Skip main navigation
Close Drawer MenuOpen Drawer Menu

Atherosclerotic Plaque Rupture

Local or Systemic Process?
Originally published25 Sep 2003https://doi.org/10.1161/01.ATV.0000097783.01596.E2Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:2123–2130

Abstract

It is generally established that the unstable plaque is the major cause of acute clinical sequelae of atherosclerosis. Unfortunately, terms indicating lesions prone to plaque instability, such as “vulnerable plaque,” and the different phenotypes of unstable plaques, such as plaque rupture, plaque fissuring, intraplaque hemorrhage, and erosion, are often used interchangeably. Moreover, the different phenotypes of the unstable plaque are mostly referred to as plaque rupture. In the first part of this review, we will focus on the definition of true plaque rupture and the definitions of other phenotypes of plaque instability, especially on intraplaque hemorrhage, and discuss the phenotypes of available animal models of plaque instability. The second part of this review will address the pathogenesis of plaque rupture from a local and a systemic perspective. Plaque rupture is thought to occur because of changes in the plaque itself or systemic changes in the patient. Interestingly, contributing factors seem to overlap to a great extent and might even be interrelated. Finally, we will propose an integrative view on the pathogenesis of plaque rupture.

Definition of Plaque Rupture

In 1995, the American Heart Association (AHA) Committee on Vascular Lesions developed a numerical classification of the composition and structure of human atherosclerotic lesions. In this classification, “complicated lesions” (type VI lesions), responsible for most of the morbidity and mortality from atherosclerosis, were defined as atheromata (type IV lesions) or fibroatheromata (type V lesions), containing 1 or more surface defects and/or hematoma-hemorrhage and/or thrombus.1

In 2000, the classification was updated by Stary2 and modified by Virmani et al.3 They introduced a more detailed description of atherothrombotic plaques. In contrast to the AHA classification of 1995, the definition of “plaque rupture” is stricter, and the possibilities for atherothrombotic events are extended. Atherothrombotic events are clearly separated into plaque rupture, erosion, and eruptive calcified nodules. Moreover, intraplaque hemorrhages are described as phenomena in lesions that are not necessarily associated with plaque rupture (Figure 1).

Figure 1. Outline of the different subtypes of the definition of atherothrombosis (AHA classification and Virmani classification).

Because terms like “plaque instability,” “plaque vulnerability,” “plaque rupture,” and “intraplaque hemorrhage” are often used interchangeably, one explanation for the apparent confusion in the literature is the use of a different definition of atherosclerotic plaque rupture. In this review, the stricter definitions of plaque rupture and intraplaque hemorrhage as proposed by Virmani et al3 are used. Plaque rupture is defined as “an area of fibrous cap disruption whereby the overlying thrombus is in continuity with the lipid core”.3 Intraplaque hemorrhage is defined as the deposition of blood products inside the plaque and is not necessarily associated with atherosclerotic plaque rupture.2 Because the pathogenesis of plaque erosion and calcified nodules is hardly known, these are excluded from this review.

Animal Models of Plaque Rupture: Do They Exist?

Until the last decade, the most widely used animal models of primary atherosclerosis were cholesterol-fed rabbits, pigs, and nonhuman primates. These models, except for primates, develop only minimal disease and require >1 year to develop significant lesions. The development of genetically engineered mice that lack genes important in lipid metabolism, like apolipoprotein E (apo E) and the LDL receptor, was a major step forward.4 Not only do these mouse models develop widespread atherosclerotic lesions in a reproducible way, but also their lesion progression shows features reminiscent of human atherogenesis.

However, one of the major drawbacks of these animal models is the lack of end-stage atherosclerosis with spontaneous plaque rupture that is characterized by an area of fibrous cap disruption, whereby the overlying thrombus is in continuity with the lipid core. However, a kind of spontaneous plaque rupture in apoE−/− mice has been reported by several groups.5–7 These plaque ruptures predominantly occur in the brachiocephalic artery after a prolonged period (age 30 to 59 weeks) of a lipid-rich diet (containing 0.15% cholesterol and 21% lard).5 The same phenomenon was observed in apoE−/− mice fed a normal chow diet for 42 to 60 weeks.6 These plaques are reported to show loss of fibrous cap continuity, intraplaque hemorrhage, and buried fibrous caps, which are interpreted as evidence of prior plaque rupture. In the mouse studies, plaque rupture was defined as the “disruption of the fibrous cap accompanied by the intrusion of blood products into the plaque itself”,5 which is a broader definition than the strict definition of plaque rupture discussed earlier. In fact, observations thus far suggest that spontaneous plaque rupture in mice is merely an intraplaque hemorrhage and not a true plaque rupture. The presence of luminal thrombi occurs only rarely in mice, and when present, thrombi are mostly not organized and nonocclusive. Part of this might be explained by the differences between humans and mice in their regulation of coagulation.8

In addition to the genetically engineered mouse models of spontaneous plaque rupture, models in which acute plaque rupture is induced mechanically or by vasoconstriction have been developed. In atherosclerotic mice, mechanical plaque rupture was induced by gently squeezing the plaque-bearing aortic segment of the abdominal aorta between blunt forceps.9 In this model, the plaque ruptures reproducibly and gives rise to fibrin-rich thrombi that protrude into the lumen, which is plaque rupture in a stricter sense. Some interventions also induce intraplaque hemorrhage and plaque rupture by altering the atherosclerotic plaque phenotype. In a model of accelerated atherosclerosis, a collar was placed around the carotid artery of apoE−/− mice. After a plaque had developed caudal from the collar, an adenoviral vector expressing p53, an oncosuppressor gene involved in apoptosis, was introduced. Overexpression of p53 induced fibrous cap thinning, and triggering with phenylephrine, a vasoconstrictor, caused the thin, fibrous cap to rupture.10 Although a limited number of organized, luminal thrombi were observed, most of the ruptures were merely intraplaque hemorrhages (Figure 2). Other interventions include treatment of apoE−/− mice with a soluble transforming growth factor-β receptor (TGFβRII:Fc). Inhibition of TGF-β also induced thin, fibrous caps and large lipid cores, with intraplaque hemorrhage, intraplaque fibrin, iron deposition, and disruption of the endothelium.11,12 The absence of Gas6, a platelet-response amplifier,13 induced large intraplaque hemorrhages in plaques of apoE−/− mice in the absence of fibrous cap fissuring.14 ApoE−/− mice deficient in scavenger receptor BI develop severe occlusive coronary atherosclerotic lesions containing cholesterol clefts and fibrin, resulting in myocardial infarctions already at the age of 5 weeks.15 The same phenotype was observed in LDL receptor−/−/apoE−/− mice, particularly after endothelin infusion at 7 to 12 months of age.16 However, whether this occlusive coronary artery disease is the result of true plaque rupture or is caused by excess lipid accumulation or vasoconstriction (induced plaque rupture) remains to be determined.

Figure 2. Photographs showing a human coronary artery (left) with a true plaque rupture and a mouse atherosclerotic plaque (brachiocephalic artery; right, ×10) containing an intraplaque hemorrhage. L indicates lumen, T indicates thrombus, IH indicates intraplaque hemorrhage.

In cholesterol-fed rabbits, intravenous injection with Russell’s Viper venom in combination with the vasoconstrictors histamine, angiotensin II, or serotonin induced acute plaque rupture.17,18 Another approach to induce plaque rupture in cholesterol-fed rabbits is balloon injury to a preexisting lesion or embedding of a balloon into a lesion followed by inflation when the lesion has progressed.19,20 All 3 models of plaque rupture in the rabbit result in rupture of the fibrous cap and in the formation of an organized thrombus that protrudes into the lumen, features that fit into the stricter definition of plaque rupture.

Although some features of plaque rupture occur spontaneously in genetically engineered mouse models of atherosclerosis, they should not be defined as plaque rupture according to the strict definition as proposed by Virmani et al.3 Mouse and rabbit models of acute plaque rupture resemble human ruptured lesions but require mechanical intervention or the use of vasoconstricting agents, which might not reflect pathogenesis in humans.

Nonfatal Plaque Rupture, Intraplaque Hemorrhage, and Plaque Growth

It is important to realize that plaque rupture does not always imply a fatal event. In patients who died of noncardiovascular causes, plaque rupture was present in 10% of atherosclerotic lesions.21 Nonfatal lesions can contain areas of (repeated) plaque rupture and thrombosis. If a thrombus remains mural rather than occlusive and its lysis is incomplete, reendothelialization followed by fibrous thrombus organization results in exponential plaque growth.3

The same exponential plaque growth can be observed after intraplaque hemorrhage. Factors triggering intraplaque hemorrhage are largely unknown, but one suggested mechanism is that intraplaque hemorrhage is the result of leakage of plasma owing to rupture of the vasa vasorum and plaque neovessels.22 In the first stages of atherosclerotic plaque development, cells in the plaque receive oxygen by diffusion from the arterial lumen. From experimental and human pathology studies, it is known that the number of both adventitial vasa vasorum and of intraplaque capillaries increases with plaque progression.23,24 When intimal thickness increases beyond the critical diffusion limits, vasa vasorum and intraplaque neovessels appear to oxygenate the plaque. However, parts of advanced plaques do become hypoxic.25 In advanced plaques, hypoxia-inducible factor (HIF)-α as well as vascular endothelial growth factor are upregulated, suggesting activation of hypoxia and angiogenesis pathways.24 These neovessels can rupture or leak and cause intraplaque hemorrhage. Consequently, plaques will grow expansively, plaque hypoxia and neovascularization will redevelop, and new intraplaque hemorrhages will occur. This cycle might eventually lead to total occlusion of the arterial lumen.

Intraplaque neovessels are also detected in advanced lesions of apoE−/− mice with the use of different markers, such as von Willebrand factor, VE-cadherin, CD31, and Flt-1.26–29 The amount of neovascularization is positively correlated with the extent of inflammatory cells.26 Angiogenesis inhibitors such as endostatin, TNP-470, and angiostatin reduce plaque neovascularization and plaque growth, whereas stimulation of angiogenesis by vascular endothelial growth factor or nicotine promotes atherosclerosis.26–29 Mouse models of spontaneous plaque rupture resemble nonfatal human plaque rupture and intraplaque hemorrhage to some extent. Although it has not been proved, it is tempting to speculate that the accumulation of blood products in the plaque and small fissures of the fibrous cap that are observed in apoE−/− mice might be the result of leakage/rupture of intraplaque microvessels.

Pathophysiology of Plaque Rupture: A Local or Systemic Phenomenon?

In the second part of the review, we will address the pathogenesis of atherosclerotic plaque rupture from a local and a systemic perspective.

Local Perspective

From a local perspective, plaque rupture is attributed to changes that occur in the atherosclerotic plaque. Most of the knowledge of this process is obtained from RNA and protein expression studies in human atherosclerotic plaques and from intervention studies in animal models of atherosclerosis. The mechanisms that have been tested most extensively are those that involve inflammation and matrix turnover in plaque progression and plaque rupture. Moreover, the coagulation system also seems to be able to trigger plaque rupture.

Inflammatory Mediators

The influx of inflammatory cells, macrophages, and T lymphocytes in atherosclerotic plaques increases with plaque progression and is increased at sites of plaque rupture.30–32 A broad spectrum of inflammatory mediators, such as leukocyte adhesion molecules (P- and E-selectins, intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule), chemokines (monocyte chemoattractant protein-1, CC chemokine receptor-2 [CCR-2], interleukin [IL]-8, CXCR3, CX3CR1), cytokines (granulocyte macrophage colony stimulating factor, IL-1, IL-6, IL-18, tumor necrosis factor-α, interferon-γ, CD40, CD40L),30,33 and C-reactive protein (CRP)34 are expressed in human atherosclerotic lesions, and most of these show increased expression at sites of plaque rupture.33 Intervention studies in atherosclerotic mouse models in which one of these molecules, such as P-selectin,35,36 ICAM-1,35 granulocyte macrophage colony stimulating factor,37 or IL-1β,38 was inhibited (genetically or pharmacological) showed a decrease in plaque progression. Moreover, after inhibition of CD40L,39–41 interferon-γ,42 IL-18,43 monocyte chemoattractant protein-1,44 CCR-2,45CXCR2,46 and CX3CR1,47,48 a change of plaque composition toward a collagen-rich plaque phenotype with a relative paucity of inflammatory cells and lipids was observed.

Mediators of Fibrosis

The second local regulator in the development of plaque rupture is matrix turnover. TGF-β, an inducer of collagen synthesis, is expressed in all atherosclerotic lesion types, but expression of its receptors decreases with lesion progression.49 Decreased plasma levels of TGF-β are associated with a poor outcome in coronary artery disease.50 Proteinases, such as the family of matrix metalloproteinases (MMP-1, −2, −3, −7, −8, −9, −12, and −14)51,52 and the cathepsin family (cathepsins S and K),53 as well as their specific inhibitors, such as tissue inhibitors of MMPs (TIMPs)51 and cystatin C54 (a cathepsin inhibitor), are expressed in human atherosclerotic lesions. Moreover, the expression of MMP-1, −3, and −9, as well as cathepsins K and S, is increased in the vulnerable shoulder region.51,53 It is assumed that proteolytic activity is driven by inflammatory activity in the plaque and that this process is responsible for the degradation and thinning of the fibrous cap, thereby favoring plaque rupture.55 Inhibition of TGF-β in apoE−/− mice induces a plaque phenotype with increased inflammation, thin fibrous caps, and intraplaque hemorrhages.11,12

Modulation of the MMP family in atherosclerotic mice has clear effects on aneurysm formation, whereas the effects on atherogenesis are ambivalent. Inhibition of MMPs with a broad-spectrum inhibitor does not affect plaque progression in LDL receptor−/− mice but merely affects medial elastin degradation.56 Furthermore, overexpression of MMP-1 in macrophages of apoE−/− mice reduces atherosclerosis.57 The absence of MMP-3 in apoE−/− mice did not affect plaque progression or phenotype but reduced aneurysm formation.58 In TIMP-1−/−/apoE−/− mice, atherosclerosis was either not affected59 or reduced.58 In both studies, the absence of TIMP-1 induced aneurysm formation.59,60

Until now, the mechanisms of aneurysm formation and atherosclerotic plaque rupture have not been linked. However, processes involved in their pathogenesis overlap. Proteolysis is involved in both processes, although elastolysis seems more important in aneurysm formation, whereas collagenolysis is more important in plaque rupture. ApoE−/− mice suffering from severe atherosclerosis develop abdominal aneurysms. Moreover, angiotensin II infusion not only accelerates and aggravates atherosclerosis in apoE−/− mice but also induces aneurysm formation, indicating that both processes might be interrelated.61 Cathepsins B, D, L, and S show increased expression in the vasculature of apoE−/− mice.62 Furthermore, cathepsin B activity could be detected in atherosclerotic lesions of apoE−/− mice in vivo by near-infrared tomography.63 Cathepsin S−/−/LDL receptor−/− mice developed smaller atherosclerotic plaques that exhibited less inflammation.64

Coagulation

A third group of local modulators of plaque rupture are those involved in coagulation.65 Both tissue factor and tissue factor pathway inhibitor (TFPI) are expressed in advanced human atherosclerotic lesions and are abundant at sites of plaque rupture.66 Protein levels of prothrombin were increased in advanced human atherosclerotic lesions, whereas the anticoagulants antithrombin III and α2-macroglobulin were decreased.67 Tissue plasminogen activator, urokinase-type plasminogen activator, and plasminogen activator inhibitor (PAI) were increased in advanced human plaques.68

In apoE−/− mice, injection of activated platelets exacerbated atherosclerotic plaque progression.69 Furthermore, TFPI+/−/apoE−/− mice70 and PAI-1−/−/apoE−/− mice71 had increased atherosclerosis. Deficiency of plasminogen attenuated transplant arteriosclerosis,72 whereas thrombin inhibition by warfarin did not affect atherosclerosis.73 The absence of Gas6, a platelet-response amplifier,13 had no effect on atherosclerosis extent, but it did induce intraplaque hemorrhage.14

Gene Profiling

Recently, we were able to identify genes that were differentially expressed between stable and ruptured human atherosclerotic plaques by using the suppressive subtraction hybridization technique. This study suggested an important role not only for perilipin and cathepsin K in plaque rupture but also for many unknown genes, such as vasculin.74,75 From expression data in human plaques and interventions in animal models, it is clear that molecules of inflammation, matrix turnover, and coagulation and yet-unknown molecules are involved in plaque progression and the development of plaque rupture. The major limitation of these studies is that we do not know when and how these processes become critical and induce plaque rupture.

Systemic Factors Associated With Plaque Rupture

From a systemic perspective of the pathogenesis of plaque rupture, it is stated that plaque rupture does not occur as an isolated phenomenon but rather as a systemic disease. In this view, it is preferred to refer to the “vulnerable patient” instead of a patient with a localized, vulnerable atherosclerotic plaque.

Vulnerable patients often present with multiple ruptured plaques. In an angiography study of patients with an acute coronary syndrome (ACS), 39.5% of the patients had multiple complex plaques that were associated with an increased incidence of recurrent ACSs.76 In another study with intravascular ultrasound, 79% of the patients presenting with an ACS had multiple ruptured plaques at sites other than the culprit lesion that caused the clinical symptoms.77 It can therefore be postulated that the occluding thrombus at the culprit lesion determines the clinical presentation but that it is only a focal manifestation of an underlying systemic disease process that includes several rupture-prone or vulnerable lesions.

Systemic factors that are correlated with plaque rupture are altered blood rheology, increased coagulability, increased systemic inflammation, and recurrent infections. These unfavorable systemic changes often interact synergistically with risk factors of atherosclerosis and plaque rupture, such as hyperlipidemia, smoking, and diabetes.78–80

Because the systemic status of a patient seems to influence the incidence of plaque rupture, attention has focused on several plasma markers that can help predict individuals at increased risk of plaque rupture. Elevated levels of the inflammatory markers CRP,81 P-selectin,82 soluble ICAM-1, soluble vascular cell adhesion molecule-1,83 IL-6,84 tumor necrosis factor-α,85 IL-18,86 and soluble CD40L87 have been shown to predict future cardiovascular risk in a variety of clinical settings. Although most of these inflammatory markers are derived from the liver (CRP, IL6), low levels might also be derived from other sources, including adipose tissue, activated endothelium, and the plaque itself. Other sets of markers that seem to predict cardiovascular risk are those associated with the coagulation cascade or those involved in proteolysis. Increased plasma levels of fibrinogen,88 von Willebrand factor,89 PAI-1,90 tissue factor,91 and tissue plasminogen activator,92 as well as increased plasma levels of MMP-9,93 indicate an increased risk of cardiovascular events.

Until now, therapies that are most successful in preventing cardiovascular events have been based on improvement of systemic parameters.94 Lowering of plasma LDL levels by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) has been proved to prevent ACSs in severe hypercholesterolemic patients,95 but it is also beneficial for patients with acceptable LDL cholesterol levels.96,97 Anticoagulation therapy with aspirin,98 heparins,99 or platelet antagonists like clopidogrel100 and glycoprotein IIb/IIIa inhibitors has been proved to prevent acute cardiovascular events in a variety of settings.101 Moreover, angiotensin-converting-enzyme inhibitors (HOPE trial),102 angiotensin II type 1 inhibitors, β-blockers, cyclooxygenase-2 inhibitors, and thiazolidinediones have been shown to prevent (recurrent) cardiovascular events. In accordance with the systemic perspective, systemic treatment often lowers serum markers that are correlated with plaque vulnerability/rupture. For example, statin therapy is able to reduce plasma levels of CRP103 and serum levels of soluble CD40L.104

The fact that these systemic therapies are most successful in preventing adverse cardiovascular events and are capable of lowering serum markers associated with cardiovascular risk stresses the systemic aspects of the disease. Plaque vulnerability might be expected to develop in a multifocal pattern, resulting in multiple ruptured plaques. Any one of these lesions might progress to the culprit lesion that is responsible for the fatal cardiovascular event.

Integrative Perspective of Atherosclerotic Plaque Rupture

Although systemic markers and systemic treatment seem to predict and prevent cardiovascular events and therefore plaque rupture, its basic mechanism is still unknown. On the other hand, it has been proved that modulation of local plaque-associated factors is capable of changing plaque progression and plaque composition, thereby preventing or inducing plaque rupture. Local therapy with rapamycin-eluting stents was able to prevent restenosis after percutaneous transluminal coronary angioplasty for at least 12 months.105

In the integrative view of plaque rupture, it is realized that factors that modulate plaque rupture locally are, to a large extent, the same factors that are also circulating systemically. This suggests a parallel local and systemic pathogenesis of plaque rupture. Alternatively, modulation of systemic modulators might have an effect on local plaque biology and vice versa. Many modulators of inflammation, fibrosis, and coagulation, such as CD40L, MMP-9, and tissue factor, are not only used as systemic biomarkers of atherosclerotic events but are also locally active partakers in the development of plaque rupture. Some studies have investigated the effects of proven beneficial systemic treatment on local plaque biology. For example, treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors not only has a favorable effect on serum lipids but is also able to reduce local plaque inflammation, increase fibrous cap thickness, and induce plaque regression.106

In conclusion, by strictly applying the classification proposed by Virmani et al,3 confusion about definitions of plaque instability, plaque rupture, and intraplaque hemorrhages can be avoided. By this definition, mouse models of spontaneous plaque rupture merely reflect intraplaque hemorrhage without true plaque rupture. Lastly, the pathogenesis of plaque rupture and its clinical symptoms are most likely a combination of (similar) changes in intraplaque and systemic biology (Figure 3). Future studies on the mechanism of plaque rupture should focus on both local plaque and systemic factors.

Figure 3. Plaque rupture from an integrative perspective.

Acknowledgment

E.L. is a postdoctoral fellow of the Dr E. Dekker program of the Dutch Heart Foundation (2000T41).

Footnotes

Correspondence to Mat Daemen, MD, PhD, Department of Pathology, P. Debeyelaan 25, 6229 HX Maastricht, the Netherlands. E-mail

References

  • 1 Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W Jr, Rosenfeld ME, Schwartz CJ, Wagner WD, Wissler RW. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis: a report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation. 1995; 92: 1355–1374.CrossrefMedlineGoogle Scholar
  • 2 Stary HC. Natural and historical classification of atherosclerotic lesions: an update. Arterioscler Thromb Vasc Biol. 2000; 20: 1177–1178.CrossrefMedlineGoogle Scholar
  • 3 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.CrossrefMedlineGoogle Scholar
  • 4 Smith JD, Breslow JL. The emergence of mouse models of atherosclerosis and their relevance to clinical research. J Intern Med. 1997; 242: 99–109.CrossrefMedlineGoogle Scholar
  • 5 Williams H, Johnson JL, Carson KG, Jackson CL. Characteristics of intact and ruptured atherosclerotic plaques in brachiocephalic arteries of apolipoprotein E knockout mice. Arterioscler Thromb Vasc Biol. 2002; 22: 788–792.LinkGoogle Scholar
  • 6 Rosenfeld ME, Polinsky P, Virmani R, Kauser K, Rubanyi G, Schwartz SM. Advanced atherosclerotic lesions in the innominate artery of the apoE knockout mouse. Arterioscler Thromb Vasc Biol. 2000; 20: 2587–2592.CrossrefMedlineGoogle Scholar
  • 7 Calara F, Silvestre M, Casanada F, Yuan N, Napoli C, Palinski W. Spontaneous plaque rupture and secondary thrombosis in apolipoprotein E-deficient and LDL receptor-deficient mice. J Pathol. 2001; 195: 257–263.CrossrefMedlineGoogle Scholar
  • 8 Carmeliet P, Moons L, Collen D. Mouse models of angiogenesis, arterial stenosis, atherosclerosis and hemostasis. Cardiovasc Res. 1998; 39: 8–33.CrossrefMedlineGoogle Scholar
  • 9 Reddick RL, Zhang SH, Maeda N. Aortic atherosclerotic plaque injury in apolipoprotein E deficient mice. Atherosclerosis. 1998; 140: 297–305.CrossrefMedlineGoogle Scholar
  • 10 der Thusen JH, van Vlijmen BJ, Hoeben RC, Kockx MM, Havekes LM, van Berkel TJ, Biessen EA. Induction of atherosclerotic plaque rupture in apolipoprotein E-/- mice after adenovirus-mediated transfer of p53. Circulation. 2002; 105: 2064–2070.LinkGoogle Scholar
  • 11 Lutgens E, Gijbels M, Smook M, Heeringa P, Gotwals P, Koteliansky VE, Daemen MJ. Transforming growth factor-β mediates balance between inflammation and fibrosis during plaque progression. Arterioscler Thromb Vasc Biol. 2002; 22: 975–982.LinkGoogle Scholar
  • 12 Mallat Z, Gojova A, Marchiol-Fournigault C, Esposito B, Kamate C, Merval R, Fradelizi D, Tedgui A. Inhibition of transforming growth factor-β signaling accelerates atherosclerosis and induces an unstable plaque phenotype in mice. Circ Res. 2001; 89: 930–934.CrossrefMedlineGoogle Scholar
  • 13 Angelillo-Scherrer A, de Frutos P, Aparicio C, Melis E, Savi P, Lupu F, Arnout J, Dewerchin M, Hoylaerts M, Herbert J, Collen D, Dahlback B, Carmeliet P. Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis. Nat Med. 2001; 7: 215–221.CrossrefMedlineGoogle Scholar
  • 14 Lutgens E, Garcia de Frutos P, Apericio C, Moons L, Daemen M, Collen D, Carmeliet P. Gas6-/-/apoE-/- mice develop a collagen-rich, disorganized plaque phenotype, prone to intraplaque hemorrhage. Circulation. 2000; 102 (suppl II): II-38. Abstract.Google Scholar
  • 15 Braun A, Trigatti BL, Post MJ, Sato K, Simons M, Edelberg JM, Rosenberg RD, Schrenzel M, Krieger M. Loss of SR-BI expression leads to the early onset of occlusive atherosclerotic coronary artery disease, spontaneous myocardial infarctions, severe cardiac dysfunction, and premature death in apolipoprotein E-deficient mice. Circ Res. 2002; 90: 270–276.CrossrefMedlineGoogle Scholar
  • 16 Caligiuri G, Levy B, Pernaw J, Thoren P, Hansson G. Myocardial infarction mediated by endothelin receptor signaling in hypercholesterolemic mice. Proc Natl Acad Sci U S A. 1999; 96: 6920–6924.CrossrefMedlineGoogle Scholar
  • 17 Abela GS, Picon PD, Friedl SE, Gebara OC, Miyamoto A, Federman M, Tofler GH, Muller JE. Triggering of plaque disruption and arterial thrombosis in an atherosclerotic rabbit model. Circulation. 1995; 91: 776–784.CrossrefMedlineGoogle Scholar
  • 18 Nakamura M, Abe S, Kinukawa N. Aortic medial necrosis with or without thrombosis in rabbits treated with Russell’s viper venom and angiotensin II. Atherosclerosis. 1997; 128: 149–156.CrossrefMedlineGoogle Scholar
  • 19 Gertz SD, Fallon JT, Gallo R, Taubman MB, Banai S, Barry WL, Gimple LW, Nemerson Y, Thiruvikraman S, Naidu SS, Chesebro JH, Fuster V, Sarembock IJ, Badimon JJ. Hirudin reduces tissue factor expression in neointima after balloon injury in rabbit femoral and porcine coronary arteries. Circulation. 1998; 98: 580–587.CrossrefMedlineGoogle Scholar
  • 20 Rekhter MD, Hicks GW, Brammer DW, Work CW, Kim JS, Gordon D, Keiser JA, Ryan MJ. Animal model that mimics atherosclerotic plaque rupture. Circ Res. 1998; 83: 705–713.CrossrefMedlineGoogle Scholar
  • 21 Arbustini E, Grasso M, Diegoli M, Pucci A, Bramerio M, Ardissino D, Angoli L, de Servi S, Bramucci E, Mussini A. Coronary atherosclerotic plaques with and without thrombus in ischemic heart syndromes: a morphologic, immunohistochemical, and biochemical study. Am J Cardiol. 1991; 68: 36B–50B.CrossrefMedlineGoogle Scholar
  • 22 Paterson JC. Capillary rupture with intimal hemorrhage as a causative factor in coronary thrombosis. 1938; 25: 474–487.Google Scholar
  • 23 Kwon HM, Sangiorgi G, Ritman EL, McKenna C, Holmes DR Jr, Schwartz RS, Lerman A. Enhanced coronary vasa vasorum neovascularization in experimental hypercholesterolemia. J Clin Invest. 1998; 101: 1551–1556.CrossrefMedlineGoogle Scholar
  • 24 Wilson SH, Herrmann J, Lerman LO, Holmes DR Jr, Napoli C, Ritman EL, Lerman A. Simvastatin preserves the structure of coronary adventitial vasa vasorum in experimental hypercholesterolemia independent of lipid lowering. Circulation. 2002; 105: 415–418.CrossrefMedlineGoogle Scholar
  • 25 Bjornheden T, Levin M, Evaldsson M, Wiklund O. Evidence of hypoxic areas within the arterial wall in vivo. Arterioscler Thromb Vasc Biol. 1999; 19: 870–876.CrossrefMedlineGoogle Scholar
  • 26 Moulton KS, Vakili K, Zurakowski D, Soliman M, Butterfield C, Sylvin E, Lo K, Gillies S, Javaherian K, Folkman J. Inhibition of plaque neovascularization reduces macrophage accumulation and progression of advanced atherosclerosis. Proc Natl Acad Sci U S A. 2003; 100: 4736–4741.CrossrefMedlineGoogle Scholar
  • 27 Moulton KS, Heller E, Konerding MA, Flynn E, Palinski W, Folkman J. Angiogenesis inhibitors endostatin or TNP-470 reduce intimal neovascularization and plaque growth in apolipoprotein-E deficient mice. Circulation. 1999; 99: 1726–1732.CrossrefMedlineGoogle Scholar
  • 28 Heeschen C, Jang JJ, Weis M, Pathak A, Kaji S, Hu RS, Tsao PS, Johnson FL, Cooke JP. Nicotine stimulates angiogenesis and promotes tumor growth and atherosclerosis. Nat Med. 2001; 7: 833–839.CrossrefMedlineGoogle Scholar
  • 29 Celletti FL, Waugh JM, Amabile PG, Brendolan A, Hilfiker PR, Dake MD. Vascular endothelial growth factor enhances atherosclerotic plaque progression. Nat Med. 2001; 7: 425–429.CrossrefMedlineGoogle Scholar
  • 30 Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999; 340: 115–126.CrossrefMedlineGoogle Scholar
  • 31 van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation. 1994; 89: 36–44.LinkGoogle Scholar
  • 32 Hosono M, de Boer O, van der Wal AC, van der Loos CM, Teeling P, Piek JJ, Ueda M, Becker AE. Increased expression of T cell activation markers (CD25, CD26, CD40L and CD69) in atherectomy specimens of patients with unstable angina and acute myocardial infarction. Atherosclerosis. 2003; 168: 73–80.CrossrefMedlineGoogle Scholar
  • 33 Glass CK, Witztum JL. Atherosclerosis: the road ahead. Cell. 2001; 104: 503–516.CrossrefMedlineGoogle Scholar
  • 34 Vainas T, Lubbers T, Stassen FR, Herngreen SB, Dieijen-Visser MP, Bruggeman CA, Kitslaar PJ, Schurink GW. Serum C-reactive protein level is associated with abdominal aortic aneurysm size and may be produced by aneurysmal tissue. Circulation. 2003; 107: 1103–1105.LinkGoogle Scholar
  • 35 Collins RG, Velji R, Guevara NV, Hicks MJ, Chan L, Beaudet AL. P-selectin or intercellular adhesion molecule (ICAM)-1 deficiency substantially protects against atherosclerosis in apolipoprotein E-deficient mice. J Exp Med. 2000; 191: 189–194.CrossrefMedlineGoogle Scholar
  • 36 Burger PC, Wagner DD. Platelet P-selectin facilitates atherosclerotic lesion development. Blood. 2003; 101: 2661–2666.CrossrefMedlineGoogle Scholar
  • 37 Qiao JH, Tripathi J, Mishra NK, Cai Y, Tripathi S, Wang XP, Imes S, Fishbein MC, Clinton SK, Libby P, Lusis AJ, Rajavashisth TB. Role of macrophage colony-stimulating factor in atherosclerosis: studies of osteopetrotic mice. Am J Pathol. 1997; 150: 1687–1699.MedlineGoogle Scholar
  • 38 Kirii H, Niwa T, Yamada Y, Wada H, Saito K, Iwakura Y, Asano M, Moriwaki H, Seishima M. Lack of Interleukin-1β decreases the severity of atherosclerosis in apoE-deficient mice. Arterioscler Thromb Vasc Biol. 2003; 23: 656–660.LinkGoogle Scholar
  • 39 Lutgens E, Gorelik L, Daemen MJ, de Muinck ED, Grewal IS, Koteliansky VE, Flavell RA. Requirement for CD154 in the progression of atherosclerosis. Nat Med. 1999; 5: 1313–1316.CrossrefMedlineGoogle Scholar
  • 40 Lutgens E, Cleutjens KB, Heeneman S, Koteliansky VE, Burkly LC, Daemen MJ. Both early and delayed anti-CD40L antibody treatment induces a stable plaque phenotype. Proc Natl Acad Sci U S A. 2000; 97: 7464–7469.CrossrefMedlineGoogle Scholar
  • 41 Mach F, Schonbeck U, Sukhova GK, Atkinson E, Libby P. Reduction of atherosclerosis in mice by inhibition of CD40 signalling. Nature. 1998; 394: 200–203.CrossrefMedlineGoogle Scholar
  • 42 Buono C, Come CE, Stavrakis G, Maguire GF, Connelly PW, Lichtman AH. Influence of interferon-γ on the extent and phenotype of diet-induced atherosclerosis in the LDLR-deficient mouse. Arterioscler Thromb Vasc Biol. 2003; 23: 454–460.LinkGoogle Scholar
  • 43 Mallat Z, Corbaz A, Scoazec A, Graber P, Alouani S, Esposito B, Humbert Y, Chvatchko Y, Tedgui A. Interleukin-18/interleukin-18 binding protein signaling modulates atherosclerotic lesion development and stability. Circ Res. 2001; 89: e41–e45.CrossrefMedlineGoogle Scholar
  • 44 Inoue S, Egashira K, Ni W, Kitamoto S, Usui M, Otani K, Ishibashi M, Hiasa K, Nishida K, Takeshita A. Anti-monocyte chemoattractant protein-1 gene therapy limits progression and destabilization of established atherosclerosis in apolipoprotein E-knockout mice. Circulation. 2002; 106: 2700–2706.LinkGoogle Scholar
  • 45 Dawson TC, Kuziel WA, Osahar TA, Maeda N. Absence of CC chemokine receptor-2 reduces atherosclerosis in apolipoprotein E-deficient mice. Atherosclerosis. 1999; 143: 205–211.CrossrefMedlineGoogle Scholar
  • 46 Boisvert WA, Santiago R, Curtiss LK, Terkeltaub RA. A leukocyte homologue of the IL-8 receptor CXCR-2 mediates the accumulation of macrophages in atherosclerotic lesions of LDL receptor-deficient mice. J Clin Invest. 1998; 101: 353–363.CrossrefMedlineGoogle Scholar
  • 47 Lesnik P, Haskell CA, Charo IF. Decreased atherosclerosis in CX3CR1-/- mice reveals a role for fractalkine in atherogenesis. J Clin Invest. 2003; 111: 333–340.CrossrefMedlineGoogle Scholar
  • 48 Combadiere C, Potteaux S, Gao JL, Esposito B, Casanova S, Lee EJ, Debre P, Tedgui A, Murphy PM, Mallat Z. Decreased atherosclerotic lesion formation in CX3CR1/apolipoprotein E double knockout mice. Circulation. 2003; 107: 1009–1016.LinkGoogle Scholar
  • 49 Bobik A, Agrotis A, Kanellakis P, Dilley R, Krushinsky A, Smirnov V, Tararak E, Condron M, Kostolias G. Distinct patterns of transforming growth factor-β isoform and receptor expression in human atherosclerotic lesions: colocalization implicates TGF-β in fibrofatty lesion development. Circulation. 1999; 99: 2883–2891.CrossrefMedlineGoogle Scholar
  • 50 Tashiro H, Shimokawa H, Sadamatu K, Yamamoto K. Prognostic significance of plasma concentrations of transforming growth factor-β in patients with coronary artery disease. Coron Artery Dis. 2002; 13: 139–143.CrossrefMedlineGoogle Scholar
  • 51 Galis ZS, Khatri JJ. Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res. 2002; 90: 251–262.LinkGoogle Scholar
  • 52 Herman MP, Sukhova GK, Libby P, Gerdes N, Tang N, Horton DB, Kilbride M, Breitbart RE, Chun M, Schonbeck U. Expression of neutrophil collagenase (matrix metalloproteinase-8) in human atheroma: a novel collagenolytic pathway suggested by transcriptional profiling. Circulation. 2001; 104: 1899–1904.CrossrefMedlineGoogle Scholar
  • 53 Sukhova GK, Shi GP, Simon DI, Chapman HA, Libby P. Expression of the elastolytic cathepsins S and K in human atheroma and regulation of their production in smooth muscle cells. J Clin Invest. 1998; 102: 576–583.CrossrefMedlineGoogle Scholar
  • 54 Shi GP, Sukhova GK, Grubb A, Ducharme A, Rhode LH, Lee RT, Ridker PM, Libby P, Chapman HA. Cystatin C deficiency in human atherosclerosis and aortic aneurysms. J Clin Invest. 1999; 104: 1191–1197.CrossrefMedlineGoogle Scholar
  • 55 Libby P. Inflammation in atherosclerosis. Nature. 2002; 420: 868–874.CrossrefMedlineGoogle Scholar
  • 56 Prescott MF, Sawyer WK, Linden-Reed J, Jeune M, Chou M, Caplan SL, Jeng AY. Effect of matrix metalloproteinase inhibition on progression of atherosclerosis and aneurysm in LDL receptor-deficient mice overexpressing MMP-3, MMP-12, and MMP-13 and on restenosis in rats after balloon injury. Ann N Y Acad Sci. 1999; 878: 179–190.CrossrefMedlineGoogle Scholar
  • 57 Lemaitre V, O’Byrne TK, Borczuk AC, Okada Y, Tall AR, D’Armiento J. ApoE knockout mice expressing human matrix metalloproteinase-1 in macrophages have less advanced atherosclerosis. J Clin Invest. 2001; 107: 1227–1234.CrossrefMedlineGoogle Scholar
  • 58 Silence J, Lupu F, Collen D, Lijnen HR. Persistence of atherosclerotic plaque but reduced aneurysm formation in mice with stromelysin-1 (MMP-3) gene inactivation. Arterioscler Thromb Vasc Biol. 2001; 21: 1440–1445.CrossrefMedlineGoogle Scholar
  • 59 Lemaitre V, Soloway PD, D’Armiento J. Increased medial degradation with pseudo-aneurysm formation in apolipoprotein E-knockout mice deficient in tissue inhibitor of metalloproteinases-1. Circulation. 2003; 107: 333–338.LinkGoogle Scholar
  • 60 Silence J, Collen D, Lijnen HR. Reduced atherosclerotic plaque but enhanced aneurysm formation in mice with inactivation of the tissue inhibitor of metalloproteinase-1 (TIMP-1) gene. Circ Res. 2002; 90: 897–903.LinkGoogle Scholar
  • 61 Daugherty A, Manning MW, Cassis LA. Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice. J Clin Invest. 2000; 105: 1605–1612.CrossrefMedlineGoogle Scholar
  • 62 Jormsjo S, Wuttge DM, Sirsjo A, Whatling C, Hamsten A, Stemme S, Eriksson P. Differential expression of cysteine and aspartic proteases during progression of atherosclerosis in apolipoprotein E-deficient mice. Am J Pathol. 2002; 161: 939–945.CrossrefMedlineGoogle Scholar
  • 63 Chen J, Tung CH, Mahmood U, Ntziachristos V, Gyurko R, Fishman MC, Huang PL, Weissleder R. In vivo imaging of proteolytic activity in atherosclerosis. Circulation. 2002; 105: 2766–2771.LinkGoogle Scholar
  • 64 Sukhova GK, Zhang Y, Pan JH, Wada Y, Yamamoto T, Naito M, Kodama T, Tsimikas S, Witztum JL, Lu ML, Sakara Y, Chin MT, Libby P, Shi GP. Deficiency of cathepsin S reduces atherosclerosis in LDL receptor-deficient mice. J Clin Invest. 2003; 111: 897–906.CrossrefMedlineGoogle Scholar
  • 65 Khrenov AV, Ananyeva NM, Griffin JH, Saenko EL. Coagulation pathways in atherothrombosis. Trends Cardiovasc Med. 2002; 12: 317–324.CrossrefMedlineGoogle Scholar
  • 66 Kaikita K, Takeya M, Ogawa H, Suefuji H, Yasue H, Takahashi K. Co-localization of tissue factor and tissue factor pathway inhibitor in coronary atherosclerosis. J Pathol. 1999; 188: 180–188.CrossrefMedlineGoogle Scholar
  • 67 Smith EB, Staples EM. Haemostatic factors in human aortic intima. Lancet. 1981; 1: 1171–1174.CrossrefMedlineGoogle Scholar
  • 68 Falkenberg M, Tjarnstrom J, Ortenwall P, Olausson M, Risberg B. Localization of fibrinolytic activators and inhibitors in normal and atherosclerotic vessels. Thromb Haemost. 1996; 75: 933–938.CrossrefMedlineGoogle Scholar
  • 69 Huo Y, Schober A, Forlow SB, Smith DF, Hyman MC, Jung S, Littman DR, Weber C, Ley K. Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nat Med. 2003; 9: 61–67.CrossrefMedlineGoogle Scholar
  • 70 Westrick RJ, Bodary PF, Xu Z, Shen YC, Broze GJ, Eitzman DT. Deficiency of tissue factor pathway inhibitor promotes atherosclerosis and thrombosis in mice. Circulation. 2001; 103: 3044–3046.CrossrefMedlineGoogle Scholar
  • 71 Luttun A, Lupu F, Storkebaum E, Hoylaerts MF, Moons L, Crawley J, Bono F, Poole AR, Tipping P, Herbert JM, Collen D, Carmeliet P. Lack of plasminogen activator inhibitor-1 promotes growth and abnormal matrix remodeling of advanced atherosclerotic plaques in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 2002; 22: 499–505.CrossrefMedlineGoogle Scholar
  • 72 Moons L, Shi C, Ploplis V, Plow E, Haber E, Collen D, Carmeliet P. Reduced transplant arteriosclerosis in plasminogen-deficient mice. J Clin Invest. 1998; 102: 1788–1797.CrossrefMedlineGoogle Scholar
  • 73 Grainger DJ, McWilliam NA, Baglin TP, Byrne CD. Suppressing thrombin generation is compatible with the development of atherosclerosis in mice. Thromb Res. 2001; 102: 71–80.CrossrefMedlineGoogle Scholar
  • 74 Faber BC, Cleutjens KB, Niessen RL, Aarts PL, Boon W, Greenberg AS, Kitslaar PJ, Tordoir JH, Daemen MJ. Identification of genes potentially involved in rupture of human atherosclerotic plaques. Circ Res. 2001; 89: 547–554.CrossrefMedlineGoogle Scholar
  • 75 Bijnens APJJ, Gils A, Jutten B, Faber BCG, Heeneman S, Kitslaar PJEHM, Tordoir JHM, de Vries CJM, Daemen MJAP, Cleutjens KBJM. Vasculin, a novel vascular protein differentially expressed in human atherogenesis. Blood. 2003; 102: 2803–2810.CrossrefMedlineGoogle Scholar
  • 76 Goldstein JA, Demetriou D, Grines CL, Pica M, Shoukfeh M, O’Neill WW. Multiple complex coronary plaques in patients with acute myocardial infarction. N Engl J Med. 2000; 343: 915–922.CrossrefMedlineGoogle Scholar
  • 77 Rioufol G, Finet G, Ginon I, Andre-Fouet X, Rossi R, Vialle E, Desjoyaux E, Convert G, Huret JF, Tabib A. Multiple atherosclerotic plaque rupture in acute coronary syndrome: a 3-vessel intravascular ultrasound study. Circulation. 2002; 106: 804–808.LinkGoogle Scholar
  • 78 Fuster V, Fayad ZA, Badimon JJ. Acute coronary syndromes: biology. Lancet. 1999; 353 (suppl 2): SII-5–SII-9.CrossrefGoogle Scholar
  • 79 Corti R, Fuster V, Badimon JJ. Pathogenetic concepts of acute coronary syndromes. J Am Coll Cardiol. 2003; 41: 7S–14S.MedlineGoogle Scholar
  • 80 Sambola A, Osende J, Hathcock J, Degen M, Nemerson Y, Fuster V, Crandall J, Badimon JJ. Role of risk factors in the modulation of tissue factor activity and blood thrombogenicity. Circulation. 2003; 107: 973–977.LinkGoogle Scholar
  • 81 Albert MA, Glynn RJ, Ridker PM. Plasma concentration of C-reactive protein and the calculated Framingham coronary heart disease risk score. Circulation. 2003; 108: 161–165.LinkGoogle Scholar
  • 82 Ridker PM, Buring JE, Rifai N. Soluble P-selectin and the risk of future cardiovascular events. Circulation. 2001; 103: 491–495.CrossrefMedlineGoogle Scholar
  • 83 Pradhan AD, Rifai N, Ridker PM. Soluble intercellular adhesion molecule-1, soluble vascular adhesion molecule-1, and the development of symptomatic peripheral arterial disease in men. Circulation. 2002; 106: 820–825.LinkGoogle Scholar
  • 84 Ridker PM, Rifai N, Stampfer MJ, Hennekens CH. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation. 2000; 101: 1767–1772.CrossrefMedlineGoogle Scholar
  • 85 Ridker PM, Rifai N, Pfeffer M, Sacks F, Lepage S, Braunwald E. Elevation of tumor necrosis factor-α and increased risk of recurrent coronary events after myocardial infarction. Circulation. 2000; 101: 2149–2153.CrossrefMedlineGoogle Scholar
  • 86 Blankenberg S, Tiret L, Bickel C, Peetz D, Cambien F, Meyer J, Rupprecht HJ. Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina. Circulation. 2002; 106: 24–30.LinkGoogle Scholar
  • 87 Heeschen C, Dimmeler S, Hamm CW, van den Brand MJ, Boersma E, Zeiher AM, Simoons ML. Soluble CD40 ligand in acute coronary syndromes. N Engl J Med. 2003; 348: 1104–1111.CrossrefMedlineGoogle Scholar
  • 88 Maresca G, Di Blasio A, Marchioli R, Di Minno G. Measuring plasma fibrinogen to predict stroke and myocardial infarction: an update. Arterioscler Thromb Vasc Biol. 1999; 19: 1368–1377.CrossrefMedlineGoogle Scholar
  • 89 Blann AD, McCollum CN. von Willebrand factor and soluble thrombomodulin as predictors of adverse events among subjects with peripheral or coronary atherosclerosis. Blood Coagul Fibrinolysis. 1999; 10: 375–380.CrossrefMedlineGoogle Scholar
  • 90 Nordt TK, Peter K, Ruef J, Kubler W, Bode C. Plasminogen activator inhibitor type-1 (PAI-1) and its role in cardiovascular disease. Thromb Haemost. 1999; 82 (suppl 1): 14–18.MedlineGoogle Scholar
  • 91 Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastelein JJ, Stalenhoef AF. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet. 2001; 357: 577–581.CrossrefMedlineGoogle Scholar
  • 92 Thogersen AM, Jansson JH, Boman K, Nilsson TK, Weinehall L, Huhtasaari F, Hallmans G. High plasminogen activator inhibitor and tissue plasminogen activator levels in plasma precede a first acute myocardial infarction in both men and women: evidence for the fibrinolytic system as an independent primary risk factor. Circulation. 1998; 98: 2241–2247.CrossrefMedlineGoogle Scholar
  • 93 Blankenberg S, Rupprecht HJ, Poirier O, Bickel C, Smieja M, Hafner G, Meyer J, Cambien F, Tiret L. Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease. Circulation. 2003; 107: 1579–1585.LinkGoogle Scholar
  • 94 Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS, Jones RH, Kereiakes D, Kupersmith J, Levin TN, Pepine CJ, Schaeffer JW, Smith EE III, Steward DE, Theroux P, Gibbons RJ, Alpert JS, Faxon DP, Fuster V, Gregoratos G, Hiratzka LF, Jacobs AK, Smith SC Jr. ACC/AHA guideline update for the management of patients with unstable angina and non–ST-segment elevation myocardial infarction—2002: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). Circulation. 2002; 106: 1893–1900.LinkGoogle Scholar
  • 95 Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high risk individuals: a randomized placebo-controlled trial. Lancet. 2003; 360: 7–22.Google Scholar
  • 96 Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994; 344: 1383–1389.MedlineGoogle Scholar
  • 97 Expert Panel on Detection EaToHBCiA. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001; 285: 2486–2497.CrossrefMedlineGoogle Scholar
  • 98 Hayden M, Pignone M, Phillips C, Mulrow C. Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the US Preventive Services Task Force. Ann Intern Med. 2002; 136: 161–172.CrossrefMedlineGoogle Scholar
  • 99 Hirsh J, Anand SS, Halperin JL, Fuster V. AHA Scientific Statement: guide to anticoagulant therapy: heparin: a statement for healthcare professionals from the American Heart Association. Arterioscler Thromb Vasc Biol. 2001; 21: e9.CrossrefMedlineGoogle Scholar
  • 100 Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001; 345: 494–502.CrossrefMedlineGoogle Scholar
  • 101 Boersma E, Harrington RA, Moliterno DJ, White H, Theroux P, Van de WF, de Torbal A, Armstrong PW, Wallentin LC, Wilcox RG, Simes J, Califf RM, Topol EJ, Simoons ML. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials. Lancet. 2002; 359: 189–198.CrossrefMedlineGoogle Scholar
  • 102 Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients: the Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000; 342: 145–153.CrossrefMedlineGoogle Scholar
  • 103 Albert MA, Danielson E, Rifai N, Ridker PM. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA. 2001; 286: 64–70.CrossrefMedlineGoogle Scholar
  • 104 Semb AG, van Wissen S, Ueland T, Smilde T, Waehre T, Tripp MD, Froland SS, Kastelein JJ, Gullestad L, Pedersen TR, Aukrust P, Stalenhoef AF. Raised serum levels of soluble CD40 ligand in patients with familial hypercholesterolemia: downregulatory effect of statin therapy. J Am Coll Cardiol. 2003; 41: 275–279.MedlineGoogle Scholar
  • 105 Morice MC, Serruys PW, Sousa JE, Fajadet J, Ban HE, Perin M, Colombo A, Schuler G, Barragan P, Guagliumi G, Molnar F, Falotico R. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med. 2002; 346: 1773–1780.CrossrefMedlineGoogle Scholar
  • 106 Corti R, Fuster V, Fayad ZA, Worthley SG, Helft G, Smith D, Weinberger J, Wentzel J, Mizsei G, Mercuri M, Badimon JJ. Lipid lowering by simvastatin induces regression of human atherosclerotic lesions: two years’ follow-up by high-resolution noninvasive magnetic resonance imaging. Circulation. 2002; 106: 2884–2887.LinkGoogle Scholar
Back to top

Submit a Response to This Article

Compose eLetter

Contributors

(all fields are required)

Statement of Competing Interests

Cancel