LIPID METABOLISM 



l8 9 



•of cholesterol esters increased in more advanced 

 lesions while phospholipid content decreased. In the 

 coronary vessels, the content of triglycerides in rela- 

 tively healthy specimens was quite high; cholesterol 

 and its esters increased with advancing atherosclerosis 

 while glyceride content fell. With respect to fatty acid 

 patterns, the trends with increasing atherosclerosis 

 in coronary and cerebral samples were similar to 

 that shown by the aorta. 



The studies reported to date on the lipid composi- 

 tion of atheromas appear to support the impression 

 that the cholesterol esters in the intima and media 

 start by being extremely saturated in comparison with 

 those circulating in the plasma; with increasing ather- 

 osclerosis of the wall the apparently healthy parts 

 contain more polyunsaturated cholesterol esters than 

 the adjacent lesions. The mechanism whereby even 

 apparently normal vascular tissue becomes infil- 

 trated by plasma lipids remains unknown. In any 

 event, it seems clear that the fatty acids of the arterial 

 wall, like those of the plasma, are responsive to dietary 

 influences. Hence, this variable (among others) must 

 be taken into account when data reported by various 

 investigators are being compared and evaluated. 



It should not be forgotten that a number of en- 

 vironmental and host factors may play a role in the 

 pathogenesis of atherosclerosis. Groen (88) has listed 

 eight exogenous and six endogenous elements that 

 have been given major attention by various investi- 

 gators. Included in this list are such items as constitu- 

 tion, age, obesity, physical exercise, social class, emo- 

 tional influence and such concomitant diseases as 

 hypertension and diabetes. This very multiplicitv of 

 considerations makes human atherosclerosis an 

 exceedingly complex problem. However, a common 

 pathway still must be defined through which a given 

 influence can operate. In the present discussion the 

 early atheroma has been viewed as a phenomenon 

 secondary to an abnormality of the serum lipids; 

 thus, the lesion can be said to be biochemical first 

 and histologic second. 



ROLE OF BLOOD CLOTTING AND THROMBOSIS 



Commonly, the dramatic clinical manifestations of 

 atherosclerosis such as myocardial infarction and 

 "stroke" result from acute thrombotic obstruction of 

 an artery. It is generallv believed that the athero- 

 sclerotic lesion acts as a nidus for thrombus formation 

 which, in turn, occludes the vessel. This assumption 

 is not invariably correct. Arterial thrombosis can 



occur at sites where atherosclerosis is minimal or 

 absent, and arterial occlusion by an atherosclerotic 

 lesion can occur without thrombosis. The events that 

 lead to thrombosis in vivo still are not clearly under- 

 stood. 



Certain inconsistencies appear if arterial thrombosis 

 is regarded as a simple epiphenomenon of athero- 

 sclerosis. Epidemiologic studies have suggested an 

 increase in mortality rates from coronary artery dis- 

 ease in the Western World during the past 25 years 

 without a corresponding increase in atherosclerosis 

 (149). The discrepancy in certain countries between 

 clinical coronary artery disease (rare) and athero- 

 sclerosis of the aorta (common) already has been 

 mentioned. In certain experimental animals, in which 

 atherosclerosis has been produced readily by dietary 

 means, production of myocardial infarction has been 

 difficult [although achieved in rats fed high fat diets 

 supplemented with cholesterol, cholic acid, and thio- 

 uracil (91)]. Thus, any attempt to relate development 

 of occlusive arterial disease to dietary fat consumption 

 must take into account the role of thrombosis (150). 

 In this regard, Duguid (56) has reviewed and modified 

 a concept introduced by Rokitansky a century ago 

 relating atherogenesis to fibrin deposition on arterial 

 intimal surfaces. Duguid has shown that arterial 

 narrowing can be produced by organization of mural 

 thrombi with subsequent endothelialization and lipid 

 deposition. The end result is difficult if not impossible 

 to distinguish from "atherosclerosis.'' Subintimal 

 hemorrhage and other "mechanical" factors have 

 been considered as initiating the process (57). From 

 such a standpoint, lipid deposition in atherosclerosis 

 is thought to be secondary to thrombus formation. 

 However, most of the available evidence still favors 

 the view that lipid deposition in the arterial wall is 

 the primary event in atherogenesis. 



The possible influence of dietary fat on blood coagu- 

 lation has been the subject of several reviews (92, 

 163). It is clear that the factors involved in main- 

 tenance of blood fluidity are complex and deserving 

 of further investigation. Methods for detecting in- 

 cipient thrombosis in the intact organism are inade- 

 quate. A distinction must be made between results 

 obtained by feeding fat on the various coagulation 

 tests in vitro and the influence of lipemia on coagula- 

 tion in vivo. There appears to be agreement concern- 

 ing the accelerating effect of certain dietary and 

 synthetic phospholipids, platelet lipid extracts, and 

 postprandial plasma on the Stypven time, a short- 

 ening of the clotting time of plasma in the presence 

 of Russell's viper venom. The relevance of these 



