TY - JOUR T1 - Effects of Hydroxychloroquine and Azithromycin on iPSC-derived Cardiomyocytes: Considerations for the Treatment of COVID-19 Patients JF - bioRxiv DO - 10.1101/2021.08.19.456950 SP - 2021.08.19.456950 AU - Wener Li AU - Xiaojing Luo AU - Mareike S. Poetsch AU - Reinhard Oertel AU - Kapil Nichani AU - Martin Schneider AU - Anna Strano AU - Marcel Hasse AU - Robert-Patrick Steiner AU - Lukas Cyganek AU - Karina Hettwer AU - Steffen Uhlig AU - Kirsten Simon AU - Kaomei Guan AU - Mario Schubert Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/08/19/2021.08.19.456950.abstract N2 - Despite known adverse effects of hydroxychloroquine (HCQ) and azithromycin (AZM) on cardiac function, HCQ and AZM have been used as combination therapy in the treatment of COVID-19 patients. Recent clinical data indicate higher complication rates with HCQ/AZM combination treatment in comparison to monotherapy. Here, we used human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to systematically investigate the effects of HCQ and AZM individually and in combination. The clinically observed QT prolongation caused by treatment with HCQ could be recapitulated in iPSC-CMs based on prolonged field potential duration (FPDc). Interestingly, HCQ-induced FPDc prolongation was strongly enhanced by combined treatment with AZM, although AZM alone slightly shortened FPDc in iPSC-CMs. Furthermore, combined treatment with AZM and HCQ leads to higher cardiotoxicity, more severe structural disarrangement, and more pronounced contractile and electrophysiological dysfunctions, compared to respective mono-treatments. First mechanistic insights underlying the synergistic effects of AZM and HCQ on iPSC-CM functionality are provided based on increased Cx43- and Nav1.5-protein levels. Taken together, our results highlight that combined treatment with HCQ and AZM strongly enhances the adverse effects on cardiomyocytes, providing mechanistic evidence for the high mortality in patients receiving HCQ/AZM combination treatment.Competing Interest StatementThe authors have declared no competing interest. ER -