Bench to Bedside: Insights from Large Animal Models and Emerging Clinical Trials of Endogenous Cardiac Regeneration and Repair.

Cardiovascular disease (CVD), particularly myocardial infarction (MI), remains a leading cause of morbidity and mortality worldwide. The irreversible loss of cardiomyocytes (CMs) and subsequent fibrosis following MI due to delayed or absent reperfusion are central drivers of heart failure progression. Recent evidence indicates that the adult mammalian heart retains a latent regenerative capacity, which can be reactivated under specific conditions. Therefore, stimulating endogenous cardiac regeneration represents a promising strategy to improve clinical outcomes following MI. This review summarizes a range of intervention strategies designed to wake up cardiac regeneration and promote myocardial repair in the setting of residual following myocardial injury. Key approaches examined include stimulating cardiomyocyte cell-cycle re-entry, leveraging growth factors and paracrine mediators as pro-regenerative signals, and applying cell-free vesicles and small molecule compounds. We discuss the translational progress of these strategies, drawing on evidence from large animal models and ongoing clinical trials, aiming to bridge mechanistic discoveries to future clinical applications in cardiac regenerative medicine.