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

Background:Femaleinfantswith congenital heart disease (CHD)facesignificantlyhigherpostoperativemortality ratesafter adjusting for cardiac complexity.Sex differences in metabolic adaptation to cardiac stressors maybe an earlycontributor tocardiac dysfunction.In adult diseases, hypoxic/ischemic cardiomyocytesundergo acardioprotectivemetabolicshift fromoxidative phosphorylation to glycolysiswhichappears to be regulated in a sexually dimorphic manner.We hypothesizesex differences incardiacmetabolismare presentincyanotic CHDand detectable asearly as theinfantperiod. Methods:RNA sequencingwas performedon blood samples(cyanotic CHD cases,n=11;controls,n=11)andanalyzedusinggene set enrichment analysis (GSEA). Global plasma metaboliteprofiling(UPLC-MS/MS)was performedusinga larger representative cohort(cyanotic CHD,n = 27;non-cyanotic CHD,n = 11;unaffectedcontrols,n = 12). Results:Hallmark gene sets in glycolysis, fatty acid metabolism, and oxidative phosphorylationwere significantly enrichedincyanotic CHDfemales compared to malecounterparts, which was consistent withmetabolomicdifferences between sexes.Minimalsex differencesinmetabolicpathwayswereobservedinnormoxicpatients(bothcontrols and non-cyanotic CHDcases). Conclusion:These observationssuggestunderlying differences inmetabolicadaptationtochronic hypoxiabetween males and females withcyanotic CHD.