Optimization of Antiplatelet Therapy to Target Platelet-Monocyte Aggregates in Myocardial Infarction

心肌梗塞中针对血小板单核细胞聚集体的抗血小板治疗的优化

• 批准号: 9979786
• 负责人: EHRIN J ARMSTRONG
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979786
• 关键词: Acute; Adhesions; Antiplatelet Drugs; Arteries; Biological Assay; Blood Platelets; Blood specimen; CD14 gene; Cardiac Catheterization Procedures; Cardiac Myocytes; Cardiovascular system; Caring; Clinical; Coronary; Coronary Arteriosclerosis; Disease; Etiology; Event; FCGR3B gene; Flow Cytometry; Formulation; Future; Hospital Mortality; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Injury; Integrins; Longterm Follow-up; Mechanics; Mediating; Mediator of activation protein; Medical; Morbidity - disease rate; Myocardial Infarction; Outcome; P-Selectin; Pathway interactions; Patients; Peripheral; Pharmacotherapy; Platelet Activation; Platelet aggregation; Population; Procedures; Recurrence; Role; Severities; Testing; Time; Vascular Cell Adhesion Molecule-1; Veterans; acute care; comorbidity; experience; follow-up; high risk population; improved; individualized medicine; inhibitor/antagonist; mimetics; monocyte; mortality; myocardial injury; novel therapeutics; patient population; percutaneous coronary intervention; receptor; recruit; thrombotic; tissue injury

Project Abstract/Summary Despite advances in medical therapy and mechanical revascularization, myocardial infarction (MI) remains a major cause of morbidity and mortality. While acute treatment of MI is associated with low in-hospital mortality, a significant proportion of patients develop recurrent ischemic events during long-term follow-up. Identifying inflammatory mechanisms underlying increased myocardial injury in the peri-MI period may help direct novel therapeutics and more intensive medical therapy focused on the etiology of disease. Recent evidence suggests that a specific monocyte subset (Mon2; CD14++/CD16+) is a major pro-inflammatory mediator of cardiomyocyte injury during MI, but the triggers leading to increased monocyte activation and recruitment are poorly defined. Platelets are also a primary mediator of thrombotic injury: monocyte-platelet aggregates (MPA) are elevated in MI, and the extent of their presence may be associated with the severity of tissue injury. These observations have led to the formulation of the central hypothesis that MPA promote recruitment and activation of pro-inflammatory monocytes during MI, and that appropriate anti-platelet drug therapy can limit myocardial injury and long-term adverse cardiovascular events among patients with elevated levels of MPA and monocyte activation. This project proposes to (1) quantitate the association between circulating monocyte platelet aggregates (MPA) and cardiovascular outcomes after myocardial infarction, as well as the circulating levels of CD14++CD16+ monocytes in myocardial infarction; (2investigate the monocyte subtypes that are activated in MPA, the effect of inhibiting platelet P2Y12 receptors on MPA formation, and the role of monocyte integrin activation in mediating monocyte adhesion; and (3) determine the differential effect of antiplatelet agents on formation of MPA and monocyte activation. To test these hypotheses, peripheral and coronary blood samples will be obtained at the time of cardiac catheterization and percutaneous coronary intervention for treatment of MI. Blood samples will be analyzed by flow cytometry to quantify MPA and monocyte subtypes. An arterial mimetic adhesion assay (A chip) will be used to quantitate monocyte subset adhesion to VCAM-1, and the relative adhesion of monocyte subtypes in MPA. Clinical follow-up will establish a relationship between MPA, monocyte subset activation, and major adverse cardiovascular events. In vitro and clinical analysis of the effect of more intensive platelet inhibition with ticagrelor or prasugrel on MPA will identify future therapeutic strategies for individualized antiplatelet treatment among patients after MI.

项目摘要/摘要 尽管医学治疗和机械血运重建取得了进展，心肌梗死（MI） 仍然是发病和死亡的主要原因。虽然MI的急性治疗与低 在住院死亡率方面，很大比例的患者在住院期间发生复发性缺血事件。 长期随访。确定心肌损伤增加的炎症机制 心肌梗死围期可能有助于指导新的治疗方法和更集中的药物治疗， 疾病的病因最近的证据表明，一个特定的单核细胞亚群（Mon 2; CD 14 ++/CD 16+）是心肌梗死时心肌细胞损伤的主要促炎介质，但 导致单核细胞活化和募集增加的触发因素定义不清。血小板是 也是血栓性损伤的主要介质：单核细胞-血小板聚集体（MPA）在MI中升高， 并且它们存在的程度可能与组织损伤的严重性有关。这些 观察导致了中心假设的形成，即MPA促进了招募， MI期间促炎性单核细胞的活化，以及适当的抗血小板药物治疗 可以限制心肌损伤和长期不良心血管事件的患者， MPA和单核细胞活化水平。本项目建议（1）量化 循环单核细胞血小板聚集体（MPA）和心肌梗死后的心血管结局， 以及心肌梗死患者外周血中CD 14 ++ CD 16+单核细胞水平;（2）检测心肌梗死患者外周血中单核细胞 MPA中活化的亚型，抑制血小板P2 Y12受体对MPA形成的影响，以及 单核细胞整合素活化在介导单核细胞粘附中的作用;以及（3）确定单核细胞整合素活化的差异。 抗血小板药物对MPA形成和单核细胞活化影响为了验证这些假设， 在心导管插入术时采集外周血和冠状动脉血样本， 经皮冠状动脉介入治疗心肌梗死。将通过流式细胞仪分析血样 流式细胞术以定量MPA和单核细胞亚型。动脉模拟粘附测定（A芯片）将 用于定量单核细胞亚群与VCAM-1的粘附，以及单核细胞与VCAM-1的相对粘附。 MPA中的亚型。临床随访将建立MPA、单核细胞亚群之间的关系 激活和主要不良心血管事件。体外及临床效果分析较多 替格瑞洛或普拉格雷对MPA强化血小板抑制作用将确定未来的治疗方法 MI后患者个体化抗血小板治疗策略。