ENDOCRINES, STRESS, AND HEREDITY ON ATHEROSCLEROSIS 



I 21)- 



derivatives are being explored, so far without worth- 

 while results. 



From all these data it is evident that gonadal 

 hormones have a significant influence upon lipid 

 metabolism and atherogenesis. 



HEREDITY 



That genetic or hereditary factors may influence 

 the development of atherosclerosis is suggested by 

 animal experimental and human studies. It has to be 

 emphasized, however, that these tendencies become 

 evident only in the presence of a potentially athero- 

 genic diet. If the environment is favorable, genetic 

 tendencies may not become evident. As in many 

 other diseases, the interplay between host and en- 

 vironment is of the utmost importance. 



Animal experiments have indicated species differ- 

 ences in the susceptibility of atherosclerosis. Man and 

 several species of birds develop atherosclerosis spon- 

 taneously (51). Also old dogs, kept as pets, have been 

 found to exhibit aortic and coronary atherosclerosis 

 (87). Most animals, however, living in their natural 

 environment do not exhibit vascular lesions, with the 

 possible exception of the baboon (55, 93) which 

 shows fatty streaks in the aorta. 



Species differences are also found in the response to 

 high-level cholesterol-fat feeding. Chicks and rabbits 

 respond to this regimen with severe hypercholestero- 

 lemia and atherosclerosis in a short period of time 

 (10, 72). It is more difficult to produce similar effects 

 in ducks, guinea pigs, and hamsters (8, 9, 59). In the 

 dog, cholesterol feeding has to be combined with 

 supression of the thyroid activity in order to produce 

 both lipid and vascular changes. In the monkey, 

 cholesterol feeding has to be combined with a de- 

 ficiency in sulfur-containing amino acids in the diet to 

 produce lesions (98). Recently, however, athero- 

 sclerosis was induced in rhesus monkeys by a high- 

 saturated fat, high-cholesterol, nondeficient diet alone 

 (29). In the rat, the species most resistant to the 

 induction of atherosclerosis, this disease has been 

 produced by a combination of multiple dietary and 

 hormonal manipulations, i.e., cholesterol, cholic acid, 

 and saturated fat in the diet, plus hypothyroidism and 

 unilateral nephrectomy (63). 



The cause of these species differences has not been 

 entirely clarified. Recent tracer studies, however, 

 indicate species differences in cholesterol synthesis, 

 turnover, and degradation rates, and in the handling 

 of dietary cholesterol (61, 62). Other studies indicate 



differences in the number of vasa vasorum in the 

 aorta — richest in resistant species and poorest in the 

 very susceptible (139). Whether or not these species 

 differences are the actual cause of the varied suscepti- 

 bility to hypercholesterolemia and atherosclerosis is 

 not known. Nor is it known how they are inherited. 



More significant perhaps than species differences, 

 are strain differences which occur within a single 

 species. These have been demonstrated in rabbits 

 (145). In chicks they have been described by Opdyke 

 & Ott (116) and others (46). They have been indi- 

 cated in dogs (100). The most recent and thorough 

 investigations into strain differences was carried out 

 by Lofland & Clarkson (88, 89, 90) who have studied 

 several breeds of pigeons, in particular: the White 

 Carneau, the White Racer, and the Autosexing King. 

 The first shows severe aortic and some coronary 

 atherosclerosis in old birds of both sexes kept on a 

 low-cholesterol, low-fat commercial diet. The second 

 strain does not show any lesions on the same diet. 

 The third, genetically a cross-breeding between the 

 first two, has intermediate incidence and severity of 

 lesions. The onset of atherosclerosis in response to 

 high cholesterol feeding of the three breeds parallels 

 the severity of the spontaneous lesions. All three 

 breeds spontaneously have high serum cholesterol 

 levels, around 400 mg per cent, with marked seasonal 

 variations (66), and resemble one another in many of 

 the biochemical aspects studied by these authors. 

 Wherein lies the definitely genetic difference in the 

 production of lesions is unexplained. 



In man, it has often been suggested that genetic 

 and hereditary factors may play a role in lipid 

 metabolism and coronary atherosclerosis. The first 

 indication of such a relationship was described in 

 1930 (65). A vast literature on statistical and genetic 

 investigations has since appeared proving the familial 

 occurrence of a xanthomatous tendency, i.e., a 

 tendencv for hypercholesterolemia and atherosclerosis 

 to appear in families. This was reviewed recently by 

 McKusick (94). The most extensive clinical studies 

 were carried out by Adlersberg et al. (2-4) and by 

 Thomas & Cohen (161). Some limited studies are 

 available on the incidence of these disorders in 

 identical and fraternal twins, living together or 

 separately, which may aid in determining the respec- 

 tive roles of heredity and the environment (118). 



Adlersberg and others (3, 17, 40, 137, 161) con- 

 sider hypercholesterolemia an inborn error of metab- 

 olism, probably inherited as an "incomplete" 

 dominant trait. Familial hypercholesterolemic xantho- 

 matosis, a disorder of lipid metabolism characterized 



