This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Biasucci, L. M. Articles by Maseri, A. Search for Related Content PubMed PubMed Citation Articles by Biasucci, L. M. Articles by Maseri, A.

(Circulation. 1996;94:874-877.)
© 1996 American Heart Association, Inc.

Articles

Elevated Levels of Interleukin-6 in Unstable Angina

Luigi M. Biasucci, MD; Alessandra Vitelli, BS; Giovanna Liuzzo, MD; Sergio Altamura, PhD; Giuseppina Caligiuri, MD; Claudia Monaco, MD; Antonio G. Rebuzzi, MD; Gennaro Ciliberto, MD; Attilio Maseri, MD

the Institute of Cardiology, Catholic University of the Sacred Heart, Rome, Italy, and Istituto di Richerche di Biologia Molecolare "P Angeletti" (A.V., S.A., G. Ciliberto), Pomezia, Italy.

Correspondence to Luigi M. Biasucci, Istituto di Cardiologia, Universita' Cattolica, Largo Francesco Vito 1, 00168 Roma, Italy.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background Elevated plasma levels of C-reactive protein have been found in the majority of patients with unstable angina. The evidence of elevated levels of acute-phase proteins in unstable angina is in line with a growing body of evidence that suggests that inflammation plays a role in this syndrome and is an indirect sign of increased production of interleukin-6, which is the major determinant of acute-phase–protein production by the liver. However, in unstable angina, there is no direct proof of the role played by interleukin-6.

Methods and Results We measured levels of interleukin-6 in 38 patients with unstable angina at the time of their admission to the coronary care unit and in 29 patients with stable angina. In the same groups of patients, we also measured C-reactive protein. Interleukin-6 (undetectable, ie, <3 pg/mL, in healthy volunteers) was detectable in 23 (61%) of 38 patients with unstable angina but in only 6 (21%) of 29 with stable angina (P<.01). Median interleukin-6 levels were 5.25 pg/mL (range, 0 to 90 pg/mL) in patients with unstable angina but were below the detection limit of the assay in patients with stable angina (range, 0 to 7 pg/mL). A significant correlation was observed between interleukin-6 and C-reactive protein levels (r=.4, P=.013).

Conclusions Our study demonstrates that raised levels of interleukin-6 are common in unstable angina, correlate with C-reactive protein, and are associated with prognosis, thus confirming the importance of the cytokine pathway for the production by the liver of acute-phase proteins and strengthening the importance of inflammation in this syndrome. Further studies are required to elucidate better the role of interleukins in unstable angina.

Key Words: interleukins • angina • proteins • prognosis • pathophysiology

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Elevated plasma levels of C-reactive protein, a pro-totypical acute-phase reactant, have been found in the majority of patients with unstable angina^{1 2 3} ; we have also observed that raised levels of acute-phase proteins are strongly associated with an unfavorable outcome.³ The evidence of elevated levels of acute-phase proteins in unstable angina is in line with a growing body of evidence suggesting that inflammation plays a pivotal role in acute coronary syndromes^{4 5 6 7 8} and is an indirect sign of the increased production of interleukins from monocytes, macrophages, and endothelial cells. IL-6 and, to a lesser extent, IL-1, are in fact the major determinants for the liver production of acute-phase proteins via direct stimulation of the hepatocytes.^{9 10 11} IL-6 is also involved in a number of other processes, because it has proinflammatory^{9 10} and procoagulant¹² properties that may have a role in the pathophysiology of acute coronary syndromes. An alternative pathway for production of acute-phase proteins by the liver implies the generation of oxidized LDL, which may also be involved in the pathogenesis of acute coronary syndromes.¹³ It is also possible that the hepatic environment itself can modulate the anabolic response of the liver to this cytokine.⁹ The present study was undertaken to assess levels of IL-6 in unstable angina and to assess its relation to CRP and prognosis to achieve direct proof of the role that cytokines play in the pathogenesis of unstable angina. We reasoned that if IL-6 is involved directly in the mechanisms that lead to instability, it should be elevated in unstable angina and should be related to levels of CRP and therefore to prognosis.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Patient Population
Between March 1994 and March 1995, we studied 38 patients (31 men, 7 women) aged 61±9 years (range, 45 to 74 years) from a total of 162 patients admitted to our CCU with a diagnosis of unstable angina. The inclusion criteria were angina at rest with at least two ischemic episodes or one episode lasting >20 minutes during the preceding 24 hours, with diagnostic ST-segment shift and no evidence of myocardial infarction detected with the use of enzymatic techniques. The exclusion criteria were dilated cardiomyopathy, valvular heart disease, myocardial infarction within the previous 4 weeks, atrial fibrillation, the presence of any ECG abnormality invalidating ST-segment analysis, and major surgery or trauma within the previous month. All patients with known or suspected thrombotic disorders (other than unstable angina), malignancy, or inflammatory diseases were also excluded. All patients were treated with various combinations of aspirin, intravenous nitrates, intravenous heparin, calcium antagonists, and/or ß-blockers (Table). All admission samples were taken under aspirin cover. The mean time from the last ischemic episode to blood sampling was 12±8 hours. In 7 patients, additional samples were taken at 6, 24, 48, and 72 hours after admission for a serial evaluation of levels of IL-6 and CRP. We also studied 29 patients (24 men; mean age, 58±9 years old) with chronic stable effort angina of at least 6 months' duration and evidence of coronary artery disease at coronary angiography. The study was approved by the Ethics Committee of the Catholic University, and all patients gave their written informed consent.

View this table: [in this window] [in a new window]   Table 1. Demographic and Angiographic Characteristics of Patients With Stable or Unstable Angina

Design of the Study
Blood samples were taken as soon as possible after patients with unstable angina had been admitted to our CCU to assess serum levels of IL-6, CRP, and troponin T, which we measured to rule out the possible role of myocardial cell damage in inducing the inflammatory response. Patients were monitored continuously in the CCU, and all patients underwent coronary angiography. All patients with stable angina had a positive exercise stress test under therapy cover (see Table), and all underwent coronary angiography. We also evaluated the in-hospital outcome of the patients with unstable angina and considered the following events as a complicated in-hospital course: death, acute myocardial infarction, and refractory angina (ie, angina refractory to full medical therapy, including intravenous heparin) requiring urgent revascularization.

Laboratory Assays
IL-6 was measured by a commercially available assay (Quantikine human IL-6, R&D Systems). IL-6 measurements were performed in duplicate, and the interassay variability was <10%. The IL-6 ELISA gave a linear response in a range from 3 (low concentration) to 300 (high concentration) pg/mL.

CRP was assayed in an automated monoclonal antibody solid-phase sandwich enzyme immunoassay (Abbott Laboratories). Troponin T was measured by use of a commercially available enzyme immunoassay (Boehringer Mannheim).

Statistical Analysis
Because data were not distributed normally, nonparametric tests were used. Results are expressed as median and range. The Mann-Whitney U test was used to evaluate differences among groups. The Friedmann test was used to evaluate differences within the same group. Spearman's rank test was used for correlations, and discontinuous variables were tested by contingency ² test. A probability value of P<.05 was assumed to be significant.

	Results

Top Abstract Introduction Methods Results Discussion References

 
IL-6 levels, which were undetectable (ie, <3 pg/mL) in healthy volunteers in our laboratory, were detectable in 23 (61%) of 38 patients with unstable angina but in only 6 (21%) of 29 patients with stable angina (P<.01). Median levels of IL-6 were 5.25 pg/mL (range, 0 to 90 pg/dL) in patients with unstable angina and were below the detection limit (range, 0 to 7 pg/dL) in patients with stable angina (Fig 1; P<.005). No differences in the demographic and angiographic characteristics of stable and unstable angina patients were observed (Table). In patients with unstable angina, levels of CRP were elevated (ie, >3 mg/L) in 28 of 38 patients (and in 20 of 23 patients with detectable levels of IL-6), and a significant correlation was found between levels of IL-6 and CRP (r=.4, P=.013; Fig 2). The median level of CRP was 6.4 µg/L (range, 0.7 to 99 mg/L). Troponin T measured <0.1 mg/dL in all samples tested. We also evaluated the outcome of patients with unstable angina according to the entry levels of IL-6. Nineteen (83%) of 23 patients with detectable levels of IL-6 at entry had a complicated in-hospital course; myocardial infarction occurred in 3 patients (1 of whom died), and 16 patients had angina refractory to full medical therapy, requiring PTCA in 7 and CABG surgery in 9. Conversely, only 6 (40%) of 15 patients with undetectable levels of IL-6 had refractory angina; of these 6 patients, 3 required PTCA and the other 3 required CABG. No myocardial infarctions or deaths were observed in this group.

View larger version (12K): [in this window] [in a new window]   Figure 1. Levels of IL-6 (in picograms per milliliter) in patients with chronic stable angina (CSA) and in patients with unstable angina (UA). In CSA, levels of IL-6 were detectable in only 6 of 29 patients, and the median value was <3 pg/mL. Conversely, in UA patients, levels of IL-6 were detectable in 23 of 38 patients (P<.01 vs CSA), and the levels ranged from 0 to 90 pg/mL (median value, 5.25 pg/mL; P<.01 vs CSA).

View larger version (13K): [in this window] [in a new window]   Figure 2. Correlation between levels of IL-6 and CRP in patients with unstable angina (r=.4, P=.013 by Spearman's rank correlation test).

In the seven patients from whom we took serial samples of IL-6 and CRP, no differences were observed over time (P=.8), with IL-6 levels remaining within a narrow range, from undetectable to 10.4 pg/mL.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Our study demonstrates that elevated levels of IL-6 (1) are common in unstable angina, (2) are associated with prognosis, and (3) correlate with levels of CRP. Thus, our study suggests the importance of IL-6 in the pathophysiology of unstable angina and confirms the hypothetical assumption that in this syndrome, elevated levels of acute-phase proteins come from the cytokine-inflammatory pathway.^{10 11} The finding that IL-6 is detectable in 61% of patients with unstable angina (and, more specifically, in 83% of those having a complicated in-hospital course) in the absence of any rise in levels of creatine kinase and troponin T and is detectable in only 21% of patients with stable angina clearly supports our assumption that detectable levels of IL-6 are a typical feature of unstable angina and that they are not secondary to myocardial cell damage. Sturk et al¹⁴ and Neumann et al¹⁵ have described raised levels of IL-6 in acute myocardial infarction after necrosis or reperfusion. However, Neumann et al¹⁵ reported elevated levels of IL-6 on admission, before reperfusion by PTCA and before the appearance of detectable signs of necrosis, suggesting a possible primary role of IL-6 in the pathogenesis of the event. A very strict correlation between IL-6 and CRP has been reported by Sturk et al,¹⁴ and we have also observed a significant, although weak, correlation between IL-6 and CRP, with the majority (87%) of patients with detectable levels of IL-6 also having elevated levels of CRP. Although these studies confirm the occurrence of a cytokine response in acute coronary syndromes, they can be compared only partially with our work because the pathological events in acute myocardial infarction, including myocardial cell necrosis and reperfusion after prolonged coronary artery occlusion, are clearly different from those in unstable angina. In the present study, the dissociation between levels of IL-6 and CRP observed in some patients likely occurred because of the differences in their half-lives (4 hours for IL-6¹⁶ and 19 hours for CRP¹⁷ ) and because of the time lag (6 hours) in the hepatic synthesis of acute-phase proteins, although in these cases, roles for the hepatic environment⁹ and the stimulation of liver cells from oxidized LDL¹⁸ cannot be excluded.

IL-6 is induced by a variety of stimuli, including interferon-,¹⁹ tumor necrosis factor,^{19 20} IL-1,²⁰ platelet-derived growth factor,²¹ viruses,²² and bacterial endotoxin.²³ In turn, IL-6 has proinflammatory properties, with stimulatory effects on T and B lymphocytes,¹⁰ and it induces the synthesis of acute-phase proteins such as CRP and fibrinogen.⁹ Intriguingly, procoagulant properties for IL-6 have also been demonstrated.¹² Apart from the importance of the activation of the coagulation system,²⁴ lymphocyte activation⁵ and raised levels of acute-phase proteins³ have also been proposed as important factors in the pathogenesis of unstable angina.

Conclusions
Our study demonstrates that raised levels of IL-6 are common in unstable angina and are associated with prognosis, thus confirming the importance of the cytokine pathway for the production by the liver of acute-phase proteins and strengthening previous observations on the importance of inflammation in this syndrome.^{3 4 5 6 7 8} However, it cannot answer questions such as the following: Is IL-6 the only determinant of plasma levels of CRP? Is the inflammatory response observed in unstable angina a primary component of the disease? What is the cause of raised levels of IL-6, and is it localized in the coronary tree or is it systemic? Further studies are required to elucidate better the role of interleukins in unstable angina.

	Selected Abbreviations and Acronyms

 

CABG = coronary artery bypass graft CCU = coronary care unit CRP = C-reactive protein IL = interleukin PTCA = percutaneous transluminal coronary angioplasty

	Acknowledgments

 
This study was supported in part by the National Research Council, targeted project "Prevention and Control Disease Factors," Rome, Italy (research grant 94,00518,PF41), and in part by the European Community (Biomed 2 research grant PL951505). We are indebted to Prof Mark B. Pepys and to Ruth Gallimore for the CRP measurements, to the nurses of the CCU at Policlinico Gemelli for their assistance, and to Vanessa Perrin for her assistance in the preparation of the manuscript.

Received May 28, 1996; revision received June 26, 1996; accepted July 2, 1996.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Pepys MB, Baltz ML. Acute phase proteins with special reference to C-reactive protein and related proteins (pentaxins) and serum amyloid A protein. Adv Immunol.. 1983;34:141-212.[Medline] [Order article via Infotrieve]
   
2. Berk BC, Weintraub WS, Alexander RW. Elevation of C-reactive protein in `active' coronary artery disease. Am J Cardiol.. 1990;65:168-172.[Medline] [Order article via Infotrieve]
   
3. Liuzzo G, Biasucci LM, Gallimore R, Grillo RL, Rebuzzi AG, Pepys MB, Maseri A. The prognostic value of C-reactive protein and serum amyloid A protein in severe unstable angina. N Engl J Med.. 1994;331:417-424.[Abstract/Free Full Text]
   
4. van der Wal A, 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.[Abstract/Free Full Text]
   
5. Neri Serneri GG, Abbate R, Gori AM, Attanasio M, Martini F, Giusti B, Dabizzi P, Poggesi L, Modesti PA, Trotta F, Rostagno C, Boddi M, Gensini GF. Transient intermittent lymphocyte activation is responsible for the instability of angina. Circulation. 1992;86:790-797.[Abstract/Free Full Text]
   
6. Moreno PR, Falk E, Palacios IF, Newell JB, Fuster V, Fallon JT. Macrophage infiltration in acute coronary syndromes: implication for plaque rupture. Circulation.. 1994;90:775-778.[Abstract/Free Full Text]
   
7. Mehta J, Dinerman J, Mehta P, Saldeen T, Lawson D, Donnelly W, Wallin R. Neutrophil function in ischemic heart disease. Circulation.. 1989;79:549-556.[Abstract/Free Full Text]
   
8. Buja LM, Willerson JT. Role of inflammation in coronary plaque disruption. Circulation.. 1994;89:503-505. Editorial.[Free Full Text]
   
9. Baumann H, Gauldie J. Regulation of hepatic acute phase plasma protein genes by hepatocyte stimulating factors and other mediators of inflammation. Mol Biol Med.. 1990;7:147-159.[Medline] [Order article via Infotrieve]
   
10. Le J, Vilcek J. Interleukin 6: a multifunctional cytokine regulating immune reactions and the acute phase protein sequence. Lab Invest.. 1989;61:588-602.[Medline] [Order article via Infotrieve]
    
11. Morrone G, Ciliberto G, Oliviero S, Arcore R, Dente L, Content J, Cortese R. Recombinant interleukin 6 regulates the transcriptional activation of a set of human acute phase genes. J Biol Chem.. 1988;263:12554-12558.[Abstract/Free Full Text]
    
12. van der Poll T, Levi M, Hack CE, ten Cate U, van Deventer SJH, Eerenberg AJM, de Groot ER, Jansen J, Gallati H, Buller HR, ten Cate JW, Aarden LA. Elimination of interleukin 6 attenuates coagulation activation in experimental endotoxemia in chimpanzees. J Exp Med.. 1994;179:1253-1259.[Abstract/Free Full Text]
    
13. Maggi E, Perani G, Falashi F, Frattoni A, Martignoni A, Finardi G, Stefano PL, Simeone F, Paolini G, De Vecchi E, Bellomo G. Autoanticorps contre les lipoproteines de basse densite oxydees chez des patients coronariens. Presse Med.. 1994;23:1158-1162.
    
14. Sturk A, Hack CE, Aarden LA, Mieke B, Koster RRW, Sanders GTB. Interleukin-6 release and the acute-phase reaction in patients with acute myocardial infarction: a pilot study. J Lab Clin Med.. 1992;119:574-579.[Medline] [Order article via Infotrieve]
    
15. Neumann FJ, Ott I, Gawaz M, Richardt G, Holzapfel H, Jochum M, Schomig A. Cardiac release of cytokines and inflammatory responses in acute myocardial infarction. Circulation.. 1995;92:748-755.[Abstract/Free Full Text]
    
16. Mestries JC, Kruithof EKO, Gascon MP, Herodin F, Agay D, Ythier A. In vivo modulation of coagulation and fibrinolysis by recombinant glycosylated human interleukin-6 in baboons. Eur Cytokine Netw.. 1994;5:275-281.[Medline] [Order article via Infotrieve]
    
17. Vigushin DM, Pepys MB, Hawkins PN. Metabolic and scintigraphic studies of radioiodinated human C-reactive protein in health and disease. J Clin Invest.. 1993;91:1351-1357.
    
18. Liao F, Andalibi A, de Beer FC, Fogelman AM, Lusis AJ. Genetic control of inflammatory gene induction and NF-kappa B-like transcription factor activation in response to an atherogenic diet in mice. J Clin Invest.. 1993;91:2572-2579.
    
19. Sanceau J, Kaisho T, Hirano T, Wietzerbin J. Triggering of the human interleukin-6 gene by interferon- and tumor necrosis factor- in monocytic cells involves cooperation between interferon regulatory factor-1, NFB, and SP1 transcription factors. J Biol Chem.. 1995;270:27920-27931.[Abstract/Free Full Text]
    
20. Ng SB, Tan YH, Guy GR. Differential induction of the interleukin-6 gene by tumor necrosis factor and interleukin-1. J Biol Chem.. 1994;269:19021-19027.[Abstract/Free Full Text]
    
21. Franchimont N, Canalis E. Platelet derived growth factor stimulates the synthesis of interleukin-6 in cells of the osteoblast lineage. Endocrinology.. 1995;136:5469-5475.[Abstract]
    
22. Tanner JE, Alfieri C, Chatila TA, Diaz-Mitoma F. Induction of interleukin-6 after stimulation of human B-cell CD21 by Epstein-Barr virus glycoproteins gp350 and gp220. J Virol.. 1996;70:570-575.[Abstract]
    
23. Neilly PJD, Gardiner KR, Kirk SJ, Jeggings G, Anderson NH, Elia M, Rowlands BJ. Endotoxemia and cytokine production in experimental colitis. Br J Surg.. 1995;82:1479-1482.[Medline] [Order article via Infotrieve]
    
24. Fuster V, Badimon L, Badimon J, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med.. 1992;326:310-318.[Medline] [Order article via Infotrieve]
    

This article has been cited by other articles:

				A. J. P. Smith, F. D'Aiuto, J. Palmen, J. A. Cooper, J. Samuel, S. Thompson, J. Sanders, N. Donos, L. Nibali, D. Brull, et al. Association of Serum Interleukin-6 Concentration with a Functional IL6 -6331T>C Polymorphism Clin. Chem., May 1, 2008; 54(5): 841 - 850. [Abstract] [Full Text] [PDF]

				H. Loppnow, K. Werdan, and M. Buerke Invited review: Vascular cells contribute to atherosclerosis by cytokine- and innate-immunity-related inflammatory mechanisms Innate Immunity, April 1, 2008; 14(2): 63 - 87. [Abstract] [PDF]

				L. Dubey, H.-S. Zeng, H.-J. Wang, and R.-Y. Liu Potential Role of Adipocytokine Leptin in Acute Coronary Syndrome Asian Cardiovasc Thorac Ann, April 1, 2008; 16(2): 124 - 128. [Abstract] [Full Text] [PDF]

				A. F. Pasini, M. Anselmi, U. Garbin, E. Franchi, C. Stranieri, M.C. Nava, V. Boccioletti, C. Vassanelli, and L. Cominacini Enhanced Levels of Oxidized Low-Density Lipoprotein Prime Monocytes to Cytokine Overproduction via Upregulation of CD14 and Toll-Like Receptor 4 in Unstable Angina Arterioscler. Thromb. Vasc. Biol., September 1, 2007; 27(9): 1991 - 1997. [Abstract] [Full Text] [PDF]

				J. L. Anderson, C. D. Adams, E. M. Antman, C. R. Bridges, R. M. Califf, D. E. Casey Jr, W. E. Chavey II, F. M. Fesmire, J. S. Hochman, T. N. Levin, et al. ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) Developed in Collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine J. Am. Coll. Cardiol., August 14, 2007; 50(7): e1 - e157. [Full Text] [PDF]

				C.-M. Yu, Q. Zhang, L. Lam, H. Lin, S.-L. Kong, W. Chan, J. W.-H. Fung, K. K K Cheng, I. H.-S. Chan, S. W.-L. Lee, et al. Comparison of intensive and low-dose atorvastatin therapy in the reduction of carotid intimal-medial thickness in patients with coronary heart disease Heart, August 1, 2007; 93(8): 933 - 939. [Abstract] [Full Text] [PDF]

				G. Salinas, U. C. Rangasetty, B. F. Uretsky, and Y. Birnbaum The Cycloxygenase 2 (COX-2) Story: It's Time to Explain, Not Inflame Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2007; 12(2): 98 - 111. [Abstract] [PDF]

				NACB WRITING GROUP MEMBERS, D. A. Morrow, C. P. Cannon, R. L. Jesse, L. K. Newby, J. Ravkilde, A. B. Storrow, A. H.B. Wu, and R. H. Christenson National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Clinical Characteristics and Utilization of Biochemical Markers in Acute Coronary Syndromes Circulation, April 3, 2007; 115(13): e356 - e375. [Full Text] [PDF]

				NACB WRITING GROUP MEMBERS, D. A. Morrow, C. P. Cannon, R. L. Jesse, L. K. Newby, J. Ravkilde, A. B. Storrow, A. H.B. Wu, R. H. Christenson, NACB COMMITTEE MEMBERS, et al. National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Clinical Characteristics and Utilization of Biochemical Markers in Acute Coronary Syndromes Clin. Chem., April 1, 2007; 53(4): 552 - 574. [Full Text] [PDF]

				R. Mehra, A. Storfer-Isser, H. L. Kirchner, N. Johnson, N. Jenny, R. P. Tracy, and S. Redline Soluble interleukin 6 receptor: a novel marker of moderate to severe sleep-related breathing disorder. Arch Intern Med, September 18, 2006; 166(16): 1725 - 1731. [Abstract] [Full Text] [PDF]

				M. Suzuki, M. Saito, T. Nagai, H. Saeki, and Y. Kazatani Systemic Versus Coronary Levels of Inflammation in Acute Coronary Syndromes Angiology, August 1, 2006; 57(4): 459 - 463. [Abstract] [PDF]

				S. Blankenberg, M. J. McQueen, M. Smieja, J. Pogue, C. Balion, E. Lonn, H. J. Rupprecht, C. Bickel, L. Tiret, F. Cambien, et al. Comparative Impact of Multiple Biomarkers and N-Terminal Pro-Brain Natriuretic Peptide in the Context of Conventional Risk Factors for the Prediction of Recurrent Cardiovascular Events in the Heart Outcomes Prevention Evaluation (HOPE) Study Circulation, July 18, 2006; 114(3): 201 - 208. [Abstract] [Full Text] [PDF]

				M. Sander, C. von Heymann, V. v. Dossow, C. Spaethe, W. F. Konertz, U. Jain, and C. D. Spies Increased interleukin-6 after cardiac surgery predicts infection. Anesth. Analg., June 1, 2006; 102(6): 1623 - 1629. [Abstract] [Full Text] [PDF]

				V. Rizzello, G. Liuzzo, S. Brugaletta, A. Rebuzzi, L. M. Biasucci, and F. Crea Modulation of CD4+CD28null T Lymphocytes by Tumor Necrosis Factor-{alpha} Blockade in Patients With Unstable Angina Circulation, May 16, 2006; 113(19): 2272 - 2277. [Abstract] [Full Text] [PDF]

				A. Ziakas, S. Gavrilidis, G. Giannoglou, E. Souliou, K. Gemitzis, D. Kalampalika, M. A. Vayona, I. Pidonia, G. Parharidis, and G. Louridas In-Hospital and Long-Term Prognostic Value of Fibrinogen, CRP, and IL-6 Levels in Patients with Acute Myocardial Infarction Treated with Thrombolysis Angiology, May 1, 2006; 57(3): 283 - 293. [Abstract] [PDF]

				A. Tedgui and Z. Mallat Cytokines in Atherosclerosis: Pathogenic and Regulatory Pathways Physiol Rev, April 1, 2006; 86(2): 515 - 581. [Abstract] [Full Text] [PDF]

				A. Koster, H. Bosma, B. W. J. H. Penninx, A. B. Newman, T. B. Harris, J. Th. M. van Eijk, G. I. J. M. Kempen, E. M. Simonsick, K. C. Johnson, R. N. Rooks, et al. Association of inflammatory markers with socioeconomic status. J. Gerontol. A Biol. Sci. Med. Sci., March 1, 2006; 61(3): 284 - 290. [Abstract] [Full Text] [PDF]

				E. J. Armstrong, D. A. Morrow, and M. S. Sabatine Inflammatory Biomarkers in Acute Coronary Syndromes: Part I: Introduction and Cytokines Circulation, February 14, 2006; 113(6): e72 - e75. [Full Text] [PDF]

				M Libra, S S Signorelli, Y Bevelacqua, P M Navolanic, V Bevelacqua, J Polesel, R Talamini, F Stivala, M C Mazzarino, and G Malaponte Analysis of G(-174)C IL-6 polymorphism and plasma concentrations of inflammatory markers in patients with type 2 diabetes and peripheral arterial disease J. Clin. Pathol., February 1, 2006; 59(2): 211 - 215. [Abstract] [Full Text] [PDF]

				M. P.S. Sie, F. A. Sayed-Tabatabaei, H.-H. S. Oei, A. G. Uitterlinden, H. A.P. Pols, A. Hofman, C. M. van Duijn, and J. C.M. Witteman Interleukin 6 -174 G/C Promoter Polymorphism and Risk of Coronary Heart Disease: Results from the Rotterdam Study and a Meta-Analysis Arterioscler. Thromb. Vasc. Biol., January 1, 2006; 26(1): 212 - 217. [Abstract] [Full Text] [PDF]

				I. Ikonomidis, G. Athanassopoulos, J. Lekakis, K. Venetsanou, M. Marinou, K. Stamatelopoulos, D. V. Cokkinos, and P. Nihoyannopoulos Myocardial Ischemia Induces Interleukin-6 and Tissue Factor Production in Patients With Coronary Artery Disease: A Dobutamine Stress Echocardiography Study Circulation, November 22, 2005; 112(21): 3272 - 3279. [Abstract] [Full Text] [PDF]

				J. Y. King, R. Ferrara, R. Tabibiazar, J. M. Spin, M. M. Chen, A. Kuchinsky, A. Vailaya, R. Kincaid, A. Tsalenko, D. X.-F. Deng, et al. Pathway analysis of coronary atherosclerosis Physiol Genomics, September 21, 2005; 23(1): 103 - 118. [Abstract] [Full Text] [PDF]

				C. Antoniades, D. Tousoulis, C. Vasiliadou, C. Pitsavos, C. Chrysochoou, D. Panagiotakos, C. Tentolouris, K. Marinou, N. Koumallos, and C. Stefanadis Genetic Polymorphism on Endothelial Nitric Oxide Synthase Affects Endothelial Activation and Inflammatory Response During the Acute Phase of Myocardial Infarction J. Am. Coll. Cardiol., September 20, 2005; 46(6): 1101 - 1109. [Abstract] [Full Text] [PDF]

				N. Werner, S. Kosiol, T. Schiegl, P. Ahlers, K. Walenta, A. Link, M. Bohm, and G. Nickenig Circulating Endothelial Progenitor Cells and Cardiovascular Outcomes N. Engl. J. Med., September 8, 2005; 353(10): 999 - 1007. [Abstract] [Full Text] [PDF]

				G Liuzzo, G Giubilato, and M Pinnelli T cells and cytokines in atherogenesis Lupus, September 1, 2005; 14(9): 732 - 735. [Abstract] [PDF]

				L M Biasucci, G Giubilato, F Graziani, and M Piro CRP is or is not a reliable marker of ischaemic heart disease? Lupus, September 1, 2005; 14(9): 752 - 755. [Abstract] [PDF]

				A. Zampetaki, Z. Zhang, Y. Hu, and Q. Xu Biomechanical stress induces IL-6 expression in smooth muscle cells via Ras/Rac1-p38 MAPK-NF-{kappa}B signaling pathways Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2946 - H2954. [Abstract] [Full Text] [PDF]

				G. K. Hansson Inflammation, Atherosclerosis, and Coronary Artery Disease N. Engl. J. Med., April 21, 2005; 352(16): 1685 - 1695. [Full Text] [PDF]

				M. Weger, I. Steinbrugger, A. Haas, W. Marz, Y. El-Shabrawi, W. Weger, O. Schmut, and W. Renner Role of the Interleukin-6 -174 G>C Gene Polymorphism in Retinal Artery Occlusion Stroke, February 1, 2005; 36(2): 249 - 252. [Abstract] [Full Text] [PDF]

				C. Monaco, E. Rossi, D. Milazzo, F. Citterio, F. Ginnetti, G. D'Onofrio, D. Cianflone, F. Crea, L. M. Biasucci, and A. Maseri Persistent systemic inflammation in unstable angina is largely unrelated to the atherothrombotic burden J. Am. Coll. Cardiol., January 18, 2005; 45(2): 238 - 243. [Abstract] [Full Text] [PDF]

				M. S. Sabatine and E. Braunwald Another look at the age-old question: Which came first, the elevated c-reactive protein or the atherothrombosis? J. Am. Coll. Cardiol., January 18, 2005; 45(2): 244 - 245. [Full Text] [PDF]

				L. M. Biasucci CDC/AHA Workshop on Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: Clinical Use of Inflammatory Markers in Patients With Cardiovascular Diseases: A Background Paper Circulation, December 21, 2004; 110(25): e560 - e567. [Abstract] [Full Text] [PDF]

				B. Schieffer, T. Selle, A. Hilfiker, D. Hilfiker-Kleiner, K. Grote, U. J.F. Tietge, C. Trautwein, M. Luchtefeld, C. Schmittkamp, S. Heeneman, et al. Impact of Interleukin-6 on Plaque Development and Morphology in Experimental Atherosclerosis Circulation, November 30, 2004; 110(22): 3493 - 3500. [Abstract] [Full Text] [PDF]

				B. Schieffer, C. Bunte, J. Witte, K. Hoeper, R. H. Boger, E. Schwedhelm, and H. Drexler Comparative effects of AT1-antagonism and angiotensin-converting enzyme inhibition on markers of inflammation and platelet aggregation in patients with coronary artery disease J. Am. Coll. Cardiol., July 21, 2004; 44(2): 362 - 368. [Abstract] [Full Text] [PDF]

				C. Smith, A. Yndestad, B. Halvorsen, T. Ueland, T. Waehre, K. Otterdal, H. Scholz, K. Endresen, L. Gullestad, S. S. Froland, et al. Potential anti-inflammatory role of activin A in acute coronary syndromes J. Am. Coll. Cardiol., July 21, 2004; 44(2): 369 - 375. [Abstract] [Full Text] [PDF]