I 1 68 HANDBOOK OF PHYSIOLOGY ^ CIRCULATION II 



of diet-induced changes in serum lipids in the de- 

 velopment of atherosclerosis has not been established. 

 In man, atherogenesis appears to be a chronic process, 

 requiring considerable time, perhaps years, to evolve. 

 The disease can culminate in an acute obstructive 

 event, frequently with disastrous consequences. At 

 such a time a disturbance in the coagulability of the 

 blood may occur resulting in the formation of an 

 arterial thrombus. Thus, attempts have been made 

 to correlate changes in serum lipids as influenced by 

 diet with the development not only of atherosclerosis 

 but also of a more acute change in coagulability of 

 the blood. 



The clinical sequelae of atherosclerosis, ischemia, 

 and infarction of the heart, brain, and other tissues, 

 have been carefully documented for years. Also, the 

 gross pathologic processes, such as lumen encroach- 

 ment, fibrosis, ulceration, calcification, and throm- 

 bosis, which underlie these clinical events base been 

 understood by pathologists since the time of Virchow. 

 Moreover, a reasonable explanation for the patho- 

 genesis of the disease was advanced more than half a 

 century ago and has not been disproved. Yet from 

 the standpoint of etiology and intimate pathogenesis 

 the basic nature of the disease remains obscure and 

 debatable. 



PATHOLOGY 



The pathologic entity atherosclerosis must be dis- 

 tinguished from other blood vessel lesions, some ot 

 which have been previously lumped together with 

 atherosclerosis under the generic designation, arterio- 

 sclerosis. Monckeberg's medial sclerosis differs patho- 

 logically, pathogenetically, and clinically from ath- 

 erosclerosis. Various inflammatory lesions of blood 

 vessel walls also can be sharply separated, although 

 the generally held concept that thromboangiitis 

 obliterans is an entity different from peripheral ath- 

 erosclerosis recently has been questioned (209). 



Another important consideration is that common 

 textbook descriptions of atherosclerosis may in fact 

 describe mostly complications or sequelae of an initial, 

 clinically silent process that may start in infancy. 

 Thus, lumen encroachment, fibrosis, calcification, 

 ulceration, hemorrhage, and thrombosis are all late 

 conditions. 



What then is the initial lesion? What is the patho- 

 logic essence of the disease? The answer to these 

 questions necessarily involves consideration of patho- 

 genesis (to be discussed later) as well as descriptive 



pathology. Fortunately, precise studies of early gross 

 and microscopic lesions from human and experi- 

 mental material are available (21, 55, 108, 109, 130, 

 162). The first gross lesion, often visible in infants, 

 is the fatty streak, a linear yellow elevation usually 

 found in the aorta. Microscopic examination of such 

 a streak reveals underneath the heaped-up intima 

 an accumulation of lipophages, cells which show a 

 foamy, reticular cytoplasm with ordinary stains con- 

 taining lipid solvents, but which are found, with 

 appropriate fat stains, to be packed with lipid. Lipid 

 is also found lying free between the lipophages. 

 Whether the lipid which makes up the fatty streak is 

 first intracellular or extracellular is as yet unknown. 

 With larger lesions, lipid is also found below the 

 internal elastic lamella in the media, but the smallest, 

 earliest, grossly invisible lesions consist of a few foam 

 cells lying directly under the endothelial surface of 

 the intima. Thus, the lipid-containing foam cell is 

 usuallv considered to be the earliest recognizable unit 

 of the atherosclerotic process. 



However, careful microscopic studies show other 

 subtle anatomic changes (39, 126, 195) occurring 

 pari passu with the appearance of lipid in the blood 

 vessel wall. Elastic tissue stains reveal stretching and 

 fragmentation of elastic fibers in the intima as an 

 early feature. Other special stains show metachro- 

 matic changes in the ground substance of the arterial 

 wall, and chemical studies have demonstrated muco- 

 polysaccharide accumulations that occur along with, 

 or possibly before, the appearance of visible lipid. An 

 abundance of evidence, clinical and experimental, 

 has shown that preceding damage to the arterial wall, 

 toxic, infectious, chemical or physical, will accelerate 

 and will influence the site of the atherosclerotic 

 proce^. These findings have given rise to the theory 

 that subtle, perhaps submicroscopic, alterations in 

 the physicochemical state of the arterial wall may 

 actually precede the more gross lipid accumulations. 



PATHOGENESIS 



Since the earliest pathologic lesions are only adum- 

 brative, even with modern histochemical techniques, 

 it follows that the intimate pathogenesis of the 

 atherosclerotic lesion also remains obscure. It is 

 understandable that nineteenth century pathologists 

 considered the disease a degenerative one, an inevi- 

 table concomitant of the aging process and a simple 

 result of wear and tear on the arterial wall. Even 

 when atherosclerosis was separated from other arte- 



