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

Coronary atherosclerosis is by far the most frequent cause of ischemic heart disease, and plaque disruption with superimposed thrombosis is the main cause of the acute coronary syndromes of unstable angina, myocardial infarction, and sudden death.1 2 3 4 5 Therefore, for event-free survival, the vital question is not why atherosclerosis develops but rather why, after years of indolent growth, it suddenly becomes complicated by life-threatening thrombosis. The composition and vulnerability of plaque rather than its volume or the consequent severity of stenosis produced have emerged as being the most important determinants for the development of the thrombus-mediated acute coronary syndromes; lipid-rich and soft plaques are more dangerous than collagen-rich and hard plaques because they are more unstable and rupture-prone and highly thrombogenic after disruption.6 This review will explore potential mechanisms responsible for the sudden conversion of a stable atherosclerotic plaque to an unstable and life-threatening atherothrombotic lesion—an event known as plaque fissuring, rupture, or disruption.7 8 

Atherosclerosis is the result of a complex interaction between blood elements, disturbed flow, and vessel wall abnormality, involving several pathological processes: inflammation, with increased endothelial permeability, endothelial activation, and monocyte recruitment9 10 11 12 13 14 ; growth, with smooth muscle cell (SMC) proliferation, migration, and matrix synthesis15 16 ; degeneration, with lipid accumulation17 18 ; necrosis, possibly related to the cytotoxic effect of oxidized lipid19 ; calcification/ossification, which may represent an active rather than a dystrophic process20 21 ; and thrombosis, with platelet recruitment and fibrin formation.1 22 23 Thrombotic factors may play a role early during atherogenesis, but a flow-limiting thrombus does not develop until mature plaques are present, which is why thrombosis often is classified as a complication rather than a genuine component of atherosclerosis. 

### Mature Plaques: Atherosis and Sclerosis 

As the name atherosclerosis implies, mature …

Coronary Plaque Disruption

Atherosclerosis: The Road Ahead

Dysregulated extracellular matrix (ECM) metabolism may contribute to vascular remodeling during the development and complication of human atherosclerotic lesions. We investigated the expression of matrix metalloproteinases (MMPs), a family of enzymes that degrade ECM components in human atherosclerotic plaques (n = 30) and in uninvolved arterial specimens (n = 11). We studied members of all three MMP classes (interstitial collagenase, MMP-1; gelatinases, MMP-2 and MMP-9; and stromelysin, MMP-3) and their endogenous inhibitors (TIMPs 1 and 2) by immunocytochemistry, zymography, and immunoprecipitation. Normal arteries stained uniformly for 72-kD gelatinase and TIMPs. In contrast, plaques' shoulders and regions of foam cell accumulation displayed locally increased expression of 92-kD gelatinase, stromelysin, and interstitial collagenase. However, the mere presence of MMP does not establish their catalytic capacity, as the zymogens lack activity, and TIMPs may block activated MMPs. All plaque extracts contained activated forms of gelatinases determined zymographically and by degradation of 3H-collagen type IV. To test directly whether atheromata actually contain active matrix-degrading enzymes in situ, we devised a method which allows the detection and microscopic localization of MMP enzymatic activity directly in tissue sections. In situ zymography revealed gelatinolytic and caseinolytic activity in frozen sections of atherosclerotic but not of uninvolved arterial tissues. The MMP inhibitors, EDTA and 1,10-phenanthroline, as well as recombinant TIMP-1, reduced these activities which colocalized with regions of increased immunoreactive MMP expression, i.e., the shoulders, core, and microvasculature of the plaques. Focal overexpression of activated MMP may promote destabilization and complication of atherosclerotic plaques and provide novel targets for therapeutic intervention.

/pdf/increased-expression-of-matrix-metalloproteinases-and-matrix-4xsiz746dq.pdf

Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques.

The acute coronary syndromes, including unstable angina and acute myocardial infarction, currently constitute a major preoccupation of clinical cardiology. This century has witnessed a remarkable evolution in our clinical concepts of these syndromes. Herrick1 described the survival of patients with acute coronary thrombosis early in the century. The introduction of the ECG led to major clinical advances in the definition of acute myocardial infarction during the first half of this century and furnished the basis of modern coronary care. 

In the latter half of this century, the advent of coronary arteriography permitted definition in the living patient of coronary stenoses due to atherosclerosis. The introduction of this diagnostic technique allowed the development of rational treatment modalities such as coronary artery bypass surgery and, subsequently, percutaneous transluminal coronary angioplasty. Until recently, it seemed that we had achieved a firm understanding of the pathophysiology of human coronary artery disease and had devised appropriate modes of therapy for its major manifestations. Yet, recent clinical data suggest that we still have much to learn about the pathophysiology of the acute coronary syndromes. 

Bypass surgery and angioplasty aim to restore blood flow to sites beyond hemodynamically significant stenoses in the coronary arteries. These revascularization therapies effectively relieve angina pectoris in many cases (although often not permanently). Quite naturally, the availability of these modalities led the cardiology community to focus on high-grade coronary stenosis, visible by angiography, as the critical issue in coronary heart disease. Much of the basis of contemporary cardiology and cardiac surgery rests on the axiom: the greater the stenosis, the greater the risk of a clinical event such as myocardial infarction or unstable angina pectoris. 

However, data emerging from clinical and pathological studies over the past decade have occasioned a reassessment of this central dogma of clinical cardiology.2 First, the …

Molecular bases of the acute coronary syndromes

OBJECTIVE--To assess the size of the lipid pool and the number of smooth muscle cells and monocyte/macrophages in human aortic plaques that were intact and to compare the results with those in aortic plaques undergoing ulceration and thrombosis. DESIGN--The lipid pool was measured as a percentage of the total cross sectional area of the plaque. Immunohistochemistry was used to identify cell types (monocytes/macrophages (M phi) by EBM11 and HAM56, smooth muscle cells by alpha actin). The area of the tissue occupied by each cell type was measured by quantitative microscopy in the peripheral (shoulder) area of the plaque and the plaque cap. Absolute counts of each cell type were expressed as the ratio of SMC:M phi. MATERIAL--Aortas were obtained at necropsy from men aged less than 69 years who died suddenly (within 6 hours of the onset of symptoms) of ischaemic heart disease. 155 plaques from 13 aortas were studied. Four aortas showed intact plaques only (group A, n = 31). Nine aortas showed both intact plaques (group B, n = 79) and plaques that were undergoing thrombosis (group C, n = 45). RESULTS--In 41 (91.1%) of the 45 plaques undergoing thrombosis (group C) lipid pools occupied more than 40% of the cross sectional area of the plaque. Only 12 (10.9%) of the 110 intact plaques (groups A + B) had lipid pools of this size. The mean size of the lipid pool in plaques of groups A, B, and C was 12.7%, 27.3% and 56.7% respectively. Compared with intact plaques those undergoing thrombosis contained a smaller volume of smooth muscle cells (2.8% v 11.8%) and a larger volume of monocyte/macrophages (13.7% v 2.9%) in the plaque cap. The ratio of the number of smooth muscle cells to monocytes/macrophages was 7.8 in group A plaques, 4.1 in group B plaques, and 1.0 in group C plaques. This gradient was the result of an absolute increase in monocyte/macrophages and an absolute decrease in smooth muscle cells. CONCLUSIONS--In the aorta ulceration and thrombosis were characteristic of plaques with a high proportion of their volume occupied by extracellular lipid, and in which there was a shift toward a preponderance of monocyte/macrophages compared with smooth muscle cells in the cap.

https://heart.bmj.com/content/heartjnl/69/5/377.full.pdf

J Mann

Papers

Risk of thrombosis in human atherosclerotic plaques: role of extracellular lipid, macrophage, and smooth muscle cell content.