The Possible Protective Effect of Atorvastatin on Azithromycin-Induced Cardiotoxicity in Adult Male Albino Rat: Light &Electron Microscopic Study.

Document Type : Original articles


1 Medical Histology & Cell Biology Department, Faculty of Medicine, Beni-Suef University

2 Medical Histology & Cell Biology Department, Faculty of Medicine, Nahda University, Egypt


Background: With its antiviral and immunomodulatory actions, Azithromycin has been used in the protocol for treating COVID-19, either in conjunction with Hydroxychloroquine or on its own more recently. Myocardial apoptosis, oxidative stress and inflammation were all seen in rat models after Azithromycin treatment. A synthetic statin called atorvastatin has antioxidant and antiapoptotic properties that help reduce the damage caused by myocardial ischemia. The purpose of this research was to see whether Atorvastatin may mitigate the cardiotoxic effects of Azithromycin. Aim of the work: This study was performed to investigate histologically the possible protective effect of Atorvastatin on Azithromycin-induced cardiotoxicity in adult male albino rats. Materials and Methods: A total of 40 adult male albino rats were randomly split into four groups of ten animals each and treated with either a placebo, Azithromycin, Atorvastatin, or both. For two weeks, an intragastric tube delivered 30 milligrams of azithromycin per kilogram of body weight and 2 milligrams of atorvastatin. Rats were sacrified twenty-four hours after the final treatment, then their hearts were removed, and apical portions were processed for examination using light and electron microscopes followed by statistical testing. Results: Cardiac myocytes in the azithromycin group had fewer cross striations, an increase in inflammatory cell infiltration, a greater deposition of collagen fibers, localized degeneration of myofibers, disruption of sarcomeres, mitochondrial damage, and nuclear pyknosis. The atorvastatin and azithromycin-treated group saw these improvements first. Conclusion: Light and electron microscopy results demonstrated that the Atorvastatin group had restored cardiac muscle fibers.


Main Subjects

  1. Zimmermann P., Ziesenitz V.C., Curtis N., Ritz N. (2018): The immunomodulatory effects of macrolides—a systematic review of the underlying mechanisms. Front. Immunol. 9. 302.
  2. Andreani J., Le Bideau M., Duflot I., Jardot P., Rolland C., Boxberger M. (2020): In vitro testing of combined hydroxychloroquine and azithromycin on SARS-CoV-2 shows synergistic effect. Microb. Pathog. 145.104228.
  3. Du X., Zuo X., Meng F., Wu F., Zhao X., Li C. (2020): Combinatorial screening of a panel of FDA-approved drugs identifies several candidates with anti-Ebola activities. Biochem. Biophys. Res. Commun. 522. 862–868.
  4. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M. (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 .
  5. El-Shitany N.A., El-Desoky K. (2016): Protective effects of carvedilol and vitamin C against azithromycin-induced cardiotoxicity in rats via decreasing ROS, IL1-β, and TNF-α production and inhibiting NF-κB and caspase-3 expression. Oxidative Med. Cell. Longev. 2016:1874762.
  6. Patel H., Calip G.S., DiDomenico R.J., Schumock G.T., Suda K.J., Lee T.A. (2019): Prevalence of cardiac risk factors in patients prescribed azithromycin before and after the 2012 FDA warning on the risk of potentially fatal heart rhythms. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy. 40. 107–115.
  7. Durrington PN, Mackness B, Mcknesss MI, (2011): Paraoxanase and atherosclerosis. Atheroscler Thromb Vasc Biol. 21. 473–480.                  
  8. Bouitbir J, Charles AL, Echaniz-Laguna A, Kindo M, Daussin F, Auwerx J, Piquard F, Geny B, Zoll J. (2012): Opposite effects of statins on mitochondria of cardiac and skeletal muscles: A ‘mitohormesis’ mechanism involving reactive oxygen species and pgc-1 Eur Heart J . 33. 1397-1407.
  9. Gao F, Ni Y, Luo Z, Liang Y, Yan Z, Xu X, Liu D, Wang J, Zhu S, Zhu Z. (2012): Atorvastatin attenuates tnf-alpha-induced increase of glucose oxidation through pgc-1alpha upregulation in cardiomyocytes. J Cardiovasc Pharmacol.59.500-506.
  10. Mihaylova B, Emberson J, Blackwell L, Keech A, Simes J, Barnes EH, Voysey M, Gray A, Collins R, Baigent C. (2012): The effects of lowering ldl cholesterol with statin therapy in people at low risk of vascular disease: Meta- analysis of individual data from 27 randomised trials. Lancet. 380. 581-590.
  11. Atli O., Ilgin S., Altuntas H., Burukoglu D. (2015): Evaluation of azithromycin induced cardiotoxicity in rats. Int. J. Clin. Exp. Med. 8. 3681–3690.
  12. Kim Y.-H., Park S.-M., Kim M., Kim S.H., Lim S.-Y., Ahn J.-C. (2012): Cardioprotective effects of rosuvastatin and carvedilol on delayed cardiotoxicity of doxorubicin in rats. Toxicol. Mech. Methods. 22. 488–498.
  13. Kiernan J K. (2001): Histological and Histochemical methods. In: Theory and practice. 3rd ed, London, New York, and New Delhy, Arnold Publisher.111-162 .
  14. Bancroft JD, Layton (2013): The hematoxylin and eosin, connective and mesenchymal tissues with their stains. In: Suvarna SK, Layton C and Bancroft JD, editors. Bancroft’s Theory and Practice of Histological Techniques. 7th edition, ch 10 and 11, Philadelphia, Churchill Living one. 173 – 212.
  15. Woods AE, Stirling JW, (2013): Transmission electron microscopy applications. In: Suvarna SK, Layton C, Bancroft JD, editors. Theory and Practical Histological Techniques. 7th edition, ch 22, Philadelphia, Churchill Living one; 493 – 538.
  16. Emsley R., Dunn G. and White I. (2010): Mediation and moderation of treatment effects in randomized controlled trials of complex interventions. Stat Methods Med Res. 19(3). 237–270.
  17. Ruan Q, Yang K, Wang W, Jiang L, Song J. (2020): Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 46. 846–848.
  18. Farías JG, Molina VM, Carrasco RA, Zepeda AB, Figueroa E, Letelier P. (2017): Antioxidant therapeutic strategies for cardiovascular conditions associated with oxidative stress. Nutrients. 9. 966.
  19. Yosef T, Damri O, Agam G.(2019): Dual role of autophagy in diseases of the central nervous system. Front Cell Neurosci. 13. 196.
  20. Dawood A and Hareedy H (2019): Differential effect of high fat diet (HFD) on the cardiac muscle of adult and aged female mice and the possible protective role of artichoke treatment: Histomorphometric and ultrastructural study. J Med Hist, Article 3, Volume 3, Issue 1, 36-54.
  21. Paradies G, Paradies V, Ruggiero FM, Petrosillo G.(2018): Mitochondrial bioenergetics and cardiolipin alterations in myocardial ischemia-reperfusion injury: implications for pharmacological cardioprotection. Am J Physiol Heart Circ Physiol. 315. 1342.
  22. Songbo M, Lang H, Xinyong C, Bin X, Ping Z, Liang S.(2019): Oxidative stress injury in doxorubicin-induced cardiotoxicity. Toxicol Lett. Vol: 307.Issue:48.
  23. -P. An, S.-K. An, X.-H. Wei, S.-Y. Fu, H.-A. Wu. (2015): Atorvastatin improves cardiac function of rats with chronic cardiac failure via inhibiting Rac1/P47phox/P67phox-mediated ROS release. 20. 3940-3946.
  24. Ramasubbu K, Estep J, White DL, Deswal A, Mann DL. (2008): Experimental and clinical basis for the use of statins in patients with ischemic and nonischemic cardiomyopathy. J Am Coll Cardiol .51. 415-426.
  25. Sharma H., Pathan R.A., Kumar V., Javed S., Bhandari U. (2011): Anti-apoptotic potential of rosuvastatin pretreatment in murine model of cardiomyopathy. Int. J. Cardiol. 150. 193–200.
  26. Anna B, Nikolas G. (2011): Aging and cardiac fibrosis. Aging and Disease. 2. 158-173.
  27. Lin J, Lopez EF, Yufang Jin Y, Remmen HV, Bauch T, Han HC , Lindsey ML.(2008): Age-Related Cardiac Muscle Sarcopenia: Combining experimental and mathematical modeling to identify mechanisms. Exp 43(4). 296–306.
  28. Datta S, Cano M, Ebrahimi K, Wang L, Handa JT.(2017): The impact of oxidative stress and inflammation on RPE degeneration in non-neovascular AMD. Prog Retin Eye Res. 60. 218.
  29. Zeng H.-T, Zhao M,  Zhang  -X, Liu  Z.-L, , Zhong S.-M. (2019):  Atorvastatin improves the cardiac function of rats after acute myocardial infarction through ERK1/2 pathway. 23(16):7120-7127.