Development of the Lipid-Rich Core in Human Atherosclerosis

In recent years the role of the atherosclerotic core in promoting plaque rupture has become well recognized. A new insight into core development is its origination early in atherogenesis, before formation of the fibrous plaque. The early core is associated with accumulation of vesicular lipid rich in free cholesterol. Later in core development, lipid deposits become more diverse. The weight of evidence points toward a direct extracellular process, probably lipoprotein aggregation and fusion, as the chief pathway of cholesteryl ester accumulation, although foam cell death may also contribute cholesteryl ester. The mechanism or mechanisms of formation of vesicular, cholesterol-rich deposits are unknown. Since the increase in free cholesterol is likely to have deleterious effects on cells bordering the core, the further elucidation of cellular and biochemical pathways leading to and responding to free cholesterol accumulation is of great importance. Complement activation and cellular stress responses are prominent in the vicinity of core lipids, but their pathogenetic roles remain to be established. Since the core appears so early in atherogenesis, these as well as other, yet to be determined cellular responses to core lipids, oxidized and unoxidized, could have a considerable effect on overall lesion development. Much remains to be learned about macrophage and smooth muscle responses, calcification, capillarization, and matrix protein alterations in the evolution of the core and surrounding arterial intima.