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Sex differences in metabolic adaptation in infants with cyanotic congenital heart disease

Pediatric Research (2024)Cite this article

Abstract

Background

Female infants with congenital heart disease (CHD) face significantly higher postoperative mortality rates after adjusting for cardiac complexity. Sex differences in metabolic adaptation to cardiac stressors may be an early contributor to cardiac dysfunction. In adult diseases, hypoxic/ischemic cardiomyocytes undergo a cardioprotective metabolic shift from oxidative phosphorylation to glycolysis which appears to be regulated in a sexually dimorphic manner. We hypothesize sex differences in cardiac metabolism are present in cyanotic CHD and detectable as early as the infant period.

Methods

RNA sequencing was performed on blood samples (cyanotic CHD cases, n = 11; controls, n = 11) and analyzed using gene set enrichment analysis (GSEA). Global plasma metabolite profiling (UPLC-MS/MS) was performed using a larger representative cohort (cyanotic CHD, n = 27; non-cyanotic CHD, n = 11; unaffected controls, n = 12).

Results

Hallmark gene sets in glycolysis, fatty acid metabolism, and oxidative phosphorylation were significantly enriched in cyanotic CHD females compared to male counterparts, which was consistent with metabolomic differences between sexes. Minimal sex differences in metabolic pathways were observed in normoxic patients (both controls and non-cyanotic CHD cases).

Conclusion

These observations suggest underlying differences in metabolic adaptation to chronic hypoxia between males and females with cyanotic CHD.

Impact

  • Children with cyanotic CHD exhibit sex differences in utilization of glycolysis vs. fatty acid oxidation pathways to meet the high-energy demands of the heart in the neonatal period.

  • Transcriptomic and metabolomic results suggest that under hypoxic conditions, males and females undergo metabolic shifts that are sexually dimorphic. These sex differences were not observed in neonates in normoxic conditions (i.e., non-cyanotic CHD and unaffected controls).

  • The involved metabolic pathways are similar to those observed in advanced heart failure, suggesting metabolic adaptations beginning in the neonatal period may contribute to sex differences in infant survival.

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Fig. 1: Comparison of differential expression of genes between cyanotic CHD females vs. males.
Fig. 2: Comparison of differential expression of genes between sexes.
Fig. 3: Overall group effects in plasma metabolic profiling between study groups.
Fig. 4: Normalized metabolite peak area levels among study groups of cyanotic congenital heart defect (C-CHD) and non-cyanotic CHD (NC-CHD) by sex (F, female; M, male).
Fig. 5: Comparison of metabolic levels in fold of change (FC) between cyanotic and non-cyanotic congenital heart defect patients by sex (F, female; M, male) in interrelated metabolic pathways (glycolysis, citric acid or TCA cycle, fatty acid oxidation, and glutamine metabolism).

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Data availability

The datasets generated during and/or analyzed during the current study are available in the Gene Expression Omnibus (GEO) link pending.

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Acknowledgements

We thank the technical support from the Cancer Prevention and Research Institute of Texas (CPRIT RP180734). This work was supported by NIH/NCATS grants UL1 TR000445 and UL1 TR001105. Study data were collected and managed using REDCap electronic data capture tools hosted at The University of Texas School of Biomedical Informatics (SBMI) at Houston.62 REDCap (Research Electronic Data Capture) is a secure, web-based application designed to support data capture for research studies, providing (1) an intuitive interface for validated data entry; (2) audit trails for tracking data manipulation and export procedures; (3) automated export procedures for seamless data downloads to common statistical packages; and (4) procedures for importing data from external sources. T.O.F. was supported by the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, through UTHealth-CCTS Grant Number UL1TR003167 and by 5KL2TR003168-02. A.C.P. was supported by NIH K01HL159032, R01HL148191, and U54GM115428. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

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Authors and Affiliations

  1. Division of Neonatal-Perinatal Medicine, Department of Pediatrics, McGovern Medical School at the University of Texas Health Science Center at Houston and Children’s Memorial Hermann Hospital, Houston, TX, USA

    Tina O. Findley & Caleb Shi

  2. Department of Surgery, University of Mississippi Medical Center, Jackson, MS, USA

    Ana Carolina Palei

  3. Center for Precision Health, School of Biomedical Informatics at the University of Texas Health Science Center Houston, Houston, TX, USA

    Kyung Serk Cho & Zhongming Zhao

  4. Human Genetics Center, School of Public Health at the University of Texas Health Science Center at Houston, Houston, TX, USA

    Zhongming Zhao

  5. Department of Pharmacology and Toxicology/Biobank, University of Mississippi Medical Center, Jackson, MS, USA

    Gouri Mahajan

  6. School of Engineering, University of Leicester, Leicester, England, UK

    Antonio Francesco Corno

  7. Children’s Heart Institute, McGovern Medical School at the University of Texas Health Science Center at Houston and Children’s Memorial Hermann Hospital, Houston, TX, USA

    Jorge Salazar

  8. Department of Neurology, McGovern Medical School at the University of Texas Health Science Center at Houston, Houston, TX, USA

    Louise McCullough

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Contributions

T.O.F. and L.M. conceived and planned the experiments, T.O.F. carried out the experiments. A.C.P., G.M., and J.S. provided the samples. Z.Z., K.S.C., and C.S. analyzed and interpreted the data and produced the figures. T.O.F. drafted the manuscript and all authors contributed to the final manuscript.

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Correspondence to Tina O. Findley.

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Findley, T.O., Palei, A.C., Cho, K.S. et al. Sex differences in metabolic adaptation in infants with cyanotic congenital heart disease. Pediatr Res (2024). https://doi.org/10.1038/s41390-024-03291-4

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