Lipid deposits in human atherosclerotic fibrous plaques exhibit marked differences in chemistry and ultrastructure from lipid deposits in fatty streaks, leading some investigators to question whether fibrous plaques originate from fatty streaks. To examine lesion transition, we employed lipid microanalysis, electron microscopy, and immunohistochemistry on fatty streaks, fibrolipid lesions (small raised lesions), and fibrous plaques from human aorta. Both fatty streaks and caps of fibrolipid lesions were high in esterified cholesterol content (mean, 62% of total cholesterol) and high in cholesteryl oleate content compared with cholesteryl linoleate content. Fatty streaks and fibrolipid lesion caps also showed similar morphology, characterized mostly by macrophage-derived foam cells in the superficial intima. Core lipids in both small and large raised lesions differed markedly from this pattern. Fibrolipid lesion cores showed mostly vesicular extracellular deposits, sometimes accompanied by cholesterol L ipid deposition in human arterial fatty streaks consists mostly of cholesteryl esters, of which cholesteryl oleate is the most prominent, occurring primarily in cytoplasmic lipid droplets with droplet profile diameters generally exceeding 0.4 /xm. Lipid deposits in large, mature fibrous plaques, in contrast, are often enriched in free cholesterol, have cholesteryl linoleate as the most prominent cholesteryl ester, and are found predominantly in the extracellular space in the form of small lipid droplets (less than 0.4 pm profile diameter) and vesicles. 16 These discrepant features have provided the impetus to question (1) whether the fibrous plaque core originates from lipids accumulated in foam cells via death of the cells and (2) whether fibrous plaque lesions have their origin in preexisting fatty streaks.Human fibrous plaque core lipids may primarily originate from direct deposition of lipoprotein lipids in the extracellular space rather than from dead foam cells. 6This suggestion is based on observations of the site of lipid deposits in the smallest detectable core regions, the small sizes of lipid particles in core regions, cholesteryl ester fatty acyl patterns, binding of lipoproteins to the extracellular matrix, and the demonstration of lipoprotein fusion. 1 -513 However, no previous studies, including our own, have examined in detail the chemis-

One-month-old male New Zealand White rabbits were fed either a cholesterol-free casein diet (n=10) or low-level cholesterol-supplemented chow (n=10) for 24 weeks, during which total plasma cholesterol levels were matched. After perfusion fixation, aortic tissue samples were taken from six predetermined locations and embedded in epoxy resin for examination by light and electron microscopy. Frozen sections were also obtained for histochemical demonstration of collagen and elastin. Lesion morphology was classified in toluidine blue-stained, semithin epoxy sections as early fatty streaks (round foam cells with little intervening extracellular matrix); advanced fatty streaks (foam cells with extracellular lipid); fibrous plaques (spindle-shaped cells within extracellular matrix); or atheromatous lesions (presence of an atheromatous core). In representative specimens, electron microscopy showed that the ultrastructure of round foam cells was consistent with macrophage derivation, whereas most spindle-shaped cells were clearly smooth muscle cells. Fibrous plaques were more common in the distal than the proximal aorta. Lesions in the casein-fed animals were essentially equally distributed among the four morphological categories, whereas lesions in the cholesterol-fed rabbits were predominantly of the atheromatous type. Thus, cholesterolfed rabbits had, in general, more advanced lesions than casein-fed rabbits with matched total plasma cholesterol levels. Moreover, the feeding of a low-level cholesterol diet (0.125% to 0.5% by weight) to rabbits for a relatively short time (6 months) led to the development of advanced lesions similar to those seen in humans. {Arterioscler Thromb. 1994;14:105-114.)

Atherosclerotic lipid deposits found in the core region of fibrous plaques are almost entirely extracellular, but it is not known whether they are derived from necrosis of cells containing accumulated lipid or from direct extracellular lipid accumulation. New evidence pertaining to this question has been obtained through the use of recently developed techniques for preserving and staining lipids in electron microscopy, and through a detailed morphologic and chemical examination of human aortic fibrolipid lesions, which are progenitor lesions for fibrous plaques. The evidence favours a substantial role, perhaps a dominant role, for extracellular lipid accumulation in the formation of the fibrous plaque core region.

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