An ovine model of chronic stable heart failure

Devlin, Gerry; Matthews, Ken; McCracken, Geoff; Stuart, Selwyn; Jensen, Joergen L.; Conaglen, John V.; Bass, J. J.

doi:10.1016/s1071-9164(00)90016-2

Cited by 17 publications

(3 citation statements)

References 11 publications

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“…One animal that was relatively refractory to doxorubicin treatment received a dose of 1.5 mg/kg for the last two doses. For 48 hours following each injection, animals were given 100 mg oral atenolol daily to prevent arrhythmia [19]. Four animals were used as controls for myocardial blood flow, histological, and molecular analyses.…”

Section: Methodsmentioning

confidence: 99%

Bovine Model of Doxorubicin‐Induced Cardiomyopathy

Bartoli

Brittian

Giridharan

et al. 2010

BioMed Research International

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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.

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Section: Methodsmentioning

confidence: 99%

Bovine Model of Doxorubicin‐Induced Cardiomyopathy

Bartoli

Brittian

Giridharan

et al. 2010

BioMed Research International

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“…MI is confirmed by elevation of S- and T-wave (ST) segment on Electrocardiogram (ECG) monitoring and the appearance of new LV segmental abnormalities on echocardiography. The procedure can be repeated until the target LVEF is reached [ 30 ].…”

Section: Sheepmentioning

confidence: 99%

Large Mammalian Animal Models of Heart Disease

Camacho

Fan

Liu

et al. 2016

JCDD

175

185

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Due to the biological complexity of the cardiovascular system, the animal model is an urgent pre-clinical need to advance our knowledge of cardiovascular disease and to explore new drugs to repair the damaged heart. Ideally, a model system should be inexpensive, easily manipulated, reproducible, a biological representative of human disease, and ethically sound. Although a larger animal model is more expensive and difficult to manipulate, its genetic, structural, functional, and even disease similarities to humans make it an ideal model to first consider. This review presents the commonly-used large animals—dog, sheep, pig, and non-human primates—while the less-used other large animals—cows, horses—are excluded. The review attempts to introduce unique points for each species regarding its biological property, degrees of susceptibility to develop certain types of heart diseases, and methodology of induced conditions. For example, dogs barely develop myocardial infarction, while dilated cardiomyopathy is developed quite often. Based on the similarities of each species to the human, the model selection may first consider non-human primates—pig, sheep, then dog—but it also depends on other factors, for example, purposes, funding, ethics, and policy. We hope this review can serve as a basic outline of large animal models for cardiovascular researchers and clinicians.

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“…Recently, the microembolization model has been used in sheep to develop a chronic model of HF over a period of 3 months. The embolizations have been conducted using injection of either microspheres (Schmitto et al, 2009) or gelfoam (Devlin et al, 2000). The advantage of the microembolization model is that the changes are irreversible and the study with the infusion of microspheres has reported a high success rate of induction of HF; however, mortality rates were high in the gelfoam study.…”

Section: Introductionmentioning

confidence: 99%

Impaired Baroreflex Function in an Ovine Model of Chronic Heart Failure Induced by Multiple Coronary Microembolizations

et al. 2019

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Testing new therapies in heart failure (HF) requires a chronic stable model of HF in large animals. Microembolization of the coronary arteries has been used to model HF previously; however, neural control has not been previously explored in this model. Thus the aim of this study was to further characterize neural control in this model of HF. HF was induced by infusion of microspheres (45 micron; 1.3 ml) into the proximal left coronary artery or left descending coronary arteries, with three sequential embolizations over 3 weeks. Twelve to 14 weeks after the final embolization, and when ejection fraction had decreased below 45%, animals were instrumented to record blood pressure and heart rate. Baroreflex control of heart rate was investigated in conscious animals. Additionally, pressure-volume loops were constructed under anesthesia. Embolization-induced HF was associated with a decrease in mean arterial pressure (67 ± 2 vs. 85 ± 4 mmHg, p < 0.05), an increase in heart rate (108 ± 4 vs. 94 ± 4 bpm, p < 0.05), and a significant increase in left ventricular end-diastolic pressure (11.4 ± 2 vs. 6.2 ± 1 mmHg, p < 0.01). Under conscious conditions, there was a significant decrease in the gain (−8.2 ± 2 vs. −4.1 ± 1 beats/min/mmHg, p < 0.05) as well as the lower plateau of the baroreflex in HF compared to control animals. HF was also associated with significantly increased respiratory rate (107 ± 4 vs. 87 ± 4 breaths/min, p < 0.01) and incidence of apneas (520 ± 24 vs. 191 ± 8 apnea periods >4 s, p < 0.05), compared to control sheep. The microembolization model of heart failure is associated with an increase in left ventricular end-diastolic pressure, impaired cardiac function, and altered baroreflex control of the heart. These findings suggest this chronic model of HF is appropriate to use for investigating interventions aimed at improving neural control in HF.

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An ovine model of chronic stable heart failure

Cited by 17 publications

References 11 publications

Bovine Model of Doxorubicin‐Induced Cardiomyopathy

Bovine Model of Doxorubicin‐Induced Cardiomyopathy

Large Mammalian Animal Models of Heart Disease

Impaired Baroreflex Function in an Ovine Model of Chronic Heart Failure Induced by Multiple Coronary Microembolizations

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