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）患者复发主要不良事件的风险较高， 心血管事件（MACE）（3年时约为20%）。血管炎症在 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 粘附于发炎或损伤的内皮，迁移到血管壁，释放蛋白水解酶， 导致斑块糜烂或破裂，并激活炎性小体和白细胞介素-1 β的合成， 作为心血管事件二级预防治疗靶点。中性粒细胞也释放中性粒细胞 细胞外陷阱（NET）和微粒，这两者都可以促进持续的炎症信号传导， 甚至在中性粒细胞死亡后血栓生成。 秋水仙碱是一种安全、耐受性好的抗炎药，优先在中性粒细胞中蓄积 与其他炎症细胞相比。秋水仙素抑制趋化性、内皮粘附和 内皮损伤或炎症部位的中性粒细胞外渗;抑制炎性小体， 介导白细胞介素-1 β的产生;并减少心脏稳定患者的炎症和MACE 疾病然而，秋水仙碱在STEMI患者中的作用尚不清楚。清晰的协同效应 研究是一项在4000例接受PCI治疗的STEMI患者中进行的秋水仙碱与安慰剂的多中心随机试验。 该提案利用CLEAR SYNERGY研究获得用于中性粒细胞表征的血液样本。 本提案的目的是：1）评估秋水仙碱对中性粒细胞活化的影响，包括中性粒细胞- 驱动的反应，如NET和微粒，2）检查可能 基于中性粒细胞活性标志物确定治疗反应的异质性，和3）产生风险 基于中性粒细胞活性标志物的评分，以预测STEMI后3年内MACE的发生，以及 评估秋水仙碱对该风险评分与MACE之间关系的影响。利用血液样本 来自CLEAR SYNERGY研究参与者在STEMI后即刻和3个月随访时， 该提案提供了机会，为这一大型随机试验的结果提供了机制性的见解; 具有成本效益地增加独立于CLEAR SYNTERGY研究结果的科学价值;可能促进 发现新的选择性靶点和治疗选择，以最小的 免疫抑制;并促进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新治疗策略打开大门。 炎症和损伤（例如，外周动脉疾病、中风）和其它疾病状态，其中嗜中性粒细胞 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