0131 : Impact of overweight on anthracycline and trastuzumab-induced cardiotoxicity: experimental study in mice

Trastuzumab (TRZ), a humanized monoclonal antibody against Human Epidermal Growth Factor Receptor 2 (HER2) oncogene, is believed to potentiate doxorubicin (DOX) cardiotoxicity, resulting in left ventricular dysfunction. Few data indicate that overweight could influence DOX-induced cardiotoxicity, and no study has already evaluated the impact of moderate overweight on the cardiotoxic effect of DOX alone or in combination with TRZ.Immediately after birth, litters of C57BL/6 mice were either maintained at 10 (normal litter, NL), or reduced to 3 (small litter, SL) in order to induce programming of ~15% overweight through postnatal overfeeding. At 4 months, in order to evaluate the potentiation of DOX cardiotoxicity by TRZ, NL and SL mice received a single intraperitoneal injection of either saline, DOX (6mg/kg), TRZ (10mg/kg) or the combination of both (DOX-TRZ). Transthoracic echocardiography was performed 24 hours before, 10 and 20 days after treatments, in order to evaluate the evolution of cardiac function.Twenty days after DOX administration, systolic dysfunction was observed only in overweight-SL group, while NL mice group kept a preserved left ventricular ejection fraction (LVEF). Moreover, in NL group, the function impairment appeared when TRZ was co-administrated. 48 hours after drug administration, gene expression of Erb-B2, the murine analog of HER2, was induced in the myocardium of DOX-treated mice, and its induction was potentiated by co-treatment with TRZ. Expression of natriuretic peptides (ANP, BNP) appeared to be potentiated in DOX-TRZ mice of both NL and SL groups, whereas the expression of b-MHC increased significantly in overweight- SL mice.In an acute model of DOX cardiotoxicity, moderately overweighed adult mice are more sensitive to cardiac systolic impairment. Moreover, our results show an early myocardial induction of TRZ-receptor after DOX and/or TRZ, and confirm the potentiating action of TRZ on DOX-induced cardiotoxicity in mic