© 1996 American Heart Association, Inc.
Articles |
Hypercholesterolemia in the Rabbit Induced by Feeding Graded Amounts of Low-Level Cholesterol
Methodological Considerations Regarding Individual Variability in Response to Dietary Cholesterol and Development of Lesion Type
the Department of Cardiovascular Pathology (F.D.K., S.J.L., R.V.), Armed Forces Institute of Pathology, Washington, DC; Cardiovascular Biological Research (A.S.K., E.E.L., S.M.W.), Medical Research Division, American Cyanamid Co, Lederle Laboratories, Pearl River, NY; the Biomedical Engineering Center (J.F.C., E.E.H.), The Ohio State University, Columbus; and the Department of Biomedical Engineering Research Institute (J.F.C.), The Cleveland Clinic Foundation, Cleveland, Ohio.
Correspondence to Renu Virmani, MD, Armed Forces Institute of Pathology, Cardiovascular Pathology, 14th and Alaska Aves NW, Washington, DC 20306-6000. E-mail virmani@email.afip.osd.mil.
While a number of studies have presented detailed examinations of lesion development in the cholesterol-fed rabbit, individual variability in response to cholesterol feeding and type of lesion produced relative to the degree of cholesterol exposure is not well defined. This study analyzed such critical parameters in an attempt to further characterize the model and establish a baseline for future testing of treatments targeted at limiting atherosclerosis. For these experiments, male New Zealand White rabbits were fed atherogenic diets consisting of 0.05%, 0.10%, 0.15%, 0.20%, or 0.25% cholesterol dissolved in 6% peanut oil for 31 to 32 weeks. Raising dietary cholesterol from 0.05% to 0.15% resulted in a less than twofold stepwise increase in total plasma cholesterol (TPC) exposure (area under plasma cholesterol versus time curve), whereas further increases in cholesterol intake resulted in an exponential four- to fivefold increase in TPC exposure. Regression analysis of TPC exposure with aortic sudanophilia demonstrated a threshold of 
5000 cholesterol weeks; below this limit lesions were minimal, and above this value, the degree of plaque correlated with TPC exposure. Furthermore, a wide biological variability occurred among rabbits with respect to individual responsiveness to dietary cholesterol. In the aorta, various types of plaques, from fatty streaks to atheromatous lesions, were observed, depending on the degree of cholesterol intake. Diets consisting of <0.15% cholesterol resulted in the development of fatty streak lesions, while transitional lesions and atheromatous plaques were mostly found with higher cholesterol feeding. Coronary artery atherosclerosis was present in >50% of animals fed diets 
0.15% cholesterol. Despite the level of TPC exposure, coronary lesions in epicardial vessels were generally the fibrous type, whereas intramyocardial arteries demonstrated predominantly intimal foam cells. In conclusion, by adjusting dietary cholesterol intake and selecting rabbits with a similar responsiveness to cholesterol, the overall cholesterol exposure can be more closely controlled to minimize the inherent individual variability among animals in this model. The nature of the target lesion must also be carefully considered, because the efficacy of some treatments may depend on the type of atherosclerotic plaque.
Key Words: atherosclerosis • rabbit • cholesterol • acyl coenzyme A:cholesterol acyltransferase • sudanophilia
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