Adriamycin cardiomyopathy in the rabbit: an animal model of low output cardiac failure with activation of vasoconstrictor mechanisms

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Abstract
Chronic administration of intravenous adriamycin (1 mg·kg−1 twice weekly for 8 weeks) to rabbits resulted in a cardiomyopathy which was similar to that occurring in patients with adriamycin cardiotoxicity. We studied systemic and renal haemodynamics and the activation of vasoconstrictor mechanisms reflected by changes in plasma renin activity (PRA), noradrenaline (NA) and vasopressin (AVP) levels during the development of heart failure in this animal model. By 8 weeks cardiac failure was clearly established. At postmortem all animals had dilated hearts, pleural and pericardial effusions, ascites and hepatic congestion. Heart weights were increased (8.1 ± 0.7 g in treated animals n = 9 vs 6.0 ± 0.2 g in controls n = 9 p < 0.05). Cardiac output (measured by thermodilution) fell at 8 weeks from 799 ± 61 ml·min−1 to 624 ± 44 ml·min−1 (n = 6 p < 0.05) with a parallel fall in mean blood pressure from 85 ± 2 mmHg to 75 ± 4 mmHg. Total peripheral resistance rose in four of the six rabbits. Renal blood flow fell from 108 ± 4 ml·min−1 to 61 ± 6 ml·min−1 (p < 0.05) by 8 weeks. Renal vascular resistance increased in all animals. PRA increased from 5.1 ± 0.5 ng AI·ml−1·h−1 to 11.6 ± 2.6 ng AI·ml−1·h−1 by 4 weeks (p < 0.05) and remained elevated thereafter. Plasma NA did not change significantly by 4 weeks but approximately doubled by eight weeks (0.7 ± 0.1 pmol·ml−1 to 1.6 ± 0.2 pmol·ml−1). Vasopressin levels did not change significantly. These results suggest that vasoconstrictor mechanisms may be activated sequentially in heart failure with early activation of the renin-angiotensin system and later activation of the sympathetic nervous system. Adriamycin cardiomyopathy in the rabbit is a good model of low output heart failure which closely resembles the human condition and thus offers considerable potential for investigating the pathophysiology, pathogenic factors and newer therapeutic modalities.