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段海拔心肌梗塞（STEMI）的患者具有重复反对的高风险 心血管事件（MACE）（三年约20％）。血管炎症在 复发性痕迹和中性粒细胞的这种发病机理是最丰富的炎症细胞。中性粒细胞 坚持发炎或受伤的内皮，迁移到容器壁中，释放可以 导致牙菌斑的侵蚀或破裂，并激活白介素1β的炎性体和合成 用于预防心血管事件的次要预防治疗的靶标。中性粒细胞也释放中性粒细胞 细胞外陷阱（NET）和微粒，这两者都可能促进持续的炎症信号传导和 甚至在中性粒细胞死亡后产生血栓。 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，内皮粘合剂和 在内皮损伤或注射部位的中性粒细胞渗出；抑制炎症体 - 介导的白介素1β的产生；并减少心脏稳定患者的感染和狼牙棒 疾病。然而，秋水仙碱对STEMI患者的影响尚不清楚。清晰的协同作用 研究是4000名接受PCI治疗的STEMI患者的秋水仙碱与安慰剂的多中心随机试验。 该建议利用清晰的协同研究来获得血液样本以进行中性粒细胞的特征。 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，例如网和微粒，2）检查可能的临床和遗传因素 确定基于中性粒细胞活性标记的治疗反应的异质性，3） 基于中性粒细胞活性的标记的评分，以预测STEMI 3年后的MACE的发生，并且 评估秋水仙碱对这种风险评分与梅斯之间关系的影响。通过使用血样 STEMI之后和3个​​月随访后立即源自清晰的协同研究参与者，这 提案提供了机会，以提供有关这项大型随机试验结果的机械洞察力； 成本效益添加科学价值与清晰的协议研究结果无关；潜在的促进 发现新颖的选择性靶标和治疗选择，以减少心血管感染的最小 免疫抑制；并在STEMI后培养一种个性化的医学方法。最后，发现 从这项研究中，在其他心血管的其他环境中也可以打开新的治疗策略之门 炎症和损伤（例如，周围动脉疾病，中风）和其他疾病状态，中性粒细胞 发挥关键作用（例如，血管炎，伤口愈合）。

项目成果

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。

• DOI: 10.1002/ccd.29378
• 发表时间: 2021
• 期刊: Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions
• 作者: Rzucidlo,Justyna;Jaspan,Vita;Paone,Darien;Jilaihawi,Hasan;Xia,Yuhe;Kapitman,Anna;Nakashima,Makoto;He,Yuxin;Ibrahim,Homam;Pushkar,Illya;Neuburger,PeterJ;Saric,Muhamed;Bamira,Daniel;Paschke,Sonja;Kalish,Chloe;Staniloae,Cezar

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

• DOI: 10.1016/s2213-2600(21)00222-8
• 发表时间: 2021-08
• 期刊: The Lancet. Respiratory medicine
• 作者: Tardif JC;Bouabdallaoui N;L'Allier PL;Gaudet D;Shah B;Pillinger MH;Lopez-Sendon J;da Luz P;Verret L;Audet S;Dupuis J;Denault A;Pelletier M;Tessier PA;Samson S;Fortin D;Tardif JD;Busseuil D;Goulet E;Lacoste C;Dubois A;Joshi AY;Waters DD;Hsue P;Lepor NE;Lesage F;Sainturet N;Roy-Clavel E;Bassevitch Z;Orfanos A;Stamatescu G;Grégoire JC;Busque L;Lavallée C;Hétu PO;Paquette JS;Deftereos SG;Levesque S;Cossette M;Nozza A;Chabot-Blanchet M;Dubé MP;Guertin MC;Boivin G;COLCORONA Investigators
• 通讯作者: COLCORONA Investigators