ENDOCRINES, STRESS, AND HEREDITY ON ATHEROSCLEROSIS 



I 20 I 



alloxan injections or by pancreatectomy failed to 

 cause atherosclerosis. When experimental diabetes 

 was combined with cholesterol-fat feeding, athero- 

 sclerosis incidence was not higher than in normal 

 animals on the same diet. Of particular interest are 

 the findings by Duff et al. (38), who showed a de- 

 creased atherogenesis in diabetic rabbits on a cho- 

 lesterol-oil diet. This trend was reversed when the 

 animals were treated with insulin. These workers 

 attributed this effect to the particular serum lipid 

 picture developing under these circumstances. 

 Alloxan diabetes produced a marked hyperphos- 

 pholipemia with hypercholesterolemia and an in- 

 crease in serum neutral fat. These animals, therefore, 

 had a low ratio of total cholesterol to phospholipids 

 (C/P ratio) in the hypercholesterolemic state. This 

 particular lipid picture is usually accompanied by a 

 low incidence and severity of vascular lesions. Insulin 

 given to these rabbits caused the lipid picture to 

 change so as to resemble the usual pattern obtained 

 by cholesterol-fat feeding alone, namely a marked 

 hypercholesterolemia with a mild hyperphospho- 

 lipemia. This, in turn, resulted in an elevated C/P 

 ratio and the attendant increased incidence and 

 severity of atherosclerosis. 



Interesting results were also obtained in studies of 

 the pancreas and atherogenesis in chicks (154, 156) 

 Pancreatectomized birds show no overt signs of 

 disturbances of lipid or glucose metabolism. However, 

 latent disturbances can be detected when these birds 

 are given a high-cholesterol, high-fat diet or when 

 adrenal steroids are administered. On this diet they 

 show enhanced hypercholesterolemia and athero- 

 sclerosis, as well as retarded healing of lesions. With 

 glucocorticoids they show a definite hyperglycemic 

 response which is much greater than occurs in normal 

 animals given these steroids. Cholesterol-fed, steroid- 

 diabetic chicks do not show increased atherogenesis. 

 Insulin, in hypoglycemic doses, when given to normal 

 chicks does not increase the atherogenic potential of 

 a high-cholesterol, high-fat diet. However, in these 

 same doses insulin prevents regression of coronary 

 artery lesions when it is given to chicks which are 

 first made atherosclerotic and then placed on a 

 plain, nonatherogenic diet — a diet which by itself 

 normally leads to rapid regression of these early 

 coronary lesions. The mechanism by which insulin 

 prevents regression, while at the same time appearing 

 to be without effect during the induction phase, is 

 not clear. Large doses of insulin were used in these 

 experiments, and this did cause marked hypoglycemia 

 which in some way acted in a detrimental manner. 



Also, the insulin probably increased the secretion of 

 catecholamines and corticoids, as evidenced by the 

 occurrence of periods of reactive hyperglycemia. 

 Furthermore, some recent observations indicate that 

 chronic insulin administration may produce pro- 

 longed hyperglycemia after the drug administration 

 is discontinued, indicating some profound hormonal 

 derangement. Local effects within an atheroma also 

 cannot be excluded. 



How much of the effect of diabetes mellitus or 

 insulin on atherosclerosis is due to the changes in 

 lipid metabolism and how much to factors influencing 

 the vascular wall is not clearly established. Further- 

 more, several authors (32, 84) have suggested that in 

 diabetics, and even in nondiabetic members of their 

 families, the ground substance of the vascular wall is 

 subtly changed, making it particularly prone to 

 atherosclerosis. In addition, blood coagulation is 

 changed in uncontrolled diabetes as in other hyper- 

 lipemia states. 



From all this it is apparent that the increased 

 tendency of the diabetic to develop atherosclerosis 

 must depend on a number of factors. 



Adrenal and Pituitary Hormones 



Adrenal cortical and medullary hormones have 

 been shown to influence lipid metabolism and the 

 vascular wall. However, the lipid metabolic responses 

 to these hormones differ among the several animal 

 species studied, including man. Also, their acute and 

 chronic effects on circulating serum lipids differ. 

 The mechanism of their action has not been satis- 

 factorily elucidated. 



adrenal cortical hormones and acth. Hyper- 

 activity of the adrenal cortex in Cushing's disease is 

 frequently associated with hypercholesterolemia and 

 hyperlipemia and a tendency to severe premature 

 atherosclerosis (64, 68, 177). In contrast, bilateral 

 destruction of the adrenals in Addison's disease is 

 accompanied by low serum cholesterol levels (142). 

 Furthermore, the adrenal cortex has a high chol- 

 esterol content and it can synthesize and discharge 

 cholesterol and steroid hormones readily (147, 1 74)- 



Adrenalectomized dogs maintained on desoxycorti- 

 costerone acetate (DCA) show a marked decrease of 

 serum cholesterol and phospholipid levels (31, 182). 

 When cortisone is substituted for DCA, a marked 

 rise in these lipids occurs. Combined DCA and corti- 

 sone administration showed no further increase over 

 cortisone alone. It was concluded from these studies 



