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
Arteriosclerosis, Thrombosis, and Vascular Biology
Abstract
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).
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
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
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.
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.
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
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
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.
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
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
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
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.
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
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. Aschoff65 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 investigators68 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
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 lipoproteins79 80 and monocytes.81
Assessment of Presence and Extent of Lesions
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 atherosclerosis92 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
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
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-shaped20 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
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.
| Terms for Thicker but Histologically Normal Intimal Segments Present in All Humans From Birth | Other Terms for Identical (and Probably Identical) Intimal Structures |
|---|---|
| Adaptive intimal thickening | |
| Eccentric type (eccentric intimal thickening) | Intimal cushion, intimal pad, spindle cell cushion, smooth muscle mass, mucoid fibromuscular plaque, focal intimal hyperplasia |
| Diffuse type (diffuse intimal thickening) | Musculoelastic intimal thickening, intimal hyperplasia |
| Terms for Atherosclerotic Lesions in Histological Classification | Other Terms for the Same Lesions Often Based on Appearance With the Unaided Eye | ||
|---|---|---|---|
| Type I lesion | Initial lesion | Early lesions | |
| Type IIa lesion | Progression-prone type II lesion | Fatty dot or streak | |
| IIb | Progression-resistant type II | ||
| Type III lesion | Intermediate lesion (preatheroma) | ||
| Type IV lesion | Atheroma | Atheromatous plaque, | |
| Type Va lesion | Fibroatheroma (type V lesion) | fibrolipid plaque, | |
| fibrous plaque, plaque | |||
| Vb | Calcific lesion (type VII lesion) | Calcified plaque | Advanced lesions, |
| Vc | Fibrotic lesion (type VIII lesion) | Fibrous plaque | raised lesions |
| Type VI lesion | Lesion with surface defect, and/or hematoma-hemorrhage, and/or thrombotic deposit | Complicated lesion, complicated plaque | |
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.
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