Doxorubicin and Trastuzumab Regimen Induces Biventricular Failure in Mice

Abstract

An increased risk for cardiac dysfunction is reported when the anti-epidermal growth factor receptor type 2 (ErbB2) antibody trastuzumab (Trz) is combined with doxorubicin (Dox) as adjuvant chemotherapy for patients with ErbB2-positive breast cancer. The aim of this study was to develop and characterize a novel mouse model of cardiotoxicity that recapitulates the clinical therapeutic protocols of consecutive cycles of Dox followed by Trz therapy. Chronic cardiotoxicity was induced in mice by administering six intraperitoneal injections of Dox weekly over a 2-week period (n = 38; cumulative dose, 24 mg/kg), Trz alone (n = 15; cumulative dose, 10 mg/kg), Trz administered 1 week after Dox treatment (n = 35), or an equivalent volume of saline (n = 24). Echocardiography and pressure-volume analysis indicated that Dox administration was responsible for both left ventricular (LV) and right ventricular (RV) systolic dysfunction and dilatation, further exacerbated by subsequent Trz treatment. Trz alone induced a short down-regulation of LV ErbB2/4 expression associated with reversible LV dysfunction but did not affect receptor expression and RV performance. Dox and Trz in combination decreased the ratio of LV weight to tibia length as well as LV and RV wall thickness compared with Dox treatment. Plasma cardiac troponin I levels and myocardial oxidative stress were higher in mice treated with Dox and Trz than in those treated with Dox alone, while a similar increase of interstitial collagen I deposition was observed in both groups. Trz alone did not affect LV and RV remodeling. These findings suggest that a combined Dox and Trz regimen provokes a detrimental synergistic global cardiac injury extending to both the LV and RV chambers.