Studies of hypercholesterolemia in the nonhuman primate. II. Fatty streak conversion to fibrous plaque

This report presents the second portion of the morphologic studies on chronic, diet-induced hypercholesterolemia in nonhuman primates (Macaca nemestrina) examined sequentially between 5 and 13 months. A direct relationship was observed between the rate of cholesterol increase, the level and duration of hypercholesterolemia, and the changes in the artery wall that led to the formation of fatty streaks and their conversion to fibrous plaques. A loss of endothelial continuity was first observed in the iliac arteries between 3 and 4 months of atherogenic diet and appears to be a critical step in the conversion of many fatty streaks to fibrous plaques. With breaks in endothelial junctions and exposure of some of the macrophages in a fatty streak, many of the lipid-filled macrophages appeared to detach and enter the circulation. The number of circulating foam cells increased precipitously between 3 and 4 months, the time when increased sites of endothelial dysjunction and macrophage egress were observed. Exposure of subendothelial macrophages also permitted adherence of platelets to these macrophages and to exposed connective tissue. Fibrous plaques were found at similar anatomic sites where endothelial denudation had been observed at earlier time points but were more prevalent in the abdominal aorta and iliac arteries. These changes subsequently occurred at every level of the aortic tree and appeared to progress in a cephalad fashion with increasing rate, level, and duration of hypercholesterolemia. The results of these studies stress the importance of following cholesterol levels of each animal throughout the entire period of the study and of sampling the entire arterial tree at every level with time. This helped us to understand the complicated interrelationships between the various cells in atherogenesis, provided further support for the "Response to Injury Hypothesis of Atherosclerosis," and helped to explain how hypercholesterolemia may be involved in the different stages of atherogenesis in nonhuman primates and possibly in humans.