title: Doxorubicin and trastuzumab regimen induces biventricular failure in mice.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino - IRCCS, Milan, Italy. Electronic address: giuseppina.milano@ccfm.it.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Milano
authors.affiliation: Laboratory of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino - IRCCS, Milan, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Raucci
authors.affiliation: Laboratory of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino - IRCCS, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Scopece
authors.affiliation: Laboratory of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino - IRCCS, Milan, Italy.
authors.forename: Ranaldi
authors.initials: R
authors.lastname: Daniele
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.
authors.forename: Uliano
authors.initials: U
authors.lastname: Guerrini
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy; Unit of Experimental Thrombosis and Imaging in Vivo, Centro Cardiologico Monzino - IRCCS, Milan, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Sironi
authors.affiliation: Cardioncology Unit, European Institute of Oncology, Milan, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Cardinale
authors.affiliation: Laboratory of Vascular Pathology, Istituto Dermopatico dell'Immacolata - IRCCS, Rome, Italy.
authors.forename: Maurizio C
authors.initials: MC
authors.lastname: Capogrossi
authors.affiliation: Laboratory of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino - IRCCS, Milan, Italy; Department of Clinical and Community Sciences, University of Milan, Milan, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Pompilio
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D004195:Disease Models, Animal; D004317:Doxorubicin; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D000068878:Trastuzumab; D014463:Ultrasonography; D018754:Ventricular Dysfunction / Q000139:chemically induced* / Q000000981:diagnostic imaging* / Q000503:physiopathology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004317:Doxorubicin; D000068878:Trastuzumab
keywords: Cardiotoxicity; Echocardiography; Hemodynamics; Mouse model