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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:1512-1531.)
© 1995 American Heart Association, Inc.

Articles

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

Herbert C. Stary, MD, Chair; A. Bleakley Chandler, MD; Robert E. Dinsmore, MD; Valentin Fuster, MD, PhD; Seymour Glagov, MD; William Insull, Jr, MD; Michael E. Rosenfeld, PhD; Colin J. Schwartz, MD; William D. Wagner, PhD; Robert W. Wissler, PhD, MD

	Abstract

Top Abstract Introduction Atherosclerotic Lesion Types... Type IV Lesions Type V Lesions Type VI Lesions Atherosclerotic Aneurysms Recommended Histological... A Brief History of... Characterization of... Assessment of Presence and... Correlation of Lesion Types... The Cells and Extracellular... References

 
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 lesion 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).

Key Words: atherosclerosis • lesion • AHA Medical/Scientific Statements

	Introduction

Top Abstract Introduction Atherosclerotic Lesion Types... Type IV Lesions Type V Lesions Type VI Lesions Atherosclerotic Aneurysms Recommended Histological... A Brief History of... Characterization of... Assessment of Presence and... Correlation of Lesion Types... The Cells and Extracellular... References

 
This report is the third and last in a series. The objective of the series was to provide a practical classification of human atherosclerotic lesions based on their histological composition and structure. Normal arterial intima, including atherosclerosis-prone regions, was defined in the first report.¹ Initial, fatty streak, and intermediate lesions were defined in the second.² This report describes the composition of advanced lesions and arranges both advanced types and their precursors in a histological classification. The types of lesions that constitute the histological classification are perceived as characteristic gradations or stages from initial minimal changes to lesions associated with clinical manifestations. The resulting classification reflects the temporal natural history of the disease. In the early stages of atherosclerosis the sequence is predictable, characteristic, and uniform, but lesions may subsequently progress in different morphogenetic sequences, resulting in several characteristic lesion types and clinical syndromes.

The descriptions and definitions in this report are based on the histological and histochemical composition as well as the structure and ultrastructure of both the cell and matrix components of the lesions. Some methods of study were discussed in the earlier reports.^{1 2} Although the purpose of this report is to classify human lesions, data on lesions found or produced in various species of animals are cited when they provide insight into the pathogenesis and sequence of human lesions. However, most of the citations and statements made in this report refer to human lesions.

Human lesions can be obtained for study as specimens during therapeutic interventions or at autopsy. At autopsy entire vessels and complete lesions are available and may be related to geometric features and transitions. Vessels may be distended to their in vivo dimensions and configurations by controlled pressure fixation procedures to minimize artifacts caused by postmortem collapse and contraction. Because most large lesions vary in composition along their length, more than one section must be examined, and a lesion of diverse histology should be classified according to its most advanced and clinically significant region. In specimens obtained during endarterectomy or atherectomy, orientation and relation to neighboring structures can be estimated only indirectly by clinical imaging. However, small partial endarterectomy and atherectomy samples can be evaluated by electron microscopic, immunochemical, and microchemical techniques, and are especially suitable for studies requiring fresh tissue.^{3 4 5 6 7 8 9 10 11 12}

	Atherosclerotic Lesion Types Advanced by Histology

Top Abstract Introduction Atherosclerotic Lesion Types... Type IV Lesions Type V Lesions Type VI Lesions Atherosclerotic Aneurysms Recommended Histological... A Brief History of... Characterization of... Assessment of Presence and... Correlation of Lesion Types... The Cells and Extracellular... References

 
Atherosclerotic lesions are considered advanced by histological criteria when accumulations of lipid, cells, and matrix components, including minerals, are associated with structural disorganization, repair, and thickening of the intima, as well as deformity of the arterial wall. Lesions considered advanced by their histology may or may not narrow the arterial lumen, may or may not be visible by angiography, and may or may not produce clinical manifestations. Such lesions may be clinically significant even though the arterial lumen is not narrowed, because complications may develop suddenly.

The initial, fatty streak, and intermediate lesions described in the second report² in this series have distinguishing features that permit classification as lesion types I, II, and III. Advanced atherosclerotic lesions can also be subdivided into three main histologically characteristic types: IV, V, and VI. Type V and VI lesions have features that permit further subdivision. The consistent distinguishable features of the different advanced types and subtypes and the likely pathogenetic mechanisms related to each type are described below.

	Type IV Lesions

Top Abstract Introduction Atherosclerotic Lesion Types... Type IV Lesions Type V Lesions Type VI Lesions Atherosclerotic Aneurysms Recommended Histological... A Brief History of... Characterization of... Assessment of Presence and... Correlation of Lesion Types... The Cells and Extracellular... References

 
In type IV lesions a dense accumulation of extracellular lipid occupies an extensive but well-defined region of the intima (Fig 1). This type of extracellular lipid accumulation is known as the lipid core. A fibrous tissue increase is not a feature, and complications such as defects of the lesion surface and thrombosis are not present. The type IV lesion is also known as atheroma. Type IV is the first lesion considered advanced in this classification because of the severe intimal disorganization caused by the lipid core. The characteristic core appears to develop from an increase and the consequent confluence of the small isolated pools of extracellular lipid that characterize type III lesions.¹³ The increase in lipid is believed to result from continued insudation from the plasma. The nature and derivations of the lipid that constitutes the core are discussed in the section on the extracellular matrix at the end of this report. Type IV lesions, when they first appear in younger people, are found in the same locations as adaptive intimal thickenings of the eccentric type. Thus, atheroma is, at least initially, an eccentric lesion.

View larger version (100K): [in this window] [in a new window]   Figure 1. Photomicrograph of atheroma (type IV lesion) in proximal left anterior descending coronary artery. Extracellular lipid forms a confluent core in the musculoelastic layer of eccentric adaptive thickening that is always present in this location. The region between the core and the endothelial surface contains macrophages and macrophage foam cells (fc), but an increase in smooth muscle cells or collagenous fibers is not marked. A indicates adventitia; M, media. From a 23-year-old man. Homicide was the cause of death. Fixation by pressure-perfusion with glutaraldehyde. Maraglas embedding. One-micron thick section. Magnification about x55. From Stary.17

Lipid cores thicken the artery wall and are generally large enough to be visible to the unaided eye when the cut surface of the lesion is examined. Nevertheless, atheroma often fails to narrow the vascular lumen. Measurements indicate that the thickening may instead be associated with an increase in the size of the external boundary of the artery.¹⁴

The usual intimal smooth muscle cells and the intercellular matrix of the deep intima are dispersed and replaced by accumulated particles of extracellular lipid. The dispersed cells have attenuated and elongated bodies and may have unusually thick basement membranes. The organelles of some smooth muscle cells may be calcified, and calcium particles are often found within the lipid cores of even young adults. Between the lipid core and the endothelial surface, the intima contains macrophages and smooth muscle cells with and without lipid droplet inclusions (Fig 2). Lymphocytes¹⁵ and mast cells have also been identified in this region. Capillaries border the lipid core, particularly at the lateral margins and facing the lumen. Frequently macrophages, macrophage foam cells, and lymphocytes are more densely concentrated in the lesion periphery. Much of the tissue between the core and the surface endothelium corresponds to the proteoglycan-rich layer of the intima, although infiltrated with the cells just described. Formation of the lipid core precedes an increase in fibrous tissue that will subsequently change the nature of the intima above the lipid core. In type IV lesions, the tissue layer between the lipid core and the endothelial surface is still largely the intima that preceded lesion development (Figs 1 and 2). When this "nearly normal" cover of a lipid core later undergoes an increase in fibrous tissue (mainly collagen), the lesion is then labeled type V. In conventional 5-micron thick histological sections, or with the unaided eye, the upper intimal layer of a type IV lesion is indistinguishable from the fibrotic cover (fibrous cap) of a type V lesion, which is why both type IV and type V lesions are indiscriminately labeled fibrous plaque.

View larger version (131K): [in this window] [in a new window]   Figure 2. Photomicrograph of thick part of atheroma (type IV lesion) in proximal left anterior descending coronary artery. Core of extracellular lipid includes cholesterol crystals. Macrophage foam cells (fc) overlie core on aspect toward lumen. Macrophages that are not foam cells (arrows) occupy proteoglycan layer (pgc) adjacent to endothelium (e) at lesion surface. A indicates adventitia; M, media. From a 19-year-old man who committed suicide. Fixation by pressure-perfusion with glutaraldehyde. Maraglas embedding. One-micron thick section. Magnification about x220.

The potential clinical significance of type IV lesions can be great, even though this advanced lesion may not cause much narrowing of the lumen. Because the region between the lipid core and the lesion surface contains proteoglycans and macrophage foam cells and only isolated smooth muscle cells and minimal collagen, it may be susceptible to formation of fissures (type VI lesion). The periphery of advanced lesions, particularly type IV, may be vulnerable to rupture because macrophages are generally abundant in this location. This is discussed further in the section on type VI lesions.

	Type V Lesions

Top Abstract Introduction Atherosclerotic Lesion Types... Type IV Lesions Type V Lesions Type VI Lesions Atherosclerotic Aneurysms Recommended Histological... A Brief History of... Characterization of... Assessment of Presence and... Correlation of Lesion Types... The Cells and Extracellular... References

 
Type V lesions are defined as lesions in which prominent new fibrous connective tissue has formed. When the new tissue is part of a lesion with a lipid core (type IV), this type of morphology may be referred to as fibroatheroma or type Va lesion. A type V lesion in which the lipid core and other parts of the lesion are calcified may be referred to as type Vb. A type V lesion in which a lipid core is absent and lipid in general is minimal may be referred to as type Vc. With these lesions, arteries are variously narrowed, generally more than with type IV. Importantly, as with type IV lesions, type V lesions may develop fissures, hematoma, and/or thrombus (type VI lesion), and for this reason too they are clinically relevant.

Sequential histological studies of the lesions of large populations indicate that reparative connective tissue forms in and around regions of the intima in which large accumulations of extracellular lipid (lipid cores) disarrange or obliterate the normal cell and intercellular matrix structure. Sometimes the new fibrous tissue accounts for more of the thickness of the lesion than does the underlying lipid accumulation. The new tissue consists of substantial increases in collagen and smooth muscle cells rich in rough-surfaced endoplasmic reticulum. In cases in which this tissue is particularly thick, some or much of it may be the remnant of thrombi that were incorporated and organized. Capillaries at the margins of the lipid core may be larger and more numerous than in type IV lesions, and they may also be present in the newly formed tissue. Lymphocytes, monocyte-macrophages, and plasma cells are frequently associated with the capillaries, and microhemorrhages may be present around them.

Type Va lesions may be multilayered: several lipid cores, separated by thick layers of fibrous connective tissue, are stacked irregularly one above the other. The term multilayered fibroatheroma can be applied to this morphology. The lipid core that is deepest and closest to the media may have formed first. Mechanical forces may play a role in the modeling of such lesions. Additional lipid cores in locations and planes different from the first could be induced as asymmetric vascular narrowing and changes in lumen configuration modify hemodynamic and tensile forces, creating a redistribution of the regions of predisposition for lesion formation.¹⁶ The architecture of some multilayered fibroatheromas could also be explained by repeated disruptions of the lesion surface, hematomas, and thrombotic deposits. Organization (fibrosis) of hematomas and thrombi could be followed by renewed accumulation of macrophage foam cells and extracellular lipid between the newly formed fibrotic layer and the endothelial surface.

Lesions containing a large amount of calcium generally also have increased fibrous connective tissue, and often there is the underlying morphology of fibroatheroma. Lesions in which mineralization is the dominant feature may be called type Vb (calcific) lesions. Mineral deposits may replace the accumulated remnants of dead cells and extracellular lipid, including entire lipid cores. Elsewhere, the calcific lesion has been labeled the type VII lesion.^{17 18 19}

In Type Vc (fibrotic) lesions, often evident in arteries of the lower extremities,²⁰ the normal intima is replaced and thickened with fibrous connective tissue, while lipid is minimal or even absent. This lesion has also been called the type VIII lesion.^{17 18 19} Fibrotic lesions could be the result of one or more processes, including organization of thrombi, extension of the fibrous component of an adjacent fibroatheroma, or resorption (regression) of lipid cores. Increased wall shear stress associated with increased hydrostatic pressure in the lower extremities may also play a role. Specific fibrogenic effects of cigarette addiction remain to be demonstrated. Some apparently fibrotic lesions contain a small amount of lipid when processed and stained for lipid or when step sections are made through the entire lesion.

The smooth muscle cells of the media adjacent to intima changed into a type V lesion may be disarranged and decreased. The media and adjacent adventitia may contain accumulations of lymphocytes, macrophages, and macrophage foam cells. Large clumps of cells that appear to be mainly lymphocytes may be adjacent to the adventitial vasa vasorum.²¹ Both increases²² and decreases²³ in the number of mast cells in adventitia that is part of a lesion have been reported.

	Type VI Lesions

Top Abstract Introduction Atherosclerotic Lesion Types... Type IV Lesions Type V Lesions Type VI Lesions Atherosclerotic Aneurysms Recommended Histological... A Brief History of... Characterization of... Assessment of Presence and... Correlation of Lesion Types... The Cells and Extracellular... References

 
Morbidity and mortality from atherosclerosis is largely due to type IV and type V lesions in which disruptions of the lesion surface, hematoma or hemorrhage, and thrombotic deposits have developed (Fig 3). Type IV or V lesions with one or more of these additional features are classified as type VI and may also be referred to as complicated lesions. Type VI may be subdivided by the superimposed features. Thus, disruption of the surface may be labeled type VIa; hematoma or hemorrhage, type VIb; and thrombosis, type VIc. Type VIabc indicates the presence of all three features.

View larger version (131K): [in this window] [in a new window]   Figure 3. Photomicrograph of type VI lesion in left anterior descending coronary artery about 2 cm distal to main bifurcation. The type VI lesion is, in this case, formed by a recent thrombus on the surface of a fibroatheroma. The region between the lipid core and thrombus (Tmb) consists of closely layered smooth muscle cells. The lipid core also contains cholesterol crystals and dark staining aggregates of microcrystalline calcium (arrows). A indicates adventitia; M, media. From a 23-year-old man who committed suicide. Fixation by pressure-perfusion with glutaraldehyde. Maraglas embedding. One-micron thick section. Magnification about x115.

While type VI lesions generally have the underlying morphology of type IV or V lesions, surface disruptions, hematoma, and thrombosis may be (although less often) superimposed on any other type of lesion and even on intima without an apparent lesion. Complicating features may arise because of individual differences in risk factors and tissue reactions. These may include differences in composition of the blood, the relative quantities and distributions in the components of the underlying lesion or intima, as well as modifications of shear and tensile forces to which the lesion or intima is exposed. Clinical imaging of lesions may be expected to contribute greatly to the understanding of type VI lesions and the associated clinical syndromes. These aspects are reviewed in later sections of this report.

Surface Defects and Hematoma
Disruptions of the lesion surface include fissures and ulcerations, but their extent and severity may differ greatly. The smallest ulcerations consist of focal loss of a part of the endothelial cell layer and are visible only under the microscope. Deep ulcerations may expose and release lipid from a lipid core. Fissures or tears of the lesion surface are of variable depth and length.

Atheromatous lesions (types IV and Va) are especially prone to disruptions of the lesion surface.^{24 25 26 27 28 29} Factors that may play a role in causing or facilitating intimal disruptions (and thus thrombosis) include the presence of inflammatory cells in lesions,^{30 31} the release of toxic substances and proteolytic enzymes by macrophages within the lesions,^{32 33} coronary spasm,³⁴ structural weakness related to lesion composition,²⁷ and shear stress.^{14 35} Tears may occur more frequently in regions of lesions with many macrophage foam cells.³⁶ Fissures probably reseal, incorporating hematomas and thrombi into the lesion.^{26 29}

Although hematoma in the intima is usually caused by tears in the lesion surface, there is evidence that some hematomas may begin within lesions as hemorrhages from newly formed blood vessels.^{37 38 39}

Thrombosis
It has been reported that advanced atherosclerotic lesions containing thrombi or the remnants of thrombi are frequent from the fourth decade of life on. In 1975 Chandler and Pope⁴⁰ compiled and reviewed studies that reported the frequency and nature of lesions with incorporated thrombi. In a recent study of a population aged 30 to 59 years, 38% of persons with advanced lesions in the aorta had thrombi on the surface of a lesion. These thrombi ranged in size from minimal (microscopic) to grossly visible deposits, and some consisted of stratified layers of different ages. Immunohistochemistry revealed wavy bandlike deposits related to fibrin within the advanced lesions of an additional 29% of persons. Because of their structure, these were thought to represent the remnants of old thrombi.⁴¹ Similar data were reported by other authors.^{42 43}

The fissures and hematomas that underlie thrombotic deposits in many cases may recur, and small thrombi may reform many times. Repeated incorporation of small recurrent hematomas and thrombi into a lesion over months or years contributes to gradual narrowing of the arterial lumen. Some thrombi continue to enlarge and occlude the lumen of a medium-sized artery within hours or days.

The components of lesions associated with thrombus formation cause or facilitate fissures, as summarized in the preceding section. Functional impairment of endothelial cells or loss of small groups of endothelial cells could also facilitate thrombus formation when other predisposing conditions are present. Capillary hemorrhages within lesions could conceivably cause sufficient disruption to precipitate thrombosis.^{37 39} Thrombotic deposits on lesions may also form without an apparent surface defect, hematoma, or hemorrhage. Possible causes include focal changes in blood flow secondary to deformity of the surface by an underlying lesion or obstruction of flow by a proximal lesion. In a recent prospective clinical study, thrombotic occlusion tended to occur at flow dividers and locations of arterial angulation, suggesting a role for shear stress in thrombosis or underlying intimal disruption and hematoma.⁴⁴

Whether surface disruption is minimal or substantial or the location is susceptible for hemodynamic reasons, systemic factors may determine whether or not a thrombus will develop. Thus, high plasma fibrinogen levels have been found in persons with clinical ischemic episodes, suggesting that thrombus formation on advanced lesions may be favored in these individuals.^{45 46 47 48 49}

High levels of low density lipoproteins may also promote thrombosis through an adverse effect on platelet function.⁵⁰ Platelets of patients with primary hypercholesterolemia show increased platelet adhesion, aggregation, and secretion.⁵¹ The relation between nutrition and platelet function in atherogenesis has been reviewed.⁵² Smokers have a significantly higher plasma fibrinogen concentration than nonsmokers, while a positive association between plasma cholesterol and fibrinogen concentration is weak.⁵³ Decreased fibrinolytic capacity is caused by increased levels of type 1 plasminogen activator inhibitor. Lipoprotein Lp(a), which is associated with high risk for clinical coronary heart disease, is structurally similar to plasminogen and may inhibit fibrinolysis by binding to fibrin and/or interfering with assembly of fibrinolytic proteins.^{54 55}

Thrombotic deposits that are not occlusive and fatal and are not lysed set in motion mechanisms that contribute to a relatively permanent increase in lesion thickness. The deposits begin to contain increasing numbers of smooth muscle cells that appear to be derived through ingrowth from the intima and that synthesize collagen. Eventually the thrombus is overgrown by endothelial cells at the lumen. Local production of cytokines and growth regulatory molecules presumably stimulates changes in smooth muscle cell phenotypes with associated increases in proliferation, migration, and collagen synthesis that result in organization of thrombotic deposits. The cytokines and mitogens that presumably mediate this response may be released from thrombic platelets and leukocytes adherent to exposed subendothelial structures in the event of a surface injury,⁵⁶ as well as factors derived from endothelial cells,⁵⁷ monocyte/macrophages, and intimal smooth muscle cells by autocrine stimulation.^{56 58} Autocrine mechanisms may be more apparent under hyperlipidemic conditions.^{56 59}

	Atherosclerotic Aneurysms

Top Abstract Introduction Atherosclerotic Lesion Types... Type IV Lesions Type V Lesions Type VI Lesions Atherosclerotic Aneurysms Recommended Histological... A Brief History of... Characterization of... Assessment of Presence and... Correlation of Lesion Types... The Cells and Extracellular... References

 
Lesion types IV, V, and VI are sometimes associated with and appear to be the cause of localized dilatations of the part of the vascular wall they occupy. Distinct localized outward bulges or aneurysms are generally associated with type VI lesions in which the intimal surface is greatly eroded. Aneurysms often contain mural thrombi, both recent and old remnants. In long-standing aneurysms, thrombotic deposits are usually layered. They may form large masses, tending to fill the aneurysm but usually preserving a lumen that approximates the dimensions of the original vessel. Evidence of lysis or incorporation into the arterial wall by collagenous organization are not prominent features.

For aneurysms to occur, matrix fibers must be degraded and/or synthesized in new proportions.⁶⁰ Proteolytic enzyme activity would be expected to be increased in relation to wall destruction and remodeling. Increases in collagenase and elastase activity have been demonstrated in rapidly enlarging and ruptured aneurysms.⁶¹ Enzyme induction or experimental enzymatic destruction of matrix architecture of the aorta results in dilation and rupture,⁶² and experimental mechanical injury with destruction of medial lamellar architecture can also result in aneurysm formation, particularly in the presence of hyperlipidemia.^{63 64} The factors that favor human aneurysm formation may be conditioned or modulated by genetic predispositions interacting with local hemodynamic and tensile stresses such as hypertension.

	Recommended Histological Classification of Atherosclerotic Lesions

Top Abstract Introduction Atherosclerotic Lesion Types... Type IV Lesions Type V Lesions Type VI Lesions Atherosclerotic Aneurysms Recommended Histological... A Brief History of... Characterization of... Assessment of Presence and... Correlation of Lesion Types... The Cells and Extracellular... References

 
The definitions of advanced types of human atherosclerotic lesions in this report and descriptions of their precursors and intimal locations susceptible to the formation of advanced lesions in previous reports have led to an overall histological classification of atherosclerotic lesions. This classification could fulfill the following needs:

Provide a standard framework of histological morphologies of lesions, including those previously not fully recognized, for investigating the pathobiological mechanisms of the disease

Allow diagnosis of the stage of development of disease in an individual, groups of individuals, or populations, and provide up-to-date measures for determining prevalence and incidence of specific stages of disease

Allow correlation of composition of lesions with clinical manifestations of disease

Provide a basis for correlation of the composition of lesions with the morphology determined by clinically applicable diagnostic measurements based on a variety of imaging techniques

Provide a basis for recognizing changes in progression, stabilization, or regression of lesions induced by a variety of interventions

Provide criteria for evaluating the suitability of animal models as surrogates for the human disease

Table 1 gives the terms for arterial segments in which minimal atherosclerotic lesions tend to develop into lesions that may produce symptoms. Table 2 lists the recommended terms in histological classification of lesions and other terms applied to lesions. In Fig 4 a constant arterial location is sketched to show adaptive thickening and characteristic changes (ie, characteristic lesion types) that may be present successively in that location as a potentially symptom-producing lesion forms. Major characteristics and possible sequences of the lesions that make up the recommended classification are summarized in Fig 5 and the following section.

View this table: [in this window] [in a new window]   Table 1. Terms Used to Designate Variants in Normal Intimal Histology

View this table: [in this window] [in a new window]   Table 2. Terms Used to Designate Different Types of Human Atherosclerotic Lesions in Pathology

View larger version (37K): [in this window] [in a new window]   Figure 4. Drawing of cross-sections of identical, most proximal part of six left anterior descending coronary arteries. The morphology of the intima ranges from adaptive intimal thickening always present in this lesion-prone location to a type VI lesion in advanced atherosclerotic disease. Other cross-sections show sequence of atherosclerotic lesion types that may lead to type VI. Identical morphologies may be found in other lesion-prone parts of the coronary and many other arteries. From Stary.19

View larger version (51K): [in this window] [in a new window]   Figure 5. Flow diagram in center column indicates pathways in evolution and progression of human atherosclerotic lesions. Roman numerals indicate histologically characteristic types of lesions enumerated in Table 2 and defined at left of flow diagram. The direction of arrows indicates sequence in which characteristic morphologies may change. From type I to type IV, changes in lesion morphology occur primarily because of increasing accumulation of lipid. The loop between types V and VI illustrates how lesions increase in thickness when thrombotic deposits form on their surfaces. Thrombotic deposits may form repeatedly over varied time spans in the same location and may be the principal mechanism for gradual occlusion of medium-sized arteries.

In the past the earliest precursors of obstructive lesions were described as thin lipid deposits in thin intima in children. It is now known that segments of thick intima (adaptive intimal thickening [Table 1 and references 1 and 2]) are also present in everyone from birth, particularly at bifurcations. These thicker intimal locations may also contain lipid deposits from childhood. Over time more lipid tends to accumulate in the thick locations, and an unmistakable morphological continuum of lesion types may transform adaptive thickening into obstructions that may cause symptoms. Thus, in the first three decades of life, lesions grow because more lipid accumulates and increases in specific, already thick segments of the intima.

Type I and II lesions, sometimes combined under the term early lesions, generally are the only ones that occur in infants and children, although they also occur in adults. Type III lesions may evolve soon after puberty and, in their composition, form the bridge between early and advanced lesions. Type IV is the first lesion considered advanced by histological criteria. In this classification the term advanced lesion is used as an umbrella term for all lesions that disrupt intimal structure, ie, all lesions following type III. Type IV lesions are frequent from the third decade on.

After the third decade of life, lesions of type V and VI composition begin to appear. In middle-aged and older persons, these often become the predominant lesion types. Type V and VI lesions develop and progress by mechanisms that are, for the most part, different from and superimposed on the continuing lipid accumulation that produced lesion types I through IV. In type IV lesions disarrangement of intimal structure is caused almost solely by an extensive accumulation of extracellular lipid localized in the deep intima (the lipid core). In type V lesions intima is thickened by substantial reparative fibrous (mainly collagenous) tissue layers. The presence of fibrous connective tissue layers in addition to one or more lipid cores may be labeled type Va (fibroatheroma). The predominant calcification of a fibrolipid lesion is type Vb (calcific lesion), and fibrous tissue layers without or with only minimal lipid (no core) and minimal or no calcium is type Vc (fibrotic lesion). In a histological classification published elsewhere,^{17 18 19} fibroatheroma was designated type V; calcific lesions, type VII; and fibrotic lesions with little or no lipid, type VIII. Surface defects, hematoma, and thrombotic deposits (type VI lesions) further damage, deform, and thicken, and accelerate conversion from clinically silent to overt disease.

Classifying a lesion histologically simply as type VI implies that the main components of type II (lipid-laden macrophages and smooth muscle cells), type IV (a core of extracellular lipid), and often type V (layers of newly formed fibrous connective tissue) are also present. This is true for most but not all lesions with type VI features (thrombus, hematoma, surface defect). A defect, hematoma, and thrombus if superimposed on only a type II lesion might be classified as type VI/II. Lesions almost always vary in histology along their extent and should be designated as a lesion type according to their pathologically most advanced (ie, clinically most significant) region.

Lesion types I through III do not thicken the arterial wall appreciably and therefore do not narrow the lumen or obstruct or modify blood flow. In medium-sized arteries type IV lesions are often only minimally obstructive and therefore generally clinically silent, while type VI lesions are often very obstructive and symptom-producing. Type V lesions may be silent or overt, depending on the degree of obstruction.

	A Brief History of Classifications of Atherosclerosis in Pathology

Top Abstract Introduction Atherosclerotic Lesion Types... Type IV Lesions Type V Lesions Type VI Lesions Atherosclerotic Aneurysms Recommended Histological... A Brief History of... Characterization of... Assessment of Presence and... Correlation of Lesion Types... The Cells and Extracellular... References

 
A review of the history of classifications of atherosclerosis will provide a perspective for the histological classification presented in this report. Many of the terms used in classifications are listed in Table 2.

At the beginning of the century two types of intimal lesion were recognized and associated with atherosclerosis. They were called fatty streak (a thin lipid deposit in thin intima in children) and fibrous plaque (a thick fibrolipidic lesion in adults). However, the two types of lesion were not universally accepted as an early and advanced expression of a single disease.

Pathologist Ludwig Aschoff was a leading proponent among those who regarded the morphologically different intimal lipid deposits of children and adults as early and late stages of one disease. Aschoff^{65 66 67} recognized two components of the disease. One, lipid, deposited in the intima from infancy and thereafter. Aschoff designated this stage as atherosis or atheromatosis. The other component, fibrosis (sclerosis, formation of collagen), added to the lipid in adults. Only the fibrolipidic stage was designated atherosclerosis. Aschoff subdivided preadult atherosis into infant and pubertal phases so that in fact he spoke of three developmental stages: atherosis in infants, atherosis in adolescents (puberty), and atherosclerosis in adults.

Atherosis in infants was described as yellow dots, visible to the unaided eye at the root of the aorta. Atherosis at puberty consisted of more extensive yellow streaks in many parts of the aorta and in coronary arteries. Microscopically, infant and pubertal dots and streaks were similar, consisting of intracellular and less extracellular lipid in the intima. Both differed from adult lesions in the absence of fibrosis. In adults, atherosis and fibrosis (now called atherosclerosis) formed fibrolipid lesions (fibrous plaques).

In the 1950s pathologists extended classifications of atherosclerosis for the purpose of estimating the prevalence of individual lesion types in epidemiological studies. In these studies, lesions seen on the intimal surface of arteries that had been opened longitudinally, flattened, and fixed in formalin were examined with the unaided eye. This method permitted rapid estimation of the percentage of the intimal surface of an artery covered with atherosclerotic lesions. The terms for lesions used in these studies were those used by Aschoff plus some additional terms. Several groups of investigators^{68 69 70} described a classification that consisted of the sequence fatty streak, fibrous plaque, and complicated lesion. The latter term was used for fibrous plaques that contained a hemorrhage or had ulcerated or fissured and developed hematoma and a thrombotic deposit or that had one or more of these components. The World Health Organization⁷⁰ classification includes, in addition to the three terms mentioned above, the term atheroma to distinguish advanced lesions with a predominantly lipid component (atheroma) from those with a predominantly collagenous component (fibrous plaque). In place of the terms fibrous plaque or atheroma, other authors have used fibroatheroma, atheromatous plaque, fibrolipid plaque, or fibrofatty plaque (Table 2). Atheroma, as used in the WHO classification and by the Committee on Vascular Lesions for a lesion type, has sometimes been used to designate the entire disease process,⁷¹ making it analogous to the term atherosclerosis.

Aschoff's sequence and the classifications established in the 1950s, including that of the WHO, appear to be correct. However, the much more sensitive techniques now used in autopsy studies allow histological characterization of the intimal locations in which deposition of lipid tends to result in advanced disease and identification of additional lesion types that indicate several possible sequences of disease progression and thus clarify some clinical syndromes.

	Characterization of Atherosclerotic Lesions by Clinical Imaging

Top Abstract Introduction Atherosclerotic Lesion Types... Type IV Lesions Type V Lesions Type VI Lesions Atherosclerotic Aneurysms Recommended Histological... A Brief History of... Characterization of... Assessment of Presence and... Correlation of Lesion Types... The Cells and Extracellular... References

 
Intensive efforts are under way to characterize atherosclerotic lesions in clinical situations as appropriate technology is developed and improved. The aim of clinical classifications is to depict as closely as possible the histology and then precisely target treatment to specific problem lesions. Until recently, clinical assessment of atherosclerotic lesions has been limited to evaluation of aneurysms and estimation of severity of stenosis. However, recent studies of the relation between pathophysiology of lesion progression and clinical events, particularly in coronary artery disease, have led to efforts to characterize clinically the types of lesions present. At the same time, new emphasis on prevention of complicated lesions (histological type VI) has made early detection of lesions and assessment of lesion extent and composition important clinical goals.

Angiography, the traditionally definitive method for evaluation of the vascular lumen, provides excellent resolution but does not show the vascular wall and therefore is insensitive for early detection and estimation of lesion volume. However, the sensitivity of coronary angiography for early detection may be increased by associated vascular reactivity studies.⁷² B-mode ultrasonography and Doppler flow studies are also widely used to measure severity of stenosis in peripheral arteries. Intravascular ultrasound provides cross-sectional images that show the vascular wall, including details that provide insight into lesion composition as well as lumen contour. Magnetic resonance angiography promises to supplant invasive angiography for study of major vessels such as the aorta and carotid arteries,^{73 74} and eventually, perhaps, the coronary arteries. Angioscopy appears to be highly specific for certain morphological features such as thrombus.⁷⁵ Ultrafast computed tomography may provide another dimension to early detection of coronary lesions by means of highly sensitive noninvasive demonstration of coronary artery calcium.⁷⁶ Other new methods that may allow noninvasive monitoring of progression or regression of atherosclerosis include the use of nuclear magnetic resonance spectroscopy,⁷⁷ labeled antiplatelet monoclonal antibody imaging,⁷⁸ and radiolabeling of low density lipoproteins^{79 80} and monocytes.⁸¹

	Assessment of Presence and Extent of Lesions

Top Abstract Introduction Atherosclerotic Lesion Types... Type IV Lesions Type V Lesions Type VI Lesions Atherosclerotic Aneurysms Recommended Histological... A Brief History of... Characterization of... Assessment of Presence and... Correlation of Lesion Types... The Cells and Extracellular... References

 
Each of the methods available has major limitations. As discussed below, histological lesion types I, II, and III are not detected by angiography. Some type IV (and even some type V) lesions have a smooth surface, and because the lumen is perfectly round and widely patent, such lesions are not detected. Lesion types IV and V, which produce configurational changes of the lumen, are detected and often may be distinguished from complicated (type VI) lesions. Intravascular ultrasound is likely to be a more sensitive method for detection of lesions that change the lumen little, if at all. Intravascular ultrasound studies of angiographically normal arterial segments in patients with known coronary disease have shown changes from intimal thickening to atheroma.^{82 83} However, in contrast to angiography, it is not yet feasible to examine more than selected portions of the arterial tree of interest with intravascular ultrasound, and quantitation of lesion volume requires three-dimensional reconstruction. The presence of coronary artery calcium, detected by ultrafast computed tomography, may be a sensitive early noninvasive marker for the presence and progression of atherosclerosis before development of ischemia-producing stenosis or complication.^{76 84}

Severity of Stenosis
The severity of stenosis of a lesion as a marker of clinical flow impairment is estimated by expressing angiographic maximum stenotic diameter as a percentage of adjacent, presumably normal arterial diameter. Coronary flow begins to decrease with stenosis greater than 50% and decreases rapidly when it exceeds 70%.⁸⁵ Percent diameter stenosis is clinically useful as a measure of obstruction to blood flow, particularly for stenoses below 50% or above 70%. However, it does not take into account other factors influencing the physiological effect of the stenosis, such as lesion length or geometry.⁸⁶ The accuracy of diameter measurements may be degraded by technical problems such as overlap of branches and inability to obtain views without foreshortening, particularly in the case of the coronary arteries.

The validity of percent diameter stenosis as an index of lesion severity or clinical flow impairment depends on the assumption that the arterial lumen measured is approximately circular in cross-section, because stenotic diameter on any single angiographic view may misrepresent the actual degree of stenosis if the cross-section is not circular. Postmortem studies of coronary arteries with perfusion-fixation at or near diastolic pressure levels have shown that the stenotic lumen is usually circular, even in the presence of advanced uncomplicated lesions (Fig 1 and references 14 and 87). A clinical study of lumen cross-section by intravascular ultrasound showed essentially round cross-sections in approximately two thirds of lesions but not in one third.⁸⁸ Sometimes there is flattening of one half of the cross-section, resulting in an elliptical or D-shaped lumen.⁸⁹ Only complicated lesions with intraluminal thrombus or massive intra-intimal thrombus have slit-like or crescentic lumens. In these cases, percent stenosis measured on any single view will either underestimate or overestimate the true cross-sectional area, depending on the x-ray beam angle, unless a densitometric method is used.⁸⁹ Nevertheless, pathological studies with controlled pressure distension have shown good agreement with both postmortem⁸⁷ and premortem angiography, particularly if quantitative analysis is used.⁹⁰ Accuracy is increased by the use of two or more views.

A more difficult problem is in the assumption that the designated "normal" reference segment has a normal diameter. Ultrasound studies show that the wall of an apparently normal coronary artery reference segment adjacent to a stenotic lesion is usually not free of disease. In addition, at the site of the lesion, lumenal size may remain nearly normal in the presence of atheroma as a compensatory response; thus, coronary artery lumen area may on the average remain virtually unchanged until a lesion occupies up to 40% of the potential lumenal area, as defined by the area within the internal elastic lamina,¹⁴ or until there has been as much as an 80% increase in external arterial size.⁸⁷ In some instances early overcompensation results in a slightly greater than normal lumen size.¹⁴ In others the artery may be uniformly ectatic, with diameter several times normal, due to extensive destruction of musculoelastic elements of the media,⁹¹ or it may be uniformly narrowed by diffuse atherosclerosis^{92 93} or increased vascular tone. Thus, angiographic overestimation or underestimation of stenosis may occur in the presence of an apparently normal reference segment.

Lesion Morphology
Atherosclerotic lesions may be clinically characterized by their morphology in addition to severity of stenosis. Pertinent descriptors include lesion length, smoothness or roughness of lumen outline, abrupt or tapered shoulders, defects due to thrombus, presence of calcification, and degree of eccentricity of the lumen within the projected "normal" arterial border.

Comparison of postmortem coronary angiograms with histological sections has defined the pathological significance of these morphological descriptors.⁹⁴ Histologically advanced lesions with intact lumen surfaces (types IV and V) have smooth borders and regular configurations on postmortem angiography. Lesions with rupture, hemorrhage, hematoma, superimposed partially occluding thrombus (type VI), or organized thrombus have irregular angiographic borders and intraluminal lucencies due to thrombus. Specific characteristics associated with thrombus include intraluminal defects partly surrounded by contrast medium, and contrast pooling at the site of abrupt occlusion.⁹⁵ While the hallmark of thrombus is an intraluminal defect, it may contribute to other aspects of the lesion, such as irregular, roughened, or ill-defined borders.

Intravascular ultrasound cross-sectional images display the vascular wall as well as the lumen and therefore allow some direct characterization of lesion composition. Fibrous, calcific, and somewhat less successfully, predominantly lipid lesions⁹⁶ and thrombus⁹⁷ can be identified. Preliminary studies analyzing ultrasound backscatter frequency are also promising but need further validation.⁹⁸ Angioscopy is probably more sensitive than angiography for detection of type VI lesions⁹⁹ and more sensitive than either angiography or intravascular ultrasound for detection of thrombus.⁷⁵

New understanding of the pathophysiology of progression of atherosclerotic lesions has shown that the composition of atherosclerotic lesions is related to the clinical status of the patient; in some patients, lesion composition and morphology may be a better predictor of clinical outcome than severity of stenosis.¹⁰⁰ The clinical significance of these morphological observations is discussed in the following section.

	Correlation of Lesion Types With Clinical Syndromes

Top Abstract Introduction Atherosclerotic Lesion Types... Type IV Lesions Type V Lesions Type VI Lesions Atherosclerotic Aneurysms Recommended Histological... A Brief History of... Characterization of... Assessment of Presence and... Correlation of Lesion Types... The Cells and Extracellular... References

 
Acute or Unstable Ischemic Coronary Syndromes
Because of the rapidity of this mechanism of progression, lesion disruption with resultant intraluminal thrombus plays a fundamental role in the pathogenesis of unstable symptoms of coronary heart disease. The degree of lesion disruption determines the nature of the ensuing clinical state. If only the endothelial surface of the lesion is disrupted, the thrombogenic stimulus is limited, and at most there is mural thrombus, without symptoms, and subsequent lesion growth. If the disruption is deeper, as with fissuring, a transient thrombotic occlusion (ie, lasting minutes) may take place and may be repetitive.^{28 29} Indeed, some patients with unstable angina may have intermittent or transient vessel occlusion and ischemia.¹⁰¹ The finding of layered thrombi overlying fissured lesions in thrombosed arteries in some patients with infarction or sudden death¹⁰² indicates that recurrent thrombosis may lead to gradual occlusion. Finally, if the disruption is very deep or ulceration exposes the lipid core, collagen, tissue factor and other elements, a thrombotic occlusion that is relatively persistent (ie, 2 to 4 hours or longer) may result in acute myocardial infarction.¹⁰¹

Angiographic studies tend to confirm this sequence of events. Retrospective studies have shown that up to two thirds of patients with unstable symptoms had rapid progression of previously relatively mild stenoses. Approximately 70% of lesions in unstable angina had less than 50% stenosis on a first angiogram.^{103 104} The clinical angiographic features associated with unstable symptoms are similar to those of complicated lesions in the postmortem studies of Levin and Fallon.⁹⁴ They include marked eccentricity, narrow neck, or abrupt shoulder with overhanging edges and scalloped irregular, rough, or sawtooth borders, and appear to represent lesion disruption with or without partially occlusive thrombus.^{89 105 106} Transient vasoconstriction is frequently present.¹⁰⁷ While the morphology of lesions that have become unstable is characteristic, it has not been possible to predict their occurrence.¹⁰⁴

Typically, angiograms performed a few hours after acute myocardial infarction when the artery has reperfused (spontaneously or after lytic therapy) show contrast staining, or pooling, because of thrombus at the site of abrupt occlusion.⁹⁵ Ulceration of the infarct-related lesion, which has been demonstrated on angiographic studies after thrombolysis, is probably due to rupture of a lesion and predicts continued instability.^{108 109} Lesions causing myocardial infarction without total occlusion or following successful thrombolysis have angiographic morphological features like those of unstable angina. As with unstable angina, a prospective angiographic study has shown that 85% of infarct-related lesions had less than 75% diameter stenosis when first examined.¹¹⁰

Chronic Stable Angina and Silent Occlusion
The clinical angiographic morphology associated with chronic stable angina is similar to that of uncomplicated lesions on postmortem studies.⁹⁴ These lesions tend to have a smooth outline and tapered shoulders and appear symmetric or eccentric with a broad neck.^{105 106} In contrast to small lipid-rich lesions that are prone to disruption, severely stenotic lesions tend to be fibrotic and stable.¹¹¹ Severe stenoses tend to progress to total thrombotic occlusion approximately three times more often than less severe lesions but less frequently lead to infarction,¹¹⁰ probably because of well-developed collateral vessels.¹¹² When occlusion is subtotal or partial lysis of the thrombus allows angiographic delineation of the lesion, residual thrombus is typically located on the downstream side of the stenosis, in contrast to the thrombus in complicated, unstable lesions.

The bulk of new coronary events occurring in prospective studies has been associated with lesions angiographically showing 35% to 65% stenosis. This further supports the concept that the lesions' thrombogenic potential does not require advanced stenosis but may be related to intimal surface characteristics.^{113 114}

Cerebrovascular Atherosclerosis
Like coronary atherosclerosis, luminal surface disruption may cause lesion instability in cerebral arteries, particularly at the carotid bifurcation. Disruptions are often a source of distal emboli as well as occlusion, resulting in transient cerebral symptoms. However, high-grade stenosis at the proximal internal carotid and in intracerebral branches may lead to obstruction, ischemia, and necrosis.

Aortic and Peripheral Atherosclerosis
Aortic atherosclerosis most severely affects the segment of abdominal aorta between the level of the renal arteries and the iliac bifurcation. Because of the size of the aorta, significant sudden obstruction is relatively uncommon; however, atrophy of the media associated with large eroded lesions may lead to aneurysm formation. Atherosclerotic disease of the iliac and femoral arteries is often severe. Advanced type VI lesions may cause distal emboli, stenosis, and occlusion.

	The Cells and Extracellular Matrix of Histological Lesion Types IV, V, and VI

Top Abstract Introduction Atherosclerotic Lesion Types... Type IV Lesions Type V Lesions Type VI Lesions Atherosclerotic Aneurysms Recommended Histological... A Brief History of... Characterization of... Assessment of Presence and... Correlation of Lesion Types... The Cells and Extracellular... References

 
Smooth Muscle Cells
Functional modulations and numerical increases in intimal smooth muscle cells stand out among cellular changes in advanced human lesions. The smooth muscle cells are in part resident intimal cells that preceded the lesions and in part their progeny that arose as a response to various stimuli. The stimuli include lipid accumulation, disruption of intimal structure, damage to intimal cells and matrix, and deposits of platelets and fibrinogen, all of which may activate resident cells to produce mitogenic factors.

The two smooth muscle cell types, myofilament-rich (contractile) and myofilament-poor but relatively rich in rough-surfaced endoplasmic reticulum (synthetic), found in normal intima,¹ and in lesion types I, II, and III² also occur in advanced lesions. The amount of rough-surfaced endoplasmic reticulum (RER) in smooth muscle cells containing it is variable. Intimal smooth muscle cells in close proximity to the thrombotic deposits of type VI lesions and those in type V lesions may contain very RER-rich smooth muscle cells (Fig 6). The basement membrane–rich¹¹⁵ or pancake-shaped^{20 116} smooth muscle cell (Fig 7) is a smooth muscle variant found in lesion types IV, V, and VI and occasionally in type III but not in types I and II or in normal intima. These cells frequently occur in and adjacent to the lipid cores of lesions and particularly in the region between the core and the arterial lumen. The basement membrane surrounding such a cell may be 10 times the thickness of the cell body.¹¹⁵ The cell bodies are thinner than usual, poor in myofilaments, and not particularly rich in RER. Basement membrane–rich intimal smooth muscle cells are encountered when the extracellular matrix that normally surrounds the cells is disrupted and changed. Basement membrane thickening could represent an attempt by the cells to restore tissue architecture, provide anchorage for cells, and guide repair processes.¹¹⁷ Fibronectin, a prominent component of basement membranes, precedes collagen formation in granulation tissue and may be involved in organization of newly formed granulation tissue.¹¹⁸ Basement membrane collagen (type IV) increases with the advance of atherosclerotic lesions,¹¹⁹ and it, together with fibronectin, is prominent around some cells in the deeper layers of advanced atherosclerotic lesions.¹²⁰

View larger version (90K): [in this window] [in a new window]   Figure 6. Electron photomicrograph of adjacent layers of rough endoplasmic reticulum–rich smooth muscle cells (S) just below endothelial cell surface (e) of a fibroatheroma (type V lesion). Layers of cells containing lipid droplets are below cells pictured here, closer to the lipid core of this lesion. The lesion is from proximal left anterior descending coronary artery of a 29-year-old man. Homicide was the cause of death. Fixation by pressure-perfusion with glutaraldehyde. Maraglas embedding. Magnification about x9200.

View larger version (92K): [in this window] [in a new window]   Figure 7. Electron photomicrograph of basement membrane (bm)–rich smooth muscle cell (S) and intercellular matrix of collagen fibers (cgf) in the region between lipid core (not visible) and endothelial surface (not visible) of a fibroatheroma (type V lesion). Lesion is from proximal part of intermediate coronary artery branch that originated at left main bifurcation. From a 38-year-old woman who died in an automobile accident. Fixation by pressure-perfusion with glutaraldehyde. Maraglas embedding. Magnification about x7800.

Macrophages
There is a difference in the levels of the lesion at which macrophages without lipid droplet inclusions are found and at which macrophage foam cells are found (Fig 2). Macrophages without lipid droplet inclusions are more frequently located near the lumen, whereas macrophage foam cells are deeper in the intima. In locations in which the intima is relatively thin or in very complicated lesions, these preferences in location may not be so apparent. When a lipid core is present, macrophage foam cells are usually most evident along the luminal aspect and at the lateral margins of the core. Laterally, macrophage foam cells are not only more numerous, but because intima thickness is less at the lesion periphery, the foam cells are also somewhat closer to the surface.

Many macrophage foam cells show ultrastructural evidence of cell injury, and some are dead and partly or wholly disintegrated. As yet there are no appropriate markers for defining these stages of cell injury. In vitro studies have relied on measures of the release of specific cytoplasmic enzymes such as lactic acid dehydrogenase as indicators of cytotoxicity and cell death.

Macrophages may express the genes for proteins that may play a role in formation and modeling of advanced lesions. For example, Nelken and colleagues¹²¹ have reported that monocyte chemotactic protein-1 (MCP-1) is expressed by cells within advanced lesions, and Barath et al¹²² have reported that tumor necrosis factor is expressed in human atheroma. Liptay et al¹²³ have suggested that in the atherosclerotic pulmonary arteries of humans with idiopathic pulmonary hypertension, smooth muscle cells adjacent to pockets of macrophages are stimulated by the macrophages to express the genes for type IV (basement membrane) collagen and fibronectin. To date there is no information on possible phenotypic and metabolic differences between macrophages in minimal (types I and II) lesions or the various advanced lesions.

The capacity of macrophages to express cytokines and growth regulatory molecules has been reviewed earlier.² However, several questions about their roles in advanced lesions should be addressed here. If lesions do indeed rupture preferentially through regions rich in monocytes and macrophage foam cells,^{29 36} then this might be due to the release of proteolytic enzymes such as collagenase and elastase by the macrophages. Whether macrophages secrete these enzymes throughout lesion formation or only as the cells die is not clear. It has been suggested that macrophage foam cell–derived oxidized lipids constitute a significant but variable component of the core of advanced lesions in both humans and laboratory animals.^{124 125 126}

Lymphocytes
Both T and B lymphocytes have been identified in advanced lesions by using monoclonal antibodies against CD antigens.¹⁵ T cells are of both the T helper (CD4+) and T killer (CD8+) phenotypes and may be capable of clonal proliferation in response to appropriate antigens. There is some evidence that B lymphocytes can be stimulated to produce antibodies while resident within the lesions, although the many possible antigens must be identified and related to progression or regression of advanced lesions.

To date, autoantibodies that recognize oxidized low density lipoprotein (LDL) have been found in both rabbit and human sera,¹²⁷ and the titers of these antibodies may be diagnostic of advanced atherosclerosis.¹²⁸ In addition, both viral and bacterial (chlamydia) antigens have been found in advanced human lesions using molecular and immunocytochemical techniques.¹²⁹

Lipid, Lipoprotein, and Fibrinogen in the Extracellular Matrix
The transfer of lipoproteins and fibrinogen from the plasma into the intima is a physiological process, but these proteins are found in advanced lesions in much larger amounts than in normal intima or in lesion types I, II, and III. Some data on plasma proteins in the extracellular matrix of human arterial intima were summarized in the first report of the Committee on Vascular Lesions.¹

The types and amounts of extracellular lipid that are demonstrable in advanced atherosclerotic lesions depend largely on methods of tissue preparation and study. When viewed by electron microscopy, some lipid that is or was present is not visible. Extracellular lipid that is visible is heterogeneous in both fine structure and particle size. Droplets are mixed with dense membranous structures and vesicles and the mixture is generally scattered diffusely and thinly in the intimal matrix of lesions, starting with type II.² There is more extracellular lipid in type III, and in lesion types IV, Va, and VI it also forms large circumscribed accumulations (ie, lipid cores). The morphological range of the particles is similar in the diffusely scattered and circumscribed dense accumulations.

The fine structure of the extracellular particles appears identical to that of the inclusions within the cytoplasm of macrophage foam cells and smooth muscle cells. The fact that lesions contain many inclusion-laden cells that are dead or in various stages of disintegration has been taken as evidence that much of the accumulated extracellular lipid visible by electron microscopy is derived from cells and lipoproteins originally internalized by cells.^{124 126} The residuals of intracytoplasmic lipid droplet digestion can also be expelled from intact cells (or the peripheral parts of the cytoplasm containing them can be detached from cells) into the extracellular space.¹³⁰ However, there also is evidence that some of the extracellular lipid visible by electron microscopy, including that of lipid cores, is derived directly from the coalescence, in the extracellular matrix, of plasma-derived lipoproteins,^{131 132} and this is supported by chemical data. Analysis of the lipid of entire advanced lesions (those in which most lipid is extracellular) showed that cholesteryl esters were predominantly cholesteryl linoleate¹³³ and thus similar to plasma low density lipoprotein.

The degree and extent to which fibrinogen accumulates in advanced lesions and parts of advanced lesions varies. When immunohistochemical techniques are used, the cores of advanced lesions stain for fibrinogen more extensively and intensively than any other aspect of advanced lesions except superimposed thrombi. Immunohistochemical staining alone does not distinguish fibrinogen that is associated with thrombus formation from fibrinogen that is part of the ubiquitous infiltration from the plasma. However, it has been proposed that characteristic, intensely fibrinogen-positive bands or wavy layers of a mesh-like matrix material that are found in the majority of advanced lesions represent the residuals of incorporated thrombi.^{42 43} In any case, fibrinogen contributes directly (and perhaps also indirectly by promoting smooth muscle cells) to the volume of most advanced lesions.

Proteoglycans
Large extracellular proteoglycans, mainly chondroitin sulfate–containing (versicanlike) molecules, function in arterial permeability, ion exchange, transport, and deposition of plasma materials such as LDL. Small extracellular proteoglycans such as dermatan sulfate–containing molecules (eg, decorin) may function to regulate collagen fibrillogenesis¹³⁴ but also may bind ionically to LDL. Extracellular basement membrane and cell surface heparan sulfate proteoglycans possessing oligosaccharide or carbohydrate sequences render functional specificity to the molecule. Functions attributed to specific oligosaccharides include antiproliferative effects on arterial smooth muscle cells,¹³⁵ fibroblast growth factor (FGF) binding,^{136 137} lipoprotein lipase binding,¹³⁸ and antithrombin III binding.¹³⁹

Mass amounts of heparan sulfate decrease or remain unchanged while dermatan sulfates increase in progressing lesions when compared with normal intima.^{140 141} Significant increases in sulfated glycosaminoglycans enhance intimal retention of plasma LDL. Dermatan sulfate binds plasma LDL¹⁴² through association of the sulfated glycosaminoglycan and lysine residues of apo B.¹⁴³ Associations of LDL and proteoglycans may result in enhanced retention of LDL, uptake of LDL by macrophages via the scavenger receptor,¹⁴⁴ or render LDL more susceptible to oxidation.¹⁴⁵

In contrast to arterial glycosaminoglycans, little is known about qualitative changes in specific proteoglycan molecules in atherosclerotic lesions. A chondroitin sulfate proteoglycan similar to versican and comprising about 60% to 70% of the total proteoglycan material has been purified from intima media minces of normal human aorta and adjacent type IV or Va lesions.¹⁴⁶ The molecular size of chondroitin sulfate proteoglycan and its capacity to form aggregates with hyaluronic acid was reduced in atherosclerotic lesions.¹⁴⁷ The predicted functional impairment includes reductions in the viscoelastic properties of the artery wall, inability of the arterial wall to resist compressive forces, and reduced water binding and impaired maintenance of a hydrated domain. These conditions facilitate increased transport of plasma materials, including LDL.

Two dermatan sulfate proteoglycans, decorin and biglycan, have been identified in human and monkey atherosclerotic lesions,¹⁴⁸ but information on structural changes with lesion progression is not available. Several types of heparan sulfate proteoglycans are associated with cell membranes and basal lamina. Although studies of human lesions are lacking, studies of heparan sulfate proteoglycans are being carried out in cultured cells. For example, a specific sequence of sugars in heparan sulfate of cultured adult human fibroblasts has been found to bind basic FGFs.^{136 137} This interaction may regulate the availability of FGF for mitogenesis of arterial smooth muscle cells. Changes in heparan sulfate structure leading to decreased FGF binding may result in increased FGF stimulation and proliferation of smooth muscle cells.

Collagen
Apart from lipid, collagen is the major extracellular component of type V lesions. The increased collagen of atherosclerotic lesions is produced by intimal smooth muscle cells. In some lipid-poor advanced lesions or parts of advanced lesions, collagen may be the major component, comprising 30% of the dry weight and up to 60% of the total protein content of advanced human lesions.^{149 150 151} The major collagen type of advanced lesions is the fibrillar collagen type I, although distinct ratios of type I to type III collagen have been reported for different vascular beds.¹⁵² Type I collagen represents about 70% of the total collagen,^{119 153 154 155} which is similar to the 65% of type I collagen in grossly normal artery. Quantitatively both type I and fibrillar collagen type III increase in the advanced human lesion and account for the majority of collagen. The ratios of types I and III are maintained according to several studies of human atherosclerotic lesions.^{154 155} Type I collagen is especially prevalent in the fibrous cap and in vascularized regions of advanced lesions.¹⁵⁶

A significant and consistent change in the minor collagen types of advanced atherosclerotic lesions is the increase in type V collagen. This collagen is prominent in advanced lesions and increases with advancing fibrosis.^{119 154 155} Type V collagen has been reported to play a role in cell migration¹⁵⁷ and may also appear to reduce the thrombogenic properties of the subendothelium.¹⁵⁸ Type IV collagen is also increased in advanced lesions.¹¹⁹ Type IV collagen is associated with the basement membranes of smooth muscle cells. The interaction between fibronectin and smooth muscle cells was described previously.

The exact stimulus for increased collagen accumulation in atherosclerosis is unknown, although macrophage and platelet products such as transforming growth factor (TGF) upregulate collagen genes in a variety of cell types.^{159 160} Mechanical stresses are likely to be redistributed and modulated as lesions develop, inducing changes in matrix production in response to mechanical stimuli.

Elastin
Depending on the location and type of lesion, microscopically visible elastin fibers may be increased, decreased, or relocated. Although the smooth muscle cells of advanced lesions produce elastin, integration of the protein into a functional elastic fiber may be impaired. However, neoformation of subendothelial, medial, and adventitial elastin does occur and may be prominent, particularly in type V lesions, where it accompanies collagen.

Elastic fibers are split or frayed and often appear to be closely associated with lipid and calcium deposits. Lipid bound to elastic fibers may change elasticity of tissue by modifying the conformation of the elastin through hydrophobic interactions. Binding may also increase sensitivity of elastin to proteolytic degradation,¹⁶¹ an effect that has been observed in vitro.¹⁶² Saulnier et al¹⁶³ examined alkali insoluble elastin prepared from human aortas with advanced atherosclerotic lesions and demonstrated that elastolysis was increased compared with elastin isolated from aortas without grossly visible lesions. The first stage of elastolysis includes adsorption of elastase to elastin, and even though lesion elastin with increased cholesterol content decreased binding of elastase, enzyme activities and elastolysis were stimulated. Calcium and magnesium have been reported to increase elastase activity,¹⁶⁴ and significant correlations have been observed between elastolytic activity and calcium, magnesium, and cholesterol content of purified atherosclerotic lesion substrate elastin. Degradation of elastin may produce peptides chemotactic for macrophages.¹⁶⁵

Kramsch et al¹⁶⁶ described the relation of cholesterol deposits in the human aorta to the amount of elastin present and the degree of severity of atherosclerosis. Elastin from lesions contained increasing amounts of lipid and polar amino acids and decreasing amounts of cross-linking amino acids. Kramsch et al believed that a prerequisite for transfer of cholesterol to elastin was an altered amino acid composition; however, Keeley and Partridge¹⁶⁷ suggested that contaminating microfibrillar protein of the elastic fiber and collagen in samples that were not properly decalcified altered amino acid composition. In addition, it has been suggested that the presence of calcium and lipid in an atherosclerotic lesion might be expected to cause changes in elastin composition as a result of selective cleavage of elastin peptides upon alkali extraction.^{168 169}

Calcium
Apatite in the form of hydroxyapatite, carbonate apatite, and calcium-deficient apatite, is the predominant mineral form in calcified lesions.^{170 171} Mineral deposits in atherosclerosis may be associated with elastic fibers. Although it has been suggested that carboxyl groups serve as nucleation sites for calcification of elastin, the apolar nature of the protein does not favor calcium binding. Urry¹⁷² proposed that elastin can act as a calcifying protein even in the absence of ionic interactions that would arise from charged amino acids. The results of those in vitro studies suggest that calcium binds at neutral binding sites that involve complexes arising from orientation of acyl oxygens in the elastin polypeptide. Vesicles in the extracellular matrix of advanced lesions, probably derived from dead cells, may serve as sites for calcification.¹⁷³ It is possible that, although elastin can bind calcium and act as a calcifying matrix, the matrix vesicles may be of primary importance in calcification of atherosclerotic lesions.

It has been proposed that calcium-binding proteins such as matrix gla protein and osteopontin produced by cultured rat arterial smooth muscle cells are involved in artery wall mineralization.¹⁷⁴ Regardless of the mechanisms involved, it is clear that calcium is a common but highly variable component in advanced atherosclerotic lesions. Unfortunately, as is true of the fibrous proteins, very little is known about the factors controlling the quantity of calcium in the lesions.

	Footnotes

 
"A Definition of Advanced Types of Atherosclerotic Lesions and a Histological Classification of Atherosclerosis" was approved by the American Heart Association SAC/Steering Committee on June 16, 1994. It is being published simultaneously in Circulation and Arteriosclerosis, Thrombosis, and Vascular Biology.

Requests for reprints should be sent to the Office of Scientific Affairs, American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231-4596.

	References

Top Abstract Introduction Atherosclerotic Lesion Types... Type IV Lesions Type V Lesions Type VI Lesions Atherosclerotic Aneurysms Recommended Histological... A Brief History of... Characterization of... Assessment of Presence and... Correlation of Lesion Types... The Cells and Extracellular... References

 
1. Stary HC, Blankenhorn DH, Chandler AB, Glagov S, Insull W Jr, Richardson M, Rosenfeld ME, Schaffer SA, Schwartz CJ, Wagner WD, Wissler RW. A definition of the intima of human arteries and of its atherosclerosis-prone regions: a report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Special report. Circulation. 1992;85:391-405. [Free Full Text]

2. Stary HC, Chandler AB, Glagov S, Guyton JR, Insull W Jr, Rosenfeld ME, Schaffer A, Schwartz CJ, Wagner WD, Wissler RW. A definition of initial, fatty streak, and intermediate lesions of atherosclerosis: a report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Special report. Arterioscler Thromb. 1994;14:840-856. [Abstract/Free Full Text]

3. Barbano EF, Newman GE, McCann RL, Hackel DB, Stack RS, Palmos LE, Mikat EM. Correlation of clinical history with quantitative histology of lower extremity atheroma biopsies obtained with the Simpson atherectomy catheter. Atherosclerosis. 1989;78:183-196. [Medline] [Order article via Infotrieve]

4. Dartsch PC, Bauriedel G, Schinko I, Weiss HD, Hofling B, Betz E. Cell constitution and characteristics of human atherosclerotic plaques selectively removed by percutaneous atherectomy. Atherosclerosis. 1989;80:149-157. [Medline] [Order article via Infotrieve]

5. Gonschior P, Hofling B, Mack B, Simpson L, Gerheuser F, Nerlich A, Bauriedel G, Welsch U. Results of directional peripheral atherectomy with reference to histology, histochemistry, and ultrastructure. Angiology. 1993;44:454-463.

6. Escaned J, van Suylen RJ, MacLeod DC, Umans VA, de Jong M, Bosman FT, de Feyter PJ, Serruys PW. Histologic characteristics of tissue excised during directional coronary atherectomy in stable and unstable angina pectoris. Am J Cardiol. 1993;71:1442-1447. [Medline] [Order article via Infotrieve]

7. Simons M, Leclerc G, Safian RD, Isner JM, Weir L, Baim DS. Relation between activated smooth-muscle cells in coronary-artery lesions and restenosis after atherectomy. N Engl J Med. 1993;328:608-613. [Abstract/Free Full Text]

8. Hofling B, Welsch U, Heimerl J, Gonschior P, Bauriedel G. Analysis of atherectomy specimens. Am J Cardiol. 1993;72:96E-107E. [Medline] [Order article via Infotrieve]

9. Waller BF, Johnson DE, Schnitt SJ, Pinkerton CA, Simpson JB, Baim DS. Histologic analysis of directional coronary atherectomy samples. Am J Cardiol. 1993;72:80E-87E. [Medline] [Order article via Infotrieve]

10. Rosenschein U, Ellis SG, Haudenschild CC, Yakubov SJ, Muller DW, Dick RJ, Topol EJ. Comparison of histopathologic coronary lesions obtained from directional atherectomy in stable angina versus acute coronary syndromes. Am J Cardiol. 1994;73:508-510. [Medline] [Order article via Infotrieve]

11. Mann JM, Kaski JC, Arie S, Pereira WI, Pileggi F, Davies MJ. Plaque constituents in patients with stable and unstable angina: an atherectomy study. J Am Coll Cardiol. February 1995(special issue):34A. Abstract.

12. O'Brien ER, Urieli-Shoval S, Garvin MR, Benditt EP, Stewart DK, Hinohara T, Simpson JB, Schwartz SM. Evaluation of proliferation in human atherectomy specimens using in situ hybridization for histone H3. J Am Coll Cardiol. February 1995(special issue):240A. Abstract.

13. Stary HC. Evolution and progression of atherosclerotic lesions in coronary arteries of children and young adults. Arteriosclerosis. 1989;9(suppl I):I-19-I-32.

14. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med. 1987;316:1371-1375. [Abstract]

15. Jonasson L, Holm J, Skalli O, Bondjers G, Hansson GK. Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis. 1986;6:131-138. [Abstract/Free Full Text]

16. Glagov S, Zarins C, Giddens DP, Ku DN. Hemodynamics and atherosclerosis: insights and perspectives gained from studies of human arteries. Arch Pathol Lab Med. 1988;112:1018-1031. [Medline] [Order article via Infotrieve]

17. Stary HC. Composition and classification of human atherosclerotic lesions. Virchows Arch A Pathol Anat Histopathol. 1992;421:277-290. [Medline] [Order article via Infotrieve]

18. Stary HC. Changes in components and structure of atherosclerotic lesions developing from childhood to middle age in coronary arteries. Basic Res Cardiol. 1994;89(suppl 1):17-32.

19. Stary HC. The histological classification of atherosclerotic lesions in human coronary arteries. In: Fuster V, Ross R, Topol E, eds. Atherosclerosis and Coronary Artery Disease. Philadelphia, Pa: Lippincott-Raven Publishers. In press.

20. Ross R, Wight TN, Strandness E, Thiele B. Human atherosclerosis, I: cell constitution and characteristics of advanced lesions of the superficial femoral artery. Am J Pathol. 1984;114:79-93. [Abstract]

21. Mitchell JRA, Schwartz CJ. Arterial Disease. Philadelphia, Pa: FA Davis Co; 1965.

22. Pomerance A. Peri-arterial mast cells in coronary atheroma and thrombosis. J Pathol Bact. 1958;76:55-70. [Medline] [Order article via Infotrieve]

23. Pouchlev A, Youroukova Z, Kiprov D. A study of changes in the number of mast cells in the human arterial wall during the stages of development of atherosclerosis. J Atheroscler Res. 1966;6:342-351. [Medline] [Order article via Infotrieve]

24. Constantinides P. Plaque fissuring in human coronary thrombosis. J Atheroscler Res. 1966;6:1-17.

25. Constantinides P. Plaque hemorrhages, their genesis and their role in supra-plaque thrombosis and atherogenesis. In: Glagov S, Newman WP, Schaffer SA, eds. Pathobiology of the Human Atherosclerotic Plaque. New York, NY: Springer-Verlag; 1990:394-411.

26. Davies MJ, Thomas AC. Plaque fissuring: the cause of acute myocardial infarction, sudden ischemic death, and crescendo angina. Br Heart J. 1985;53:363-373. [Free Full Text]

27. Richardson PD, Davies MJ, Born GV. Influence of plaque configuration and stress distribution on fissuring of coronary atherosclerotic plaques. Lancet. 1989;2:941-944. [Medline] [Order article via Infotrieve]

28. Falk E. Morphologic features of unstable atherothrombotic plaques underlying acute coronary syndromes. Am J Cardiol. 1989;63:114E-120E. [Medline] [Order article via Infotrieve]

29. Falk E. Why do plaques rupture? Circulation. 1992;86(suppl III):III-30-III-42.

30. Tracy RE, Devaney K, Kissling G. Characteristics of the plaque under a coronary thrombus. Virchows Arch A Pathol Anat Histopathol. 1985;405:411-427. [Medline] [Order article via Infotrieve]

31. van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation. 1994;89:36-44. [Abstract/Free Full Text]

32. Steinberg D, Witztum JL. Lipoproteins and atherogenesis: current concepts. JAMA. 1990;264:3047-3052. [Abstract/Free Full Text]

33. Henney AM, Wakeley PR, Davies MJ, Foster K, Hembry R, Murphy G, Humphries S. Localization of stromelysin gene expression in atherosclerotic plaques by in situ hybridization. Proc Natl Acad Sci U S A. 1991;88:8154-8158. [Abstract/Free Full Text]

34. Nobuyoshi M, Tanaka M, Nosaka H, Kimura T, Yokoi H, Hamasaki N, Kim K, Shindo T, Kimura K. Progression of coronary atherosclerosis: is coronary spasm related to progression? J Am Coll Cardiol. 1991;18:904-910. [Abstract]

35. Ku DN, Giddens DP, Zarins CK, Glagov S. Pulsatile flow and atherosclerosis in the human carotid bifurcation: positive correlation between plaque location and low oscillating shear stress. Arteriosclerosis. 1985;5:293-302. [Abstract/Free Full Text]

36. Davies MJ, Richardson PD, Woolf N, Katz DR, Mann J. Risk of thrombosis in human atherosclerotic plaques: role of extracellular lipid, macrophage, and smooth muscle cell content. Br Heart J. 1993;69:377-381. [Abstract/Free Full Text]

37. Paterson JC. Vascularization and hemorrhage of the intima of arteriosclerotic coronary arteries. Arch Pathol. 1936;22:313-324.

38. Barger AC, Beeuwkes R III, Lainey LL, Silverman KJ. Hypothesis: vasa vasorum and neovascularization of human coronary arteries—a possible role in the pathophysiology of atherosclerosis. N Engl J Med. 1984;310:175-177. [Medline] [Order article via Infotrieve]

39. Beeuwkes R III, Barger AC, Silverman KJ, Lainey LL. Cinemicrographic studies of the vasa vasorum of human coronary arteries. In: Glagov S, Newman WP, Schaffer SA, eds. Pathobiology of the Human Atherosclerotic Plaque. New York, NY: Springer-Verlag; 1990:425-432.

40. Chandler AB, Pope JT. Arterial thrombosis in atherogenesis: a survey of the frequency of incorporation of thrombi into atherosclerotic plaques. In: Hautvast JGAJ, Hermus RJJ, Van der Haar F, eds. Blood and Arterial Wall in Atherogenesis and Arterial Thrombosis. IFMA Scientific Symposia No. 4. Leiden, Netherlands: EJ Brill; 1975:112-118.

41. Yin J, Stary HC. Differences in thrombosis and composition of advanced atherosclerotic lesions between natives and non-natives of Alaska. FASEB J. 1994;8:A268. Abstract.

42. Woolf N, Crawford T, ed. Pathology of Atherosclerosis. London, England: Butterworth & Co Publishers Ltd; 1982.

43. Bini A, Fenoglio JJ Jr, Mesa-Tejada R, Kudryk B, Kaplan KL. Identification and distribution of fibrinogen, fibrin, and fibrin(ogen) degradation products in atherosclerosis: use of monoclonal antibodies. Arteriosclerosis. 1989;9:109-121. [Abstract/Free Full Text]

44. Taeymans Y, Theroux P, Lesperance J, Waters D. Quantitative angiographic morphology of the coronary artery lesions at risk of thrombotic occlusion. Circulation. 1992;85:78-85. [Abstract/Free Full Text]

45. Meade TW, North WR, Chakrabarti R, Stirling Y, Haines AP, Thompson SG, Brozovie M. Haemostatic function and cardiovascular death: early results of a prospective study. Lancet. 1980;1:1050-1054. [Medline] [Order article via Infotrieve]

46. Yarnell JW, Baker IA, Sweetnam PM, Bainton D, O'Brien JR, Whitehead PJ, Elwood PC. Fibrinogen, viscosity, and white blood cell count are major risk factors for ischemic heart disease: the Caerphilly and Speedwell collaborative heart disease studies. Circulation. 1991;83:836-844. [Abstract/Free Full Text]

47. Moller L, Kristensen TS. Plasma fibrinogen and ischemic heart disease risk factors. Arterioscler Thromb. 1991;11:344-350. [Abstract/Free Full Text]

48. Tracy RP, Bovill EG. Thrombosis and cardiovascular risk in the elderly. Arch Pathol Lab Med. 1992;116:1307-1312. [Medline] [Order article via Infotrieve]

49. Ernst E. The role of fibrinogen as a cardiovascular risk factor. Atherosclerosis. 1993;100:1-12. [Medline] [Order article via Infotrieve]

50. Aviram M, Brook JG. Platelet activation by plasma lipoproteins. Prog Cardiovasc Dis. 1987;30:61-72. [Medline] [Order article via Infotrieve]

51. Brook JG, Aviram M. Platelet lipoprotein interactions. Semin Thromb Hemost. 1988;14:258-265. [Medline] [Order article via Infotrieve]

52. Betteridge J. Nutrition and platelet function in atherogenesis. Proc Nutr Soc. 1987;46:345-359. [Medline] [Order article via Infotrieve]

53. Miller GJ. Hemostasis and cardiovascular risk: the British and European experience. Arch Pathol Lab Med. 1992;116:1318-1321. [Medline] [Order article via Infotrieve]

54. Loscalzo J. Lipoprotein(a): a unique risk factor for atherothrombotic disease. Arteriosclerosis. 1990;10:672-679. [Free Full Text]

55. Scanu AM. Lp(a) as a marker for coronary heart disease risk. Clin Cardiol. 1991;14(suppl I):I-35-I-39.

56. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:801-809. [Medline] [Order article via Infotrieve]

57. DiCorleto PE, Bowen-Pope DF. Cultured endothelial cells produce a platelet-derived growth factor-like protein. Proc Natl Acad Sci U S A. 1983;80:1919-1923. [Abstract/Free Full Text]

58. Marcus AJ, Hajjar DP. Vascular transcellular signaling. J Lipid Res. 1993;34:2017-2031. [Abstract]

59. Pomerantz KB, Hajjar DP. Eicosanoids in regulation of arterial smooth muscle cell phenotype, proliferative capacity, and cholesterol metabolism. Arteriosclerosis. 1989;9:413-429. [Free Full Text]

60. Dobrin PB, Baker WH, Gley WC. Elastolytic and collagenolytic studies of arteries: implications for the mechanical properties of aneurysms. Arch Surg. 1984;119:405-409. [Abstract/Free Full Text]

61. Tilson MD. Status of research on abdominal aortic aneurysm disease. J Vasc Surg. 1989;9:367-369. [Medline] [Order article via Infotrieve]

62. Langille BL, O'Donnell F. Reductions in arterial diameter produced by chronic decreases in blood flow are endothelium-dependent. Science. 1986;231:405-407. [Abstract/Free Full Text]

63. Zatina MA, Zarins CK, Gewertz BL, Glagov S. Role of medial lamellar architecture in the pathogenesis of aortic aneurysms. J Vasc Surg. 1984;1:442-448. [Medline] [Order article via Infotrieve]

64. Bomberger RA, Zarins CK, Glagov S. Medial injury and hyperlipidemia in development of aneurysms or atherosclerotic plaques. Surg Forum. 1980;31:338-340.

65. Aschoff L. Lectures on Pathology. New York, NY: Paul B Hoeber, Inc; 1924.

66. Aschoff L. Die arteriosklerose. Mediz Klinik. 1930;(suppl 1):1-20.

67. Aschoff L. Introduction. In: Cowdry EV, ed. Arteriosclerosis: A Survey of the Problem. New York, NY: Macmillan Publishing Co; 1933:1-18.

68. Gore I, Tejada C. The quantitative appraisal of atherosclerosis. Am J Pathol. 1957;33:875-885.

69. Holman RL, McGill HC Jr, Strong JP, Geer JC. Techniques for studying atherosclerotic lesions. Lab Invest. 1958;7:42-47. [Medline] [Order article via Infotrieve]

70. World Health Organization. Classification of atherosclerotic lesions: report of a study group. WHO Techn Rep Ser. 1958;143:1-20.

71. Davies MJ. Colour Atlas of Cardiovascular Pathology. London, England: Harvey Miller Publishers; 1986:73.

72. Nabel EG, Selwyn AP, Ganz P. Large coronary arteries in humans are responsive to changing blood flow: an endothelium-dependent mechanism that fails in patients with atherosclerosis. J Am Coll Cardiol. 1990;16:349-356. [Abstract]

73. Litt AW, Eidelman EM, Pinto RS, Riles TS, McLachlan SJ, Schwartzenberg S, Weinreb JC, Kricheff II. Diagnosis of carotid artery stenosis: comparison of 2DFT time-of-flight MR angiography with contrast angiography in 50 patients. AJNR Am J Neuroradiol. 1991;12:149-154. [Abstract]

74. Arlart IP, Guhl L, Edelman RR. Magnetic resonance angiography of the abdominal aorta. Cardiovasc Intervent Radiol. 1992;15:43-50. [Medline] [Order article via Infotrieve]

75. Siegel RJ, Ariani M, Fishbein MC, Chae JS, Park JC, Maurer G, Forrester JS. Histopathologic validation of angioscopy and intravascular ultrasound. Circulation. 1991;84:109-117. [Abstract/Free Full Text]

76. Janowitz WR, Agatston AS, Kaplan G, Viamonte M Jr. Differences in prevalence and extent of coronary artery calcium detected by ultrafast computed tomography in asymptomatic men and women. Am J Cardiol. 1993;72:247-254. [Medline] [Order article via Infotrieve]

77. Pearlman JD, Zajicek J, Merickel MB, Carman CS, Ayers CR, Brookeman JR, Brown MF. High-resolution 1H NMR spectral signature from human atheroma. Magn Reson Med. 1988;7:262-279. [Medline] [Order article via Infotrieve]

78. Miller DD, Rivera FJ, Garcia OJ, Palmaz JC, Berger HJ, Weisman HF. Imaging of vascular injury with 99mTc-labeled monoclonal antiplatelet antibody S12: preliminary experience in human percutaneous transluminal angioplasty. Circulation. 1992;85:1354-1363. [Abstract/Free Full Text]

79. Lees RS, Lees AM, Strauss HW. External imaging of human atherosclerosis. J Nucl Med. 1983;24:154-156. [Abstract/Free Full Text]

80. Virgolini I, O'Grady J, Lupattelli G, Rauscha F, Angelberger P, Ventura S, Sinzinger H. In vivo quantification of cholesterol content in human carotid arteries by quantitative gamma-camera imaging after injection of autologous low density lipoproteins (LDL). Int J Radiol Appl Instrum (B). 1992;19:245-250.

81. Virgolini I, Muller C, Fitscha P, Chiba P, Sinzinger H. Radiolabelling autologous monocytes with 111-indium-oxine for reinjection in patients with atherosclerosis. Prog Clin Biol Res. 1990;355:271-280. [Medline] [Order article via Infotrieve]

82. Tobis JM, Mallery J, Mahon D, Lehmann K, Zalesky P, Griffith J, Gessert J, Moriuchi M, McRae M, Dwyer ML, Greep N, Henry WL. Intravascular ultrasound imaging of human coronary arteries in vivo: analysis of tissue characterizations with comparison to in vitro histological specimens. Circulation. 1991;83:913-926. [Abstract/Free Full Text]

83. St. Goar FG, Pinto FJ, Alderman EL, Valantine HA, Schroeder JS, Gao SZ, Stinson EB, Popp RL. Intracoronary ultrasound in cardiac transplant recipients: in vivo evidence of angiographically silent intimal thickening. Circulation. 1992;85:979-987. [Abstract/Free Full Text]

84. Wong ND, Kouwabunpat D, Vo AN, Detrano RC, Eisenberg H, Goel M, Tobis JM. Coronary calcium and atherosclerosis by ultrafast computed tomography in asymptomatic men and women: relation to age and risk factors. Am Heart J. 1994;127:422-430. [Medline] [Order article via Infotrieve]

85. Gould KL, Lipscomb K. Effects of coronary stenoses on coronary flow reserve and resistance. Am J Cardiol. 1974;34:48-55.[Medline] [Order article via Infotrieve]

86. Goldstein RA, Kirkeeide RL, Demer LL, Merhige M, Nishikawa A, Smalling RW, Mullani NA, Gould KL. Relation between geometric dimensions of coronary artery stenoses and myocardial perfusion reserve in man. J Clin Invest. 1987;79:1473-1478.

87. Zarins CK, Weisenberg E, Kolettis G, Stankunavicius R, Glagov S. Differential enlargement of artery segments in response to enlarging atherosclerotic plaques. J Vasc Surg. 1988;7:386-394. [Medline] [Order article via Infotrieve]

88. Nissen SE, Gurley JC, Grines CL, Booth DC, McClure R, Berk M, Fischer C, DeMaria AN. Intravascular ultrasound assessment of lumen size and wall morphology in normal subjects and patients with coronary artery disease. Circulation. 1991;84:1087-1099. [Abstract/Free Full Text]

89. Thomas AC, Davies MJ, Dilly S, Dilly N, Franc F. Potential errors in the estimation of coronary arterial stenosis from clinical arteriography with reference to the shape of the coronary arterial lumen. Br Heart J. 1986;55:129-139. [Abstract/Free Full Text]

90. Brown BG, Bolson E, Frimer M, Dodge HT. Quantitative coronary arteriography: estimation of dimensions, hemodynamic resistance, and atheroma mass of coronary artery lesions using the arteriogram and digital computation. Circulation. 1977;55:329-337. [Abstract/Free Full Text]

91. Markis JE, Joffe CD, Cohn PF, Feen DJ, Herman MV, Gorlin R. Clinical significance of coronary arterial ectasia. Am J Cardiol. 1976;37:217-222. [Medline] [Order article via Infotrieve]

92. Blankenhorn DH, Curry PJ. The accuracy of arteriography and ultrasound imaging for atherosclerosis measurement: a review. Arch Pathol Lab Med. 1982;106:483-489. [Medline] [Order article via Infotrieve]

93. Arnett EN, Isner JM, Redwood DR, Kent KM, Baker WP, Ackerstein H, Roberts WC. Coronary artery narrowing in coronary heart disease: comparison of cineangiographic and necropsy findings. Ann Intern Med. 1979;91:350-356.

94. Levin DC, Fallon JT. Significance of the angiographic morphology of localized coronary stenoses: histopathologic correlations. Circulation. 1982;66:316-320. [Abstract/Free Full Text]

95. Bresnahan DR, Davis JL, Holmes DR Jr, Smith HC. Angiographic occurrence and clinical correlates of intraluminal coronary artery thrombus: role of unstable angina. J Am Coll Cardiol. 1985;6:285-289. [Abstract]

96. Potkin BN, Bartorelli AL, Gessert JM, Neville RF, Almagor Y, Roberts WC, Leon MB. Coronary artery imaging with intravascular high-frequency ultrasound. Circulation. 1990;81:1575-1585. [Abstract/Free Full Text]

97. Pandian NG, Kreis A, Brockway B. Detection of intraarterial thrombus by intravascular high frequency two-dimensional ultrasound imaging: in vitro and in vivo studies. Am J Cardiol. 1990;65:1280-1283. [Medline] [Order article via Infotrieve]

98. Linker DT, Yock PG, Gronningsaether A, Johansen E, Angelsen BA. Analysis of backscattered ultrasound from normal and diseased arterial wall. Int J Card Imaging. 1989;4:177-185. [Medline] [Order article via Infotrieve]

99. Sherman CT, Litvack F, Grundfest W, Lee M, Hickey A, Chaux A, Kass R, Blanche C, Matloff J, Morgenstern L, Ganz W, Swan HJC, Forrester J. Coronary angioscopy in patients with unstable angina pectoris. N Engl J Med. 1986;315:913-919. [Abstract]

100. Johnson JM, Kennelly MM, Decesare D, Morgan S, Sparrow A. Natural history of asymptomatic carotid plaque. Arch Surg. 1985;120:1010-1012. [Abstract/Free Full Text]

101. Fuster V, Badimon L, Cohen M, Ambrose JA, Badimon JJ, Chesebro J. Insights into the pathogenesis of acute ischemic syndromes. Circulation. 1988;77:1213-1220. [Free Full Text]

102. Falk E. Unstable angina with fatal outcome: dynamic coronary thrombosis leading to infarction and/or sudden death—autopsy evidence of recurrent mural thrombosis with peripheral embolization culminating in total vascular occlusion. Circulation. 1985;71:699-708. [Abstract/Free Full Text]

103. Ambrose JA, Winters SL, Arora RR, Eng A, Riccio A, Gorlin R, Fuster V. Angiographic evolution of coronary artery morphology in unstable angina. J Am Coll Cardiol. 1986;7:472-478. [Abstract]

104. Little WC, Constantinescu M, Applegate RJ, Kutcher MA, Burrows MT, Kahl FR, Santamore WP. Can coronary angiography predict the site of a subsequent myocardial infarction in patients with mild-to-moderate coronary artery disease? Circulation. 1988;78:1157-1166. [Abstract/Free Full Text]

105. Ambrose JA, Winters SL, Stern A, Eng A, Teichholz LE, Gorlin R, Fuster V. Angiographic morphology and the pathogenesis of unstable angina pectoris. J Am Coll Cardiol. 1985;5:609-616. [Abstract]

106. Ellis S, Alderman EL, Cain K, Wright A, Bourassa M, Fisher L. Morphology of left anterior descending coronary territory lesions as a predictor of anterior myocardial infarction: a CASS Registry Study. J Am Coll Cardiol. 1989;13:1481-1491. [Abstract]

107. Hackett D, Davies G, Maseri A. Pre-existing coronary stenoses in patients with first myocardial infarction are not necessarily severe. Eur Heart J. 1988;9:1317-1323. [Abstract/Free Full Text]

108. Nakagawa S, Hanada Y, Koiwaya Y, Tanaka K. Angiographic features in the infarct-related artery after intracoronary urokinase followed by prolonged anticoagulation: role of ruptured atheromatous plaque and adherent thrombus in acute myocardial infarction in vivo. Circulation. 1988;78:1335-1344. [Abstract/Free Full Text]

109. Davies SW, Marchant B, Lyons JP, Timmis AD, Rothman MT, Layton CA, Balcon R. Irregular coronary lesion morphology after thrombolysis predicts early clinical instability. J Am Coll Cardiol. 1991;18:669-674. [Abstract]

110. Webster MSI, Chesebro JH, Smoth HC, et al. Myocardial infarction and coronary artery occlusion: a prospective 5-year angiographic study. J Am Coll Cardiol. 1990;15(suppl):218A. Abstract.

111. Kragel AH, Gertz SD, Roberts WC. Morphologic comparison of frequency and types of acute lesions in the major epicardial coronary arteries in unstable angina pectoris, sudden coronary death and acute myocardial infarction. J Am Coll Cardiol. 1991;18:801-808. [Abstract]

112. Fuster V, Frye RL, Kennedy MA, Connolly DC, Mankin HT. The role of collateral circulation in the various coronary syndromes. Circulation. 1979;59:1137-1144. [Free Full Text]

113. Brown G, Albers JJ, Fisher LD, Schaefer SM, Lin JT, Kaplan C, Zhao XQ, Bisson BD, Fitzpatrick VF, Dodge HT. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med. 1990;323:1289-1298. [Abstract]

114. Brown BG, Zhao XQ, Sacco DE, Albers JJ. Lipid lowering and plaque regression: new insights into prevention of plaque disruption and clinical events in coronary disease. Circulation. 1993;87:1781-1791. [Abstract/Free Full Text]

115. Stary HC. The sequence of cell and matrix changes in atherosclerotic lesions of coronary arteries in the first forty years of life. Eur Heart J. 1990;11(suppl E):3-19.

116. Gown AM, Tsukada T, Ross R. Human atherosclerosis, II: immunocytochemical analysis of the cellular composition of human atherosclerotic lesions. Am J Pathol. 1986;125:191-207. [Abstract]

117. Timpl R, Dziadek M. Structure, development, and molecular pathology of basement membranes. Int Rev Exp Pathol. 1986;29:1-112. [Medline] [Order article via Infotrieve]

118. Kurkinen M, Vaheri A, Roberts PJ, Stenman S. Sequential appearance of fibronectin and collagen in experimental granulation tissue. Lab Invest. 1980;43:47-51. [Medline] [Order article via Infotrieve]

119. Murata K, Motayama T, Kotake C. Collagen types in various layers of the human aorta and their changes with the atherosclerotic process. Atherosclerosis. 1986;60:251-262. [Medline] [Order article via Infotrieve]

120. Shekhonin BV, Domogatsky SP, Idelson GL, Koteliansky VE, Rukosuev VS. Relative distribution of fibronectin and type I, III, IV, V collagens in normal and atherosclerotic intima of human arteries. Atherosclerosis. 1987;67:9-16. [Medline] [Order article via Infotrieve]

121. Nelken NA, Coughlin SR, Gordon D, Wilcox JN. Monocyte chemoattractant protein-1 in human atheromatous plaques. J Clin Invest. 1991;88:1121-1127.

122. Barath P, Fishbein MC, Cao J, Berenson J, Helfant RH, Forrester JS. Detection and localization of tumor necrosis factor in human atheroma. Am J Cardiol. 1990;65:297-302. [Medline] [Order article via Infotrieve]

123. Liptay MJ, Parks WC, Mecham RP, Roby J, Kaiser LR, Cooper JD, Botney MD. Neointimal macrophages colocalize with extracellular matrix gene expression in human atherosclerotic pulmonary arteries. J Clin Invest. 1993;91:588-594.

124. Mitchinson MJ, Hothersall DC, Brooks PN, De Burbure CY. The distribution of ceroid in human atherosclerosis. J Pathol. 1985;145:177-183. [Medline] [Order article via Infotrieve]

125. Rosenfeld ME, Ross R. Macrophage and smooth muscle cell proliferation in atherosclerotic lesions of WHHL and comparably hypercholesterolemic fat-fed rabbits. Arteriosclerosis. 1990;10:680-687. [Abstract/Free Full Text]

126. Ball RY, Stowers EC, Burton JH, Cary NRB, Skepper JN, Mitchinson MJ. Evidence that the death of macrophage foam cells contributes to the lipid core of atheroma. Atherosclerosis. 1995;114:45-54.[Medline] [Order article via Infotrieve]

127. Palinski W, Rosenfeld ME, Yla-Herttuala S, Gurtner GC, Socher SS, Butler SW, Parthasarathy S, Carew TE, Steinberg D, Witztum JL. Low density lipoprotein undergoes oxidative modification in vivo. Proc Natl Acad Sci U S A. 1989;86:1372-1376. [Abstract/Free Full Text]

128. Salonen JT, Yla-Herttuala S, Yamamoto R, Butler S, Korpela H, Salonen R, Nyyssonen K, Palinski W, Witztum JL. Autoantibody against oxidised LDL and progression of carotid atherosclerosis. Lancet. 1992;339:883-887. [Medline] [Order article via Infotrieve]

129. Kuo CC, Shor A, Campbell LA, Fukushi H, Patton DL, Grayston JT. Demonstration of Chlamydia pneumoniae in atherosclerotic lesions of coronary arteries. J Infect Dis. 1993;167:841-849. [Medline] [Order article via Infotrieve]

130. Schmitz G, Muller G. Structure and function of lamellar bodies, lipid-protein complexes involved in storage and secretion of cellular lipids. J Lipid Res. 1991;32:1539-1570. [Abstract]

131. Guyton JR, Klemp KF. The lipid-rich core region of human atherosclerotic fibrous plaques: prevalence of small lipid droplets and vesicles by electron microscopy. Am J Pathol. 1989;134:705-717. [Abstract]

132. Guyton JR, Klemp KF. Development of the atherosclerotic core region: chemical and ultrastructural analysis of microdissected atherosclerotic lesions from human aorta. Arterioscler Thromb. 1994;14:1305-1314. [Abstract/Free Full Text]

133. Smith EB, Smith RH. Early changes in aortic intima. In: Paoletti R, Gotto AM, eds. Atherosclerosis Reviews. New York, NY: Raven Press; 1976;1:119-236.

134. Vogel KG, Paulsson M, Heinegard D. Specific inhibition of type I and type II collagen fibrillogenesis by the small proteoglycan of tendon. Biochem J. 1984;223:587-597. [Medline] [Order article via Infotrieve]

135. Schmidt A, Yoshida K, Buddecke E. The antiproliferative activity of arterial heparan sulfate resides in domains enriched with 2-0-sulfated uronic acid residues. J Biol Chem. 1992;267:19242-19247. [Abstract/Free Full Text]

136. Turnbull JE, Fernig DG, Ke Y, Wilkinson MC, Gallagher JT. Identification of the basic fibroblast growth factor binding sequence in fibroblast heparan sulfate. J Biol Chem. 1992;267:10337-10341. [Abstract/Free Full Text]

137. Tyrrell DJ, Ishihara M, Rao N, Horne A, Kiefer MC, Stauber GB, Lam LH, Stack RJ. Structure and biological activities of a heparin-derived hexasaccharide with high affinity for basic fibroblast growth factor. J Biol Chem. 1993;268:4684-4689. [Abstract/Free Full Text]

138. Parthasarathy N, Goldberg IJ, Sivaram P, Mulloy B, Flory DM, Wagner WD. Oligosaccharide sequences of endothelial cell surface heparan sulfate proteoglycan with affinity for lipoprotein lipase. J Biol Chem. 1994;269:22391-22396. [Abstract/Free Full Text]

139. Rosenberg RD. Role of heparin and heparinlike molecules in thrombosis and atherosclerosis. Fed Proc. 1985;44:404-409. [Medline] [Order article via Infotrieve]

140. Stevens RL, Colombo M, Gonzales JJ, Hollander W, Schmid K. The glycosaminoglycans of the human artery and their changes in atherosclerosis. J Clin Invest. 1976;58:470-481.

141. Tammi M, Seppala PO, Lehtonen A, Mottonen M. Connective tissue components in normal and atherosclerotic human coronary arteries. Atherosclerosis. 1978;29:191-194. [Medline] [Order article via Infotrieve]

142. Iverius PH. The interaction between human plasma lipoproteins and connective tissue glycosaminoglycans. J Biol Chem. 1972;247:2607-2613. [Abstract/Free Full Text]

143. Camejo G, Olofsson SO, Lopez F, Carlsson P, Bondjers G. Identification of apo B-100 segments mediating the interaction of low density lipoproteins with arterial proteoglycans. Arteriosclerosis. 1988;8:368-377. [Abstract/Free Full Text]

144. Vijayagopal P, Srinivasan SR, Jones KM, Radhakrishnamurthy B, Berenson GS. Complexes of low-density lipoproteins and arterial proteoglycan aggregates promote cholesteryl ester accumulation in mouse macrophages. Biochim Biophys Acta. 1985;837:251-261. [Medline] [Order article via Infotrieve]

145. Camejo G, Hurt-Camejo E, Rosengren B, Wiklund O, Lopez F, Bondjers G. Modification of copper-catalyzed oxidation of low density lipoprotein by proteoglycans and glycosaminoglycans. J Lipid Res. 1991;32:1983-1991. [Abstract]

146. Wagner WD, Salisbury GJ, Rowe HA. A proposed structure of chondroitin 6-sulfate proteoglycan of human normal and adjacent atherosclerotic plaque. Arteriosclerosis. 1986;6:407-417. [Abstract/Free Full Text]

147. Wagner WD, Hardingham TE, Edwards I. Decreased amount and size of artery chondroitin sulfate proteoglycan-hyaluronic acid aggregate in atherosclerosis. Arteriosclerosis. 1983;3:471a. Abstract.

148. Register TC, Wagner WD. Heterogeneity in glycosylation of dermatan sulfate proteoglycan core proteins isolated from human aorta. Connect Tissue Res. 1990;25:35-48. [Medline] [Order article via Infotrieve]

149. Bertelsen S. Chemical studies on the arterial wall in relation to atherosclerosis. Ann N Y Acad Sci. 1968;149:643-654. [Medline] [Order article via Infotrieve]

150. Levene CI, Poole JCF. The collagen content of normal and atherosclerotic human aortic intima. Br J Exp Pathol. 1962;43:469-471. [Medline] [Order article via Infotrieve]

151. Smith EB. The influence of age and atherosclerosis on the chemistry of aortic intima, 1: the lipids. J Atheroscler Res. 1965;5:224-240; 241-248.

152. Miller EJ, Furuto DK, Narkates AJ. Quantitation of type I, III, and V collagens in human tissue samples by high performance liquid chromatography of selected cyanogen bromide peptides. Anal Biochem. 1991;196:54-60. [Medline] [Order article via Infotrieve]

153. McCullagh KA, Balian G. Collagen characterisation and cell transformation in human atherosclerosis. Nature. 1975;258:73-75. [Medline] [Order article via Infotrieve]

154. Ooshima A. Collagen alpha B chain: increased proportion in human atherosclerosis. Science. 1981;213:666-668. [Abstract/Free Full Text]

155. Morton LF, Barnes MJ. Collagen polymorphism in the normal and diseased blood vessel wall: investigation of collagen types I, III, and V. Atherosclerosis. 1982;42:41-51. [Medline] [Order article via Infotrieve]

156. Rekhter MD, Zhang K, Narayanan AS, Phan S, Schork MA, Gordon D. Type I collagen gene expression in human atherosclerosis: localization to specific plaque regions. Am J Pathol. 1993;143:1634-1648. [Abstract]

157. Stenn KS, Madri JA, Roll FJ. Migrating epidermis produces AB2 collagen and requires continual collagen synthesis for movement. Nature. 1979;277:229-232. [Medline] [Order article via Infotrieve]

158. Madri JA, Dreyer B, Pitlick FA, Furthmayr H. The collagenous components of the subendothelium: correlation of structure and function. Lab Invest. 1980;43:303-315. [Medline] [Order article via Infotrieve]

159. Roberts AB, Sporn MB, Assoian RK, Smith JM, Roche NS, Wakefield LM, Heine UI, Liotta LA, Falanga V, Kehrl JH, Fauci AS. Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci U S A. 1986;83:4167-4171. [Abstract/Free Full Text]

160. Ignotz RA, Massague J. Transforming growth factor-beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J Biol Chem. 1986;261:4337-4345. [Abstract/Free Full Text]

161. Guantieri V, Tamburro AM, Gordini DD. Interactions of human and bovine elastins with lipids: their proteolysis by elastase. Connect Tissue Res. 1983;12:79-83. [Medline] [Order article via Infotrieve]

162. Chaudiere J, Derouette JC, Mendy F, Jacotot B, Robert L. In vitro preparation of elastin-triglyceride complexes: fatty acid uptake and modification of the susceptibility to elastase action. Atherosclerosis. 1980;36:183-194. [Medline] [Order article via Infotrieve]

163. Saulnier JM, Hauck M, Fulop T Jr, Wallach JM. Human aortic elastin from normal individuals and atherosclerotic patients: lipid and cation contents; susceptibility to elastolysis. Clin Chim Acta. 1991;200:129-136. [Medline] [Order article via Infotrieve]

164. Bernier F, Bakala H, Wallach J. Effect of Mg²⁺ and Ca²⁺ on enzymatic elastolysis of insoluble elastin determined by a conductimetric method. Connect Tissue Res. 1981;8:71-75. [Medline] [Order article via Infotrieve]

165. Senior RM, Griffin GL, Mecham RP. Chemotactic activity of elastin-derived peptides. J Clin Invest. 1980;66:859-862.

166. Kramsch DM, Franzblau C, Hollander W. The protein and lipid composition of arterial elastin and its relationship to lipid accumulation in the atherosclerotic plaque. J Clin Invest. 1971;50:1666-1677.

167. Keeley FW, Partridge SM. Amino acid composition and calcification of human aortic elastin. Atherosclerosis. 1974;19:287-296. [Medline] [Order article via Infotrieve]

168. Robert L, Poullain N. Etudes sur la structure de l'elastine et le mode d'action de l'elastase, I: nouvelle methode de preparation de derives solubles de l'elastine. Bull Soc Chim Biol (Paris). 1963;45:1317-1326. [Medline] [Order article via Infotrieve]

169. Jordan RE, Hewitt N, Lewis W, Kagan H, Franzblau C. Regulation of elastase-catalyzed hydrolysis of insoluble elastin by synthetic and naturally occurring hydrophobic ligands. Biochemistry. 1974;13:3497-3503. [Medline] [Order article via Infotrieve]

170. Yu SY. Calcification processes in atherosclerosis. Adv Exp Med Biol. 1974;43:403-425. [Medline] [Order article via Infotrieve]

171. Schmid K, McSharry WO, Pameijer CH, Binette JP. Chemical and physicochemical studies on the mineral deposits of the human atherosclerotic aorta. Atherosclerosis. 1980;37:199-210. [Medline] [Order article via Infotrieve]

172. Urry DW. Neutral sites for calcium ion binding to elastin and collagen: a charge neutralization theory for calcification and its relationship to atherosclerosis. Proc Natl Acad Sci U S A. 1971;68:810-814. [Abstract/Free Full Text]

173. Kim KM. Calcification of matrix vesicles in human aortic valve and aortic media. Fed Proc. 1976;35:156-162. [Medline] [Order article via Infotrieve]

174. Shanahan CM, Weissberg PL, Metcalfe JC. Isolation of gene markers of differentiated and proliferating vascular smooth muscle cells. Circ Res. 1993;73:193-204.[Abstract]

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				D. W. Sommeijer, A. Beganovic, C. G. Schalkwijk, H. Ploegmakers, C. M. van der Loos, B. E. van Aken, H. ten Cate, and A. C. van der Wal More Fibrosis and Thrombotic Complications but Similar Expression Patterns of Markers for Coagulation and Inflammation in Symptomatic Plaques from DM2 Patients J. Histochem. Cytochem., September 1, 2004; 52(9): 1141 - 1149. [Abstract] [Full Text] [PDF]

				K. K. Henderson, J. R. Turk, J. W. E. Rush, and M. H. Laughlin Endothelial function in coronary arterioles from pigs with early-stage coronary disease induced by high-fat, high-cholesterol diet: effect of exercise J Appl Physiol, September 1, 2004; 97(3): 1159 - 1168. [Abstract] [Full Text] [PDF]

				N. Kalinina, A. Agrotis, Y. Antropova, O. Ilyinskaya, V. Smirnov, E. Tararak, and A. Bobik Smad Expression in Human Atherosclerotic Lesions: Evidence for Impaired TGF-{beta}/Smad Signaling in Smooth Muscle Cells of Fibrofatty Lesions Arterioscler. Thromb. Vasc. Biol., August 1, 2004; 24(8): 1391 - 1396. [Abstract] [Full Text] [PDF]

				U. J. Schoepf, C. R. Becker, B. M. Ohnesorge, and E. K. Yucel CT of Coronary Artery Disease Radiology, July 1, 2004; 232(1): 18 - 37. [Abstract] [Full Text] [PDF]

				J. Golledge, M. McCann, S. Mangan, A. Lam, and M. Karan Osteoprotegerin and Osteopontin Are Expressed at High Concentrations Within Symptomatic Carotid Atherosclerosis Stroke, July 1, 2004; 35(7): 1636 - 1641. [Abstract] [Full Text] [PDF]

				S. Bro, F. Moeller, C. B. Andersen, K. Olgaard, and L. B. Nielsen Increased Expression of Adhesion Molecules in Uremic Atherosclerosis in Apolipoprotein-E-Deficient Mice J. Am. Soc. Nephrol., June 1, 2004; 15(6): 1495 - 1503. [Abstract] [Full Text] [PDF]

				N. Stadler, R. A. Lindner, and M. J. Davies Direct Detection and Quantification of Transition Metal Ions in Human Atherosclerotic Plaques: Evidence for the Presence of Elevated Levels of Iron and Copper Arterioscler. Thromb. Vasc. Biol., May 1, 2004; 24(5): 949 - 954. [Abstract] [Full Text]

				A. M. Troen, E. Lutgens, D. E. Smith, I. H. Rosenberg, and J. Selhub The atherogenic effect of excess methionine intake PNAS, December 9, 2003; 100(25): 15089 - 15094. [Abstract] [Full Text] [PDF]

				T. T. Tuomisto, A. Korkeela, J. Rutanen, H. Viita, J. H. Brasen, M. S. Riekkinen, T. T. Rissanen, K. Karkola, Z. Kiraly, K. Kolble, et al. Gene Expression in Macrophage-Rich Inflammatory Cell Infiltrates in Human Atherosclerotic Lesions as Studied by Laser Microdissection and DNA Array: Overexpression of HMG-CoA Reductase, Colony Stimulating Factor Receptors, CD11A/CD18 Integrins, and Interleukin Receptors Arterioscler. Thromb. Vasc. Biol., December 1, 2003; 23(12): 2235 - 2240. [Abstract] [Full Text] [PDF]

				D. de Kleijn and G. Pasterkamp Toll-like receptors in cardiovascular diseases Cardiovasc Res, October 15, 2003; 60(1): 58 - 67. [Abstract] [Full Text] [PDF]

				E. K. Arkenbout, M. van Bragt, E. Eldering, C. van Bree, J. M. Grimbergen, P. H.A. Quax, H. Pannekoek, and C. J.M. de Vries TR3 Orphan Receptor Is Expressed in Vascular Endothelial Cells and Mediates Cell Cycle Arrest Arterioscler. Thromb. Vasc. Biol., September 1, 2003; 23(9): 1535 - 1540. [Abstract] [Full Text] [PDF]

				T. Q. Nhan, W. C. Liles, A. Chait, J. T. Fallon, and S. M. Schwartz The p17 Cleaved Form of Caspase-3 Is Present Within Viable Macrophages In Vitro and in Atherosclerotic Plaque Arterioscler. Thromb. Vasc. Biol., July 1, 2003; 23(7): 1276 - 1282. [Abstract] [Full Text] [PDF]

				R. E. Murphy, A. R. Moody, P. S. Morgan, A. L. Martel, G.S. Delay, S. Allder, S. T. MacSweeney, W. G. Tennant, J. Gladman, J. Lowe, et al. Prevalence of Complicated Carotid Atheroma as Detected by Magnetic Resonance Direct Thrombus Imaging in Patients With Suspected Carotid Artery Stenosis and Previous Acute Cerebral Ischemia Circulation, June 24, 2003; 107(24): 3053 - 3058. [Abstract] [Full Text] [PDF]

				L. M. Belalcazar, A. Merched, B. Carr, K. Oka, K.-H. Chen, L. Pastore, A. Beaudet, and L. Chan Long-Term Stable Expression of Human Apolipoprotein A-I Mediated by Helper-Dependent Adenovirus Gene Transfer Inhibits Atherosclerosis Progression and Remodels Atherosclerotic Plaques in a Mouse Model of Familial Hypercholesterolemia Circulation, June 3, 2003; 107(21): 2726 - 2732. [Abstract] [Full Text] [PDF]

				M.E. Kooi, V.C. Cappendijk, K.B.J.M. Cleutjens, A.G.H. Kessels, P.J.E.H.M. Kitslaar, M. Borgers, P.M. Frederik, M.J.A.P. Daemen, and J.M.A. van Engelshoven Accumulation of Ultrasmall Superparamagnetic Particles of Iron Oxide in Human Atherosclerotic Plaques Can Be Detected by In Vivo Magnetic Resonance Imaging Circulation, May 20, 2003; 107(19): 2453 - 2458. [Abstract] [Full Text] [PDF]

				V. de Waard, T. A.E. van Achterberg, N. J. Beauchamp, H. Pannekoek, and C. J.M. de Vries Cardiac Ankyrin Repeat Protein (CARP) Expression in Human and Murine Atherosclerotic Lesions: Activin Induces Carp in Smooth Muscle Cells Arterioscler. Thromb. Vasc. Biol., January 1, 2003; 23(1): 64 - 68. [Abstract] [Full Text] [PDF]

				S. de Jongh, M. R. Lilien, J. op't Roodt, E. S. G. Stroes, H. D. Bakker, and J. J. P. Kastelein Early statin therapy restores endothelial function in children with familial hypercholesterolemia J. Am. Coll. Cardiol., December 18, 2002; 40(12): 2117 - 2121. [Abstract] [Full Text] [PDF]

				T. Naruko, M. Ueda, K. Haze, A. C. van der Wal, C. M. van der Loos, A. Itoh, R. Komatsu, Y. Ikura, M. Ogami, Y. Shimada, et al. Neutrophil Infiltration of Culprit Lesions in Acute Coronary Syndromes Circulation, December 3, 2002; 106(23): 2894 - 2900. [Abstract] [Full Text] [PDF]

				M. Sandrock, D.-C. Cheng, D. Schmitz, and A. Schmidt-Trucksass Quantification of the Wall Inhomogeneity in B-mode Sonographic Images of the Carotid Artery J. Ultrasound Med., December 1, 2002; 21(12): 1395 - 1404. [Abstract] [Full Text] [PDF]

				H. Sun, H. Unoki, X. Wang, J. Liang, T. Ichikawa, Y. Arai, M. Shiomi, S. M. Marcovina, T. Watanabe, and J. Fan Lipoprotein(a) Enhances Advanced Atherosclerosis and Vascular Calcification in WHHL Transgenic Rabbits Expressing Human Apolipoprotein(a) J. Biol. Chem., November 27, 2002; 277(49): 47486 - 47492. [Abstract] [Full Text] [PDF]

				N. Kataoka, K. Iwaki, K. Hashimoto, S. Mochizuki, Y. Ogasawara, M. Sato, K. Tsujioka, and F. Kajiya Measurements of endothelial cell-to-cell and cell-to-substrate gaps and micromechanical properties of endothelial cells during monocyte adhesion PNAS, November 26, 2002; 99(24): 15638 - 15643. [Abstract] [Full Text] [PDF]

				C. R. Kiefer, J. B. McKenney, J. F. Trainor, and L. M. Snyder Maturation-Dependent Acquired Coronary Structural Alterations and Atherogenesis in the Dahl Sodium-Sensitive Hypertensive Rat Circulation, November 5, 2002; 106(19): 2486 - 2490. [Abstract] [Full Text] [PDF]

				C. Kluft, R. Kleemann, and M.P.M. de Maat How best to counteract the enemies? By controlling inflammation in the coronary circulation Eur. Heart J. Suppl., November 1, 2002; 4(suppl_G): G53 - G65. [Abstract] [PDF]

				R Ezzahiri, H.J.M.G Nelissen-Vrancken, H.A.J.M Kurvers, F.R.M Stassen, I Vliegen, G.E.L.M Grauls, M.M.L van Pul, P.J.E.H.M Kitslaar, and C.A Bruggeman Chlamydophila pneumoniae (Chlamydia pneumoniae) accelerates the formation of complex atherosclerotic lesions in Apo E3-Leiden mice Cardiovasc Res, November 1, 2002; 56(2): 269 - 276. [Abstract] [Full Text] [PDF]

				J.H.P. Lardenoye, M.R. de Vries, C.W.G.M. Lowik, Q. Xu, C.R. Dhore, J.P.M. Cleutjens, V.W.M. van Hinsbergh, J.H. van Bockel, and P.H.A. Quax Accelerated Atherosclerosis and Calcification in Vein Grafts: A Study in APOE*3 Leiden Transgenic Mice Circ. Res., October 4, 2002; 91(7): 577 - 584. [Abstract] [Full Text] [PDF]

				E. K. Arkenbout, V. de Waard, M. van Bragt, T. A.E. van Achterberg, J. M. Grimbergen, B. Pichon, H. Pannekoek, and C. J.M. de Vries Protective Function of Transcription Factor TR3 Orphan Receptor in Atherogenesis: Decreased Lesion Formation in Carotid Artery Ligation Model in TR3 Transgenic Mice Circulation, September 17, 2002; 106(12): 1530 - 1535. [Abstract] [Full Text] [PDF]

				P.J. Gallagher More histological information in acute coronary death Eur. Heart J., September 2, 2002; 23(18): 1406 - 1408. [Full Text] [PDF]

				G. Marsche, A. Hammer, O. Oskolkova, K. F. Kozarsky, W. Sattler, and E. Malle Hypochlorite-modified High Density Lipoprotein, a High Affinity Ligand to Scavenger Receptor Class B, Type I, Impairs High Density Lipoprotein-dependent Selective Lipid Uptake and Reverse Cholesterol Transport J. Biol. Chem., August 23, 2002; 277(35): 32172 - 32179. [Abstract] [Full Text] [PDF]

				H. C. McGill Jr, C. A. McMahan, E. E. Herderick, A. W. Zieske, G. T. Malcom, R. E. Tracy, J. P. Strong, and for the Pathobiological Determinants of Atheroscle Obesity Accelerates the Progression of Coronary Atherosclerosis in Young Men Circulation, June 11, 2002; 105(23): 2712 - 2718. [Abstract] [Full Text] [PDF]

				M. Van Eck, I. S. T. Bos, W. E. Kaminski, E. Orso, G. Rothe, J. Twisk, A. Bottcher, E. S. Van Amersfoort, T. A. Christiansen-Weber, W.-P. Fung-Leung, et al. Leukocyte ABCA1 controls susceptibility to atherosclerosis and macrophage recruitment into tissues PNAS, April 30, 2002; 99(9): 6298 - 6303. [Abstract] [Full Text] [PDF]

				K. Edfeldt, J. Swedenborg, G. K. Hansson, and Z.-q. Yan Expression of Toll-Like Receptors in Human Atherosclerotic Lesions: A Possible Pathway for Plaque Activation Circulation, March 12, 2002; 105(10): 1158 - 1161. [Abstract] [Full Text] [PDF]

				A. C. Terentis, S. R. Thomas, J. A. Burr, D. C. Liebler, and R. Stocker Vitamin E Oxidation in Human Atherosclerotic Lesions Circ. Res., February 22, 2002; 90(3): 333 - 339. [Abstract] [Full Text] [PDF]

				J. T.B. Crawley, D. A. Goulding, V. Ferreira, N. J. Severs, and F. Lupu Expression and Localization of Tissue Factor Pathway Inhibitor-2 in Normal and Atherosclerotic Human Vessels Arterioscler. Thromb. Vasc. Biol., February 1, 2002; 22(2): 218 - 224. [Abstract] [Full Text] [PDF]

				J. M. Upston, X. Niu, A. J. Brown, R. Mashima, H. Wang, R. Senthilmohan, A. J. Kettle, R. T. Dean, and R. Stocker Disease Stage-Dependent Accumulation of Lipid and Protein Oxidation Products in Human Atherosclerosis Am. J. Pathol., February 1, 2002; 160(2): 701 - 710. [Abstract] [Full Text] [PDF]

				A. P. Burke, F. D. Kolodgie, A. Farb, D. Weber, and R. Virmani Morphological Predictors of Arterial Remodeling in Coronary Atherosclerosis Circulation, January 22, 2002; 105(3): 297 - 303. [Abstract] [Full Text] [PDF]

				P. M. McCabe, J. A. Gonzales, J. Zaias, A. Szeto, M. Kumar, A. J. Herron, and N. Schneiderman Social Environment Influences the Progression of Atherosclerosis in the Watanabe Heritable Hyperlipidemic Rabbit Circulation, January 22, 2002; 105(3): 354 - 359. [Abstract] [Full Text] [PDF]

				A. J. Taylor, A. Bobik, M. C. Berndt, D. Ramsay, and G. Jennings Experimental Rupture of Atherosclerotic Lesions Increases Distal Vascular Resistance: A Limiting Factor to the Success of Infarct Angioplasty Arterioscler. Thromb. Vasc. Biol., January 1, 2002; 22(1): 153 - 160. [Abstract] [Full Text] [PDF]

				M. A Engelse, J. M Neele, A. L.J.J Bronckers, H. Pannekoek, and C. J.M de Vries Vascular calcification: expression patterns of the osteoblast-specific gene core binding factor {alpha}-1 and the protective factor matrix gla protein in human atherogenesis Cardiovasc Res, November 1, 2001; 52(2): 281 - 289. [Abstract] [Full Text] [PDF]

				R. S. Hundal, B. S. Salh, J. W. Schrader, A. Gomez-Munoz, V. Duronio, and U. P. Steinbrecher Oxidized low density lipoprotein inhibits macrophage apoptosis through activation of the PI 3-kinase/PKB pathway J. Lipid Res., September 1, 2001; 42(9): 1483 - 1491. [Abstract] [Full Text] [PDF]

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