FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 349:2316-2325 December 11, 2003 Number 24 Next

Abstract PDF PDA Full Text PowerPoint Slide Set Perspective by Heistad, D. D. Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

ABSTRACT

Background Intraplaque hemorrhage is common in advanced coronary atherosclerotic lesions. The relation between hemorrhage and the vulnerability of plaque to disruption may involve the accumulation of free cholesterol from erythrocyte membranes.

Methods We stained multiple coronary lesions from 24 randomly selected patients who had died suddenly of coronary causes with an antibody against glycophorin A (a protein specific to erythrocytes that facilitates anion exchange) and Mallory's stain for iron (hemosiderin), markers of previous intraplaque hemorrhage. Coronary lesions were classified as lesions with pathologic intimal thickening, fibrous-cap atheromas with cores in an early or late stage of necrosis, or thin-cap fibrous atheromas (vulnerable plaques). The arterial response to plaque hemorrhage was further defined in a rabbit model of atherosclerosis.

Results Only traces of glycophorin A and iron were found in lesions with pathologic intimal thickening or fibrous-cap atheromas with cores in an early stage of necrosis. In contrast, fibroatheromas with cores in a late stage of necrosis or thin caps had a marked increase in glycophorin A in regions of cholesterol clefts surrounded by iron deposits. Larger amounts of both glycophorin A and iron were associated with larger necrotic cores and greater macrophage infiltration. Rabbit lesions with induced intramural hemorrhage consistently showed cholesterol crystals with erythrocyte fragments, foam cells, and iron deposits. In contrast, control lesions from the same animals had a marked reduction in macrophages and lipid content.

Conclusions By contributing to the deposition of free cholesterol, macrophage infiltration, and enlargement of the necrotic core, the accumulation of erythrocyte membranes within an atherosclerotic plaque may represent a potent atherogenic stimulus. These factors may increase the risk of plaque destabilization.

The aim of this study was to demonstrate erythrocyte membranes within the necrotic cores of human atherosclerotic plaques, even those without recent hemorrhages, and relate them to the progression and instability of the lesions. We also examined the fate of erythrocytes in established plaques in atherosclerotic rabbits to provide a model of hemorrhage-induced progression of lesions. Establishment of a link between intraplaque hemorrhage and the expansion of the lesions would provide another potential mechanism of plaque progression and vulnerability.

Methods

Selection of Patients

An institutional review board approved the study. Hearts of patients who had died suddenly of coronary causes were obtained as described previously.⁸ Of 270 such patients, 100 were randomly selected for investigation to determine the incidence of hemorrhage in nonculprit plaques with luminal narrowing of more than 50 percent. The mean (±SD) number of intraplaque hemorrhages per heart was 5.0±0.4 in patients with coronary thrombosis resulting from acute plaque rupture, as compared with 0.6±0.3 in those with thrombosis caused by plaque erosion (P<0.002) and 2.8±0.8 in those with stenosis of at least 75 percent of the lesion in the absence of acute thrombi (P<0.04).

The high incidence of intraplaque hemorrhage in hearts with ruptured plaques prompted further study of lesions in another 24 randomly selected patients who had died suddenly of coronary causes. In each case, if the necrotic core showed a predominance of erythrocytes on conventional staining with hematoxylin and eosin, the sections were excluded from analysis. The remaining sections were examined for glycophorin A, a protein specific to erythrocytes that facilitates anion exchange.⁹ Nonculprit plaques were categorized morphologically to gain insights into the role of intraplaque hemorrhage in the progression and instability of lesions. Finally, we reviewed patients' records from our institute to identify those with nonvascular lesions containing hemorrhagic areas associated with pericarditis, hemangiomas, and cholesterol granulomas of the lung.

Tissue Processing

Formalin-fixed coronary segments were embedded in paraffin, and 4-µm sections were stained with hematoxylin and eosin and Movat pentachrome. Parallel sections were prepared to identify collagen matrix (with the use of picrosirius red stain) and iron (with the use of Mallory's stain), as well as for immunohistochemical analysis.

Classification of Lesions

We examined 810 sections for lesions and classified the lesions using an American Heart Association scheme modified by our laboratory.¹⁰ We included lesions with pathologic intimal thickening, fibroatheromas whose cores were in an early stage ("early core") or late stage ("late core") of necrosis, and thin-cap fibroatheromas. Early cores contain cholesterol clefts, macrophages, and proteoglycans or collagen; late cores have more numerous cholesterol clefts and cellular debris with an absence of extracellular matrix. Using these criteria, we analyzed 365 plaques: 129 plaques with pathologic intimal thickening, 79 fibroatheromas with early cores, 105 fibroatheromas with late cores, and 52 thin-cap fibroatheromas.

Immunohistochemical Studies

Paraffin sections were incubated with an antibody against glycophorin A to identify sites of previous plaque hemorrhage. Macrophages were identified by staining with antibody against CD68, and endothelial cells by staining with antibody against von Willebrand factor. Primary antibodies were labeled with a biotinylated link antibody directed against mouse antigen with the use of a peroxidase-based kit (LSAB, Dako) and visualized with use of a 3-amino-9-ethylcarbazole substrate.

The percentage of the necrotic core or lipid pool that was made up of glycophorin A and iron was graded semiquantitatively by two independent observers using a scale from 0 to 4, with higher scores indicating higher percentages. Only specimens with staining of erythrocyte fragments were included in the analysis. Computer-based morphometry was used to measure the size of the lipid core, plaque area, and macrophage content as described previously.¹¹

Proof-of-Concept Study in Rabbits

            Rabbit Model of Simulated Intraplaque Hemorrhage

Six New Zealand white rabbits that were three to four months old were fed an atherogenic diet (containing 1 percent cholesterol and 6 percent peanut oil) to initiate the formation of atheromas. After one week, lesions were produced in the abdominal aorta by balloon-induced injury. The animals were fed the atherogenic diet for another 4 weeks and then given purified rabbit chow with no added cholesterol until they were killed at 14 weeks.

            Rabbit Model of Intramural Hemorrhage

After eight weeks of the nonatherogenic diet, the rabbits underwent a left-sided lateral laparotomy while under general anesthesia, and a 4-cm segment of the abdominal aorta was exposed. A 30-gauge needle was introduced into the arterial lumen at the sites of lesions and then slowly withdrawn until the beveled tip was within the arterial wall. Washed autologous erythrocytes (25 to 50 µl) were slowly delivered into established atherosclerotic plaques with the use of a handheld 1-ml syringe. A slightly raised hematoma provided visual confirmation that erythrocytes were trapped within the plaque. Injections were made in two to three lesions per animal; noninjected lesions served as controls. The animals continued to be fed a normal-chow diet for another six weeks.

            Tissue Preparation and Staining

The rabbits were killed, the arterial tree was perfused and fixed, and the abdominal aorta was excised and cut into 3-mm segments. Frozen blocks were prepared, and cryosections (6 µm) were stained with hematoxylin and eosin and Movat pentachrome. Additional sections were used to determine the lipid content (with oil red O stain) and the iron content and for immunohistochemical analysis. Macrophages were identified with a specific monoclonal antibody against rabbit alveolar macrophages (RAM11). To identify erythrocyte membranes, we stained the sections with isolectin B4 from Bandeiraea simplicifolia conjugated with biotin.¹²

Statistical Analysis

Data are presented as means ±SE. We used a t-test with Dunnett's correction to compare continuous variables by analysis of variance. Differences between measured variables were considered significant if the resultant P value was 0.05 or less.

Results

Human Coronary Plaques

            Hemorrhage in Coronary Plaques

Table 1 shows the glycophorin A and iron scores, the sizes of the necrotic cores, and the extent of macrophage infiltration in the specific types of lesions. As compared with lesions with pathologic intimal thickening or early-core fibroatheromas, fibroatheromas with late cores and thin-cap fibroatheromas had significantly greater mean scores for glycophorin A and iron (P<0.001). Previous hemorrhage was identified in 8 of 129 plaques with pathologic intimal thickening (6 percent), 15 of 79 fibroatheromas with early cores (19 percent), and 56 of 105 fibroatheromas with late cores (53 percent). The incidence of hemorrhage was greatest among thin-cap fibroatheromas, with 40 of 52 lesions (77 percent) positive for glycophorin A or iron. Advanced lesions with erythrocytes often contained extensive areas of neovascularization, with diffuse perivascular staining for von Willebrand factor (Figure 1). The area of the necrotic core was significantly greater in fibroatheromas with late cores or thin caps than in fibroatheromas with early cores (P<0.001). The larger necrotic cores were associated with an increased density of CD68-positive macrophages, especially toward the fibrous cap. Notably, higher glycophorin A or iron scores were associated with larger necrotic cores (Figure 2).

View this table: [in this window] [in a new window]   Table 1. Morphometric Analysis of 365 Plaques in Coronary Arteries from Patients Who Died Suddenly of Coronary Causes.

 

View larger version (50K): [in this window] [in a new window]   Figure 1. Intraplaque Hemorrhage in Fibroatheroma with a Core in a Late Stage of Necrosis (Panels A, B, C, D, and E) and Thin-Cap Fibroatheroma (Panels F, G, H, I, and J). Panel A shows a low-power view of a fibroatheroma with a late-stage necrotic core (NC) (Movat pentachrome, x20). Panel B shows intense staining of CD68-positive macrophages within the necrotic core (x200). Panel C shows extensive staining for glycophorin A in erythrocyte membranes localized with numerous cholesterol clefts within the necrotic core (x200). Panel D shows iron deposits (blue pigment) within foam cells (Mallory's stain, x200). Panel E shows microvessels bordering the necrotic core with perivascular deposition of von Willebrand factor (vWF) (x400). Panel F shows a low-power view of a fibroatheroma with a thin fibrous cap (arrow) overlying a relatively large necrotic core (Movat pentachrome, x20). The fibrous cap is devoid of smooth-muscle cells (not shown) and is heavily infiltrated by CD68-positive macrophages (Panel G, x200). Panel H shows intense staining for glycophorin A in erythrocyte membranes within the necrotic core, together with cholesterol clefts (x100). Panel I shows an adjacent coronary segment with iron deposits (blue pigment) in a macrophage-rich region deep within the plaque (Mallory's stain, x200). Panel J shows diffuse, perivascular deposits of von Willebrand factor in microvessels, indicating that leaky vessels border the necrotic core (x400).

 

View larger version (10K): [in this window] [in a new window]   Figure 2. Relation of Glycophorin A Scores (Panel A) and Iron Scores (Panel B) to the Mean (±SE) Size of the Necrotic Core. The amounts of glycophorin A and iron in plaque are predictive of the size of the necrotic core. Glycophorin A scores are as follows: 0 indicates no detectable staining, 1 indicates focal granular staining in less than 5 percent of the plaque, 2 indicates mild granular staining in 5 to 10 percent of the plaque, 3 indicates moderate granular staining in 11 to 25 percent of the plaque, and 4 indicates marked granular staining in more than 25 percent of the plaque. Only lesions with staining of erythrocyte fragments were included in the analysis. Iron staining was scored in a similar manner: 0 indicates no detectable staining, 1 indicates trace staining (1 to 2 macrophages), 2 indicates mild staining (3 to 5 macrophages), 3 indicates moderate staining (6 to 20 macrophages), and 4 indicates marked staining (more than 20 macrophages).

 
            Hemorrhage in Noncoronary Lesions

Selected specimens from patients with hemorrhage in noncoronary lesions were examined. In one example, a right atrial hemangioma contained a large collection of erythrocytes, cholesterol clefts, and foamy cells; perivascular staining for von Willebrand factor was also evident. In a specimen from a patient with hemorrhagic pericarditis, there was intense staining for glycophorin A with extensive deposition of free cholesterol in the absence of inflammatory cells; however, CD68-positive macrophages and extracellular iron deposits were present in the periphery of the lesion (Figure 3).

View larger version (105K): [in this window] [in a new window]   Figure 3. Atherogenic Changes Associated with Extravasated Erythrocytes in Noncoronary Lesions. Panel A shows a section of a right atrial hemangioma stained with hematoxylin and eosin (x4). Panel B shows a higher-power magnification of the area in the black box in Panel A, in which a large number of erythrocytes as well as cholesterol clefts are present (x200). Panel C shows intense staining for CD68-positive macrophages in an area of extravasated erythrocytes (x200). Panel D shows intact erythrocytes and membrane remnants identified on the basis of staining with antibody against glycophorin A (x200). Panel E shows iron deposits (blue pigment), macrophages, and cholesterol clefts (Mallory's stain, x200). Panel F shows perivascular accumulation of von Willebrand factor (vWF) in capillaries (x400). Panel G shows a section of pericardium (from a patient with acute hemorrhagic pericarditis) containing erythrocytes and cholesterol clefts (arrow, x100). Panel H shows the results of staining with antibody against glycophorin A in a region similar to that shown in Panel G (x400). Erythrocyte membranes and crystalline cholesterol are present, but macrophages are absent. Panel I shows the presence of macrophages at the periphery of accumulated erythrocytes; staining for iron (Mallory's stain; inset, x400) was also noted.

 
Rabbit Model of Induced Intramural Hemorrhage

            Plasma Lipids

The mean total cholesterol levels in the rabbits were 45±19 mg per deciliter (1.2±0.5 mmol per liter) before the experiment was initiated and 2216±466 mg per deciliter (57.3±12.0 mmol per liter) after five weeks of the atherogenic diet. At the time of the erythrocyte injection (after eight weeks of a control diet devoid of supplemental lipids), the cholesterol levels were dramatically lower and thereafter were equivalent to base-line levels (33±10 mg per deciliter [0.9±0.3 mmol per liter]).

            Histologic Appearance of Aortic Lesions with Intramural Hemorrhage

Rabbit atheromas with injected erythrocytes had more extensive macrophage infiltration than control lesions (17±3.6 percent vs. 3.7±2.2 percent, P=0.03), despite the fact that the sizes of the plaques were similar in the two groups. The lipid content on staining with oil red O was also significantly higher in the plaques with injected erythrocytes than in control lesions (34±6 percent vs. 22.1±4.5 percent, P=0.05). Histologically, plaques with injected erythrocytes showed discrete dissection planes with circumferential infiltration of macrophages within the arterial wall.

Numerous lipid-laden RAM11-positive foam cells were found in the superficial and deep layers of the arterial wall. The lipid content was extensive in plaques that had received an injection of erythrocytes. Cholesterol crystals were frequently found with erythrocyte fragments (as evidenced by staining with isolectin B4) and macrophage foam cells containing iron deposits (Figure 4). In contrast, control lesions contained smooth-muscle cells, particularly toward the areas of the lumen and media and collagen matrix. Furthermore, control lesions had fewer macrophages in parallel with reduced staining for oil red O, and the erythrocytes were confined to the adventitial layer (Figure 4).

View larger version (56K): [in this window] [in a new window]   Figure 4. Serial Cryosections Showing a Rabbit Atheroma with Intramural Hemorrhage (Panels A, B, C, and D) and a Control Lesion (Panels E, F, G, and H). Autologous erythrocytes were injected into established plaques eight weeks after the animals had stopped receiving a high-cholesterol diet; the arteries were harvested six weeks later. Panel A shows a high-power view of an arterial section at a site of injected erythrocytes (Movat pentachrome, x200). In Panel B, an area similar to that shown in Panel A contains numerous macrophages (as evidenced by staining with RAM11 antibody) in the deep and superficial region of the plaque (x200). In Panel C, staining with oil red O shows extensive lipid accumulation within macrophages (x200). In Panel D, the top part shows erythrocyte membranes (as evidenced by staining with isolectin B4) and cholesterol crystals deep within the intima (x400). There are iron deposits (blue pigment in bottom part of panel) within macrophages (x400). Panel E shows a high-power view of a control lesion without experimentally induced hemorrhage (Movat pentachrome, x200). In Panel F, macrophage infiltration is minimal in the control lesion (x200). In Panel G, staining with oil red O reveals mild lipid accumulation (x200). Panel H shows intact erythrocytes (as evidenced by staining with isolectin B4) confined to the adventitial layer of the control lesion (x200). Staining of control lesions for iron was negative (not shown).

 
Discussion

Our findings indicate that there is an association among intraplaque hemorrhage, an increase in the size of the necrotic core, and lesion instability in coronary plaques. Immunostaining with antibody against glycophorin A revealed previous hemorrhages in lesions with late cores and those prone to rupture. The degree of reactivity of glycophorin A and the level of iron accumulation corresponded to the size of the necrotic core, and the increase in these variables paralleled the increase in the density of macrophages, raising the possibility that the hemorrhage itself serves as an inflammatory stimulus. To test the hypothesis that erythrocytes actively participate in the progression of atheromas, we devised an experimental model of intramural hemorrhage in the rabbit. The injection of autologous erythrocytes into existing lesions produced plaques with crystalline cholesterol, lipid, iron, and foam cells, whereas control lesions had little free cholesterol and few macrophages. The finding that intramural hemorrhage in an experimental atherosclerotic lesion induces the formation of cholesterol crystals with the recruitment of macrophages supports our hypothesis that erythrocyte membranes in the necrotic core of human coronary lesions can cause an abrupt increase in the levels of free cholesterol, resulting in expansion of the necrotic core and the potential for the destabilization of plaque.

In the first half of the 20th century, Wartman and others suggested that intraplaque hemorrhage is a major contributor to the progression of coronary lesions.^13,14,15 Studies involving the injection of silicon polymer into atherosclerotic human coronary arteries¹⁶ demonstrated an elaborate microvascular network (the vasa vasorum) extending from the adventitia through the media and into the thickened intima; nonatherosclerotic vessels rarely had vasa vasorum. Intraplaque hemorrhage is believed to arise from the disruption of thin-walled microvessels that are lined by a discontinuous endothelium without supporting smooth-muscle cells.¹⁷ Moreover, several investigators, including some from our laboratory, have suggested that intraplaque hemorrhage and rupture of the fibrous cap are associated with an increased density of microvessels.^18,19,20 A greater number of vasa vasorum in ruptured plaques and hemorrhages suggests that a larger pool of erythrocytes is available to participate in necrotic-core enlargement within these lesions. Our finding of diffuse, perivascular staining of vasa vasorum with von Willebrand factor and evidence of erythrocyte membranes within necrotic cores points to microvascular disruption as a source of erythrocyte-derived cholesterol. Plaque fissures could also account for the accumulation of erythrocytes; however, fissures are often accompanied by luminal thrombi, which we did not find in any specimen.

Lipid composition is believed to influence the stability of atherosclerotic plaques, given that the level of free cholesterol is significantly increased in disrupted lesions.²¹ Furthermore, the percentage of cholesterol clefts is greater in lesions that have ruptured than in fibrocalcific plaques.¹⁰ Although apoptotic macrophages may be a source of free cholesterol, it is unlikely that the total free cholesterol content in plaques could be derived from foam cells alone, since most of the cholesterol in foam cells is esterified.²² Our finding of both cholesterol crystals and glycophorin A in the necrotic cores of advanced coronary plaques is similar to the finding of cholesterol clefts, macrophages, and iron in large areas of extravasated erythrocytes outside the coronary circulation. Although it is conceivable that the cholesterol crystals in these nonvascular lesions are derived from foam cells, cholesterol clefts often reside exclusively in areas of erythrocytes lacking macrophages. In these instances, cholesterol derived from erythrocyte membranes may exceed a critical level, forming an immiscible cholesterol phase and ultimately crystallizing.²³

The cholesterol content of erythrocyte membranes may represent an independent risk factor for acute ischemic events, since it reflects the levels of circulating cholesterol.²⁴ In rats and rabbits, hypercholesterolemia causes the cholesterol content of erythrocyte membranes to increase substantially.^25,26 The cholesterol content of erythrocyte membranes is also elevated in patients with familial hypercholesterolemia and decreases with short-term treatment with statins.^27,28 The positive association between an elevated serum cholesterol level and an increased number of vulnerable plaques,⁸ together with our findings of intense staining for glycophorin A in advanced lesions and the dependence of erythrocyte-membrane cholesterol on circulating lipids, lends support to the hypothesis that the instability of plaques may be mediated in part by erythrocyte-membrane cholesterol.

The cellular response to extravasated erythrocytes appears to be influenced by the unique properties of the atherosclerotic intima. In the brain, skin, and normal arterial wall, experimental hematomas provoke a healing response characterized by the lysis of erythrocytes at 24 hours, followed within four to five days by an influx of macrophages, erythrophagocytosis, and the accumulation of iron.^29,30,31 Most of the hemorrhage in these tissues resolves by 7 to 14 days. In contrast, the intima of an atherosclerotic plaque appears to provide the appropriate milieu for the retention of erythrocyte-membrane cholesterol and foam cells.³² Hemorrhage within the necrotic core of a plaque may attract macrophages that eventually become trapped within the core and are unable to survive.

The signals erythrocytes may use to stimulate inflammation in coronary and noncoronary hemorrhages are not fully understood. The crystallization of cholesterol from erythrocyte membranes may incite a foreign-body reaction, as seen in cholesterol granulomas.³³ Alternatively, the migration of macrophages may be promoted by multispecific receptors on erythrocyte membranes, which can bind a wide array of chemokines in the blood, including monocyte chemotactic peptide 1.^34,35 Furthermore, the products of lipid oxidation from senescent erythrocytes or iron-catalyzed reactions may liberate potent chemoattractants.³⁶ On the basis of our experimental data in rabbits, acute hemorrhagic events promote the accumulation of free cholesterol and stimulate the excessive influx of macrophages. Our findings of intramural hemorrhage may further explain the episodic growth of human atherosclerotic plaque and may also explain why a coronary lesion can remain quiescent for extended periods and then suddenly become unstable.

Recent studies of carotid plaques suggest that lipids derived from erythrocyte membranes may contribute to the formation of foam cells. In an analysis of microvessels in carotid-endarterectomy specimens, Kockx et al. found excessive perivascular accumulation of von Willebrand factor, inducible nitric oxide synthase, and ceroid (a marker of previous oxidative events) within foam cells in 27 percent of plaques.³⁷ Macrophages frequently contain hemoglobin and iron, suggesting that phagocytosis of erythrocytes may contribute to the formation of foam cells.³⁸ Similar lipid-containing cells, expressing both ceroid and inducible nitric oxide synthase, have been generated in an atherosclerosis-free setting by incubating murine macrophages with oxidized erythrocytes. Moreover, erythrophagocytosis as a result of microhemorrhages may have additional consequences; the iron accumulated from the breakdown of hemoglobin can act as a catalyst in the formation of free radicals, which may contribute to the modification of low-density lipoprotein cholesterol and cell death.^39,40

Our finding of erythrocyte membranes in the necrotic core of advanced coronary atheromas may widen our view regarding the origin of free cholesterol in developing vulnerable lesions. Erythrocyte membranes are capable of providing a substantial amount of lipid and may promote the recruitment of macrophages into the fibrous cap. Therefore, intraplaque hemorrhage represents a critical event in the induction of instability in these lesions.

Supported in part by a research grant from the National Institutes of Health (R01 HL61799-02).

We are indebted to Hedwig Avallone, Lila Adams, and Addis Taye, Armed Forces Institute of Pathology, for their excellent technical assistance.

Source Information

From the Department of Cardiovascular Pathology, Armed Forces Institute of Pathology, Washington, D.C. (F.D.K., A.P.B., D.K.W., A.F., R.K., R.V.); the Cardiac Unit, Department of Internal Medicine, Massachusetts General Hospital, Boston (H.K.G., L.J.G., M.H., A.V.F.); the Department of Pathology, University of Maryland, Baltimore (D.R.F.); the Section of Experimental Atherosclerosis, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md. (H.S.K.); and Drexel University College of Medicine, Philadelphia (J.N.).

Address reprint requests to Dr. Virmani at the Department of Cardiovascular Pathology, Armed Forces Institute of Pathology, Bldg. 54, Rm. 2005, 6825 16th St., Washington, DC 20306-6000, or at virmani{at}afip.osd.mil.

References

1. Guyton JR, Klemp KF. Development of the lipid-rich core in human atherosclerosis. Arterioscler Thromb Vasc Biol 1996;16:4-11. [Free Full Text]
2. Kruth HS. Localization of unesterified cholesterol in human atherosclerotic lesions: demonstration of filipin-positive, oil-red-O-negative particles. Am J Pathol 1984;114:201-208. [Abstract]
3. Bloch K. Cholesterol: evolution of structure and function. In: Vance DE, Vance JE, eds. Biochemistry of lipids, lipoproteins, and membranes. Vol. 20. Amsterdam: Elsevier, 1991:363-81.
4. Yeagle PL. Cholesterol and the cell membrane. Biochim Biophys Acta 1985;822:267-287. [Medline]
5. Virmani R, Roberts WC. Pulmonary arteries in congenital heart disease: a structure-function analysis. In: Roberts WC, ed. Adult congenital heart disease. Philadelphia: F.A. Davis, 1987:77-130.
6. Virmani R, Burke AP, Farb A. Non-neoplastic diseases of the pericardium. In: Virmani R, ed. Atlas of cardiovascular pathology. Philadelphia: W.B. Saunders, 1996:103-10.
7. Arbustini E, Morbini P, D'Armini AM, et al. Plaque composition in plexogenic and thromboembolic pulmonary hypertension: the critical role of thrombotic material in pultaceous core formation. Heart 2002;88:177-182. [Free Full Text]
8. Burke AP, Farb A, Malcom GT, Liang YH, Smialek J, Virmani R. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med 1997;336:1276-1282. [Free Full Text]
9. Auffray I, Marfatia S, de Jong K, et al. Glycophorin A dimerization and band 3 interaction during erythroid membrane biogenesis: in vivo studies in human glycophorin A transgenic mice. Blood 2001;97:2872-2878. [Free Full Text]
10. Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000;20:1262-1275. [Free Full Text]
11. Burke AP, Kolodgie FD, Farb A, Weber D, Virmani R. Morphological predictors of arterial remodeling in coronary atherosclerosis. Circulation 2002;105:297-303. [Free Full Text]
12. Ito N, Nishi K, Nakajima M, Okamura Y, Hirota T. Relationship between lectin binding properties and the expression of blood group ABH antigens in vascular endothelia and red blood cells from 18 primate species. Histochem J 1990;22:113-118. [Medline]
13. Wartman WB. Occlusion of the coronary arteries by hemorrhage into their walls. Am Heart J 1938;15:459-470. [CrossRef][Web of Science]
14. Winternitz MC, Thomas RM, Le Compte PM. Thrombosis. In: Thomas CC, ed. The biology of atherosclerosis. Springfield, Ill.: Charles C Thomas, 1938:94-103.
15. Patterson JC. The reaction of the arterial wall to intramural hemorrhage. In: Symposium of Atherosclerosis. Washington, D.C.: National Academy of Sciences, 1954.
16. Barger AC, Beeuwkes R III, Lainey LL, Silverman KJ. Hypothesis: vasa vasorum and neovascularization of human coronary arteries: a possible role in the pathophysiology of atherosclerosis. N Engl J Med 1984;310:175-177. [Web of Science][Medline]
17. Virmani R, Narula J, Farb A. When neoangiogenesis ricochets. Am Heart J 1998;136:937-939. [CrossRef][Web of Science][Medline]
18. Burke AP, Farb A, Malcom GT, Liang Y, Smialek JE, Virmani R. Plaque rupture and sudden death related to exertion in men with coronary artery disease. JAMA 1999;281:921-926. [Free Full Text]
19. McCarthy MJ, Loftus IM, Thompson MM, et al. Angiogenesis and the atherosclerotic carotid plaque: an association between symptomatology and plaque morphology. J Vasc Surg 1999;30:261-268. [CrossRef][Web of Science][Medline]
20. Mofidi R, Crotty TB, McCarthy P, Sheehan SJ, Mehigan D, Keaveny TV. Association between plaque instability, angiogenesis and symptomatic carotid occlusive disease. Br J Surg 2001;88:945-950. [CrossRef][Web of Science][Medline]
21. Felton CV, Crook D, Davies MJ, Oliver MF. Relation of plaque lipid composition and morphology to the stability of human aortic plaques. Arterioscler Thromb Vasc Biol 1997;17:1337-1345. [Free Full Text]
22. Tabas I. Cholesterol and phospholipid metabolism in macrophages. Biochim Biophys Acta 2000;1529:164-174. [Medline]
23. Tulenko TN, Chen M, Mason PE, Mason RP. Physical effects of cholesterol on arterial smooth muscle membranes: evidence of immiscible cholesterol domains and alterations in bilayer width during atherogenesis. J Lipid Res 1998;39:947-956. [Free Full Text]
24. Schick BP, Schick PK. Cholesterol exchange in platelets, erythrocytes and megakaryocytes. Biochim Biophys Acta 1985;833:281-290. [Medline]
25. Balkan J, Oztezcan S, Aykac-Toker G, Uysal M. Effects of added dietary taurine on erythrocyte lipids and oxidative stress in rabbits fed a high cholesterol diet. Biosci Biotechnol Biochem 2002;66:2701-2705. [Medline]
26. Kempaiah RK, Srinivasan K. Integrity of erythrocytes of hypercholesterolemic rats during spices treatment. Mol Cell Biochem 2002;236:155-161. [CrossRef][Web of Science][Medline]
27. Koter M, Broncel M, Chojnowska-Jezierska J, Klikczynska K, Franiak I. The effect of atorvastatin on erythrocyte membranes and serum lipids in patients with type-2 hypercholesterolemia. Eur J Clin Pharmacol 2002;58:501-506. [CrossRef][Web of Science][Medline]
28. Martinez M, Vaya A, Marti R, et al. Erythrocyte membrane cholesterol/phospholipid changes and hemorheological modifications in familial hypercholesterolemia treated with lovastatin. Thromb Res 1996;83:375-388. [CrossRef][Web of Science][Medline]
29. Koeppen AH, Dickson AC, McEvoy JA. The cellular reactions to experimental intracerebral hemorrhage. J Neurol Sci 1995;134:102-112.
30. Lalonde JM, Ghadially FN. Ultrastructure of experimentally produced subcutaneous haematomas in the rabbit. Virchows Arch B Cell Pathol 1977;25:221-232. [Web of Science][Medline]
31. Wartman WB, Laipply TC. The fate of blood injected into the arterial wall. Am J Pathol 1949;25:383-388. [Medline]
32. Schwartz SM, deBlois D, O'Brien ER. The intima: soil for atherosclerosis and restenosis. Circ Res 1995;77:445-465. [Free Full Text]
33. Leon ME, Chavez C, Fyfe B, Nagorsky MJ, Garcia FU. Cholesterol granuloma of the maxillary sinus. Arch Pathol Lab Med 2002;126:217-219. [Web of Science][Medline]
34. Darbonne WC, Rice GC, Mohler MA, et al. Red blood cells are a sink for interleukin 8, a leukocyte chemotaxin. J Clin Invest 1991;88:1362-1369. [Web of Science][Medline]
35. Neote K, Darbonne W, Ogez J, Horuk R, Schall TJ. Identification of a promiscuous inflammatory peptide receptor on the surface of red blood cells. J Biol Chem 1993;268:12247-12249. [Free Full Text]
36. Ishikawa K, Sugawara D, Wang X, et al. Heme oxygenase-1 inhibits atherosclerotic lesion formation in ldl-receptor knockout mice. Circ Res 2001;88:506-512. [Free Full Text]
37. Kockx MM, Cromheeke KM, Knaapen MW, et al. Phagocytosis and macrophage activation associated with hemorrhagic microvessels in human atherosclerosis. Arterioscler Thromb Vasc Biol 2003;23:440-446. [Free Full Text]
38. Sambrano GR, Parthasarathy S, Steinberg D. Recognition of oxidatively damaged erythrocytes by a macrophage receptor with specificity for oxidized low density lipoprotein. Proc Natl Acad Sci U S A 1994;91:3265-3269. [Free Full Text]
39. Yuan XM, Brunk UT, Olsson AG. Effects of iron- and hemoglobin-loaded human monocyte-derived macrophages on oxidation and uptake of LDL. Arterioscler Thromb Vasc Biol 1995;15:1345-1351. [Free Full Text]
40. Coffey MD, Cole RA, Colles SM, Chisolm GM. In vitro cell injury by oxidized low density lipoprotein involves lipid hydroperoxide-induced formation of alkoxyl, lipid, and peroxyl radicals. J Clin Invest 1995;96:1866-1873. [Web of Science][Medline]

Abstract PDF PDA Full Text PowerPoint Slide Set Perspective by Heistad, D. D. Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

This article has been cited by other articles:

• Matter, C. M., Stuber, M., Nahrendorf, M. (2009). Imaging of the unstable plaque: how far have we got?. Eur Heart J 30: 2566-2574 [Abstract] [Full Text]  
• Ota, H., Yu, W., Underhill, H. R., Oikawa, M., Dong, L., Zhao, X., Polissar, N. L., Neradilek, B., Gao, T., Zhang, Z., Yan, Z., Guo, M., Zhang, Z., Hatsukami, T. S., Yuan, C. (2009). Hemorrhage and Large Lipid-Rich Necrotic Cores Are Independently Associated With Thin or Ruptured Fibrous Caps: An In vivo 3T MRI Study. Arterioscler. Thromb. Vasc. Bio. 29: 1696-1701 [Abstract] [Full Text]  
• Ortiz-Munoz, G., Houard, X., Martin-Ventura, J.-L., Ishida, B. Y., Loyau, S., Rossignol, P., Moreno, J.-A., Kane, J. P., Chalkley, R. J., Burlingame, A. L., Michel, J.-B., Meilhac, O. (2009). HDL antielastase activity prevents smooth muscle cell anoikis, a potential new antiatherogenic property. FASEB J. 23: 3129-3139 [Abstract] [Full Text]  
• Sirol, M., Moreno, P. R., Purushothaman, K.-R., Vucic, E., Amirbekian, V., Weinmann, H.-J., Muntner, P., Fuster, V., Fayad, Z. A. (2009). Increased Neovascularization in Advanced Lipid-Rich Atherosclerotic Lesions Detected by Gadofluorine-M-Enhanced MRI: Implications for Plaque Vulnerability. Circ Cardiovasc Imaging 2: 391-396 [Abstract] [Full Text]  
• Ni, M, Chen, W Q, Zhang, Y (2009). Animal models and potential mechanisms of plaque destabilisation and disruption. Heart 95: 1393-1398 [Abstract] [Full Text]  
• Le Dall, J., Ho-Tin-Noe, B., Louedec, L., Meilhac, O., Roncal, C., Carmeliet, P., Germain, S., Michel, J.-B., Houard, X. (2009). Immaturity of microvessels in haemorrhagic plaques is associated with proteolytic degradation of angiogenic factors. Cardiovasc Res 0: cvp253v2-cvp253 [Abstract] [Full Text]  
• Yunoki, K., Naruko, T., Komatsu, R., Ehara, S., Shirai, N., Sugioka, K., Nakagawa, M., Kitabayashi, C., Ikura, Y., Itoh, A., Kusano, K., Ohe, T., Haze, K., Becker, A. E., Ueda, M. (2009). Enhanced expression of haemoglobin scavenger receptor in accumulated macrophages of culprit lesions in acute coronary syndromes. Eur Heart J 30: 1844-1852 [Abstract] [Full Text]  
• Zhang, W., Sun, K., Zhen, Y., Wang, D., Wang, Y., Chen, J., Xu, J., Hu, F. B., Hui, R. (2009). VEGF Receptor-2 Variants Are Associated With Susceptibility to Stroke and Recurrence. Stroke 40: 2720-2726 [Abstract] [Full Text]  
• Hoshino, T., Chow, L. A., Hsu, J. J., Perlowski, A. A., Abedin, M., Tobis, J., Tintut, Y., Mal, A. K., Klug, W. S., Demer, L. L. (2009). Mechanical stress analysis of a rigid inclusion in distensible material: a model of atherosclerotic calcification and plaque vulnerability. Am. J. Physiol. Heart Circ. Physiol. 297: H802-H810 [Abstract] [Full Text]  
• Chu, B., Ferguson, M. S., Chen, H., Hippe, D. S., Kerwin, W. S., Canton, G., Yuan, C., Hatsukami, T. S. (2009). Cardiac Magnetic Resonance Features of the Disruption-Prone and the Disrupted Carotid Plaque. J Am Coll Cardiol Img 2: 883-896 [Abstract] [Full Text]  
• Moreno, P. R., Sanz, J., Fuster, V. (2009). Promoting Mechanisms of Vascular Health: Circulating Progenitor Cells, Angiogenesis, and Reverse Cholesterol Transport. J Am Coll Cardiol 53: 2315-2323 [Abstract] [Full Text]  
• Landesberg, G., Beattie, W. S., Mosseri, M., Jaffe, A. S., Alpert, J. S. (2009). Perioperative Myocardial Infarction. Circulation 119: 2936-2944 [Full Text]  
• Phinikaridou, A., Hallock, K. J., Qiao, Y., Hamilton, J. A. (2009). A robust rabbit model of human atherosclerosis and atherothrombosis. J. Lipid Res. 50: 787-797 [Abstract] [Full Text]  
• Sluimer, J. C., Kolodgie, F. D., Bijnens, A. P.J.J., Maxfield, K., Pacheco, E., Kutys, B., Duimel, H., Frederik, P. M., van Hinsbergh, V. W.M., Virmani, R., Daemen, M. J.A.P. (2009). Thin-walled microvessels in human coronary atherosclerotic plaques show incomplete endothelial junctions relevance of compromised structural integrity for intraplaque microvascular leakage.. J Am Coll Cardiol 53: 1517-1527 [Abstract] [Full Text]  
• Boyle, J. J., Harrington, H. A., Piper, E., Elderfield, K., Stark, J., Landis, R. C., Haskard, D. O. (2009). Coronary Intraplaque Hemorrhage Evokes a Novel Atheroprotective Macrophage Phenotype. Am. J. Pathol. 174: 1097-1108 [Abstract] [Full Text]  
• Magnoni, M., Coli, S., Marrocco-Trischitta, M. M., Melisurgo, G., De Dominicis, D., Cianflone, D., Chiesa, R., Feinstein, S. B., Maseri, A. (2009). Contrast-enhanced ultrasound imaging of periadventitial vasa vasorum in human carotid arteries. Eur J Echocardiogr 10: 260-264 [Abstract] [Full Text]  
• Virmani, R., Finn, A. V., Kolodgie, F. D. (2009). Carotid Plaque Stabilization and Progression After Stroke or TIA. Arterioscler. Thromb. Vasc. Bio. 29: 3-6 [Full Text]  
• Hamm, C. W., Möllmann, H., Bassand, J.-P., van de Werf, F. (2009). CHAPTER 16 Acute Coronary Syndromes. ESC Textbook of Cardiovascular Medicine 2: med-9780199566990-chapter-med-9780199566990-chapter [Abstract] [Full Text]  
• Tziakas, D. N., Chalikias, G. K., Tentes, I. K., Stakos, D., Chatzikyriakou, S. V., Mitrousi, K., Kortsaris, A. X., Kaski, J. C., Boudoulas, H. (2008). Interleukin-8 is increased in the membrane of circulating erythrocytes in patients with acute coronary syndrome. Eur Heart J 29: 2713-2722 [Abstract] [Full Text]  
• Pasterkamp, G., Daemen, M. (2008). Circulating cells: the biofactory for markers of atherosclerotic disease. Eur Heart J 29: 2701-2702 [Full Text]  
• Bitar, R., Moody, A. R., Leung, G., Symons, S., Crisp, S., Butany, J., Rowsell, C., Kiss, A., Nelson, A., Maggisano, R. (2008). In Vivo 3D High-Spatial-Resolution MR Imaging of Intraplaque Hemorrhage. Radiology 249: 259-267 [Abstract] [Full Text]  
• Asleh, R., Blum, S., Kalet-Litman, S., Alshiek, J., Miller-Lotan, R., Asaf, R., Rock, W., Aviram, M., Milman, U., Shapira, C., Abassi, Z., Levy, A. P. (2008). Correction of HDL Dysfunction in Individuals With Diabetes and the Haptoglobin 2-2 Genotype. Diabetes 57: 2794-2800 [Abstract] [Full Text]  
• Arbustini, E., Gambarin, F. I. (2008). Theranostic strategy against plaque angiogenesis.. J Am Coll Cardiol Img 1: 635-637 [Full Text]  
• Underhill, H. R., Yarnykh, V. L., Hatsukami, T. S., Wang, J., Balu, N., Hayes, C. E., Oikawa, M., Yu, W., Xu, D., Chu, B., Wyman, B. T., Polissar, N. L., Yuan, C. (2008). Carotid Plaque Morphology and Composition: Initial Comparison between 1.5- and 3.0-T Magnetic Field Strengths. Radiology 248: 550-560 [Abstract] [Full Text]  
• Coli, S., Magnoni, M., Sangiorgi, G., Marrocco-Trischitta, M. M., Melisurgo, G., Mauriello, A., Spagnoli, L., Chiesa, R., Cianflone, D., Maseri, A. (2008). Contrast-enhanced ultrasound imaging of intraplaque neovascularization in carotid arteries correlation with histology and plaque echogenicity.. J Am Coll Cardiol 52: 223-230 [Abstract] [Full Text]  
• Li, W., Xu, L.-H., Forssell, C., Sullivan, J. L., Yuan, X.-M. (2008). Overexpression of Transferrin Receptor and Ferritin Related to Clinical Symptoms and Destabilization of Human Carotid Plaques. Exp. Biol. Med. 233: 818-826 [Abstract] [Full Text]  
• Nakashima, Y., Wight, T. N., Sueishi, K. (2008). Early atherosclerosis in humans: role of diffuse intimal thickening and extracellular matrix proteoglycans. Cardiovasc Res 79: 14-23 [Abstract] [Full Text]  
• Redgrave, J. N., Gallagher, P., Lovett, J. K., Rothwell, P. M. (2008). Critical Cap Thickness and Rupture in Symptomatic Carotid Plaques: The Oxford Plaque Study. Stroke 39: 1722-1729 [Abstract] [Full Text]  
• Bunch, T. J., Rihal, C. S., Gumina, R. J., Cooper, L., Caplice, N. M. (2008). Progression of Nonculprit Plaque Stenosis Following Successful Percutaneous Intervention. ANGIOLOGY 59: 236-239 [Abstract]  
• Siegel-Axel, D., Daub, K., Seizer, P., Lindemann, S., Gawaz, M. (2008). Platelet lipoprotein interplay: trigger of foam cell formation and driver of atherosclerosis. Cardiovasc Res 78: 8-17 [Abstract] [Full Text]  
• Svilaas, T., Vlaar, P. J., van der Horst, I. C., Diercks, G. F.H., de Smet, B. J.G.L., van den Heuvel, A. F.M., Anthonio, R. L., Jessurun, G. A., Tan, E.-S., Suurmeijer, A. J.H., Zijlstra, F. (2008). Thrombus Aspiration during Primary Percutaneous Coronary Intervention. NEJM 358: 557-567 [Abstract] [Full Text]  
• Raman, S. V., Winner, M. W. III, Tran, T., Velayutham, M., Simonetti, O. P., Baker, P. B., Olesik, J., McCarthy, B., Ferketich, A. K., Zweier, J. L. (2008). In vivo atherosclerotic plaque characterization using magnetic susceptibility distinguishes symptom-producing plaques.. J Am Coll Cardiol Img 1: 49-57 [Abstract] [Full Text]  
• Leclercq, A., Houard, X., Philippe, M., Ollivier, V., Sebbag, U., Meilhac, O., Michel, J.-B. (2007). Involvement of intraplaque hemorrhage in atherothrombosis evolution via neutrophil protease enrichment. J. Leukoc. Biol. 82: 1420-1429 [Abstract] [Full Text]  
• Altaf, N., MacSweeney, S. T., Gladman, J., Auer, D. P (2007). Response to Letters by Hsieh and Chen, and by Tang et al. Stroke 38: e160-e161 [Full Text]  
• Spagnoli, L. G., Bonanno, E., Sangiorgi, G., Mauriello, A. (2007). Role of Inflammation in Atherosclerosis. JNM 48: 1800-1815 [Abstract] [Full Text]  
• Gossl, M., Lerman, L. O., Lerman, A. (2007). Frontiers in Nephrology: Early Atherosclerosis A View Beyond the Lumen. J. Am. Soc. Nephrol. 18: 2836-2842 [Abstract] [Full Text]  
• Wang, T. H., Bhatt, D. L., Fox, K. A.A., Steinhubl, S. R., Brennan, D. M., Hacke, W., Mak, K.-H., Pearson, T. A., Boden, W. E., Steg, P. G., Flather, M. D., Montalescot, G., Topol, E. J., on behalf of the CHARISMA Investigators, (2007). An analysis of mortality rates with dual-antiplatelet therapy in the primary prevention population of the CHARISMA trial. Eur Heart J 28: 2200-2207 [Abstract] [Full Text]  
• Sullivan, J. l. (2007). Macrophage Iron, Hepcidin, and Atherosclerotic Plaque Stability. Exp. Biol. Med. 232: 1014-1020 [Abstract] [Full Text]  
• Ritman, E. L., Lerman, A. (2007). The dynamic vasa vasorum. Cardiovasc Res 75: 649-658 [Abstract] [Full Text]  
• Groyer, E., Nicoletti, A., Ait-Oufella, H., Khallou-Laschet, J., Varthaman, A., Gaston, A.-T., Thaunat, O., Kaveri, S. V., Blatny, R., Stockinger, H., Mallat, Z., Caligiuri, G. (2007). Atheroprotective Effect of CD31 Receptor Globulin Through Enrichment of Circulating Regulatory T-Cells. J Am Coll Cardiol 50: 344-350 [Abstract] [Full Text]  
• Saam, T., Hatsukami, T. S., Takaya, N., Chu, B., Underhill, H., Kerwin, W. S., Cai, J., Ferguson, M. S., Yuan, C. (2007). The Vulnerable, or High-Risk, Atherosclerotic Plaque: Noninvasive MR Imaging for Characterization and Assessment. Radiology 244: 64-77 [Abstract] [Full Text]  
• Minetti, M., Agati, L., Malorni, W. (2007). The microenvironment can shift erythrocytes from a friendly to a harmful behavior: Pathogenetic implications for vascular diseases. Cardiovasc Res 75: 21-28 [Abstract] [Full Text]  
• Nuotio, K., Isoviita, P. M., Saksi, J., Ijas, P., Pitkaniemi, J., Sonninen, R., Soinne, L., Saimanen, E., Salonen, O., Kovanen, P. T., Kaste, M., Lindsberg, P. J. (2007). Adipophilin Expression Is Increased in Symptomatic Carotid Atherosclerosis: Correlation With Red Blood Cells and Cholesterol Crystals * Online Data. Stroke 38: 1791-1798 [Abstract] [Full Text]  
• Kolodgie, F. D., Narula, J., Yuan, C., Burke, A. P., Finn, A. V., Virmani, R. (2007). Elimination of Neoangiogenesis for Plaque Stabilization: Is There a Role for Local Drug Therapy?. J Am Coll Cardiol 49: 2093-2101 [Abstract] [Full Text]  
• Doyle, B., Caplice, N. (2007). Plaque Neovascularization and Antiangiogenic Therapy for Atherosclerosis. J Am Coll Cardiol 49: 2073-2080 [Abstract] [Full Text]  
• Arbustini, E. (2007). Total Erythrocyte Membrane Cholesterol: An Innocent New Marker or an Active Player in Acute Coronary Syndromes?. J Am Coll Cardiol 49: 2090-2092 [Full Text]  
• Tziakas, D. N., Kaski, J. C., Chalikias, G. K., Romero, C., Fredericks, S., Tentes, I. K., Kortsaris, A. X., Hatseras, D. I., Holt, D. W. (2007). Total Cholesterol Content of Erythrocyte Membranes Is Increased in Patients With Acute Coronary Syndrome: A New Marker of Clinical Instability?. J Am Coll Cardiol 49: 2081-2089 [Abstract] [Full Text]  
• Bot, I., de Jager, S. C.A., Zernecke, A., Lindstedt, K. A., van Berkel, T. J.C., Weber, C., Biessen, E. A.L. (2007). Perivascular Mast Cells Promote Atherogenesis and Induce Plaque Destabilization in Apolipoprotein E-Deficient Mice. Circulation 115: 2516-2525 [Abstract] [Full Text]  
• Kolodgie, F. D., Burke, A. P., Nakazawa, G., Virmani, R. (2007). Is Pathologic Intimal Thickening the Key to Understanding Early Plaque Progression in Human Atherosclerotic Disease?. Arterioscler. Thromb. Vasc. Bio. 27: 986-989 [Full Text]  
• Chyu, K.-Y., Shah, P. K. (2007). Choking off Plaque Neovascularity: A Promising Atheroprotective Strategy or A Double-Edged Sword?. Arterioscler. Thromb. Vasc. Bio. 27: 993-995 [Full Text]  
• von Lukowicz, T., Silacci, M., Wyss, M. T., Trachsel, E., Lohmann, C., Buck, A., Luscher, T. F., Neri, D., Matter, C. M. (2007). Human Antibody Against C Domain of Tenascin-C Visualizes Murine Atherosclerotic Plaques Ex Vivo. JNM 48: 582-587 [Abstract] [Full Text]  
• Jackson, C. L., Bennett, M. R., Biessen, E. A.L., Johnson, J. L., Krams, R. (2007). Assessment of Unstable Atherosclerosis in Mice. Arterioscler. Thromb. Vasc. Bio. 27: 714-720 [Abstract] [Full Text]  
• Kanter, J. E., Johansson, F., LeBoeuf, R. C., Bornfeldt, K. E. (2007). Do Glucose and Lipids Exert Independent Effects on Atherosclerotic Lesion Initiation or Progression to Advanced Plaques?. Circ. Res. 100: 769-781 [Abstract] [Full Text]  
• Yamada, N., Higashi, M., Otsubo, R., Sakuma, T., Oyama, N., Tanaka, R., Iihara, K., Naritomi, H., Minematsu, K., Naito, H. (2007). Association between Signal Hyperintensity on T1-Weighted MR Imaging of Carotid Plaques and Ipsilateral Ischemic Events. Am. J. Neuroradiol. 28: 287-292 [Abstract] [Full Text]  
• Schrijvers, D. M., De Meyer, G. R.Y., Herman, A. G., Martinet, W. (2007). Phagocytosis in atherosclerosis: Molecular mechanisms and implications for plaque progression and stability. Cardiovasc Res 73: 470-480 [Abstract] [Full Text]  
• Amirbekian, V., Lipinski, M. J., Briley-Saebo, K. C., Amirbekian, S., Aguinaldo, J. G. S., Weinreb, D. B., Vucic, E., Frias, J. C., Hyafil, F., Mani, V., Fisher, E. A., Fayad, Z. A. (2007). Detecting and assessing macrophages in vivo to evaluate atherosclerosis noninvasively using molecular MRI. Proc. Natl. Acad. Sci. USA 104: 961-966 [Abstract] [Full Text]  
• Levy, A. P., Levy, J. E., Kalet-Litman, S., Miller-Lotan, R., Levy, N. S., Asaf, R., Guetta, J., Yang, C., Purushothaman, K. R., Fuster, V., Moreno, P. R. (2007). Haptoglobin Genotype Is a Determinant of Iron, Lipid Peroxidation, and Macrophage Accumulation in the Atherosclerotic Plaque. Arterioscler. Thromb. Vasc. Bio. 27: 134-140 [Abstract] [Full Text]  
• Joner, M., Farb, A., Cheng, Q., Finn, A. V., Acampado, E., Burke, A. P., Skorija, K., Creighton, W., Kolodgie, F. D., Gold, H. K., Virmani, R. (2007). Pioglitazone Inhibits In-Stent Restenosis in Atherosclerotic Rabbits by Targeting Transforming Growth Factor-{beta} and MCP-1. Arterioscler. Thromb. Vasc. Bio. 27: 182-189 [Abstract] [Full Text]  
• Ijas, P., Nuotio, K., Saksi, J., Soinne, L., Saimanen, E., Karjalainen-Lindsberg, M.-L., Salonen, O., Sarna, S., Tuimala, J., Kovanen, P. T., Kaste, M., Lindsberg, P. J. (2007). Microarray Analysis Reveals Overexpression of CD163 and HO-1 in Symptomatic Carotid Plaques. Arterioscler. Thromb. Vasc. Bio. 27: 154-160 [Abstract] [Full Text]  
• Gross, M.-L., Meyer, H.-P., Ziebart, H., Rieger, P., Wenzel, U., Amann, K., Berger, I., Adamczak, M., Schirmacher, P., Ritz, E. (2007). Calcification of Coronary Intima and Media: Immunohistochemistry, Backscatter Imaging, and X-Ray Analysis in Renal and Nonrenal Patients. CJASN 2: 121-134 [Abstract] [Full Text]  
• Assmus, B., Walter, D. H., Lehmann, R., Honold, J., Martin, H., Dimmeler, S., Zeiher, A. M., Schachinger, V. (2006). Intracoronary infusion of progenitor cells is not associated with aggravated restenosis development or atherosclerotic disease progression in patients with acute myocardial infarction. Eur Heart J 27: 2989-2995 [Abstract] [Full Text]  
• Shaw, J. A., White, A. J., Reddy, R., Duffy, S. J., Walton, A. S., Kingwell, B. A., Dart, A. M. (2006). Evaluation of Differences in Coronary Plaque Mechanical Behavior in Individuals With and Without Type 2 Diabetes Mellitus.. Arterioscler. Thromb. Vasc. Bio. 26: 2826-2827 [Full Text]  
• Waxman, S., Ishibashi, F., Muller, J. E. (2006). Detection and Treatment of Vulnerable Plaques and Vulnerable Patients: Novel Approaches to Prevention of Coronary Events. Circulation 114: 2390-2411 [Full Text]  
• Li, W., Ostblom, M., Xu, L.-H., Hellsten, A., Leanderson, P., Liedberg, B., Brunk, U. T., Eaton, J. W., Yuan, X.-M. (2006). Cytocidal effects of atheromatous plaque components: the death zone revisited. FASEB J. 20: 2281-2290 [Abstract] [Full Text]  
• Kockx, M M, Knaapen, M W (2006). Pathological changes in the coronary arteries in the acute coronary syndromes.. Heart 92: 1557-1558 [Full Text]  
• Kolodgie, F. D., Burke, A. P., Skorija, K. S., Ladich, E., Kutys, R., Makuria, A. T., Virmani, R. (2006). Lipoprotein-Associated Phospholipase A2 Protein Expression in the Natural Progression of Human Coronary Atherosclerosis. Arterioscler. Thromb. Vasc. Bio. 26: 2523-2529 [Abstract] [Full Text]  
• Houard, X., Leclercq, A., Fontaine, V., Coutard, M., Martin-Ventura, J.-L., Ho-Tin-Noe, B., Touat, Z., Meilhac, O., Michel, J.-B. (2006). Retention and Activation of Blood-Borne Proteases in the Arterial Wall: Implications for Atherothrombosis. J Am Coll Cardiol 48: A3-A9 [Abstract] [Full Text]  
• Bochkov, V. N., Philippova, M., Oskolkova, O., Kadl, A., Furnkranz, A., Karabeg, E., Afonyushkin, T., Gruber, F., Breuss, J., Minchenko, A., Mechtcheriakova, D., Hohensinner, P., Rychli, K., Wojta, J., Resink, T., Erne, P., Binder, B. R., Leitinger, N. (2006). Oxidized Phospholipids Stimulate Angiogenesis Via Autocrine Mechanisms, Implicating a Novel Role for Lipid Oxidation in the Evolution of Atherosclerotic Lesions. Circ. Res. 99: 900-908 [Abstract] [Full Text]  
• Choudhary, S., Higgins, C. L., Chen, I. Y., Reardon, M., Lawrie, G., Vick, G. W. III, Karmonik, C., Via, D. P., Morrisett, J. D. (2006). Quantitation and Localization of Matrix Metalloproteinases and Their Inhibitors in Human Carotid Endarterectomy Tissues. Arterioscler. Thromb. Vasc. Bio. 26: 2351-2358 [Abstract] [Full Text]  
• Isobe, S., Tsimikas, S., Zhou, J., Fujimoto, S., Sarai, M., Branks, M. J., Fujimoto, A., Hofstra, L., Reutelingsperger, C. P., Murohara, T., Virmani, R., Kolodgie, F. D., Narula, N., Petrov, A., Narula, J. (2006). Noninvasive Imaging of Atherosclerotic Lesions in Apolipoprotein E-Deficient and Low-Density-Lipoprotein Receptor-Deficient Mice with Annexin A5. JNM 47: 1497-1505 [Abstract] [Full Text]  
• Caligiuri, G., Kaveri, S. V., Nicoletti, A. (2006). IL-20 and Atherosclerosis: Another Brick In the Wall.. Arterioscler. Thromb. Vasc. Bio. 26: 1929-1930 [Full Text]  
• Winter, P. M., Neubauer, A. M., Caruthers, S. D., Harris, T. D., Robertson, J. D., Williams, T. A., Schmieder, A. H., Hu, G., Allen, J. S., Lacy, E. K., Zhang, H., Wickline, S. A., Lanza, G. M. (2006). Endothelial {alpha}{nu}{beta}3 Integrin-Targeted Fumagillin Nanoparticles Inhibit Angiogenesis in Atherosclerosis. Arterioscler. Thromb. Vasc. Bio. 26: 2103-2109 [Abstract] [Full Text]  
• Saam, T., Cai, J., Ma, L., Cai, Y.-Q., Ferguson, M. S., Polissar, N. L., Hatsukami, T. S., Yuan, C. (2006). Comparison of Symptomatic and Asymptomatic Atherosclerotic Carotid Plaque Features with in Vivo MR Imaging.. Radiology 240: 464-472 [Abstract] [Full Text]  
• Feinstein, S. B. (2006). Contrast Ultrasound Imaging of the Carotid Artery Vasa Vasorum and Atherosclerotic Plaque Neovascularization. J Am Coll Cardiol 48: 236-243 [Abstract] [Full Text]  
• Bitar, R., Moody, A. R., Leung, G., Kiss, A., Gladstone, D., Sahlas, D. J., Maggisano, R. (2006). In vivo identification of complicated upper thoracic aorta and arch vessel plaque by MR direct thrombus imaging in patients investigated for cerebrovascular disease.. Am. J. Roentgenol. 187: 228-234 [Abstract] [Full Text]  
• MacDougall, E. D., Kramer, F., Polinsky, P., Barnhart, S., Askari, B., Johansson, F., Varon, R., Rosenfeld, M. E., Oka, K., Chan, L., Schwartz, S. M., Bornfeldt, K. E. (2006). Aggressive Very Low-Density Lipoprotein (VLDL) and LDL Lowering by Gene Transfer of the VLDL Receptor Combined with a Low-Fat Diet Regimen Induces Regression and Reduces Macrophage Content in Advanced Atherosclerotic Lesions in LDL Receptor-Deficient Mice. Am. J. Pathol. 168: 2064-2073 [Abstract] [Full Text]  
• Moreno, P. R., Purushothaman, K-R., Sirol, M., Levy, A. P., Fuster, V. (2006). Neovascularization in Human Atherosclerosis. Circulation 113: 2245-2252 [Full Text]  
• Zernecke, A., Bidzhekov, K., Ozuyaman, B., Fraemohs, L., Liehn, E. A., Luscher-Firzlaff, J. M., Luscher, B., Schrader, J., Weber, C. (2006). CD73/Ecto-5'-Nucleotidase Protects Against Vascular Inflammation and Neointima Formation. Circulation 113: 2120-2127 [Abstract] [Full Text]  
• Falk, E. (2006). Pathogenesis of atherosclerosis.. J Am Coll Cardiol 47: C7-C12 [Abstract] [Full Text]  
• Tedgui, A., Mallat, Z. (2006). Cytokines in Atherosclerosis: Pathogenic and Regulatory Pathways. Physiol. Rev. 86: 515-581 [Abstract] [Full Text]  
• Stewart, F. A., Heeneman, S., te Poele, J., Kruse, J., Russell, N. S., Gijbels, M., Daemen, M. (2006). Ionizing Radiation Accelerates the Development of Atherosclerotic Lesions in ApoE-/- Mice and Predisposes to an Inflammatory Plaque Phenotype Prone to Hemorrhage. Am. J. Pathol. 168: 649-658 [Abstract] [Full Text]