An ovine model of toxic, nonischemic cardiomyopathy--assessment by cardiac magnetic resonance imaging.
BACKGROUND
There is a paucity of published experience investigating novel treatment strategies in preclinical and clinical studies of nonischemic cardiomyopathy. We set out to validate an ovine model of doxorubicin-induced cardiomyopathy, using cardiac magnetic resonance (CMR) to assess cardiac function.


RESULTS
Ten Merino sheep (51 +/- 8 kg) underwent intracoronary infusions of doxorubicin (1 mg/kg dose) every 2 weeks. Cardiac magnetic resonance was performed at baseline and at 6 weeks after final doxorubicin dose, along with transthoracic echocardiography, measurement of right heart pressure, and cardiac output. After final CMR examination, heart specimens were harvested for histologic analysis. The total dose of doxorubicin administered per animal was 3.8 +/- 0.5 mg/kg. Two animals died prematurely during the study protocol, with evidence of myocarditis. In the remaining 8 sheep, left ventricular ejection fraction dropped from 46.2 +/- 4.7% to 31.3 +/- 8.5% (P < .001), accompanied by reductions in fractional shortening (31.6 +/- 1.8% baseline versus 18.2 +/- 3.9% final, P < .01), cardiac output (3.8 +/- 0.6 L/min versus 3.0 +/- 0.4 L/min, P < .05) and right ventricular ejection fraction (39.5 +/- 5.6% versus 28.9 +/- 9.6%, P < .05). However, significant end-diastolic dilatation of the left ventricle was not observed. Delayed gadolinium uptake was detected by CMR in 2 sheep, in a typical nonischemic pattern. Widespread, multifocal histologic abnormalities consisted of cardiomyocyte degeneration, vasculopathy, inflammatory infiltrates, and replacement fibrosis.


CONCLUSIONS
Moderate-severe cardiac dysfunction was reproducibly achieved through high-dose intracoronary doxorubicin, with acceptable animal mortality. CMR provides a powerful tool for assessing myocardial function, structural remodeling, and viability in such models.
Psaltis
Peter J
PJ
Cardiovascular Research Centre, Royal Adelaide Hospital; Departments of Medicine and Physiology, The University of Adelaide, Adelaide, Australia. peter.psaltis@adelaide.edu.au
Carbone
Angelo
A
Nelson
Adam
A
Lau
Dennis H
DH
Manavis
Jim
J
Finnie
John
J
Teo
Karen S
KS
Mackenzie
Lorraine
L
Sanders
Prashanthan
P
Gronthos
Stan
S
Zannettino
Andrew C W
AC
Worthley
Stephen G
SG
D000818:Animals; D009202:Cardiomyopathies / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000473:pathology; D004195:Disease Models, Animal; D004452:Echocardiography / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods*; D034561:Sheep, Domestic