An Intense and Short-Lasting Burst of Neutrophil Activation Differentiates Early Acute Myocardial Infarction from Systemic Inflammatory Syndromes

BackgroundNeutrophils are involved in thrombus formation. We investigated whether specific features of neutrophil activation characterize patients with acute coronary syndromes (ACS) compared to stable angina and to systemic inflammatory diseases.
Methods and FindingsThe myeloperoxidase (MPO) content of circulating neutrophils was determined by flow cytometry in 330 subjects: 69 consecutive patients with acute coronary syndromes (ACS), 69 with chronic stable angina (CSA), 50 with inflammation due to either non-infectious (acute bone fracture), infectious (sepsis) or autoimmune diseases (small and large vessel systemic vasculitis, rheumatoid arthritis). Four patients have also been studied before and after sterile acute injury of the myocardium (septal alcoholization). One hundred thirty-eight healthy donors were studied in parallel. Neutrophils with normal MPO content were 96% in controls, >92% in patients undergoing septal alcoholization, 91% in CSA patients, but only 35 and 30% in unstable angina and AMI (STEMI and NSTEMI) patients, compared to 80%, 75% and 2% of patients with giant cell arteritis, acute bone fracture and severe sepsis. In addition, in 32/33 STEMI and 9/21 NSTEMI patients respectively, 20% and 12% of neutrophils had complete MPO depletion during the first 4 hours after the onset of symptoms, a feature not observed in any other group of patients. MPO depletion was associated with platelet activation, indicated by P-selectin expression, activation and transactivation of leukocyte β2-integrins and formation of platelet neutrophil and -monocyte aggregates. The injection of activated platelets in mice produced transient, P-selectin dependent, complete MPO depletion in about 50% of neutrophils.
ConclusionsACS are characterized by intense neutrophil activation, like other systemic inflammatory syndromes. In the very early phase of acute myocardial infarction only a subpopulation of neutrophils is massively activated, possibly via platelet-P selectin interactions. This paroxysmal activation could contribute to occlusive thrombosis.

背景：中性粒细胞（neutrophils）参与血栓形成。本研究旨在探究，相较于稳定型心绞痛患者及全身性炎症性疾病患者，急性冠状动脉综合征（acute coronary syndromes, ACS）患者是否存在特征性的中性粒细胞活化表型。
方法与结果：本研究采用流式细胞术（flow cytometry）检测了330名受试者循环中性粒细胞的髓过氧化物酶（myeloperoxidase, MPO）含量：其中纳入69例连续确诊的急性冠状动脉综合征（ACS）患者、69例慢性稳定型心绞痛（chronic stable angina, CSA）患者，以及50例因非感染性（急性骨折）、感染性病因（脓毒症sepsis）或自身免疫性疾病（大小血管系统性血管炎small and large vessel systemic vasculitis、类风湿关节炎rheumatoid arthritis）引发炎症的患者。另有4名患者在接受心肌无菌性损伤术前（间隔酒精消融术septal alcoholization）及术后分别完成检测。同时平行纳入138名健康受试者（healthy donors）作为对照。对照组中MPO水平正常的中性粒细胞占比为96%；接受间隔酒精消融术的患者该占比＞92%，慢性稳定型心绞痛（CSA）患者为91%；但不稳定型心绞痛及急性心肌梗死（acute myocardial infarction, AMI）患者（其中分为ST段抬高型心肌梗死ST-segment elevation myocardial infarction, STEMI与非ST段抬高型心肌梗死non-ST-segment elevation myocardial infarction, NSTEMI）的该占比仅为35%与30%。相较而言，巨细胞动脉炎（giant cell arteritis）、急性骨折及重度脓毒症患者的MPO正常中性粒细胞占比分别为80%、75%与2%。此外，在32/33例STEMI患者与9/21例NSTEMI患者中，分别有20%与12%的中性粒细胞在症状发作后的最初4小时内出现MPO完全耗竭，这一特征在其余所有组别患者中均未观察到。MPO耗竭与血小板活化密切相关，具体表现为P选择素（P-selectin）表达上调、白细胞β2整合素（β2-integrins）活化与反式激活，以及血小板-中性粒细胞与单核细胞聚集物（platelet neutrophil and monocyte aggregates）的形成。向小鼠体内注射活化的血小板后，约50%的中性粒细胞出现了短暂的、依赖P选择素的MPO完全耗竭。
结论：与其他全身性炎症综合征类似，急性冠状动脉综合征（ACS）以显著的中性粒细胞活化为特征。在急性心肌梗死的极早期，仅存在一个亚群的中性粒细胞被大规模活化，这一过程可能通过血小板-P选择素相互作用介导。这种阵发性活化可能参与了闭塞性血栓（occlusive thrombosis）的形成。