Febuxostat exacerbates doxorubicin-induced cardiac remodelling in a murine model of cardiomyopathy
S Jezsoviczky, A Toth, M E Jakab, Sz Farkas, P Ferdinandy, Z V Varga, Zs Gulyas-OnodiAbstract
Introduction
Clinical trials evaluating the cardiovascular risk of the anti-gout medication febuxostat (FEBU) show contradictory results in cardiovascular and all-cause mortality. As FEBU is often prescribed alongside cardiotoxic chemotherapeutics like doxorubicin (DOXO), assessing their combined cardiac risk is clinically relevant.
Purpose
This study investigated whether FEBU exacerbates DOXO-induced cardiotoxicity in a murine model of cardiomyopathy.
Methods
Ten-week-old female BALB/c mice were randomised into four groups based on body weight and baseline echocardiography: control (n=12), FEBU (n=12), DOXO (n=13), and DOXO+FEBU (n=13). To induce subacute cardiomyopathy, mice received DOXO (5 mg/kg) or saline intraperitoneally twice weekly to reach a cumulative dose of 20 mg/kg. Concurrent FEBU (20 mg/kg) or vehicle was administered via oral gavage. Body and tibia-normalised organ weights were recorded to examine systemic effects, while cardiac structure and function was assessed via echocardiography and histology.
Results
Both DOXO and DOXO+FEBU groups exhibited significant weight loss compared to controls, however, the combination therapy caused significantly greater weight loss than DOXO alone (-2.23 ± 0.34 g vs. -3.39 ± 0.32 g, p=0.017). In both DOXO and DOXO+FEBU groups the ex vivo heart weights were significantly reduced. While both treatments decreased cardiac output, only the DOXO+FEBU group showed significantly elevated left ventricular end-diastolic and systolic volume indices (0.79 ± 0.03 vs. 0.94 ± 0.03, p=0.007 and 0.36 ± 0.02 vs. 0.47 ± 0.03, p=0.03). Furthermore, co-administration significantly reduced key structural parameters, namely diastolic and systolic left ventricular posterior wall thickness, as well as the relative wall thickness of the heart (0.31 ± 0.01 vs. 0.27 ± 0.01, p=0.03). Picrosirius red staining confirmed increased myocardial fibrosis in both DOXO and DOXO+FEBU groups compared to controls (p<0.01).
Conclusions
FEBU co-administration exacerbates adverse cardiac remodelling and functional impairment in DOXO-induced cardiomyopathy. These findings suggest a potential drug interaction that warrants further mechanistic investigation to ensure patient safety in oncologic settings requiring urate-lowering therapy.