Regenerating the heart: The past, present, & future

Coronary artery disease, with subsequent ischemic cardiomyopathy, is the leading cause of mortality worldwide. Following an ischemic insult, a remodeling process ensues that replaces damaged cardiomyocytes with fibrotic tissue, leading to further cardiomyocyte depletion, ventricular dysfunction, and eventually heart failure. Loss of cardiac muscle is especially relevant here given the limited regenerative capacity of the adult heart. The past several decades have witnessed the evolution of numerous therapeutic approaches for repairing and regenerating the heart, with varied success. Strategies include cell-based approaches such as transplantation of induced pluripotent stem cell-derived cardiomyocytes, cell-free approaches such as manipulation of cardioprotective secretory factors and direct reprogramming of resident fibroblasts, and stimulation of endogenous cardiac repair mechanisms. Overall, preclinical outcomes of cardiac regenerative therapy have not translated to clinical trials given issues with low engraftment rates and safety. Newer technologies such as genome editing and modulation of the cardiac microenvironment hold promise, but much work needs to be done before these therapies come of age.