Improvement of cardiac function by Ivabradine in a doxorubicin-induced cardiomyopathy murine model is associated with a normal renal angiotensin II type I receptor expression but not with a reduction in fibrosis

Ivabradine (IVAB) is an effective drug in patients with heart failure (HF). However, data in the context of chemotherapy-induced cardiomyopathy are limited. This study investigated the cardioprotective potential of IVAB in a doxorubicin (DOXO)-induced HF murine model, evaluating its effects on cardiac function, fibrosis, and its interaction with the renin-angiotensin system. C57BLC/6 female mice (n = 36) completed the protocol and were allocated into 2 groups: control (CTRL, n = 4) and treatment by DOXO (n = 32). DOXO administration (4 mg/kg/week, intraperitoneal) was performed over 5 weeks and followed by a 10-week gavage treatment with either water (H2O), IVAB (10 mg/kg/day), or metoprolol (METO, 100 mg/kg/day). Cardiac and kidney remodeling were assessed by echocardiography, pathology (with fibrosis assessed by picrosirius red (PSR) staining), and in vitro 125I-Sar1,Ile8Angiotensin II autoradiography for the measurement of AT1R levels. After completion of DOXO injections, all mice demonstrated a lower cardiac function versus baseline (p < 0.0001). During therapy administration, only IVAB reduced heart rate (p < 0.0001) and improved cardiac function (p < 0.05). One week after the end of therapy , 1) cardiac function in IVAB group declined to levels similar to the other groups; 2) there was no difference in cardiac mass between groups, but fibrosis was increased in all DOXO-groups vs. CTRL (H2O +47%, p = 0.055; IVAB +90%, p < 0.001 and METO +47% in kidneys, p = 0.058); and 3) renal AT1R level was reduced only in the H2O group versus CTRL (-421%, p < 0.01), while IVAB and METO groups maintained renal levels comparable to controls. IVAB transiently improved systolic function in this model, but this benefit was not sustained after treatment cessation and did not prevent late structural fibrosis remodeling. Both IVAB and METO prevented the reduction of renal AT1R expression observed in DOXO treated animals. Overall, these findings indicate that HR-lowering therapy with IVAB alone is insufficient to prevent fibrotic remodeling, highlighting the need for longer-term studies to evaluate its sustained efficacy and impact on structural remodeling, and to assess its translational potential in managing DIC in patients.