Association between Citrullinated Histone H3 and White Matter Lesions Burden in Patients with Ischemic Stroke

Abstract

Introduction: Neutrophil extracellular traps play a role in the pathophysiology of stroke and are associated with severity and mortality. We aimed to investigate whether the citrullinated histone H3 (CitH3), a biomarker for neutrophil extracellular traps formation, is associated with the white matter lesion (WML) burden in ischemic stroke patients.

Methods: Between September 2021 and April 2022, 322 patients were enrolled in this prospective observational cohort study. Serum CitH3 levels were measured after admission using an enzyme-linked immunosorbent assay. WMLs severity was graded according to the Fazekas scale and conceptually defined as mild (total Fazekas score 0-2) and severe (total Fazekas score 3-6). We used multivariable regression models to determine the relationship between CitH3 concentrations and the severity of WMLs burden.

Results: One-hundred and forty-eight (46.0%) patients were diagnosed with severe WMLs burden after admission. Increased CitH3 levels (first quartile vs. fourth quartile of H3Cit, odds ratio, 3.311, 95% confidence interval, 1.336-8.027; p = 0.011) were independently associated with a greater WML burden in the fully adjusted multivariable model. Similar results were found when the H3Cit was analyzed as a continuous variable. Furthermore, the multiple-adjusted spline regression model showed a linear association between H3Cit levels and severe WMLs (P = 0.001 for linearity).

Conclusions: In the present study, increased CitH3 levels were positively associated with extensive WMLs in ischemic stroke patients, indicating a role of neutrophil extracellular traps formation in the pathogenesis of WMLs.

Keywords: CitH3; ischemic stroke; neutrophil extracellular traps; white matter lesions.

Figure 1

Association of serum citrullinated histone H3 (CitH3) with risk of severe WMLs in ischemic stroke patients. Odds ratios and 95% confidence intervals derived from restricted cubic spline regression, with knots placed at the 5th, 50th, and 95th percentiles of the distribution of CitH3 levels. The reference point for serum CitH3 is the midpoint (32.7 ng/mL) of the reference group from categorical analysis. Odds ratios were adjusted for age, sex, and variables with a p value < 0.1 in the univariate analysis.