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

Tina O Findley1, Ana Carolina Palei2, Kyung Serk Cho3

  • 1Division 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@uth.tmc.edu.

Pediatric Research
|June 5, 2024
PubMed

Insights

Infants with cyanotic congenital heart disease (CHD) show sex-based differences in cardiac metabolism, utilizing glycolysis and fatty acid oxidation differently under hypoxic conditions. These metabolic shifts may explain survival disparities in male and female infants with cyanotic CHD.

Area of Science:

  • Cardiology
  • Metabolomics
  • Neonatal Research

Background:

  • Female infants with congenital heart disease (CHD) exhibit higher postoperative mortality than males, irrespective of cardiac complexity.
  • Sex differences in metabolic adaptation to cardiac stressors may contribute to cardiac dysfunction.
  • Hypoxic cardiomyocytes in adults shift metabolism towards glycolysis, a process known to be sexually dimorphic.

Purpose of the Study:

  • To investigate sex differences in cardiac metabolism in infants with cyanotic CHD.
  • To determine if these metabolic differences are detectable in the neonatal period.
  • To explore the role of metabolic adaptation in sex-based survival disparities in cyanotic CHD.

Main Methods:

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

Main Results:

  • Significant enrichment of hallmark gene sets in glycolysis, fatty acid metabolism, and oxidative phosphorylation in cyanotic CHD females compared to males.
  • Metabolomic data corroborated these sex-based differences in metabolic pathways.
  • Minimal sex differences in metabolic pathways were observed in normoxic infants (controls and non-cyanotic CHD).

Conclusions:

  • Cyanotic CHD infants display sex differences in the utilization of glycolysis versus fatty acid oxidation pathways to meet cardiac energy demands.
  • Transcriptomic and metabolomic findings indicate sexually dimorphic metabolic shifts in males and females under hypoxic conditions.
  • These neonatal metabolic adaptations may underlie observed sex differences in infant survival rates for cyanotic CHD.
Abstract

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