Untargeted metabolomics identifies altered cardiac metabolite and gene expression patterns in late preterm growth-restricted newborn lambs

Fetal growth restriction (FGR) may impair early postnatal cardiopulmonary function by limiting the heart's ability to shift from glycolytic to fatty acid metabolism. We investigated whether the cardiac metabolic milieu is altered in newborn FGR lambs compared with control lambs 24 h after birth. Twin-bearing ewes at 89 days of gestation (term = 148 days) underwent single umbilical artery ligation to induce FGR or sham surgery (control). Lambs were delivered late preterm at 136 days (∼0.92 gestation) and monitored for 24 h before postmortem tissue collection. Left ventricles were snap-frozen for untargeted metabolomics analysis via liquid chromatography/mass spectroscopy (LC-MS) and reverse transcriptase quantitative PCR (RT-qPCR) or fixed for immunohistochemical analysis. FGR lambs had lower body weights at birth (2.7 ± 0.3 vs. 4.3 ± 0.2; <i>P</i> = 0.0002) and at 24 h (2.7 ± 0.2 vs. 4.4 ± 0.2; <i>P</i> < 0.0001) compared with controls. LC-MS identified 14 significantly altered metabolites in FGR hearts, with upregulated peptide and uric acid metabolism and downregulated lipid, carnitine, and serotonin metabolism (fold change from control >1.5; <i>P</i> < 0.05). RT-qPCR identified higher gene expression of long-chain fatty acid transport proteins <i>SLC27A6</i> and <i>ACADL</i> and lower gene expression of serotonin receptor <i>HTR4</i>. No differences in the gene expression of carnitine metabolism (<i>CPT1A</i> and <i>CPT1B</i>) or uric acid metabolism (<i>XDH</i>, <i>HPRT1</i>, <i>GDA</i>, and <i>PNP</i>) were observed. Serotonin (5-hydroxytryptamine) density was reduced in FGR hearts (<i>P</i> = 0.048). These findings suggest early shifts in postnatal cardiac metabolic adaptations in FGR lambs, particularly in lipid and serotonin pathways, and provide a foundation for future studies exploring the functional consequences of these changes.<b>NEW & NOTEWORTHY</b> Within 24 h of birth, growth-restricted (FGR) newborn lambs exhibited altered lipid and serotonin metabolites, suggesting disrupted postnatal cardiac metabolic adaptation. Despite upregulation of the fatty acid transporter gene <i>SLC27A6</i>, with other fatty acid oxidation genes remaining largely unchanged, reductions in lipid and carnitine metabolites indicate potential impairments in fatty acid utilization. Decreased serotonin bioavailability further suggests metabolic reprogramming in FGR hearts, highlighting the need for future studies on the implications for postnatal cardiac function.