outcome; randomized trial; resistance gene; responders and non-responders; response; systemic inflammatory response; targeted treatment; treatment response; vascular inflammation; wound healing

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).

ST 段抬高型心肌梗死 (STEMI) 患者发生重大不良反应的风险很高 心血管事件 (MACE)（三年内约 20%）血管炎症在其中起关键作用。 这种复发性MACE的发病机制，而中性粒细胞是最丰富的炎症细胞。 粘附在发炎或受伤的内皮上，迁移到血管壁中，释放蛋白水解酶， 导致斑块侵蚀或破裂，并激活炎症小体和白介素-1β（一种已知的白细胞介素-1β）的合成 心血管事件二级预防的治疗目标中性粒细胞也释放中性粒细胞。 细胞外陷阱（NET）和微粒，两者都可能促进持续的炎症信号传导和 即使中性粒细胞死亡后也会产生血栓。 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中 与其他炎症细胞相比，秋水仙碱抑制趋化性、内皮粘附和 内皮损伤或炎症部位的中性粒细胞外渗抑制炎症小体； 介导白细胞介素 1β 的产生；并减少心脏稳定患者的炎症和 MACE 然而，秋水仙碱对 STEMI 患者的作用尚不清楚。 该研究是一项针对 4000 名接受 PCI 治疗的 STEMI 患者进行秋水仙碱与安慰剂对比的多中心随机试验。 该提案利用 CLEAR SYNERGY 研究来获取血液样本以进行中性粒细胞表征。 该提案的目的是 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 驱动的反应，如 NET 和微粒，2) 检查可能的临床和遗传因素 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) 制定风险 基于中性粒细胞活性标记的评分，以预测 STEMI 后 3 年内 MACE 的发生，以及 利用血液样本评估秋水仙碱对该风险评分与 MACE 之间关系的影响。 来自 STEMI 后立即和 3 个月随访的 CLEAR SYNERGY 研究参与者，该 该提案提供了对这项大型随机试验的结果提供机制洞察的机会； 经济有效地增加独立于 CLEAR SYNTERGY 研究结果的科学价值； 发现新的选择性靶点和治疗方案，以最小的限度减少心血管炎症 免疫抑制；并促进 STEMI 后的个性化治疗方法。 这项研究还可能为其他心血管疾病的新治疗策略打开一扇大门 炎症和损伤（例如外周动脉疾病、中风）以及中性粒细胞的其他疾病状态 发挥关键作用（例如，血管炎、伤口愈合）。

项目成果

Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial.

秋水仙碱用于社区治疗的 COVID-19 患者 (COLCORONA)：一项 3 期、随机、双盲、适应性、安慰剂对照、多中心试验。

• 发表时间: 2021
• 作者: Tardif, Jean;Bouabdallaoui, Nadia;L'Allier, Philippe L;Gaudet, Daniel;Shah, Binita;Pillinger, Michael H;Lopez;da Luz, Protasio;Verret, Lucie;Audet, Sylvia;Dupuis, Jocelyn;Denault, André;Pelletier, Martin;Tessier, Philippe
• 通讯作者: Tessier, Philippe

Long-term outcomes after transcatheter aortic valve replacement with minimal contrast in chronic kidney disease.

经导管主动脉瓣置换术后的长期结果与慢性肾病的对比最小。

• 发表时间: 2021
• 作者: Rzucidlo, Justyna;Jaspan, Vita;Paone, Darien;Jilaihawi, Hasan;Xia, Yuhe;Kapitman, Anna;Nakashima, Makoto;He, Yuxin;Ibrahim, Homam;Pushkar, Illya;Neuburger, Peter J;Saric, Muhamed;Bamira, Daniel;Paschke, Sonja;Kalish, Chloe;Staniloae, Cezar
• 通讯作者: Staniloae, Cezar