ABSTRACT
The traditional view of the heart as a postmitotic organ incapable of regeneration has been challenged by animal and human data demonstrating the presence of extracardiac progenitors.1-6
These progenitors offer great hope for augmenting cardiac repair post myocardial infarction. Promising preliminary experimental data have been greeted with enthusiasm by the clinical community and have led to clinical trials of cellbased cardiac therapy. Although one or more definitive and pre-eminent cardiac progenitor cells remain to be identified, putative sources of such cells include bone marrow-derived progenitor cells of hematopoietic, angioblastic, and mesenchymal lineages and, more recently, resident cardiac stem cells.7-9 Clinical trials of cell therapy in the heart so far have used cells of varying lineages, with differing endpoints determining efficacy. Moreover, many studies have used heterogeneous mixtures of cells rather than a purified or clonal population of a particular cell type. Nothwitstanding differing cell types, differing endpoints, and the uncontrolled nature of such clinical trials, cell-based therapy has shown universal improvement in cardiac function.10-15
Early clinical success has also led to questions regarding the mechanisms of action and the short-and long-term safety of cardiac cell therapy. Although many beneficial mechanisms have
been postulated,4,16-18 animal and human studies to date have failed to point to a specific mechanism underlying the improvement in cardiac performance. Initial enthusiasm about stem cell plasticity has also been tempered by recent animal data demonstrating a lack of transdifferentiation of hematopoietic progenitors following injection into an injured heart.19-21 The lack of understanding of a precise mechanism has led some basic science researchers to propose slowing the pace of all clinical trials until the true risks and benefits of such therapy can be fully evaluated in more extensive animal studies. Unfortunately, experimental models are an imprecise predictor of subsequent clinical events, and, more importantly, unanticipated clinical adverse events may not always be detected in preclinical models. A compromise approach to further clinical trials of cell therapy may therefore be to proceed cautiously with larger, doubleblinded, randomized, controlled clinical trials while adhering to the most rigorous safety standards applicable to pharmacologic clinical trials.
