Neutrophil-activating peptide 2 as a novel modulator of fibrin clot properties in patients with atrial fibrillation

Abstract

Abstract Introduction: Neutrophil-activating peptide 2 (NAP-2, CXCL7), a platelet-derived neutrophil chemoattractant, is involved in inflammation. We investigated associations between NAP-2 levels, neutrophil extracellular traps (NETs) formation, and fibrin clot properties in atrial fibrillation (AF). Materials and Methods: We recruited 237 consecutive patients with AF (mean age, 68±11 years; median CHA2DS2VASc score of 3 [2-4]) and 30 apparently healthy controls. Plasma NAP-2 concentrations were measured, along with plasma fibrin clot permeability (Ks) and clot lysis time (CLT), thrombin generation, citrullinated histone H3 (citH3), as a marker of NETs formation, and 3-nitrotyrosine reflecting oxidative stress. Results: NAP-2 levels were 89% higher in AF patients than in controls (626 [448-796] vs. 331 [226-430] ng/ml; p<0.0001). NAP-2 levels were not associated with demographics, CHA2DS2-VASc score, or the AF manifestation. Patients with NAP-2 in the top quartile (>796 ng/ml) were characterized by higher neutrophil count (+31.7%), fibrinogen (+20.8%), citH3 (+86%), and 3-nitrotyrosine (+111%) levels, along with 20.2% reduced Ks and 8.4% prolonged CLT as compared to the remaining subjects (all p<0.05). NAP-2 levels were positively associated with fibrinogen in AF patients (r=0.41, p=0.0006) and controls (r=0.65, p<0.01), along with citH3 (r=0.36, p<0.0001) and 3-nitrotyrosine (r=0.51, p<0.0001) in the former group. After adjustment for fibrinogen, higher citH3 (per 1 ng/ml β=-0.046, 95% CI -0.029; -0.064) and NAP-2 (per 100 ng/ml β=-0.21, 95% CI -0.14; -0.28) levels were independently associated with reduced Ks. Conclusions: Elevated NAP-2, associated with increased oxidative stress, has been identified as a novel modulator of prothrombotic plasma fibrin clot properties in patients with AF.