Background Tetralogy of Fallot (ToF), accounting for 7%–10% of congenital heart defects, represents the most prevalent cause of cyanotic CHD and is increasingly recognized as a lifelong condition characterized by progressive right ventricular (RV) dysfunction and heart failure. Objective Since genetic variants explain only a minority of cases, this minireview highlights the role of microRNAs (miRNAs) as important epigenetic regulators in ToF pathogenesis. Methods By integrating evidence from in silico bioinformatic pipelines, in vitro cellular validation, and ex vivo analyses of myocardial and circulating samples, we characterize a distinct miRNA signature that governs both early cardiac morphogenesis and postnatal remodeling in ToF. Results Bioinformatic investigations have revealed extensive miRNome reprogramming, identifying master regulators such as miR-124, miR-222, and miR-1275 that converge on critical pathways involving inflammation, ferroptosis, and metabolic adaptation. Complementary, in vitro models have confirmed that miRNAs like miR-222 and miR-421 impair cardiomyocyte differentiation and trigger hypertrophic responses. These findings are further corroborated by ex vivo studies of human RV tissue and serum/plasma, where dysregulated miRNAs levels (i.e., miR-1, miR-133, and miR-21) correlate with clinical deterioration and structural maladaptation. Notably, a maternal–fetal miRNA axis emerges as a potential mediator between environmental factors and fetal development, shaping lifelong disease trajectories. Conclusions Despite these advances, the causal relationships and temporal dynamics of miRNA regulation remain largely unresolved. Future integrative longitudinal studies and functional validations are essential to translate these epigenetic insights into novel biomarkers and targeted therapeutic interventions, ultimately improving long-term clinical outcomes in ToF patients.
Calcaterra et al. (Tue,) studied this question.