33
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INTRODUCTION
The death rate from coronary artery disease has declined in
the past few decades through greater understanding of risk factors of coronary heart disease as well as through better treatment, including the creation of coronary care units. However,
because of the lack of an animal model of unstable plaque, our
understanding of atherosclerotic plaque morphology comes
only from static histology of lesion morphology in patients
dying of acute coronary syndromes (1). Although transgenic
models of atherosclerosis have markedly enhanced our understanding of certain aspects of plaque progression and regression, they have failed thus far to explain the relationship of the
coagulation parameters and plaque morphology that precipitate coronary thrombosis (1). Until we are able to create a better
model or study plaque morphology prospectively and determine the mechanisms and the anatomic markers of progression, we will make progress very slowly. This review is based
on examination of human coronary artery pathology in patients
dying a sudden coronary death, in order to ascertain the pathologic lesion morphologies that are linked to plaque progression
and thrombosis, which will be necessary for us to be able to
recognized by invasive or noninvasive means the prospective
lesions that are likely to produce symptoms.
CLASSIFICATION OF ATHEROSCLEROSIS
Our understanding of atherosclerosis has been enhanced by
the development of the various classifications that have come
from the insights of scientists like Virchow, who was a pioneer
in pathology. Systematic studies of lesion development,
described by the giants of atherosclerosis including Robert
Wissler, Herbert Stary (Table 1), Henry McGill, and Michael
Davies in the last century, have made enormous contributions
to the better understanding of early lesions, the influence of risk
factors on plaque progression, and the role of plaque rupture in
the occurrence of luminal thrombosis.
The cellular participants of atherosclerosis include smooth
muscle cells, endothelial cells, macrophages, T- and B-lymphocytes, red cells, platelets, neutrophils, and basophils. The
From: Contemporary Cardiology: CT of the Heart:
Principles and Applications
Edited by: U. Joseph Schoepf Humana Press, Inc., Totowa, NJ
351
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VIRMANI ET AL.
Table 1
Atherosclerotic Plaque Classifications
Virmani et al.
Initial
Early plaques
Intermediate plaque
Late lesions
Miscellaneous/
complicated features
Intimal thickening
None
Intimal xanthoma
None
Pathologic intimal
thickening
Fibrous cap atheroma
Thrombosis (erosion)
Thrombus (rupture)
Repeated rupture or erosion
with or without total
occlusion
Thrombosis (Erosion) a
Progression
Calcified nodule
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Fig. 1. Adaptive intimal thickening (A) and intimal xanthoma (B). Lesions uniformly present in all populations, although intimal xanthomas
are more prevalent with exposure to a Western diet. Intimal xanthomas are commonly produced in animal models; however, they usually do
not develop into progressive atherosclerotic lesions. Both lesions occur soon after birth; the intimal xanthoma (otherwise known as a fatty
streak) is known to regress. Intimal thickening consists mainly of smooth muscle cells in a proteoglycan-rich matrix, while intimal xanthomas
primarily contain macrophage-derived foam cells, T lymphocytes, and varying degrees of smooth muscle cells. Reproduced from ref. 1, with
permission.
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Fig. 2. Pathological intimal thickening (A) vs atheroma (B). Pathological intimal thickening is a poorly defined entity sometimes referred to
in the literature as an intermediate lesion. True necrosis is not apparent, and there is no evidence of cellular debris; some lipid may be present
deep in the lesion near the elastic lamina (EL), but it is dispersed. The fibrous cap overlying the areas of lipid is rich in smooth muscle cells
and proteoglycans. Some scattered macrophages and lymphocytes may also be present, but are usually sparse. The more definitive lesion or
fibrous cap atheroma classically shows a true necrotic core (NC), containing cholesterol esters, free cholesterol, phospholipids, and triglycerides. The fibrous cap consists of smooth muscle cells in a proteoglycan-collagenous matrix, with a variable number of macrophages and
lymphocytes. The media underneath the plaque is often thin. Reproduced from ref. 1, with permission.
Table 2
Approximate Sizes of Necrotic Core in Fibroatheroma, Thin Cap Atheroma, and Acute Rupture
Plaque type
Dimension
Length, mm, mean/range
Cross sectional area, mm2
% cross sectional area
Fibroatheroma
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Fig. 3. Morphologic variants of the thin-cap atheroma. Thin caps may emerge in fibroatheromas with insignificant plaque burden and insignificant luminal narrowing, in fibroatheromas with large cores that are eccentric or eccentric, and frequently in plaques with evidence of prior
rupture. (A) In this plaque with insignificant plaque burden, there is an area of proteoglycan-rich smooth muscle cells (arrowheads) suggestive
of a prior rupture, and multiple areas of thin caps (arrows). (B) The necrotic core (NC) is large, with an area of thinned cap (arrow). (C) The
necrotic core (NC) is concentric with an extensive area of cap thinning (arrow). (D) There may be a healed rupture (arrows) with a proteoglycanrich smooth muscle cell reparative layer (arrowhead).
Fig. 4. The distribution frequency of plaque ruptures (A,B) and thin-cap atheromas (C,D) by size of lipid core or lipid core as a percent of plaque
area (x axis). The majority of plaque ruptures occur when lipid core area forms 2550% of plaque area, or 13 mm 2 lipid core area. In the case
of thin-cap atheromas, the degree of cross-sectional area luminal narrowing and area of necrotic core is shifted to the left (lesser or smaller)
as compared to plaque ruptures. Reproduced from ref. 27, with permission.
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Fig. 5. Lesions with thrombi. Ruptured plaques are thin fibrous-cap atheromas with luminal thrombi (Th). These lesions usually have an
extensive necrotic core containing large numbers of cholesterol crystals, and a thin fibrous cap (<65 m) infiltrated by foamy macrophages
and a paucity of T-lymphocytes. The fibrous cap is thinnest at the site of rupture and consists of a few collagen bundles and rare smooth muscle
cells. The luminal thrombus is in communication with the lipid-rich necrotic core. Erosions occur over lesions rich in smooth muscle cells and
proteoglycans. Luminal thrombi overly areas lacking surface endothelium. The deep intima of the eroded plaque often shows extracellular lipid
pools, but necrotic cores are uncommon; when present, the necrotic core does not communicate with the luminal thrombus. Inflammatory
infiltrate is usually absent, but if present, it is sparse and consists of macrophages and lymphocytes. Calcified nodules are plaques with luminal
thrombi showing calcific nodules protruding into the lumen through a disrupted thin fibrous cap (FC). There is absence of endothelium at the
site of the thrombus, and inflammatory cells (macrophages, T-lymphocytes) are absent. Reproduced from ref. 1, with permission.
There are relatively few macrophages and lymphocytes adjacent to the thrombus in the majority of plaque erosions. Plaque
erosion accounts for 20% of all sudden coronary deaths and
35% of coronary thrombi in patients dying suddenly with coronary thrombosis (1,6). The mean age of patients dying with
plaque erosion is less than that of patients dying with acute
rupture, and there is less severe narrowing at sites of thrombosis in plaque erosion. Plaque erosion accounts for over 80% of
thrombi occurring in women less than 50 yr of age. The lesions
tend to be eccentric and are infrequently calcified (6). Plaque
erosions tend to embolize more frequently than plaque rupture (74%, vs 40%, respectively) (6). The risk factors for erosion are poorly understood; similar to acute rupture, there is an
increased risk among smokers, but there appears to be a lesser
association with dyslipidemia, as compared to plaque rupture.
The underlying plaque in erosions is generally pathologic intimal thickening or fibrous cap atheroma. The most frequent
location for both erosion and rupture is the proximal left anterior descending coronary artery (nearly two-thirds of patients)
followed by the right coronary artery and the left circumflex.
However, patients dying with plaque erosion frequently do not
have extensive disease, unlike patients dying with stable plaque
or plaque rupture. Over one-half of deaths are seen in patients
with single-vessel disease, and one-quarter with double-vessel
disease. The etiology of plaque erosion is poorly understood;
however, it is believed that coronary vasospasm may be
involved.
357
Fig. 6. Healed plaque rupture. (A) demonstrates areas of intraintimal lipid-rich core with hemorrhage and cholesterol clefts. (B) shows a higher
magnification of the looser smooth muscle cell formation within a collagenous proteoglycanrich neointima showing a clear demarcation with
the more fibrous regions of the old plaque to the right. (C) and (D) demonstrate the layers of collagen by Sirius red staining. (C), note the area
of dense dark red collagen surrounding the lipid hemorrhagic cores seen in corresponding view in panel A. (D) demonstrates an image taken
with polarized light. The dense collagen (Type 1) which forms the fibrous cap is lighter reddish-yellow and is disrupted (arrow), with the newer
greenish Type III collagen on the right and above the rupture site. (A and B, Movat pentachrome). Reproduced from ref. 28, with permission.
CALCIFIED NODULE
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VIRMANI ET AL.
PLAQUE HEMORRHAGE
Fig. 8. Healed erosion shows deep multilayering of collagen separated by elastin layers (arrowheads) and a paucity of smooth muscle
cells. The superficial plaque is rich in smooth muscle cells, collagen,
and proteoglycans.
intraplaque hemorrhage as identified by glycophorin A staining, a red-cell specific anion-exchange protein. In a recent study
of pulmonary artery atherosclerotic plaques by Arbustini et al.,
glycophorin A positive erythrocyte membranes were shown to
be a major component of the necrotic core in patients with
chronic thromboembolic pulmonary hypertension (19).
Rupture of vasa vasorum is not the sole etiology of
intraplaque hemorrhage. As Constantinides originally suggested, plaque hemorrhage may occur from cracks or fissures
originating from the lumen (20). Intraplaque hemorrhage,
whether from vasa vasorum or the lumen, may be critical to the
lesion progression, as it may provide a significant source of
nonmetabolic cholesterol (21).
CORONARY CALCIFICATION
In early coronary atherosclerotic plaques, coronary calcification is identified using sensitive histochemical stains, such as
the von Kossa stain. When such tests are applied to fatty streaks,
359
there is little if any calcium present. However, pathologic intimal thickening and fibrous plaques have a high propensity for
microscopic calcification, especially when there is evidence of
smooth muscle cell apoptosis. The biology of intimal calcification within atherosclerotic regions is complex, and involves
smooth muscle cell matrix vesicles (related to apoptotic bodies), bone-associated proteins, lipids, and inflammation in the
formation of extracellular intimal calcifications (22). Almost
all necrotic cores with apoptotic smooth muscle cells contain
calcification (at least 90%), and those cores with predominantly
macrophage infiltrates are less likely to initially calcify. The
nature of the calcifications differs by cell type, in that fibrous
cores contain finely granular calcifications, occasionally coalescing into masses, whereas macrophage necrotic cores
often contain larger crystalline deposits. Calcification of
fibrous plaques in which there is smooth muscle cell death
cores progresses to plate-like sheets of calcification and often
pipestem-like arteries. However, calcification of necrotic,
inflamed, macrophage-rich cores tends to be more irregular,
resulting in a radiographic appearance of irregular calcification. Ultrastructural study of coronary plaques will demonstrate
calcifications in close contact with dying smooth muscle cells,
macrophages, and surrounding cholesterol clefts (Fig. 10). In
less than 5% of plaques, actual ossification may occur, with
osteoblasts, osteoclasts, and even marrow formation (Fig. 11).
Calcification does not in itself appear to play a role in the
thrombotic process, except under the unusual circumstances of
nodular calcification. Successive ruptures or fissures of the
fibrous cap result in layering of the plaque, and the deeper
layers close to the internal elastic lamina typically demonstrate
more severe calcification than the surface layers.
We have performed quantitative analysis of calcified matrix
in intermediate and later plaque stages, including fibroatheromas, acute and healed plaque ruptures, total occlusions,
and plaque erosion. In contrast to rupture, plaque erosion does
not expose the contents of the necrotic core to the lumen. Eroded
plaques, perhaps partly as a function of their pathogenesis, do
not typically occur in calcified arteries, and demonstrate far
less calcified matrix than acute or healed ruptures. The degree
of calcification by plaque type is illustrated in Fig. 12.
The relationship between coronary plaque calcification and
plaque instability has been debated. Biomechanical studies
have calculated stress at different regions of the plaque. Mathematical models using large-strain finite element analysis have
shown that increased lipids are associated with areas of weakness of the fibrous cap, but not calcification (23). Although
calcification is a good marker for plaque burden, absolute calcium scores do not indicate plaques that are unstable or prone
to result in clinical events. It has been stated that calcification
is a disease marker as opposed to a process marker, unlike
markers of inflammation(24). These findings are corroborated
by autopsy studies that demonstrate a good correlation between
plaque size and morphometric analysis of calcification, but no
correlation between residual lumen and calcification (Table 3).
Few studies have correlated the radiologic pattern of calcification with plaque instability (25), but there is some suggestion
that speckled or fragmented calcification patterns as determined
radiologically are most likely associated with unstable plaque
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Fig. 9. Vasa vasorum within plaque. (A) At low magnification, there is thinning of the media with dilated spaces within the plaque. (B) A higher
magnification of the boxed area in (A) shows dilated channels to be blood vessels (arrows). (C) A higher magnification of the boxed area in
B shows a muscular artery feeder vessel traversing the media. (D) A different segment of near-total occlusion stained with Ulex europaeus lectin
highlighting neovessels brown within the adventitia and intima.
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361
Fig. 10. Ultrastructural images of coronary atherosclerotic plaques show extracellular calcifications adjacent to an apoptotic smooth muscle
cell (SMC) (A), spherical calcification associated with degenerating smooth muscle cell organelles (B), and small calcifications surrounding
cholesterol clefts in area of macrophage degeneration (C).
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362
VIRMANI ET AL.
Fig. 11. Ossification in coronary plaque. (A) demonstrates a low-magnification image of a coronary artery section (proximal left anterior
descending artery) in the left anterior descending coronary artery of an obese elderly woman with hypertensive atherosclerotic heart disease.
(A) is a low magnification of the cross-section of the artery; contrast material (black) was injected into the artery postmortem. (B) demonstrates
the bony trabeculae and (C) a higher magnification of lacunae containing osteoblasts.
363
Fig. 12. Amount of calcification by plaque morphology. Morphometric measurements were made of calcified matrix in several hundred
coronary lesions classified by plaque type. (A) Healed ruptures demonstrated the greatest mean area of calcification; plaque erosions demonstrate almost no calcification. (B) When expressed as a percentage of the plaque area, total occlusion and plaque ruptures have relatively
little calcium, and plaque erosions the least. Fibroatheroma and healed ruptures demonstrate the greatest amount of calcified matrix. Reproduced from ref. 13, with permission.
Table 3
Relationship Between Calcification
and % Luminal Narrowing and Residual Lumen, by Arterial Section
Artery
Men
LM
PLAD
MLAD
DLAD
LD
PLC
MLC
LOM
PRC
MRC
DRC
aT
bT
Calcified area vs
residual lumen area
(simple regression)
Women
ra
DF
ra
DF
rb
.20
.56
.45
.64
.59
.30
.02
.60
.12
.29
.32
.20
<.0001
<.0001
.0003
.001
.01
.90
.0001
.15
.001
.0004
30
122
91
27
26
78
35
34
143
127
116
.15
.15
.50
.31
.75
.25
.31
.72
.09
.63
.36
.59
.27
<.0001
.11
.0004
.07
.29
0.01
.54
<.0001
.06
14
53
66
24
17
51
13
11
54
68
27
.14
.07
.10
.18
.13
.11
.21
.13
.09
.09
.17
.58
.53
.29
28
.71
.32
.40
.30
.38
.37
.29
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VIRMANI ET AL.
Fig. 13. Relationship between plaque morphology and radiographic calcification. Plaque erosions (A) were exclusively present in areas with
stippled or no calcification. Plaque ruptures (B) were most frequently seen in areas of speckled calcification, but were also present in blocked
or diffuse calcification. Curiously, there were no ruptures in segments devoid of any calcification. Thin-capped atheromas were most frequently
present in areas of speckled calcification (C), but were also seen in heavily calcified or uncalcified areas, suggesting that calcification pattern
is not helpful in diagnosing these lesions. Healed ruptures are almost always seen in areas of calcification, and most frequently in diffusely
calcified areas (D). Reproduced from ref. 13, with permission.