Higher sensitivity to ouabain-induced toxicity in human induced pluripotent stem cell-derived cardiomyocytes than human adult heart tissue despite similar Na⁺/K⁺-ATPase pump current amplitudes

Abstract

Background and Purpose: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) have gained interest as a pharmacological model but their immaturity leads to uncertainty regarding translation. We studied the key player in maintaining ionic homeostasis, the Na+/K+-ATPase (NKA), in hiPSC-CM. Experimental Approach: Atrial and ventricular engineered heart tissues (EHTs) were produced from hiPSC-CMs. For comparison, adult atrial and ventricular tissues were obtained from patients undergoing open heart surgery. We measured NKA gene expression, NKA pump currents (INKA) and ouabain effects on action potentials and contractility. Computational modelling was used to further investigate the direct and indirect impacts of NKA inhibition. Key Results: The mRNA abundance of the major NKA isoforms was higher in ventricular than atrial cardiomyocytes (adult and hiPSC-CM). Consistently, INKA was also higher in ventricular than in atrial hiPSC-CM and higher in ventricular than in atrial adult cardiomyocytes. Ouabain potency to block INKA did not differ between hiPSC-derived and adult cardiomyocytes. Ouabain shortened plateau phase in EHT and adult tissue. However, lower ouabain concentrations depolarized diastolic potential and depressed force more in EHTs, demonstrating a higher integrated sensitivity to NKA inhibition. Computational modelling indicated that weaker IK1 increases the susceptibility to depolarisation by NKA block. Conclusions and Implications:: HiPSC-EHTs express NKA with biophysical characteristics and ouabain-sensitivity that are not different from human tissue. Action potential duration responses in EHT reproduces chamber-specific response pattern as seen in human heart. The higher sensitivity of EHTs to depolarize under ouabain-induced block of NKA needs to be considered when employing hiPSC-CM in drug research.