HANDBOOK OF PHYSIOLOGY 



CIRCULATION II 



ham Heart Program (47, 114) is of interest because it 

 has used the prospective approach. In this study, 

 approximately 5,000 individuals originally free of 

 manifestations of overt coronary heart disease in the 

 town of Framingham, Massachusetts, have been fol- 

 lowed for 8 years, and the study continues. From the 

 Framingham data, it has been shown that an associa- 

 tion exists between a number of factors, other than 

 age and sex, and an increased risk of developing 

 coronary heart disease: these are obesity, hyperten- 

 sion, electrocardiographic evidence of left ventricular 

 hypertrophy, heavy smoking, and hypercholesteremia. 

 Increasing levels of serum cholesterol were found to 

 be associated with increasing risk of developing cor- 

 onary heart disease. Among the various lipid meas- 

 urements (excluding cholesterol esters and trigly- 

 cerides about which data were lacking) serum total 

 cholesterol was found to be the best measurement for 

 predicting the occurrence of overt coronary heart 

 disease. While the results of the Framingham study 

 have been interesting and provocative, the relatively 

 small number of subjects studied make it difficult to 

 arrive at firm conclusions about the relationship 

 between such variables as the serum cholesterol and 

 incidence of obstructive coronary disease. Until 

 larger samples can be obtained there is always a risk 

 of drawing too many unqualified conclusions from 

 insufficient data (132). 



In addition to the increased risk of heart disease 

 associated with hypercholesteremia, the increased 

 incidence of coronary atherosclerosis in patients with 

 essential hyperlipemia (hypertriglyceridemia) (139) 

 should be mentioned, as well as the reports that 

 patients with coronary heart disease tend to display 

 elevated levels of serum triglycerides (6) and impair- 

 ment of rate of clearing of alimentary lipemia (186). 

 Such preliminary observations suggest that the lower- 

 density lipoproteins carrying an increased burden of 

 triglyceride may play a more important etiologic 

 role in coronary atherosclerosis than has been hitherto 

 appreciated. 



Although it is common practice to use the term 

 "atherosclerosis" as though it described one disease, 

 evidence has been accumulating that in certain 

 countries where clinically manifest coronary-artery 

 disease is rare, atherosclerosis of the aorta may be 

 quite common (86). Similarly, American women 

 possess a relative immunity to coronary heart disease 

 during their reproductive years; yet they are not 

 equally immune from atherosclerosis at other ana- 

 tomic sites (174). It is worthy of comment that al- 

 though coronary heart disease is very common in 



patients with familial hypercholesteremic xantho- 

 matosis (primary hypercholesteremia), this disease 

 does not seem to predispose to the development of 

 peripheral or cerebrovascular disease (89). Con- 

 versely, coronary heart disease is rare among the 

 South African Bantu, a group in whom serum choles- 

 terol levels tend to be very low; yet, cerebral catas- 

 trophes occur as frequently among Bantu as among 

 populations with substantially higher levels of choles- 

 terol (128, 205). Thus, coronary heart disease may 

 prove to be a special manifestation of atherosclerosis, 

 with its own epidemiology and, perhaps, its own bio- 

 chemical pathology. 



Chemical studies of the atheroma have supported 

 the belief that a number of the fatty constituents of 

 the atheroma are derived from the plasma. Studies 

 have demonstrated that the distribution of lipids in 

 early atheroma is roughly similar to that in plasma 

 (104). As the atheromas of human aortas progress in 

 severity, they exhibit a parallel increase in content 

 of carotenoid and cholesterol (25). Since carotenoid 

 is derived entirely from the diet, such observations 

 also suggest that atheromatous lipid derives from the 

 circulation and does not originate de novo within 

 the arterial wall. A similar interpretation can be 

 made of the demonstration that linoleic acid, a sub- 

 stance which the body apparently cannot synthesize, 

 is a significant constituent of atheromas (187). 



With the advent of gas-liquid chromatography and 

 other improved techniques for lipid separation and 

 identification, it has become possible to obtain more 

 precise information about the lipid constituents of 

 atheromas at various sites and at various stages of 

 evolution (30, 31, 54, 133, 136, 199, 208). It has been 

 reported that the saturated and monounsaturated 

 fatty acid moieties of cholesterol esters tend to accumu- 

 late preferentially in early atheromatous lesions. 

 However, linoleic acid also can be found in atheromas 

 in appreciable quantities. A report from Leiden (32) 

 has described the results of detailed analyses of the 

 lipids in aortas and coronary and cerebral arteries in 

 various stages of atherosclerosis. It was found that 

 as the aortic lesions became more advanced their 

 relative content of cholesterol and cholesterol esters 

 increased strikingly. A comparison of the fatty acid 

 composition of "early" and "late" atheromas with 

 uninvolved aorta showed an increase in the propor- 

 tion of the polyunsaturated fatty acids of cholesterol 

 esters in the older lesions. The phospholipids exhibited 

 a slight increase in their proportion of long-chain 

 saturated fatty acids. Generally similar results were 

 obtained for the circle of Willis, in which the content 



