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.

This study was supported by the National Science and Technology Council (NSTC 112-2314-B-400-022-MY3), National Health Research Institutes (NHRI-EX111-11132HT), and Taipei Medical University-Shuang Ho Hospital Project (112TMU-SHH-21). Han-Chun Lin, Yi-Chen Hsieh, Hung-Yi Chiou and Li-Kai Huang contributed equally to this work. Institute of Population Health Sciences, National Health Research Institutes, Miaoli County, Taiwan Han-Chun Lin, Yu-Ling Li & Hung-Yi Chiou Ph.D.

Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan Department of Neurology, Taipei Medical University-Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan Li-Kai Huang, Lung Chan, Chaur-Jong Hu & Li-Ming Lien Division of Neurology, Cardinal Tien Hospital and Fu Jen Catholic University, New Taipei City, Taiwan Taipei Neuroscience Institute, Taipei Medical University, Taipei, Taiwan Lung Chan, Chaur-Jong Hu & Yi-Chen Hsieh Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan Department of Neurology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan Department of Neurology, Chi-Mei Medical Center, Tainan, Taiwan School of Public Health, College of Public Health, Taipei Medical University, Taipei, Taiwan Correspondence to Yi-Chen Hsieh or Hung-Yi Chiou. The authors declare no competing interests. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.