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(Circulation. 1996;93:1354-1363.)
© 1996 American Heart Association, Inc.

Articles

Coronary Plaque Erosion Without Rupture Into a Lipid Core

A Frequent Cause of Coronary Thrombosis in Sudden Coronary Death

Andrew Farb, MD; Allen P. Burke, MD; Anita L. Tang; Youhui Liang, MD; Poonam Mannan, MS; John Smialek, MD; Renu Virmani, MD

From the Department of Cardiovascular Pathology, Armed Forces Institute of Pathology, Washington, DC, and Office of the Chief Medical Examiner (J.S.), Baltimore, Md.

	Abstract

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Background Coronary thrombosis has been reported to occur most frequently in lipid-rich plaques with rupture of a thin fibrous cap and contact of the thrombus with a pool of extracellular lipid. However, the frequency of coronary artery thrombosis with or without fibrous cap rupture in sudden coronary death is unknown. In this study, we compared the incidence and morphological characteristics of coronary thrombosis associated with plaque rupture versus thrombosis in eroded plaques without rupture.

Methods and Results Fifty consecutive cases of sudden death due to coronary artery thrombosis were studied by histology and immunohistochemistry. Plaque rupture of a fibrous cap with communication of the thrombus with a lipid pool was identified in 28 cases. Thrombi without rupture were present in 22 cases, all of which had superficial erosion of a proteoglycan-rich plaque. The mean age at death was 53±10 years in plaque rupture cases versus 44±7 years in eroded plaques without rupture (P<.02). In the plaque-rupture group, 5 of 28 (18%) were women versus 11 of 22 (50%) with eroded plaques (P=.03). The mean percent luminal area stenosis was 78±12% in plaque rupture and 70±11% in superficial erosion (P<.03). Plaque calcification was present in 69% of ruptures versus 23% of erosions (P<.002). In plaque ruptures, the fibrous cap was infiltrated by macrophages in 100% and T cells in 75% of cases compared with 50% (P<.0001) and 32% (P<.004), respectively, in superficial erosions. Clusters of smooth muscle cells adjacent to the thrombi were present in 95% of erosions versus 33% of ruptures (P<.0001). HLA-DR expression was more often seen in macrophages and T cells in ruptures (25 of 28 cases) compared with expression in macrophages in superficial erosion arteries (8 of 22 cases, P=.0002).

Conclusions Erosion of proteoglycan-rich and smooth muscle cell–rich plaques lacking a superficial lipid core or plaque rupture is a frequent finding in sudden death due to coronary thrombosis, comprising 44% of cases in the present study. These lesions are more often seen in younger individuals and women, have less luminal narrowing and less calcification, and less often have foci of macrophages and T cells compared with plaque ruptures.

Key Words: plaque • thrombosis • death, sudden • coronary disease

	Introduction

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Atherosclerosis consists of the intra-arterial accumulation of varying quantities of intracellular and extracellular lipids, macrophages, T cells, smooth muscle cells, proteoglycan, collagen, calcium, and necrotic debris. Sudden changes in coronary plaque luminal surface morphology consisting of plaque rupture or fissure have been recognized as an important mechanism of thrombosis and in the clinical presentation of unstable angina, acute myocardial infarction, and sudden death.^{1 2} Recent attention has focused on identifying "vulnerable" plaques, especially in view of angiographic studies that have shown new coronary occlusion in vessels that were only mildly or moderately stenotic on previous arteriography.^{3 4}

A typical vulnerable plaque has been reported to consist of an eccentric plaque that is rich in extracellular lipid within a large lipid pool with a thin overlying fibrous cap.^{5 6 7 8 9} In these lesions, the fibrous cap is frequently infiltrated with activated T cells and macrophages. Plaque rupture of a thin fibrous cap resulting in exposure of flowing blood to the lipid core is believed to comprise the vast majority of coronary thrombi.^{1 2} This conclusion has emerged from studies of diverse populations that included individuals with sudden and nonsudden death with thrombi of different ages.^{10 11 12 13 14 15 16 17 18 19 20 21} The morphology of the underlying plaque associated with the thrombus has been examined in varying degrees of detail. The purpose of this study was to systematically describe the pathological substrate of coronary thrombosis in a defined group of individuals with sudden coronary death.

	Methods

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Selection of Cases
Cases of sudden coronary death were identified as part of a consultative service provided to the Office of the Chief Medical Examiner for the State of Maryland.²² Sudden coronary death was defined as witnessed sudden unexpected death within 6 hours of the onset of symptoms or death of an individual who had been seen in stable condition less than 24 hours antemortem. To be included in the study, at least one major coronary artery had to have a histologically confirmed acute luminal thrombus. No other potentially lethal cardiac or noncardiac cause of death could be present, including alcohol and drug causes identified on toxicology testing. Associated nonlethal medical conditions were recorded. Cases of mechanical cardiac complications secondary to acute myocardial infarction (such as free wall, septal, or papillary muscle rupture) were excluded. Consecutive sudden death hearts with acute coronary thrombosis were collected between July 1993 and November 1994.

Coronary Artery Evaluation
All hearts were examined fresh and uncut, with fixation performed on the day of autopsy. No previously cut hearts were included in this study. Hearts with a short segment of attached aortic stump were excised and weighed. The coronary arterial tree was perfusion-fixed with 10% neutral-buffered formalin for 15 minutes at 100 mm Hg. Postmortem coronary angiography was performed in most cases by selective injection of the left and right ostium with a mixture of barium gelatin followed by radiography after 15 minutes of further fixation. The major epicardial coronary arteries (left main, left anterior descending, left circumflex, and right coronary arteries) and their main branches (left diagonals, left obtuse marginals, and posterior descending coronary artery) were cut transversely at 2- to 3-mm intervals (following decalcification if necessary). Those segments that had a >50% cross-sectional luminal stenosis by visual inspection were submitted for light microscopy (after 24 hours of immersion-fixation in formalin), histological examination, and morphometric measurements. The severity and extent of coronary atherosclerosis determined the number of histological sections examined per case. Between one and six arterial segments were placed in each cassette. Arterial segments were dehydrated in a series of graded alcohols, cleared with xylene, embedded in paraffin, cut at 4 µm, and stained with hematoxylin-eosin and Movat pentachrome stains. With Movat pentachrome, elastic fibers stain black, collagen stains yellow, and proteoglycan stains green.

Coronary thrombosis cases were separated into two categories based on the morphology of the underlying plaque. (1) Coronary thrombosis with plaque rupture was defined as a disruption of a fibrous cap over a lipid core with contact of the acute thrombus with the lipid pool. (2) Coronary thrombosis with superficial erosion (without plaque rupture) consisted of an acute thrombus in direct contact with the intimal plaque without rupture of a lipid pool. A lipid core could be present deep within the plaque, but there could be no communication between the thrombus and lipid pool. Segments that demonstrated luminal thrombus but no rupture into a lipid core underwent serial step-sectioning and staining (at every 40 µm for at least 1 to 2 cm) to determine whether rupture of a fibrous cap was present deeper in the section.

Coronary artery segments that had an acute thrombus by light microscopy (luminal collections of platelets and/or fibrin with or without trapped erythrocytes and white blood cells) were selected for immunohistochemical stains and morphometry. For immunohistochemical stains, the avidin-biotin complex method was applied to deparaffinized sections. The following antibodies (dilution in parentheses) were used: smooth muscle–specific -actin (1:5000, Sigma Chemical Co); KP-1, a macrophage marker (1:75, Dako Corp); UCHL-1, a T-cell marker (1:75, Dako); HLA-DR, an antigen expressed in activated cells (1:200, Dako); and factor VIII (1:3200, Dako). For KP-1 and factor VIII, tissue sections were predigested with protease K (0.1 mg/mL) at 37°C for 20 minutes. Biotinylated rabbit or mouse IgG was used as the secondary antibody, and the detection system was Vectastain Elite ABC kit (Vector Laboratories). Sections were counterstained with hematoxylin. Positive and negative controls were run in parallel for every stain.

The most severely narrowed arterial segment containing the thrombus was magnified and digitized. From this segment, the arterial size (defined by the area within the internal elastic lamina) and lumen area (excluding the thrombus) were measured (IPLab image analysis software, version 2.5) and used to determine cross-sectional area percent stenosis [100x(1-lumen area/arterial size)].

Myocardial Evaluation
The right and left ventricles were cut at 1.0-cm intervals parallel to the posterior AV groove from apex to base. The myocardium was examined for the presence of healed and/or acute myocardial infarction. In hearts without gross evidence of myocardial infarction (acute or healed), at least one section of the myocardium was submitted (from the mid-ventricular slice) from the anterior left ventricular wall, lateral wall, posterior wall, interventricular septum, and posterior right ventricular wall (total of five myocardial sections). In hearts with myocardial infarction identified on gross examination, sections from all acute and healed infarcts in addition to the above listed sections were submitted. Each myocardial section was approximately 1.5- to 2.0-cm in length and extended from the endocardium to epicardium. Healed myocardial infarction was identified by focal macroscopic replacement of the myocardium by scarring with histological confirmation. Acute myocardial infarction was diagnosed by the presence of coagulation necrosis of myocytes with or without an associated inflammatory infiltrate.

Statistical Analysis
Numerical data are presented as mean±SD. Continuous variables were compared with ANOVA, and categorical variables were compared with a ² test (Statview software, version 4.01). A value of P.05 was considered significant.

	Results

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There were 96 cases of sudden coronary death; of the 96, 50 had an acute thrombus in a major epicardial coronary artery. The population consisted of 34 men and 16 women (36 white, 14 black; mean age, 49±10 years). Twenty-five individuals were found dead, and 25 had a witnessed collapse. Of those with a witnessed collapse, 14 complained of chest pain and/or dyspnea and 11 did not report symptoms. Other known medical conditions in these sudden death victims consisted of the following: ischemic heart disease in 3, hypertension in 3, diabetes in 3, renal disease in 2, peptic ulcer disease in 2, cerebral vascular disease in 1, mitral valve prolapse in 1, asthma in 1, schizophrenia in 1, glaucoma in 1, and hypothyroidism in 1.

The extent of epicardial coronary artery atherosclerosis was as follows: one-vessel disease in 28 (56%), two-vessel disease in 13 (26%), and three-vessel disease in 9 (18%). Of the 50 coronary arteries with acute thrombi, the left anterior descending was thrombosed in 33, left circumflex in 7, right coronary in 9, and ramus intermedius in 1. The mean percent cross-sectional area stenosis for all 50 arteries (excluding the thrombus itself) was 74±12% (range, 50 to 98%). An acute myocardial infarction was confirmed histologically in 16 cases (32%), of which 9 had only an acute infarct, and 7 had both an acute and healed infarct. A healed infarct in the absence of an acute infarct was present in 10 (20%), and no myocardial infarct (neither acute nor healed) was present in 24 cases (48%).

Coronary Pathology
Of the 50 acutely thrombosed coronary artery plaques, there were 22 superficial erosions and 28 ruptures. In plaque rupture cases (Figs 1 and 2), a thin collagenous fibrous cap separated the lumen from the underlying lipid core. The plaque rupture site was characterized by discontinuity of the fibrous cap and contact of the acute thrombus with the lipid core. The site of rupture was in the center of the cap in 16 cases (57%), toward the periphery of the cap (near the junction of the cap with the adjacent intima) in 10 (36%), and indeterminate in 2.

View larger version (143K): [in this window] [in a new window]   Figure 1. Acute thrombosis of the left anterior descending coronary artery was found in this 54-year-old man with witnessed cardiac arrest and death 2.5 hours after the onset of chest pain. A, Concentric plaque with a large hemorrhagic lipid core (L) and focal calcification (arrows) is seen at low power; an occlusive thrombus (arrowheads) is present. B, The platelet-rich thrombus (T) is adjacent to the rupture of the fibrous cap (high power). Immunohistochemical staining demonstrates abundant macrophages (in C), an absence of smooth muscle cells (in D), and scattered T cells (in E) with HLA-DR–positive macrophages and T cells (in F). (A: Movat pentachrome, x15; B: Movat pentachrome, x150; C: anti–KP-1, x300; D: anti–smooth muscle actin, x300; E: anti–UCHL-1, x300; and F: anti–HLA-DR, x300. Scale bars: A, 375 µm; B, 120 µm; and C through F, 120 µm.)

View larger version (146K): [in this window] [in a new window]   Figure 2. A, A 41-year-old man had sudden onset of dyspnea followed by witnessed collapse. In the left anterior descending coronary artery, an eccentric plaque with a large lipid core (LC) and focal calcification (arrows) was present (low power); a nonocclusive thrombus (arrowheads) is present, and the remainder of the lumen (L) is filled with dark-gray barium gelatin. B, Thrombus (T) is seen adjacent to the site of fibrous cap rupture (arrows). The rupture site is at the junction of the end of the fibrous cap with its attachment with the intimal plaque. Immunohistochemical staining demonstrates numerous macrophages (in C) and occasional smooth muscle cells (in D) and T cells (in E) at the site of plaque rupture. HLA-DR–positive macrophages and T- cells are as seen in F. (A: Movat pentachrome, x15; B: Movat pentachrome, x150; C: anti–KP-1, x300; D: anti–smooth muscle actin, x300; E: anti–UCHL-1, x300; and F: anti–HLA-DR, x300. Scale bars: A, 375 µm; B, 120 µm; and C through F, 120 µm.)

In coronary thrombosis without rupture into a lipid core (Figs 3 through 5), the plaque luminal surface was irregular, eroded, and lacked endothelial cells (negative factor VIII staining). Occasionally, the erosion extended into the upper layers of the plaque forming foci of intraplaque thrombi. The plaque in contact with the thrombus was cellular and proteoglycan-rich (green staining with Movat pentachrome stain). Deep to the cellular, proteoglycan-rich luminal surface of the plaque, the plaque was typically fibrous and hypocellular with variable foci of loose collagen containing mononuclear cells. Lipid pools deep within the plaque were occasionally seen; however, after serial step-sectioning, in no case was there plaque rupture or contact of the luminal thrombus with the deep lipid core. In all plaque erosion cases in which the thrombus was nonocclusive, the thrombus formed adjacent to the thickest portion of the plaque.

View larger version (56K): [in this window] [in a new window]   Figure 3. This 36-year-old man with a history of hypertension collapsed suddenly and suffered a cardiac arrest after playing basketball. A, Acutely thrombosed left anterior descending coronary artery is shown at low power. A concentric plaque is present with a deep lipid core (L) that does not communicate with the lumen. B, Thrombus/luminal plaque surface is seen at high power. The luminal surface is focally eroded and lacks endothelial cells, and the superficial plaque is highly cellular. The thrombus (T) consists predominantly of platelets, and the luminal plaque surface is cellular and rich in proteoglycans (green color by Movat staining). In C, actin immunohistochemical staining for smooth muscle cell actin identifies the cells at the luminal surface in contact with the thrombus as smooth muscle cells. (A: Movat pentachrome, x15; B: Movat pentachrome, x150; and C: anti–smooth muscle actin, x300. Scale bars: A, 375 µm; B, 120 µm; and C, 120 µm.)

View larger version (152K): [in this window] [in a new window]   Figure 4. This 33-year-old woman had sudden collapse and witnessed cardiac arrest shortly after eating. Acute thrombosis of the left anterior descending coronary artery was found at autopsy, and the thrombosed segment is shown at low power in A. An eccentric plaque containing a nonocclusive thrombus (T) is present, and the remainder of the lumen (L) is filled with dark-gray barium gelatin. The eroded plaque surface is seen at high power in B, and numerous spindle-shaped cells are present in the plaque. The thrombus (T) consists predominantly of platelets, and the luminal plaque surface is cellular and rich in proteoglycans (green color by Movat staining in A). In D, actin immunohistochemical staining identifies the cells at the luminal surface in contact with the thrombus as smooth muscle cells. Occasional macrophages are present in the plaque and thrombus (in C). Stains for T cells (in E) and HLA-DR (in F) are negative. (A: Movat pentachrome, x15; B: hematoxylin-eosin, x150; C: anti–KP-1, x300; D: anti–smooth muscle actin, x300; E: anti–UCHL-1, x300; and F: anti–HLA-DR, x300. Scale bars: A, 375 µm; B, 120 µm; and C through F, 120 µm.)

View larger version (96K): [in this window] [in a new window]   Figure 5. This 38-year-old woman died suddenly at home approximately 4 hours after complaining of chest pain. Autopsy demonstrated acute nonocclusive thrombosis (arrowheads) of the left anterior descending coronary artery (shown at low power in A); the remainder of the lumen (L) is filled with dark-gray barium gelatin. The luminal plaque surface is eroded and rich in proteoglycans (green color by Movat staining in A and B), and fibrin thrombus (F) extends into the superficial portions of the cellular plaque (seen at high power in B). Immunohistochemical stains demonstrate numerous smooth muscle cells at the luminal plaque surface in contact with the thrombus (in C). Occasional macrophages (in D) are present with negative staining for HLA-DR (in E). (A: Movat pentachrome, x15; B: Movat pentachrome, x150; C: anti–smooth muscle actin, x300; D: anti–KP-1, x300; and E: anti–HLA-DR, x300. Scale bars: A, 375 µm; B, 120 µm; and C through E, 120 µm.)

In applying the definitions of advanced atherosclerotic lesions by the AHA Council on Atherosclerosis,²³ all lesions (ruptures overlying a lipid pool and plaque erosions without lipid core rupture) are type VIc on the basis of the presence of an acute thrombus. However, the underlying plaque in the 28 cases with fibrous cap rupture would best fit a type IV. The underlying plaque in the superficially eroded arteries is more difficult to classify but can be viewed as a form of a type Va lesion (fibroatheroma) modified by the presence of abundant smooth muscle cells (see immunohistochemical staining results below) and proteoglycans.

Plaque Rupture Versus Superficial Erosion
The mean age in cases of coronary thrombosis due to plaque rupture was 53±10 years versus 44±7 years in erosion (P<.003; Table 1). In the plaque-rupture group, 5 of 28 (18%) were women versus 11 of 22 (50%) in eroded plaques (P=.03). The mean percent cross-sectional area stenosis (excluding the thrombus itself) was greater in plaque-rupture group (78±12%) versus the eroded-plaque group (70±11%, P<.03). The frequency distribution of luminal narrowing is depicted in Table 2. Plaque calcification was present in 19 ruptures (69%) compared with 5 erosions (23%, P=.002; Table 1). The thrombus was occlusive in 12 rupture cases (43%) and nonocclusive in 16 (57%); only 4 eroded plaques (18%) demonstrated complete thrombotic occlusion (P=.08 versus rupture into a necrotic core). Thrombi were predominantly composed of platelets in 13 (48%) plaque-rupture cases and of fibrin in 15 (52%), a similar distribution to the eroded-plaque group in which 14 (52%) were predominantly composed of platelets and 8 (35%) were predominantly fibrin (P=.26). Increased fibrin content may represent early organization of the thrombus progressing from initial platelet deposition to infiltration and stabilization by fibrin. Thirteen ruptured arteries (46%) were concentric, and 15 (54%) were eccentric. Only 4 eroded arteries without lipid core rupture (18%) were concentric, and the remaining 18 (82%) were eccentric (P=.07 versus rupture into a necrotic core). An acute myocardial infarction was present in 10 coronary rupture cases (36%) compared with 6 erosion cases (27%, P=.56). The frequency of healed myocardial infarction was similar in coronary ruptures and erosions (11 [39%] ruptures and 7 erosions [32%], P=.77).

View this table: [in this window] [in a new window]   Table 1. Coronary Thrombosis With Rupture Into a Lipid Core (Plaque Rupture) Compared With Thrombosis Associated With Eroded Plaque Without Lipid Pool Rupture (Plaque Erosion)

View this table: [in this window] [in a new window]   Table 2. Frequency Distribution of Percent Cross-Sectional Area Stenosis by Plaque in Coronary Thrombosis With Rupture Into a Lipid Core (Plaque Rupture) Compared With Thrombosis Associated With Eroded Plaque Without Lipid Pool Rupture (Plaque Erosion)

Immunohistochemical stains demonstrated several differences between ruptures and erosions (Table 1, Figs 1 through 5). Foci of macrophages, identified by anti–KP-1 staining, at the luminal surface adjacent to the thrombus were present in all 28 plaque-rupture cases versus 11 plaque-erosion cases (50%) (P<.0001). In plaque ruptures, macrophages typically infiltrated the thin fibrous cap and were present at the margins of the rupture site. When present in eroded plaques without lipid core rupture, macrophages were sparsely distributed in the upper layers of the plaque near the luminal surface. Clusters of spindle-shaped cells, identified as smooth muscle cells by actin staining, were seen at the luminal surface adjacent to the thrombus in 21 plaque erosions (95%) compared with 11 cases (33%) with smooth muscle cells in the fibrous cap adjacent to the plaque rupture (P<.0001). T cells were present in 21 ruptured plaques (75%) at the luminal surface in the vicinity of the rupture site versus occasional scattered T cells in 7 eroded arteries (32%, P<.004). Cell activation, indicated by HLA-DR staining, was identified in macrophages and T cells in 25 plaque ruptures (89%) and in macrophages in 8 plaque erosions (36%) (P=.0002).

	Discussion

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The present study demonstrates plaque variability in sudden death due to acute coronary thrombosis. In this series of 50 consecutive coronary thrombosis cases, 28 were associated with rupture of a fibrous cap overlying a lipid pool, and 22 occurred in superficially eroded plaques without lipid core rupture. These eroded plaques were rich in smooth muscle cells and proteoglycan at their luminal surface and were less often calcified versus ruptures. Trends toward a higher frequency of eccentric plaques and nonocclusive thrombi were found in eroded plaques. Eroded plaques were more frequent in women and in younger individuals and had less underlying luminal stenosis by plaque compared with plaque ruptures. The data from this study suggest plaques with endothelial loss and surface erosion associated with clusters of smooth muscle cells and proteoglycans at the luminal surface may be similarly vulnerable to acute thrombosis as are lipid-rich plaques.

Few data are available on differences in plaque morphology between men and women. Cumulative coronary plaque composition studies by Dollar et al²⁴ and Mautner et al²⁵ have demonstrated increased cellular fibrous tissue and less calcified and dense fibrous tissue in women (17 hearts from women examined). The arteries studied had severe atherosclerosis without acute coronary thrombi. Cellular fibrous plaques are associated with an earlier stage of evolution of atherosclerotic lesions compared with dense hypocellular plaques^{24 25} ; however, smooth muscle content and distribution have not been specifically evaluated. In the present study, the mean ages of men and women were similar (49±9 and 49±13 years, respectively), and it is well established that the development of atherosclerosis is delayed in women, probably due to estrogen effects. Therefore, the increased frequency of smooth muscle cell–rich plaques in women may be a function of plaque age. Thrombosis of smooth muscle cell–rich plaques in younger individuals (compared with plaque ruptures) may represent a form of plaque progression in those who survive the thrombotic event.

The results in the present study are consistent with previous serial angiographic studies that found that myocardial infarction due to coronary occlusion often occurred in mildly to moderately narrowed arteries on the initial angiogram.^{3 4} The mean percent luminal area stenosis of all thrombosed arteries (occlusive and nonocclusive thrombi) in the present study was 74%, which corresponds (if we assume a circular lumen) to an estimated diameter stenosis of 49%, ie, a moderate stenosis. Arteries that had an occlusive thrombus were narrowed 77% by plaque (equivalent to a 52% diameter stenosis). However, these histological measurements are not directly comparable to angiography in which the severity of stenosis is based on the diameter of the nearest normal-appearing arterial segment that may or may not have some degree of atherosclerosis. Previous autopsy studies have shown that occlusive thrombi are typically found in severely stenosed arteries (luminal area narrowing 90%^{16 26} ). Differences between these results and those of the present study may be explained by the differences in the populations; in the present study, individuals presented with sudden coronary death and only 32% had histological evidence of an acute myocardial infarction versus individuals with well-established infarcts²⁶ or with thrombi of varying ages.¹⁶ Our data suggest that both occlusive and nonocclusive coronary thromboses are important causes of sudden death.

Previous Studies of Coronary Thrombosis
Since the recognition that acute ischemic syndromes (acute myocardial infarction, unstable angina, and sudden coronary death) are often precipitated by coronary atherosclerotic plaque disruption and thrombosis, a search for thrombus-prone plaques has progressed over several decades. Davies and Thomas¹ have concluded that nearly all coronary thrombi leading to fatal myocardial infarction are associated with plaque rupture in which there is contact between luminal blood and the lipid core of the plaque. Falk² has similarly stated that ruptured plaques account for >75% of fatal coronary thrombi with the thrombus typically associated with displaced atheromatous plaque material. In Falk's experience, only 20% of thrombi examined at postmortem demonstrated minor or superficial intimal injury, usually in combination with severe underlying atherosclerotic stenosis, without rupture into a lipid pool. However, in previous studies (as detailed below), coronary morphology associated with thrombi of varying ages has been examined from a diverse population of sudden and nonsudden cardiac deaths. One could speculate that different ages of thrombi may affect arterial morphology as the thrombus organizes.

Studies of Combined Sudden and Nonsudden Death
Friedman and Van Den Bovenkamp¹⁰ found that 30 of 40 occlusive coronary thrombi were associated with direct communication of the thrombus with intraplaque atheromatous abscesses with the site of rupture infiltrated with lipid-laden macrophages. In this study of 40 patients, 93% were men, of which only 11 (28%) died suddenly, and the remainder died between 1 and 28 days after the onset of chest pain, dyspnea, or collapse. Constantinides¹² examined 17 coronary arteries with "recent" thrombi, and all 17 had cracks in the atherosclerotic plaque wall. No data on patient characteristics were provided. Chapman¹³ reported on 19 recent occlusive coronary thrombi, all of which had direct contact with atheromatous debris. No data were provided on patient characteristics or clinical presentation. Ridolfi and Hutchins¹⁴ studied 17 thrombosed coronary arteries associated with myocardial infarction <48 hours old; 16 had intimal erosion, plaque erosion, or ruptured plaque. Coronary arteries from 108 patients with acute myocardial infarction were examined by Horie et al¹⁵ ; sudden death cases without myocardial necrosis were excluded. Only 18 (17%) died within 24 hours of acute infarction. A ruptured plaque was noted in 69 of 76 thrombosed coronary arteries (91%).

In a detailed coronary morphology study of plaque disruption and coronary thrombosis, Falk¹⁶ performed postmortem examination on 44 cases of sudden and nonsudden coronary death. He found 103 ruptured plaques defined as disruption of a fibrous cap resulting in contact of blood with pultaceous debris of a lipid core. Of these 103, 63 had intimal hemorrhage without luminal thrombus, and 40 had luminal thrombus (38 of 40 occlusive). Forty of 49 recently thrombosed arteries (82%) had plaque rupture, and the ruptured cap was always thin and usually infiltrated by foam cells. There were 11 cases with occlusive thrombosis and intimal irregularities but no plaque rupture; 9 of these 11 had a 90% luminal area stenosis. Differences between the present study and the study by Falk¹⁶ may be due to patient selection; 49% of the thrombi were interpreted to be greater than 24 hours old (from 1 day to 2 weeks) so that interval changes in plaque morphology may have occurred. Further, the patients from Falk's study were all hospital-based (compared with medical examiner's cases in the present study) and were older (mean age, 69 years).

Tracy et al¹⁸ examined 21 longitudinally sectioned thrombosed coronary arteries from 18 hearts selected on the basis of the presence of acute thrombosis on gross inspection. Data on sudden versus nonsudden death were not provided. All arteries had a necrotic core, and 86% had plaque rupture. Cliff et al¹⁹ studied 25 cases of sudden coronary death and 9 cases of death within 14 days of myocardial infarction. All cases were in men, and there were 10 occlusive and 4 mural thrombi. Pultaceous material was identified in 33 of 34 cases (97%), but there was no mention of any association with plaque disruption or communication of the intraluminal thrombus with a lipid core. Richardson et al²⁰ examined 85 arterial segments with recent thrombi containing platelets and fibrin and plaque fissures defined by postmortem angiography. There were 71 arteries (84%) with a lipid pool; 67 of these 71 had fissure extension into an eccentric lipid core, and 4 had a concentric lipid pool with an intimal tear. Foam cells were present at the tear site in 53 of 71 (75%). Fourteen arterial segments (17%) had an intimal fissure without rupture into a lipid pool. Patient characteristics and circumstances at the time of death (sudden versus nonsudden death) were not provided.

Studies Limited to Sudden Death
Among 37 sudden death cases, Friedman et al¹¹ identified 20 acute coronary thrombi, 19 of which had luminal plaque rupture and an underlying focus of necrotic plaque. Men comprised 89% of the 37 individuals examined, consistent with the finding of 82% men in the plaque-rupture group in the present study. Davies and Thomas¹⁷ identified intraluminal thrombi in 74% of 100 consecutive cases. The mean percent cross-sectional luminal stenosis was 79% in arteries with luminal thrombi. Of the 74 thrombi, 90% were associated with plaque fissuring, but it is unknown how many arteries had direct contact of an acute thrombus with a ruptured lipid core. When thrombi occurred in arteries with <50% stenosis (14 of 74 cases), a major fissure of a lipid-rich plaque was seen. Data on patient age and sex distribution were not provided. Morphology similar to the smooth muscle cell–rich and proteoglycan-rich plaques observed in the present study were not reported by either Friedman et al¹¹ or Davies and Thomas.¹⁷

Inflammatory Cells and Smooth Muscle Cells in Coronary Thrombosis
The role of inflammation in coronary thrombosis was previously explored by van der Wal et al.²⁷ They studied 20 thrombosed coronary arteries from patients dying within 1 day of a pathologically confirmed myocardial infarct. There were 12 deep plaque ruptures extending into a lipid core and 8 superficial erosions defined as an eroded plaque surface with loss of endothelial cells and superficial intimal injury but no cap rupture or intraplaque hemorrhage. In ruptures, the rupture site contained abundant HLA-DR–positive macrophages and T cells, which is similar to the results in the present study. However, in their 8 erosion cases, smooth muscle cells were absent, and HLA-DR–positive macrophages and T cells were contiguous with the thrombus. They did note HLA-DR–positive smooth muscle cells in the connective tissue beneath the plaque surface in 6 erosions. In contrast, in the present study, a morphologically distinct lesion was identified; superficial erosions demonstrated abundant smooth muscle cells at the luminal surface, HLA-DR–positive macrophages were present in only 8 cases (36%), and inflammatory cells were sparse. On the basis of these findings, we would categorize the smooth muscle cell–rich thrombotic plaques in the present study as noninflammatory erosions. Because of the paucity of inflammatory cells in these eroded arteries, plaque inflammation may play a smaller role in the development of acute thrombosis compared with plaque ruptures.

Smooth muscle cell proliferation within the intima plays a central role in the development of atherosclerotic plaque.²⁸ In addition to intraluminal thrombi and plaque rupture,^{1 29 30 31 32} smooth muscle cell–rich plaques, obtained by directional atherectomy, have been frequently seen in patients with unstable angina.³³ To the best of our knowledge, the present study is the first to demonstrate an association between smooth muscle cell foci at the luminal surface and acute coronary thrombosis. In the eroded coronary arteries that lacked rupture into a lipid core, the plaque luminal surface was irregular and lacked endothelial cells. We postulate that endothelial injury leads to platelet deposition followed by plaque smooth muscle proliferation and extracellular matrix synthesis. This hypothesis may be considered a modification of Ross's "response-to-injury" theory of the development of atherosclerotic plaque.³⁴ The response-to-injury model as originally proposed attempted to explain plaque growth in a normal artery rather than coronary thrombosis of an artery with an advanced plaque. We propose that chronic endothelial loss over an atherosclerotic plaque increases the risk of arterial thrombosis.

Smooth muscle cells synthesize the bulk of the connective tissue in atherosclerotic plaque,³⁵ and the presence of proteoglycan-rich plaque at the luminal surface in thrombosed eroded coronary arteries may be important in the mechanism of thrombosis. The main proteoglycans that comprise the extracellular matrix in vascular structures are enriched in chondroitin sulfate, dermatan sulfate, and heparan sulfate.³⁶ In the development of atherosclerotic lesions, there is a progressive accumulation of chondroitin sulfate and dermatan sulfate with no change or a reduction in heparan sulfate.^{36 37 38} Heparan sulfate is an anticoagulant³⁹ and inhibits thrombin-induced platelet aggregation.⁴⁰ The procoagulant platelet factor 4 (PF4) is a heparin antagonist and is complexed to chondroitin sulfate.^{36 41} In vitro studies demonstrate competitive binding of heparin and PF4 to the surface of endothelial cells.⁴² The inactivation of thrombin by anti–thrombin III may be dependent on its binding to heparan sulfate on the surface of endothelial cells.⁴³ One could speculate that changes in the distribution and composition of proteoglycans (ie, reduced heparan sulfate and increased chondroitin sulfate content) may contribute to coronary thrombosis via reduced inhibition of the clotting cascade.

The results of the present study underscore the heterogeneity of atherosclerotic plaques in sudden coronary thrombosis and support the concept that multiple mechanisms are likely to be involved in thrombus formation. Certain hemodynamic factors such as bending and twisting of the coronary arteries during the cardiac cycle, pulse pressure, vasomotion/spasm, and increased shear stress at the site of stenosis may be responsible for increasing the likelihood of endothelial damage and acute thrombosis in atherosclerotic arteries.⁵ Within the plaque itself, the presence of tissue factor and plasminogen activator inhibitor–1 may augment the thrombotic potential of an atherosclerotic lesion.^{44 45} Increased circulating levels of hemostatic factors such as fibrinogen, von Willebrand factor, and tissue plasminogen activator antigen have been shown to be independent predictors of acute coronary syndromes.⁴⁶ It should not be surprising that plaque morphologies may differ in acute thrombosis, and future studies are needed to determine whether certain hemostatic factors, hemodynamic profiles, and/or risk factors for the development of atherosclerosis can be associated with plaque rupture or erosion.

Study Limitations
As an autopsy study, the results presented may not be representative of persons who develop coronary thrombosis and survive. Furthermore, all cases in the present study are from individuals with sudden death so that the findings may not be applicable to coronary thrombi associated with other acute ischemic syndromes (acute myocardial infarction or unstable angina).

Conclusions
By critical examination of the underlying plaque in acute coronary thrombosis, the present study expands the definition of thrombus-prone plaques to include smooth muscle cell–rich and proteoglycan-rich plaques associated with chronic endothelial loss. The data presented suggest that rupture of a thin fibrous cap overlying a lipid core is not necessarily the only final common pathway in the formation of coronary thrombi.

	Footnotes

 
Reprint requests to Renu Virmani, MD, Department of Cardiovascular Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000.

The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the views of the US Department of the Army or the US Department of Defense.

Received August 28, 1995; revision received November 1, 1995; accepted November 3, 1995.

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