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Characterization of the Changes in Cardiac Structure and Function in Mice Treated With Anthracyclines Using Serial
Hoshang Farhad1, Pedro V Staziaki1, Daniel Addison1
1From 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.
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.
Insights
Anthracycline chemotherapy causes cardiotoxicity. This study in mice shows early cardiac edema predicts later myocardial fibrosis and mortality, aiding in understanding and managing this side effect.
Area of Science:
- Cardiovascular Research
- Oncology
- Toxicology
Background:
- Anthracyclines are known cardiotoxins, but detailed serial changes in cardiac function are not well-characterized.
- Limited data exists on the temporal sequence of cardiac structural and functional alterations following anthracycline treatment.
Purpose of the Study:
- To utilize cardiac magnetic resonance (CMR) imaging to characterize the serial changes in cardiac structure and function induced by anthracyclines in a mouse model.
- To investigate the relationship between early cardiac changes and later cardiotoxicity.
Main Methods:
- A longitudinal study involving 45 wild-type male mice, randomized to doxorubicin or placebo.
- Cardiac magnetic resonance imaging was performed at baseline and at 5, 10, and 20 weeks post-randomization.
- Key CMR measures included left ventricular ejection fraction, myocardial edema (T2 values), and myocardial fibrosis (extracellular volume).
Main Results:
- Doxorubicin-treated mice showed increased myocardial edema at 5 weeks (T2: 32±4 ms vs. 21±3 ms).
- Left ventricular ejection fraction decreased (54±6% vs. 63±5%) and myocardial fibrosis increased (ECV: 0.34±0.03 vs. 0.27±0.03) at 10 weeks.
- A strong correlation (r=0.90) was observed between early edema and subacute fibrosis, both predicting late mortality.
Conclusions:
- Anthracycline-induced cardiotoxicity in mice is characterized by an early onset of cardiac edema followed by myocardial fibrosis.
- The early edema and subsequent fibrosis are closely linked and serve as predictors of mortality.
- These findings highlight potential imaging biomarkers for early detection and risk stratification of anthracycline cardiotoxicity.
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