DNA Methylation and Fetal Programming of Cardiovascular Disease: From Congenital Heart Diseases to Adult Cardiovascular Dysfunction.

DNA methylation, the most extensively studied epigenetic mechanism, acts as a critical interface between maternal environmental influences and fetal cardiovascular development. During embryogenesis, tightly orchestrated methylation remodeling regulates the transcriptional networks required for cardiogenesis, including chamber septation, valve formation, and myocardial maturation. Disruption of these methylation patterns contributes to congenital heart disease (CHD), with distinct methylation signatures identified in tetralogy of Fallot, double-outlet right ventricle, bicuspid aortic valve, and coarctation of the aorta. Maternal exposures, including smoking, alcohol intake, folic acid status, hypertension, diabetes, and hyperlipidemia, modify fetal DNA methylation in placental, myocardial, and cord blood tissues. These alterations affect key developmental pathways, including Wnt, Notch, and mitogen-activated protein kinase signaling, as well as genes that regulate oxidative stress, thereby increasing the risk of structural defects and predisposing offspring to long-term cardiovascular vulnerability. Epigenetic reprogramming in adverse intrauterine environments has been linked to hypertension, pulmonary vascular disease, atherosclerosis, and ischemia-sensitive phenotypes in later life, supporting a continuum from fetal life to adult cardiovascular dysfunction. Unlike genetic mutations, DNA methylation is dynamic and reversible, highlighting the potential of this modification as a biomarker of early risk and a target for preventive strategies. Optimizing maternal health, ensuring appropriate folate intake, and reducing harmful exposures may help preserve normal methylation landscapes and improve offspring cardiovascular outcomes. Advances in high-resolution epigenomic profiling, including single-cell methylation technologies, now enable delineation of cell-specific trajectories that connect CHD with adult cardiovascular disease and may inform precision interventions aimed at modifying pathogenic epigenetic states. Thus, understanding the role of DNA methylation in fetal programming can clarify the developmental origins of CHD and adult cardiovascular disorders, and lay the foundation for cardiovascular prevention strategies that extend from preconception through the earliest stages of life.