Background: Preventive use of statin or angiotensin receptor blocker during chemotherapy has been reported to attenuate cardiotoxicity of doxorubicin (Dox) and trastuzumab (Trz) in patients with breast cancer. However, the effect of combination of two drugs has not been determined.
Purpose: The aim of this study was to investigate the protective effects of rosuvastatin, candesartan and combination therapy in Dox and Trz induced cardiotoxicity rat models.
Methods: For the induction of chronic cardiotoxicity, female rats were treated with Dox and Trz. Sprague Dawley rats were grouped according to drug regimen (each group n=7): (G1) control, (G2) Dox only, (G3) Dox plus Trz, (G4) Dox plus Trz plus rosuvastatin, (G5) Dox plus Trz plus candesartan, (G6) Dox plus Trz plus rosuvastatin plus candesartan. Left ventricular end systolic dimension (LVSd) and global longitudinal strain (GLS) were measured at baseline, day 14 and day 28. At day 28 just before sacrifice, LV dP/dt was measured using 1.5 Fr microcatheter. Blood for C-reactive protein (CRP), glutathione (GSH) and markers of reactive oxygen species (ROS) was sampled from inferior vena cava.
Results: Compared to G1, Dox treated rats (G2) showed larger LVSd, higher GLS, lower dP/dt and higher GSH and ROS (LVSd: 3.3±0.2 vs 2.5±0.3 mm, GLS: -22.5±2.2 vs -24.6±1.5%, dP/dt: 745±57 vs 964±157 mmHg/sec, GSH: 0.26±0.05 vs 0.18±0.01 uM/min, ROS: 5.7±1.6 vs 1.9±0.5 nM, p for all <0.05). The addition of Trz to Dox (G3) induced more worsening of LV systolic function than G2 (LVSd: 4.1±0.2 vs 3.3±0.2 mm, GLS: -19.8±0.8 vs -22.5±2.2%, p for all <0.05). Deterioration of LV systolic function was associated with increase of GSH, ROS and dP/dt (GSH: β=0.422, ROS: β=0.580, dP/dt: β=-0.353, p for all <0.05). Both rosuvastatin (G4) and candesartan (G5) attenuated the increase of LVSd and worsening of GLS induced by Dox and Trz (G3) (LVSd for G4: 3.2±0.5, G5: 3.2±0.3 mm, GLS for G4: -23.0±1.2, G5: -22.9±1.7%, p for all <0.05). Compared to G3, GSH and ROS release were diminished in rosuvastatin treated group (G4) only (GSH: 0.17±0.01 vs 0.23±0.03 uM/min, p=0.007, ROS 2.7±0.3 vs 4.3±1.0 Nm, p=0.025), whereas dP/dt was increased in candesartan treated group (G5) only (dP/dt: 856±64 vs 750±27 mmHg/sec, p=0.011). In combination treatment group (G6), GLS worsening was much less than that of G4 or G5 (G6: -25.4±1.0%, p<0.05 for G4 vs G6 and G5 vs G6).
Conclusions: Preventive use of rosuvastatin and candesartan alleviated cardiotoxicity induced by Dox and Trz and showed synergetic protective effect by combination therapy in rat models. The mechanism of protection appears to be different and complementary between rosuvastatin and candesartan.