Association of inflammatory markers with angiographic severity and extent of coronary artery disease

Atherosclerosis 206 (2009) 335–339

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Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis

Review

Association of inflammatory markers with angiographic severity and extent of coronary artery disease Maria Drakopoulou , Konstantinos Toutouzas ∗ , Elli Stefanadi , Eleftherios Tsiamis , Dimitris Tousoulis , Christodoulos Stefanadis 1st Department of Cardiology, Medical School of Athens University, Hippokration Hospital, Athens, Greece

a r t i c l e

i n f o

Article history: Received 26 November 2008 Received in revised form 26 January 2009 Accepted 26 January 2009 Available online 7 February 2009 Keywords: C-reactive protein Atherosclerosis Inflammation Coronary angiography

a b s t r a c t Inflammatory processes play a pivotal role in the pathogenesis of atherosclerosis and mediate many of the stages of atheroma development, from initial leukocyte recruitment to eventual rupture of the unstable atherosclerotic plaque. Several systemic inflammatory markers reflect different degrees of inflammation and have been indicated as independent risk factors in cardiovascular disease, especially in unstable coronary syndromes. However, whether elevated levels of circulating inflammatory markers play a role in the extent and severity of atherosclerosis remains controversial. The present review summarizes our current understanding of the relationship between inflammatory markers and the presence and extent of coronary atherosclerosis, in order to assess the potential utility of these markers in identifying patients with higher levels of atherosclerotic burden. © 2009 Elsevier Ireland Ltd. All rights reserved.

Contents 1. 2. 3. 4. 5. 6. 7. 8.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Angiographic classification of coronary atheromatic lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Limitations of angiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Correlation between inflammation and atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C-reactive protein as a direct mediator of plaque inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inflammatory markers and burden of atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The impact of new imaging modalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Cardiovascular disease is the leading cause of morbidity and mortality in the western world and atherosclerosis is the major common underlying disease [1]. The pathogenesis of atherosclerosis involves a number of local inflammatory mechanisms, including endothelial dysfunction, leukocyte migration, extracellular matrix degradation, and platelet activation [2,3]. Several systemic inflammatory markers may reflect different degrees of

Abbreviations: ACS, acute coronary syndromes; CAD, coronary artery disease; CRP, C-reactive protein; (IL), interleukin; SA, stable angina; TNF, tumor necrosis factor. ∗ Corresponding author at: 24 Karaoli and Dimitriou str., 15562 Holargos, Athens, Greece. Tel.: +302 10 6510860; fax: +302 10 7250153. E-mail address: [email protected] (K. Toutouzas). 0021-9150/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2009.01.041

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coronary inflammation and especially in acute coronary syndromes (ACS), they may provide unique information, not related with the biomarkers of myocyte necrosis and hemodynamic stress [4]. Angiography, the most commonly performed invasive procedure for the illustration of arterial anatomy and luminal narrowing, is not an established surrogate measure of coronary atherosclerosis. Moreover, the association between inflammatory markers and severity and extent of coronary artery disease (CAD) remains controversial, although a more consistent relationship between systemic inflammatory markers and major adverse cardiac events has been observed [3,5,6]. Currently there is no consensus if increased inflammatory levels may predict the presence of atherosclerosis. The question of how to use these biomarkers as part of a broader risk stratification strategy is still an issue of debate. The aim of this manuscript is to review the literature for the evaluation of the relationship

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of inflammatory markers with the presence and extent of coronary atherosclerosis, as assessed by coronary angiography in order to evaluate the potential utility of these markers in identifying patients with higher levels of coronary atherosclerosis and predicting the atheromatic burden. Thus, we performed a computerized search, using the keywords coronary angiography and inflammation, to identify relevant English language articles published in Pub Med until November 2008. Individual articles had to meet the following criteria to be included: (1) articles examining the relationship between C-reactive protein (CRP) and coronary angiography and (2) articles or reviews relating atherosclerosis to local and systemic inflammation. We also examined the references of all the studies from our initial search to locate additional references that would be useful for this review. To ensure the quality of our data we limited our review to the studies published as full text in peer-reviewed journals. 2. Angiographic classification of coronary atheromatic lesions The classic angiographic features of lesions associated with the ACS, including irregular ragged borders and intraluminal lucency, have been previously demonstrated [7,8]. Ambrose et al., has shown that concentric lesions are symmetrical and usually smooth, whereas eccentric are asymmetrical. Eccentric lesions of type I are smooth, whereas lesions of type II, are either smooth with a narrow neck, due to overhanging edges, or have irregular borders. Lesions with multiple irregularities are serial lesions or severe diffuse [7]. Goldstein et al. has shown that lesions likely to precede major cardiac events more frequently are eccentric, asymmetric with a narrow neck or irregular borders, complex with irregular or ill-defined margins, inhomogeneous, ulcerated with evidence of thrombus [8]. 3. Limitations of angiography Although angiography is one of the most commonly performed invasive procedures for the illustration of arterial anatomy and luminal narrowing and has been characterized as the “gold standard”, it is not an established a surrogate measure of coronary atherosclerosis. It only provides information about the vessel lumen, and does not provide direct information on plaque composition, plaque burden and plaque changes within the vessel wall. In addition, visual assessment of the degree of stenosis is subjected to significant operator variability. More importantly, inflammation is more strongly related to rupture and thrombosis rather than the presence and severity of atherosclerosis as reflected by coronary angiography so that the degree of luminal stenosis does not correlate with the risk of a lesion leading to ACS [9]. For these reasons, angiography is not the optimal modality for identifying “high-risk” lesions. 4. Correlation between inflammation and atherosclerosis Evidence supports a pivotal role of inflammation in all phases of atherosclerosis from the initiation of the fatty streak to the culmination in ACS [5,10]. The earliest event in atherogenesis appears to be endothelial cell dysfunction. Endothelial dysfunction manifests itself primarily as nitric oxide and prostacyclin deficiency and increased circulating levels of endothelin-1, angiotensin II, and plasminogen activator inhibitor-1. Attachment of mononuclear cells such as monocytes and T lymphocytes is promoted by selectins, intercellular and vascular adhesion molecule-1 [11]. Following attachment to the endothelium, the entry of monocytes into the subendothelial space is enhanced by monocyte chemoattractant

protein-1 and IL-8 [12]. Thereafter, macrophage colony stimulating factor differentiates monocytes into macrophages. Macrophages incorporating lipids from oxidized low-density lipoprotein become foam cells, the hallmark of the early fatty streak lesion. After formation of the fatty streak lesion, smooth muscle cells migrate into the intima, proliferate and form the fibrous cap. Foam cells after the process of necrosis and apoptosis, release matrix metalloproteinases, which cause a rent in the endothelium [5]. Tissue factor released by foam cells comes in contact with the circulating platelets, resulting in thrombus formation and ACS. 5. C-reactive protein as a direct mediator of plaque inflammation Among the numerous circulating inflammatory markers of atherosclerotic process, CRP received the greatest attention mostly because of its easy measurement as an analyte. Beyond its role as an inflammatory marker, CRP has also been considered as a mediator of atherosclerosclerosis [13]. There are two issues regarding the pro-atherogenic effect of CRP. Firstly, the site of CRP production and secondly the direct effect of CRP on the arterial wall. Recent data challenge the hypothesis that CRP is exclusively produced by the liver. Indeed, several studies suggest that it is also produced in the atherosclerotic lesion, especially by smooth muscle cells and macrophages [4,14–16]. In specific, CRP co-localizes with the membrane attack complex in early atheromatous lesions, and together with complement proteins, and their messenger ribonucleic acid are all substantially upregulated in atheromatous plaque. Interestingly, experimental data support that in patients with ACS, CRP is localized in the vessel wall and its levels are higher in the coronary sinus than in the aorta, suggesting its cardiac origin [17]. Lately, there is evidence that CRP has proinflammatory and proatherogenic effect via modulation of endothelial, inflammatory and smooth muscle cells of the arterial wall. The proinflammatory, proatherogenic effects of CRP that have been documented in endothelial cells include: (1) decreased nitric oxide and prostacyclin production, and (2) stimulation for increased production of endothelin-1, cell adhesion molecules, monocyte chemoattractant protein-1, IL-8, and plasminogen activator inhibitor-1 [12,18–20]. In monocyte-macrophages, CRP induces tissue factor secretion, increases reactive oxygen species and proinflammatory cytokine release, promotes monocyte chemotaxis and adhesion, and increases oxidized low-density lipoprotein uptake. Nabata et al., has demonstrated the direct proinflammatory effects of CRP on human mononuclear cells in addition to its proinflammatory actions on endothelial cells [21]. Recent data suggest that CRP itself potently attracts monocytes and facilitates the uptake of LDL by macrophages thus increasing foam cell formation and activating complement [22]. Also, CRP has been shown in vascular smooth muscle cells to increase inducible nitric oxide production and, most importantly, upregulate angiotensin type-1 receptor resulting in increased reactive oxygen species and vascular smooth muscle cell proliferation. Therefore, CRP exerts direct proatherosclerotic effects at the level of vascular smooth muscle cell [23]. All the above suggest that CRP may exert a pathogenic role in the atherosclerotic process. However, serum CRP is a nonspecific systemic marker of tissue damage, infection and inflammation and recent data show that its addition to conventional risk factors remains controversial. 6. Inflammatory markers and burden of atherosclerosis Several studies have shown that the association between inflammatory markers and the extent of CAD is weak and is mostly explained by concomitant burden of cardiovascular risk factors

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Table 1 Studies demonstrating no correlation of inflammatory markers with coronary artery disease. Study

Population

Marker studied

Results

Abdelmouttaleb et al. [27]

189 patients with CAD

CRP

Azar et al. [26]a

98 patients with CAD

CRP

Yip et al. [31]a

128 patients for elective PCI and 40 healthy volunteers 131 patients with and 103 without CAD

CRP, VCAM, WBC, ICAM

CRP was higher in patients with CAD (7.1 ± 11.2 mg/l) compared with patients with normal coronary angiograms (4.8 ± 4.0 mg/l) and healthy subjects (2.3 ± 3.6 mg/l) There was no correlation between CRP and coronary atherosclerosis score (Pearson correlation coefficient 0.17, R2 = 0.03) No significant differences in CRP between multi-vessel and single-vessel disease (2.50 ± 2.60 mg/dl vs 2.82 ± 2.48 mg/dl, p = 0.31) There were no significant differences between patients with Grade 0 vs Grade 1 or 2 with the markers of inflammation

a

Videm et al. [32]a

Surkhija et al. [29]a Inoue et al. [25]a Hoffmeister et al. [24]a

CRP, abs for CMV, Helicobacter pylori Chlamydia CRP, (IL)-6, TNF

249 patients undergoing PCI 158 patients with CAD

(IL)-1␤,2,4,5,6,8,10, TNF-␣, GM-SF, IFN-␥ CRP, SAA, fibrinogen, albumin, neutrophils

312 patients with CAD and 479 healthy volunteers

In adjusted models there was no correlation between the measured markers and the severity of obstructive CAD The severity of CAD as indicated by Gensini score was not correlated with CRP (R = 0.020, p = 0.80) No relation between severity or extension of CAD and CRP (1-vessel: 1.55 mg/dl, 2-vessel: 1.91 mg/dl, 3-vessel: 1.37 mg/dl, p = 0.70)

a Prospective; CAD: coronary artery disease; CRP: C-reactive protein; CMV: Cytomegalovirus; (IL): interleukin; ICAM: intercellular adhesion molecule; PCI: percutaneus coronary intervention; VCAM: vascular cell adhesion molecule; WBC: white blood cell.

(Table 1). Previous studies, reported no correlations between inflammatory markers and any of the applied scores [24,25]. However, all patients had known CAD whereas patients with normal angiograms and consecutively low levels of inflammatory markers were not included. In addition, some patients were on statin therapy and 62% of patients had myocardial infarction. Azar et al. found no correlation of CRP with the extent score and the number of stenosed (>50%) vessels in patients undergoing coronary angiography [26]. Most of the patients had severe CAD and <10% had a normal angiogram. Thus, conclusions could not be extrapolated regarding the presence of coronary atherosclerosis, but only the extent or the severity. Abdelmouttaleb et al. revealed a strong association between CRP and the clinical syndrome, although no correlation was found between the extent of CAD and CRP [27]. The “extent” of atherosclerosis was defined as the number of diseased levels. Arroyo-Espliguero et al., examined patients with chronic stable angina (SA) and patients with ACS separately. This study showed

that CRP correlated with the extent of CAD and predicted future cardiovascular events independently of CAD severity [28]. In the large ECAT study no association between fibrinogen, Pai-1 activity, leukocyte count and extent of CAD was found. In a prospective study including 249 patients who were admitted with acute chest pain and underwent coronary angiography CRP, IL-6, and TNF were measured [29]. Although hs-CRP and IL-6 were associated with some parameters of atherosclerotic burden in the unadjusted model, this association between inflammatory markers and atherosclerotic burden was lost after adjustment for conventional CAD risk factors. Moreover, Zebrack et al. showed that although CRP significantly correlates with the extent of vascular disease, the degree of association was small and the independent contribution of CRP to risk assessment remained significant [30]. Yip et al., conducted a prospective cohort study including patients with ACS and SA undergoing coronary stenting [31]. He failed to demonstrate a link between circulating levels of hs-CRP and multivessel disease.

Table 2 Studies demonstrating a correlation of inflammatory markers with coronary artery disease. Study

Population

Marker studied

Results

Lombardo et al. [37]a

283 patients scheduled for coronary artery bypass 103 patients undergoing PCI for CAD

CRP

Tataru et al. [40]a

1413 post-myocardial infarction patients

CRP

Zebrack et al. [30]a

2,554 patients with angina but without AMI 225 patients undergoing PCI

CRP

Espinola-Klein et al. [6]a

720 patients undergoing PCI.

CRP, (IL)-18,6, fibrinogen

Erren et al. [49]a

147 undergoing PCI

CRP, SAA, (IL)-6, TGF-␤

Memon et al. [35]a

138 patients with CAD and 183 healthy subjects

CRP, fibrinogen

Gotsman et al. [34]a

314 patients undergoing PCI for stable CAD 55 patients with non-STEMI and CAD

(IL)-1, 6,8,10, TNF

CRP was higher in patients with complex (7.55 mg/l) than with simple (3.94 mg/l; p < 0.05) or without plaques (2.45 mg/l; p < 0.05) In multivariate modeling, the odds of a high-risk/acute lesion increased 1.76-fold (95% CI, 0.86–3.58; p = 0.072) per each 10-fold increase in CRP concentration CRP was associated with the number of stenosed coronary vessels (p < 0.001). However, there was no association between CRP and severity of stenosis, graded by the DeBakey score or the number of stenoses in the same vessel CRP correlated with the extent of CAD, but correlation coefficients were low (0.02–0.08) Positive associations were found between coronary atherosclerosis and CRP according to the Gensini score: 0: 138.4 ± 1.2 mg/dl, 1–14: 232,8 ± 1.2, 15–42: 337.0 ± 1.2, >43: 323.8 ± 1.2 mg/dl, p = 0.003 Significant association between elevation of CRP and atherosclerosis was found (control: 2.6 (1.4–6.8) mg/l; CAD: 4.5 (2.1–12.1) mg/l; multi-vascular: 5.2 (2.0–15.6) mg/l, p < 0.001) Patients with CAD demonstrated significantly increased CRP (No CAD, No peripheral artery disease: 0.20 (0.02, 4.5), CAD, No peripheral artery disease: 0.40 (0.03, 14.00), CAD, peripheral artery disease: 0.55 (0.14, 1.90), p < 0.001 CRP increased depending on the number of stenotic vessels: 1.85 mg/dl in 0-VD, 2.03 in 1-vessel, 2.60 in 2-vessel, and 2.76 in 3-vessel disease, p < 0.01. Statistically significant differences were observed between subgroups There was no significant correlation, neither in the whole cohort nor in the patients subsets, between atherosclerosis and the other inflammatory markers CRP correlated with the number of complex lesions (R = 0.33, p = 0.02). Patients with multiple complex stenosis had higher CRP compared to patients with smooth lesions (log transformed): 1.08 (0.63) vs 0.6 (0.6), p = 0.03

Katritsis et al. [39]a

Mori et al. [33]a

Avanzas et al. [28]a

CRP

Glycoprotein, CRP

Neutrophils, CRP

a Prospective; AMI: acute myocardial infarction; CAD: coronary artery disease; CRP: C-reactive protein; (IL): interleukin; PCI: percutaneous coronary intervention; SAA: serum amyloid protein; STEMI: ST elevation myocardial infarction; TNF: tumor necrosis factor; TGF-␤: transforming growth factor-␤.

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Accordingly, variations in CRP were not related to the presence or absence of coronary artery stenosis [32]. Despite variations in the population sample sizes, inclusion criteria, inflammatory markers studied, and analysis techniques, the results in these studies are mostly uniform in their lack of association between measures of inflammation and CAD presence and severity. However, there is controversy regarding the significant independent association between CRP concentration and atherosclerosis burden. There is evidence that inflammation plays a pivotal role in atherosclerosis and is a marker for increased cardiovascular risk (Table 2). Several studies have shown positive associations between CRP and the extent of CAD [33–36]. Lombardo et al., investigated the association between coronary instability and the potential causal role of inflammation. CRP was higher in patients with complex than in those with simple plaques or without plaques [37]. In the study by Taniguchi et al., CRP did not correlate with the number of stenotic vessels. After the exclusion however, of patients who were taking statins, CRP was found to be associated with the presence and extent of coronary atherosclerosis [38]. In a crosssectional study, 103 patients undergoing cardiac catheterization for suspected CAD were examined [39]. In this study, increased CRP is strongly associated with ACS and with specific high-risk features of the culprit coronary lesions. This is the first study to link CRP concentrations with lesion morphology. In specific, CRP was associated with the presence of features such as thrombus or eccentric location and irregularity. On the contrary, patients with totally occluded lesions tended to have low CRP, consistent with the hypothesis that CRP reflects acute inflammatory pathophysiology, not established events. Investigations of Tataru et al. in survivors of myocardial infarction showed a significant association of CRP with angiographically detected degree of coronary heart disease defined as numbers of stenosed coronary vessels [40]. Haverkate et al., demonstrated that CRP weakly correlated with the number of stenotic vessels in 2121 patients undergoing coronary angiography, although 50% of patients had ACS [41]. The presence of multiple angiographically complex coronary stenosis correlated well with CRP concentration and neutrophil count [41]. By coronary sinus thermography we have shown that CRP correlates with increased temperature of coronary sinus compared to right atrium and is higher in patients with CAD compared to controls [42]. In the subgroup analysis however, CRP was similar between patients with multivessel and single vessel disease [39]. An important issue to consider in all the above study groups is the possible contribution of atherosclerosis in vascular beds other than coronary arteries towards higher CRP. All the above studies have their own limitations. Large, wellplanned comprehensive studies aimed at answering these key questions will help accurately identify the combined role of measuring inflammatory markers in assessment of atherosclerotic disease. Nevertheless, even if the use of a novel risk factor does not improve prediction of future events, this does not imply that this factor is pathophysiologically unimportant or unsuitable as a target for intervention. Individuals with evidence of increased inflammation may benefit most from an aggressive modification of lifestyle and an intensification of proven preventive therapies such as aspirin and statins. Moreover, the benefits of an early invasive strategy may also be greatest among those with elevated levels of inflammatory biomarkers recommended for use in primary prevention for this purpose.

7. The impact of new imaging modalities The need of improved diagnostic accuracy and superior visualization of atheromatic burden has resulted in the development of newer imaging techniques that minimize the limitations of

conventional angiography and has promoted interest in alternative invasive or catheter-based techniques to directly visualize the arterial wall and to characterize plaque. Most of the studies have used intravascular ultrasound for the quantitative and qualitative assessment of atheromatic burden. Several studies have addressed the relation between lesion morphology by intravascular ultrasound and CRP. In the study of Sano et al., the presence of ruptured plaque has been related to elevated CRP, although no relation was found with the number of lesions [43]. In a prospective study with intravascular ultrasound, CRP could not predict the extent of arterial remodeling [44]. However, other studies have shown that patients with elevated CRP have more severe plaque ruptures and more multiple plaque ruptures than the controls [45]. Accordingly virtual histology has shown a positive correlation between CRP and necrotic core in patients with ACS both in culprit and non-culprit lesions [46]. By using angioscopy, complex plaques revealed a higher intimal CRP and tissue factor expression than white/yellow plaques [47]. Raffel et al., by optical coherence tomography, correlated a systemic inflammatory marker with the macrophage density, and the presence of thick-cap-fibroatheromas. Macrophage density correlated with the white blood cell count, and both parameters independently predicted the presence of thick-cap-fibroatheromas [48]. Moreover, CRP in patients with thincap-fibroatheromas was significantly higher compared to patients with thick-cap-fibroatheromas [49]. Limited data however exist concerning the extent of CAD and inflammatory markers using these novel imaging techniques. 8. Conclusions Currently there is no consensus if increased inflammatory levels may predict presence and increased burden of atherosclerosis. Further research efforts should be directed at investigating the effect of CRP on other atherogenic mediators and at elucidating the proinflammatory, prothrombotic molecular mechanisms of atherosclerosis. References [1] Rosamond W, Flegal K, Furie K, et al. Heart disease and stroke statistics–2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2008;117(4):e25–146. [2] Thim T, Hagensen MK, Bentzon JF, Falk E. From vulnerable plaque to atherothrombosis. J Intern Med 2008;263(5):506–16. [3] Hingorani AD, Shah T, Casas JP, Humphries SE, Talmud PJ. C-reactive protein and coronary heart disease: predictive test or therapeutic target? Clin Chem 2008. [4] Maier W, Altwegg LA, Corti R, et al. Inflammatory markers at the site of ruptured plaque in acute myocardial infarction: locally increased interleukin6 and serum amyloid A but decreased C-reactive protein. Circulation 2005;111(11):1355–61. [5] Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359(21):2195–207. [6] Espinola-Klein C, Rupprecht HJ, Bickel C, et al. Inflammation, atherosclerotic burden and cardiovascular prognosis. Atherosclerosis 2007;195(2):e126–134. [7] Ambrose JA, Tannenbaum MA, Alexopoulos D, et al. Angiographic progression of coronary artery disease and the development of myocardial infarction. J Am Coll Cardiol 1988;12(1):56–62. [8] Goldstein JA, Demetriou D, Grines CL, et al. Multiple complex coronary plaques in patients with acute myocardial infarction. N Engl J Med 2000;343(13):915–22. [9] Fishbein MC, Siegel RJ. How big are coronary atherosclerotic plaques that rupture? Circulation 1996;94(10):2662–6. [10] Ross R. Atherosclerosis is an inflammatory disease. Am Heart J 1999;138(5 Pt 2):S419–20. [11] Nakashima Y, Raines EW, Plump AS, Breslow JL, Ross R. Upregulation of VCAM-1 and ICAM-1 at atherosclerosis-prone sites on the endothelium in the ApoEdeficient mouse. Arterioscler Thromb Vasc Biol 1998;18(5):842–51. [12] Mantovani A, Bussolino F, Dejana E. Cytokine regulation of endothelial cell function. FASEB J 1992;6(8):2591–9. [13] Jialal I, Devaraj S, Venugopal SK. C-reactive protein: risk marker or mediator in atherothrombosis? Hypertension 2004;44(1):6–11. [14] Calabro P, Willerson JT, Yeh ET. Inflammatory cytokines stimulated C-reactive protein production by human coronary artery smooth muscle cells. Circulation

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