title: Characterization of the Changes in Cardiac Structure and Function in Mice Treated With Anthracyclines Using Serial Cardiac Magnetic Resonance Imaging.
abstract: BACKGROUND
  Anthracyclines are cardiotoxic; however, there are limited data characterizing the serial changes in cardiac structure and function after anthracyclines. The aim of this study was to use cardiac magnetic resonance to characterize anthracycline-induced cardiotoxicity in mice.
  
  
  RESULTS
  This was a longitudinal cardiac magnetic resonance and histological study of 45 wild-type male mice randomized to doxorubicin (n=30, 5 mg/kg of doxorubicin/week for 5 weeks) or placebo (n=15). A cardiac magnetic resonance was performed at baseline and at 5, 10, and 20 weeks after randomization. Measures of primary interest included left ventricular ejection fraction, myocardial edema (multiecho short-axis spin-echo acquisition), and myocardial fibrosis (Look-Locker gradient echo). In doxorubicin-treated mice versus placebo, there was an increase in myocardial edema at 5 weeks (T2 values of 32±4 versus 21±3 ms; P<0.05), followed by a reduction in left ventricular ejection fraction (54±6 versus 63±5%; P<0.05) and an increase in myocardial fibrosis (extracellular volume of 0.34±0.03 versus 0.27±0.03; P<0.05) at 10 weeks. There was a strong association between the early (5 weeks) increase in edema and the subacute (10 weeks) increase in fibrosis (r=0.90; P<0.001). Both the increase in edema and fibrosis predicted the late doxorubicin-induced mortality in mice (P<0.001).
  
  
  CONCLUSIONS
  Our data suggest that, in mice, anthracycline-induced cardiotoxicity is associated with an early increase in cardiac edema and a subsequent increase in myocardial fibrosis. The early increase in edema and subacute increase in fibrosis are strongly linked and are both predictive of late mortality.
authors.affiliation: From the Non-Invasive Cardiovascular Imaging Program and the Cardiovascular Division, Department of Medicine (H.F., S.A.A., R.V.S., R.Y.K.), Department of Pathology (R.N.M.), and Department of Radiology (M.J.-H.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Faculty of Medical Science, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil (O.R.C.-F.); and Cardiac MR PET CT Program, Division of Radiology (P.V.S., D.A., B.S., U.H., T.G.N.) and Division of Cardiology, Department of Medicine (M.S.-C., T.G.N.), Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: Hoshang
authors.initials: H
authors.lastname: Farhad
authors.affiliation: From the Non-Invasive Cardiovascular Imaging Program and the Cardiovascular Division, Department of Medicine (H.F., S.A.A., R.V.S., R.Y.K.), Department of Pathology (R.N.M.), and Department of Radiology (M.J.-H.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Faculty of Medical Science, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil (O.R.C.-F.); and Cardiac MR PET CT Program, Division of Radiology (P.V.S., D.A., B.S., U.H., T.G.N.) and Division of Cardiology, Department of Medicine (M.S.-C., T.G.N.), Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: Pedro V
authors.initials: PV
authors.lastname: Staziaki
authors.affiliation: From the Non-Invasive Cardiovascular Imaging Program and the Cardiovascular Division, Department of Medicine (H.F., S.A.A., R.V.S., R.Y.K.), Department of Pathology (R.N.M.), and Department of Radiology (M.J.-H.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Faculty of Medical Science, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil (O.R.C.-F.); and Cardiac MR PET CT Program, Division of Radiology (P.V.S., D.A., B.S., U.H., T.G.N.) and Division of Cardiology, Department of Medicine (M.S.-C., T.G.N.), Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Addison
authors.affiliation: From the Non-Invasive Cardiovascular Imaging Program and the Cardiovascular Division, Department of Medicine (H.F., S.A.A., R.V.S., R.Y.K.), Department of Pathology (R.N.M.), and Department of Radiology (M.J.-H.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Faculty of Medical Science, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil (O.R.C.-F.); and Cardiac MR PET CT Program, Division of Radiology (P.V.S., D.A., B.S., U.H., T.G.N.) and Division of Cardiology, Department of Medicine (M.S.-C., T.G.N.), Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: Otavio R
authors.initials: OR
authors.lastname: Coelho-Filho
authors.affiliation: From the Non-Invasive Cardiovascular Imaging Program and the Cardiovascular Division, Department of Medicine (H.F., S.A.A., R.V.S., R.Y.K.), Department of Pathology (R.N.M.), and Department of Radiology (M.J.-H.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Faculty of Medical Science, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil (O.R.C.-F.); and Cardiac MR PET CT Program, Division of Radiology (P.V.S., D.A., B.S., U.H., T.G.N.) and Division of Cardiology, Department of Medicine (M.S.-C., T.G.N.), Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: Ravi V
authors.initials: RV
authors.lastname: Shah
authors.affiliation: From the Non-Invasive Cardiovascular Imaging Program and the Cardiovascular Division, Department of Medicine (H.F., S.A.A., R.V.S., R.Y.K.), Department of Pathology (R.N.M.), and Department of Radiology (M.J.-H.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Faculty of Medical Science, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil (O.R.C.-F.); and Cardiac MR PET CT Program, Division of Radiology (P.V.S., D.A., B.S., U.H., T.G.N.) and Division of Cardiology, Department of Medicine (M.S.-C., T.G.N.), Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: Richard N
authors.initials: RN
authors.lastname: Mitchell
authors.affiliation: From the Non-Invasive Cardiovascular Imaging Program and the Cardiovascular Division, Department of Medicine (H.F., S.A.A., R.V.S., R.Y.K.), Department of Pathology (R.N.M.), and Department of Radiology (M.J.-H.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Faculty of Medical Science, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil (O.R.C.-F.); and Cardiac MR PET CT Program, Division of Radiology (P.V.S., D.A., B.S., U.H., T.G.N.) and Division of Cardiology, Department of Medicine (M.S.-C., T.G.N.), Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: Balint
authors.initials: B
authors.lastname: Szilveszter
authors.affiliation: From the Non-Invasive Cardiovascular Imaging Program and the Cardiovascular Division, Department of Medicine (H.F., S.A.A., R.V.S., R.Y.K.), Department of Pathology (R.N.M.), and Department of Radiology (M.J.-H.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Faculty of Medical Science, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil (O.R.C.-F.); and Cardiac MR PET CT Program, Division of Radiology (P.V.S., D.A., B.S., U.H., T.G.N.) and Division of Cardiology, Department of Medicine (M.S.-C., T.G.N.), Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: Siddique A
authors.initials: SA
authors.lastname: Abbasi
authors.affiliation: From the Non-Invasive Cardiovascular Imaging Program and the Cardiovascular Division, Department of Medicine (H.F., S.A.A., R.V.S., R.Y.K.), Department of Pathology (R.N.M.), and Department of Radiology (M.J.-H.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Faculty of Medical Science, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil (O.R.C.-F.); and Cardiac MR PET CT Program, Division of Radiology (P.V.S., D.A., B.S., U.H., T.G.N.) and Division of Cardiology, Department of Medicine (M.S.-C., T.G.N.), Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: Raymond Y
authors.initials: RY
authors.lastname: Kwong
authors.affiliation: From the Non-Invasive Cardiovascular Imaging Program and the Cardiovascular Division, Department of Medicine (H.F., S.A.A., R.V.S., R.Y.K.), Department of Pathology (R.N.M.), and Department of Radiology (M.J.-H.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Faculty of Medical Science, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil (O.R.C.-F.); and Cardiac MR PET CT Program, Division of Radiology (P.V.S., D.A., B.S., U.H., T.G.N.) and Division of Cardiology, Department of Medicine (M.S.-C., T.G.N.), Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: Marielle
authors.initials: M
authors.lastname: Scherrer-Crosbie
authors.affiliation: From the Non-Invasive Cardiovascular Imaging Program and the Cardiovascular Division, Department of Medicine (H.F., S.A.A., R.V.S., R.Y.K.), Department of Pathology (R.N.M.), and Department of Radiology (M.J.-H.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Faculty of Medical Science, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil (O.R.C.-F.); and Cardiac MR PET CT Program, Division of Radiology (P.V.S., D.A., B.S., U.H., T.G.N.) and Division of Cardiology, Department of Medicine (M.S.-C., T.G.N.), Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: Udo
authors.initials: U
authors.lastname: Hoffmann
authors.affiliation: From the Non-Invasive Cardiovascular Imaging Program and the Cardiovascular Division, Department of Medicine (H.F., S.A.A., R.V.S., R.Y.K.), Department of Pathology (R.N.M.), and Department of Radiology (M.J.-H.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Faculty of Medical Science, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil (O.R.C.-F.); and Cardiac MR PET CT Program, Division of Radiology (P.V.S., D.A., B.S., U.H., T.G.N.) and Division of Cardiology, Department of Medicine (M.S.-C., T.G.N.), Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: Michael
authors.initials: M
authors.lastname: Jerosch-Herold
authors.affiliation: From the Non-Invasive Cardiovascular Imaging Program and the Cardiovascular Division, Department of Medicine (H.F., S.A.A., R.V.S., R.Y.K.), Department of Pathology (R.N.M.), and Department of Radiology (M.J.-H.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Faculty of Medical Science, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil (O.R.C.-F.); and Cardiac MR PET CT Program, Division of Radiology (P.V.S., D.A., B.S., U.H., T.G.N.) and Division of Cardiology, Department of Medicine (M.S.-C., T.G.N.), Massachusetts General Hospital, Harvard Medical School, Boston, MA. tneilan@mgh.harvard.edu.
authors.forename: Tomas G
authors.initials: TG
authors.lastname: Neilan
mesh_terms: D000818:Animals; D066126:Cardiotoxicity; D004195:Disease Models, Animal; D004317:Doxorubicin; D004489:Edema, Cardiac / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D005355:Fibrosis; D006331:Heart Diseases / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D008297:Male; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000473:pathology*; D011237:Predictive Value of Tests; D013318:Stroke Volume; D013997:Time Factors; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: D004317:Doxorubicin
keywords: anthracyclines; cardiotoxicity; doxorubicin; magnetic resonance imaging; myocardium