"98 



HANDBOOK OF PHYSIOLOGY 



CIRCULATION II 



liver is finely attuned to the amount of ingested 

 cholesterol (61). This homeostatic mechanism is 

 disturbed or may even be exhausted by a high-fat, 

 high-cholesterol diet over the life span. This could 

 explain the slowly increasing serum cholesterol 

 levels with aging in our population. Recent findings 

 also suggest that cholesterol synthesis by extrahepatic 

 tissues, not regulated by dietary intake, may con- 

 tribute significantly to the development of hyper- 

 cholesterolemia and, therefore, atherosclerosis (i). 

 Animal experiments lead us to suspect that the daily 

 pattern of eating, the number of meals, for example, 

 may help to determine the metabolic fate of the 

 constituents of a potentially atherogenic diet (28). 



In the case of a particular individual, the tendency 

 to develop this increase in blood cholesterol and to 

 acquire vascular disease will be subject to many 

 factors other than the nature of the diet (73, 114). 

 These other factors per se do not actually produce or 

 prevent atherosclerosis, but they are capable of 

 influencing it in the presence of a potentially athero- 

 genic diet. Those which will be considered in this 

 chapter are: a) the endocrines, b) heredity, and c) 

 stress. They are the most significant ancillary factors 

 so far known. 



Because of discrepancies between the amount of 

 anatomical vascular disease and the occurence and 

 magnitude of organ involvement, doubt has recently 

 been expressed as to the relationship of atherosclerosis 

 and, for instance, coronary heart disease (129, 163). 

 However, no evidence is available that ischemic heart 

 disease and ischemic disease of the brain, the extrem- 

 ities, or other organs occur without vascular disease 

 (except on rare occasion). The major exception is one 

 in which, with only minimal atheroma formation, it 

 is possible to produce experimental coronary and 

 renal thrombosis, and myocardial and renal infarction 

 in rats (63), but even here vascular abnormalities 

 were produced only in the presence of a high 

 saturated-fat diet. 



It is safe to state that without the basic arterial 

 process of atheroma no morbid consequences would 

 exist except as a rare phenomenon. Equally well 

 documented is the fact that even with moderate and 

 se\ ere atherosclerosis no such morbid or mortal 

 consequences need occur. These findings clearly point 

 out that in atherosclerosis research we have to deal 

 with two major questions: /) What produces the 

 basic vascular lesions? 2) What factor or factors may 

 lead to the complications — ulceration, thrombosis, 

 hemorrhage into a plaque— that will ultimately 

 determine the clinical fate of an individual? It is 



possible that the same factors may determine both 

 aspects. For example, prolonged hyperlipemia and 

 hypercholesterolemia produce lipid deposition and 

 atheroma in the arteries, and these blood changes also 

 facilitate blood clotting, so that after an atheroma has 

 developed in this fashion the stimulus is there to give 

 rise to subsequent thrombus formation. Similarly, 

 different neurogenic or hormonal factors, or both, 

 may conceivably influence both processes. However, 

 their effect may be preferential upon one or the other 

 of these two stages. It must also be remembered that 

 the vascular wall as an organ is capable of synthesizing 

 cholesterol in small amounts and phospholipids in 

 larger quantities (170, 183). Furthermore, it has 

 been shown that species differences exist in the 2 

 uptake between normal and atherosclerotic aortas, 

 the ()•> uptake being higher in susceptible species 

 and in atherosclerotic specimens (173). Permeability 

 of the vascular endothelium is another factor that 

 may be influenced by metabolic alterations due to 

 hormonal, genetic, or stressful circumstances mediated 

 by hormone release. Electron microscopy has con- 

 firmed the concept that lipids are being deposited 

 in the intima by permeation from the blood stream 



('59)- 



Furthermore, differences in the responses of the 

 vessels in different vascular beds to hormonal and 

 other influences must not be overlooked. Whether 

 these differences are due to the particular metabolism 

 within the organ, to the nervous influences acting 

 upon it, or to anatomical differences — possibly due to 

 genetic factors — is not known at present. Some evi- 

 dence for each of these causes is available (83, 94, 

 138). 



Whether a given duration and intensity of hyper- 

 lipemia and hypercholesterolemia will or will not 

 lead to the emergence of atherosclerotic disease, 

 either in the form of the anatomical substrate alone or 

 accompanied by the associated sequelae, is deter- 

 mined by the genetic make-up of the individual and 

 very likely also In the nature of the environmental 

 conditions under which he lives out his existence. 

 Emotional factors, dependent in part upon genetic 

 make-up and in part upon external environment, 

 have recently been implicated in aberrations of lipid 

 metabolism, in the genesis of atherosclerosis, and in 

 the transformation of a silent vascular disease into a 

 clinically overt one. Whether emotional states 

 operate through hormones, or by way of the auto- 

 nomic nervous system, or both, is not known at 

 present. It is possible that hormonal and nervous 

 factors themselves produce the emotional upsets as a 



