An Ovine Model of Toxic, Nonischemic Cardiomyopathy-Assessment by Cardiac Magnetic Resonance Imaging

Peter J. Psaltis, Angelo Carbone, Adam Nelson, Dennis H. Lau, Jim Manavis, John Finnie, Karen S. Teo, Lorraine Mackenzie, Prashanthan Sanders, Stan Gronthos, Andrew C W Zannettino, Stephen G. Worthley

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

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. Methods and 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. Crown

LanguageEnglish
Pages785-795
Number of pages11
JournalJournal of Cardiac Failure
Volume14
Issue number9
DOIs
Publication statusPublished - 1 Nov 2008

Keywords

  • Cardiomyopathy
  • animal model
  • magnetic resonance imaging
  • nonischemic

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Psaltis, Peter J. ; Carbone, Angelo ; Nelson, Adam ; Lau, Dennis H. ; Manavis, Jim ; Finnie, John ; Teo, Karen S. ; Mackenzie, Lorraine ; Sanders, Prashanthan ; Gronthos, Stan ; Zannettino, Andrew C W ; Worthley, Stephen G. / An Ovine Model of Toxic, Nonischemic Cardiomyopathy-Assessment by Cardiac Magnetic Resonance Imaging. In: Journal of Cardiac Failure. 2008 ; Vol. 14, No. 9. pp. 785-795.
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title = "An Ovine Model of Toxic, Nonischemic Cardiomyopathy-Assessment by Cardiac Magnetic Resonance Imaging",
abstract = "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. Methods and 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. Crown",
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Psaltis, PJ, Carbone, A, Nelson, A, Lau, DH, Manavis, J, Finnie, J, Teo, KS, Mackenzie, L, Sanders, P, Gronthos, S, Zannettino, ACW & Worthley, SG 2008, 'An Ovine Model of Toxic, Nonischemic Cardiomyopathy-Assessment by Cardiac Magnetic Resonance Imaging', Journal of Cardiac Failure, vol. 14, no. 9, pp. 785-795. https://doi.org/10.1016/j.cardfail.2008.06.449

An Ovine Model of Toxic, Nonischemic Cardiomyopathy-Assessment by Cardiac Magnetic Resonance Imaging. / Psaltis, Peter J.; Carbone, Angelo; Nelson, Adam; Lau, Dennis H.; Manavis, Jim; Finnie, John; Teo, Karen S.; Mackenzie, Lorraine; Sanders, Prashanthan; Gronthos, Stan; Zannettino, Andrew C W; Worthley, Stephen G.

In: Journal of Cardiac Failure, Vol. 14, No. 9, 01.11.2008, p. 785-795.

Research output: Contribution to journalArticle

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T1 - An Ovine Model of Toxic, Nonischemic Cardiomyopathy-Assessment by Cardiac Magnetic Resonance Imaging

AU - Psaltis, Peter J.

AU - Carbone, Angelo

AU - Nelson, Adam

AU - Lau, Dennis H.

AU - Manavis, Jim

AU - Finnie, John

AU - Teo, Karen S.

AU - Mackenzie, Lorraine

AU - Sanders, Prashanthan

AU - Gronthos, Stan

AU - Zannettino, Andrew C W

AU - Worthley, Stephen G.

PY - 2008/11/1

Y1 - 2008/11/1

N2 - 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. Methods and 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. Crown

AB - 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. Methods and 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. Crown

KW - Cardiomyopathy

KW - animal model

KW - magnetic resonance imaging

KW - nonischemic

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U2 - 10.1016/j.cardfail.2008.06.449

DO - 10.1016/j.cardfail.2008.06.449

M3 - Article

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