Myocardial Regeneration: Feasible or Fantasy?

genetic therapy; heart diseases; regenerationHeart regeneration is the holy grail of cardiology.Despite the therapeutic benefits of lipid-lowering drugs, β-blockers, antihypertensives, and other medications, heart failure stemming from the loss or dysfunction of cardiomyocytes remains the primary cause of human morbidity and mortality, highlighting the need for innovative strategies for cardiac regeneration and repair.Recent decades have seen numerous efforts toward this goal, but thus far, this clinical challenge has been largely unmet.This Perspective considers the biologic processes associated with cardiac injury and regeneration and the challenges in the path toward myocardial regeneration.Coronary artery occlusion, as occurs in atherosclerosis, and consequent myocardial infarction can cause irreversible loss of millions or billions of terminally differentiated cardiomyocytes, leading to compromised cardiac function (Figure).Numerous biologic barriers prevent regeneration of the adult heart, paramount among them being the inability of adult cardiomyocytes to divide.14 C-radiolabeling studies revealed that human cardiomyocytes are extremely long-lived, with a turnover rate estimated at ~1% per year.There is no intrinsic mechanism for replenishment of cardiomyocytes lost during injury or disease.1,2 Effective cardiac regeneration, in addition to replacing lost cardiomyocytes, would require maturation of new cardiomyocytes, their seamless electrical coupling with the preexisting myocardium, and revascularization.In contrast to the adult mammalian heart, the neonatal mouse heart can regenerate shortly after birth, when cardiomyocytes retain vestiges of proliferative potential from embryogenesis.The hearts of zebrafish can also regenerate throughout life.The ability of neonatal mice and zebrafish to regenerate their hearts indicates that cardiac regeneration is