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(Circulation. 1996;94:2013-2020.)
© 1996 American Heart Association, Inc.
Articles |
Stability and Instability: Two Faces of Coronary Atherosclerosis
The Paul Dudley White Lecture 1995
St George's Hospital Medical School, University of London, UK.
Correspondence to Michael J. Davies, MD, Cardiovascular Pathology Unit, St George's Hospital Medical School, Cranmer Terrace, London SW17 ORE, UK.
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Introduction |
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Top
Introduction
Thrombosis and PlaquesPaul Dudley White was an astute observer of ischemic heart disease who emphasized the unity of acute myocardial infarction and chronic exertional angina as facets of the clinical expression of coronary atherosclerosis. He knew that plaque ulceration was a precipitator of thrombosis, but in the days before angiography was widely used, he reasoned that thrombosis occurred at sites of previous high-grade stenosis. He would be fascinated by the explosion of knowledge concerning the mechanisms of the two major expressions of coronary heart disease that has occurred since his death in 1973.
Any consideration of how symptoms arise in coronary atherosclerosis must begin with plaque. By early adult life, most individuals in developed countries will have some coronary plaques that, in pathological terms, are advanced. This simply means that within the plaque there has been considerable accumulation of extracellular lipid, lipid within foam cells of macrophage origin, and collagen produced by smooth muscle cells.
Plaques occupy space; yet, as pathology studies have shown in the past, the arterial lumen is not necessarily compromised, implying that the angiogram would be a poor tool to assess atherosclerosis in living subjects, however good it might be at detecting high-grade stenosis that causes symptoms. The insensitivity of angiography in the detection of plaques has been amply demonstrated by intravascular ultrasound.1 2 The landmark work of Glagov et al,3 which showed that the arterial wall is not a static, immutable structure but rather can remodel itself by increasing its external diameter to accommodate the plaque without narrowing the lumen, is one explanation of angiographically silent plaques. This process has been confirmed by intravascular ultrasound.4 5 A second explanation is the occurrence of medial atrophy confined to the area immediately behind the plaque.6 This allows the plaque to bulge outward rather than inward toward the lumen; rupture of the internal elastic lamina may occur, allowing the plaque to be almost extruded from the vessel wall.
Advanced plaques are heterogeneous with regard to the relative amounts of their various components. The American Heart Association (AHA) has adopted a committee recommendation on a nomenclature for plaques.7 Plaques of AHA types IV and Va have a lipid core separated from the lumen by a cap of fibrous tissue (Fig 1
). The cap has a high concentration of type I collagen arranged in a densely woven pattern; within lacunae in the tissue there are smooth muscle cells that produce the connective tissue matrix proteins, including the collagens. The cap tissue has morphological characteristics that suggest that it is capable of bearing considerable tensile stress without breaking. Use of compounds that bind specifically to collagen, such as Sirius red, allows the generation of high-contrast images of the collagenous skeleton of the plaque (Fig 2). Such images show several important points. The lipid core may, at one extreme, occupy a relatively small proportion or, at the other extreme, a large proportion of overall plaque volume. The core itself does not contain collagen; this implies that if the lipid is removed, there is a potential space in the plaque. The cap varies widely in thickness and may be uniform or may have thick and thin areas.
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The core is largely acellular. This is taken to indicate that cell death must have occurred. Surrounding the core are numerous macrophages, usually identified by immunohistochemistry with antibodies to specific cell antigens such as CD68. Colocalization of tissue factor, also identified by immunohistochemistry, shows that many but not all of the macrophages are positive (Fig 3). Studies of the relative thrombogenicity of different components of the plaque confirm that the core is the most active site for thrombus formation.8 The number of macrophages present in plaques varies widely, even in those with a lipid core. Many subjects also have plaques that do not have a lipid core (AHA type Vc). The essential fact is that any individual patient is likely to have numerous coronary plaques, none of which are identical to each other.
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Thrombosis and Plaques |
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I do not intend to review the evidence that links acute myocardial infarction and the crescendo type of unstable angina with coronary thrombosis. Fibrinolytic therapy is effective in the former, less so in the latter; some explanation must exist for this phenomenon.
Thrombosis occurs over plaques for two different reasons.9 In the first situation, thrombus is formed on the surface of a plaque (Fig 4). The cause is denudation and erosion of the endothelial surface. In the second, there is a disruption or tear in the cap of a lipid-rich plaque; blood from the lumen enters the lipid core of the plaque, where thrombus is formed. Thus, there is an initial phase of intraplaque hemorrhage and thrombosis that may or may not be followed by thrombosis within the lumen. Plaque disruption has been reported to be more common, by a ratio on the order of 3 to 1, as a factor precipitating major thrombi than the more superficial process of endothelial denudation.9 Another study of sudden death due to ischemic heart disease in relatively young subjects, however, has put the ratio of thrombi due to plaque rupture compared with endothelial erosion as 1.3 to 1.10
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There are demographic differences between the two forms of thrombosis (Table 1). Disruption causing major thrombi usually occurs in plaques that have lower degrees of initial stenosis, whereas thrombi due to endothelial erosion often occur at sites of preexisting high-grade stenosis. Smaller arteries, such as the posterior descending coronary artery, are more often the seat of the endothelial denudation/erosion type of thrombosis. Thrombosis due to endothelial erosion has also been reported to be relatively more common at a younger age and in women.10
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Thrombosis Due to Endothelial Erosion |
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Superficial thrombosis over plaques is due to endothelial denudation with exposure of collagen and tissue factor. On an ultrastructural scale, once plaques have reached an advanced state (AHA type IV to V), some focal platelet deposition is almost ubiquitous.11 12 Such microscopic platelet thrombi have no clinical significance other than perhaps to stimulate smooth muscle growth. These very small focal areas of loss of endothelial cells must also be a stimulus for endothelial regeneration, with the implication that function of the new endothelial cells may be abnormal, predisposing to vasoconstriction.
Larger areas of denudation of endothelial cells cause bigger thrombi that contain fibrin and red cells in addition to platelets and can cause sufficient lumen obstruction to be symptomatic.4 10 This form of endothelial loss and erosion has been associated with marked accumulation of activated lipid-filled macrophages beneath the endothelium, an increase in T lymphocytes, and the expression of major histocompatibility complex type II antigens by adjacent smooth muscle cells.13 These studies suggest that the endothelial destruction is associated with inflammatory activity. Another recent study,10 however, showed that particularly in women, plaques rich in smooth muscle cells and proteoglycans but relatively poor in lipids, macrophages, and inflammatory cells can also develop endothelial erosion and undergo thrombosis.
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Plaque Disruption: Deep Intimal Injury |
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Common to the great majority of episodes of plaque disruption is a tear or crack in the fibromuscular cap of a plaque that has a lipid core. This process inevitably involves endothelial destruction, but the major cause of thrombosis is that blood from the lumen of the artery enters the core and comes into contact with both tissue factor and collagen fibrils. There is a broad spectrum of both the severity and the morphology of disruption episodes (Figs 5 through 8
). At the minor end of the scale, the break in the cap is small, and although the plaque is expanded by blood within the core, the overall shape of the plaque is retained. More significant tears allow sufficient blood to enter the core that stenosis rapidly increases. The torn cap may project into the lumen (Fig 5). Thrombotic material may project into the lumen from the core via the cap tear. Very major episodes of disruption may involve spiral or multiple tears in the cap, with extrusion of plaque contents into the lumen.
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The response to an episode of plaque disruption has several stages and components (Figs 6 through 8
). The initial stage is the entry of blood into the core from the lumen. This initial stage has been given many names, including plaque or intimal hemorrhage,14 15 plaque hematoma,16 and hemorrhagic dissection.17 Such names, however, tend to disguise the fact that although red cells and fibrin are present, the larger component of this intraplaque mass is platelets (Table 2). For this reason, it can be regarded as an intraplaque thrombus.18 Platelets in these numbers suggest that at least for a time, blood enters and leaves the core. Lipid washout into the lumen occurs with large tears.
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Thrombus that forms within the immediate area of the cap break will ultimately prevent further ingress of blood into the core. The exception is when the whole cap has been lost, thus creating from the core a wide-mouthed open crater. The second stage in the process is made up of thrombus, which has a larger component of densely packed fibrin but also has a platelet component (Table 2). Thrombus is now exposed to the blood flow in the artery (mural thrombus) but does not totally prevent antegrade flow. At this stage, distal emboli occur, and their predominantly platelet structure19 20 suggests that the active surface facing the lumen is covered by platelets. The final stage in the process is total arterial occlusion by thrombus. In the immediate zone of the disruption, this thrombus has a predominantly fibrin/platelet component, but immediately distal to this, it is made up of a loose network of fibrin with intermeshed red cells. The phased response to plaque disruption has been studied by injection of radiolabeled fibrinogen into subjects who develop acute infarction.17 At subsequent necropsy, the proximal portion of the thrombus closest to the tear was negative; ie, it antedated infarction. The distal thrombus was rich in labeled fibrin; ie, it occurred in part after the onset of infarction.
Unstable angina due to plaque disruption indicates that the patient has mural thrombus exposed to the arterial lumen for significant periods of time. This probably represents a balance between factors that promote and those that inhibit thrombosis (Table 3). The active surface of the thrombus is covered by platelets, but beneath this is densely packed fibrin. The relative lack of therapeutic response to fibrinolysis suggests that this fibrin is not easily accessed by therapeutic agents, although specific antiplatelet drugs may be able to influence events on the active surface.
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Plaque disruption is a stimulus to the formation of coronary thrombosis within the lumen. Whether thrombus that significantly interferes with blood flow occurs depends on many opposing factors (Table 3). Acute myocardial infarction represents a predominance of the thrombus-promoting factors that lead to occlusion.
Study of the pathology of plaques in the human aorta and coronary arteries that have undergone disruption has been used to determine the characteristics of intact plaques that have a risk of disruption, ie, are vulnerable. Autopsy studies augmented by the study of material retrieved at atherectomy in stable and unstable angina show vulnerability to be a function of increased numbers of macrophages, increased expression of tissue factor, reduced numbers of smooth muscle cells, a lipid core that occupies a high proportion of overall plaque volume, and a thin plaque cap.21 22 23 24 When all these factors coincide, the plaque is at high risk of disruption (Fig 9). Each of the parameters that determine vulnerability has a wide variation, and they are not directly linked. Every combination of the variables exists; thus, it is possible to have a plaque with a very large lipid core but a thick cap and minimal macrophage content that is at low risk of disruption. The implication is that any individual patient may have one, several, or many plaques with vulnerable characteristics. No clinical method exists as yet to determine this number. No correlation exists between, for example, core size and angiographic stenosis or plaque size.
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Pathogenesis of Plaque Disruption |
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The fracture of any biological tissue is dependent on the two variables of the stress imposed and the innate mechanical strength of the tissue. Computer modeling of the circumferential wall stress distribution across the arterial wall in systole shows it to become very uneven in the presence of a lipid core.25 26 The core, being soft and deformable, cannot carry circumferential stress; the stress that would have been carried by the core is redistributed onto the cap. Moreover, it is often concentrated onto relatively small focal areas of the cap, whose position is determined by the stiffness of the cap relative to the adjacent intima and by the circumferential angle the core occupies. Focal concentrations of load up to seven or eight times normal systolic wall stress may occur on the cap. These elevations of stress are enhanced if the cap is thin or uneven in thickness and are also higher in the absence of high-grade stenosis. Thus, the configuration of a lipid-rich plaque determines the elevation of stress on the cap. In other words, plaques with a lipid core are mechanically inefficient.
The other side of the equation in cap tearing is the innate mechanical strength of the tissue itself. Caps that are infiltrated with macrophages and lose the normal densely woven pattern of collagen are mechanically weak when tested in vitro even after adjustment for the cross-sectional area of the tissue.27 Libby28 established the concept that the cap must be viewed as a structure in which there is a dynamic state, with collagen synthesis by smooth muscle cells being balanced against collagen degradation (Fig 10). Loss of smooth muscle cells, possibly by apoptotic death,29 would ultimately lead to a reduction in collagen, but a more rapidly acting factor may be suppression of collagen synthesis by cytokines, such as interferon-
, released by lymphocytes.
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Macrophages within plaques are capable of producing a range of proteases with specificity against all of the connective tissue matrix proteins.30 The metalloproteinases are released in an inactive form and activated in the tissue by plasmin. Activation of macrophages by tumor necrosis factor-
is a potent stimulus for metalloproteinase production. Tissue inhibitors of metalloproteinases are also produced, which may neutralize lytic activity. Observational studies have shown metalloproteinases to be present in plaques both as mRNA and as the enzymes themselves,31 32 with high levels of tissue inhibitors within the plaque. The Libby group,32 however, showed that if tissue sections of plaques are laid on gelatin, proteolytic activity occurs. This implies that in focal areas within the plaque, proteolytic destruction of connective tissue matrix is occurring; such areas coincided with points of likely plaque cap disruption. The key cell in this regard appears to be the activated macrophage initiating "self-destruction" in the cap. Basophils (mast cells) are also capable of producing collagenases and, perhaps more important, of directly activating metalloproteinases without the intervention of plasmin and are reported to be increased in vulnerable plaques.33 Their number, however, is very small in comparison with monocytes.
A wide range of proteases, including all the metalloproteinases and a serine protease, appear to be produced at focal sites in plaques. It is uncertain which is the most important in collagen destruction; all probably act in concert. The gelatinase B (MMP9) metalloproteinase is the most prevalent form, being expressed by virtually all activated macrophages, and has been shown to be more common in atherectomy material from unstable angina than that from stable angina.34
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Dynamics of Lipid Core Formation |
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Considering that the lipid core is the single most important feature of vulnerable plaques, relatively little is known about its formation. It is a space in the connective tissue matrix of the plaque filled with acellular lipid. The lipid derives in large part from the death of lipid-filled macrophage foam cells at the margins of the core (Fig 11
). The core lipid has therefore been derived from oxidized LDL originally taken up by macrophages via the scavenger receptor.35 At least part of the core lipid, however, may have been derived from LDL bound to proteoglycans or fibrinogen in the intima that has not been processed by macrophages.36 Macrophage death for a long time was regarded as due to the direct toxicity of hydroxylipids, but two other possibilities have now become apparent. Apoptotic cell death has been demonstrated in a very high proportion of the macrophages surrounding the core.29 37 38 T lymphocytes, many of which have a cytotoxic potential because they contain perforin and granzyme A, are also present.
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It is not clear how the defect in the connective tissue matrix is created. It may be that lipid passively pushes the collagen fibers apart. Morphological studies, however, suggest that a far more active destruction of matrix by macrophages and metalloproteinases is occurring. Some lipid cores have large amounts of metalloproteinase bound to the surviving matrix at the edge of the core (Fig 12). The edges of the connective tissue matrix abutting the core have sharp edges reminiscent of bone resorption by osteoclasts. A striking feature is that such macrophage activity rarely occupies all the circumference of the core and may be totally absent in some plaques with a lipid core. Thus, macrophage activation and phenotype vary even within one plaque. It is also possible for a lipid core to become inert and the inflammatory process to be burnt out.
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Disease Progression and Plaque Thrombosis |
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The enthusiasm for plaque disruption as the basis for crescendo angina and acute infarction in the 1980s fostered the belief that such episodes were usually major and came to the clinician's notice by producing symptoms. Four pathological studies contradicted this view. In up to 8% of subjects with coronary atheroma who died of nonvascular causes such as accidents, a small recent disruption was found after detailed study of the coronary artery tree at autopsy.39 The thrombi were almost entirely within the plaque. In three studies40 41 42 of subjects who died of ischemic heart disease, the number of acute plaque disruptions exceeded the number of patients by a factor of between 2 and 3, although one of the thrombi in each case was larger and was considered the culprit lesion causing death. Thus, plaque disruption must be considered to be a common complication of plaques, and a high proportion of such episodes are clinically silent. Some support for this view came from comparison of the presence of thrombus in atherectomy samples of stable versus unstable angina.43 44 45 In all these studies, although thrombus was found in a far higher proportion of patients with unstable angina, some apparently stable plaques also showed thrombus. The introduction of angioscopy has provided more sensitive data on this point.46 In 95 subjects with unstable angina, 70 (73.9%) had visible thrombus at the culprit site; in stable angina, thrombus was visible in 4 of 27 subjects (14.9%).
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Coronary Disease Progression |
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The number of acute ischemic clinical events that occur and the angiographic development of new stenotic segments and/or the progression of existing stenoses are used as measures of the progression of coronary disease. The question arises whether these parameters represent a common mechanism or two separate mechanisms. One would be mediated by thrombosis, the other by smooth muscle proliferation in conjunction with lipid accumulation, a process that could be called primary atherogenesis. Some angiographic studies47 48 show that angiographic progression predicts new clinical events, supporting a unitary view in the mechanism of progression.
The healing response after balloon angioplasty in humans is well known and consists of the proliferation of smooth muscle cells followed by the deposition of new collagen. This new connective tissue may then encroach on the lumen and produce restenosis. Natural disruption of plaques invokes an identical repair process. Examination of high-grade stenoses in arteries that supply healed regional infarcts and therefore have a very high probability that a thrombotic event has occurred in the past allows this healing process to be studied. With staining methods such as Sirius red, old collagen and that more recently laid down can be identified in tissue sections under polarized light (Fig 13). Examination of high-grade stenoses unrelated to prior infarction shows a proportion of them to have a structure identical to that of stenoses related to myocardial scars.
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This shows that one method for plaque growth and thus angiographic progression is healing of a subclinical plaque disruption.
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Patient-to-Patient Variability |
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Paul Dudley White was intrigued by the patients at each extreme of the clinical expression of ischemic heart disease, ie, those who had only stable angina or predominantly had repeated episodes of acute ischemia. The basis probably lies in the patient-to-patient variability in plaque composition. When large numbers of plaques causing high-grade coronary stenosis from groups of subjects with coronary disease are taken together, their collagen content overall is higher than that of plaques causing lesser degrees of obstruction.49 Such composite data, valid as they are, still obscure the patient-to-patient variability. A detailed autopsy study of 54 subjects who died after having had stable angina for more than 2 years revealed this variation.50 In 13% of the subjects, all the plaques present were predominantly fibrous in character, ie, nonvulnerable. In contrast, in 14.8% of patients, the majority of plaques had lipid cores. This leads to the concept that for any patient with coronary disease, there is a vulnerability index for future acute ischemic events determined by the absolute number of vulnerable plaques present. It is this number that determines the subsequent risk of acute infarction. Unfortunately, the angiogram cannot and does not give any information in this regard.
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The Future |
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It is now clear that plaque composition is a major determinant of the risk of an acute ischemic event in the future. In patients who have not yet suffered extensive myocardial damage, plaque composition may be the major determinant of life expectancy. Technological advances such as intravascular ultrasound and thermal imaging may allow such vulnerable plaques to be identified in vivo.51 52 Two studies now show incontrovertible evidence that lowering plasma lipid levels leads to a reduction in the risk of acute ischemic events and death.53 54 The most logical explanation is that plaque composition has been altered to improve stability, ie, a reduction in the risk of thrombosis. The unanswered question is how this change is mediated. Has the lipid core been replaced by new connective tissue after removal of some of the lipid, thus restoring the mechanical efficiency of the plaque? Experimental studies in primates with atherosclerosis induced by high-lipid diets suggest that this hypothesis is tenable.55 56 Have macrophage activation and inflammation been reduced? In the Watanabe rabbit, lowering of plasma lipids reduces the macrophage content of the arterial lesions.57 What seems certain is that the human plaque biology has been altered by lowering of plasma lipids.
Received February 26, 1996; revision received April 25, 1996; accepted May 1, 1996.
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G. Ghilardi, M. L. Biondi, M. DeMonti, O. Turri, E. Guagnellini, and R. Scorza Matrix Metalloproteinase-1 and Matrix Metalloproteinase-3 Gene Promoter Polymorphisms Are Associated With Carotid Artery Stenosis Stroke, October 1, 2002; 33(10): 2408 - 2412. [Abstract] [Full Text] [PDF]
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 G. K. Hansson, P. Libby, U. Schonbeck, and Z.-Q. Yan Innate and Adaptive Immunity in the Pathogenesis of Atherosclerosis Circ. Res., August 23, 2002; 91(4): 281 - 291. [Abstract] [Full Text] [PDF]
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G. Rioufol, G. Finet, I. Ginon, X. Andre-Fouet, R. Rossi, E. Vialle, E. Desjoyaux, G. Convert, J.F. Huret, and A. Tabib Multiple Atherosclerotic Plaque Rupture in Acute Coronary Syndrome: A Three-Vessel Intravascular Ultrasound Study Circulation, August 13, 2002; 106(7): 804 - 808. [Abstract] [Full Text] [PDF]
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A. Tedgui and Z. Mallat Platelets in Atherosclerosis: A New Role for {beta}-Amyloid Peptide Beyond Alzheimer's Disease Circ. Res., June 14, 2002; 90(11): 1145 - 1146. [Full Text] [PDF]
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J.H.F. Rudd, E.A. Warburton, T.D. Fryer, H.A. Jones, J.C. Clark, N. Antoun, P. Johnstrom, A.P. Davenport, P.J. Kirkpatrick, B.N. Arch, et al. Imaging Atherosclerotic Plaque Inflammation With [18F]-Fluorodeoxyglucose Positron Emission Tomography Circulation, June 11, 2002; 105(23): 2708 - 2711. [Abstract] [Full Text] [PDF]
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P. R. Moreno, K. R. Purushothaman, V. Fuster, and W. N. O'Connor Intimomedial Interface Damage and Adventitial Inflammation Is Increased Beneath Disrupted Atherosclerosis in the Aorta: Implications for Plaque Vulnerability Circulation, May 28, 2002; 105(21): 2504 - 2511. [Abstract] [Full Text] [PDF]
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C.L. de Korte, S.G. Carlier, F. Mastik, M.M. Doyley, A.F.W. van der Steen, P.W. Serruys, and N. Bom Morphological and mechanical information of coronary arteries obtained with intravascular elastography. Feasibility study in vivo Eur. Heart J., March 1, 2002; 23(5): 405 - 413. [Abstract] [Full Text] [PDF]
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B. Salobir, M. Sabovic, P. Peternel, and M. Stegnar Fibrinolytic Parameters and Lipoprotein(a) in Young Women with Myocardial Infarction Angiology, March 1, 2002; 53(2): 157 - 163. [Abstract] [PDF]
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 A. Farzaneh-Far, J. Rudd, and P. L Weissberg Inflammatory mechanisms: Ischaemic heart disease Br. Med. Bull., October 1, 2001; 59(1): 55 - 68. [Abstract] [Full Text] [PDF]
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X.-Q. Zhao, C. Yuan, T. S. Hatsukami, E. H. Frechette, X.-J. Kang, K. R. Maravilla, and B. G. Brown Effects of Prolonged Intensive Lipid-Lowering Therapy on the Characteristics of Carotid Atherosclerotic Plaques In Vivo by MRI: A Case-Control Study Arterioscler Thromb Vasc Biol, October 1, 2001; 21(10): 1623 - 1629. [Abstract] [Full Text] [PDF]
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S. W.E. van de Poll, T. J. Romer, O. L. Volger, D. J.M. Delsing, T. C. Bakker Schut, H. M.G. Princen, L. M. Havekes, J. W. Jukema, A. van der Laarse, and G. J. Puppels Raman Spectroscopic Evaluation of the Effects of Diet and Lipid-Lowering Therapy on Atherosclerotic Plaque Development in Mice Arterioscler Thromb Vasc Biol, October 1, 2001; 21(10): 1630 - 1635. [Abstract] [Full Text] [PDF]
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E.G. Zouridakis, R. Schwartzman, X. Garcia-Moll, I.D. Cox, S. Fredericks, D.W. Holt, and J.C. Kaski Increased plasma endothelin levels in angina patients with rapid coronary artery disease progression Eur. Heart J., September 1, 2001; 22(17): 1578 - 1584. [Abstract] [PDF]
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J S Sidhu and J C Kaski Peroxisome proliferator activated receptor {gamma}: a potential therapeutic target in the management of ischaemic heart disease Heart, September 1, 2001; 86(3): 255 - 258. [Full Text] [PDF]
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P. Amarenco Hypercholesterolemia, lipid-lowering agents, and the risk for brain infarction Neurology, September 1, 2001; 57(90002): S35 - 44. [Abstract] [Full Text]
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D. A. Smith, S. D. Irving, J. Sheldon, D. Cole, and J. C. Kaski Serum Levels of the Antiinflammatory Cytokine Interleukin-10 Are Decreased in Patients With Unstable Angina Circulation, August 14, 2001; 104(7): 746 - 749. [Abstract] [Full Text] [PDF]
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M. Schartl, W. Bocksch, D. H. Koschyk, W. Voelker, K. R. Karsch, J. Kreuzer, D. Hausmann, S. Beckmann, and M. Gross Use of Intravascular Ultrasound to Compare Effects of Different Strategies of Lipid-Lowering Therapy on Plaque Volume and Composition in Patients With Coronary Artery Disease Circulation, July 24, 2001; 104(4): 387 - 392. [Abstract] [Full Text] [PDF]
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P. Libby Current Concepts of the Pathogenesis of the Acute Coronary Syndromes Circulation, July 17, 2001; 104(3): 365 - 372. [Full Text] [PDF]
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 G.K. Hansson The stabilized plaque: will the dream come true? Eur. Heart J. Suppl., June 1, 2001; 3(suppl_C): C69 - C75. [PDF]
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