Background Neutrophil extracellular traps formation (NETosis) is currently considered as an important mediator in atherosclerosis and atherothrombosis. However, the impact of high-dose statin treatment, as potent cholesterol-lowering agents with pleiotropic effects, on NETosis in coronary artery disease (CAD) has been poorly described. Purpose We sought to assess whether in CAD patients the recommended statin treatment intensification is associated with changes in NETs-related markers and if such changes can alter fibrin clot properties. Methods 130 patients with advanced CAD, who did not achieve the target low-density lipoprotein cholesterol (LDL-C) were included. Before and at least 6 months after initiation of high-dose statin therapy (rosuvastatin 40 mg/d or atorvastatin 80 mg/d) citrullinated histone H3 (H3cit), myeloperoxidase (MPO) and neutrophil elastase (NE) as markers associated with NETosis were assessed in relation to C-reactive protein (CRP), thrombin generation, plasma clot permeability (Ks), clot lysis time (CLT), and fibrinolysis proteins. Results At baseline, NETosis did not differ depending on gender and cardiovascular risk factors but H3cit correlated with MPO (R=0.543, P<0.001) and CRP (R=0.540, P<0.001). All NETosis markers were inversely correlated with Ks. Median LDL-C reduction by 25% (P<0.001) on high-dose statin treatment was independent from H3cit reduction by 30.4%, MPO by 28.1%, and NE by 25.5% (in all P<0.001, Figure 1). The ΔH3cit and ΔMPO, but not ΔNE were associated with ΔCRP (R=0.855, P<0.001; R=0.250, P=0.004, respectively), Δthrombin activatable fibrinolysis inhibitor (TAFI) (R=0.385, P<0.001; R=0.245, P=0.005), and inversely with ΔKs (R=-0.315, P<0.001; R=-0.395, P=0.001). In multivariable analysis the H3cit decrease was independently associated with ΔCRP (β=0.771, P<0.001), ΔTAFI (β=0.125, P=0.013) and Δfibrinogen (β=0.106, P=0.034) but not with ΔLDL-C. Conclusions As has been shown for the first time high-dose statin treatment reduces levels of NETs-related markers, regardless of lipid-lowering effect in CAD patients.

中文翻译：

---

大剂量他汀类药物治疗可减少冠状动脉疾病患者的中性粒细胞细胞外陷阱形成


背景 中性粒细胞胞外陷阱形成 （NETosis） 目前被认为是动脉粥样硬化和动脉粥样硬化血栓形成的重要介质。然而，大剂量他汀类药物治疗作为具有多效性作用的强效降胆固醇药物，对冠状动脉疾病 （CAD） NETosis 的影响描述甚少。目的： 我们试图评估在 CAD 患者中，推荐的他汀类药物治疗强化是否与 NETs 相关标志物的变化相关，以及这种变化是否会改变纤维蛋白凝块特性。方法 纳入 130 例未达到目标低密度脂蛋白胆固醇 （LDL-C） 的晚期 CAD 患者。在大剂量他汀类药物治疗（瑞舒伐他汀 40 mg/d 或阿托伐他汀 80 mg/d）开始之前和至少 6 个月，瓜氨酸组蛋白 H3 （H3cit）、髓过氧化物酶 （MPO） 和中性粒细胞弹性蛋白酶 （NE） 作为与 NETosis 相关的标志物，评估与 C 反应蛋白 （CRP） 、凝血酶生成、血浆凝块通透性 （Ks）、凝块裂解时间 （CLT） 和纤维蛋白溶解蛋白的关系。结果 基线时，NETosis 不因性别和心血管危险因素而异，但 H3cit 与 MPO （R=0.543，P<0.001） 和 CRP （R=0.540，P<0.001） 相关。所有 NETosis 标志物与 Ks 呈负相关。高剂量他汀类药物治疗的中位 LDL-C 降低 25% （P<0.001） 与 H3cit 降低 30.4% 、MPO 降低 28.1% 和 NE 降低 25.5% 无关 （在所有 P<0.001 中，图 1）。ΔH3cit 和 ΔMPO 与 ΔCRP 相关，而 ΔNE 与 ΔCRP 无关 （R=0.855，P<0.001;R=0.250，P=0.004）、δ凝血酶激活纤维蛋白溶解抑制剂 （TAFI） （R=0.385，P<0.001;R=0.245，P=0.005），与 ΔK 成反比 （R=-0.315，P<0.001;R=-0.395，P=0.001）。 在多变量分析中，H3cit 降低与 ΔCRP （β=0.771，P<0.001）、ΔTAFI （β=0.125，P=0.013） 和 Δ纤维蛋白原 （β=0.106，P=0.034） 独立相关，但与 ΔLDL-C 无关。结论 正如首次显示的那样，无论 CAD 患者的降脂作用如何，大剂量他汀类药物治疗都能降低 NETs 相关标志物的水平。