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Early Systemic Glycolytic Shift After Aneurysmal Subarachnoid Hemorrhage is Associated with Functional Outcomes

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Abstract

Background

Aneurysmal subarachnoid hemorrhage (aSAH) leads to a robust systemic inflammatory response. We hypothesized that an early systemic glycolytic shift occurs after aSAH, resulting in a unique metabolic signature and affecting systemic inflammation.

Methods

Control patients and patients with aSAH were analyzed. Samples from patients with aSAH were collected within 24 h of aneurysmal rupture. Mass spectrometry–based metabolomics was performed to assess relative abundance of 16 metabolites involved in the tricarboxylic acid cycle, glycolysis, and pentose phosphate pathway. Principal component analysis was used to segregate control patients from patients with aSAH. Dendrograms were developed to depict correlations between metabolites and cytokines. Analytic models predicting functional outcomes were developed, and receiver operating curves were compared.

Results

A total of 122 patients with aSAH and 38 control patients were included. Patients with aSAH had higher levels of glycolytic metabolites (3-phosphoglycerate/2-phosphoglycerate, lactate) but lower levels of oxidative metabolites (succinate, malate, fumarate, and oxalate). Patients with higher clinical severity (Hunt-Hess Scale score ≥ 4) had higher levels of glyceraldehyde 3-phosphate and citrate but lower levels of α-ketoglutarate and glutamine. Principal component analysis readily segregated control patients from patients with aSAH. Correlation analysis revealed distinct clusters in control patients that were not observed in patients with aSAH. Higher levels of fumarate were associated with good functional outcomes at discharge (odds ratio [OR] 1.76, 95% confidence interval [CI] 1.15–2.82) in multivariable models, whereas higher levels of citrate were associated with poor functional outcomes at discharge (OR 0.36, 95% CI 0.16–0.73) and at 3 months (OR 0.35, 95% CI 0.14–0.81). No associations were found with delayed cerebral ischemia. Levels of α-ketoglutarate and glutamine correlated with lower levels of interleukin-8, whereas fumarate was associated with lower levels of tumor necrosis factor alpha.

Conclusions

Aneurysmal subarachnoid hemorrhage results in a unique pattern of plasma metabolites, indicating a shift toward glycolysis. Higher levels of fumarate and lower levels of citrate were associated with better functional outcomes. These metabolites may represent targets to improve metabolism after aSAH.

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Acknowledgements

The authors acknowledge all patients who participated in this study.

Funding

This study was supported by intramural funding awarded to AMG by University of Texas Health Neurosciences. Funding for metabolomics experiments were partially supported by a grant awarded to NP for the operation of a metabolomics shared resource (National Cancer Institute, 5P30CA125123).

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Authors and Affiliations

  1. Division of Neurocritical Care, Department of Neurosurgery, McGovern School of Medicine, University of Texas Health Science Center, Houston, TX, USA

    Aaron M. Gusdon, Atzhiry S. Paz, Hua Chen, Xuefang Ren, Huimahn A. Choi & Jude P. J. Savarraj

  2. Department of Neurobiology and Anatomy, McGovern School of Medicine, University of Texas Health Science Center, Houston, TX, USA

    Aaron M. Gusdon & Pramod Dash

  3. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    Chenlian Fu, Vasanta Putluri, Mohammed Khurshidul Hassan, Cristian Coarfa & Nagireddy Putluri

  4. Department of Biology, Harvey Mudd College, Claremont, CA, USA

    Chenlian Fu

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  1. Aaron M. Gusdon
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Contributions

AMG designed the study, analyzed data, and wrote the article. CF analyzed data and edited the article. VP acquitted and analyzed data and edited the article. ASP acquired data. HC acquired data. XR analyzed data and revised the article. MKH acquired data and edited the article. PD contributed to experimental design and revised the article. CC contributed to experimental design and analyzed data. NP contributed to experimental design, acquired data, and analyzed data. HAC contributed to experimental design and edited the article. JPS helped to design the study, analyzed data, and wrote and revised the article. The final manuscript was approved by all authors.

Corresponding author

Correspondence to Aaron M. Gusdon.

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Conflicts of interest

Dr. Gusdon reports an intramural grant from University of Texas Health Neurosciences during the conduct of the study. Dr. Coarfa reports grants from the National Cancer Institute (NCI), National Institute of Environmental Health Sciences (NIEHS), National Institute on Minority Health and Health Disparities (NIMHD), and Cancer Prevention and Research Institute of Texas (CPRIT) during the conduct of the study. Dr. N. Putluri reports grants from the NCI during the conduct of the study. The remaining authors have no conflicts to disclose.

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This manuscript adheres to all ethical guidelines and was approved by the University of Texas McGovern School of Medicine Institutional Review Board (HSC-MS-12–0637).

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Gusdon, A.M., Fu, C., Putluri, V. et al. Early Systemic Glycolytic Shift After Aneurysmal Subarachnoid Hemorrhage is Associated with Functional Outcomes. Neurocrit Care 37, 724–734 (2022). https://doi.org/10.1007/s12028-022-01546-8

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