Background: Adults with congenital heart disease (ACHD) having undergone palliative surgery experience chronic stress due to altered physiology and repeated surgical interventions since infancy.
Objectives: To investigate whether ACHD, who had experienced chronic physiological stress from their underlying condition and early-life cardiac surgeries, was associated with epigenetic age acceleration (EAA) and other DNA methylation (DNAm)-based biomarkers, and to assess the potential contribution of derived inflammatory markers to EAA.
Methods: A case-control study comparing ACHD patients and healthy adults. Whole blood DNAm profile was used to estimate DNAm-based blood cell type proportions, multiple epigenetic age measures, and interleukin-6 (IL-6) and C-reactive protein (CRP) scores. Two ACHD subgroups were recruited: one with multiple palliative surgeries since birth (Fontan group, n = 13), and another with a single corrective surgery as an infant (SS group, n = 5). Healthy controls (n = 20) had no chronic medical conditions. EAA was calculated using four epigenetic clocks (Horvath, Hannum, GrimAge, PhenoAge) and the pace of aging (DunedinPACE). Comparisons were made across groups using robust linear regression models, adjusting for age, sex, self-reported ethnicity, and estimated cell type proportions. Associations between DNAm-based IL-6 and CRP scores and surgery group were tested, and their potential contribution to differences in EAA was evaluated.
Results: Participants were 20-30 years (25.6 ± 2.7 years), predominantly non-Hispanic white. After controlling for age/sex/ethnicity/immune-cell-type proportions, the Fontan group had significantly higher GrimAge (Cohen's f = 0.90, p < 0.001) and PhenoAge (Cohen's f = 0.82, p < 0.001) and higher DunedinPACE (Cohen's f = 0.69, p = 0.01). The Fontan group also had statistically higher predicted IL-6 (Cohen's f = 0.84, p < 0.001) and CRP scores (Cohen's f = 0.62, p < 0.001).
Conclusions: Young ACHD patients who undergo multiple childhood surgeries for Fontan palliation were associated with accelerated aging. These changes could reflect the long-term effects of underlying CHD condition, early-life physiological stress and other factors, potentially involving inflammatory pathways. Further research is needed to identify and validate the key factors contributing to EAA in this population and to clarify the role of chronic stress and physiological alterations over time.
Keywords: Congenital heart disease; Epigenetic age acceleration; Epigenetic clocks; Fontan circulation.
© 2026. The Author(s).