Stem cell-derived cardiomyocytes demonstrate arrhythmic potential

Background - Cardiomyocytes (CMs) derived from pluripotent embryonic stem cells (ESCs) and embryonal carcinoma cells (ECCs) have some but not all characteristics of adult myocytes. ESCs have shown the ability to engraft in areas of myocardial damage, which suggests their use in cell transplantation therapy for cardiomyopathy. We studied the arrhythmogenic properties of CMs differentiated from mouse ESCs and ECCs. Methods and Results - CMs derived in vitro were studied in the whole-cell patch-clamp mode. CMs from both sources showed action potential (AP) morphology heterogeneity, with reduced maximum upstroke velocities (dV/dt) and prolonged AP durations. CMs demonstrated prolonged, spontaneous electrical activity in culture. Frequent triggered activity was observed with and without pharmacological enhancement. Phase 2 or 3 early afterdepolarizations could be induced easily by Bay K8644 plus tetraethylammonium chloride (TEA) or [TEA]_o after Cs⁺ replacement for [K⁺]_i, respectively. A combination of bradycardic stimulation, hypokalemia, and quinidine resulted in early afterdepolarizations. Delayed afterdepolarizations could be induced easily and reversibly by hypercalcemia or isoproterenol. Conclusions - ESCs or ECCs differentiated into at least 3 AP phenotypes. CMs showed spontaneous activity, low dV/dt, prolonged AP duration, and easily inducible triggered arrhythmias. These findings raise caution about the use of totipotent ESCs in cell transplantation therapy, because they may act as an unanticipated arrhythmogenic source from any of the 3 classic mechanisms (reentry, automaticity, or triggered activity).