Regenerative and molecular therapies for myocardial repair (Review)

Despite considerable progress being made in reperfusion, drugs and device-based therapies, myocardial infarction remains a primary cause of heart failure due to irreversible cardiomyocyte loss and maladaptive ventricular remodeling. Conventional surgical and interventional methods cannot regenerate functional myocardium, although they can restore perfusion. Limited endogenous cardiac renewal has driven the development of regenerative, molecular and bioengineering-based therapies aimed at myocardial repair after MI. The present narrative overview summarizes current approaches, including gene and RNA therapeutics, cell-based therapies, extracellular vesicles, engineered cardiac patches and pharmacological strategies. Only modest improvements in left ventricular function were shown in early clinical trials employing mesenchymal stromal cells and bone marrow-derived mononuclear cells; these benefits were mostly attributable to immunomodulatory and paracrine effects rather than true remuscularization. Recent advancements, including cardiac progenitor cells, allogeneic platforms and intraoperative delivery during coronary artery bypass grafting, improved safety but showed mixed outcomes. Induced pluripotent stem cell-derived cardiomyocytes and engineered cardiac patches are a step toward structural myocardial replacement with encouraging preclinical and early human safety data; however, problems with arrhythmogenic risk, immunological rejection, scalability and long-term durability remain unresolved. Parallel developments in gene and RNA therapies, particularly cardiotropic adeno-associated viral vectors, lipid nanoparticle-mediated mRNA delivery and RNA interference, have highlighted the importance of vector design, myocardial targeting and appropriate molecular selection, as evidenced by the inconsistent clinical outcomes of SERCA2a-based gene therapy. Pharmacological management of post-myocardial infarction inflammation, fibrosis, metabolism, and cellular senescence promotes regenerative methods by improving the cardiac milieu and decreasing detrimental remodeling. Both regenerative and molecular therapies have shown encouraging effects on cardiac repair, but successful clinical translation remains a work in progress. With ongoing technological advances and carefully controlled clinical studies, these innovative approaches could ultimately provide effective treatments to regenerate the damaged myocardium and improve outcomes for patients.