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.

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.

• Authors: Hoshang Farhad, Pedro V Staziaki, Daniel Addison, Otavio R Coelho-Filho, Ravi V Shah, Richard N Mitchell, Balint Szilveszter, Siddique A Abbasi, Raymond Y Kwong, Marielle Scherrer-Crosbie, Udo Hoffmann, Michael Jerosch-Herold, Tomas G Neilan
• Journal: Circulation. Cardiovascular imaging (Circ Cardiovasc Imaging) Vol. 9 Issue 12 (Dec 2016) ISSN: 1942-0080 [Electronic] United States
• PMID: 27923796 (Publication Type: Journal Article)
• Copyright: © 2016 American Heart Association, Inc.

Chemical References

• Doxorubicin

Topics

• Animals
• Cardiotoxicity
• Disease Models, Animal
• Doxorubicin
• Edema, Cardiac (chemically induced, diagnostic imaging, pathology, physiopathology)
• Fibrosis
• Heart Diseases (chemically induced, diagnostic imaging, pathology, physiopathology)
• Magnetic Resonance Imaging
• Male
• Mice, Inbred C57BL
• Myocardium (pathology)
• Predictive Value of Tests
• Stroke Volume
• Time Factors
• Ventricular Function, Left
• Ventricular Remodeling