Abstract 4364628: Relationship between heart function, fibrosis and AT ₁ receptors in the heart and the kidneys of a mouse model of doxorubicin-induced cardiomyopathy

Introduction: Ivabradine (IVAB) is an effective heart-rate lowering drug used in patients with heart failure. However, its potential protective effect in the context of doxorubicin (DOXO)-induced cardiomyopathy, a serious complication of anthracycline chemotherapy, remain poorly understood. Aims: 1) To assess the effects of IVAB on cardiac remodeling in a murine model of DOXO-induced cardiomyopathy, and 2) to investigate its potential interaction with the renin-angiotensin system, as the cardioprotective effects of IVAB may extend beyond heart rate reduction. Methods: C57BLC/6 female mice (n=36) were allocated into 2 groups: control (n=4) and treatment by DOXO (n=32). DOXO administration (4 mg/kg/week, intraperitoneal injections) was performed over 5 weeks and followed by a 10 weeks gavage treatment with either water (H 2 O), IVAB (10 mg/kg/day), or metoprolol (METO) (100 mg/kg/day). Heart function was assessed by echocardiography every two weeks over a 16-week period. At the end of the study, fibrosis levels and angiotensin II type 1 receptor (AT 1 R) expression in the heart and kidneys were evaluated using picrosirius red (PSR) staining and in vitro 125 I-[Sar 1 , Ile 8 ]-Angiotensin II autoradiography, respectively. Statistical analyses were conducted using One-Way ANOVA and paired t-tests. Results: After completion of DOXO injections, all mice demonstrated a lower cardiac function versus baseline (-19%, p<0.0001) and higher heart rate (+5%, p<0.05). During treatment, only IVAB reduced heart rate (-9%, p<0.0001) and improved the cardiac function (+8%, p<0.05) when compared to H 2 O group. One week after treatment completion, 1) cardiac function in IVAB group was decreased (-8%, p<0.01) when compared to end of treatment; and was similar to the other groups; 2) there was no difference in cardiac mass between groups; 3) cardiac fibrosis was increased in METO (+40%, p<0.05) when compared to control; 4) renal fibrosis was increased in all DOXO-groups vs controls (H 2 O +47%, p=0.055; IVAB +90%, p<0.001 and METO +47%, p=0.058); and 5) renal AT 1 Rs were reduced (-47%, p<0.01) only in the DOXO-H 2 O group, while treatment with IVAB and METO preserved these levels at values comparable to controls. Conclusions: Improved cardiac function by IVAB is not due to reduced fibrosis, despite sustained normal renal AT 1 R expression. This may explain the rapid relapse in cardiac dysfunction once the drug is stopped.