Bovine model of doxorubicin-induced cardiomyopathy.
Left ventricular assist devices (LVADs) constitute a recent advance in heart failure (HF) therapeutics. As the rigorous experimental assessment of LVADs in HF requires large animal models, our objective was to develop a bovine model of cardiomyopathy. Male calves (n = 8) were used. Four animals received 1.2 mg/kg intravenous doxorubicin weekly for seven weeks and four separate animals were studied as controls. Doxorubicin-treated animals were followed with weekly echocardiography. Target LV dysfunction was defined as an ejection fraction ≤ 35%. Sixty days after initiating doxorubicin, a terminal study was performed to determine hemodynamic, histological, biochemical, and molecular parameters. All four doxorubicin-treated animals exhibited significant (P < 0.05) contractile dysfunction, with target LV dysfunction achieved in three animals. Doxorubicin-treated hearts exhibited significantly reduced coronary blood flow and interstitial fibrosis and significantly increased apoptosis and myocyte size. Gene expression of atrial natriuretic factor increased more than 3-fold. Plasma norepinephrine and epinephrine levels were significantly increased early and late during the development of cardiomyopathy, respectively. We conclude that sequential administration of intravenous doxorubicin in calves induces a cardiomyopathy with many phenotypic hallmarks of the failing human heart. This clinically-relevant model may be useful for testing pathophysiologic responses to LVADs in the context of HF.
Department of Physiology and Biophysics, University of Louisville, Louisville, KY 40202, USA.
Carlo R
CR
Bartoli
Kenneth R
KR
Brittian
Guruprasad A
GA
Giridharan
Steven C
SC
Koenig
Tariq
T
Hamid
Sumanth D
SD
Prabhu
D000818:Animals; D017209:Apoptosis; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology; D002417:Cattle; D003326:Coronary Circulation / Q000502:physiology; D004195:Disease Models, Animal; D004317:Doxorubicin; D004837:Epinephrine / Q000097:blood; D005355:Fibrosis; D005786:Gene Expression Regulation; D006439:Hemodynamics / Q000502:physiology; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000473:pathology; D009638:Norepinephrine / Q000097:blood; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014463:Ultrasonography
D012333:RNA, Messenger; D004317:Doxorubicin; D009638:Norepinephrine; D004837:Epinephrine
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