Cardiac regenerative therapy: Many paths to repair.

Cardiovascular disease remains the primary cause of death in the United States and in most nations worldwide, despite ongoing intensive efforts to promote cardiac health and treat heart failure. Replacing damaged myocardium represents perhaps the most promising treatment strategy, but also the most challenging given that the adult mammalian heart is notoriously resistant to endogenous repair. Cardiac regeneration following pathologic challenge would require proliferation of surviving tissue, expansion and differentiation of resident progenitors, or transdifferentiation of exogenously applied progenitor cells into functioning myocardium. Adult cardiomyocyte proliferation has been the focus of investigation for decades, recently enjoying a renaissance of interest as a therapeutic strategy for reversing cardiomyocyte loss due in large part to ongoing controversies and frustrations with myocardial cell therapy outcomes. The promise of cardiac cell therapy originated with reports of resident adult cardiac stem cells that could be isolated, expanded and reintroduced into damaged myocardium, producing beneficial effects in preclinical animal models. Despite modest functional improvements, Phase I clinical trials using autologous cardiac derived cells have proven safe and effective, setting the stage for an ongoing multi-center Phase II trial combining autologous cardiac stem cell types to enhance beneficial effects. This overview will examine the history of these two approaches for promoting cardiac repair and attempt to provide context for current and future directions in cardiac regenerative research.