Arteriosclerosis

Abstract: This report is the continuation of two earlier reports that defined human arterial intima and precursors of advanced atherosclerotic lesions in humans. This report describes the characteristic components and pathogenic mechanisms of the various advanced atherosclerotic lesions. These, with the earlier definitions of precursor lesions, led to the histological classification of human atherosclerotic lesions found in the second part of this report. The Committee on Vascular Lesions also attempted to correlate the appearance of lesions noted in clinical imaging studies with histological lesion types and corresponding clinical syndromes. In the histological classification, lesions are designated by Roman numerals, which indicate the usual sequence of lesions progression. The initial (type I) lesion contains enough atherogenic lipoprotein to elicit an increase in macrophages and formation of scattered macrophage foam cells. As in subsequent lesion types, the changes are more marked in locations of arteries with adaptive intimal thickening. (Adaptive thickenings, which are present at constant locations in everyone from birth, do not obstruct the lumen and represent adaptations to local mechanical forces). Type II lesions consist primarily of layers of macrophage foam cells and lipid-laden smooth muscle cells and include lesions grossly designated as fatty streaks. Type III is the intermediate stage between type II and type IV (atheroma, a lesion that is potentially symptom-producing). In addition to the lipid-laden cells of type II, type III lesions contain scattered collections of extracellular lipid droplets and particles that disrupt the coherence of some intimal smooth muscle cells. This extracellular lipid is the immediate precursor of the larger, confluent, and more disruptive core of extracellular lipid that characterizes type IV lesions. Beginning around the fourth decade of life, lesions that usually have a lipid core may also contain thick layers of fibrous connective tissue (type V lesion) and/or fissure, hematoma, and thrombus (type VI lesion). Some type V lesions are largely calcified (type Vb), and some consist mainly of fibrous connective tissue and little or no accumulated lipid or calcium (type Vc).

Abstract: PERSPECTIVES AND SUMMARY ............................... .... ....................................... 224 UPTAKE OF LIPOPROTEIN-BOUND CHOLESTEROL BY MACROPHAGES ................................................................................................ 226 Receptor for Acetyl-LDL .......................................................................................... 227 Receptor for LDLIDextran Sulfate Complexes ...................................................... 235 Receptor for f3-VLDL ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,.,,,,,,,,.,,,,.,,.\", ... ,,,, .... ,, ............. ,,.............. 237 Receptors for Cholesteryl Ester/Protein Complexes from Atherosclerotic Plaques .............................................................. ,................... 241 PROCESSING AND STORAGE OF LIPOPROTEIN-BOUND CHOLESTEROL BY MACROPHAGES ............................... . ................................................ 243 Endocytosis and Lysosomal Hydrolysis .................................................................... 243 Cytoplasmic Re-esterification and Hydrolysis of Lipoprotein-Derived Cholesteryl Esters ........................................................................ \".\".\" . . . . . . . . . . .. . . . . . \".\".. 244 The Cho{estery{ Ester Cycle \" ... \" ... \" .... \" ....... \" .. \"....................................................... 247 SECRETION OF CHOLESTEROL AND APOPROTEIN E BY MACROPHAGES ........................................................................................ 249 Cholesterol Excretion Dependent on Cholesterol Acceptors .................................... 249 Synthesis and Secretion of Apoprotein E in Response to Cholesterol Loading , .. \"\", 252 IMPLICATIONS FOR FOAM CELL FORMATION IN ATHEROSCLEROSIS . . . . . . . . . . . . . . . . . ...... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..... . . . . . . . . . . . . . . . 255 The Foam Cell in Familial Hypercholesterolemia .................................................. 257

Abstract: NDiviDuAI with homocystinuria 12 have been found to lack normal activity of the enzyme cystathionine synthetase.3 In many of the patients progressive arterial disease develops in ildhood, frequently resulting in death from thrombosis in a vital organ45 In addition, congenital dislocation of the lenses, mental retardation, and skeletal abnormalitieseg, osteoporosis, arachnodactyly, and pectus excavatum or pectus carinatum-usually are foundL5' The vascular changes and other abnormalities encoumtered in homocystinuria have been attributed either to the metabolic effects of the elevated tissue concentrations of methionine, homocysteine, or homocystine, or to the metabolic consequences of decreased tissue concentrations of cystathionine found in the disease.7 In a child dying with homocystinuria, cystathioninuria, and methyl malonic aciduria, secondary to an abnormality of cobalamin (B12 ) metabolism, arterial lesions have been discovered that resemble in a striking way many of those found in cystathionine synthetase deficiency. The vascular findigs i this patient will be presented and compared with those in a patient with cystathionine synthetase deficiency. Since the enzymatic abnormalities in both disorders share certain metabolic consequences, the conclusion has been reached that an elevated concentration of homocysteine, homocystine, or a derivative of hornocysteine is the common factor leading to arterial damage. The possible role of elevated concentrations of homocysteine or its derivatives in the pathogenesis of arteriosclerosis in individls free of known enzyme deficiencies will be discussed and interpreted with particular reference to the findings in experimentally produced arteriosclerosis.

Abstract: Initial description of apolipoprotein (apo) E-deficient transgenic mice demonstrated the development of severe hypercholesterolemia due to probable delayed clearance of large atherogenic particles from the circulation. Examination of these mice demonstrated foam cell accumulation in the aortic root and pulmonary arteries by 10 weeks of age. In the present study, the animals were fed either chow or a high-fat, Western-type diet and examined at ages ranging from 6 to 40 weeks. Gross examination by dissection microscopy revealed a predilection for development of lesions in the aortic root, at the lesser curvature of the aortic arch, the principal branches of the aorta, and in the pulmonary and carotid arteries. Monocyte attachment to endothelial cells was observed by light and electron microscopic examination at 6 weeks, the earliest time point examined. Foam cell lesions developed as early as 8 weeks, and after 15 weeks advanced lesions (fibrous plaques) were observed. The latter consisted of a fibrous cap containing smooth muscle cells surrounded by connective tissue matrix that covered a necrotic core with numerous foamy macrophages. Mice fed the Western-type diet generally had more advanced lesions than those fed a chow diet. The apoE-deficient mouse contains the entire spectrum of lesions observed during atherogenesis and is the first mouse model to develop lesions similar to those in humans. This model should provide numerous opportunities to study the pathogenesis and therapy of atherosclerosis in a small, genetically defined animal.