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Preoperative Plasma Metabolites Associated With Intracranial In-Stent Restenosis: A Matched Case-Control
Xiaoxin He1, Xuebing Feng1, Muyuan Li1
1Departments of Neurosurgery and Interventional Neuroradiology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China; China International Neuroscience Institute (China-INI) and National Center for Neurological Disorders, Beijing 100053, China.
Background:
Intracranial in-stent restenosis (ISR) remains an important complication after intracranial stenting, and validated preoperative biomarkers for subsequent ISR are lacking. In this exploratory study, we aimed to characterize preoperative plasma metabolic profiles associated with subsequent intracranial ISR and to assess their discriminatory performance in the internal validation subset.
Methods:
We conducted a single-center, age- and sex-frequency-matched case-control study of 96 patients with ISR and 96 non-ISR controls selected from 285 eligible patients who underwent intracranial stenting. Untargeted LC-MS metabolomics was performed in a discovery subset (30 ISR and 30 non-ISR), followed by targeted UPLC-MS/MS quantification in the remaining non-overlapping subset (66 ISR and 66 non-ISR). All plasma samples were obtained before stent implantation.
Results:
Untargeted profiling identified preoperative metabolic differences spanning amino acid/peptide, lipid/membrane, bile acid, and nucleotide/redox domains, with amino acid-related differences prominently represented. Targeted analysis showed lower citrulline, phenylalanine, glycine, isoleucine, glutamine, and valine and higher ornithine and cystine in ISR. Citrulline showed the strongest single-metabolite discrimination (AUC 0.860, 95% CI 0.794-0.926), whereas a citrulline-phenylalanine-ornithine panel achieved an AUC of 0.911 (95% CI 0.865-0.958) and a cross-validated AUC of 0.895. Several metabolites remained associated with ISR after adjustment for clinical covariates.
Conclusions:
Preoperative plasma metabolic profiles differed between patients who did and did not subsequently develop intracranial ISR. In the targeted stage, lower citrulline together with higher ornithine was the most prominent finding. These associations are hypothesis-generating, and the identified metabolites should be considered candidate biomarkers requiring independent prospective validation before clinical use.