Semaglutide preserves myocardial function in a murine model of sequential anthracycline trastuzumab induced early cardiotoxicity: insights from speckle tracking echocardiography

Abstract Introduction Cardiotoxicity is a well-recognized adverse effect of sequential anthracycline and HER2-targeted therapies in cancer patients. While GLP-1 receptor agonists (GLP-1 RAs) have demonstrated cardiovascular benefits in diabetic individuals, their role in preventing chemotherapy-induced cardiotoxicity in non-diabetic settings remains unclear. Purpose To evaluate the cardioprotective effects of semaglutide in a murine model of short-term cardiotoxicity induced by sequential administration of doxorubicin and trastuzumab, using advanced echocardiographic parameters and biochemical profiling. Methods Female C57Bl/6 mice (6–7 weeks old) were randomized into four groups (n = 6/group): control, doxorubicin + trastuzumab (DOXO+TRAST), semaglutide alone, and DOXO+TRAST with semaglutide. Doxorubicin was administered intraperitoneally at 2.17 mg/kg/day for 5 consecutive days, followed by trastuzumab at 2.25 mg/kg/day for 5 days. Semaglutide (140 µg/kg/day s.c.) was co-administered throughout the 10-day protocol. Cardiac function was assessed by transthoracic echocardiography (Vevo 2100, 40 MHz) at baseline and day 10. Parameters included left ventricular ejection fraction (EF), fractional shortening (FS), and myocardial strain (radial and longitudinal) using speckle-tracking analysis. Systemic and cardio-renal biochemical markers (e.g., troponin, NT-proBNP, creatinine, inflammatory cytokines) were also evaluated. Immuneistochemical studies were performed in liver and heart of mice detecting tissue expression of MYD88, NLRP3, IL-1, IL-6, IL18. Results Mice treated with DOXO+TRAST exhibited a significant decline in EF (−20%), FS (−18%), and radial/longitudinal strain (−27% , -32%) versus controls (all p