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).

A Definition of Advanced Types of Atherosclerotic Lesions and a Histological Classification of Atherosclerosis A Report From the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association

This review focuses on the role of oxidative processes in atherosclerosis and its resultant cardiovascular events. There is now a consensus that atherosclerosis represents a state of heightened oxidative stress characterized by lipid and protein oxidation in the vascular wall. The oxidative modification hypothesis of atherosclerosis predicts that low-density lipoprotein (LDL) oxidation is an early event in atherosclerosis and that oxidized LDL contributes to atherogenesis. In support of this hypothesis, oxidized LDL can support foam cell formation in vitro, the lipid in human lesions is substantially oxidized, there is evidence for the presence of oxidized LDL in vivo, oxidized LDL has a number of potentially proatherogenic activities, and several structurally unrelated antioxidants inhibit atherosclerosis in animals. An emerging consensus also underscores the importance in vascular disease of oxidative events in addition to LDL oxidation. These include the production of reactive oxygen and nitrogen species by vascular cells, as well as oxidative modifications contributing to important clinical manifestations of coronary artery disease such as endothelial dysfunction and plaque disruption. Despite these abundant data however, fundamental problems remain with implicating oxidative modification as a (requisite) pathophysiologically important cause for atherosclerosis. These include the poor performance of antioxidant strategies in limiting either atherosclerosis or cardiovascular events from atherosclerosis, and observations in animals that suggest dissociation between atherosclerosis and lipoprotein oxidation. Indeed, it remains to be established that oxidative events are a cause rather than an injurious response to atherogenesis. In this context, inflammation needs to be considered as a primary process of atherosclerosis, and oxidative stress as a secondary event. To address this issue, we have proposed an "oxidative response to inflammation" model as a means of reconciling the response-to-injury and oxidative modification hypotheses of atherosclerosis.

Role of Oxidative Modifications in Atherosclerosis

Background. Overweight in adults is associated with increased morbidity and mortality. In contrast, the long-term effect of overweight in adolescence on morbidity and mortality is not known. Methods. We studied the relation between overweight and morbidity and mortality in 508 lean or overweight adolescents 13 to 18 years old who participated in the Harvard Growth Study of 1922 to 1935. Overweight adolescents were defined as those with a body-mass index that on two occasions was greater than the 75th percentile in subjects of the same age and sex in a large national survey. Lean adolescents were defined as those with a body-mass index between the 25th and 50th percentiles. Subjects who were still alive were interviewed in 1988 to obtain information about their medical history, weight, functional capacity, and other risk factors. For those who had died, information on the cause of death was obtained from death certificates. Results. Overweight in adolescent subjects was associated with an increase...

https://www.nejm.org/doi/pdf/10.1056/NEJM199211053271904

Long-term morbidity and mortality of overweight adolescents. A follow-up of the Harvard Growth Study of 1922 to 1935.

Glycoprotein staining following electrophoresis on acrylamide gels.

• The contribution of obesity to cardiovascular risk has not been adequately appreciated because of a failure to recognize the involvement of upper-body predominance of body weight with hypertension, diabetes, and hypertriglyceridemia even in the absence of significant overall obesity. This article examines the evidence that upper-body obesity, as usually induced by caloric excess in the presence of androgens, mediates these problems by way of hyperinsulinemia. Because of these interrelationships, there is a need to identify and prevent upper-body obesity or, failing that, to provide therapies that will control the associated problems without aggravating hyperinsulinemia. ( Arch Intern Med . 1989;149:1514-1520)

The Deadly Quartet: Upper-Body Obesity, Glucose Intolerance, Hypertriglyceridemia, and Hypertension

Lipoprotein-acid mucopolysaccharide complexes of human atherosclerotic lesions.

Recent advances in molecular pathology. Carbohydrate-protein macromolecules and arterial wall integrity--a role in atherogenesis.

Complexing of serum pre-β- and β-lipoproteins and acid mucopolysaccharides☆

Plasma glucose and insulin levels were determined in a total biracial community of 3313 children, ages 5-17 years. Black children have significantly higher insulin and lower glucose levels than white children of comparable age and sex. Children of diabetic parents have elevated levels of age- and weight-adjusted fasting cholesterol. Moderate tracking (r = 0.31) of glucose levels over a 3-year period was seen. Insulin levels, however, track well (r = 0.36) only in older children (ages 9-14 years at initial examination). Fasting insulin levels are positively related to measures of obesity, systolic and diastolic blood pressure, triglyceride, beta-lipoprotein cholesterol and pre-beta-lipoprotein cholesterol levels. In addition, insulin levels are negatively related to alpha-lipoprotein cholesterol levels. Fasting glucose levels are positively related to systolic and diastolic blood pressure, triglycerides, pre-beta-lipoprotein cholesterol, and obesity levels. The relationship of plasma glucose and insulin levels to the traditional cardiovascular risk factors in children emphasizes the importance of subtle abnormalities in carbohydrate metabolism in the early natural history of cardiovascular disease.

Bhandaru Radhakrishnamurthy

Papers

Lipoprotein-acid mucopolysaccharide complexes of human atherosclerotic lesions.

Recent advances in molecular pathology. Carbohydrate-protein macromolecules and arterial wall integrity--a role in atherogenesis.

Complexing of serum pre-β- and β-lipoproteins and acid mucopolysaccharides☆

Fasting plasma glucose and insulin levels and their relationship to cardiovascular risk factors in children: Bogalusa Heart Study.

Interaction of serum lipoproteins and a proteoglycan from bovine aorta.