© 1997 American Heart Association, Inc.
Articles |
Relation of Plaque Lipid Composition and Morphology to the Stability of Human Aortic Plaques
Correspondence to C.V. Felton, PhD, Wynn Department of Metabolic Medicine, 21 Wellington Rd, St John's Wood, London NW8 9SQ, United Kingdom.
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Abstract The propensity of atherosclerotic plaques to disrupt may be influenced by their lipid content and the distribution of these lipids within the plaque. To investigate this, we analyzed the morphological and lipid profiles of 668 human aortic plaques from 30 males who had died of ischemic heart disease. Plaques were classified as disrupted or as intact types A or B, the latter distinction being based on the absence or presence, respectively, of disrupted plaques within the same aorta. Disrupted plaques have a greater content of lipid (P<.001) and macrophages (P<.001) as well as a thinner cap (P<.001) than intact plaques. Lipid concentrations are positively associated with macrophage accumulation in all plaque types and are negatively associated with minimum cap thickness at the edge of disrupted plaques (P<.05). Free cholesterol concentration is inversely associated with minimum cap thickness at the center of type B plaques only (P<.05). At the center of intact type A and B and disrupted plaques, the free-to-esterified cholesterol ratios were 0.9 (range, 0.0 to 2.7), 0.8 (0.0 to 3.9), and 1.6 (0.2 to 4.0), respectively. Esterified cholesterol concentrations were higher at the center of type B plaques, and those of free cholesterol were higher at the center of disrupted plaques. At the edge of disrupted plaques, the free-to-esterified cholesterol ratio was 0.5 (0.0 to 2.7) because of the accumulation of esterified cholesterol. Concentrations of all fatty acids were increased at the edge of disrupted plaques compared with the center, but as a proportion of total fatty acids, omega6-polyunsaturated fatty acids (PUFAs) were lower (44% versus 46%, P<.01), possibly reflecting oxidation of PUFAs. These data demonstrate differences in lipid composition and intraplaque lipid distribution between intact and disrupted plaques. At the edge of advanced plaques, increased esterified lipid concentrations, inversely associated with cap thickness, may reflect macrophage activity and a predisposition to rupture.
Key Words: plaque disruption • lipids • fatty acids • atherosclerosis • thrombosis
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Introduction |
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Thrombus formation following disruption of a coronary artery plaque is responsible for the majority of incidents of acute myocardial ischemia.1 2 The majority of coronary thrombi found in cases of fatal myocardial infarction are due to plaque disruption.3 Thrombus formation may occur after plaque disruption when the plaque core becomes exposed to blood from the arterial lumen. The plaque core is rich in tissue factor, collagen, and lipid, all of which are potent thrombogenic agents.4
The reasons why some plaques fissure and others do not are not fully understood. The propensity to disruption depends on the balance between the forces acting on the plaque and its inherent mechanical strength.5 In more than 60% of cases, disruption occurs at the edge of coronary plaques,3 6 7 where the circumferential wall stress is greatest,6 suggesting that disruption occurs as a result of hemodynamic stresses acting on a weakened area of the cap. Because hemodynamic influences operate on all plaques, it is possible that some plaques may be more vulnerable because of their location or composition.8 9
Histological techniques have shown that the majority of disrupted plaques have a necrotic lipid core6 10 occupying more than 40% of the plaque volume,5 a thin fibrous cap,11 fewer smooth muscle cells than intact plaques,5 12 and an accumulation of lipid-filled macrophages at their edge.13 The high content of macrophages at the plaque edge has led to suggestions that plaques grow centrifugally and that this process is most active at the edge.14
Smooth muscle cells synthesize cap connective tissue proteins, such as collagen, elastin, and glycosaminoglycans.15 Reduced numbers of smooth muscle cells, and consequently connective tissue proteins, may therefore weaken the cap.16 T cells also predominate at sites of plaque disruption.17 Chronic immune stimulation within atheroma resulting in T-cell production of interferon-gamma may impair collagen synthesis.18 Further dissolution of structural proteins may occur because of the release of matrix metalloproteinases from macrophage-derived foam cells.19 20 21 Increased activities of interstitial collagenase, gelatinase, and stromelysin have been observed in areas of foam-cell accumulation at the edge of human atherosclerotic plaques.22 As atherosclerosis progresses, lipids accumulate within the plaque at the expense of matrix proteins and smooth muscle cells.21 Intimal macrophages contain substantial amounts of cholesterol esters,24 25 which are rich in PUFAs. Both PUFAs and cholesterol may form oxidized derivatives26 that are toxic to most types of arterial cells. Oxidation of plaque lipids may further contribute to connective tissue degradation by activating macrophages and stimulating matrix metalloproteinase synthesis.27 Oxidized lipids may also influence platelet adhesion and thrombus formation.28 Plaque disruption therefore appears to result from connective tissue degradation, a process possibly influenced by intraplaque lipid content and macrophage activity.5 10 16 29 Differences in lipid composition and distribution between stable and unstable plaques may reflect differences in lipid pools and the degree of macrophage involvement. The study of these differences and their interactions with indices of plaque stability, such as cap thickness, may help determine whether plaque lipids influence plaque stability and lead to strategies to render unstable plaques less vulnerable to disruption.
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Methods |
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Samples were taken from 334 plaques taken from the aortas of 30 men aged 44 to 69 years who died as a result of an acute ischemic event. Because the association between plaque disruption and thrombosis has been noted in both coronary and aortic plaques,10 30 we studied the aorta to ensure sufficient tissue for analyses. Subjects who were known to have a history of hypertension or diabetes mellitus were excluded because of the possibility of atypical plaques. Providing that the cadaver had been kept at 4°C within 1 hour of death, ascending and thoracic aorta from consecutive cadavers were examined to the level of the renal arteries by the same pathologist (M.J.D.) within 2 days of death. A previous study showed that arterial tissue can be used for postmortem lipid analysis for up to 4 to 5 days if it is kept at 4°C.31 Visibly raised plaques were sampled by taking two adjacent transverse sections of tissue, each 2 mm in width in the short axis (Fig 1
). One piece was used
for histological analysis, and the other, for
biochemical analysis. Tissue for histological
analysis was fixed in 10% formal saline and processed to
paraffin wax. The media on the cross section of the plaque used for
biochemical analysis was stripped away under a dissecting
microscope as previously described.32 Sections for the
histological measurements were taken as close as
possible to the site where biopsy samples had been taken for
biochemical evaluation.
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Intact (n=259) plaques were subclassified as occurring in the absence
(type A, n=60) or presence (type B, n=199) of disrupted plaques within
the same aorta (Table 1). Disrupted plaques
(n=75) were defined as those exhibiting macroscopic evidence of
disruption, with or without thrombosis. In such cases samples were
taken outside the site of disruption; crater-like plaques with no
residual structure were excluded. This nomenclature is based on the
probability that type B plaques represent an intermediary stage
of plaque development and have a greater predisposition to disruption
than type A plaques.
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Histological Analyses
For each plaque sample, measures were made of the overall
cross-sectional area occupied by lipid (%), the areas occupied by
macrophages in the plaque cap and at the plaque edge (%), and
the maximum and minimum cap thicknesses. Four immediately adjacent
6-micron-thick sections were stained with hematoxylin and eosin, the
collagen-binding dye Sirius Red, elastic van Gieson, and by
immunohistochemistry to demonstrate the macrophage cytoplasmic
antigen CD68. Alkaline phosphatase was used in the immunohistochemical
tests to generate a red color as the positive signal. The section
stained with elastic van Gieson was used to outline the external
dimensions of the plaque on the video screen of an automated
multiphasic screening quantifying microscope. This observer-derived
outline was used as a template on which all subsequent slides were
superimposed. The histological section stained with
Sirius Red was viewed through a narrow-band green filter to generate a
high-contrast image in which collagen was black. The lipid core area
was measured as the proportion of the area of the plaque within the
defined template that did not contain collagen. The section stained to
show CD68 was also examined with a narrow-band green filter to generate
a black positive image. The observer watching the video screen then
divided the plaque into three equal portions (Fig 1
), excluding the
acellular portion of the lipid core. Within these three defined fields
(one central, two peripheral), the area occupied by CD68
antigen was measured as a proportion of the total field.
Biochemical Analyses
The media on the cross section of the plaque used for
biochemical analysis was stripped away under a dissecting
microscope. The tissue was then divided into two lateral thirds and a
central third in a manner similar to that used in the
histological measurements (Fig 1). These samples were
stored at -80°C before extraction of lipids using redistilled
chloroform/methanol (2:1 vol/vol containing 0.01% wt/vol butylated
hydroxytoluene as antioxidant), followed by a Folch wash to remove
nonlipid contaminants.33 Triheptadecanoic,
L-
-phosphatidylcholine diheptadecanoic, and cholesteryl
heptadecanoic acids (C17:0) were added as internal standards. The lipid
extracts were subjected to thin-layer chromatography to
isolate the phospholipid, triglyceride, and
cholesterol ester fractions. Component fatty acids in each
fraction were transmethylated with methanolic HCl at 50°C for 12
hours.34 Under these conditions, this reagent readily
transesterifies free fatty acids, O-acyl lipids, and
N-acyl lipids such as sphingolipids.35 Fatty
acid composition was determined using a PU4400 gas–liquid
chromatograph (Phillips Scientific, Cambridge, United Kingdom)
fitted with an SP-2330 100-mx0.53-mm widebore capillary column
(Supelchem Ltd, Essex, United Kingdom). Mean fatty acid recoveries,
determined from triplicate analysis of commercially available
standards,36 were as follows: C14:0, 97.6%; C16:0,
99.8%; C18:0, 103.2%; C20:0, 105.0%; C22:0, 98.2%; and C24:0,
98.0%. Retention times were compared with those of high-purity
(>99%) standards (Sigma Chemical Co Ltd, Dorset, United Kingdom).
Peaks were analyzed using an IBM PS/2 microcomputer and Nelson
2600 software (Perkin-Elmer Nelson Systems, Inc, Buckinghamshire,
United Kingdom).
A 0.5-mL aliquot of the lipid extract was used to determine free and esterified cholesterol concentrations. Immediately after extraction, tridecanoylglycerol was added to this aliquot as an internal standard. After formation of butyldimethylsilylether derivatives, lipids were separated on a 0.9-mx2.0-mm inner-diameter glass column packed with 1% Dexil 300 on 100/120 Supelcoport (Supelchem).37 Aortic water content was determined in 20% of samples, which were taken from each aorta and dried at 50°C to constant weight. When possible, these represented paired samples from the center and edge of both intact and disrupted plaques. The overall mean water loss in intact plaques (62±8%) was not significantly different from that of disrupted plaques (63±9%, unpaired Student's t test). Mean water loss at the plaque center (62±9%) was not significantly different from that at the plaque edge (65±9%, paired Student's t test), showing that there was no appreciable difference in water content between aortas.
Individual fatty acids are expressed as both a concentration (mg/g ww of tissue relative to the appropriate internal standard) and a percentage of total fatty acids identified. Cholesterol ester, phospholipid, and triglyceride concentrations were calculated from fatty acid concentrations using reported conversion factors.
Data Analysis
Data were analyzed using the Wilcoxon ranked
pairs test to compare the fatty acid content at the center and the edge
of plaques. For comparisons of fatty acids in different plaque types,
the Mann-Whitney U test was used. Comparison of
histological features between plaque types were made
using the Mann-Whitney U test, and associations between
plaque lipid and histological features were determined
from both Pearson and Spearman ranked correlation coefficients.
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Results |
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Histological Characteristics
The plaque cross-sectional area occupied by lipid was significantly greater in disrupted plaques (median, 64.1%; range; 0.0 to 92.9) than in type A (6.8%; 0.0 to 58.3; P<.001) and type B (14.2%; 0.0 to 72.7; P<.001) plaques (Fig 2
, left). Minimum cap thickness was
significantly lower in disrupted plaques (median, 0.13 mm; range,
0.02 to 0.81) than in both type A (0.40; 0.09 to 0.76;
P<.001) and type B (0.44; 0.00 to 1.20; P<.001)
plaques (Fig 2, right). No difference was found in minimum cap
thickness between type A and type B plaques. Maximum cap thickness was
significantly greater in type B plaques (median, 0.61 mm; range,
0.11 to 1.50) than in type A plaques (0.51; 0.22 to 0.90;
P<.05). There was no difference in maximum cap thickness
between type B and disrupted plaques. The plaque area occupied by
macrophages (ie, mean of center and edge) was significantly
greater in disrupted plaques (median, 16.8; range, 0.0 to 61.9) than in
both type A (2.0; 0.0 to 29.7; P<.001) and B (2.1; 0.0 to
52.5; P<.001) plaques. This trend was observed at both the
center and the edge of the plaque. No differences were apparent between
type A and type B plaques.
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indicates outliers (>1.5xinterquartile
range). Minimum cap thickness was not measured on samples with no lipid
core. ***P<.001, Mann-Whitney U test.
Correlations Between Plaque Histological Features
The plaque cross-sectional area occupied by lipid was negatively
associated with minimum cap thickness in type B (r=-.38,
P<.001) and disrupted plaques (r=-.36,
P<.01). No significant associations were seen with maximum
cap thickness. There were no significant associations between the lipid
content and cap thickness of type A plaques (Table 2). In all plaque types, lipid area was
positively associated with macrophage area (mean of center and
edge), and mean macrophage area was negatively associated with
minimum cap thickness. These associations were found at both the center
and the edge of the plaque. In type A plaques, no associations were
found between mean macrophage area and maximum cap thickness,
but significant negative associations were observed in type B plaques
(r=-.32, P<.001) and in disrupted plaques
(r=-.28, P<.05). These associations were
observed at the center and edge of type B plaques, at the center of
disrupted plaques, but not at the edge of disrupted plaques.
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Histological Comparisons in Individual
Aortas
The area of plaque occupied by lipid-filled macrophages
was positively associated with the plaque area occupied by lipid and
negatively associated with minimum cap thickness in all aortas.
Although generally weaker, these trends were also observed in aortas
containing only type A plaques.
Plaque Lipid Content
Free cholesterol, cholesterol esters,
phospholipids, and triglycerides represent
approximately 25% (15 mg/g ww), 52% (30 mg/g ww), 14% (7 mg/g ww),
and 9% (4 mg/g ww) of total plaque lipids, respectively. In
progressing from type A to type B to disrupted plaques, total plaque
lipid concentrations were increased (28.9, 52.0, and 85.3 mg/g ww,
respectively). The concentrations of free cholesterol and
cholesterol esters were significantly increased in
progressing from type A to type B to disrupted plaques (Fig 3). In type B plaques, the concentrations of
free cholesterol and cholesterol esters (and
hence esterified cholesterol) were approximately double
those in type A plaques (P<.001). In disrupted plaques, the
concentration of free cholesterol was increased a further
twofold compared with type B plaques, whereas the
cholesterol ester concentration was increased by only 50%.
Phospholipid and triglyceride concentrations were
significantly increased in disrupted plaques compared with type B
plaques (P<.001 and P<.01, respectively), but
there were no significant differences between type A and type B
plaques. Phospholipid concentrations were significantly increased in
disrupted compared with type A plaques (P<.05), but there
was no difference in triglyceride concentration between
disrupted and type A plaques.
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Associations Between Plaque Lipid and Histological
Characteristics
Cholesterol ester concentration was positively
associated with macrophage area at the center and edge of all
plaque types (Table 3). In the case of free
cholesterol, this association was apparent only at the
center and edge of type B plaques. Cholesterol ester
concentration was also negatively associated with minimum cap thickness
at the edge of type B and disrupted plaques, and free
cholesterol was negatively associated with minimum cap
thickness at the center of disrupted plaques. No associations were
found between cholesterol ester or free
cholesterol concentration and minimum cap thickness in type
A plaques. At the edge of disrupted plaques, phospholipid concentration
was also negatively associated with minimum cap thickness
(r=-.52, P<.01). These associations for
individual lipid fractions reflect similar trends observed for the
concentrations of component esterified fatty acids. No other
associations were apparent between phospholipid or
triglyceride concentration and plaque
histological features.
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Free and Esterified Cholesterol
The F/E ratio was significantly greater at the center of all
plaques than at the edge (Fig 4, left). There
was no difference in F/E ratio at the center of type A and type B
plaques. Although concentrations of free and esterified
cholesterol are greater at the center of type B plaques
compared with the center of type A plaques, the increase in esterified
cholesterol concentration is proportionately greater in the
former. The F/E ratio exceeded 1 only at the center of disrupted
plaques (1.6) and was significantly greater than the F/E ratio at the
center of type A (0.9, P<.001) and type B (0.8,
P<.001) plaques. This was due to an increased concentration
of free cholesterol at the center of disrupted plaques. In
contrast, at the edge of disrupted plaques, esterified
cholesterol concentrations were nearly double those of free
cholesterol. There was no difference in the esterified
cholesterol concentration between the center of type B and
disrupted plaques (22 and 25 mg/g ww, respectively; Fig 4, right).
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Fatty Acid Composition Within Plaques
Cholesterol Esters
Cholesterol esters are the predominant lipid fraction
in all plaque types, representing 14.6, 30.0, and 43.6 mg/g
ww tissue (52% of plaque lipid) in type A, type B, and disrupted
plaques, respectively. In going from type A through type B to disrupted
plaques, the concentration of SFAs is moderately increased (Fig 5, left), with the SFA concentration in
disrupted plaques (2.9 mg/g ww) being significantly greater than in
type A (2.1 mg/g ww, P<.01) and type B plaques (2.3 mg/g
ww, P<.01). In contrast, going from type A through type B
to disrupted plaques, the concentrations of MUFAs and total PUFAs
(omega6-+omega3-PUFAs) are increased by approximately threefold (6.6
versus 1.8 mg/g ww, P<.001) and fivefold (10.1 versus 2.2
mg/g ww, P<.001), respectively.
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In cholesterol esters of type A, type B, and disrupted
plaques, SFAs, MUFAs, and total PUFAs average 20%, 30%, and 50% of
fatty acids, respectively (Fig 5, right). In going from type A to type
B to disrupted plaques, the proportion of SFAs is decreased by 16%
(32% to 16%, P<.001). In contrast with SFAs, the
proportions of MUFAs and total PUFAs are increased in disrupted plaques
(34% versus 28% and 49% versus 39%, respectively;
P<.01) compared with type A plaques. There were lower
proportions of total PUFAs in disrupted plaques compared with type B
plaques. This was due to lower proportions of omega6-PUFAs (-4.0%,
P<.01). In contrast, there was no reduction in the
proportions of omega3-PUFAs in disrupted plaques. Because omega3-PUFAs
represent <5% of plaque fatty acids, this may
represent a proportion effect.
Phospholipids
Phospholipids represent 6.2, 5.6, and 8.1 mg/g ww tissue
(14% of plaque lipid) in type A, type B, and disrupted plaques,
respectively (Fig 3). Irrespective of plaque type, the average
concentrations of phospholipid SFAs, MUFAs, and total PUFAs were 2.5,
1.0, and 1.5 mg/g ww, respectively. There were no significant
differences in the concentrations of the major fatty acid groups
between type A and type B plaques. In disrupted plaques, the
concentrations of SFAs, MUFAs, and total PUFAs were significantly
increased compared with type B plaques (ie, SFAs, 3.0 versus 2.0 mg/g,
P<.001; MUFAs, 1.2 versus 0.75 mg/g, P<.001;
total PUFAs, 1.8 versus 1.3 mg/g, P<.01). Similar trends
were seen for both omega6-PUFAs and omega3-PUFAs (ie, omega6-PUFAs, 1.5
versus 1.1 mg/g ww, P<.01; omega3-PUFAs, 0.30 versus 0.20
mg/g ww, P<.05).
Irrespective of plaque type, SFAs, MUFAs, and PUFAs represent 50%, 20%, and 30% of fatty acids, respectively. There were no differences in the proportions of SFAs between plaque types, and the only difference between type A and type B plaques was an increased proportion of omega6-PUFAs in type B plaques (27.6% versus 26.3%, P<.001). In disrupted plaques, the proportions of omega6-PUFAs, omega3-PUFAs, and accordingly total PUFAs were lower than in type B plaques (omega6-PUFAs, -1.3%, P<.01; omega3-PUFAs, -0.65%, P<.01; total PUFAs, -2.0%; P<.001), whereas proportions of MUFAs were higher (2.0%, P<.001).
Triglycerides
Triglycerides are the least abundant lipid in all
plaque types and represent 4.2, 3.6, and 5.4 mg/g ww
tissue (average 9% of plaque lipid) in type A, type B, and disrupted
plaques, respectively (Fig 3). The average concentrations of
triglyceride SFAs, MUFAs, and PUFAs were 1.5, 1.5,
and 0.75 mg/g ww, respectively. SFAs, MUFAs, and total PUFAs therefore
constitute 40%, 40%, and 20% of triglyceride fatty
acids, respectively.
The relative concentrations of SFAs, MUFAs, and PUFAs in the different plaque types were similar to those found in the phospholipid fraction. There were no significant differences in concentrations of the major fatty acid groups between type A and type B plaques, except for a lower concentration of SFAs in type B plaques (-0.4 mg/g ww, P<.01). In disrupted plaques, the concentrations of SFAs, MUFAs, and total PUFAs were significantly increased compared with type B plaques (ie, SFAs, 1.8 versus 1.3, P<.01; MUFAs, 2.2 versus 1.6, P<.01; total PUFAs, 1.2 versus 0.7 mg/g, P<.01). Again, similar trends were seen for both omega6-PUFAs (1.1 versus 0.7 mg/g ww, P<.001) and omega3-PUFAs (0.15 versus 0.10 mg/g ww, P<.001).
In progressing from type A to type B to disrupted plaques, the proportions of SFA decreased (41% to 33%, P<.001), and the proportions of MUFA increased (32% to 40%, P<.001). In contrast, there was no change in the proportions of total PUFA.
P/S Ratio
The P/S ratio in cholesterol esters was significantly
greater in type B (3.1, P<.001) and disrupted plaques (3.0,
P<.001) compared with type A plaques (1.3, Table 4). There was no difference in the
cholesterol ester P/S ratio between type B and disrupted
plaques. In progressing from type A through type B to disrupted
plaques, there were no differences in the respective P/S ratios of
phospholipids (0.5, 0.6, and 0.6) or triglycerides (0.6,
0.6, and 0.7).
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Comparison of Plaque Center and Edge Composition
Cholesterol Esters
Relatively few center-versus-edge differences were found in type A
plaques in any lipid fraction. In the cholesterol ester
fraction, a lower concentration of total PUFAs (2.4 versus 2.7 mg/g ww,
P<.05, Table 4), and consequently a lower P/S ratio (1.1
versus 1.4, P<.05), was found at the plaque edge. The most
pronounced center-versus-edge differences were found in the
cholesterol ester fraction of type B and disrupted plaques.
The edge of type B plaques is characterized by lower concentrations
(mg/g ww) of SFAs (1.8 versus 2.6, P<.001), MUFAs (3.4
versus 4.7, P<.01), omega6-PUFAs (5.0 versus 7.9,
P<.01), and total PUFAs (5.5 versus 8.4,
P<.001), and accordingly a lower cholesterol
ester concentration (24.0 versus 35.3, P<.001), compared
with the center. There was no difference in the P/S ratio between the
center and edge of type B plaques. In contrast, the edge of disrupted
plaques is characterized by greater concentrations of SFAs (3.5 versus
2.9, P<.05), MUFAs (6.8 versus 6.4, P<.05),
omega6-PUFAs (8.9 versus 8.6, P<.05), total PUFAs (9.8
versus 9.4, P<.01), and cholesterol esters
(45.1 versus 42.0, P<.05) than the center. The P/S ratio
was also lower at the plaque edge compared with the center (2.8 versus
3.2, P<.05). These contrasting trends at the edges of type
B and disrupted plaques reflect accumulation of esterified
cholesterol at the edge of disrupted plaques (Fig 4, B).
Although the concentration of omega6-PUFAs was increased at the edge of
disrupted plaques compared with the center, as a proportion of total
fatty acids, omega6-PUFAs were lower (44% versus 46%,
P<.01), and SFAs were higher (17% versus 15%,
P<.05).
Phospholipids and Triglycerides
Irrespective of plaque type, there were relatively few
center-versus-edge differences in the phospholipid and
triglyceride fractions. Phospholipid concentrations (mg/g
ww) were lower at the edge of type A plaques (5.8 versus 6.4,
P<.05), similar at the edge of type B plaques (5.3 versus
5.4), and greater at the edge of disrupted plaques (8.8 versus 7.3,
P<.001) compared with the respective centers. The edges of
disrupted plaques were also characterized by increased concentrations
(mg/g ww) of SFAs (3.2 versus 2.5, P<.05) and omega6-PUFAs
(2.0 versus 1.5, P<.05). Triglyceride
concentrations (mg/g ww) were significantly lower at the edge of
disrupted plaques than in the center (4.9 versus 5.5,
P<.01). There were no differences in
triglyceride concentration between the center and edge of
either type A or type B plaques.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This study shows that histological determinants of plaque stability, such as cap thickness, are inversely associated with increased plaque lipid concentration. Previous studies have demonstrated that disrupted plaques have a lipid area typically in excess of 40%,5 suggesting a threshold above which disruption is more likely. Our data confirm that disrupted plaques are characterized by an increased cross-sectional area occupied by lipid and macrophages when compared with intact type A and type B plaques. In addition, we have now shown that disrupted plaques have a significantly reduced minimum cap thickness compared with type A and type B plaques and also that minimum cap thickness is negatively associated with lipid area in type B and disrupted plaques.
Atherosclerotic plaques are heterogeneous structures. The American Heart Association has suggested a nomenclature in which plaques with a lipid core are designated as type Va plaques and solid fibrous plaques as type Vc plaques.38 In the present study, consistent positive associations were found in individual aortas between the area of plaque occupied by macrophages and the lipid core size. Similar consistent but negative associations were found between macrophage area and cap thickness. These data are in accordance with the macrophages, playing a role in both the expansion of the lipid core and cap thinning.
On average, free cholesterol, cholesterol esters, phospholipids, and triglycerides represented 25%, 52%, 14%, and 9% of total plaque lipids, respectively, in accordance with previously reported values.32 In progressing from type A to disrupted plaques, the increase in total plaque lipid concentration is predominantly due to increased concentrations of free cholesterol and cholesterol esters, the latter being reflected in increased concentrations of all major fatty acid types. Accordingly, disrupted plaques have the highest concentrations of PUFAs and a P/S ratio threefold greater than that in type A plaques.
The suggestion made in the 1950s that most fatty streaks are gradually converted into mature fibrolipid plaques39 is now supported by evidence from numerous studies.40 41 This transition is generally associated with (1) a shift from predominantly esterified cholesterol in fatty streaks and intermediary preatheroma to free cholesterol in mature fibrolipid plaques and (2) a proportionately greater increase in PUFA compared with MUFA content.41 42 In our study, plaque nomenclature is based on the possibility that type B plaques represent an intermediary stage of plaque development between type A and disrupted plaques. The predominance of esterified cholesterol at the center of type B compared with type A plaques and free cholesterol at the center of disrupted compared with type B plaques suggests that type A, type B, and disrupted plaques represent transitional stages of plaque development. This is supported by a proportionately greater increase in the concentration of PUFA, compared with MUFA, in going from type A through type B to disrupted plaques.
The edges of disrupted plaques predominantly contain cholesterol esters. Minimum cap thickness is inversely associated with the concentration of cholesterol esters and phospholipids (and component fatty acids) at the edge of type B and disrupted plaques and with the concentration of free cholesterol at the center of disrupted plaques. This suggests that increased lipid concentration has an adverse influence on plaque stability.
The reduced proportions of omega6-PUFAs and total PUFAs at the edge of disrupted plaques compared with the center may reflect oxidative damage. Such damage to PUFAs, particularly at the edge of disrupted plaques, where concentrations of omega6-PUFAs are greatest, may promote connective tissue degradation and influence the prevalence of disruption at this site. Both PUFAs and sterol oxidation products have been detected in the human arterial wall.26 43 These are toxic to most arterial cells44 and to macrophages in particular45 46 and may provide a milieu for connective tissue degradation. Increased concentrations of proaggregatory SFAs and oxidized derivatives of PUFAs, which can inhibit endothelial prostacyclin synthetase,47 48 at a site of disruption may influence the degree of thrombus formation.
This study has provided links between histological and biochemical features of plaque composition in intact and disrupted plaques. These may involve the accumulation of esterified lipid at the edge of disrupted plaques, possibly reflecting the presence of metabolically active macrophages.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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We gratefully acknowledge the British Heart Foundation for financial support (project grant PG 92082) and the Stanley Foundation for the gift of a gas–liquid chromatograph. Charlotte McCue provided expert technical assistance.
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Footnotes |
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From the Wynn Department of Metabolic Medicine (C.V.F., D.C.) and the Department of Cardiac Medicine (M.F.O.), Imperial College School of Medicine, National Heart and Lung Institute, London, United Kingdom, and the Cardiovascular Pathology Unit, British Heart Foundation, St. George's Hospital Medical School (M.J.D.), London, United Kingdom.
Received May 21, 1996; accepted August 10, 1996.
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