RT Journal Article
SR Electronic
T1 Effects of Hydroxychloroquine and Azithromycin on iPSC-derived Cardiomyocytes: Considerations for the Treatment of COVID-19 Patients
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.08.19.456950
DO 10.1101/2021.08.19.456950
A1 Wener Li
A1 Xiaojing Luo
A1 Mareike S. Poetsch
A1 Reinhard Oertel
A1 Kapil Nichani
A1 Martin Schneider
A1 Anna Strano
A1 Marcel Hasse
A1 Robert-Patrick Steiner
A1 Lukas Cyganek
A1 Karina Hettwer
A1 Steffen Uhlig
A1 Kirsten Simon
A1 Kaomei Guan
A1 Mario Schubert
YR 2021
UL http://biorxiv.org/content/early/2021/08/19/2021.08.19.456950.abstract
AB 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.