Bovine Model of Doxorubicin-Induced Cardiomyopathy

Abstract EN

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.