Neutrophil extracellular trap levels in the prediction of adverse outcomes for hyperglycemia ischemic stroke patients

Hyperglycemia (HG) affects nearly 50% of acute ischemic stroke (AIS) patients, regardless of diabetes mellitus (DM) status, and is associated with an adverse prognosis. Conventional HG treatments have not significantly improved prognosis, suggesting an unclear underlying mechanism. This study explores novel biomarkers contributing to adverse outcomes in post-stroke HG. This two-stage retrospective study first screened seven AIS patients with HG and ten without HG using RNA sequencing to identify biomarkers linked to adverse post-stroke outcomes. In the second stage, candidate biomarkers were validated via ELISA in a cohort of 900 AIS patients, including 448 non-hyperglycemic and 452 hyperglycemic patients. They were further stratified into four groups based on HG and DM status in order to minimize confounding effects from DM. Neutrophil extracellular traps (NETs) emerged as a key biomarker associated with poor prognosis in post-stroke HG. Circulating citrullinated histone H3 (CitH3) levels, a specific marker of NET formation, were highest in HG/non-DM patients, with each standard deviation increase linked to a 3.80-fold rise in adverse outcomes at one month (95% CI: 1.37–10.50). At 12 months, the HG/non-DM group showed an area under the curve (AUC) of 0.71 (95% CI: 0.55–0.86), indicating moderate discriminatory ability. Integrating CitH3 levels with conventional risk factors enhanced prognostic accuracy, with combined model AUCs consistently exceeding 80% across three time points. Elevated CitH3 levels are associated with unfavorable functional outcomes in AIS patients, particularly those with HG without DM. These findings suggest a potential association between NET-related inflammatory pathways and the relationship between HG and stroke recovery.