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(Circulation. 1995;92:1355-1374.)
© 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
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Abstract |
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Top
Abstract
IntroductionAbstract 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
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Introduction |
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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
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Atherosclerotic Lesion Types Advanced by Histology |
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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.
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Type IV Lesions |
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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.
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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.
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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.
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Type V Lesions |
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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.
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Type VI Lesions |
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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.
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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
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Atherosclerotic Aneurysms |
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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.
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Recommended Histological Classification of Atherosclerotic Lesions |
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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.
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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.
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A Brief History of Classifications of Atherosclerosis in Pathology |
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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.
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Characterization of Atherosclerotic Lesions by Clinical Imaging |
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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
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Assessment of Presence and Extent of Lesions |
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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.
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Correlation of Lesion Types With Clinical Syndromes |
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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.
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The Cells and Extracellular Matrix of Histological Lesion Types IV, V, and VI |
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