Key result
Combined treatment with hydroxychloroquine and azithromycin strongly enhanced adverse effects on iPSC-derived cardiomyocytes, including prolonged field potential duration, compared to monotherapy.
Why the study?
HCQ and AZM have been used in combination for COVID-19 despite known cardiac adverse effects and clinical data indicating higher complication rates with combination therapy versus monotherapy.
Does combined treatment with hydroxychloroquine and azithromycin increase cardiotoxicity and electrophysiological dysfunction in human iPSC-derived cardiomyocytes compared to monotherapy?
Does combined treatment with hydroxychloroquine and azithromycin increase cardiotoxicity and electrophysiological dysfunction in human iPSC-derived cardiomyocytes compared to monotherapy?
Combined treatment with hydroxychloroquine and azithromycin synergistically enhances cardiotoxicity and electrophysiological dysfunction in human iPSC-derived cardiomyocytes, providing a mechanistic basis for observed clinical adverse events.
May warrant caution with hydroxychloroquine-azithromycin combinations; leaves open clinical translation of iPSC findings.
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.
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Li et al. (2021) studied Cardiotoxicity in the context of COVID-19 treatment. Hydroxychloroquine and Azithromycin combination vs. Hydroxychloroquine or Azithromycin monotherapy was evaluated on Cardiotoxicity, structural disarrangement, and electrophysiological dysfunctions (e.g., prolonged field potential duration). Combined treatment with hydroxychloroquine and azithromycin strongly enhanced adverse effects on iPSC-derived cardiomyocytes, including prolonged field potential duration, compared to monotherapy.
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