Cardiac EndMT and EpiMT as a developmental continuum: integration of mechanical, metabolic, and epigenetic regulation.

Cardiac epithelial-mesenchymal transition (EMT) is a conserved morphogenetic program that shapes embryonic heart development and contributes to disease when aberrantly reactivated. Two major forms of cardiac EMT, endocardial-to-mesenchymal transition (EndMT) and epicardial epithelial-to-mesenchymal transition (EpiMT), support valve and septal formation, outflow tract remodeling, coronary vascular maturation, myocardial growth, and cardiac fibroblast generation. Increasing evidence indicates that these processes are not binary cell fate switches, but dynamic and context-dependent continua governed by coordinated signaling, mechanical, metabolic, extracellular matrix, and epigenetic inputs. In this review, we synthesize classical and emerging mechanisms regulating EndMT and EpiMT, including TGF-β/BMP, Notch, ErbB, Wnt/β-catenin, FGF, YAP/TAZ, chromatin remodeling, and non-coding RNA networks. We propose that developmental EndMT is best understood as a regionally licensed continuum of endocardial cell states in the atrioventricular canal and outflow tract, whereas developmental EpiMT represents a niche-dependent lineage continuum shaped by epicardial competence, myocardial-derived cues, mechanical environment, and post-EMT lineage allocation. This framework helps explain why similar regulatory pathways can generate distinct morphogenetic, fibrotic, or reparative outcomes depending on developmental stage, anatomical context, and cellular state. We further discuss how aberrant EndMT and EpiMT contribute to congenital heart disease, including valve malformations, septal defects, outflow tract defects, coronary abnormalities, and ventricular hypoplasia. Finally, we evaluate emerging approaches, including single-cell multi-omics, spatial transcriptomics, lineage tracing, live imaging, patient-specific induced pluripotent stem cell models, organoids, and human-based new alternative methodologies, as tools for resolving EMT heterogeneity, testing causal mechanisms, and defining therapeutic safety boundaries. Understanding cardiac EndMT and EpiMT as evidence-aware, context-dependent developmental continua may refine the interpretation of congenital and adult cardiac disease and inform future studies evaluating whether pathological EMT-related plasticity can be selectively modulated without impairing repair or vascular homeostasis.