Metabolomic profiling reveals amino acid dysregulation in congenital heart disease: Arginine‑induced embryonic malformations and pathogenic insights

Congenital heart disease (CHD) is the most common form of malformation seen in China. In most cases, its pathogenesis is unclear. The present study aimed to identify the differential metabolites and novel screening markers to discover the potential pathogenesis of CHD. Cultured amniotic fluid cells from pregnant patients carrying CHD-affected (n=24) or healthy (n=24) fetuses were collected. Untargeted metabolomics was performed on the cells. A total of 292 metabolites (172 up- and 120 downregulated) were significantly different between the CHD and control groups (variable importance on projection >1 and P<0.05). Significantly different metabolites were screened and analyzed using hierarchical clustering and Kyoto Encyclopedia of Genes and Genomes metabolic pathway enrichment. These data demonstrated that amino acid metabolism was considerable elevated. The most notable differential metabolites were lysine and arginine, suggesting they may play an important role in heart development. When arginine were used to treat pregnant mice, embryos (embryonic day 15.5) demonstrated increased malformation rate, the litter size decreased (4.3±1.03 vs. 6.5±1.05, P<0.01) and the naked deformity rate significantly increased (30.8 vs. 0.0%, P<0.001), compared with the controls. The embryonal heart cavity was larger and the heart wall became thinner. The present study suggested that amino acid metabolites may serve a crucial role in heart development and could serve as potential screening markers for CHD. Additionally, the adverse effects of arginine treatment on embryonic development highlight its role in CHD pathogenesis.