Doxorubicin (DOX) is a potent anticancer drug, but its clinical use is limited by cardiotoxicity. This study examined the effects of an eight-week high-intensity interval training (HIIT) program, dalteparin (DAL), and their combination on myocardial fibrosis, cardiac function, and FoxO4 expression in a rat model of DOX-induced cardiotoxicity. Thirty-six rats were divided into six groups: Sedentary (SED), HIIT, DOX (4 mg/kg, i.p), DOX + HIIT, DOX + DAL, and DOX + HIIT + DAL. The HIIT program (initiated 2 h after DOX) and DAL treatment (100 U/kg, i.p, administered 1 h after DOX) were conducted three days per week for eight weeks following DOX administration. At the study's end, myocardial fibrosis, cardiac function, and FoxO4 levels were assessed using Masson's trichrome staining, echocardiography, and western blotting, respectively. The combination of HIIT and DAL significantly reduced myocardial fibrosis (p < 0.001) and improved both ejection fraction (%EF) and fractional shortening (%FS). These interventions also normalized electrocardiogram parameters, including QRS (p < 0.01) and QT intervals (p < 0.001). DOX treatment significantly elevated FoxO4 protein levels, whereas interventions with HIIT or DAL (p < 0.01) and, especially, their combination (p < 0.001) markedly reduced these levels. The HIIT program and DAL treatment significantly reduced tissue damage, enhanced cardiac function, and decreased FoxO4 expression in rats. These findings suggest that these strategies may help mitigate DOX-related cardiac injury.
Keywords: Dalteparin; Doxorubicin; Fibrosis; FoxO4; HIIT; Heart; Rats; Toxicity.
© 2025. The Author(s).