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(Stroke. 1997;28:95-100.)
© 1997 American Heart Association, Inc.

Articles

Carotid Plaque Morphology and Clinical Events

Thomas S. Hatsukami, MD; Marina S. Ferguson, MT(ASCP); Kirk W. Beach, PhD, MD; David Gordon, MD; Paul Detmer, PhD; David Burns, PhD; Charles Alpers, MD D. Eugene Strandness, Jr, MD

the Surgical Service, Seattle Veterans Affairs Medical Center (T.S.H.); Departments of Pathology (M.S.F., C.A.) and Surgery (K.W.B., P.D., D.E.S.), University of Washington, Seattle; Department of Pathology, University of Michigan, Ann Arbor (D.G.); and Department of Chemistry, McGill University, Toronto, Canada (D.B.).

Correspondence to Thomas S. Hatsukami, Seattle VA Medical Center, Surgical Service (112), 1660 S Columbian Way, Seattle, WA 98108. E-mail tomhat@u.washington.edu.

	Abstract

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Background and Purpose Studies have suggested that B-mode ultrasonography can be used to determine carotid plaque composition and that specific plaque characteristics are associated with a worse clinical outcome. However, histological studies examining the relationship between carotid plaque morphology and clinical outcome have reported conflicting findings. Furthermore, few investigators have described plaque morphology in quantifiable terms. This study examines the association between the volume of carotid plaque constituents and preoperative ischemic neurological symptoms. Constituents examined were chosen based on their potential for identification by current diagnostic imaging modalities such as ultrasound or MRI.

Methods Atherosclerotic plaques from 43 patients undergoing carotid endarterectomy were examined histologically, with sections obtained every 0.5 to 1 mm. The lesions were examined for the presence and quantity of fibrous intimal tissue, intraplaque hemorrhage, lipid core, necrotic plaque core, and calcification. The quantity of each constituent was compared in plaques removed from symptomatic patients with those excised from asymptomatic individuals. Differences were analyzed with a Kolmogorov-Smirnov statistic.

Results There was no difference between plaques removed from asymptomatic and symptomatic patients with regard to the presence and volume of fibrous intimal tissue, intraplaque hemorrhage, the lipid core, the necrotic core, or calcification.

Conclusions In patients with highly stenotic carotid lesions who are undergoing carotid endarterectomy, gross plaque composition is similar regardless of preoperative symptom status. Given this similarity, it is unlikely that differences in the volume of intraplaque hemorrhage, lipid core, necrotic core, or calcification in atherosclerotic carotid plaques explain their embolic history.

Key Words: atherosclerosis • carotid arteries • histology • magnetic resonance imaging • ultrasonics

	Introduction

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A number of investigators have observed that the majority of patients with highly stenotic, atherosclerotic carotid plaques remain asymptomatic. For example, in the Asymptomatic Carotid Atherosclerosis Study (ACAS), unoperated patients with a greater than 60% diameter reducing carotid artery stenosis had only an 11.0% risk for ipsilateral hemispheric stroke at 5 years and a 19.2% 5-year risk for ipsilateral transient ischemic attack or stroke.¹ Factors other than the degree of stenosis must also be important in determining whether the carotid lesion will remain clinically silent. Plaques that are more prone to disruption, fracture, or fissuring may be at higher risk for embolization, occlusion, and consequent ischemic neurological events. Glagov and Zarins² suggest that differences in plaque structure, composition, and consistency may account for the relative instability of some atherosclerotic lesions.

Several investigators have proposed the use of diagnostic imaging techniques, such as B-mode ultrasonography, to characterize plaque composition and to identify the higher-risk, unstable carotid lesion.^{3 4 5} O'Holleran et al⁵ suggested that carotid plaques with a "soft" appearance on ultrasound correlated with lesions containing intraplaque hemorrhage or lipid and that these lesions were at higher risk for stroke than "dense" lesions that were primarily fibrous tissue. Furthermore, plaques exhibiting sonographic findings consistent with calcification were found to have the lowest risk for subsequent stroke or transient ischemic attack.

However, the literature on histological studies examining the association between carotid plaque composition and neurological symptoms is inconsistent. Imparato et al⁶ found that macroscopic intraplaque hemorrhage was the only feature that was significantly more common in plaques removed from symptomatic patients. Similarly, Lusby et al⁷ noted acute or recent intraplaque hemorrhage in 49 of 53 plaques (92%) from symptomatic patients compared with 7 of 26 plaques (27%) from asymptomatic patients. Avril et al⁸ classified carotid plaques as "hard" (predominantly composed of collagen or calcium) or "soft" (containing atheromatous debris or intraplaque hemorrhage). Soft plaques were significantly more common in symptomatic carotid lesions.

In contrast to these reports, in a postmortem study involving individuals who had asymptomatic carotid disease, Svindland and Torvik⁹ noted that small recent and old hemorrhages were a common finding in carotid plaques that resulted in a greater than 60% stenosis. Furthermore, numerous healed ulcerations and organized thrombi were seen. The authors concluded that plaque complications are frequent in cases with stenosis and that most of them apparently heal without giving rise to symptoms. Bassiouny et al¹⁰ similarly concluded that intraplaque hemorrhage was commonly seen in carotid plaques, including those without severe stenosis, and did not discriminate between symptomatic and asymptomatic stenotic lesions.

Factors that may account for these conflicting findings include the use of differing techniques of tissue examination, sampling errors, and differences in the definition of specific histological features. Some studies report gross macroscopic findings, while others examine the tissue microscopically. Many studies that incorporate histological examination do not examine the lesion in its entirety. Furthermore, there is a lack of standardization of histological definitions. For example, Lusby et al⁷ made a distinction between acute, recent hemorrhage and old hemorrhage, while others did not. Lastly, most of the previous studies have noted the presence or absence of specific features, but not in quantifiable terms.

The aim of this study was to determine whether there is a quantifiable difference in the composition of plaques in symptomatic and asymptomatic patients undergoing carotid endarterectomy. Constituents examined were chosen based on their potential for identification by current diagnostic imaging modalities such as ultrasound, CT, or MRI.

	Subjects and Methods

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Patient Population
Forty-three consecutive patients undergoing carotid endarterectomy at the University of Washington and Seattle Veterans Affairs Medical Centers were recruited after informed consent was obtained. The consent forms and protocol were approved by each facility's institutional review board. Median age was 70 years (range, 48 to 89 years). Of the 43 patients, 33 were male. Twenty-one patients underwent carotid endarterectomy for symptomatic, high-grade carotid stenosis. Ten of the patients had a recent ipsilateral hemispheric stroke with some recovery, 7 patients had an ipsilateral hemispheric transient ischemic attack, and 4 patients had transient monocular blindness. The median interval between symptoms and carotid endarterectomy was 3.6 weeks. Twenty-two patients underwent carotid endarterectomy for an asymptomatic high-grade carotid stenosis.

Histological Analysis and Outlining Procedure
Endarterectomy specimens were fixed in 10% neutral buffered formalin and subsequently decalcified in formic acid. The plaques were dehydrated in graded alcohols and embedded in paraffin. Cross sections (6 µm thick) were obtained every millimeter throughout the length of the plaque. Additional sections were obtained every 0.5 mm in the region of the carotid bifurcation. The resulting sections were mounted on glass slides and stained with hematoxylin and eosin. A digitized image was created for each section with a Matrox video frame grabber and printed on a laser printer. Specific plaque constituents were traced on a transparency overlying the print. These constituents were identified under the microscope and outlined under the direct supervision of experienced cardiovascular pathologists who were unaware of the patient's clinical status.

Plaque constituents were defined as follows: (1) fibrous intimal tissue: plaque regions rich in collagen bundles (Fig 1a); (2) intraplaque hemorrhage: regions of fibrin deposits and lysed red blood cells with some surrounding inflammatory cell infiltrate (Fig 1b). These areas are in contradistinction to hemorrhage caused by operative manipulation, in which intact red blood cells without surrounding tissue reaction are seen; (3) lipid core: distinct regions containing diffusely distributed clefts from which cholesterol crystals have been extracted (Fig 1c); (4) necrotic core: discrete regions with loosely aggregated necrotic debris, no viable cells, and without admixed collagen (Fig 1d); and (5) calcification: aggregates of prominent calcification, usually of either necrotic cellular debris or collagenous stroma, but devoid of cells (Fig 1e).

View larger version (745K): [in this window] [in a new window]   Figure 1. Photomicrographs of fibrous intimal tissue (a), intraplaque hemorrhage (b), lipid core (c), necrotic core (d), and calcification (e). Feature of interest is marked with arrow. Lu indicates lumen; FC, fibrous cap.

The histological tracings on transparency were then converted to a computer-assisted drawing format with a Gateway 486 33-MHz personal computer with a Matrox video frame grabber, digitizing pad, and modified software developed on Optimas (BioScan). The outlines were then joined as a complete three-dimensional drawing with the use of SilverScreen (Schroff Development Corp) (Fig 2).¹¹

View larger version (22K): [in this window] [in a new window]   Figure 2. Simplified representation of histological reconstruction with outlines generated in Silverscreen.

Output from the SilverScreen outlines provided the distribution of each constituent within the excised specimen and the area of each constituent per 0.5- to 1.0-mm section. The volume of each constituent was estimated with the stereological method described by Cavalieri¹² :

where V(obj)=volume of the object, t=the distance between parallel sections, and a=area of the object in each cross section.

The reproducibility of our pathologists for estimating plaque constituent volumes with this technique has been previously published by Thackray et al.¹¹ In that study, the total volume for each constituent was measured in three adjacent sets of cross sections, offset by 10 µm. The technique has an average standard deviation of 2.17 mm³ over a range of constituent volumes from 250 mm³ to 0.3 mm³. For constituent volumes greater than 1 mm³, the variability was acceptable.

Statistical Analysis
The estimated volumes of each constituent in the symptomatic and asymptomatic groups were displayed in box/whisker charts and cumulative distribution plots. Kolmogorov-Smirnov statistics were calculated with Statview 4.01 statistical software (Abacus Concepts, Inc) to compare differences between the two groups.

	Results

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Degree of Stenosis
The severity of internal carotid artery stenosis was similar between the symptomatic and asymptomatic groups of patients. By duplex spectral waveform criteria,^{13 14} 7 symptomatic patients had a 50% to 79% diameter reducing internal carotid stenosis, and 14 patients had an 80% to 99% stenosis. In the asymptomatic group, 5 patients had a 50% to 79% diameter reducing internal carotid stenosis, and 17 patients had an 80% to 99% stenosis. The peak systolic velocity was similar in the symptomatic and asymptomatic groups (mean±SEM, 433±25 and 433±41 cm/s, respectively).

Volumes
The estimated volume of each plaque constituent is displayed in Figs 3 through 7. The graphs in the left panels (panel a) demonstrate the median estimated volume, the top and bottom quartiles, and the top and bottom deciles. The top, bottom, and line through the middle of each box correspond to the 75th percentile (top quartile), 25th percentile (bottom quartile), and 50th percentile (median), respectively. The whiskers extend from the 10th percentile (bottom decile) to the 90th percentile (top decile). The cumulative distribution plots in the right panels (panel b) document each data point in the asymptomatic and symptomatic groups. If there is a significant difference in the volume of a constituent between the two groups, one would expect a separation of the lines connecting the data points in each group. There was no difference in fibrous intimal tissue, intraplaque hemorrhage, lipid core, necrotic core, or calcification volumes when we compared plaques removed from symptomatic and asymptomatic individuals.

View larger version (17K): [in this window] [in a new window]   Figure 3. Box plot chart (a) and corresponding cumulative distribution plot (b) of the estimated volume of fibrous intimal tissue in plaques harvested from asymptomatic and symptomatic individuals. The top, bottom, and line through the middle of the box in panel a correspond to the 75th percentile (top quartile), 25th percentile (bottom quartile), and 50th percentile (median), respectively. The whiskers extend from the 10th percentile (bottom decile) and to the 90th percentile (top decile). There was no difference between asymptomatic and symptomatic plaques with regard to the volume of fibrous intimal tissue (P=.28).

View larger version (15K): [in this window] [in a new window]   Figure 4. Box plot chart (a) and corresponding cumulative distribution plot (b) of the estimated volume of intraplaque hemorrhage in plaques harvested from asymptomatic and symptomatic individuals. There was no difference between asymptomatic and symptomatic plaques with regard to the volume of intraplaque hemorrhage (P>.99).

View larger version (14K): [in this window] [in a new window]   Figure 5. Box plot chart (a) and corresponding cumulative distribution plot (b) of the estimated volume of the lipid core in plaques harvested from asymptomatic and symptomatic individuals. There was no difference between asymptomatic and symptomatic plaques with regard to the lipid core volume (P=.47).

View larger version (15K): [in this window] [in a new window]   Figure 6. Box plot chart (a) and corresponding cumulative distribution plot (b) of the estimated volume of the necrotic core in plaques harvested from asymptomatic and symptomatic individuals. There was no difference between asymptomatic and symptomatic plaques with regard to the necrotic core volume (P>.99).

View larger version (15K): [in this window] [in a new window]   Figure 7. Box plot chart (a) and corresponding cumulative distribution plot (b) of the estimated volume of the calcification in plaques harvested from asymptomatic and symptomatic individuals. There was no difference between asymptomatic and symptomatic plaques with regard to the volume of calcification (P=.29).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In recent years, considerable attention has been devoted to atherosclerotic plaque characterization with imaging techniques such as ultrasound and MRI.^{3 15 16 17 18 19 20 21 22 23} A reliable, preferably noninvasive method of quantitatively characterizing these lesions in vivo would provide several benefits. First, imaging methods that better characterize plaque structure and composition would help determine which factors lead to the development of unstable atherosclerotic lesions and aid in identifying patients at increased risk for plaque disruption. Second, it would permit the performance of serial examinations. Histological analysis of excised arterial specimens provides accurate data on plaque composition, but from only a single point in time. Quantitative in vivo assessment of the plaque would allow prospective studies that serially monitor the progression or regression of atherosclerosis. Third, direct in vivo assessment of atherosclerotic plaque would permit smaller, less time-consuming epidemiological studies and clinical trials. The ACAS trial demonstrated that the majority of atherosclerotic carotid lesions remain clinically silent.¹ In such circumstances, studies that use adverse clinical outcomes as end points would require large numbers of subjects followed for many years. Quantitative imaging would provide a more direct evaluation of the effect of atherosclerotic risk factors on plaque progression. Similarly, quantitative imaging would provide direct assessment of the efficacy of interventions intended to halt the progression or cause regression of atherosclerotic disease.

Advancements in ultrasound and MRI technology continually improve the prospects for precise quantitative imaging of arterial wall pathology. In this histological study, the volumes of the lipid core, necrotic plaque core, intraplaque hemorrhage, and calcification failed to discriminate lesions removed from patients who had clinically recognizable ischemic neurological events from those who were asymptomatic. These findings suggest that in highly stenotic plaques, identification and quantification of these features by MRI or ultrasound will be unlikely to distinguish lesions that are at high risk for ischemic events from those that are likely to remain clinically silent.

Characterizing the nature of the fibrous cap that overlies the lipid-rich plaque core may be more productive. For example, a thinned fibrous cap may be more prone to plaque rupture. Defining the surface morphology of the lesion may also be important. In a review of patients enrolled in the North American Carotid Endarterectomy Trial, Eliasziw et al²⁴ found a higher risk for subsequent stroke if angiographic evidence of a plaque ulcer was demonstrated. In unoperated patients with a nonulcerated 85% carotid stenosis, the risk for ipsilateral stroke at 24 months was 21.3% compared with 43.9% in patients with an ulcerated 85% stenosis. In patients with a 95% carotid stenosis, the 2-year risk for ipsilateral stroke was 21.3% in patients without evidence of ulcer and 73.2% in patients with ulcerated lesions.

However, the inability of angiography to detect plaque ulceration is well documented, in part because of the limited number of views that are typically obtained.^{25 26} In a review of the first 500 patients recruited into the North American Symptomatic Carotid Endarterectomy Trial, Streifler et al²⁶ found that the sensitivity and specificity of detecting ulcerated plaques were only 45.9% and 74.1%, respectively. The positive predictive value of identifying an ulcer was 71.8%.

Characterization of the fibrous cap and plaque surface morphology remains a significant challenge for ultrasound and MRI. As with angiography, physical restrictions limit the number of views obtainable with transcutaneous B-mode ultrasonography. As a result of anisotropic effects, the plaque surface morphology can be reliably characterized only where the ultrasound beam is orthogonal to the plaque-lumen interface.²⁷ Difficulties with MRI include flow and motion artifacts, for example, from patient movement and pulsation of the arterial wall.

Unfortunately, the surface morphology of the excised carotid plaques could not be well characterized in this study because of artifacts introduced during the removal of the lesion. During endarterectomy, the full thickness of the plaque was incised, thereby disrupting the luminal surface of the lesion. Future studies examining surface morphology will require excision of the plaque intact, without incising through to the luminal surface.

Another plaque feature that may be of interest is the age of intraplaque hemorrhage and mural thrombus. Lusby et al⁷ noted evidence of recent hemorrhage in a significantly greater proportion of plaques removed from symptomatic individuals. However, evidence of remote hemorrhage was noted in 18 of 20 asymptomatic patients with a greater than 50% stenosis. If one were to assume that lesions with recent hemorrhage are acutely unstable, as opposed to plaques with remote hemorrhage, where the lesion has undergone a process of healing as suggested by Svindland and Torvik,⁹ then distinguishing recent from remote hemorrhage would be another important goal for diagnostic imaging.

In conclusion, this study found that intraplaque hemorrhage, the lipid core, necrotic core, and calcification are commonly found in highly stenotic carotid plaques. Furthermore, the volumes of these materials are similar in plaques removed from asymptomatic and symptomatic individuals. From an imaging perspective, it is unlikely that identification of these plaque features will distinguish severe carotid stenoses that are at higher risk for developing ischemic neurological symptoms.

	Acknowledgments

 
This study was supported by the National Institutes of Health Specialized Center for Organized Research, grant P50HL42270. The authors gratefully acknowledge Randy Small, Department of Neuropathology, University of Washington, for the excellent histological sectioning of this difficult material, and Brett Thackray, MSE, for his assistance in developing the image processing software.

Received July 1, 1996; revision received September 5, 1996; accepted September 5, 1996.

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