Electrophysiological Challenges of Cell-Based Myocardial Repair

C ardiovascular diseases remain the major cause of death in the Western world. Possible beneficial mechanisms of cell-based therapies include generation of new and mature ventricular cardiomyocytes (cardiomyogenesis), recruitment of endogenous SPCs for cardiomyogenesis, and salvage of native myocardium through paracrine, angiogenic, and antiapoptotic effects. 3] Although adverse outcomes after cell therapies, such as lethal arrhythmias, occurred in early clinical trials of skeletal myoblast transplantation, 5-8 recent clinical trials using various sources of SPCs, novel modes of cell delivery, better cell selection, and different timing of cell transplantation did not show any significant increase in arrhythmic incidence. It is tempting to conclude on this basis that cell-based therapies are "safe" and nonarrhythmogenic (reviewed in References 2 and 4); however, the negligible production of new cardiomyocytes documented for many SPCs employed makes it difficult to extrapolate their safety records toward future trials in which substantial numbers of new cardiomyocytes might be generated or introduced. Clinical trials to test cardiomyocyte replacement (cardiomyogenesis), long a goal of SPC-based therapy, are bound to take place in the near future, thanks to many investigators who are developing technologies for efficient generation of cardiomyocytes from SPCs and for increasing their retention after transplantation. In weighing the benefits of replacement therapies, we should not overlook the fact that SPC-derived cardiomyocytes exhibit variable electrophysiological properties and are typically immature compared with adult cardiomyocytes (see below). This immaturity of primitive SPC-derived cardiomyocytes remains a major hurdle toward developing safe cell therapies. In anticipation of improved cardiomyogenesis in future cell therapies, we will review here developmental and electrophysiological challenges, common to all SPC-derived cardiomyocytes, that need to be resolved to improve the maturation of primitive SPC-derived cardiomyocytes and to avoid unwanted risks of increasing arrhythmic incidence (proarrhythmia) after transplantation.