Anti-inflammatory therapy during percutaneous coronary intervention

经皮冠状动脉介入治疗期间的抗炎治疗

基本信息

批准号：
10268158
负责人：
Binita Shah
金额：
--
依托单位：
VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10268158
关键词：
Acute Adhesions Adhesiveness Anti-Inflammatory Agents Antiinflammatory Effect Atherosclerosis Attenuated Basic Science Biology Blood Circulation Blood Platelets Cardiac Death Cardiology Cardiovascular system Cause of Death Cell Adhesion Molecules Cell surface Certification Clinical Clinical Research Clinical Sciences Coagulation Process Colchicine Collaborations Coronary artery Data Development Plans Dose Double-Blind Method Endothelial Cells Environment Event Experimental Animal Model Experimental Models Generations Goals Gout Heart Heart Diseases Hour Immunosuppression Inflammation Inflammatory Institutes Integrins Intervention Intervention Studies Ischemia K-Series Research Career Programs Knowledge L-Selectin Leukocytes Link Master of Science Mediator of activation protein Modeling Mus Myocardial Myocardial Ischemia Necrosis Neutrophil Activation Neutrophil Infiltration New York Outcome Pathogenicity Pathology Pathway interactions Patients Peripheral arterial disease Pharmaceutical Preparations Phenotype Placebo Effect Placebos Play Population Postoperative Period Prevention Randomized Research Research Design Research Methodology Research Personnel Resources Rheumatology Risk Role Safety Selectins Series Site Structure Surface T-Lymphocyte TFPI Testing Thrombin Thromboplastin Time Translational Research Universities Woman acute coronary syndrome adverse outcome arm atherogenesis base career career development clinical investigation extracellular improved outcome insight interdisciplinary approach intervention effect macrophage men neutrophil new therapeutic target novel percutaneous coronary intervention programs public health relevance randomized trial response side effect specific biomarkers therapeutically effective tool translational approach vascular inflammation vascular injury

项目摘要

DESCRIPTION (provided by applicant): My long-term research goal is to leverage translational research methodologies to develop novel and effective therapeutic strategies and improve outcomes in patients with ischemic heart disease. The primary focus of this proposal is to characterize pathophysiological mechanisms linking neutrophil activation and adverse outcomes after acute coronary syndrome and/or percutaneous coronary intervention (PCI). Much of our current knowledge about the potential role of neutrophils is based on observations from experimental models in mice, or microvascular models of inflammation. I propose to bridge the current gap in knowledge through detailed study of neutrophil biology and the association between neutrophil phenotype and adverse cardiovascular outcomes in patients who undergo clinically indicated PCI, a model of acute vascular injury. I further propose to use colchicine, an agent with direct neutrophil suppressive action, as a tool to elucidate the role of neutrophil activation during acute vascular injury. Colchicine may be particularly useful in the PCI setting due to its rapid onset of action and excellent side-effect profile at low doses, as well as its known mechanisms of action on neutrophil adhesion molecules. Patients referred for possible PCI will be randomized in a double-blinded fashion to placebo or colchicine (1.8mg PO over 1 hour prior to PCI). In this two by two study design (post- versus pre-PCI and colchicine versus placebo), the effect of PCI and study drug will be examined on neutrophil-specific biomarkers and neutrophil-endothelial cell and neutrophil-platelet interactions. I will also explore the association between neutrophil phenotype and adverse cardiovascular outcomes after PCI and the effects of colchicine on these outcomes. In-depth characterization of neutrophil biology in acute vascular injury will allow for exploration of new avenues in prevention and treatment, with a goal to identify novel selective targets that induce anti-inflammatory effects with minimal systemic immunosuppression. Characterization of post-cellular mediators via neutrophil extracellular trap and neutrophil-derived microparticle pathways may provide additional novel therapeutic targets. In addition, increased understanding of neutrophil biology gained in this proposal may provide novel insight into pathology of type 2 MI populations (e.g. demand ischemia in post-operative settings) and other atherosclerosis populations (e.g. peripheral artery disease). I completed a 5- year program at New York University (NYU) resulting in certification in general and Interventional Cardiology, as well as a Master's of Science degree in Clinical Investigation. A VA Career Development Award will provide me with the stepping stone on which to advance to investigative independence, by supporting me through a series of courses and providing protected time for structured tutorials on the effective utilization of translational approaches an topics in inflammation. The strong environment and resources of the Manhattan VA and its academic affiliates, the Clinical and Translational Science Institute and the Cardiovascular Clinical Research Center at NYU, will allow me to successfully execute the career development plan outlined in this proposal. This proposal features a multi-disciplinary approach, with support from experts in cardiology and rheumatology in both basic and clinical science, to reduce adverse outcomes after PCI. Such cross-disciplinary collaboration is necessary to effectively conduct translational research and will help prepare me for my career as a successful independent investigator.

描述（由申请人提供）：我的长期研究目标是利用转化研究方法来开发新颖有效的治疗策略并改善缺血性心脏病患者的预后，该提案的主要重点是确定中性粒细胞激活与急性冠脉综合征后不良后果之间的病理生理机制。我们目前关于中性粒细胞潜在作用的大部分知识都是基于对小鼠实验模型或炎症微血管模型的观察，我建议通过详细的研究来弥补目前的知识差距。中性粒细胞生物学的研究以及接受有临床指征的 PCI（一种急性血管损伤模型）患者的中性粒细胞表型与不良心血管结局之间的关系，我进一步建议使用秋水仙碱（一种具有直接中性粒细胞抑制作用的药物）作为阐明其作用的工具。秋水仙碱在急性血管损伤期间的中性粒细胞激活可能特别有用，因为它在低剂量下起效快，副作用小，而且其已知的作用机制。接受可能 PCI 的患者将以双盲方式随机接受安慰剂或秋水仙碱（PCI 前 1 小时口服 1.8 毫克）（PCI 后与 PCI 前和秋水仙碱对比）。（安慰剂），将检查 PCI 和研究药物与中性粒细胞特异性生物标志物以及中性粒细胞-内皮细胞和中性粒细胞-血小板相互作用的效果，我还将探讨其中的关联。 PCI 后中性粒细胞表型与不良心血管结局之间的关系以及秋水仙碱对这些结局的影响将有助于对急性血管损伤中的中性粒细胞生物学进行深入表征。探索预防和治疗的新途径，目标是确定新的选择性靶点，以最小的全身免疫抑制诱导抗炎作用，通过中性粒细胞胞外陷阱和中性粒细胞衍生的微粒途径表征细胞后介质可能会提供额外的新疗法。此外，在该提案中获得的对中性粒细胞生物学的更多了解可能会为 2 型 MI 人群的病理学（例如术后环境中的需求缺血）和其他疾病提供新的见解。我在纽约大学 (NYU) 完成了为期 5 年的课程，获得了普通心脏病学和介入心脏病学认证，并获得了 VA 职业发展奖的理学硕士学位。通过支持我完成一系列课程并为有效利用炎症主题的转化方法提供受保护的时间，为我提供了迈向独立调查的垫脚石曼哈顿强大的环境和资源。 VA 及其学术附属机构、纽约大学临床与转化科学研究所和心血管临床研究中心将使我能够成功执行本提案中概述的职业发展计划。该提案采用多学科方法，并得到了各领域专家的支持。心脏病学和风湿病学的基础和临床科学，以减少 PCI 后的不良后果，这种跨学科合作对于有效地进行转化研究是必要的，并将帮助我为作为一名成功的独立研究者的职业生涯做好准备。

项目成果

期刊论文数量（28）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Late breaking trials of 2015 in coronary artery disease: Commentary covering ACC, EuroPCR, SCAI, TCT, ESC, and AHA.

2015 年冠状动脉疾病最新突破性试验：评论涵盖 ACC、EuroPCR、SCAI、TCT、ESC 和 AHA。

DOI：
10.1002/ccd.26474
发表时间：
2016
期刊：
Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions
影响因子：
0
作者：
Seto,ArnoldH;JordanSafirstein;Anwaruddin,Saif;Dehghani,Payam;Shah,Binita;Tremmel,JenniferA
通讯作者：
Tremmel,JenniferA

Glycemic Control in Coronary Revascularization.

DOI：
10.1007/s11936-015-0434-6
发表时间：
2016-02-01
期刊：
Current treatment options in cardiovascular medicine
影响因子：
0
作者：
Ujueta, Francisco;Weiss, Ephraim N;Shah, Binita
通讯作者：
Shah, Binita

Consensus Statement Regarding the Efficacy and Safety of Long-Term Low-Dose Colchicine in Gout and Cardiovascular Disease.

DOI：
10.1016/j.amjmed.2021.07.025
发表时间：
2022-01
期刊：
The American journal of medicine
影响因子：
0
作者：
Robinson PC;Terkeltaub R;Pillinger MH;Shah B;Karalis V;Karatza E;Liew D;Imazio M;Cornel JH;Thompson PL;Nidorf M
通讯作者：
Nidorf M

Size Matters: Moving Toward a Slender Transradial Artery Approach.

尺寸很重要：走向细长的经桡动脉入路。

DOI：
10.1016/j.carrev.2018.06.012
发表时间：
2018
期刊：
Cardiovascular revascularization medicine : including molecular interventions
影响因子：
0
作者：
Villablanca,Pedro;Shah,Binita
通讯作者：
Shah,Binita

Long-term dietary and weight changes following a short-term dietary intervention study: EVADE-CAD trial follow-up.