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

• Published in: Archives of Cardiovascular Diseases Supplements Vol. 10; no. 2; p. 246
• Main Authors: Nicol, M., Sadoune, M., Dupland, P., Polidano, E., Azibani, F., Launay, J.M., Samuel, J.L., Solal, A. Cohen
• Format: Journal Article
• Language: English
• Published: Elsevier Masson SAS 01.04.2018
• ISSN: 1878-6480
• DOI: 10.1016/j.acvdsp.2018.02.152

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 C57Bl/6 mice (n=60) were injected during 2 weeks with intraperitoneal (IP) doxorubicin (total dose: 24mg/kg) or saline, and then with IP trastuzumab (total dose of 10mg/kg) or saline for 2 more weeks. Half of mice received metoprolol (100mg/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 prevent the increases of Troponin I, BNP, the decrease of SERCA2a, nor the cardiac atrophy. Metoprolol did not modify the cardiomyocyte atrophy, the excess of cardiac apoptosis and autophagy, which were 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.