Kluge Karsten E, Langseth Miriam S, Opstad Trine B, Pettersen Alf Å, Arnesen Harald, Tønnessen Theis, Seljeflot Ingebjørg, Helseth Ragnhild
Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Norway.
University of Oslo, Norway.
Mediators Inflamm. 2020 Mar 26;2020:5080743. doi: 10.1155/2020/5080743. eCollection 2020.
Complement activation and neutrophil extracellular traps (NETs) have both been suggested to drive atherosclerotic plaque progression. Although experimental studies suggest interplay between these two innate immunity components, the relevance in patients with coronary artery disease (CAD) is unclear. The aim of this study was to assess associations between complement activation and NETs in patients with stable CAD and examine the role of complement activation on clinical outcome. Blood samples from a cohort of patients with angiographically verified stable CAD ( = 1001) were analyzed by ELISA for the terminal complement complex (TCC) and by relative quantification for gene expression of the C5a receptor 1 (C5aR1) as markers of complement activation. As markers of NETs, dsDNA was analyzed by fluorescent nucleic acid stain and myeloperoxidase-DNA (MPO-DNA) by ELISA. Clinical outcome was defined as unstable angina, nonhemorrhagic stroke, acute myocardial infarction (MI), or death ( = 106, whereof 36 MI). Levels of TCC and C5aR1 were not significantly correlated to dsDNA (TCC: = -0.045, = 0.153; C5aR1: = -0.060, = 0.434) or MPO-DNA (TCC: = 0.026, = 0.414; C5aR1: = 0.123, = 0.107). When dividing TCC and C5aR1 levels into quartiles (Q), levels of MPO-DNA differed significantly across quartiles (TCC: = 0.008, C5aR1: 0.049), while dsDNA did not (TCC: = 0.181, C5aR1: = 0.771). Patients with TCC levels in Q4 had significantly higher levels of MPO-DNA than Q1-3 ( = 0.019), and C5aR1 levels in Q3-4 had significantly higher levels of MPO-DNA than Q1-2 ( = 0.046). TCC levels did not differ between patients experiencing a clinical endpoint or not, but high levels were associated with increased risk of acute MI (OR. 1.97, 95% CI: 0.99-3.90, = 0.053) during two-year follow up, also when adjusted for relevant covariates. In conclusion, TCC and C5aR1 were moderately associated with the NET marker MPO-DNA, and TCC levels were related to the risk of future MI in this cohort of patients with stable CAD.
补体激活和中性粒细胞胞外诱捕网（NETs）均被认为会推动动脉粥样硬化斑块进展。尽管实验研究表明这两种固有免疫成分之间存在相互作用，但在冠心病（CAD）患者中的相关性尚不清楚。本研究的目的是评估稳定型CAD患者中补体激活与NETs之间的关联，并研究补体激活对临床结局的作用。通过ELISA检测终末补体复合物（TCC），并通过相对定量检测C5a受体1（C5aR1）的基因表达，以此作为补体激活的标志物，对一组经血管造影证实为稳定型CAD的患者（n = 1001）的血样进行分析。作为NETs的标志物，通过荧光核酸染色分析双链DNA（dsDNA），并通过ELISA分析髓过氧化物酶-DNA（MPO-DNA）。临床结局定义为不稳定型心绞痛、非出血性中风、急性心肌梗死（MI）或死亡（n = 106，其中36例为MI）。TCC和C5aR1水平与dsDNA（TCC：r = -0.045，P = 0.153；C5aR1：r = -0.060，P = 0.434）或MPO-DNA（TCC：r = 0.026，P = 0.414；C5aR1：r = 0.123，P = 0.107）均无显著相关性。当将TCC和C5aR1水平分为四分位数（Q）时，MPO-DNA水平在四分位数间存在显著差异（TCC：P = 0.008，C5aR1：P = 0.049），而dsDNA则无差异（TCC：P = 0.181，C5aR1：P = 0.771）。TCC水平处于Q4的患者MPO-DNA水平显著高于Q1-3（P = 0.019），C5aR1水平处于Q3-4的患者MPO-DNA水平显著高于Q1-2（P = 0.046）。经历临床终点的患者与未经历临床终点的患者TCC水平无差异，但在两年随访期间，高水平与急性MI风险增加相关（OR = 1.97，95%CI：0.99-3.90，P = 0.053），在调整相关协变量后亦是如此。总之，TCC和C5aR1与NET标志物MPO-DNA中度相关，在这组稳定型CAD患者中，TCC水平与未来发生MI的风险相关。
