Development of atherosclerosis in genetically hyperlipidemic rabbits during chronic fish-oil ingestion.

Abstract

The evidence for a reduction In cardiovascular mortality from fish oil is based on epidemlologic observations. To test whether fish-oil supplementation Influences the development of atherosclerosis, we treated Watanabe heritable hyperlipidemic rabbits (WHHL), an Inbred strain that spontaneously develops atherosclerosis, with 2.5 ml of MaxEPA flsh-oll concentrate dally and compared them to a control group fed un8upplemented rabbit chow. Serial cholesterol and trlglyceride levels were monitored as were plasma llpld hydroperoxldes. The animals were given fish oil from the time of weaning until 1 year of age, when they were sacrificed and their aortas were compared for the extent of atherosclerosis. No significant differences In the cholesterol or trlglyceride levels were noted between the two groups. Fatty acid hydroperoxlde levels were also similar and were noted to Increase from weaning (1.0±0.7/£M) to the time of sacrifice (1.8± 1.5/xM, p<0.01). Fish oil had no Influence on the extent of aortic atherosclerosis (25%± 14% surface area for controls vs. 28%± 19% for treated, p=NS), plaque thickness, or plaque volume after 1 year. We conclude that fish oil does not reduce the levels of serum cholesterol, llpld hydroperoxldes, or aortic atherosclerosis In WHHL rabbits. The hypothesis that fish oil protects against atherosclerosis was not supported by this study. I n the past several years, there has been a heightened interest in the possible cardioprotective effects of dietary fish oil. Initiated by the observation of a low incidence in cardiac disease-related mortality in the Greenland Eskimo, 1 a population whose diet is high in fish consumption, this interest has been strengthened by studies suggesting that fish-oil ingestion may reduce atherosclerosis, possibly via a mechanism that relates to its influence on eicosanoid metabolism. 234 Other studies have suggested that circulating lipid hydroperoxldes represent a chronic oxidant stress that is capable of promoting atherogenesis directly or indirectly via the stimulation of intracellular hydroperoxides.5 There is evidence, as well, that omega-3 fatty acids can decrease the rate of generation of hydroperoxides by cyclooxygenase 8 or decrease the amount of oxidants produced locally by leukocytes via a reduction in eicosanoid biosynthesis.7 If the omega-3 fatty acids found in fish oil affect eicosanoid synthesis or lower peroxide levels, then increasing the consumption of fish oil in a population that is prone to atherosclerosis (such as the U.S. adult population) might prevent or retard the development of atherosclerotic heart disease, independent of serum cholesterol levels or genetic predisposition.The protective effect of chronic fish-oil ingestion on naturally occurring atherosclerosis has been based on supposition, however. No necropsy studies have been published on the Greenland Eskimos, and the presumed low incidence of atherosclerosis attributable to fish oil has been extrapolated from observations comparing populations with high and low fish consumption. 8 ...

Reproductive performance and changes in blood lipids in breeding females and in growing Watanabe Heritable Hyperlipidaemic and New Zealand White rabbits

“…The heterozygous WHHL rabbits have the same blood lipid levels as other normolipidaemic rabbits and develop only minimal spontaneous atherosclerosis which is not observed until the age of approximately 2 years (Atkinson et al 1989, Esper et al 1993b, Hansen et al 1994. The WHHL rabbits have been used in dietary and medicamental intervention studies (Rich et al 1989, Chubb et al 1990, Lichtenstein & Chobanian 1990, Mao et al 1991, Hansen et al 1995. The intervention often begins just after the weaning period in 6-week-old rabbits.…”

Fish oil and the prevention and regression of atherosclerosis

“…In this respect it is of interest to cite the recent paper by Ravnskov [77] in which he compared the frequency of citation with the outcome of all cholesterol lowering trials using coronary heart disease or death as endpoints and found that positive studies were cited almost six times more often than negative ones. That sample size can be of major importance in determining the out- come of the study was shown by Rich and colleagues [69] who after having analyzed one third of the rabbits, found a statistically significant effect favouring the fish oil treated group. However, because of the variability of aortic atherosclerosis as found in Watanabe hyperlipidemic rabbits it was judged to expand the dietary groups to improve the validity of the results.…”

“…Animal studies with hypercholesterolemia Tables 2-4 list the in vivo studies in rabbits [58][59][60][61][62][63][64][65][66][67][68][69], swine [23,28,[70][71][72][73] and monkeys [74][75][76], respectively, on the effects of fish oil on the prevention of atherosclerosis and provides details such as the dietary regimen, duration of study, etc. Except in the Watanabe hereditary hyperlipidemic rabbit and one study in pigs [73], all atherogenic diets are highcholesterol diets, and in case of the swine model [28,[70][71][72], bile acids were also needed to enhance hypercholesterolemia.…”

“…In all studies the number of anireals used is comparable (from five to twelve). After judging the results of the twelve rabbit studies and classifying them very globally one can conclude that an equal number of studies report a favorable [60,64,66,67], unfavorable [58,62,65,68] or no effect [59,61,63,69). For the swine studies four [23,[71][72][73] are favorable and two [28,70] show no effect, while in the non-human primates two [74,75] are beneficial and one study [76] shows no effect at all.…”

Antiatherogenic effects of n-3 fatty acids - evidence and mechanisms

“…In WHHL rabbits, n-3 fatty acids were initially reported to have either no effect on plasma lipids and aortic lesion size (39), or to lower triglycerides, total lipoproteins and cholesterol in female rabbits, but to be ineffective on lesion size of treated vs. untreated controls (40). With a similar experimental protocol, but with different criteria for lesion evaluation, fish oil reduced triglyceride and cholesterol levels and aortic lesions (41).…”