In silico investigation of pro-arrhythmic effects of azithromycin on the human ventricle
The macrolide antibiotic azithromycin (AZM) is widely used for respiratory infections and has been suggested to be a possible treatment for the Coronavirus Disease of 2019 (COVID-19). However, AZM-associated QT interval prolongation and arrhythmias have been reported. Integrated mechanistic informat...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-09-01
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| Series: | Biochemistry and Biophysics Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405580821001370 |
| _version_ | 1818644296821112832 |
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| author | Yizhou Liu Rai Zhang Jules C. Hancox Henggui Zhang |
| author_facet | Yizhou Liu Rai Zhang Jules C. Hancox Henggui Zhang |
| author_sort | Yizhou Liu |
| collection | DOAJ |
| description | The macrolide antibiotic azithromycin (AZM) is widely used for respiratory infections and has been suggested to be a possible treatment for the Coronavirus Disease of 2019 (COVID-19). However, AZM-associated QT interval prolongation and arrhythmias have been reported. Integrated mechanistic information on AZM actions on human ventricular excitation and conduction is lacking. Therefore, this study was undertaken to investigate the actions of AZM on ventricular cell and tissue electrical activity. The O'Hara- Virag-Varro-Rudy dynamic (ORd) model of human ventricular cells was modified to incorporate experimental data on the concentration-dependent actions of AZM on multiple ion channels, including INa, ICaL, IKr, IKs, IK1 and INaL in both acute and chronic exposure conditions. In the single cell model, AZM prolonged the action potential duration (APD) in a concentration-dependent manner, which was predominantly attributable to IKr reduction in the acute condition and potentiated INaL in the chronic condition. High concentrations of AZM also increased action potential (AP) triangulation (determined as an increased difference between APD30 and APD90) which is a marker of arrhythmia risk. In the chronic condition, the potentiated INaL caused a modest intracellular Na + concentration accumulation at fast pacing rates. At the 1D tissue level, the AZM-prolonged APD at the cellular level was reflected by an increased QT interval in the simulated pseudo-ECG, consistent with clinical observations. Additionally, AZM reduced the conduction velocity (CV) of APs in the acute condition due to a reduced INa, and it augmented the transmural APD dispersion of the ventricular tissue, which is also pro-arrhythmic. Such actions were markedly augmented when the effects of chronic exposure of AZM were also considered, or with additional IKr block, as may occur with concurrent use of other medications. This study provides insights into the ionic mechanisms by which high concentrations of AZM may modulate ventricular electrophysiology and susceptibility to arrhythmia. |
| first_indexed | 2024-12-17T00:12:36Z |
| format | Article |
| id | doaj.art-550636db16d24eaa9d20bed630b2b3d3 |
| institution | Directory Open Access Journal |
| issn | 2405-5808 |
| language | English |
| last_indexed | 2024-12-17T00:12:36Z |
| publishDate | 2021-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biochemistry and Biophysics Reports |
| spelling | doaj.art-550636db16d24eaa9d20bed630b2b3d32022-12-21T22:10:48ZengElsevierBiochemistry and Biophysics Reports2405-58082021-09-0127101043In silico investigation of pro-arrhythmic effects of azithromycin on the human ventricleYizhou Liu0Rai Zhang1Jules C. Hancox2Henggui Zhang3Biological Physics Group, School of Physics and Astronomy, University of Manchester, Manchester, United KingdomSchool of Civil, Aerospace and Mechanical Engineering, University of Bristol, United KingdomBiological Physics Group, School of Physics and Astronomy, University of Manchester, Manchester, United Kingdom; School of Physiology, Pharmacology and Neuroscience, Cardiovascular Research Laboratories, School of Medical Sciences, University of Bristol, Bristol, United Kingdom; Corresponding author. School of Physiology, Pharmacology and Neuroscience, Cardiovascular Research Laboratories, School of Medical Sciences, University of Bristol, Bristol, United Kingdom.Biological Physics Group, School of Physics and Astronomy, University of Manchester, Manchester, United Kingdom; Qingdao National Laboratory for Marine Science and Technology, Qingdao, China; Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China; Corresponding author. Biological Physics Group, School of Physics and Astronomy, University of Manchester, Manchester, United Kingdom.The macrolide antibiotic azithromycin (AZM) is widely used for respiratory infections and has been suggested to be a possible treatment for the Coronavirus Disease of 2019 (COVID-19). However, AZM-associated QT interval prolongation and arrhythmias have been reported. Integrated mechanistic information on AZM actions on human ventricular excitation and conduction is lacking. Therefore, this study was undertaken to investigate the actions of AZM on ventricular cell and tissue electrical activity. The O'Hara- Virag-Varro-Rudy dynamic (ORd) model of human ventricular cells was modified to incorporate experimental data on the concentration-dependent actions of AZM on multiple ion channels, including INa, ICaL, IKr, IKs, IK1 and INaL in both acute and chronic exposure conditions. In the single cell model, AZM prolonged the action potential duration (APD) in a concentration-dependent manner, which was predominantly attributable to IKr reduction in the acute condition and potentiated INaL in the chronic condition. High concentrations of AZM also increased action potential (AP) triangulation (determined as an increased difference between APD30 and APD90) which is a marker of arrhythmia risk. In the chronic condition, the potentiated INaL caused a modest intracellular Na + concentration accumulation at fast pacing rates. At the 1D tissue level, the AZM-prolonged APD at the cellular level was reflected by an increased QT interval in the simulated pseudo-ECG, consistent with clinical observations. Additionally, AZM reduced the conduction velocity (CV) of APs in the acute condition due to a reduced INa, and it augmented the transmural APD dispersion of the ventricular tissue, which is also pro-arrhythmic. Such actions were markedly augmented when the effects of chronic exposure of AZM were also considered, or with additional IKr block, as may occur with concurrent use of other medications. This study provides insights into the ionic mechanisms by which high concentrations of AZM may modulate ventricular electrophysiology and susceptibility to arrhythmia.http://www.sciencedirect.com/science/article/pii/S2405580821001370AzithromycinArrhythmiaCardiac modellingHuman ventricleCOVID-19 |
| spellingShingle | Yizhou Liu Rai Zhang Jules C. Hancox Henggui Zhang In silico investigation of pro-arrhythmic effects of azithromycin on the human ventricle Biochemistry and Biophysics Reports Azithromycin Arrhythmia Cardiac modelling Human ventricle COVID-19 |
| title | In silico investigation of pro-arrhythmic effects of azithromycin on the human ventricle |
| title_full | In silico investigation of pro-arrhythmic effects of azithromycin on the human ventricle |
| title_fullStr | In silico investigation of pro-arrhythmic effects of azithromycin on the human ventricle |
| title_full_unstemmed | In silico investigation of pro-arrhythmic effects of azithromycin on the human ventricle |
| title_short | In silico investigation of pro-arrhythmic effects of azithromycin on the human ventricle |
| title_sort | in silico investigation of pro arrhythmic effects of azithromycin on the human ventricle |
| topic | Azithromycin Arrhythmia Cardiac modelling Human ventricle COVID-19 |
| url | http://www.sciencedirect.com/science/article/pii/S2405580821001370 |
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