LIPID METABOLISM 



I l6g 



rial lesions, it must still have appeared to pathologists 

 of that era to be another phenomenon of aging, found 

 along with cataracts, osteoarthritis and wrinkled skin, 

 and occurring with increasing frequency with advanc- 

 ing years. 



The pendulum did not swing until Ignatowski (1 10) 

 in 1908 succeeded, by administering lipid-rich foods 

 to rabbits, in producing arterial lesions similar to 

 those occurring spontaneously in human subjects. A 

 few years later Anitschkow (10) demonstrated con- 

 vincingly that cholesterol in the diet was the athero- 

 genic factor in experimental rabbit atherosclerosis. 

 Since that time, a large body of evidence has led 

 away from the degenerative theory. Some of these 

 evidences are: the finding at autopsy of an occasional 

 octogenarian virtually free of arterial disease; the 

 contrary finding of fatal atherosclerosis in soldiers in 

 their twenties; the relative freedom from the disease 

 of premenopausal women; the increased incidence at 

 autopsy of atheromatous lesions in patients with 

 diseases involving lipid abnormalities such as diabetes, 

 hypothyroidism, and other processes associated with 

 hypercholesteremia and hyperlipidemia. Further 

 information resulted from the epidemiologic finding 

 of certain population groups relatively free of the 

 disease at postmortem examination. Pathologists 

 made further contributions to this change in concept 

 by their studies in experimental animals; it is now 

 recognized that, although man, certain other pri- 

 mates, birds, and swine are the only animals which 

 seem regularly to acquire atherosclerosis sponta- 

 neously, there is a wide variety of species which can 

 be caused to develop arterial lesions similar to those 

 found in human material, providing only that appro- 

 priate experimental manipulations involving lipid 

 metabolism are made. 



All this pathologic evidence, along with a huge 

 volume of clinical, epidemiologic, and biochemical 

 studies, has led to the modern concept that athero- 

 sclerosis is potentially a preventable disease, a result 

 of metabolic disorder rather than a degenerative 

 process. This lipid concept of the pathogenesis of 

 atherosclerosis can be stated in simple terms: man 

 ingests an excess of lipid which overwhelms the mech- 

 anisms for its disposal; lipid then accumulates in the 

 circulating blood and is deposited in the arterial wall. 



How does this rather simple concept fit with the 

 facts of the earliest recognizable pathologic lesion 

 described above? At first glance, the fit seems perfect. 

 An excess of lipoprotein material in the circulating 

 blood filters through the endothelium of the arterial 

 wall and is taken up there by tissue histiocytes to 



form foam cells; the simple accumulation of these 

 lipophages results in the gross arterial atheroma and 

 sets off the chain of events leading to fibrosis, throm- 

 bosis, and the rest. Yet there are a number of ques- 

 tions which cast doubt on this simple hypothesis. 



First, if the mechanism is merely one of filtration 

 through the endothelium to the arterial intima, why- 

 are the anatomically similar veins not more susceptible 

 to the atheromatous process? That intraluminal pres- 

 sure plays some role is shown by the increased inci- 

 dence of atherosclerosis in hypertensive patients, the 

 occurrence of pulmonary artery atherosclerosis in 

 individuals with pulmonary hypertension, and the 

 finding of phlebosclerosis adjacent to arteriovenous 

 fistulas. 



Another disturbing question concerns the fact 

 that the lipid deposit is not a universal arterial finding, 

 coating the intima of the entire arterial tree, but 

 rather a spotty, localized one, involving certain seg- 

 ments of certain arteries. A number of possible ex- 

 planations for this finding have been offered. One 

 argument is that localized changes in filtration pres- 

 sure, occasioned by intraluminal physical forces such 

 as whirlpool and eddy formation, determine the site 

 at which lipid is deposited; the frequent occurrence 

 of atheromatous lesions at bifurcations, branches and 

 coarctations favors this theory (175). Another pro- 

 posal relates the clinical predilection for thrombosis 

 in atherosclerosis to its pathogenesis; the earliest 

 lesion, by this concept, is a chance fibrin deposit on 

 the endothelial surface, the spotty lipid lesion occur- 

 ring secondarily to fibrin deposition (56). Another 

 explanation depends on the clinical and experimental 

 evidence that preceding arterial wall damage, physi- 

 cal, chemical, mechanical, or bacterial, will foster 

 premature and extensive lipid deposits; by this theory, 

 occult damage to the elastic tissue or ground sub- 

 stance (or both) of the arterial wall, from degenera- 

 tive or extraneous cause, serves as the spotty focus for 

 lipid deposit. Still another theory explains the spotti- 

 ness on the basis of localized differences in various 

 areas of the arterial wall, in the mechanisms for 

 removal of lipid, either metabolic (enzyme overload), 

 scavenging (number of histiocytes present) or ana- 

 tomic (number of lymph channels present). Yet 

 another hypothesis explains localization by denying 

 filtration from the lumen; according to this concept, 

 atheromatous lesions are preceded by a localized 

 overproduction in the arterial wall of the lipids which 

 make up the lesion (105). Sensitive radioactive tracer 

 studies have indeed shown that arterial tissue can 

 synthesize lipids, but recent reports (214) have indi- 



