BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Cardiotoxicity induced by the combination therapy of chloroquine and azithromycin in human embryonic stem cell-derived cardiomyocytes

  • Kim, Ye Seul (Department of Physiology, School of Medicine, Pusan National University) ;
  • Lee, Soo Yong (Division of Cardiology, Department of Internal Medicine and Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine) ;
  • Yoon, Jung Won (Department of Physiology, School of Medicine, Pusan National University) ;
  • Kim, Dasol (Department of Physiology, School of Medicine, Pusan National University) ;
  • Yu, Sangbin (Department of Physiology, School of Medicine, Pusan National University) ;
  • Kim, Jeong Su (Division of Cardiology, Department of Internal Medicine and Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine) ;
  • Kim, Jae Ho (Department of Physiology, School of Medicine, Pusan National University)
  • Received : 2020.08.09
  • Accepted : 2020.08.26
  • Published : 2020.10.31
Download PDF
⟨ Previous Next ⟩

Abstract

Combination therapy using chloroquine (CQ) and azithromycin (AZM) has drawn great attention due to its potential anti-viral activity against SARS-CoV-2. However, clinical trials have revealed that the co-administration of CQ and AZM resulted in severe side effects, including cardiac arrhythmia, in patients with COVID-19. To elucidate the cardiotoxicity induced by CQ and AZM, we examined the effects of these drugs based on the electrophysiological properties of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) using multi-electrode arrays. CQ treatment significantly increased the field potential duration, which corresponds to prolongation of the QT interval, and decreased the spike amplitude, spike slope, and conduction velocity of hESC-CMs. AZM had no significant effect on the field potentials of hESC-CMs. However, CQ in combination with AZM greatly increased the field potential duration and decreased the beat period and spike slope of hESC-CMs when compared with CQ monotherapy. In support of the clinical data suggesting the cardiovascular side effects of the combination therapy of CQ and AZM, our results suggest that AZM reinforces the cardiotoxicity induced by CQ in hESC-CMs.

Keywords

References

  1. Savarino A, Boelaert JR, Cassone A, Majori G and Cauda R (2003) Effects of chloroquine on viral infections: an old drug against today's diseases? Lancet Infect Dis 3, 722-727 https://doi.org/10.1016/S1473-3099(03)00806-5
  2. Savarino A, Di Trani L, Donatelli I, Cauda R and Cassone A (2006) New insights into the antiviral effects of chloroquine. Lancet Infect Dis 6, 67-69 https://doi.org/10.1016/S1473-3099(06)70361-9
  3. Vincent MJ, Bergeron E, Benjannet S et al (2005) Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J 2, 69 https://doi.org/10.1186/1743-422X-2-69
  4. Wang M, Cao R, Zhang L et al (2020) Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 30, 269-271 https://doi.org/10.1038/s41422-020-0282-0
  5. Yao X, Ye F, Zhang M et al (2020) In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis 71, 732-739 https://doi.org/10.1093/cid/ciaa237
  6. Gautret P, Lagier JC, Parola P et al (2020) Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 56, 105949 https://doi.org/10.1016/j.ijantimicag.2020.105949
  7. Colson P, Rolain JM and Raoult D (2020) Chloroquine for the 2019 novel coronavirus SARS-CoV-2. Int J Antimicrob Agents 55, 105923 https://doi.org/10.1016/j.ijantimicag.2020.105923
  8. Satarker S, Ahuja T, Banerjee M et al (2020) Hydroxychloroquine in COVID-19: Potential mechanism of action against SARS-CoV-2. Curr Pharmacol Rep 6, 203-211 https://doi.org/10.1007/s40495-020-00231-8
  9. Das S, Bhowmick S, Tiwari S and Sen S (2020) An Updated Systematic Review of the Therapeutic Role of Hydroxychloroquine in Coronavirus Disease-19 (COVID-19). Clin Drug Investig 40, 591-601 https://doi.org/10.1007/s40261-020-00927-1
  10. Pillat MM, Kruger A, Guimaraes LMF et al (2020) Insights in chloroquine action: perspectives and implications in Malaria and COVID-19. Cytometry A 97, 872-881 https://doi.org/10.1002/cyto.a.24190
  11. Boulware DR, Pullen MF, Bangdiwala AS et al (2020) A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Engl J Med 383, 517-525 https://doi.org/10.1056/NEJMoa2016638
  12. Chatre C, Roubille F, Vernhet H, Jorgensen C and Pers YM (2018) Cardiac Complications Attributed to Chloroquine and Hydroxychloroquine: A Systematic Review of the Literature. Drug Saf 41, 919-931 https://doi.org/10.1007/s40264-018-0689-4
  13. White NJ (2007) Cardiotoxicity of antimalarial drugs. Lancet Infect Dis 7, 549-558 https://doi.org/10.1016/S1473-3099(07)70187-1
  14. Min JY and Jang YJ (2012) Macrolide therapy in respiratory viral infections. Mediators Inflamm 2012, 649570
  15. Tran DH, Sugamata R, Hirose T et al (2019) Azithromycin, a 15-membered macrolide antibiotic, inhibits influenza A (H1N1)pdm09 virus infection by interfering with virus internalization process. J Antibiot (Tokyo) 72, 759-768 https://doi.org/10.1038/s41429-019-0204-x
  16. Scherrmann JM (2020) Intracellular ABCB1 as a Possible Mechanism to Explain the Synergistic Effect of Hydroxychloroquine-Azithromycin Combination in COVID-19 Therapy. AAPS J 22, 86 https://doi.org/10.1208/s12248-020-00465-w
  17. Ohe M, Shida H, Jodo S et al (2020) Macrolide treatment for COVID-19: Will this be the way forward? Biosci Trends 14, 159-160 https://doi.org/10.5582/bst.2020.03058
  18. Chorin E, Dai M, Shulman E et al (2020) The QT interval in patients with COVID-19 treated with hydroxychloroquine and azithromycin. Nat Med 26, 808-809 https://doi.org/10.1038/s41591-020-0888-2
  19. Ramireddy A, Chugh H, Reinier K et al (2020) Experience With Hydroxychloroquine and Azithromycin in the Coronavirus Disease 2019 Pandemic: Implications for QT Interval Monitoring. J Am Heart Assoc 9, e017144
  20. Juurlink DN (2014) The cardiovascular safety of azithromycin. CMAJ 186, 1127-1128 https://doi.org/10.1503/cmaj.140572
  21. Mitra RL, Greenstein SA and Epstein LM (2020) An algorithm for managing QT prolongation in coronavirus disease 2019 (COVID-19) patients treated with either chloroquine or hydroxychloroquine in conjunction with azithromycin: Possible benefits of intravenous lidocaine. Heart Rhythm Case Rep 6, 244-248
  22. Ray WA, Murray KT, Hall K, Arbogast PG and Stein CM (2012) Azithromycin and the risk of cardiovascular death. N Engl J Med 366, 1881-1890 https://doi.org/10.1056/NEJMoa1003833
  23. Juurlink DN (2020) Safety considerations with chloroquine, hydroxychloroquine and azithromycin in the management of SARS-CoV-2 infection. CMAJ 192, E450-E453 https://doi.org/10.1503/cmaj.200528
  24. Gintant G, Sager PT and Stockbridge N (2016) Evolution of strategies to improve preclinical cardiac safety testing. Nat Rev Drug Discov 15, 457-471 https://doi.org/10.1038/nrd.2015.34
  25. Satsuka A and Kanda Y (2020) Cardiotoxicity Assessment of Drugs Using Human iPS Cell-Derived Cardiomyocytes: Toward Proarrhythmic Risk and Cardio-Oncology. Curr Pharm Biotechnol 21, 765-772 https://doi.org/10.2174/1389201020666190628143345
  26. Sharma A, McKeithan WL, Serrano R et al (2018) Use of human induced pluripotent stem cell-derived cardiomyocytes to assess drug cardiotoxicity. Nat Protoc 13, 3018-3041 https://doi.org/10.1038/s41596-018-0076-8
  27. Thomson JA, Itskovitz-Eldor J, Shapiro SS et al (1998) Embryonic stem cell lines derived from human blastocysts. Science 282, 1145-1147 https://doi.org/10.1126/science.282.5391.1145
  28. Cheng DK, Tung L and Sobie EA (1999) Nonuniform responses of transmembrane potential during electric field stimulation of single cardiac cells. Am J Physiol 277, H351-362
  29. Rast G, Weber J, Disch C, Schuck E, Ittrich C and Guth BD (2015) An integrated platform for simultaneous multiwell field potential recording and Fura-2-based calcium transient ratiometry in human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes. J Pharmacol Toxicol Methods 75, 91-100 https://doi.org/10.1016/j.vascn.2015.04.005
  30. Inciardi RM, Lupi L, Zaccone G et al (2020) Cardiac Involvement in a Patient With Coronavirus Disease 2019 (COVID-19). JAMA Cardiol 5, 819-824 https://doi.org/10.1001/jamacardio.2020.1096
  31. Sala S, Peretto G, Gramegna M et al (2020) Acute myocarditis presenting as a reverse Tako-Tsubo syndrome in a patient with SARS-CoV-2 respiratory infection. Eur Heart J 41, 1861-1862 https://doi.org/10.1093/eurheartj/ehaa286
  32. Tavazzi G, Pellegrini C, Maurelli M et al (2020) Myocardial localization of coronavirus in COVID-19 cardiogenic shock. Eur J Heart Fail 22, 911-915 https://doi.org/10.1002/ejhf.1828
  33. Sirenko O, Crittenden C, Callamaras N et al (2013) Multiparameter in vitro assessment of compound effects on cardiomyocyte physiology using iPSC cells. J Biomol Screen 18, 39-53 https://doi.org/10.1177/1087057112457590
  34. Traebert M, Dumotier B, Meister L, Hoffmann P, Dominguez-Estevez M and Suter W (2004) Inhibition of hERG K+ currents by antimalarial drugs in stably transfected HEK293 cells. Eur J Pharmacol 484, 41-48 https://doi.org/10.1016/j.ejphar.2003.11.003
  35. Mubagwa K (2020) Cardiac effects and toxicity of chloroquine: a short update. Int J Antimicrob Agents 56, 106057 https://doi.org/10.1016/j.ijantimicag.2020.106057
  36. Vicente J, Zusterzeel R, Johannesen L et al (2019) Assessment of Multi-Ion Channel Block in a Phase I Randomized Study Design: Results of the CiPA Phase I ECG Biomarker Validation Study. Clin Pharmacol Ther 105, 943-953 https://doi.org/10.1002/cpt.1303
  37. Haeusler IL, Chan XHS, Guerin PJ and White NJ (2018) The arrhythmogenic cardiotoxicity of the quinoline and structurally related antimalarial drugs: a systematic review. BMC Med 16, 200 https://doi.org/10.1186/s12916-018-1188-2
  38. Lian X, Zhang J, Azarin SM et al (2013) Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/beta-catenin signaling under fully defined conditions. Nat Protoc 8, 162-175 https://doi.org/10.1038/nprot.2012.150
  39. Lian X, Hsiao C, Wilson G et al (2012) Robust cardiomyocyte differentiation from human pluripotent stem cells via temporal modulation of canonical Wnt signaling. Proc Natl Acad Sci U S A 109, E1848-1857 https://doi.org/10.1073/pnas.1200250109
  40. Tohyama S, Hattori F, Sano M et al (2013) Distinct metabolic flow enables large-scale purification of mouse and human pluripotent stem cell-derived cardiomyocytes. Cell Stem Cell 12, 127-137 https://doi.org/10.1016/j.stem.2012.09.013