Anti-inflammatory therapy during percutaneous coronary intervention

经皮冠状动脉介入治疗期间的抗炎治疗

• 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
• 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

 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。本提案的主要重点是描述急性冠状动脉综合征和/或经皮冠状动脉介入治疗（PCI）后中性粒细胞活化与不良结局之间的病理生理机制。我们目前对中性粒细胞潜在作用的认识大多是基于对小鼠实验模型或炎症微血管模型的观察。我建议通过详细研究中性粒细胞生物学以及中性粒细胞表型与接受临床指征PCI（急性血管损伤模型）患者的不良心血管结局之间的相关性来弥合目前的知识差距。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，作为一种工具来阐明中性粒细胞活化在急性血管损伤中的作用。秋水仙碱可能是特别有用的PCI设置，由于其快速起效的行动和优秀的副作用，在低剂量，以及其对中性粒细胞粘附分子的作用机制。可能接受PCI的患者将以双盲方式随机分配至安慰剂组或秋水仙碱组（PCI前1小时内口服1.8 mg）。在该2 × 2研究设计（PCI后与PCI前和秋水仙碱与安慰剂）中，将检查PCI和研究药物对嗜中性粒细胞特异性生物标志物以及嗜中性粒细胞-内皮细胞和嗜中性粒细胞-血小板相互作用的影响。我还将探讨中性粒细胞表型和PCI术后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。急性血管损伤中中性粒细胞生物学的深入表征将允许 探索预防和治疗的新途径，目的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嗜中性粒细胞衍生的微粒途径表征细胞后介质可能提供额外的新的治疗靶点。此外，在本提案中获得的对中性粒细胞生物学的更多理解可能为2型MI人群（例如术后环境中的需求性缺血）和其他动脉粥样硬化人群（例如外周动脉疾病）的病理学提供新的见解。我在纽约大学（NYU）完成了为期5年的课程，获得了普通和介入心脏病学证书，以及临床研究理学硕士学位。VA职业发展奖将为我提供一个垫脚石，通过一系列课程支持我，并为有效利用翻译方法的结构化教程提供受保护的时间。曼哈顿退伍军人管理局及其学术分支机构，临床和转化科学研究所和纽约大学心血管临床研究中心的强大环境和资源，将使我能够成功地执行本建议书中概述的职业发展计划。该提案采用多学科方法，在基础和临床科学的心脏病学和流变学专家的支持下，减少PCI后的不良结局。这种跨学科的合作是必要的，有效地进行转化研究，并将帮助我准备我的职业生涯作为一个成功的独立调查员。

项目成果

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
• 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
• 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
• 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
• 作者: Villablanca,Pedro;Shah,Binita
• 通讯作者: Shah,Binita

Treatment and outcomes of type 2 myocardial infarction and myocardial injury compared with type 1 myocardial infarction.

• DOI: 10.1097/mca.0000000000000545
• 发表时间: 2018-01
• 期刊: Coronary artery disease
• 影响因子: 1.8
• 作者: Smilowitz NR;Subramanyam P;Gianos E;Reynolds HR;Shah B;Sedlis SP
• 通讯作者: Sedlis SP