Abstract
Adverse effects of drug combinations and their underlying mechanisms are highly relevant for safety evaluation, but often not fully studied. Hydroxychloroquine (HCQ) and azithromycin (AZM) were used as a combination therapy in the treatment of COVID-19 patients at the beginning of the pandemic, leading to higher complication rates in comparison to respective monotherapies. Here, we used human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to systematically investigate the effects of HCQ, AZM, and their combination on the structure and functionality of cardiomyocytes, and to better understand the underlying mechanisms. Our results demonstrate synergistic adverse effects of AZM and HCQ on electrophysiological and contractile function of iPSC-CMs. HCQ-induced prolongation of field potential duration (FPDc) was gradually increased during 7-day treatment period and was strongly enhanced by combination with AZM, although AZM alone slightly shortened FPDc in iPSC-CMs. Combined treatment with AZM and HCQ leads to higher cardiotoxicity, more severe structural disarrangement, more pronounced contractile dysfunctions, and more elevated conduction velocity, compared to respective monotreatments. Mechanistic insights underlying the synergistic effects of AZM and HCQ on iPSC-CM functionality are provided based on increased cellular accumulation of HCQ and AZM as well as increased Cx43- and Nav1.5-protein levels.
Highlights
Cardiotoxicity represents one of the top reasons for drug withdrawal from clinical trials and the market, with increasing attrition rates over the past decades [1]
Since conduction disorders were the most frequent side effect that appeared in COVID-19 patients who were administrated with HCQ and AZM [38], we examined the impact of the two drugs on cardiac conduction velocity (CV) in iPSC-CM model
In contrast to acute functional changes caused by inhibition of ion channels, cardioIn contrast to acute functional changes caused by inhibition of ion channels, cartoxic effects and reduced cell viability induced through mitochondrial dysfunction or imdiotoxic effects and reduced cell viability induced through mitochondrial dysfunction or paired autophagy may establish during longer time scales
Summary
Cardiotoxicity represents one of the top reasons for drug withdrawal from clinical trials and the market, with increasing attrition rates over the past decades [1]. One of the major cardiotoxic effects is fatal cardiac arrhythmia due to direct drug interactions with cardiac electrophysiology. Pharmaceuticals 2022, 15, 220 has been focused primarily on the investigation of ion channel functions and their associated abnormalities in action potentials and conduction velocity. Many studies reveal that mechanisms of cardiotoxicity are more complex, go beyond effects on cardiac electrophysiology [1,2], and involve dysregulation of a variety of cellular processes such as calcium cycling, cellular trafficking, mitochondrial function, and apoptosis [1]. Consequences of impaired trafficking or apoptosis may establish during prolonged exposure to a drug, especially if drug accumulation occurs even though the compound is applied in a rather low, clinically relevant concentration
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