Atherosclerosis in rabbits fed a low cholesterol diet for five years.

Abstract

Rabbits were fed a low cholesterol atherogenic diet for up to 5 years. Arterial lesions during the first 12 months consisted of smooth muscle cell and lipid accumulation in the intima, with smaller amounts of elastin and collagen. By 24 months, considerable degeneration and necrosis of smooth muscle foam cells had occurred, lipid had decreased in relative proportion, and collagen was predominant. These trends continued during the final 3 years. By 48 months most plaques were calcified and a few had hemorrhage. Atherosclerosis was extensive in rabbits with serum cholesterol concentrations greater than 300 mg/100 ml and minimal in rabbits with concentrations consistently less than 150 mg/100 ml. Thicker lesions tended to have more atheromas while thinner ones were more fibrous and less fatty. Significant regression of fatty streaks occurred in a group of rabbits fed the atherogenic diet for 2 years and a stock diet during the third year but more advanced lesions did not regress. This study illustrates the importance of time as a variable in atherogenesis, and demonstrates that modest hypercholesterolemia can lead to atherosclerosis in rabbits that is qualitatively unlike atherosclerosis induced in rabbits by cholesterol rich diets and that resembles several stages of human atherosclerosis. A theromatous lesions have been produced in rabbits for more than 70 years by feeding cholesterol-supplemented (0.5% to 3.0%) stock diets, but feeding periods have seldom been longer than 16 weeks because of the toxicity of dietary cholesterol in this species. 1 " 4 Occasionally, feeding times were extended by intermittent feeding of a high cholesterol diet.4 ' 5 During the past two decades, a number of low cholesterol and cholesterol-free atherogenic diets have been used, but experiments, with few exceptions, have been less than 1 year. " 17On the other hand, atherosclerosis in humans probably begins early in life and progresses over several decades.18 ' 19 Time itself may be an important variable in atherogenesis, a factor largely ignored in previous studies. In the present study, arterial lesions were evaluated at various times in rabbits fed a low cholesterol diet for up to 5 years. Changes in arterial lesions were also studied in rabbits fed the atherogenic diet for 2 years and then a stock diet for 1 year. Methods AnimalsWe purchased 250 weanling male rabbits of the Dutch-Belted breed from a single supplier. The rabbits were housed individually in wire-bottomed cages in temperature-and humidity-controlled rooms, with 12 hours of light and 12 hours of darkness daily. The rabbits were observed daily and weighed once a month.

Atherosclerosis and myocardial ischemic lesions in alloxan-diabetic rabbits fed a low cholesterol diet.

“…With low cholesterol diets, the atherogenesis is milder and slower in development, and smooth muscle cell proliferation is more prominent. 17 The cholesterol/phospholipid ratio was elevated in diabetic rabbits in this experiment, but the ratio was lower in diabetic rabbits fed much larger amounts of cholesterol. 4 Higher cholesterol/phospholipid ratios are usually associated with more extensive atherosclerosis.…”

“…In a study using the same diet as this experiment, 17 only three myocardial infarcts were found in about 70 normal rabbits fed the diet for as long as 5 years. Epidemiologic studies have indicated that ischemic myocardial disease and myocardial infarction are two to three times more frequent in diabetic than in nondiabetic people and that primary mortality is two to three times higher in diabetic patients.…”

Altered Metabolism of LDL in the Arterial Wall Precedes Atherosclerosis Regression

“…[17][18][19][20] This is also supported by data in mice, where genetic ablation of hepatic MTTP expression in LDL receptor-deficient mice (LDLr −/− ) reduced plasma very low-density lipoprotein (VLDL) and LDL and led to more stable, less inflamed plaques. 21 More recent studies where aortic segments from atherosclerotic donor mice with high plasma VLDL/LDL levels were transplanted into healthy recipient mice with low plasma VLDL/LDL levels suggest that atherosclerotic plaques are highly dynamic.…”

Cholesterol-induced atherosclerosis. Clonal characteristics of arterial lesions in the hybrid hare.

“…Most studies in animal models have relied on gross morphologic or histologic comparisons with human lesions. Multiple techniques have been used to produce atherosclerotic lesions in a variety of animal species, with cholesterol feeding 10 " 13 or mechanical trauma to the intima of the artery 14 " 18 being the most widely used. On the basis of studies using these lesions, numerous conclusions about the natural history, cellular biology, and biochemistry of the atherosclerotic plaque have been drawn.…”

“…These include lack or paucity of ulceration, hemorrhage, or fibrous cap in the lesion; location of the lesion in the proximal parts of the aorta rather than the distal; predominant involvement of intramyocardial branches of the coronary arteries rather than of epicardial arteries; and the widespread deposition of cholesterol in such organs as the liver, spleen, skin, and eye. 13 '…”