Studies of Hypercholesterolemia in the Nonhuman Primate: I. Changes that Lead to Fatty Streak Formation

Morphologic studies resulting from events that occur during the development of the lesions of atherosclerosis were studied In chronic, diet-induced hypercholesterolemia In a series of nonhuman primates. Within 12 days of hypercholesterolemia In Macaca nemestrina, monocytes became adherent to the surface of the endothelium. These monocytes appeared to migrate subendothelially, accumulate lipid, and become lipld-laden macrophages (foam cells). Within a month, a “seroflbrinous insudate” formed together with variable numbers of subendothellal llpid-laden macrophages. By the second month, foam cells increased In number, often in multilayers, to form a fatty streak. Concomitantly, the luminal surface of the arteries became increasingly Irregular due to the subendothelial accumulation of foam cells. Numerous monocytes continued to attach to the endothelial surface over the fatty streaks, and many of them appeared to enter the Intlma and participate In the growth of the fatty streaks. Lipid-laden smooth muscle cells appeared in small numbers and formed two to four layers between the macrophages and the internal elastic lamella at 2 to 3 months. During the third month of hypercholesterolemla, endothelial cell continuity over the llpid-laden macrophages became Interrupted, exposing the underlying foam cells to circulating blood. Foam cells were then readily observed In whole blood smears, suggesting that many of the lipld-laden macrophages leave the intima and enter the circulation.After 4 months, significant endothelial denudation was found In the lilac artery and many exposed macrophages were covered by adherent platelets in the form of a mural thrombus. Thus, the early components of atherosclerosis induced by chronic hypercholesterolemla centered around the monocyte-macrophage and its interaction with endothelium In the induction of the fatty streak. Subsequent changes that lead to macrophage-smooth muscle Interactions, platelet-macrophage Interactions, and platelet-endothelial interactions appeared to set the stage for the development of more advanced proliferatlve lesions.