Regulation of ICa,L and force by phosphodiesterases in human induced pluripotent stem cell‐derived cardiomyocytes

BACKGROUND AND PURPOSE: Phosphodiesterases (PDE) are important regulators of beta-adrenergic signalling in the heart. While PDE4 is the most important isoform to regulate ICa,L and force in rodent cardiomyocytes, the dominating isoform in adult human cardiomyocytes is PDE3. EXPERIMENTAL APPROACH: Given the potential of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) for biomedical research, this study characterised the contribution of PDE isoforms to the regulation of ICa,L and force in hiPSC-CMs in an engineered heart tissue (EHT) model. KEY RESULTS: This study revealed lower mRNA abundance of PDE3A and 4A in hiPSC-CM EHT than in non-failing human heart samples. Selective inhibition of PDE3 and 4 with cilostamide and rolipram, respectively, revealed that in hiPSC-CM PDE4 was the predominant isoform for the regulation of ICa,L (cilostamide: +1.44 fold, 95% confidence interval: 1.26-1.64, n = 18; rolipram: +1.77 fold, 95% confidence interval: 1.50-2.09, n = 11). Furthermore, in contrast to cilostamide, rolipram decreased the EC50 of isoprenaline (EC50 from 3.0 nM to 0.2 nM, n = 10). CONCLUSION AND IMPLICATIONS: The predominance of PDE4 over PDE3 is a peculiarity of hiPSC-CMs and likely an indicator of immaturity. This finding has implications for the use of hiPSC-CM as a pharmacological model to investigate the effects of PDE inhibitors.