Hoshang Farhad1, Pedro V Staziaki1, Daniel Addison1, Otavio R Coelho-Filho1, Ravi V Shah1, Richard N Mitchell1, Balint Szilveszter1, Siddique A Abbasi1, Raymond Y Kwong1, Marielle Scherrer-Crosbie1, Udo Hoffmann1, Michael Jerosch-Herold1, Tomas G Neilan2. 1. 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. 2. 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.
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. METHODS AND 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.
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. METHODS AND 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.
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