Arrhythmogenic mechanisms of interleukin-6 combination with hydroxychloroquine and azithromycin in inflammatory diseases.

Abstract

Inflammatory diseases including COVID-19 are associated with a cytokine storm characterized by high interleukin-6 (IL-6) titers. In particular, while recent studies examined COVID-19 associated arrhythmic risks from cardiac injury and/or from pharmacotherapy such as the combination of azithromycin (AZM) and hydroxychloroquine (HCQ), the role of IL-6 per se in increasing the arrhythmic risk remains poorly understood. The objective is to elucidate the electrophysiological basis of inflammation-associated arrhythmic risk in the presence of AZM and HCQ. IL-6, AZM and HCQ were concomitantly administered to guinea pigs in-vivo and in-vitro. Electrocardiograms, action potentials and ion-currents were analyzed. IL-6 alone or the combination AZM + HCQ induced mild to moderate reduction in heart rate, PR-interval and corrected QT (QTc) in-vivo and in-vitro. Notably, IL-6 alone was more potent than the combination of the two drugs in reducing heart rate, increasing PR-interval and QTc. In addition, the in-vivo or in-vitro combination of IL-6 + AZM + HCQ caused severe bradycardia, conduction abnormalities, QTc prolongation and asystole. These electrocardiographic abnormalities were attenuated in-vivo by tocilizumab (TCZ), a monoclonal antibody against IL-6 receptor, and are due in part to the prolongation of action potential duration and selective inhibition of Na+, Ca2+ and K+ currents. Inflammation confers greater risk for arrhythmia than the drug combination therapy. As such, in the setting of elevated IL-6 during inflammation caution must be taken when co-administering drugs known to predispose to fatal arrhythmias and TCZ could be an important player as a novel anti-arrhythmic agent. Thus, identifying inflammation as a critical culprit is essential for proper management.

• Authors: Xiaojia Zhu, Yuwei Wang, Yujie Xiao, Qianwen Gao, Li Gao, Wenhui Zhang, Xiaofeng Xin, Kesu Chen, Ujala Srivastava, Vamsi Krishna Murthy Ginjupalli, Michael Cupelli, Pietro Enea Lazzerini, Pier Leopoldo Capecchi, Long Chen, Mohamed Boutjdir
• Journal: Scientific reports (Sci Rep) Vol. 12 Issue 1 Pg. 1075 (01 20 2022) ISSN: 2045-2322 [Electronic] England
• PMID: 35058480 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Antibodies, Monoclonal, Humanized
• Interleukin-6
• Hydroxychloroquine
• Azithromycin
• tocilizumab

Topics

• Animals
• Antibodies, Monoclonal, Humanized (pharmacology)
• Arrhythmias, Cardiac (etiology, metabolism, physiopathology, prevention & control)
• Azithromycin (pharmacology)
• COVID-19 (complications, metabolism, physiopathology)
• Female
• Guinea Pigs
• Humans
• Hydroxychloroquine (pharmacology)
• Inflammation (drug therapy, metabolism, physiopathology)
• Interleukin-6 (antagonists & inhibitors, metabolism)
• Male
• SARS-CoV-2 (metabolism)
• COVID-19 Drug Treatment