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(Circulation. 1996;94:928-931.)
© 1996 American Heart Association, Inc.

Articles

Vulnerable Plaque

Relation of Characteristics to Degree of Stenosis in Human Coronary Arteries

Jessica M. Mann, MD; Michael J. Davies, MD, FACC, FRCP

the British Heart Foundation Cardiovascular Pathology Unit, St George's Hospital Medical School, London, United Kingdom.

Correspondence to Dr M.J. Davies, British Heart Foundation Cardiovascular Pathology Unit, St George's Hospital Medical School, Cranmer Terrace, London SW17 ORE, UK.

	Abstract

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Background The microanatomic features of the atherosclerotic plaque at risk of disruption include a large lipid core, a high macrophage content, and a thin cap. The relation between lipid core size, plaque size, and cap thickness either with each other or with the degree of stenosis has yet to be evaluated in human coronary arteries.

Methods and Results Atherosclerotic coronary plaques (n=160) were obtained from 31 subjects who died suddenly of ischemic heart disease. In coronary arteries perfused with formol saline at a pressure of 100 mm Hg, stenosis was measured by comparison of the minimal lumen size at the site of a plaque with that of the lumen in an adjacent normal segment of artery. Plaque size, the size of the lipid core, and the thickness of the cap were measured in histological sections. Lipid core size ranged from 0% to 82% of overall plaque size. Seventeen percent of plaques had a core size of >50%. Linear regression showed no relation of core size to stenosis (r=.21). Absolute plaque size bore no relation to core size (r=.14). Minimal cap thickness was not related to core size (r=.06). Ten percent of plaques predicted to be angiographically invisible had cores of >50%.

Conclusions Two major determinants of plaque vulnerability, core size and cap thickness, are not statistically related. Neither of these two factors that confer vulnerability are related to absolute plaque size or to the degree of stenosis.

Key Words: plaque • stenosis • coronary disease

	Introduction

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Intravascular ultrasound shows that segments of coronary arteries that are angiographically normal may contain atherosclerotic plaques.^{1 2} The insensitivity of the angiogram for the detection of plaques is due both to localized medial atrophy, which allows the plaque to bulge outward rather than inward toward the lumen, and to an overall remodeling of the vessel wall leading to an increase in external diameter accommodating the plaque while preserving the lumen dimensions.³

The ways in which plaques with a lipid core and a fibromuscular cap containing collagen (designated as types IV or Va by the Committee on Vascular Lesions of the American Heart Association⁴ ) progress to cause symptoms is of major interest. It is established that disruption of a type IV or Va atherosclerotic plaque is the event that initiates the coronary thrombi, which in turn causes both the crescendo form of unstable angina and acute myocardial infarction. This view is the culmination of work on necropsy material,^{5 6 7 8 9} the angiographic characteristics of the culprit lesion,^{10 11} the use of angioscopy,¹² and the success of thrombolytic therapy in reopening occluded arteries in acute infarction.

The morphological characteristics of plaques that are vulnerable and have a high risk of disruption have been inferred from analysis of lesions that have already undergone disruption. Observational studies by pathologists using both necropsy and atherectomy material show that plaques that cause thrombosis are rich in lipid.^{13 14 15} The lipid core of such plaques occupies a high proportion of the overall plaque volume.¹⁶ In addition, the plaque cap is thin and the macrophage density high.^{17 18} Solid fibrous plaques (AHA type Vc) without a lipid core have no risk of disruption. The nature of the core material, which is rich in tissue factor produced by macrophages,¹⁹ enhances the thrombotic response when a lipid rich plaque undergoes disruption.

There is little work relating the characteristics that confer vulnerability, ie, a large core and thin cap,¹⁸ with factors such as stenosis and plaque size. It is known that an individual coronary artery usually contains a spectrum of plaques ranging from the lipid-rich to the fibrous in type.²⁰ While most subjects have a spectrum of plaque types, some have a preponderance of one or other type.²⁰ Previous studies of plaque composition have suggested that with increasing stenosis, the relative proportion of the plaque occupied by acellular fibrous tissue and the lipid core increases in a linear fashion.^{21 22 23}

	Methods

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Thirty-one white subjects (4 women, 27 men) who were 69 years old and had died suddenly of ischemic heart disease were studied. The subjects formed a consecutive series of patients who collapsed outside the hospital and who died in the receiving room of one hospital. Autopsy carried out by one of us (M.J.D.) showed no cause of death other than coronary artery disease. All had resuscitation attempted in the ambulance and/or receiving room. The mean age was 59 years, with a range of 46 to 69. Twenty-five of the subjects (81%) had experienced chest pain in the 6 hours before death. Prior (healed) myocardial infarction was found at necropsy in 2 (6%) and acute infarction in 4 (13%). Five patients (16%) had been clinically diagnosed as suffering from ischemic heart disease on the basis of a prior history of exertional angina.

The coronary arteries were fixed by perfusion with 10% formaldehyde at a pressure of 120 mm Hg against the closed aortic valve for 24 hours. The arteries were then dissected intact from the heart and decalcified. The coronary arteries then were divided into 2-mm transverse slices throughout their entirety. These thin tissue slices then were analyzed for the area and diameter of the lumen with the use of an image analyzer (Analytical Medical Systems) with a Canon macrolens attached to a JVC TK-870E video camera. The depth of field of the lens allowed focusing on the point of maximal lumen narrowing. Lumen measurements were plotted against the distance from the ostium of the artery. Many plaques extended through more than one 2-mm segment. In such instances, the measurements were made at the point of maximum stenosis.

Tissue slices then were processed for histology. The segments were embedded in paraffin wax and each tissue block cut at four-step levels 500 µm apart to provide histological sections 6 µm in thickness. Sections were stained with Sirius red,^{22 23} which binds to collagen types I, II, and III and when viewed under polarized light produces very high contrast images. With the use of this technique, images not unlike those seen in intravascular ultrasound are produced (Fig 1). The similarity is not surprising: Collagen surfaces are major reflectors of ultrasound. For all plaques, the sections were analyzed in the AMS system with use of the Optomax program. The plaque at the point of maximal lumen narrowing was outlined on the screen by the observer. With the use of automatic edge detection at a constant intensity of illumination, the size of the lipid core of the plaque not occupied by collagen then was measured as a percentage of the overall cross-sectional area of the plaque. The thickness (maximum and minimum) of the cap was measured with the use of the same system. Acute culprit lesions were excluded from analysis, as were 19 totally chronically occluded arteries that could not be perfusion-fixed. Data sets were compared with the use of simple linear regression to calculate an r value.

View larger version (77K): [in this window] [in a new window]   Figure 1. Sirius red binds to collagen types I and III; this property is used to generate a single color-coded image (yellow) under polarized light. The plaque core shows up as a collagen-free area separated from the lumen () by a thin fibrous cap.

Forty-nine entire coronary arteries that contained 160 plaques of types IV and V were studied. Lesions of type I-III were not included in the study. Twenty-two of the 31 patients (71%) had a major thrombus occluding more than 30% of the lumen cross-sectional area at that point. These 22 plaques, taken to be the culprit lesion precipitating death, were excluded. Of these 22 plaques, 17 had undergone disruption with both an intraplaque thrombus and an intraluminal thrombus. Five of the 22 plaques had thrombosis as the result of erosion of the surface without an intraplaque component. A further 10 plaques were present in which there were small intraplaque recent thrombi; these were also excluded from the study. The exclusions ensured that only plaques in a stable phase were studied.

	Results

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There was considerable heterogeneity in the relative amounts of collagen and extracellular lipids in the plaques (Table 1). Seven percent of plaques overall were entirely fibrous and would be classified as type Vc by the AHA-recommended nomenclature. Every permutation of the variables of plaque size, stenosis, core size, and cap thickness occurs (Fig 2). The core size relative to overall plaque size in the types IV and Va plaques ranged from 5% to 82%. There was no correlation (r=.21) (Fig 3) between core size and the degree of stenosis. Absolute plaque size had a mean value of 496 mm², with an upper limit of 1576 mm². There was no relation (r=.14) to lipid core size. Minimal cap thickness had a mean of 0.25 mm (range, 0.02 to 1.14 mm) and had no relation to core size (r=.06). The results are shown in Table 2.

View this table: [in this window] [in a new window]   Table 1. Lipid Core Size as a Proportion of Overall Plaque Size in 160 Plaques

View larger version (79K): [in this window] [in a new window]   Figure 2. Spectrum of relation of core size to cap thickness. A, The plaque is almost solid apart from small discontinuous lipid-containing areas. B, The plaque that causes high-grade stenosis has a very large lipid core but with a thick cap, in contrast to Fig 1.

View larger version (18K): [in this window] [in a new window]   Figure 3. Lipid core size as a percentage of overall plaque size plotted against percentage of diameter stenosis. There is no significant correlation (r=.21). Plaques with a very large lipid core can cause stenosis ranging from negligible to high grade.

View this table: [in this window] [in a new window]   Table 2. Variables Correlated

	Discussion

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This study set out to test the hypothesis that angiography could predict the characteristics of stable plaques that determine vulnerability. To do this, a method of measuring stenosis in necropsy material had to be developed that would be directly comparable to that used in clinical angiography. Cardiologists measure coronary artery stenosis in angiograms by the reduction in lumen diameter at a specific point compared with that at a nearby normal segment. Coronary vasodilation is induced before the measurement. In the present study, the lumen was perfusion-fixed to mimic maximal vasodilation. In such pathology preparations, the internal elastic lamina is smooth and not crenated, suggesting the objective was achieved. The lumen area at the site of plaques was compared with that of an adjacent arterial segment without plaques. This method eliminates the variable of arterial wall remodeling at the site of plaques.²⁴

The time course of progression of coronary disease has been reported in a number of sequential angiographic studies.^{25 26 27 28} These studies have shown that progression is episodic and unpredictable. The sites at which the thrombotic lesions responsible for acute infarction develop are usually of moderate stenosis severity with a mean of 48% by diameter.²⁹ A significant number both of the thrombotic occlusions and of the high-grade stenoses that develop between angiograms occur in arterial segments that were regarded as angiographically normal or mildly irregular in the first angiogram.³⁰ The present study confirms that segments of artery in which the lumen is normal in size contain plaques. Of the 160 plaques studied, 55 (34.4%) would have been predicted to have been angiographically visible. Of these 55 plaques, 7% had lipid cores >50% of overall plaque volume and were thus at high risk for a disruption episode. The clinical angiographic data showing that new lesions can suddenly appear in normal arteries thus have a sound pathological explanation in that disruption of a previously occult vulnerable plaque has occurred. The present study, however, shows that vulnerable plaques occur across the full spectrum of severity of stenosis. However, disruption of a plaque causing minimal stenosis is more likely to invoke an acute ischemic episode because of the lack of prior collateral development.

The AHA-recommended classification^{4 23} of plaques has unified descriptions of lesions, allowing the work of different groups to be comparable. Nevertheless, within plaques that are types IV and Va with a lipid core and fibrous cap, there is still considerable heterogeneity in core size and cap thickness (Fig 2). The lack of correlation between absolute plaque size, core size, and cap thickness may suggest that these variables are independent. Little is known of what determines core size, although death of lipid-filled macrophages by apoptosis is a potential mechanism for increasing the lipid core content.¹⁸ The factor determining cap thickness may be in part the activity of macrophages and in particular their production of metalloproteinases concerned with connective tissue degradation.^{31 32 33 34} A thick cap may reflect that local repair by smooth muscle cells producing collagen is in the ascendant.³³ What appears established is that the concordance of a large core and a thin cap is the major determinant of plaque vulnerability.¹⁸ These parameters cannot be determined by angiography, although intravascular ultrasound and magnetic resonance may in the future become sufficiently sensitive to determine plaque characteristics in life.

Patient selection will inevitably influence the results of any study of plaque composition. This study selected subjects who were not chronically ill from heart failure and who died suddenly of ischemic heart disease outside the hospital. There was a low frequency of acute or old myocardial infarction. The subjects were still at a stage in which the coronary lesions were discrete and represent the moderate levels of disease found in many living symptomatic patients in whom the mechanisms of disease progression are of interest. Inclusion of patients with end-stage triple-vessel disease might well have produced data in which collagenous plaques are more predominant. The data reported by Kragel and colleagues^{34 35 36} also have related plaque constituents to the degree of stenosis in stable angina, unstable angina, and acute myocardial infarction. There was a linear increase in the mean proportion of the plaque occupied by acellular collagen and the lipid core with increasing stenosis. However, the use of mean data based on large numbers of plaques obscures the scatter of individual values. For this reason, in this study scatterplots were used. The studies by Kragel et al also included arteries in which the degree of stenosis was so great that chronic total occlusion was present. Fibrosis and smooth muscle proliferation is the ubiquitous repair response of the vessel wall and is the final common end point of disease progression. In the present study, such arteries were not included in the analysis because the purpose was to relate the plaque constituents to stenosis in patent arteries.

Individual patients vary in the proportion of plaque types that exist in their coronary arteries. While most patients have mixtures of all types of plaques, a small minority either have all fibrous or all lipid-rich plaques.²⁰ The former may have slowly progressive stable angina as their main clinical expression; the latter have a very high risk of repeated acute ischemic episodes as the result of plaque disruption. Angiography, however, will not separate patients whose ultimate course will be to different ends of the clinical spectrum of ischemic heart disease, since it gives no information on plaque composition.

A limitation of the present study is the relatively small number of patients and lack of detailed knowledge of their lipid levels and risk profiles. They represent a small sample of white subjects without a known history of familial hypercholesterolemia or diabetes. Further studies are needed to ascertain whether the composition and distribution of plaque types in diabetics, nonwhite subjects, and men and women differ.

Received November 20, 1995; revision received February 21, 1996; accepted March 4, 1996.

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