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Hydroxychloroquine and azithromycin alter the contractility of living porcine heart slices

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 mechanism...

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Autores principales: Wu, Qin, Ross, Abigail J., Ipek, Tugce, Thompson, Georgina H., Johnson, Robert D., Wu, Changhao, Camelliti, Patrizia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10196358/
https://www.ncbi.nlm.nih.gov/pubmed/37214466
http://dx.doi.org/10.3389/fphar.2023.1127388
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author Wu, Qin
Ross, Abigail J.
Ipek, Tugce
Thompson, Georgina H.
Johnson, Robert D.
Wu, Changhao
Camelliti, Patrizia
author_facet Wu, Qin
Ross, Abigail J.
Ipek, Tugce
Thompson, Georgina H.
Johnson, Robert D.
Wu, Changhao
Camelliti, Patrizia
author_sort Wu, Qin
collection PubMed
description 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.
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spelling pubmed-101963582023-05-20 Hydroxychloroquine and azithromycin alter the contractility of living porcine heart slices Wu, Qin Ross, Abigail J. Ipek, Tugce Thompson, Georgina H. Johnson, Robert D. Wu, Changhao Camelliti, Patrizia Front Pharmacol Pharmacology 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. Frontiers Media S.A. 2023-05-05 /pmc/articles/PMC10196358/ /pubmed/37214466 http://dx.doi.org/10.3389/fphar.2023.1127388 Text en Copyright © 2023 Wu, Ross, Ipek, Thompson, Johnson, Wu and Camelliti. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Wu, Qin
Ross, Abigail J.
Ipek, Tugce
Thompson, Georgina H.
Johnson, Robert D.
Wu, Changhao
Camelliti, Patrizia
Hydroxychloroquine and azithromycin alter the contractility of living porcine heart slices
title Hydroxychloroquine and azithromycin alter the contractility of living porcine heart slices
title_full Hydroxychloroquine and azithromycin alter the contractility of living porcine heart slices
title_fullStr Hydroxychloroquine and azithromycin alter the contractility of living porcine heart slices
title_full_unstemmed Hydroxychloroquine and azithromycin alter the contractility of living porcine heart slices
title_short Hydroxychloroquine and azithromycin alter the contractility of living porcine heart slices
title_sort hydroxychloroquine and azithromycin alter the contractility of living porcine heart slices
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10196358/
https://www.ncbi.nlm.nih.gov/pubmed/37214466
http://dx.doi.org/10.3389/fphar.2023.1127388
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