| Summary: | The physiological importance of NCX in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) is not well characterized but may depend on the relative strength of the current, compared to adult cardiomyocytes, and on the exact spatial arrangement of proteins involved in Ca<sup>2+</sup> extrusion. Here, we determined NCX currents and its contribution to action potential and force in hiPSC-CMs cultured in engineered heart tissue (EHT). The results were compared with data from rat and human left ventricular tissue. The NCX currents in hiPSC-CMs were larger than in ventricular cardiomyocytes isolated from human left ventricles (1.3 ± 0.2 pA/pF and 3.2 ± 0.2 pA/pF for human ventricle and EHT, respectively, <i>p</i> < 0.05). SEA0400 (10 µM) markedly shortened the APD<sub>90</sub> in EHT (by 26.6 ± 5%, <i>p</i> < 0.05) and, to a lesser extent, in rat ventricular tissue (by 10.7 ± 1.6%, <i>p</i> < 0.05). Shortening in human left ventricular preparations was small and not different from time-matched controls (TMCs; <i>p</i> > 0.05). Force was increased by the NCX block in rat ventricle (by 31 ± 5.4%, <i>p</i> < 0.05) and EHT (by 20.8 ± 3.9%, <i>p</i> < 0.05), but not in human left ventricular preparations. In conclusion, hiPSC-CMs possess NCX currents not smaller than human left ventricular tissue. Robust NCX block-induced APD shortening and inotropy makes EHT an attractive pharmacological model.
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