Observation of azithromycin-induced cardiotoxicity in mice and its mechanism

ZHEN Xiaolan; LIU Hua; XING Didi; QI Jiayu; GAI Lunan; ZHONG Ming

doi:10.3969/j.issn.1002-266X.2025.02.009

Abstract：Objective To investigate the cardiotoxicity of azithromycin in mice and to explore its potential mecha-nisms.Methods Animal experiment:healthy adult male C57BL/6 mice were randomly divided into low-dose(15 mice),medium-dose(15 mice),high-dose(15 mice),and control(10 mice)groups.Mice in the low-dose,medium-dose,and high-dose groups were intravenously injected with azithromycin at doses of 65,130,and 260 mg/(kg·d),re-spectively,while mice in the control group received normal saline.All mice were treated for 5 days with slow intravenous injection.Twenty-four hours after the last dose,echocardiography and electrocardiography were performed to assess car-diac function.Blood samples were collected from the angular vein to measure serum biomarkers of myocardial injury,in-cluding N-terminal pro-brain natriuretic peptide(NT-proBNP),cardiac troponin I(cTnI),and fatty acid-binding protein 3(FABP3).After euthanasia,heart tissue from the apex was collected for HE staining to observe pathological changes.Cell experiment:HEK293 cells transfected with potassium channel-related genes HERG and KCNQ1/KCNE1 were di-vided into the low-,medium-,high-dose,and control groups.The low-,medium-,and high-dose groups were treated with 0.5,1,and 5 µmol/L of azithromycin,respectively,while the control group received no treatment.After 48 and 72 h of culture,Western blotting was performed to detect the HERG and KCNQ1 protein expression.Results Animal experi-ment showed that,compared with the control group,the medium-dose and high-dose groups showed increased left ventricu-lar ejection fraction(LVEF),increased left ventricular fractional shortening(LVFS),decreased left ventricular internal di-ameter at systole(LVIDs),and prolonged corrected QT interval(QTc)(all P<0.05).There were no significant differ-ences in serum levels of NT-proBNP,cTnI,or FABP3 among the groups(all P>0.05).In the high-dose group,mild inter-stitial congestion and inflammatory cell infiltration were observed in the myocardial tissues.Cell experiment showed that,the relative expression of KCNQ1 protein decreased in the low-,medium-,and high-dose groups after 72 h of culture as compared with that after 48 h treatment(P<0.05).There was no significant difference in the relative expression of HERG protein among these groups(P>0.05).Conclusions Azithromycin exhibits cardiotoxicity,which enhances left ventricular contraction and prolongs the QTc interval in mice.Its cardiotoxic effects may be mediated through inhibiting the expression of the KCNQ1 protein in the myocardial cells.