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Association of Ferroptosis with Severity and Outcomes in Acute Ischemic Stroke Patients Undergoing Endovascular Thrombectomy: A Case-control Study

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Abstract

Ferroptosis, an iron-dependent form of cell death, is characterized by intracellular accumulation of iron and reactive oxygen species-induced lipid peroxidation. Animal experiments have shown the important roles of ferroptosis in ischemic stroke, but the evidence in human stroke is insufficient. This prospective study evaluated the associations between plasma ferroptosis biomarkers at hyperacute stage and long-term outcomes in patients with acute ischemic stroke undergoing endovascular thrombectomy (EVT). The plasma samples were collected immediately before and after EVT (T1 and T2) and at 24 h (T3) for the 126 stroke patients and once for the 50 stroke-free control subjects. Compared with controls, stroke patients had higher 4-hydroxynonenal (4-HNE) levels at T1 and T2 while lower homocysteine and soluble transferrin receptor (sTfR) levels at T3. In stroke patients, higher National Institutes of Health Stroke Scale scores at admission were correlated with higher 4-HNE and lower sTfR levels. Lower Alberta Stroke Program Early CT (ASPECT) scores and larger infarct core volumes on CT perfusion before EVT were correlated with higher 4-HNE and homocysteine levels. After adjusting for significant parameters, homocysteine levels at T2 were significantly associated with poor functional outcome and mortality at 3 months. In the receiver operating characteristic (ROC) models, adding homocysteine levels at T2 and hemoglobin levels to the reference model for predicting poor functional outcome significantly increased the area under the ROC curve. In summary, this study provides evidence that ferroptosis is associated with stroke severity and outcomes in patients with acute ischemic stroke undergoing EVT.

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Data Availability

The datasets generated and analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We are thankful for the support of Yu-Chiao Chi and the 3rd Core Facility of the National Taiwan University Hospital.

Funding

This work was supported by National Taiwan University Hospital (Grant numbers [111-S0222]).

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Authors and Affiliations

  1. Department of Neurology, National Taiwan University Hospital, No. 7, Zhongshan S. Rd., Zhongzheng Dist, Taipei, 100225, Taiwan

    Shin-Joe Yeh, Chih-Hao Chen, Li-Kai Tsai, Sung-Chun Tang & Jiann-Shing Jeng

  2. Department of Medical Imaging, National Taiwan University Hospital, No. 7, Zhongshan S. Rd., Zhongzheng Dist, Taipei, 100225, Taiwan

    Yen-Heng Lin & Chung-Wei Lee

  3. Department of Neurology, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan

    Li-Kai Tsai

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Contributions

SJY and SCT analyzed and interpreted the patient data. YHL and CWL performed EVT procedures and collected the blood samples of patients. SJY was a major contributor in writing the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Chung-Wei Lee or Sung-Chun Tang.

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The authors have no relevant financial or non-financial interests to disclose.

Ethics Approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Research Ethics Committee of the National Taiwan University Hospital (Reference number: 201807029RINA).

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Informed consent was obtained from all individual participants included in the study.

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Yeh, SJ., Chen, CH., Lin, YH. et al. Association of Ferroptosis with Severity and Outcomes in Acute Ischemic Stroke Patients Undergoing Endovascular Thrombectomy: A Case-control Study. Mol Neurobiol 60, 5902–5914 (2023). https://doi.org/10.1007/s12035-023-03448-y

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