Congenital heart diseases require early reconstructive surgery involving cardiopulmonary bypass (CPB). Although life-saving, these procedures trigger a systemic and cellular stress response. This response remains poorly characterized in pediatric patients, whose metabolic profile and stress-adaptation mechanisms differ markedly from those of adults due to developmental immaturity. Protein O-GlcNAcylation, a post-translational modification linking cellular metabolism to stress-response signaling, has emerged as a regulator of cardiac stress adaptation, yet its role in the pediatric response to CPB remains unknown.

Pediatric ( n = 63) and adult ( n = 172) patients undergoing cardiac surgery with CPB were included. Blood samples were collected before CPB, at aortic declamping, and 6 and 12 hours postoperatively. Global protein O-GlcNAcylation was measured by Western blot. In pediatric patients, O-GlcNAcylated proteins were isolated using a Click-iT–based immunoprecipitation approach followed by proteomic analysis. Associations between perioperative O-GlcNAcylation changes and postoperative outcomes (VIS, mechanical ventilation duration, bleeding, and fluid resuscitation) were assessed.

In pediatric patients, global protein O-GlcNAcylation significantly decreased after CPB, with reduced levels at aortic declamping ( P < 0.05) that persisted at 6 and 12 hours postoperatively ( P < 0.001). The magnitude of this decline correlated with greater postoperative severity, including higher VIS at H + 6 ( r = 0.61, P < 0.01), prolonged mechanical ventilation, increased bleeding, and higher fluid requirements. In contrast, adults showed an intraoperative increase in O-GlcNAcylation ( P < 0.05), consistent with an adaptive stress response. Proteomic analysis of pediatric samples identified carbonic anhydrase as an O-GlcNAcylated protein, supporting a link between metabolic stress and acid–base regulation.

This pediatric-specific pattern suggests a distinct metabolic adaptation to perioperative stress and highlights the need for age-tailored strategies to optimize myocardial protection in children with congenital heart disease. It also supports the value of integrative omics approaches to better characterize age-dependent stress signatures in pediatric cardiac surgery.