PDF(Pubmed)
Abstract：
The cardiotoxicity risk of hydroxychloroquine (HCQ) and azithromycin (AZM) has been the subject of intensive research triggered by safety concerns in COVID-19 patients. HCQ and AZM have been associated with QT interval prolongation and drug-induced arrhythmias, however other cardiotoxicity mechanisms remain largely unexplored. Our group has pioneered the living heart slice preparation, an ex-vivo platform that maintains native cardiac tissue architecture and physiological electrical and contractile properties. Here, we evaluated the cardiotoxic effect of HCQ and AZM applied alone or in combination on cardiac contractility by measuring contractile force and contraction kinetics in heart slices prepared from porcine hearts. Our results show that clinically relevant concentrations of HCQ monotherapy (1-10 µM) reduced contractile force and contraction kinetics in porcine slices in a dose-dependent manner. However, AZM monotherapy decreased contractile force and contraction kinetics only at higher concentrations (30 µM). Combination of HCQ and AZM induced a dose-dependent effect similar to HCQ alone. Furthermore, pre-treating porcine heart slices with the L-type calcium channel agonist Bay K8644 prevented the effect of both drugs, while administration of Bay K8644 after drugs interventions largely reversed the effects, suggesting a mechanism involving inhibition of L-type calcium channels. These findings indicate that HCQ and AZM alter cardiac function beyond QT prolongation with significant contractile dysfunction in intact cardiac tissue. Our porcine heart slices provide a powerful platform to investigate mechanisms of drug cardiotoxicity.
摘要：
羟氯喹（HCQ）和阿奇霉素（AZM）的心脏毒性风险一直是COVID-19患者安全性问题引发的深入研究主题。HCQ和AZM与QT间期延长和药物诱发的心律失常有关，然而，其他心脏毒性机制仍未被探索。我们小组开创了活体心脏切片的制备，维持天然心脏组织结构以及生理电和收缩特性的离体平台。这里,我们通过测量由猪心脏制备的心脏切片的收缩力和收缩动力学,评估了HCQ和AZM单独或联合应用对心脏收缩力的心脏毒性作用.我们的结果表明，HCQ单一疗法的临床相关浓度（1-10µM）以剂量依赖性方式降低了猪切片中的收缩力和收缩动力学。然而,AZM单一疗法仅在较高浓度（30µM）时降低了收缩力和收缩动力学。HCQ和AZM的组合诱导类似于单独的HCQ的剂量依赖性效应。此外，用L型钙通道激动剂BayK8644预处理猪心脏切片可防止两种药物的作用，而在药物干预后，BayK8644的管理在很大程度上扭转了这种影响，提示涉及抑制L型钙通道的机制。这些发现表明HCQ和AZM改变了超过QT延长的心脏功能，在完整的心脏组织中具有明显的收缩功能障碍。我们的猪心脏切片为研究药物心脏毒性机制提供了强大的平台。
