How Close Are We to Using Stem Cells in Routine Cardiac Therapy

Stem cells have already entered the clinical arena. Multiple trials have been undertaken and their outcomes have been reported in several meta-analyses encompassing the 3 major indications (ie, acute myocardial infarction, refractory angina, and chronic heart failure). What emerges from the overall picture is that the benefit of stem cell transplantation is inconsistent and that the commonly used surrogate trial end points do not necessarily translate into clinically relevant improvements in patient outcomes. Nevertheless, encouraging hints do exist that suggest that cell-based products could have therapeutic effects but there is still a large gap between the tightly controlled environment of proof-of-concept trials and the “real world” of routine clinical practice. The challenge is thus to determine how this gap can be successfully filled. To address this issue, it might be useful to take into account the 3 major paradigm changes that have emerged from the first generation of laboratory and clinical studies. (1) A mechanistic shift: although the initial objective was to transplant cells intended to physically replace those of the damaged recipient heart, thereby rebuilding a neomyocardium, there is now compelling evidence that the grafted cells act differently in that their primary role seems to harness endogenous repair mechanisms. This hypothesis is largely based on the consistent discrepancy between the small numbers of transplanted cells remaining alive over time and the sustained improvement in cardiac function (whenever it occurs). It is striking that even transplanted cardiac cells endowed with an intrinsic contractile activity yield such an improvement despite their lack of coupling with host cardiomyocytes, suggesting that their beneficial effects on pump function are not directly related to their synchronized contractions, but rather to paracrine actions. (2) The recognition of the limitations of cell delivery approaches: regardless of their mechanism of action, it is obvious that cells need to engraft, at least for a while, and multiple studies have addressed the 2 temporally