High-dose atorvastatin and rosuvastatin reduce neutrophil extracellular traps-related proteins in coronary artery disease: association with prothrombotic state.

Abstract

Neutrophil extracellular traps (NETs) formation is involved in atherothrombosis. We sought to investigate whether statins affect NETosis in coronary artery disease (CAD) and if such changes show associations with statin-induced additional effects. We studied 130 patients with advanced CAD before and at least 6 months after initiation of high-dose statin therapy with rosuvastatin 40 mg/d or atorvastatin 80 mg/d. Circulating citrullinated histone H3 (H3cit), myeloperoxidase (MPO), and neutrophil elastase (NE) were assessed as proteins associated with NETosis along with thrombin generation, plasma clot permeability (Ks), clot lysis time (CLT), and fibrinolysis inhibitors. Following statin therapy intensification, we observed reductions in H3cit (-30.4%), MPO (-28.1%), and NE (-25.5%, all P <0.001), all not associated with low-density lipoprotein cholesterol (LDL-C) lowering (-25%). However, H3cit was lower in 50 patients (38.5%) who achieved the target LDL-C <1.8 mmol/L (-16.5%, P = 0.004) and 19 (14.6%) with LDL-C <1.4 mmol/L (-25.5%, P = 0.001) compared with the remainder. Reductions in H3cit and MPO were associated with a 42.9% decrease in C-reactive protein (CRP) on high-dose statins (R = 0.855, P <0.001; R = 0.250, P = 0.004, respectively), along with increases in Ks and reduction in thrombin activatable fibrinolysis inhibitor (TAFI) activity, but not with CLT or thrombin generation (all |R| 0.24-0.4, P <0.01). On multivariable analysis, changes in CRP (β = 0.771, P <0.001), TAFI activity (β = 0.125, P = 0.013), and fibrinogen (β = 0.106, P = 0.034) were independently associated with decrease in H3cit. We showed for the first time that high-dose statins can reduce NETs-related proteins in association with anti-inflammatory and antithrombotic actions in CAD patients.