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Integrative metabolomics dictate distinctive signature profiles in patients with Tetralogy of Fallot

Pediatric Research volume 97, pages 785–797 (2025)Cite this article

Abstract

Background

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease (CCHD) with multifactorial etiology. We aimed to investigate the metabolic profiles of CCHD and their independent contributions to TOF.

Methods

A cohort comprising 42 individuals with TOF and atrial septal defect (ASD) was enrolled. Targeted ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) was employed to systematically analyze metabolite levels and identify TOF-associated metabolic profiles.

Results

Of 370 identified metabolites in tissue and 284 in plasma, over one-third of metabolites showed an association with microbiome. Differential metabolic pathways including amino acids biosynthesis, ABC (ATP-binding cassette) transporters, carbon metabolism, and fatty acid biosynthesis, shed light on TOF biological phenotypes. Additionally, ROC curves identified potential biomarkers, such as erythronic acid with an AUC of 0.868 in plasma, and 3-β-hydroxy-bisnor-5-cholenic acid, isocitric acid, glutaric acid, ortho-Hydroxyphenylacetic acid, picolinic acid with AUC close to 1 in tissue, whereas the discriminative performance of those substances significantly improved when combined with clinical phenotypes.

Conclusions

Distinct metabolic profiles exhibited robust discriminatory capabilities, effectively distinguishing TOF from ASD patients. These metabolites may serve as biomarkers or key molecular players in the intricate metabolic pathways involved in CCHD development.

Impact

  • Distinct metabolic profiles exhibited robust discriminatory capabilities, effectively distinguishing Tetralogy of Fallot from atrial septal defect patients.

  • Similar profiling but inconsistent differential pathways between plasma and tissue.

  • More than one-third metabolites in plasma and tissue are associated with the microbiome.

  • The discovery of biomarkers is instrumental in facilitating early detection and diagnosis of Tetralogy of Fallot.

  • Disturbed metabolism offers insights into interpretation of pathogenesis of Tetralogy of Fallot.

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Fig. 1: Metabolites profiling in tissue and plasma.
Fig. 2: Differential metabolites screening by multivariate analysis.
Fig. 3: Differential metabolites profiles based on the univariate analysis.
Fig. 4: Analysis of differential metabolites distinguish TOF from control.
Fig. 5: Metabolic pathway enrichment analysis of differential metabolites.
Fig. 6: Receiving operating characteristic (ROC) curve analysis and correlation analysis.

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Data availability

Data will be made available on request.

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Acknowledgements

We are grateful for the support of our colleagues and teachers in the Department of Cardiac Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences. And we also want to thank all participants in our studies. Fundings This research was supported by the National Key Research and Development Program of China (No. 2022YFC2407406), Guangzhou Science and Technology Planning Project (No. 2023B03J0596), Science and Technology Fundation of Guangzhou Health (No. 2023A031004), 2022 Stability Support for Innovative Capacity Building of Guangdong Provincial Scientific Research Institutions (No. KD022022015).

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Author notes

  1. These authors contributed equally: Ying Li, Miao Tian, Ziqin Zhou.

Authors and Affiliations

  1. Department of Cardiac Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China

    Ying Li, Miao Tian, Ziqin Zhou, Ruyue Zhang, Yong Zhang, Hujun Cui, Jian Zhuang & Jimei Chen

  2. Department of Cardiac Surgery, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China

    Ying Li, Miao Tian, Ziqin Zhou, Jiazichao Tu, Ruyue Zhang, Yong Zhang, Hujun Cui, Jian Zhuang & Jimei Chen

  3. Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangzhou, 510080, China

    Ying Li, Miao Tian, Ziqin Zhou, Jiazichao Tu, Ruyue Zhang, Yong Zhang, Hujun Cui, Jian Zhuang & Jimei Chen

  4. School of Medicine, South China University of Technology, Guangzhou, 510006, China

    Jiazichao Tu

  5. Department of Pediatric cardiology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China

    Yu Huang

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Contributions

Ying Li: Conceptualization; formal analysis; investigation; methodology; visualization, writing-original draft; Miao Tian: Data curation; methodology; visualization; Ziqin Zhou: Conceptualization; data curation; methodology; Jiazichao Tu: Data curation; methodology; Ruyue Zhang: Methodology; formal analysis; Yu Huang: Data curation; Hujun Cui: Data curation; Yong Zhang: Data curation; Jian Zhuang: Writing – review & editing; investigation; Jimei Chen: Conceptualization; writing – review & editing, funding acquisition, project administration; investigation; validation. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Jimei Chen.

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Li, Y., Tian, M., Zhou, Z. et al. Integrative metabolomics dictate distinctive signature profiles in patients with Tetralogy of Fallot. Pediatr Res 97, 785–797 (2025). https://doi.org/10.1038/s41390-024-03328-8

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