Stem Cells Are Not Proarrhythmic: Letting the Genie out of the Bottle

I schemic heart disease remains a leading cause of mortality worldwide.Myocardial infarction (MI) accounts for more than half of cardiovascular-related deaths. 1 With rising numbers of surviving MI patients and an aging population, congestive heart failure has become a major health concern, with symptomatic patients having a poorer prognosis.2 Despite substantial advances in medical and device strategies for congestive heart failure, there remains a growing unmet clinical need.Accordingly, various novel therapies have been explored in recent years, with the potential offered by stem cells (SCs) arguably garnering the most attention.3,4 Cardiac SC therapy has emerged as a promising option to repair ischemic/dysfunctional myocardium through a variety of potential mechanisms (Figure 1).[5][6][7] Continuing debates over unresolved mechanistic issues and the rapid transition toward clinical application, with already-demonstrated modest but tangible benefits for cardiac structure and function, underscore the fact that the field is still in its infancy.8 -10 As with other emerging therapies, safety concerns have arisen in relation to potential hazards of SC therapy.11 Among the most contentious issues, the risk of proarrhythmia has sparked debate and generated lingering doubts, which run the risk of paralyzing a potentially revolutionary opportunity.[12][13][14][15] Although findings that have raised concerns about proarrhythmic potential of SC transplants cannot be discounted, we contend that the available data are encouraging rather than damning.Here, we highlight experimental and clinical data on SC-related arrhythmogenesis, discuss possible confounding issues, and argue that SC therapy, rather than being considered intrinsically proarrhythmic, must be understood to have controllable proarrhythmic risks along with unique antiarrhythmic potential. Are SCs Intrinsically Proarrhythmic?Initial clinical trials involved satellite cells or skeletal myoblasts (SkMs) 16,17 and suggested proarrhythmic potential, 17 despite a lack of proarrhythmia in early preclinical studies.18,19 In the first phase I clinical trial using autologous SkMs, Menasché et al selected patients eligible for coronary artery bypass grafting (CABG), with severe left ventricular dysfunction (left ventricular ejection fraction [LVEF] Ն35%) and akinetic scars, to undergo multiple transepicardial cell injections to deliver an average of 87ϫ10 6 cells.17 Clinically significant ventricular arrhythmias were later documented in 4 of the 9 patients included in this study (3 of whom had a history of significant prior ventricular arrhythmia), which led to the mandatory use of automatic implanted cardioverterdefibrillators.Subsequently, other trials investigating the adjunctive use of autologous SkMs in patients with chronic ischemic cardiomyopathy undergoing surgical revascularization also reported postoperative ventricular tachyarrhythmias (VTs), despite notable differences in the number of cells delivered at the time of surgery (from 0.2ϫ10 7 to 30ϫ10 8 ).20 -22 With a percutaneous intramyocardial route, Smits et al reported proarrhythmic effects of autologous SkMs in postinfarction patients with depressed LVEF.23 Similarly, the use of bone marrow-derived cells (BMCs) has been linked, albeit to a lesser degree, with increased occurrence of VT.Hendrix et alThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

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