Endothelial-to-Mesenchymal Transition in Post-Myocardial Infarction Fibrosis: A Maladaptive but Targetable Pathway

Myocardial infarction (MI) initiates a healing response in which fibroblasts and other cells deposit extracellular matrix to form a stabilizing scar. This scarring is essential for preventing ventricular rupture, yet when excessive or diffuse, it becomes maladaptive: fibrosis stiffens the ventricle, impairs filling, and drives progression to heart failure. Traditional antifibrotic approaches, such as broad TGF-β blockade or collagen cross-linking inhibition, have largely failed because fibroblast activity is required for early scar integrity, while established fibrosis is difficult to reverse. This review highlights endothelial-to-mesenchymal transition (EndMT) as a distinct and underappreciated contributor to post-MI fibrosis. Experimental studies indicate that EndMT supplies 10-30% of fibroblast-like cells, and evidence of EndMT is present in human ischemic cardiomyopathy. Unlike fibroblast-driven repair, EndMT is maladaptive in the adult heart: it promotes fibrosis without enhancing scar strength and reduces endothelial cell numbers, leading to microvascular rarefaction and impaired perfusion. EndMT is regulated by discrete, targetable pathways-including TGF-β/Smad, Notch, Wnt/β-catenin, HIF-1α, and microRNA networks (e.g., miR-21, miR-29)-and exhibits partial reversibility. This opens opportunities for time-limited, pathway-specific interventions during the proliferative phase of healing. Emerging diagnostic tools, such as extracellular volume mapping, fibroblast activation protein PET, collagen peptide assays, and circulating fibrosis-related microRNAs, provide clinical means to detect EndMT activity. By integrating mechanistic insights with advances in molecular imaging and biomarker profiling, this review proposes EndMT-directed, biomarker-guided therapies as a precision strategy to limit maladaptive fibrosis, preserve vascular networks, and improve outcomes after MI.