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.
Department of Surgery, University of Mississippi Medical Center, Jackson, MS, USA.
Pediatr Res. 2024 Oct;96(5):1201-1209. doi: 10.1038/s41390-024-03291-4. Epub 2024 Jun 5.
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.
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).
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).
These observations suggest underlying differences in metabolic adaptation to chronic hypoxia between males and females with cyanotic CHD.
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.
在调整心脏复杂性后，患有先天性心脏病 (CHD) 的女婴术后死亡率显著更高。性别差异在代谢适应心脏应激方面可能是导致心脏功能障碍的早期因素。在成人疾病中，缺氧/缺血的心肌细胞经历从氧化磷酸化到糖酵解的心脏保护性代谢转变，这种转变似乎以性别二态的方式调节。我们假设在发绀性 CHD 中存在心脏代谢的性别差异，并且早在婴儿期就可以检测到。
对血液样本（发绀性 CHD 病例，n=11；对照组，n=11）进行 RNA 测序，并使用基因集富集分析 (GSEA) 进行分析。使用更大的代表性队列（发绀性 CHD，n=27；非发绀性 CHD，n=11；未受影响的对照组，n=12）进行全血浆代谢产物谱分析（UPLC-MS/MS）。
与男性相比，发绀性 CHD 女性中糖酵解、脂肪酸代谢和氧化磷酸化的标志性基因集显着富集，这与性别之间的代谢差异一致。在正常氧合患者（对照组和非发绀性 CHD 病例）中观察到代谢途径的性别差异很小。
这些观察结果表明，发绀性 CHD 男性和女性在代谢适应慢性缺氧方面存在潜在差异。
患有发绀性 CHD 的儿童在新生儿期利用糖酵解与脂肪酸氧化途径来满足心脏的高能量需求方面存在性别差异。转录组学和代谢组学结果表明，在缺氧条件下，男性和女性的代谢转变存在性别二态性。在正常氧合条件下（即非发绀性 CHD 和未受影响的对照组）未观察到这些性别差异。涉及的代谢途径与在晚期心力衰竭中观察到的相似，这表明新生儿期开始的代谢适应可能导致婴儿存活率的性别差异。
