Circulating markers of inflammation for vascular risk prediction: are they ready for prime time.

Abstract

HomeCirculationVol. 101, No. 15Circulating Markers of Inflammation for Vascular Risk Prediction Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBCirculating Markers of Inflammation for Vascular Risk Prediction Are they Ready for Prime Time Prediman K. Shah Prediman K. ShahPrediman K. Shah Search for more papers by this author Originally published18 Apr 2000https://doi.org/10.1161/01.CIR.101.15.1758Circulation. 2000;101:1758–1759Over the last several years, the idea that inflammation plays a key role in atherosclerosis and its complications has received considerable attention.1 Inflammatory cell infiltration is observed in atherosclerotic plaques at virtually all stages, from the fatty streak to the advanced atheromatous lesions with plaque disruption and thrombosis.12 Atherosclerosis is substantially prevented when the biological effects of genes critical for the initiation or maintenance of inflammatory cell recruitment, survival, proliferation, and activation, such as monocyte chemotactic protein-1, interleukin-8, and macrophage colony stimulating factor, are eliminated by gene knockout in atherosclerosis-prone dyslipidemic mice.345 Similarly, the inhibition of inflammatory signaling pathways mediated by the ligation of CD-40 also results in reduced atherosclerosis in mice.6Inflammatory cells may also play a key role in promoting plaque disruption by stimulating matrix degradation, inhibiting smooth muscle cell function or survival, and promoting thrombosis by producing tissue factor.2 Similarly, the atheroprotective effects of a variety of interventions such as statins, apolipoprotein A-1/HDL, aspirin, and fibrates are often associated with the evidence of reduced inflammation, further bolstering the notion that inflammation and atherosclerosis are causally related.278 Although all of the potential triggers of inflammation are not fully known, cytokines, oxidized lipoproteins, and local (arterial) and distant infections (gingivitis, bronchitis) have been implicated.29 Early reports from small, randomized trials have shown a reduced clinical event rate with the use of macrolide antichlamydial antibiotics.2 These preliminary observations support the notion that Chlamydia pneumoniae infection may be causally related to atherothrombosis, although a direct anti-inflammatory effect of macrolides, independent of antichlamydial action, cannot be excluded.In view of the persuasive evidence implicating inflammation in atherothrombosis, several investigators have examined a variety of circulating markers of inflammation to predict either the presence of vascular disease or the risk of vascular events in a variety of clinical settings.10 These markers have included C-reactive protein (CRP), serum amyloid A protein (SAA), heat shock protein 65, interleukin-6 (IL-6), and a number of leukocyte adhesion molecules.Of the variety of circulating markers, CRP, an acute phase reactant produced by the liver in response to IL-6 (a cytokine induced by interleukin-1 and tumor necrosis factor-α) has been the best studied, with the most consistent relationship to future risk under diverse clinical settings (ie, asymptomatic, otherwise healthy subjects; patients with peripheral and stable coronary artery disease; and patients with unstable angina).10 Furthermore, the availability of a reliable, reproducible assay with a high sensitivity for CRP adds to its attractiveness as a circulating marker of risk. Because CRP gene transcription in the liver is stimulated by IL-6, a pleiotropic cytokine, CRP levels are generally well correlated with circulating levels of IL-6. Therefore, it is not surprising that like CRP, circulating IL-6 also provides prognostic information. This was first suggested by Biasucci et al11 and is now further established by Ridker et al.12Ridker et al12 continue to take advantage of the Physician’s Health Study Database, which provides valuable prospective information on the predictive value of various markers in asymptomatic subjects. In the present study, they measured circulating IL-6 levels in 202 subjects who had suffered a myocardial infarction during a 6-year follow-up and compared them with those of 202 matched control subjects who had remained free of the intervening clinical events.12 Although IL-6 and CRP levels were modestly correlated (r=0.4), multivariate analysis revealed a graded risk associated with increasing quartiles of IL-6 levels that was independent of CRP and many other traditional risk factors.12 As with CRP levels in seemingly healthy subjects, the circulating IL-6 levels had prognostic value within the normal range for IL-6.The results of this study are in general agreement with smaller studies reported previously and a recent prospective study in the geriatric population.13 As with CRP, it is unclear whether IL-6 is simply a messenger of risk or whether it is pathophysiologically involved in atherothrombosis. The potential causal role of IL-6 in atherothrombosis is suggested by its selective expression in macrophages in murine and human atheroma, its stimulatory effect on smooth muscle cell proliferation and tissue factor induction in macrophages, and its ability to accelerate early atherosclerosis in murine models.141516 Furthermore, the IL-6–induced hepatic production of SAA may promote the incorporation of SAA with plasma HDL, rendering the HDL proinflammatory.17Although this study and the body of data previously reported by Ridker et al10 have continued to enhance our knowledge of new risk factors for vascular disease, several limitations continue to preclude the routine use of these novel markers for risk stratification in clinical practice. First, many markers have been studied by various investigators, but comparative data regarding which ones are incremental and which ones are redundant are limited. It remains to be proven that any of the inflammatory markers provide incremental information over and above the traditional risk stratification algorithms developed by the Framingham Study Groups and the European Working Group.18Ridker recently analyzed data from the Physician’s Health Study and demonstrated that circulating CRP levels provided significant incremental prognostic information over and above the total cholesterol to HDL ratio.19 It would have been of great interest to know whether circulating IL-6 also provides incremental prognostic data over and above that provided by a model that takes into account traditional risk factors and CRP levels. Unfortunately, the present report does not provide this critical piece of information. Given the ever-increasing list of inflammatory markers, their practical utility will likely remain uncertain until the issue of which marker is incrementally useful (instead of redundant) is resolved.Another limitation of the routine use of these markers is the increasing use in clinical practice of several new, noninvasive imaging techniques for the detection of subclinical atherosclerosis. These techniques include electron beam computerized tomographic scanning and brachial artery reactivity for coronary atherosclerosis and ultrasound and MRI for carotid and aortic atherosclerosis. How will circulating inflammatory markers fare when stacked against these imaging tests? Answers to these questions can only be provided by properly designed prospective studies in which traditional risk factors and the novel inflammatory markers are measured along with imaging information to test both the incremental usefulness of the markers and the cost-effectiveness of various tests.Despite the usefulness of inflammatory markers in predicting relative risks in populations, the prediction of absolute risk in individuals remains a challenging task, especially in low-risk populations in which event rates are low. Also, to be clinically useful, the assays must be precise, reproducible, relatively nontedious, easily standardizable, and inexpensive. Finally, new techniques to identify gene expression patterns should help decipher the complex nature of atherosclerosis at a molecular genetic level, providing insights about genetic modulations of susceptibility to disease and response to therapy.20 Down the road, the incorporation of this information may add a whole new dimension to our ability to identify at-risk individuals for intervention. When that happens, it is quite possible that many of our more remote and indirect markers will end up relegated to history.Not withstanding these limitations and although inflammatory markers such as IL-6 may not yet be ready for prime time, the evidence linking inflammation to atherothrombosis keeps piling up. The focus on inflammation as a critical player in atherothrombosis will likely lead to novel anti-inflammatory strategies against atherothrombotic vascular disease in the future. That may yet be the more important outcome of studies like that of Ridker and colleagues. References 1 Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med.1999; 340:115–126.CrossrefMedlineGoogle Scholar2 Shah PK. Plaque disruption and thrombosis: potential role of inflammation and infection. Cardiol Clin.1999; 17:271–281.CrossrefMedlineGoogle Scholar3 Gosling J, Slaymaker S, Gu L, et al. MCP-1 deficiency reduces susceptibility to atherosclerosis in mice that overexpress human apolipoprotein B. J Clin Invest.1999; 103:773–778.CrossrefMedlineGoogle Scholar4 Boisvert WA, Santiago R, Curtiss LK, et al. 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; 101:353–63.CrossrefMedlineGoogle Scholar5 Rajavashisth T, Qiao JH, Tripathi S, et al. Heterozygous osteopetrotic (op) mutation reduces atherosclerosis in LDL receptor-deficient mice. J Clin Invest.1998; 101:2702–2710.CrossrefMedlineGoogle Scholar6 Mach F, Schonbeck U, Sukhova GK, et al. Reduction of atherosclerosis in mice by inhibition of CD40 signaling. Nature.1998; 394:200–203.CrossrefMedlineGoogle Scholar7 Ridker PM, Nader R, Pfeffer MA, et al. The CARE investigators: inflammation, pravastatin and the risk for coronary events after myocardial infarction in patients with average cholesterol levels. Circulation.1998; 98:839–844.CrossrefMedlineGoogle Scholar8 Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med.1997; 336:973–979.CrossrefMedlineGoogle Scholar9 Libby P, Egan D, Skarlatos S. Roles of infectious agents in atherosclerosis and restenosis: an assessment of the evidence and need for future research. Circulation.1997; 96:4095–4103.CrossrefMedlineGoogle Scholar10 Ridker PM. Evaluating novel cardiovascular risk factors: can we do better predict heart attacks? Ann Intern Med.1999; 130:933–937.CrossrefMedlineGoogle Scholar11 Biasucci LM, Bitelli A, Liuzzo G, et al. Elevated levels of interleukin-6 in unstable angina. Circulation.1996; 94:874–877.CrossrefMedlineGoogle Scholar12 Ridker PM, Rifai N, Stampfer M, et al. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation..2000; 101:1767–1772.CrossrefMedlineGoogle Scholar13 Harris TB, Ferucci L, Tracy RP, et al. Associations of elevated interleukin-6 and c-reactive protein levels with mortality in the elderly. Am J Med.1999; 106:506–512.CrossrefMedlineGoogle Scholar14 Rus HG, Vlaicu R, Niculescu F. Interleukin-6 and interleukin-8 protein and gene expression in human atherosclerotic wall. Atherosclerosis.1996; 127:263–371.CrossrefMedlineGoogle Scholar15 Neuman FJ, Ott I, Marx N, et al. Effect of recombinant interleukin-6 and interleukin-8 on monocyte procoagulant activity. Arterioscler Thromb Vasc Biol.1997; 17:3399–3405.CrossrefMedlineGoogle Scholar16 Van Lenten BJ, Hama SY, de Beer FC, et al. Anti-inflammatory HDL becomes pro-inflammatory during the acute phase response: loss of protective effect of HDL against LDL oxidation in aortic wall cell cocultures. J Clin Invest.1995; 96:2758–2767.CrossrefMedlineGoogle Scholar17 Huber SA, Sakkinen P, Conze D, et al. Interleukin-6 exacerbates early atherosclerosis in mice. Arterioscler Thromb Vasc Biol.1999; 19:2364–2367.CrossrefMedlineGoogle Scholar18 Haq IU, Ramsay LE, Yeo WW, et al. Is the Framingham risk function valid for northern European populations? A comparison of methods for estimating absolute coronary risk in high risk men. Heart.1999; 81:40–46.CrossrefMedlineGoogle Scholar19 Ridker PM, Glynn RJ, Hennekens CH. C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation.1998; 97:2007–2011.CrossrefMedlineGoogle Scholar20 DeRisi J, Penland L, Brown PO, et al. Use of a cDNA microarray to analyze gene expression patterns in human cancer. Nat Genet.1996; 14:457–460.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Jin Z, Chen Y, Weng X, Huang A, Lin S and Li H (2020) Cleavage of cyclic AMP-responsive element-binding protein H aggravates myocardial hypoxia reperfusion injury in a hepatocyte–myocardial cell co-culture system, Journal of International Medical Research, 10.1177/0300060520904835, 48:5, (030006052090483), Online publication date: 1-May-2020. Saskin H, Ozcan K, Duzyol C, Baris O and Koçoğulları U (2016) Are inflammatory parameters predictors of amputation in acute arterial occlusions?, Vascular, 10.1177/1708538116652995, 25:2, (170-177), Online publication date: 1-Apr-2017. Giannini D, Kuschnir M, de Oliveira C and Szklo M (2017) Waist-to-Height Ratio as a Predictor of C-Reactive Protein Levels, Journal of the American College of Nutrition, 10.1080/07315724.2017.1338631, 36:8, (624-630), Online publication date: 17-Nov-2017. Hu Q, Wei B, Wei L, Hua K, Yu X, Li H and Ji H (2015) Sodium tanshinone IIA sulfonate ameliorates ischemia-induced myocardial inflammation and lipid accumulation in Beagle dogs through NLRP3 inflammasome, International Journal of Cardiology, 10.1016/j.ijcard.2015.05.152, 196, (183-192), Online publication date: 1-Oct-2015. Dukkipati R, Molnar M, Park J, Jing J, Kovesdy C, Kajani R and Kalantar-Zadeh K (2013) Association of Vascular Access Type with Inflammatory Marker Levels in Maintenance Hemodialysis Patients, Seminars in Dialysis, 10.1111/sdi.12146, 27:4, (415-423), Online publication date: 1-Jul-2014. Yang J, Lin Y, Su M, Li W and Liu M (2013) Use of Magnetic Nanoparticles and a Microplate Reader with Fluorescence Detection to Detect C-reactive Protein, Journal of the Chinese Chemical Society, 10.1002/jccs.201300377, 61:2, (221-226), Online publication date: 1-Feb-2014. Lin Y, Yang J, Shu T, Lin T, Chen Y, Su M, Li W and Liu M (2013) Detection of C-reactive protein based on magnetic nanoparticles and capillary zone electrophoresis with laser-induced fluorescence detection, Journal of Chromatography A, 10.1016/j.chroma.2013.09.042, 1315, (188-194), Online publication date: 1-Nov-2013. Parekh H, Nguyen H, Hall S, Rehage M, Anholm J, Specht L and Linkhart T (2012) Direct Pro-Inflammatory Effect of C-Reactive Protein on Human Pulmonary Artery Endothelial Cells, European Journal of Inflammation, 10.1177/1721727X1201000311, 10:3, (357-363), Online publication date: 1-Sep-2012. Tsai M, Chang C, Yu Y, Lin T, Chong C, Lin Y, Su M, Yang J, Shu T, Lu X, Chen C and Liu M (2012) Chemical Analysis of C-Reactive Protein Synthesized by Human Aortic Endothelial Cells Under Oxidative Stress, Analytical Chemistry, 10.1021/ac302856v, 84:21, (9646-9654), Online publication date: 6-Nov-2012. Yang G, Fang Z, Liu Y, Zhang H, Shi X, Ji Q, Lin Q and Lin R (2011) Protective Effects of Chinese Traditional Medicine Buyang Huanwu Decoction on Myocardial Injury, Evidence-Based Complementary and Alternative Medicine, 10.1093/ecam/nep013, 2011, (1-7), . Toprak D, Toprak A, Chen W, Xu J, Srinivasan S and Berenson G (2012) Adiposity in Childhood Is Related to C-Reactive Protein and Adiponectin in Young Adulthood: From the Bogalusa Heart Study, Obesity, 10.1038/oby.2010.75, 19:1, (185-190), Online publication date: 1-Jan-2011. Wang Q, Qiu Y, Zhu Y, Zhu J, Wang L, Hu X, Hu S, Zheng L, Tao Q, Zhang F and Zhang Y (2009) Cyclophosphamide protects against myocardial ischemia/reperfusion injury in rats: One of the therapeutic targets is high sensitivity C-reactive protein, The Journal of Thoracic and Cardiovascular Surgery, 10.1016/j.jtcvs.2008.04.033, 137:4, (991-996), Online publication date: 1-Apr-2009. Peng Y, Ho Y, Wu C and Liu M (2009) Investigation of C-reactive protein binding to phosphatidyl choline by CZE and ESI-Mass analysis, ELECTROPHORESIS, 10.1002/elps.200800608, 30:9, (1564-1571), Online publication date: 1-May-2009. Barceló-Coblijn G and Murphy E (2009) Alpha-linolenic acid and its conversion to longer chain n−3 fatty acids: Benefits for human health and a role in maintaining tissue n−3 fatty acid levels, Progress in Lipid Research, 10.1016/j.plipres.2009.07.002, 48:6, (355-374), Online publication date: 1-Nov-2009. Fernandez A (2008) Peroxisome Proliferator-Activated Receptors in the Modulation of the Immune/Inflammatory Response in Atherosclerosis, PPAR Research, 10.1155/2008/285842, 2008, (1-7), . El-Menyar A (2008) Cytokines and Coronary Artery Disease, Critical Pathways in Cardiology: A Journal of Evidence-Based Medicine, 10.1097/HPC.0b013e31816713d9, 7:2, (139-151), Online publication date: 1-Jun-2008. Kobusiak-Prokopowicz M, Orzeszko J, Mazur G, Mysiak A, Orda A, Poreba R and Mazurek W (2007) Chemokines and left ventricular function in patients with acute myocardial infarction, European Journal of Internal Medicine, 10.1016/j.ejim.2007.02.001, 18:4, (288-294), Online publication date: 1-Jul-2007. Hu W, Qian S and Li J (2007) Decreased C-reactive protein-induced resistin production in human monocytes by simvastatin, Cytokine, 10.1016/j.cyto.2007.09.011, 40:3, (201-206), Online publication date: 1-Dec-2007. Plaisance E and Grandjean P (2006) Physical Activity and High-Sensitivity C-Reactive Protein, Sports Medicine, 10.2165/00007256-200636050-00006, 36:5, (443-458), . Haider D, Leuchten N, Schaller G, Gouya G, Kolodjaschna J, Schmetterer L, Kapiotis S and Wolzt M (2006) C-reactive protein is expressed and secreted by peripheral blood mononuclear cells, Clinical and Experimental Immunology, 10.1111/j.1365-2249.2006.03224.x, 146:3, (533-539), Online publication date: 13-Oct-2006. Yip H, Sun C, Chang L and Wu C (2006) Strong Correlation Between Serum Levels of Inflammatory Mediators and Their Distribution in Infarct-Related Coronary Artery, Circulation Journal, 10.1253/circj.70.838, 70:7, (838-845), . Christov A, Korol R, Dai E, Liu L, Guan H, Bernards M, Cavers P, Susko D and Lucas A (2007) In Vivo Optical Analysis of Quantitative Changes in Collagen and Elastin During Arterial Remodeling¶, Photochemistry and Photobiology, 10.1111/j.1751-1097.2005.tb00208.x, 81:2, (457-466) Christov A, Korol R, Dai E, Liu L, Guan H, Bernards M, Cavers P, Susko D and Lucas A (2005) In Vivo Optical Analysis of Quantitative Changes in Collagen and Elastin During Arterial Remodeling¶, Photochemistry and Photobiology, 10.1562/2004-03-10-RA-107.1, 81:2, (457), . KIBAYASHI E, URAKAZE M, KOBASHI C, KISHIDA M, TAKATA M, SATO A, YAMAZAKI K and KOBAYASHI M (2005) Inhibitory effect of pitavastatin (NK-104) on the C-reactive-protein-induced interleukin-8 production in human aortic endothelial cells, Clinical Science, 10.1042/CS20040315, 108:6, (515-521), Online publication date: 1-Jun-2005. Doo Y, Han S, Park W, Kim S, Choi S, Cho G, Hong K, Han K, Lee N, Oh D, Gryu K, Rhim C, Lee K and Lee Y (2006) Associations between C-reactive protein and circulating cell adhesion molecules in patients with unstable angina undergoing coronary intervention and their clinical implication, Clinical Cardiology, 10.1002/clc.4960280112, 28:1, (47-51), Online publication date: 1-Jan-2005. Ashida K, Miyazaki K, Takayama E, Tsujimoto H, Ayaori M, Yakushiji T, Iwamoto N, Yonemura A, Isoda K, Mochizuki H, Hiraide H, Kusuhara M and Ohsuzu F (2005) Characterization of the Expression of TLR2 (Toll-like Receptor 2) and TLR4 on Circulating Monocytes in Coronary Artery Disease, Journal of Atherosclerosis and Thrombosis, 10.5551/jat.12.53, 12:1, (53-60), . Hermann M, Enseleit F and Ruschitzka F (2005) Anti-inflammatory strategies in hypertension: Focus on COX-1 and COX-2, Current Hypertension Reports, 10.1007/s11906-005-0055-7, 7:1, (52-60), Online publication date: 1-Jan-2005. Li J (2004) Silent myocardial ischemia may be related to inflammatory response, Medical Hypotheses, 10.1016/S0306-9877(03)00305-0, 62:2, (252-256), Online publication date: 1-Feb-2004. Yip H, Wu C, Chang H, Yang C, Yeh K, Chua S and Fu M (2004) Levels and Values of Serum High-Sensitivity C-Reactive Protein Within 6 Hours After the Onset of Acute Myocardial Infarction, Chest, 10.1378/chest.126.5.1417, 126:5, (1417-1422), Online publication date: 1-Nov-2004. Ohsuzu F (2004) The Roles of Cytokines, Inflammation and Immunity in Vascular Diseases, Journal of Atherosclerosis and Thrombosis, 10.5551/jat.11.313, 11:6, (313-321), . Akbulut M, Ozbay Y, Gundogdu O, Daglı N, Durukan P, Ilkay E and Arslan N (2004) Effects of tirofiban on acute systemic inflammatory response in elective percutaneous coronary interventions, Current Medical Research and Opinion, 10.1185/030079904X4400, 20:11, (1759-1767), Online publication date: 1-Nov-2004. Cuijpers P and Schoevers R (2004) Increased mortality in depressive disorders: A review, Current Psychiatry Reports, 10.1007/s11920-004-0007-y, 6:6, (430-437), Online publication date: 1-Dec-2004. Ventura H and Mehra M (2003) C-Reactive protein and cardiac allograft vasculopathy, Journal of the American College of Cardiology, 10.1016/S0735-1097(03)00646-6, 42:3, (483-485), Online publication date: 1-Aug-2003. Valantine H (2003) Cardiac allograft vasculopathy: central role of endothelial injury leading to transplant ???atheroma???, Transplantation, 10.1097/01.TP.0000080981.90718.EB, 76:6, (891-899), Online publication date: 1-Sep-2003. (2003) Guidelines for clinical use of the statins Statins, 10.1201/b14304-15, (200-212), Online publication date: 4-Dec-2003. Tsiara S, Elisaf M and Mikhailidis D (2008) Early vascular benefits of statin therapy, Current Medical Research and Opinion, 10.1185/030079903125002225, 19:6, (540-556), Online publication date: 1-Jan-2003. Rallidis L, Paschos G, Liakos G, Velissaridou A, Anastasiadis G and Zampelas A (2003) Dietary α-linolenic acid decreases C-reactive protein, serum amyloid A and interleukin-6 in dyslipidaemic patients, Atherosclerosis, 10.1016/S0021-9150(02)00427-6, 167:2, (237-242), Online publication date: 1-Apr-2003. Feuerstein G, Firestein R, Libby P and Mann D (2003) A biomarker of inflammation in cardiovascular disease Inflammation and Cardiac Diseases, 10.1007/978-3-0348-8047-3_2, (9-20), . Ikeda U, Takahashi M and Shimada K (2003) C-Reactive Protein Directly Inhibits Nitric Oxide Production by Cytokine-stimulated Vascular Smooth Muscle Cells, Journal of Cardiovascular Pharmacology, 10.1097/00005344-200311000-00005, 42:5, (607-611), Online publication date: 1-Nov-2003. Rallidis L, Zolindaki M, Manioudaki H, Papasteriadis E, Laoutaris N and Velissaridou A (2002) Prognostic Value of C-Reactive Protein, Fibrinogen, Interleukin-6, and Macrophage Colony Stimulating Factor in Severe Unstable Angina, Clinical Cardiology, 10.1002/clc.4960251106, 25:11, (505-510), Online publication date: 1-Nov-2002. Navab M, Hama S, Ready S, Ng C, Van Lenten B, Laks H and Fogelman A (2002) Oxidized lipids as mediators of coronary heart disease, Current Opinion in Lipidology, 10.1097/00041433-200208000-00003, 13:4, (363-372), Online publication date: 1-Aug-2002. Shin W, Szuba A and Rockson S (2002) The role of chemokines in human cardiovascular pathology: enhanced biological insights, Atherosclerosis, 10.1016/S0021-9150(01)00571-8, 160:1, (91-102), Online publication date: 1-Jan-2002. Korkmaz M, Tayfun E, Müderrisoglu H, Yildirir A, Özin B, Uluçam M and Turan M (2016) Carbon Coating of Stents Has No Effect on Inflammatory Response to Primary Stent Deployment, Angiology, 10.1177/000331970205300510, 53:5, (563-568), Online publication date: 1-Sep-2002. Iturbe Hernández T, Moreno Chulilla J, Romero Colás M and Gutiérrez Martín M (2002) Fibrinógeno y recuento monocitario en la fase inicial del ictus isquémico, Medicina Clínica, 10.1016/S0025-7753(02)72319-1, 118:4, (159), Online publication date: 1-Jan-2002. Okura T, Watanabe S, Jiang Y, Nakamura M, Takata Y, Yang Z, Kohara K, Kitami Y and Hiwada K (2002) Soluble Fas ligand and atherosclerosis in hypertensive patients, Journal of Hypertension, 10.1097/00004872-200205000-00024, 20:5, (895-898), Online publication date: 1-May-2002. Labarrere C, Lee J, Nelson D, Al-Hassani M, Miller S and Pitts D (2002) C-reactive protein, arterial endothelial activation, and development of transplant coronary artery disease: a prospective study, The Lancet, 10.1016/S0140-6736(02)11473-5, 360:9344, (1462-1467), Online publication date: 1-Nov-2002. Eren E, Yılmaz N, Pençe S, Koçoğlu H, Göksu S, Kocabaş R and Kadayıfcı S (2019) Diagnostic Value of C-Reactive Protein in Patients with Angiographically Documented Coronary Heart Disease, Acta Medica (Hradec Kralove, Czech Republic), 10.14712/18059694.2019.73, 45:4, (155-160), . Zalai C, Kolodziejczyk M, Pilarski L, Christov A, Nation P, Lundstrom-Hobman M, Tymchak W, Dzavik V, Humen D, Kostuk W, Jablonsky G, Pflugfelder P, Brown J and Lucas A (2001) Increased circulating monocyte activation in patients with unstable coronary syndromes, Journal of the American College of Cardiology, 10.1016/S0735-1097(01)01570-4, 38:5, (1340-1347), Online publication date: 1-Nov-2001. Sato T, Tani Y, Murao S, Fujieda H, Sato H, Matsumoto M, Takeuchi T and Ohtsuki Y (2001) Focal enhancement of expression of c-Met/hepatocyte growth factor receptor in the myocardium in human myocardial infarction, Cardiovascular Pathology, 10.1016/S1054-8807(01)00079-5, 10:5, (235-240), Online publication date: 1-Sep-2001. Hunt M, O'Malley P, Vernalis M, Feuerstein I and Taylor A (2001) C-reactive protein is not associated with the presence or extent of calcified subclinical atherosclerosis, American Heart Journal, 10.1067/mhj.2001.112488, 141:2, (206-210), Online publication date: 1-Feb-2001. Mazzone A, Cusa C, Mazzucchelli I, Vezzoli M, Ottini E, Pacifici R, Zuccaro P and Falcone C (2001) Increased production of inflammatory cytokines in patients with silent myocardial ischemia, Journal of the American College of Cardiology, 10.1016/S0735-1097(01)01660-6, 38:7, (1895-1901), Online publication date: 1-Dec-2001. Higazi A, Cines D and Bdeir K (2001) α-Defensins Atherosclerosis and Autoimmunity, 10.1016/B978-044450669-6/50009-8, (73-85), . Madan M, Amar S and Giannobile W (2008) Toll-Like Receptor-2 Mediates Diet and/or Pathogen Associated Atherosclerosis: Proteomic Findings, PLoS ONE, 10.1371/journal.pone.0003204, 3:9, (e3204) Labarrere C, Woods J, Hardin J, Jaeger B, Zembala M, Deng M, Kassab G and Verma S (2014) Early Inflammatory Markers Are Independent Predictors of Cardiac Allograft Vasculopathy in Heart-Transplant Recipients, PLoS ONE, 10.1371/journal.pone.0113260, 9:12, (e113260) April 18, 2000Vol 101, Issue 15 Advertisement Article InformationMetrics Copyright © 2000 by American Heart Associationhttps://doi.org/10.1161/01.CIR.101.15.1758 Originally publishedApril 18, 2000 KeywordsatherosclerosisinflammationEditorialsPDF download Advertisement