Cardiotoxicity induced by the combination therapy of chloroquine and azithromycin in human embryonic stem cell-derived cardiomyocytes

Abstract

Combination therapy using chloroquine (CQ) and azithromycin (AZM) has drawn great attention due to its potential anti-viral activity against SARS-CoV-2. However, clinical trials have revealed that the co-administration of CQ and AZM resulted in severe side effects, including cardiac arrhythmia, in patients with COVID-19. To elucidate the cardiotoxicity induced by CQ and AZM, we examined the effects of these drugs based on the electrophysiological properties of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) using multi-electrode arrays. CQ treatment significantly increased the field potential duration, which corresponds to prolongation of the QT interval, and decreased the spike amplitude, spike slope, and conduction velocity of hESC-CMs. AZM had no significant effect on the field potentials of hESC-CMs. However, CQ in combination with AZM greatly increased the field potential duration and decreased the beat period and spike slope of hESC-CMs when compared with CQ monotherapy. In support of the clinical data suggesting the cardiovascular side effects of the combination therapy of CQ and AZM, our results suggest that AZM reinforces the cardiotoxicity induced by CQ in hESC-CMs.

The SARS-CoV-2/Receptor Axis in Heart and Blood Vessels: A Crisp Update on COVID-19 Disease with Cardiovascular Complications

“…Furthermore, an array of cytokines and chemokines (IL-6, IL-8, tumor necrosis factor (TNF)-α, CXCL1 and CXCL2) from iPSC-cardiomyocytes were released to assist further injury [ 261 ]. Recently employed drugs such as chloroquine (CQ) and azithromycin (AZM) to treat SARS-CoV-2 infection, were also tested on the human embryonic stem cell derived cardiomyocytes to investigate the drug induced cardiotoxicity, which reinforced the findings obtained from clinical data [ 262 ]. Apart, a demand for more complex physiological environment could be fulfilled using suitable animal models, including mice, humanized mice, hamsters, ferrets, non-human primates [ 259 ].…”