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 尽管医疗疗法和机械血运重建方面取得了进步，但心肌梗塞（MI） 仍然是发病率和死亡率的主要原因。而MI的急性治疗与低有关 院内死亡率，很大一部分患者在 长期随访。确定炎症机制增加了心肌损伤 Peri-MI时期可能有助于指导新颖的治疗剂和更强化的医疗疗法 疾病的病因。最近的证据表明，特定的单核细胞子集（MON2； CD14 ++/CD16+）是MI期间心肌细胞损伤的主要促炎介质，但 导致单核细胞激活和募集的触发因素的定义很差。血小板是 也是血栓损伤的主要介质：单核细胞 - 骨骼聚集体（MPA）在MI中升高， 它们的存在程度可能与组织损伤的严重程度有关。这些 观察结果导致了中心假设的提出，即MPA促进招募和 MI期间的促炎单核细胞的激活，以及适当的抗血域药物治疗 可以限制升高患者的心肌损伤和长期不良心血管事件 MPA和单核细胞激活水平。该项目建议（1）定量 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，如 以及心肌梗塞中CD14 ++ CD16+单核细胞的循环水平； （2investing单核细胞 在MPA中激活的亚型，抑制血小板P2Y12受体对MPA形成的作用，以及 单核细胞整合素激活在介导单核细胞粘附中的作用； （3）确定差异 抗血小板药物对MPA和单核细胞激活形成的影响。为了检验这些假设， 在心脏导管插入术时将获得外围和冠状动脉血液样本 经皮冠状动脉干预用于治疗MI。血液样本将通过流量进行分析 量化MPA和单核细胞亚型的细胞仪。动脉模拟粘附测定（芯片）将 用于定量单核细胞子集粘附于VCAM-1，单核细胞的相对粘附 MPA中的亚型。临床随访将建立MPA，单核细胞子集之间的关系 激活和主要的不良心血管事件。体外和临床分析更多的影响 在MPA上使用Ticagrelor或Prasugrel抑制密集的血小板将确定未来的治疗 MI后患者中个性化抗血小板治疗的策略。