Biomarkers in Congenital Heart Disease: Current Evidence and Future Directions

Abstract

Congenital heart diseases (CHDs) are the most prevalent congenital anomalies worldwide and are a leading cause of infant morbidity and mortality, particularly in low- and middle-income countries. Despite advances in fetal imaging and pediatric cardiac care, most CHDs are diagnosed only after structural defects have formed, limiting opportunities for prevention. This narrative review synthesizes evidence on established and emerging biomarkers for early detection, risk stratification, and prevention of CHD. Studies published between 2000 and 2025 in PubMed were reviewed, focusing on metabolic, nutritional, immunological, molecular, and imaging biomarkers from maternal, fetal, and postnatal contexts. Advances in omics technologies—including metabolomics, proteomics, transcriptomics, and epigenomics—have revealed alterations in pathways related to one-carbon metabolism, oxidative stress, lipid metabolism, hypoxia signaling, immune regulation, and chromatin remodeling in CHD-affected pregnancies and patients. Biomarkers such as homocysteine, acylcarnitines, branched-chain amino acids, natriuretic peptides, inflammatory cytokines, microRNAs, and epigenetic regula tors show potential for reflecting early pathogenic processes and disease severity. However, heterogeneity across studies and limited longitudinal validation currently restrict clinical translation. Overall, evidence supports a multimodal biomarker approach integrated with imaging and clinical assessment, with early risk identification during the periconceptional and early gestational periods offering the greatest opportunity to reduce the global burden of CHD.