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

项目摘要/摘要 尽管药物治疗和机械血管重建术取得了进展，但心肌梗死(MI) 仍然是发病率和死亡率的主要原因。而急性心肌梗死的治疗与低血压有关 住院死亡率，相当大比例的患者在治疗期间发生复发的缺血事件 长期随访。确定心肌损伤增加的炎症机制 心肌梗死围手术期可能有助于指导新的治疗方法和更集中的医学治疗 疾病的病因学。最近的证据表明，一个特定的单核细胞亚群(Mon2； CD14+/CD16+)是心肌梗死时心肌细胞损伤的主要促炎介质，但 导致单核细胞激活和募集增加的触发因素定义不明确。血小板是 也是血栓损伤的主要介质：单核细胞-血小板聚集物(MPA)在心肌梗死时升高， 它们的存在程度可能与组织损伤的严重程度有关。这些 观察结果导致了核心假设的形成，即MPA促进招募和 心肌梗死时促炎症单核细胞的激活及适当的抗血小板药物治疗 可以限制高血压患者的心肌损伤和长期不良心血管事件 甲孕酮水平和单核细胞活化。该项目建议(1)量化两者之间的联系 心肌梗死后循环单核细胞血小板聚集率与心血管预后的关系 心肌梗死患者外周血CD14++CD16+单核细胞水平；(2)单核细胞 MPA中活化的亚型，抑制血小板P2Y12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黏附中的作用；以及(3)决定区别 抗血小板药物对单核细胞活化和抗凝血活性的影响。为了检验这些假设， 外周血和冠脉血样本将在心导管插入术时和 经皮冠状动脉介入治疗心肌梗死。血液样本将通过流动分析 用流式细胞术对MPA和单核细胞亚型进行定量。动脉模拟黏附分析(芯片)将 用来定量单核细胞亚群与VCAM-1的黏附以及单核细胞与VCAM-1的相对黏附 以兆帕为单位的亚型。临床随访将确定单核细胞亚群与MPA之间的关系 激活，以及主要的不良心血管事件。多柔比星的体外和临床疗效分析 替卡格雷或普拉格雷强化抑制血小板对MPA的作用将确定未来的治疗方法 心肌梗塞后患者个体化抗血小板治疗的策略。

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.