Kindberg Kristine Mørk, Broch Kaspar, Andersen Geir Øystein, Anstensrud Anne Kristine, Åkra Sissel, Woxholt Sindre, Tøllefsen Ingvild Maria, Ueland Thor, Amundsen Brage Høyem, Kløw Nils-Einar, Halvorsen Bente, Dahl Tuva B, Huse Camilla, Murphy Sarah Louise, Damås Jan Kristian, Opdahl Anders, Wiseth Rune, Gullestad Lars, Aukrust Pål, Santos-Gallego Carlos, Seljeflot Ingebjørg, Stokke Mathis Korseberg, Helseth Ragnhild
Department of Cardiology, Center for Clinical Heart Research, Oslo University Hospital Ullevaal, Oslo, Norway.
Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
JACC Adv. 2024 Aug 15;3(9):101193. doi: 10.1016/j.jacadv.2024.101193. eCollection 2024 Sep.
Interleukin-6-receptor inhibition with tocilizumab improves myocardial salvage in patients with ST-segment elevation myocardial infarction (STEMI). Reduced levels of neutrophil extracellular traps (NETs), which consist of nuclear material studded with proteins released upon neutrophil activation, might contribute to this effect.
The purpose of this study was to evaluate the effect of tocilizumab on NETs and investigate the association between NETs and myocardial injury in patients with STEMI.
In the ASSAIL-MI study, 199 patients with STEMI were randomized to tocilizumab or placebo during percutaneous coronary intervention. In this substudy, we analyzed blood levels of the NET markers double-stranded deoxyribonucleic acid (dsDNA), myeloperoxidase-DNA, and citrullinated histone 3 (H3Cit) at admission and after 24 hours and 3 to 7 days. In a subgroup of patients, we assessed regulation of transcripts related to the formation of NETs. We also investigated associations between NET markers and the myocardial salvage index (MSI).
All NET markers were lower in the tocilizumab group than in the placebo group at 3 to 7 days (all < 0.04). Several NET-related pathways were downregulated in the tocilizumab group. The beneficial effect of tocilizumab on the MSI seemed to be partly dependent on reduction of NETs (structural equation modeling: 0.05, = 0.001 [dsDNA] and 0.02, = 0.055 [H3Cit]). Patients with NETs in the 3 lowest quartiles had higher MSI than patients in quartile 4 (10.9 [95% CI: 4.0-15.0] [dsDNA] and 8.9 [95% CI: 2.0-15.9] [H3Cit], both = 0.01).
NETs were reduced by tocilizumab and associated with myocardial injury. The effect of tocilizumab on MSI might be mediated through reduced NETs. (ASSessing the Effect of Anti-IL-6 Treatment in Myocardial Infarction: The ASSAIL-MI Trial [ASSAIL-MI]; NCT03004703).
使用托珠单抗抑制白细胞介素-6受体可改善ST段抬高型心肌梗死（STEMI）患者的心肌挽救。中性粒细胞胞外陷阱（NETs）水平降低可能有助于此效应，NETs由中性粒细胞激活时释放的、布满蛋白质的核物质组成。
本研究旨在评估托珠单抗对NETs的影响，并研究STEMI患者中NETs与心肌损伤之间的关联。
在ASSAIL-MI研究中，199例STEMI患者在经皮冠状动脉介入治疗期间被随机分配至托珠单抗组或安慰剂组。在本亚组研究中，我们分析了入院时、24小时后以及3至7天时NET标志物双链脱氧核糖核酸（dsDNA）、髓过氧化物酶-DNA和瓜氨酸化组蛋白3（H3Cit）的血液水平。在一组患者亚组中，我们评估了与NET形成相关的转录物的调控情况。我们还研究了NET标志物与心肌挽救指数（MSI）之间的关联。
在3至7天时，托珠单抗组的所有NET标志物均低于安慰剂组（均P<0.04）。托珠单抗组中几个与NET相关的途径被下调。托珠单抗对MSI的有益作用似乎部分取决于NETs的减少（结构方程模型分析：P=0.05，β=0.001[dsDNA]；P=0.02，β=0.0'55[H3Cit]）。NETs处于最低四分位数的患者的MSI高于处于第四四分位数的患者（dsDNA为10.9[95%CI：4.0-15.0]，H3Cit为8.9[95%CI：2.0-15.9]，均P=0.01）。
托珠单抗可降低NETs水平，且NETs与心肌损伤相关。托珠单抗对MSI的作用可能是通过降低NETs介导的。（评估抗白细胞介素-6治疗在心肌梗死中的作用：ASSAIL-MI试验[ASSAIL-MI]；NCT编号03004703）
