Doxorubicin-induced and trastuzumab-induced cardiotoxicity in mice is not prevented by metoprolol

Aims Our objectives were to validate a murine model of chronic cardiotoxicity induced by Doxorubicin (Dox) and Trastuzumab (Trast) and to test the potential cardio-protective effect of metoprolol. Methods and results Male C57Bl6 mice were intraperitoneally injected during 2 weeks with Dox (24 mg/kg) or saline, and then with Trast (10 mg/kg) or saline for two more weeks. Half of the mice received metoprolol (100 mg/kg). Cardiotoxicity was defined by a decline in left ventricular ejection fraction (LVEF) >= 10 points. At Day 42, Dox + Trast-treated mice exhibited a 13-points decline in LVEF (74 +/- 2.6% vs. 87 +/- 0.8% for control mice, P < 0.001) and a severe cardiac atrophy (heart weight: 105 +/- 2.7 mg vs. 119 +/- 3.9 mg for control mice, P < 0.01). This cardiac atrophy resulted from an excess of cardiac necrosis (assessed by plasma cardiac troponin I level: 3.2 +/- 0.4 ng/L vs. 1.3 +/- 0.06 ng/L for control mice, P < 0.01), an increase in apoptosis (caspase 3 activity showing a six-fold increase for Dox + Trast-treated mice vs. controls, P < 0.001), and cardiomyocyte atrophy (myocyte size: 0.67 +/- 0.08 mu m(2) vs. 1.36 +/- 0.10 mu m(2) for control mice, P < 0.001). In addition, Dox + Trast-treated mice were shown to have an increased cardiac oxidative stress (164 +/- 14 dihydroethidine-marked nuclei per area vs. 56 +/- 9.5 for control mice, P < 0.01) and increased cardiac fibrosis (the semi-quantitative fibrosis score was three-fold higher for Dox + Trast-treated mice as compared with controls, P < 0.01). Metoprolol was not able to prevent either the decrease in LVEF or the severe cardiac atrophy, the cardiac necrosis, and the cardiac remodelling induced by chemotherapies. Conclusion A murine model of chronic cardiotoxicity induced by Dox and Trast was characterized by a decrease in cardiac function, a cardiac apoptosis and necrosis leading to cardiomyocyte atrophy. Metoprolol did not prevent this cardiotoxicity.

Automated summary

The study validated a murine model of chronic cardiotoxicity induced by Doxorubicin and Trastuzumab, resulting in severe cardiac damage in mice. Metoprolol did not alleviate this toxicity.