Protective Effects of Statin and Angiotensin Receptor Blocker in a Rat Model of Doxorubicin- and Trastuzumab-Induced Cardiomyopathy

Abstract

Background: Chemotherapy has led to improved survival in patients with breast cancer; however, it is associated with an increased risk of cardiac dysfunction and heart failure. We investigated the protective effects of rosuvastatin and candesartan, alone and in combination, in a doxorubicin- and trastuzumab-induced rat model of cardiomyopathy.

Methods: Forty-two rats were allocated into six groups (G1-G6): G1, control; G2, doxorubicin only; G3, doxorubicin + trastuzumab; G4, doxorubicin + trastuzumab + rosuvastatin; G5, doxorubicin + trastuzumab + candesartan; and G6, doxorubicin + trastuzumab + rosuvastatin + candesartan. Doxorubicin and trastuzumab were sequentially administered for 28 days. Left ventricular end-systolic dimension and longitudinal strain (LS) were assessed via echocardiography. Left ventricular (LV) performance was evaluated using a microcatheter in the LV apex on day 28. Blood for biomarker analysis was collected from the inferior vena cava before sacrifice.

Results: Doxorubicin in combination with trastuzumab increased the LV end-systolic dimension but worsened LS compared with the control group (all P < .05). The level of C-reactive protein was lower in the rosuvastatin treatment group (P = .007) than in the controls but not in the candesartan treatment group. Both rosuvastatin and candesartan attenuated the increase in glutathione. Candesartan treatment improved +dP/dt (P = .011), whereas rosuvastatin did not. In the combination treatment group, the worsening of LS was significantly attenuated compared with that in either the rosuvastatin or candesartan group (all P < .05).

Conclusions: In a rat model of doxorubicin- and trastuzumab-induced cardiomyopathy, rosuvastatin alleviated systemic inflammation, while candesartan improved LV performance. Combination therapy with rosuvastatin and candesartan demonstrated additional preventive effects on myocardial strain. The protective mechanisms of rosuvastatin and candesartan appear to be different but complementary in chemotherapy-induced cardiomyopathy.