Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Oslo, Norway
Clinic of Cardiology, St. Olavs Hospital, Trondheim, Norway.
Open Heart. 2021 May;8(1). doi: 10.1136/openhrt-2020-001492.
Beyond reducing inflammation and troponin T (TnT) release, the interleukin-6 receptor antagonist tocilizumab reduces neutrophil counts in patients with non-ST segment elevation myocardial infarction (NSTEMI). It is unclear if this is related to formation of neutrophil extracellular traps (NETs), carrying inflammatory and thrombotic properties.
In a placebo-controlled trial, 117 patients with NSTEMI were randomised to a single dose of tocilizumab (n=58) or placebo (n=59) before coronary angiography. The NETs related markers double-stranded DNA (dsDNA), myloperoxidase-DNA (MPO-DNA) and citrullinated histone 3 (H3Cit) were measured at five consecutive time points during hospitalisation (days 1-3).
Our major findings were: (1) H3Cit levels were significantly higher in the tocilizumab compared with the placebo group at all time points (all p<0.05), and H3Cit area under the curve (AUC) was 2.3 fold higher in the tocilizumab compared with placebo group (p<0.0001). (2) MPO-DNA and dsDNA did not differ between the groups. (3) In both treatment arms, dsDNA AUC was associated with TnT AUC. (4) Neutrophil count AUC correlated inversely to H3Cit AUC (p=0.015) in the total population.
In patients with NSTEMI, treatment with tocilizumab is associated with increased circulating H3Cit levels, suggesting that tocilizumab enhances NETosis. Further studies should clarify whether NETosis is a relevant side effect of tocilizumab. Regardless of tocilizumab, dsDNA associated with TnT release, indicating a link between extracellular nuclear material and myocardial injury.
除了降低炎症和肌钙蛋白 T（TnT）释放外，白细胞介素-6 受体拮抗剂托珠单抗还可降低非 ST 段抬高型心肌梗死（NSTEMI）患者的中性粒细胞计数。目前尚不清楚这是否与中性粒细胞胞外诱捕网（NETs）的形成有关，后者具有炎症和血栓形成的特性。
在一项安慰剂对照试验中，117 例 NSTEMI 患者在冠状动脉造影前随机分为托珠单抗（n=58）或安慰剂（n=59）单次剂量组。在住院期间（第 1-3 天）的连续 5 个时间点测量与 NETs 相关的标志物双链 DNA（dsDNA）、髓过氧化物酶-DNA（MPO-DNA）和瓜氨酸化组蛋白 3（H3Cit）。
我们的主要发现是：（1）与安慰剂组相比，托珠单抗组在所有时间点的 H3Cit 水平均显著升高（所有 p<0.05），且托珠单抗组的 H3Cit 曲线下面积（AUC）比安慰剂组高 2.3 倍（p<0.0001）。（2）两组之间 MPO-DNA 和 dsDNA 无差异。（3）在两个治疗组中，dsDNA AUC 与 TnT AUC 相关。（4）在总人群中，中性粒细胞计数 AUC 与 H3Cit AUC 呈负相关（p=0.015）。
在 NSTEMI 患者中，托珠单抗治疗与循环 H3Cit 水平升高相关，表明托珠单抗增强了 NETosis。进一步的研究应阐明 NETosis 是否是托珠单抗的一个相关副作用。无论是否使用托珠单抗，dsDNA 与 TnT 释放相关，表明细胞外核物质与心肌损伤之间存在联系。
