© 1999 American Heart Association, Inc.
Brief Review |
Ultrasound and Lipoproteins as Predictors of Lipid-Rich, Rupture-Prone Plaques in the Carotid Artery
From the Department of Vascular Surgery, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark.
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Abstract |
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 Top Abstract IntroductionUltrasound in Predicting...Ultrasound in Predicting...Histological Plaque Constituents...Predictive Value of Plasma...Plasma Cholesterol and Stroke...Conclusion and PerspectivesReferences |
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Abstract—The aim of this review is to summarize present knowledge of the ultrasonic detection and determinants of carotid atherosclerosis with lipid-rich cores and to review the evidence that these measures of plaque type may predict cerebral events. With the use of high-resolution ultrasound B-mode imaging, carotid plaques evaluated as only weakly reflecting the ultrasound beam (echolucent) have been associated with a higher risk of neurological events than are plaques reflecting the ultrasound signal strongly (echorich). Histologically, these echolucent plaques have a higher content of lipid and hemorrhage than do echorich plaques, which contain more calcification and fibrous tissue. Findings in the coronary arteries indicate that a lipid-rich plaque with a thin, fibrous cap is more vulnerable, is more prone to rupture, and cause symptoms compared with fibrous plaques. A search for determinants in the blood for these vulnerable plaques suggests that low density lipoprotein (LDL) cholesterol is the best lipid predictor for the extent of atherosclerosis, whereas triglyceride-rich lipoproteins in particular seem to predict an echolucent plaque. Lowering of LDL cholesterol and triglyceride-rich lipoproteins in plasma is associated with reduced progression of coronary atherosclerosis and coronary events. LDL cholesterol reduction is also associated with a reduced stroke rate. These improvements in the prognosis are thought to be the result of a reduction in the lipid content of the plaques, making them more stable and resistant to rupture rather than an actual reduction in plaque volume and degree of stenosis. In conclusion, it appears that ultrasound B-mode imaging as well as lipoproteins presumably may predict dangerous and rupture-prone, lipid-rich plaques in the carotid arteries, thereby being potential diagnostic tools in the prevention of neurological events.
Key Words: arteriosclerosis • carotid artery disease • ultrasound • lipoproteins • histology
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Introduction |
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TopAbstractIntroductionUltrasound in Predicting...Ultrasound in Predicting...Histological Plaque Constituents...Predictive Value of Plasma...Plasma Cholesterol and Stroke...Conclusion and PerspectivesReferences |
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Atherosclerosis due to accumulation of atherogenic lipoproteins in the carotid arterial wall may lead to cerebrovascular events, causing physical and mental disability and, in one third of these cases, even death. To prevent the possibly fatal course of atherosclerosis, it seems important to understand why this otherwise-benign disease suddenly develops into a life-threatening condition. The questions raised in this article are therefore the following: Which risk factor(s) in the blood determines the development of a vulnerable, unstable plaque? How do we identify these plaques, and what do they contain histologically? (Figure 1
).
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Ultrasound in Predicting Occurrence of Neurological Symptoms |
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TopAbstractIntroductionUltrasound in Predicting...Ultrasound in Predicting...Histological Plaque Constituents...Predictive Value of Plasma...Plasma Cholesterol and Stroke...Conclusion and PerspectivesReferences |
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Stroke is the third leading cause of death in Europe and the United States, requiring enormous resources to be spent on rehabilitation each year. Stroke is defined as a nontransient, acute neurological injury resulting from disruption of blood flow to cerebral tissue. The disruption of blood flow is thought to be a result of embolization arising from degenerative breakdown or thrombotic occlusion of complex plaques in the extracranial vessels,1 2 3 4 areas that are readily accessible to ultrasound imaging. The spectrum of clinical presentation is probably related to the size of the embolus, its composition, its propensity to disaggregate, and the state of the collateral circulation. Most strokes occur without warning. Only 5% to 15% of patients experience a transient ischemic attack (TIA) as a premonitory symptom of stroke.5 Because the primary purpose of noninvasive screening is to identify potentially treatable lesions in patients at increased risk of stroke and to treat these patients medically or surgically, it is important to consider all factors that may lead to a cerebrovascular event.
The European Carotid Surgery Trial6 and North American Symptomatic Carotid Endarterectomy Trial7 have shown the benefit of carotid endarterectomy in symptomatic patients with a high-grade stenosis (>70%). Despite the relatively higher risk associated with high-grade stenoses, evaluated in absolute numbers most patients experiencing neurological symptoms have stenoses of <50% in the ipsilateral carotid artery, according to a study by Langsfield et al8 (from 0% to 49% stenosis, 24 new symptoms versus 15 with 50% to 99% stenosis). As a key point in the natural history of carotid plaque development, another multicenter trial, the Asymptomatic Carotid Atherosclerosis Study (ACAS9), has shown that the majority of asymptomatic patients with highly stenotic, atherosclerotic plaques remain asymptomatic. The ACAS trial9 found an 11% 5-year risk of ipsilateral stroke in patients having a 60% or greater diameter-reducing stenosis in the relevant asymptomatic carotid artery.
Recent studies support the notion that not only the degree of
stenosis but also the morphology of the carotid artery plaque,
as evaluated with ultrasound B-mode imaging, and surface
characteristics like ulceration may be of pathogenetic importance
(Table 1).1 8 10 11 12 13 14 15 16 17 18 19 20 21 22
Concerning surface characteristics, ulceration is believed to be
important because it causes exposure of the thrombogenic layers of the
plaque, with the possibility of subsequent thrombus adhering to the
plaque, leading to embolus formation and resultant neurological
symptoms. Unfortunately, there is no standardized definition of
ulceration. Ulceration can be classified from ultrasonic and
angiographic findings or from macroscopic or microscopic pathology of
the endarterectomy specimen. Ultrasonographically,
an ulceration is an irregularity or break in the echoreflective surface
of the plaque. Moore et al25 defined ulcer size
on angiograms as the multiplication of length and width of a crater (in
millimeters), and these authors divided ulceration into 3 groups
according to size. Macroscopically, Comerata et al26
defined ulcers according to crater width and a depth of 1 mm or
more, whereas O'Donnell et al27 defined them as
a definite surface irregularity with a punched-out characteristic. Seen
microscopically, ulceration according to the definitions varies from
loss of surface endothelium to deep, undermining
depressions in the plaque.28 29 The correlation
of histology to ulceration investigated with the use of
ultrasound26 30 31 32 33 and
angiography26 27 is, however, poor. The ability
to detect ulceration is affected by the degree of stenosis.
With the use of B-mode ultrasound, the sensitivity for identification
of ulceration was 77% in plaques with 50% stenosis or less
but only 41% in plaques of >50% stenosis
(P=0.03).26 The sensitivity for
arteriography was similar: 77% and 48%,
respectively.26 Differing time intervals from the
occurrence of symptoms to surgery may also lead to conflicting results,
since re-endothelialization was reported by Lusby et
al34 when this interval was >3 weeks. It may be
that ulcers heal after neurological events and therefore cannot be
found on ultrasound or angiography when performed some time after the
occurrence of symptoms. Reviewing ulcers on 593 angiograms of medically
treated patients, Eliasziw et al35 found a 2-year
risk of nonfatal stroke or vascular death in 30% of the medical group
with ulcers as opposed to 17% in the group without ulcers
(P=0.005). These findings indicate that the presence of
ulcers may be of prognostic relevance, but if one considers the fact
that most patients undergoing surgery have severe lesions in which
ulcers are not easily seen preoperatively, this parameter
may be difficult to use as an indication for surgery.
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Angiography merely yields information on the degree and location of the
stenosis, whereas high-resolution B-mode imaging allows
characterization of carotid plaques (Table 2) by echogenicity, defined as
reflectance of the ultrasound signal. Echogenicity can be classified
according to the criteria of Johnson et al10 from
1985 (calcified, dense, and soft) or alternatively, the criteria of
Gray-Weale et al23 from 1988 describing 4 plaque
types, from dominantly echolucent with a thin, echogenic cap to
dominantly echogenic with small areas of echolucency, through 2 types
of mixed echogenicity. Reilly et al24 introduced
characterization of plaque structure into homogeneous,
having uniform high- or medium-level echoes, and
heterogeneous, having high-, medium-, and low-level echoes
and containing areas with echogenicity similar to that of blood. Other
groups use the criteria of the European Carotid Plaque Study
Group36 from 1994: echorich, intermediate, and
echolucent, combined with surface and structural
characteristics.36 37 With the use of either of
these sets of criteria or the modified Gray-Weale criteria (whereby a
fifth plaque type includes those impossible to classify according to
calcification or acoustic shadowing), the interobserver agreement has
been found to be good (
=0.79 and 0.61,
respectively).18 37 To our knowledge, results of
intraobserver studies on plaque morphology have not been published but
are regarded as better than the results from the interobserver studies.
Given the slow formation of atherosclerotic deposition, day-to-day
variation seems negligible.
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Most studies relating ultrasonic plaque morphology to clinical outcome
agree that echolucent and heterogeneous as well as
ulcerated plaques carry a higher risk of neurological symptoms compared
with echorich and homogeneous plaques (Table 1
).8 10 11 13 15 17 19 Langsfield et
al8 studied 419 patients with
asymptomatic plaques for 15 to 22 months and found the
echolucent or heterogeneous plaques to be at increased risk
of becoming symptomatic compared with dense, echorich
plaques (P<0.02). These findings were reproduced by Belcaro
et al.19 Following up on a group of both
asymptomatic and symptomatic patients,
Sterpetti et al13 found new neurological events
occurring in 19 of 71 carotid arteries (27%) with
heterogeneous plaques, whereas new events were only seen in
6 carotid arteries of 167 (4%) with homogeneous plaques
(P<0.001). In prolongation of the work by Johnson et
al,10 the study by O'Holleran et
al11 followed up 293 patients for an average of
46 months. Over a 4-year period, all 42 patients with a soft lesion of
>75% stenosis became symptomatic while only 60%
of those with dense plaques became symptomatic
(P<0.05). Confirming these results, Bock et
al17 showed that echolucent plaques were
associated with a 5.7% incidence of TIA and stroke, compared with only
2.4% for echogenic plaques (P<0.0001). In a
cross-sectional study Geroulakos et al38 found
echolucent plaques to be associated with a higher incidence of brain
infarcts on CT scans (P<0.02). As opposed to positive
associations of plaque character to events found by the above-listed
studies, Holdsworth et al20 in a cross-sectional
study of 4258 patients only found amaurosis fugax to be associated with
echolucent and heterogeneous plaques, whereas the degree of
stenosis overall seemed more predictive of events
(P<0.00001). They concluded that plaque morphology and
degree of carotid stenosis are mutually dependent factors,
whereas morphology does not add to the sensitivity of stenosis
in predicting the presence of symptoms. Fitzgerald and
O'Farrell39 found heterogeneous
structure (P<0.01) and irregular surface
(P<0.01) to be associated with the development of
subsequent events. Opposed to this, the degree of stenosis and
size of a low-echo "pool" within the lesion were not associated
with events. However, results are difficult to interpret, as they
include, for example, myocardial infarction (MI) in the event
group.
The main problem in the majority of these studies is that stroke and
TIA were not separated as clinical end points. This seems an important
goal for future trials, because a stroke is a condition to be
prevented, being the most severe, disabling, and even life-threatening
neurological event. Furthermore, these studies are mostly based on
symptomatic clinical populations (Table 1), whereas it
would be more important to evaluate only asymptomatic
patients prospectively in a large sample to gain evidence for the
significance of plaque composition. The results of the multicenter
studies ACSRS (Asymptomatic Carotid Stenosis and
Risk of Stroke Study) and ACST (Asymptomatic Carotid
Surgery Trial) are therefore much awaited.40
Summarily, it appears that patients with an echolucent and heterogeneous plaque evaluated by ultrasound B-mode have a higher risk of developing neurological events than do patients with homogeneous, echorich plaques.
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Ultrasound in Predicting Histological Plaque Content |
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TopAbstractIntroductionUltrasound in Predicting...Ultrasound in Predicting...Histological Plaque Constituents...Predictive Value of Plasma...Plasma Cholesterol and Stroke...Conclusion and PerspectivesReferences |
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Table 3
lists the results of studies
investigating the histological content of carotid
plaques. The echolucent plaques were associated with a high content of
lipid and hemorrhage, whereas echorich plaques contained more
calcification (causing acoustic shadowing) and fibrous tissue (collagen
rich). Ultrasound could not reliably distinguish between lipid and
hemorrhage46 in the plaque, and this is
why some studies have combined these 2 constituents in the term soft
tissue.36 46 Heterogeneous plaques
were found to contain more intraplaque
hemorrhage24 27 41 and
calcification,36 37 categorizing them as complex,
mature plaques. Homogeneous plaques, in contrast, consisted
predominantly of dense fibrous tissue.24 33 To
characterize B-mode images of plaques more objectively, digital image
processing or videodensitometric analysis has been
introduced.47 48 49 Using this method, El-Barghouty
et al50 found the content of soft tissue (lipid
and hemorrhage) in the plaque to be associated with a low
gray-scale median value of the plaque. Conversely, a high fibrous
tissue content was associated with a high gray-scale value.
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Although all of the findings listed seem consistent,
there are many different opinions in the literature: eg, differences
exist in the subjective evaluation of B-mode images, techniques of
pathological tissue characterization (examined either microscopically
or macroscopically), and definitions of specific
histological features. This lack of standardization
also includes histological sampling errors when only
semiquantitative or nonquantitative data were collected and different
amounts or parts of the plaque were investigated. In a review by
Reilly51 results of the studies using sonographic
imaging to determine carotid plaque histology were summarized to yield
an accuracy for ultrasonography of 81% (443 of 549), a sensitivity of
90% (287 of 319), and a specificity of 68% (156 of 230). However, in
contrast to earlier findings from nonquantitative and semiquantitative
studies, recent quantitative studies agree that intraplaque
hemorrhage occupies only a very small area of the plaque
(
1%).36 37 45 51 52 53 54 Bassiouny et
al52 identified hemorrhage in 68% of
plaques, comprising 2.5% of the plaque area on average. In the study
by Leen et al53 hemorrhage occupied <1%
in 65% of the cases and was present in 68% of plaques, whereas
Grønholdt et al37 found hemorrhage
occupying 0.2% (0% to 4%) of the plaque area on average. Therefore,
ultrasound may not reliably identify this small constituent in a
plaque, making use of the term soft tissue reasonable.
In summary, correlation of subjective ultrasonic evaluation with
histological findings showed that echolucent plaques
were associated with a higher content of lipid and hemorrhage,
whereas echorich plaques contained more calcification and fibrous
tissue (Table 3).
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Histological Plaque Constituents Associated With Neurological Symptoms |
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TopAbstractIntroductionUltrasound in Predicting...Ultrasound in Predicting...Histological Plaque Constituents...Predictive Value of Plasma...Plasma Cholesterol and Stroke...Conclusion and PerspectivesReferences |
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Controversy also exists on plaque constituents and their prognostic value for developing neurological symptoms (Table 4
). Unfortunately, studies concerning
plaque constituents as prognostic indicators have used different
definitions of symptoms as well as different time intervals from
neurological event to surgery, if documented at all. Plaque remodeling
is presumed to occur after an event, and this process could have a
great influence on the interpretation of results when the time interval
before surgery, normally 1 to 3 months, is taken into account. The
essence of early articles published on this topic revealed that the
finding of intraplaque hemorrhage was associated with a higher
rate of symptoms55 56 60 64 (Table 4). All but
one60 of these studies did not use quantitative
histological methods and apparently did not use
"blinded" assessment of the data, whereas more recent blinded
studies indicate that this association does not
exist.45 52 54 63 However, problems of
interpretation of these studies exist, especially where differences in
the definition of hemorrhage are concerned. Moreover,
intraplaque hemorrhage seems to be more common in plaques
causing high-grade stenosis.52 56 59
Because most centers operate only on asymptomatic patients
in the presence of high-grade stenosis, the
asymptomatic group in a study often includes more
high-grade lesions than does the symptomatic group, and
this factor could affect the results. Lusby et
al34 discovered that the age of the
hemorrhage was correlated with time elapsed since the
neurological event. They described the stages as (1) operative; (2)
acute (<1 week), with little inflammatory cell infiltrate; (3) recent
(1 to 6 weeks old), characterized by
hemosiderin-containing macrophages; and finally
(4) remote (>6 weeks) hemorrhage, characterized by amorphous
material with cholesterol crystals but without an
inflammatory reaction. Erroneously, the lattermost stage has also been
recognized as hemorrhage by other authors, resulting in the
reporting of a high content of intraplaque hemorrhage, leading
to incorrect results and conclusions. In contrast, newer studies
suggest that the atheromatous material should not be
recognized as intraplaque hemorrhage but rather as lipid or
necrosis in the plaque.36 37 45 53 Furthermore, 4
studies did not confirm any correlation between age of the plaque
hemorrhage and symptoms.24 45 52 59
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Thrombus was found in many studies, though not always present in plaques from patients with recent symptoms.63 65 66 This constituent is thought to be associated with the theory of plaque disruption, allowing the thrombogenic lipid core to communicate with the arterial lumen. Its presence may be intermittent, reflecting the dynamic process of rupture, thrombus formation, healing, and remodeling of the plaque.2 3 4
Recent work with quantified data, especially concerning the relation of
atheromatous material (lipid) in the plaque to
neurological symptoms, has been reported by Avril et
al,60 Seeger et al,62
Feeley et al,45 Widder et
al,44 and Hatsukami et al54
(Table 4). Only Hatsukami et al54 did not find
any correlation between symptoms and the measured quantitative
pathological constituents. Feeley et al45 showed
a significant correlation between plaques containing amorphous material
mixed with cholesterol and neurological symptoms
(P=0.017). Interestingly, the amount of fibrous tissue found
in asymptomatic patients was higher than in patients
experiencing increasing numbers of ischemic
events.45
Also associated with progression of atherosclerotic disease and neurological symptoms are other plaque features like foam cell infiltration in the fibrous cap; thinning or rupture of the fibrous cap; soft, lipid-rich cores beneath this cap; cholesterol crystals; and necrosis.45 52 53 59 63 Carr et al63 recently found patients with symptomatic plaques (n=19) to have more frequent plaque rupture, fibrous cap thinning, and fibrous cap foam cell infiltration when compared with asymptomatic (n=25) plaques (P<0.006). Bearing in mind that this is a nonquantitative study with relatively few patients, no differences existed for constituents like plaque hemorrhage, presence of a necrotic core, luminal thrombus, smooth muscle cell infiltration, eccentric shape, or plaque type (fibrous, necrotic, or calcified). Leen et al53 found that an eosinophilic amorphous material mixed with cholesterol was the predominant nonfibrous component in symptomatic plaques. Roof rupture (break in the fibrous cap of a nonfibrous plaque) was seen in 66% of these plaques, but this study lacks statistical information.
The above-mentioned findings support the plaque rupture theories mainly based on pathological findings in the coronary arteries.2 3 4 These theories may not be far from those based on findings in the carotid arteries, because atherogenesis of coronary and cerebrovascular vessels is closely related.67 68 Rupture-prone coronary plaques in particular are thought to consist of a thin, fibrous cap covering an atheromatous, lipid-rich core (cholesterol and its esters).2 3 4 This plaque may be triggered to rupture by intrinsic stresses (ie, the continued accumulation of lipoproteins from plasma with or without uptake in macrophage foam cells) or extrinsic stresses to rupture. A plaque rupture may lead to intraplaque hemorrhage, formation of superimposed thrombosis, embolism, and subsequent neurological symptoms. Leen et al53 concluded that cholesterol deposition precedes intraplaque hemorrhage rather than the reverse, indicating that intraplaque hemorrhage is a sign of previous plaque rupture rather than a pathogenetic factor itself. A growing lipid-rich core due to lipoprotein accumulation itself makes the plaque vulnerable to rupture, which explains the findings of Grønholdt et al,37 wherein the presence and amount of hemorrhage in the plaque were positively associated with lipid and negatively associated with fibrous tissue content of the plaque.
An alternative pathogenesis to plaque rupture/intraplaque hemorrhage is bleeding and/or transudation into plaques from thin-walled new vessels originating from the vasa vasorum and frequently found at the plaque base.69 70 This bleeding could theoretically increase intraplaque pressure, with resultant cap rupture from the inside.71 However, it is difficult to imagine this phenomenon's happening against a much higher luminal pressure and with the small amount of hemorrhage found in carotid plaques.52 53 Leen et al53 moreover found that most blood vessels located at the base of plaques were unrelated to hemorrhage in the plaque.
Intrinsic stresses also include ongoing inflammation with degradation of the extracellular matrix, thereby weakening the fibrous cap. The cells involved in inflammation are activated macrophages and/or mast cells that by either phagocytosis or secretion of proteolytic enzymes72 73 74 degrade collagen, thereby thinning and destabilizing the fibrous cap. Smooth muscle cells, on the contrary, are thought to stabilize the plaque by producing collagen.75 76
The exact pathogenesis of calcification in a plaque is still unknown. The amount of calcification increases in plaques with age and the overall plaque burden, but not with the degree of stenosis in coronary arteries.77 78 79 It is interesting that calcium seems to stabilize the plaque against disruption and thrombosis, as this element is found less frequently in culprit lesions responsible for unstable angina77 and MI.79 This explains the findings of Grønholdt et al,37 in which the amount of calcification in carotid plaques was found to increase with elapsed time since symptoms occurred. On the contrary, in a multicenter study, a higher content of soft tissue (lipid and hemorrhage) was seen in plaques from patients with recent symptoms, whereas no difference was found in the amount of calcification.36 Regarding the carotid arteries, great controversies exist on the influence of calcification on the risk of neurological events. Some authors believe that calcification of a plaque decreases the risk of subsequent events,10 whereas others19 believe calcification leads to increased risk. Some investigators18 ignore plaques with acoustic shadowing, and no evidence exists that shadowing is actually caused by calcification. Not even the few quantitative histological studies36 37 43 concerning evaluation of calcification are able to prove that the detected calcification is actually producing an echogenic reflectance or acoustic shadowing on ultrasound.
Extrinsic stresses on a plaque are, eg, hemodynamic forces (ie, shear stress, a sudden increase in blood flow, blood pressure, and pulse rate) acting on the weak shoulders of the cap. The carotid plaque is typically situated in the bifurcation of the artery, where a mismatch in flow impedance, abnormal wall tension, and turbulent flow predispose to further atherogenesis and eventually to plaque rupture at this location. According to the equation by Bernoulli, a flow-restricting stenosis causes a decrease in pressure but a proportional increase in velocity in the stenotic segment. The resulting difference in pressure across the lesion together with the high proximal pressure produces an unroofing force downstream that can cause acute rupture of the plaque, embolization of its contents, or progression to thrombus formation or thrombotic occlusion. Superimposed thrombosis can also build on an intact plaque if hyperthrombogenicity exists because of plate-let activation, hypercoagulability, and/or impaired fibrinolysis.80
In summary, the most dangerous, rupture-prone plaques causing neurological events are thought to consist of an atheromatous, lipid-rich core covered by a thin, fibrous cap.
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Predictive Value of Plasma Lipoproteins |
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TopAbstractIntroductionUltrasound in Predicting...Ultrasound in Predicting...Histological Plaque Constituents...Predictive Value of Plasma...Plasma Cholesterol and Stroke...Conclusion and PerspectivesReferences |
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Plaque vulnerability is assumed to increase with accumulation of lipoproteins derived from the vessel lumen, either stored extracellularly and thereby increasing the lipid-rich core, or phagocytosed by macrophages, typically situated in the shoulders of the fibrous cap.81 82 Therefore, the plasma concentration of lipoproteins is of importance in the development of atherosclerosis.83 84 85 Whereas the independent association of high levels of LDL cholesterol and low levels of HDL cholesterol to coronary atherosclerosis and disease has long been known,86 it is still debated whether they also play a similar role in cerebrovascular atherosclerosis and infarctions. The different pathogenesis underlying the 2 diseases probably contributes to this controversy: whereas overlying thrombosis is almost always the reason for MI's becoming culprit, ischemic stroke has numerous precursors, such as embolism from or thrombosis on an atherosclerotic plaque in an extracranial or intracranial vessel, embolism from the heart, small-vessel disease in the brain, and inflammatory arterial disease.
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Plasma Cholesterol and Stroke Risk |
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TopAbstractIntroductionUltrasound in Predicting...Ultrasound in Predicting...Histological Plaque Constituents...Predictive Value of Plasma...Plasma Cholesterol and Stroke...Conclusion and PerspectivesReferences |
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A number of earlier prospective studies showed no associations between total cholesterol levels and risk of cerebral infarction or total stroke.87 However, a review published in 198887 of 26 studies concluded that lipoprotein levels are related to the extent and/or severity of cerebrovascular atherosclerosis, especially with increasing age. In 23 of the studies abnormal lipid profiles were found, with either elevated total cholesterol, increased LDL, or occasionally reduced HDL cholesterol.87 A more recent review and meta-analysis88 of 10 prospective studies revealed a pooled relative risk of 1.31 (95% confidence interval, 1.11 to 1.54; P<0.01) for the relations between plasma cholesterol concentration >5.7 mmol/L and stroke risk, also indicating that this association is not log-linear: only relatively high cholesterol concentrations are associated with significantly increased risk.89 Only a few prospective studies investigated the effect of lipid fractions on risk of stroke; again the results were not uniform.89 90 91 The most recent study by Tanne et al91 found an independent negative association between HDL cholesterol and ischemic stroke during a 21-year follow-up of 8586 men. Problems with these studies include interstudy variation in lipoprotein fractions analyzed, investigation methods of the arterial segment, populations sampled, controls for case-control studies, and statistical management of the data. The worst problem, however, is that most earlier prospective studies did not distinguish between ischemic and hemorrhagic stroke, which are supposed to have opposed relationships to plasma cholesterol levels: the incidence of ischemic stroke is found to be positively and of hemorrhagic stroke to be negatively related to total cholesterol levels.92 Finally, stroke is accompanied by a temporary reduction in plasma lipoprotein levels, and lipoprotein results from acute-stroke studies can therefore be biased for this reason.87
Plasma Lipoproteins and Carotid Intima-Media Thickness
Since the reviews87 88 were published, a
number of studies have used ultrasound B-mode to measure the wall
thickness of the extracranial part of the carotid arteries
(intima-media thickness, or IMT) as an indicator of atherosclerotic
diseases.93 94 There is evidence that an increase
in IMT is linked to different risk factors for
atherosclerosis, such as age, systolic blood
pressure, a history of coronary heart disease, diabetes
mellitus, levels of LDL cholesterol, and smoking
habits,95 96 and patients with familial
hypercholesterolemia have also been shown to
have increased IMT.97 98 IMT has in addition been
recognized as a useful measure in evaluating regression and progression
of atherosclerosis in clinical trials. Unfortunately,
however, the carotid IMT methodology varies from study to study
according to the number of measurements in the different
arterial segments. The interobserver and intraobserver
reliability (coefficients of variation) of performing repeated
measurements of IMT has been tested by Salonen and
Salonen94 and found to be 10.5% and 8.3%,
respectively.
In 1 case-control study, IMT was correlated positively with plasma cholesterol (r=0.59), LDL cholesterol (r=0.60), and plasma triglycerides (r=0.27).98 In another study in women, premenopausal values of triglycerides and postmenopausal values of LDL cholesterol were independently positively related to average IMT.99 In a third study, multiple regression analysis showed that age directly and HDL cholesterol indirectly were related to IMT (P<0.05).100 Furthermore, in a Japanese population study, IMT was related directly to age, systolic blood pressure, smoking, and total cholesterol both in men and women and indirectly to HDL cholesterol in men only.101 IMT was positively correlated with lipoprotein(a) [Lp(a)] and triglycerides levels but negatively with HDL cholesterol in a prospective study of 59 hypercholesterolemic men without symptomatic cerebrovascular disease.102 Baldassare et al103 reported that IMT in the common carotid artery is higher in hypercholesterolemic patients with plasma Lp(a) levels >30 mg/dL than in those with lower levels (P<0.01). IMT was correlated also directly and independently with plasma levels of Lp(a).103
In summary, recent studies found ischemic stroke correlated positively with LDL cholesterol and negatively with HDL cholesterol levels in plasma.
Influence of Plasma Cholesterol Lowering on Stroke
Risk
The lipid composition influences the consistency of a
plaque, such that liquid cholesterol esters soften whereas
crystalline cholesterol stiffens the
atheromatous "gruel."104
Lipid-lowering therapy (reducing plasma cholesterol to less
than 150 mL/dL105) is expected to influence
the relative amounts of these 2 lipid components by depleting the
cholesterol esters and matrix-degenerating
macrophages and resulting in a stiffer and more stable
plaque,73 106 but not necessarily by decreasing
the volume of the plaque. This may be why an effect of lipid-lowering
therapy on a lower incidence of MI107 108 and
stroke109 110 111 can be seen without a major change
in plaque size or volume (ie, degree of
stenosis).104 106 112 Lowering of plasma
and LDL cholesterol levels has been shown to lead to
reduced progression or even regression of atherosclerotic disease in
coronary,113
femoral,114 and carotid arteries
(IMT)115 116 117 118 and to reduced incidence of
MI,114 cerebrovascular
events,109 110 111 and even
death.111 There are several reasons why
lipid-lowering therapy has not shown a pronounced benefit to stroke
patients until recently. First, the number of stroke incidences in the
studies designed for ischemic heart disease (middle-aged men at
low risk for stroke) was small, and consequently the power to detect an
effect on stroke was limited. Second, the distinction between
hemorrhagic and ischemic stroke was not made, which could
confuse the results. Third, cholesterol seems to be a less
potent risk factor for ischemic stroke than for
ischemic heart disease,92 and therefore
large reductions in cholesterol or higher numbers of
patient-years of observations would be required to demonstrate
benefit.88
Triglycerides and Stroke Risk
Controversies still exist on the relation of
triglycerides to cerebrovascular disease. While some
studies did not find any association between fasting levels of
triglycerides and stroke,89 119 120
others found a positive association to total
stroke121 or ischemic
stroke.90 122 Like LDL,
triglyceride-rich lipoproteins can transfer from plasma
into the arterial intima,85 where
such particles appear to be retained
selectively.85 122 In contrast to LDL, which
requires previous oxidation, triglyceride-rich lipoproteins
can be taken up directly by macrophages to produce lipid-rich
foam cells.123 According to
Zilversmit83 accumulation of
triglyceride-rich dietary particles in some individuals,
due to reduced clearance, results in a prolonged exposure of the
endothelial surface, thereby promoting the formation of
atherosclerosis. Accumulating evidence suggest that
postprandial triglyceride-rich lipoproteins and their
remnants as well as reduced levels of HDL cholesterol are
independent predictors of carotid IMT,125 126 127
carotid plaque echolucency128 129 (Table 5), and coronary artery
disease.67 130 131 132 133 Three intervention trials
have found a beneficial effect associated with reduction of
triglyceride-rich lipoprotein in plasma, leading to a
reduction in the progression of coronary
atherosclerosis134 and
coronary events,135 136 whereas no
beneficial influence on carotid atherosclerosis and
cerebral events has been demonstrated. In conclusion therefore, more
evidence on the role of triglycerides in cerebrovascular
disease and on the risk of stroke is needed.
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Conclusion and Perspectives |
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TopAbstractIntroductionUltrasound in Predicting...Ultrasound in Predicting...Histological Plaque Constituents...Predictive Value of Plasma...Plasma Cholesterol and Stroke...Conclusion and PerspectivesReferences |
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Both echolucency on ultrasound B-mode imaging and triglyceride-rich lipoprotein levels in plasma appear to predict a lipid-rich plaque in the carotid artery. These plaques may be particularly rupture prone, predicting neurological events.
Studies on carotid and coronary
endarterectomy specimens indicate the existence of
a dynamic process of rupture, thrombus formation, healing, and
remodeling of the plaque. A plaque from a symptomatic
patient may not show any signs of plaque rupture if the plaque has
healed or evolved since the debut of symptoms. Examination of carotid
and coronary specimens may give clues to the mechanisms of
plaque disruption but cannot entirely explain the above-mentioned
dynamic process.105 137 138 139 140 141 142 The shoulders of a
plaque are often heavily infiltrated with
activated-macrophage foam cells, indicating ongoing
inflammation. Future studies on the inflammatory cell infiltrate in
plaques may give more information on the possible role of the foam
cell, smooth muscle cells, and other components in plaque
rupture.143 144 145 The subjective evaluation of
plaque morphology on B-mode ultrasound should be complemented with or
substituted by objective evaluation such as videodensitometric
analysis. This method is a commercially available, relatively
inexpensive, and investigator-independent solution. More studies on the
natural history of carotid artery plaques are needed to predict more
reliably which plaque types or features are the most dangerous (Figure 2). Earlier identification by noninvasive
imaging techniques, screening for inflammatory markers, or measuring
plasma lipoprotein levels in the fasting and postprandial state in
plasma may allow us to select asymptomatic patients for
endarterectomy before they experience a disabling
or fatal stroke.
|
|
Acknowledgments |
|---|
The author thanks Henrik Sillesen, MD, DMSc, Børge G. Nordestgaard, MD, DMSc, and Torben V. Schroeder, MD, DMSc, for constructive criticism and comments.
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Footnotes |
|---|
Reprint requests to Dr Marie-Louise Moes Grønholdt, Department of Vascular Surgery, RK 3112, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark.
Received October 27, 1997; accepted June 9, 1998.
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References |
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