Association of Neutrophil Serine Proteinases Levels with the Outcomes of Acute Ischemic Stroke: A Prospective Cohort Study

Abstract Background: Neutrophil serine proteinases (NSPs), released by activated neutrophils, are key proteins involved in the pathophysiologic processes of stroke. This study aimed to analyze three NSPs (neutrophil elastase, cathepsin G, and proteinase 3) in relation to acute ischemic stroke (AIS) outcomes and in relation to the outcomes of patients treated with intravenous recombinant tissue plasminogen activator (IV-rtPA).Methods: Among 736 patients prospectively recruited at the stroke center from 2018 to 2019, 342 patients diagnosed with confirmed AIS were included. Plasma neutrophil elastase (NE), cathepsin G (CTSG), and proteinase 3 (PR3) concentrations were measured on admission. Endpoints included symptomatic intracerebral hemorrhage (sICH), mortality, and unfavorable outcome (modified Rankin Scale score > 2) at 3 months. In the subgroup of patients received IV-rtPA, 24hΔNIHSS (NIHSSbaseline - NIHSS24hours) and 7dΔNIHSS (NIHSSbaseline – NIHSS7days) were also included as the short-term endpoints. Univariate and multivariate logistic regression analyses were performed to evaluate the association between NSPs levels and AIS outcomes.Results: Higher NE and PR3 plasma levels were associated with the 3-month mortality and 3-month unfavorable outcome. Higher NE plasma levels were also associated with the risk of sICH after AIS. After adjusting for potential confounders, plasma NE level > 229.56 ng/mL (odds ratio [OR] = 4.503 [2.427-8.355]) and PR3 > 388.77 ng/ml (OR = 2.798 [1.551-5.047]) independently predicted the 3-month unfavorable outcome. Regarding rtPA treatment, patients with NE plasma concentration > 177.22 ng/ml were 6 times more likely to suffer unfavorable outcomes after rtPA treatment (OR = 6.318 [1.861-21.450]). The addition of NE and PR3 to clinical predictors of unfavorable functional outcome after AIS and the outcome after rtPA treatment improved accuracy (lifted AUC from 82.6% to 86.7%, and from 80.6% to 87.2%, respectively), and discrimination as well as reclassification (integrated discrimination improvement = 9.5% and 13.7%, continuous net reclassification improvement = 93.1% and 89.7%, respectively). Conclusions: Plasma NE and PR3 are novel and independent predictors of 3-month functional outcomes after AIS. Plasma NE also possesses predictive value to identify patients with unfavorable outcomes after rtPA treatment. NE is probably an important mediator of the effects of neutrophils on stroke outcomes, which worth further investigation.