Effect of metoprolol in a chronic murine model of cardiotoxicity induced by doxorubicin and trastuzumab

Trastuzumab (anti ErbB2 targeted therapy) and anthracyclin can lead to a synergistic cardiotoxicity with a severe decrease of cardiac function. To date, a cardioprotective treatment is not recommended in all patients. Our objective was to define whether metoprolol (β1blocker) used as a cardioprotective treatment was efficient to prevent signs of chronic cardiotoxicity induced by doxorubicin and trastuzumab. Males C57B8l6 mice ( n = 60) were injected during 2 weeks with intraperitoneal (IP) doxorubicin (total dose: 24 mg/kg) or saline, and then with IP trastuzumab (total dose of 10 mg/kg) or saline for 2 more weeks. Half of mice received metoprolol (100 mg/kg) in drinking water 10 days before starting protocol and during all the study (42 days). A functional exploration was carried out by transthoracic echocardiography. Biological analysis included quantification of plasma troponin I, cardiac transcript using RT-qPCR, signaling pathways using Western Blotting and immunohistology. We observed an excess of mortality in the metroprolol group (22% vs. 7%, P < 0.05). Metoprolol did not prevent the decrease of cardiac function assessed by shortening fraction (SF): 41% and 39% in the chemotherapy groups with and without metoprolol, respectively. Metoprolol did not protect mice from heart failure assessed by an increase of BNP and a decrease of SERCA2a. Mice treated with doxorubicin developped a cardiac atrophy. Metoprolol did not modify the cardiomyocyte atrophy (assessed by cardiomyocyte size), the excess of cardiac apoptosis (assessed by caspase 3 activity) nor the cardiac necrosis (assessed by troponin I) all induced by chemotherapies. Albeit previous work suggested a cross-regulation between ErbB2 and β adrenergic signaling pathway, our data indicated that metoprolol used as cardioprotective treatment, did not protect heart from toxicity induced by doxorubicin and trastuzumab.