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Subacute Inflammatory Activation in Subjects with Acute Coronary Syndrome and Left Ventricular Dysfunction

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Abstract

Several lines of evidence indicate that increased inflammatory cytokine levels can be used for risk prediction in patients with acute coronary syndrome (ACS). This study therefore aimed to evaluate correlations between levels of soluble interleukin (IL)-2 receptor (sIL-2r), IL-6, and IL-8 and in-hospital incidence of acute heart failure (AHF) and left ventricular (LV) systolic dysfunction in the subacute phase of ACS. In 48 consecutive patients with ACS, circulating levels of sIL-2r, IL-6, and IL-8 were ascertained 72–96 h after onset of symptoms. Clinical data, LV function, and in-hospital incidence of AHF were also evaluated. IL-8 levels were significantly higher in patients with pulmonary edema (1,829 ± 2,496 vs 456 ± 624 pg/ml, p < 0.05); sIL-2r, IL-6, and IL-8 levels were increased proportionally to Killip class (r = 0.35, p < 0.05; r = 0.48, r = 0.47, p < 0.01) and in patients with LV ejection fraction (LVEF) < 30%. Levels of sIL-2r were inversely related to LVEF in subjects with acute myocardial infarction (r = −0.51, p < 0.05). Soluble IL-2r and IL-8 levels were related to mitral regurgitation severity (r = 0.34, p < 0.05; r = 0.37, p < 0.05). Levels of sIL-2 were proportional to LV end-diastolic diameter (r = 0.49, p < 0.001) and LV end-systolic diameter (r = 0.58, p < 0.001). Number of cytokines with circulating values above upper level of normal was significantly correlated with Killip class and LVEF (r = 0.40, r = −0.38, p < 0.05). sIL-2r, IL-6, and IL-8 are increased in patients with ACS and systolic dysfunction or AHF. These data suggest that inflammatory cytokine activity detectable in peripheral blood may be useful in identifying subjects with a worse clinical course.

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REFERENCES

  1. Biasucci, L.M., A. Vitelli, G. Liuzzo, S. Altamura, G. Caligiuri, C. Monaco, A.G. Rebuzzi, G. Ciliberto, and A. Maseri. 1996. Elevated levels of IL-6 in unstable angina. Circulation 94: 874–877.

    PubMed  CAS  Google Scholar 

  2. Manten, A., R.J. de Winter, M.C. Minnema, H. ten Cate, J.G. Lijmer, R. Adams, R.J. Peters, and S.J. van Deventer. 1998. Procoagulant and proinflammatory activity in acute coronary syndromes. Cardiovascular Research 40: 389–395.

    Article  PubMed  CAS  Google Scholar 

  3. Biasucci, L.M., G. Liuzzo, A. Fantuzzi, G. Caligiuri, A.G. Rebuzzi, F. Ginetti, C.A. Dinarello, and A. Maseri. 1999. Increasing levels of interleukin (IL)-1Ra and IL-6 during the first two days of hospitalization in unstable angina are associated with increased risk of in-hospital coronary events. Circulation 99: 2079–2084.

    PubMed  CAS  Google Scholar 

  4. Simon, A.D., S. Yazdani, W. Wang, A. Schwartz, and L.E. Rabbani. 2000. Circulating levels of IL-1beta, a prothrombotic cytokine, are elevated in unstable angina versus stable angina. Journal of Thrombosis and Thrombolysis 9: 217–222.

    Article  PubMed  CAS  Google Scholar 

  5. Packer, M. 1992. Pathophysiology of chronic heart failure. Lancet 340: 88–92.

    Article  PubMed  CAS  Google Scholar 

  6. Sato, Y., Y. Takatsu, K. Kataoka, et al. 1999. Serial circulating concentrations of C-reactive protein, interleukin (IL)-4, and IL-6 in patients with acute left heart decompensation. Clinical Cardiology 22: 811–813.

    Article  PubMed  CAS  Google Scholar 

  7. Puhakka, M., J. Magga, S. Hietakorpi, I. Penttilä, P. Uusimaa, J. Risteli, and K. Peuhkurinen. 2003. Interleukin-6 and tumor necrosis factor alpha in relation to myocardial infarct size and collagen formation. Journal of Cardiac Failure 9: 325–332.

    Article  PubMed  CAS  Google Scholar 

  8. Brunetti, N.D., R. Troccoli, M. Correale, P.L. Pellegrino, and M. Di Biase. 2006. C-reactive protein in patients with acute coronary syndrome: Correlation with diagnosis, myocardial damage, ejection fraction and angiographic findings. International Journal of Cardiology 109: 248–256.

    Article  PubMed  Google Scholar 

  9. Thaik, C.M., A. Calderone, N. Takahashi, and W.S. Colucci. 1995. Interleukin-1b modulates the growth and phenotype of neonatal rat cardiac myocytes. Journal of Clinical Investigation 96: 1093–1099.

    Article  PubMed  CAS  Google Scholar 

  10. Kubota, T., C.F. McTiernan, C.S. Frye, S.E. Slawson, B.H. Lemster, A.P. Koretsky, A.J. Demetris, and A.M. Feldman. 1997. Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-alpha. Circulation Research 81: 627–635.

    PubMed  CAS  Google Scholar 

  11. Seta, Y., K. Shan, B. Bozkurt, H. Oral, and D.L. Mann. 1996. Basic mechanisms in heart failure: The cytokine hypothesis. Journal of Cardiac Failure 2: 243–249.

    Article  PubMed  CAS  Google Scholar 

  12. van Deventer, S.J., H.R. Büller, J.W. ten Cate, L.A. Aarden, C.E. Hack, and A. Sturk. 1990. Experimental endotoxemia in humans: Analysis of cytokine release and coagulation, fibrinolytic and complement pathways. Blood 76: 2520–2526.

    PubMed  Google Scholar 

  13. Ng, S.B., Y.N. Tan, and G.R. Guy. 1994. Differential induction of the interleukin-6 gene by tumor necrosis factor and interleukin-1. The Journal of Biological Chemistry 269: 19021–19027.

    PubMed  CAS  Google Scholar 

  14. Sanceau, J., T. Kaisho, T. Hirano, and J. Wietzerbin. 1995. Triggering of the human interleukin-6 gene by interferon-gamma and tumor necrosis factor-alpha in monocyte cells involves cooperation between interferon regulatory factor-1, NFkB, and SP1 transcription factors. The Journal of Biological Chemistry 270: 27920–27931.

    Article  PubMed  CAS  Google Scholar 

  15. Baumann, H., and J. Gauldie. 1990. Regulation of hepatic acute phase plasma protein genes by hepatocyte stimulating factors and other mediators of inflammation. Molecular Biology & Medicine 7: 147–159.

    CAS  Google Scholar 

  16. Heinrich, P.C., J.V. Castell, and T. Andus. 1990. Interleukin-6 and the acute phase response. The Biochemical Journal 265: 621–636.

    PubMed  CAS  Google Scholar 

  17. Tsutamoto, T., T. Hisanaga, A. Wada, K. Maeda, M. Ohnishi, D. Fukai, N. Mabuchi, M. Sawaki, and M. Kinoshita. 1998. Interleukin-6 spillover in the peripheral circulation increases with the severity of heart failure, and the high plasma level of interleukin-6 is an important prognostic predictor in patients with congestive heart failure. Journal of the American College of Cardiology 31: 391–398.

    Article  PubMed  CAS  Google Scholar 

  18. Testa, M., M. Yeh, P. Lee, R. Fanelli, F. Loperfido, J.W. Berman, and T.H. Le Jemtel. 1996. Circulating levels of cytokines and their endogenous modulators in patients with mild to severe congestive heart failure due to coronary artery disease or hypertension. Journal of the American College of Cardiology 28: 964–971.

    Article  PubMed  CAS  Google Scholar 

  19. Torre-Amione, G., S. Kapadia, C. Benedict, H. Oral, J.B. Young, and D.L. Mann. 1996. Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: A report from the studies of left ventricular dysfunction (SOLVD). Journal of the American College of Cardiology 27: 1201–1206.

    Article  PubMed  CAS  Google Scholar 

  20. Mohler 3rd, E.R., L.C. Sorensen, J.K. Ghali, D.D. Schocken, P.W. Willis, J.A. Bowers, A.B. Cropp, and M.L. Pressler. 1997. Role of cytokines in the mechanism of action of amlodipine: the PRAISE Heart Failure Trial: Prospective Randomized Amlodipine Survival Evaluation. Journal of the American College of Cardiology 30: 35–41.

    Article  PubMed  CAS  Google Scholar 

  21. Deswal, A., N.J. Petersen, A.M. Feldman, B.G. White, and D.L. Mann. 2001. Cytokines and cytokine receptors in advanced heart failure: an analysis of the cytokine database from the Vesnarinone trial (VEST). Circulation 103: 2055–2059.

    PubMed  CAS  Google Scholar 

  22. Sugishita, K., K. Kinugawa, T. Shimizu, K. Harada, H. Matsui, T. Takahashi, T. Serizawa, and O. Kohmoto. 1999. Cellular basis for the acute inhibitory effects of IL-6 and TNF on excitation–contraction coupling. Journal of Molecular and Cellular Cardiology 31: 1457–1467.

    Article  PubMed  CAS  Google Scholar 

  23. Suzuki, H., R. Sato, T. Sato, M. Shoji, Y. Iso, T. Kondo, M. Shibata, S. Koba, and T. Katagiri. 2005. Time-course of changes in the levels of interleukin 6 in acutely decompensated heart failure. International Journal of Cardiology 100: 415–420.

    Article  PubMed  Google Scholar 

  24. Chin, B.S., D.S. Conway, N.A. Chung, A.D. Blann, C.R. Gibbs, and G.Y. Lip. 2003. Interleukin-6, tissue factor and von Willebrand factor in acute decompensated heart failure: Relationship to treatment and prognosis. Blood Coagulation & Fibrinolysis 14: 515–521.

    Article  CAS  Google Scholar 

  25. Damås, J.K., H.G. Eiken, E. Oie, V. Bjerkeli, A. Yndestad, T. Ueland, T. Tonnessen, O.R. Geiran, H. Aass, S. Simonsen, G. Christensen, S.S. Froland, H. Attramadal, L. Gullestad, and P. Aukrust. 2000. Myocardial expression of CC and CXC-chemokines and their receptors in human end-stage heart failure. Cardiovascular Research 47: 778–787.

    Article  PubMed  Google Scholar 

  26. Xu, L., D.J. Kelvin, G.O. Ye, D.D. Taub, A. Ben-Baruch, J.J. Oppenheim, and J.M. Wang. 1995. Modulation of IL-8 receptor expression on purified human lymphocytes is associated with changed chemotactic responses to IL-8. Journal of Leukocyte Biology 57: 335–342.

    PubMed  CAS  Google Scholar 

  27. Gerszten, R.E., E.A. Garcia-Zepeda, Y.C. Lim, M. Yoshida, H.A. Ding, M.A. Gimbrone Jr., A.D. Luster, F.W. Luscinskas, and A. Rosenzweig. 1999. MCP-1 and IL-8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions. Nature 398: 718–723.

    Article  PubMed  CAS  Google Scholar 

  28. Yue, T.L., X. Wang, C.P. Sung, B. Olson, P.J. McKenna, J.L. Gu, and G.Z. Feuerstein. 1994. Interleukin-8. A mitogen and chemoattractant for vascular smooth muscle cells. Circulation Research 75: 1–7.

    PubMed  CAS  Google Scholar 

  29. Moreau, M., I. Brocheriou, L. Petit, E. Ninio, M.J. Chapman, and M. Rouis. 1999. IL-8 mediates down-regulation of tissue inhibitor of metalloproteinase-1 expression in cholesterol-loaded human macrophages: Relevance to stability of atherosclerotic plaque. Circulation 99: 420–426.

    PubMed  CAS  Google Scholar 

  30. Purushothaman, K.R., V. Fuster, W.N. O’Connor, and P.R. Moreno. 2003. Neovascularization is the most powerful independent predictor for progression to disruption in high risk atherosclerotic plaques. Journal of the American College of Cardiology 41: 352–353.

    Article  Google Scholar 

  31. Moreno, P.R., K.R. Purushothaman, V. Fuster, D. Echeverri, H. Truszczynska, S.K. Sharma, J.J. Badimon, and W.N. O’Connor. 2004. Plaque neovascularization is increased in ruptured atherosclerotic lesions of human aorta. Implications for plaque vulnerability. Circulation 110: 2032–2038.

    Article  PubMed  Google Scholar 

  32. Virmani, R., F.D. Kolodgie, A.P. Burke, A.V. Finn, H.K. Gold, T.N. Tulenko, S.P. Wrenn, and J. Narula. 2005. Atherosclerotic plaque progression and vulnerability to rupture: Angiogenesis as a source of intraplaque hemorrhage. Arteriosclerosis, Thrombosis, and Vascular Biology 25: 2054–2061.

    Article  PubMed  CAS  Google Scholar 

  33. Johnson, K., L.A. Aarden, Y. Choi, E. De Groot, and A. Creasey. 1996. The proinflammatory cytokine response to coagulation and endotoxin in whole blood. Blood 12: 5051–5060.

    Google Scholar 

  34. Aukrust, P., T. Ueland, F. Müller, A.K. Andreassen, I. Nordøy, H. Aas, J. Kjekshus, S. Simonsen, S.S. Frøland, and L. Gullestad. 1998. Elevated circulating levels of CC chemokines in patients with congestive heart failure. Circulation 97: 1136–1143.

    PubMed  CAS  Google Scholar 

  35. Damås, J.K., L. Gullestad, T. Ueland, N.O. Solum, S. Simonsen, S.S. Frøland, and P. Aukrust. 2000. CXC-chemokines, a new group of cytokines in congestive heart failure—possible role of platelets and monocytes. Cardiovascular Research 45: 428–436.

    Article  PubMed  Google Scholar 

  36. Damås, J.K., L. Gullestad, H. Aass, S. Simonsen, J.G. Fjeld, L. Wikeby, T. Ueland, H.G. Eiken, S.S. Frøland, and P. Aukrust. 2001. Enhanced gene expression of chemokines and their corresponding receptors in mononuclear blood cells in chronic heart failure—modulatory effect of intravenous immunoglobulin. Journal of the American College of Cardiology 38: 187–193.

    Article  PubMed  Google Scholar 

  37. Limas, C.J., I.F. Goldenberg, and C. Limas. 1995. Soluble interleukin 2 receptor levels in patients with dilated cardiomyopathy. Correlation with disease severity and cardiac autoantibodies. Circulation 91: 631–634.

    PubMed  CAS  Google Scholar 

  38. Young, J.B., N.T. Windsor, F.W. Smart, N.S. Kleiman, D.G. Weilbaecher, G.P. Noon, D.L. Nelson, and E.C. Lawrence. 1991. Inability of isolated soluble interleukin-2 receptor levels to predict biopsy rejection scores after heart transplantation. Transplantation 51: 636–641.

    Article  PubMed  CAS  Google Scholar 

  39. Romagnani, S. 1994. Lymphokine production by human T cells in disease states. Annual Review of Immunology 12: 227–257.

    Article  PubMed  CAS  Google Scholar 

  40. Ferrari, R., T. Bachetti, R. Confortini, C. Opasich, O. Febo, A. Corti, G. Cassani, and O. Visioli. 1995. Tumor necrosis factor soluble receptors in patients with various degrees of chronic heart failure. Circulation 92: 1479–1486.

    PubMed  CAS  Google Scholar 

  41. Kelly, R.A., and T.W. Smith. 1997. Cytokines and cardiac contractile function. Circulation 95: 778–781.

    PubMed  CAS  Google Scholar 

  42. de Belder, A.J., M.W. Radomski, H.J. Why, P.J. Richardson, C.A. Bucknall, E. Salas, J.F. Martin, and S. Moncada. 1993. Nitric oxide synthase activities in human myocardium. Lancet 341: 84–85.

    Article  PubMed  Google Scholar 

  43. Haywood, G.A., P.S. Tsao, H.E. von der Leyen, M.J. Mann, P.J. Keeling, P.T. Trindade, N.P. Lewis, C.D. Byrne, P.R. Rickenbacher, N.H. Bishopric, J.P. Cooke, W.J. McKenna, and M.B. Fowler. 1996. Expression of inducible nitric oxide synthase in human heart failure. Circulation 93: 1087–1094.

    PubMed  CAS  Google Scholar 

  44. Narula, J., N. Haider, R. Virmani, T.G. DiSalvo, F.D. Kolodgie, R.J. Hajjar, U. Schmidt, M.J. Semigran, G.W. Dec, and B.A. Khaw. 1996. Apoptosis in myocytes in end-stage heart failure. The New England Journal of Medicine 335: 1182–1189.

    Article  PubMed  CAS  Google Scholar 

  45. Olivetti, G., R. Abbi, F. Quaini, J. Kajstura, W. Cheng, J.A. Nitahara, E. Quaini, C. Di Loreto, C.A. Beltrami, S. Krajewski, J.C. Reed, and P. Anversa. 1997. Apoptosis in the failing human heart. The New England Journal of Medicine 336: 1131–1141.

    Article  PubMed  CAS  Google Scholar 

  46. Brunetti, N.D., R. Padalino, L. De Gennaro, A. Cuculo, L. Ziccardi, P.L. Pellegrino, and M. Di Biase. 2009. Acute phase proteins activation in subjects with coronary atherosclerosis and micro-vessel coronary circulation impairment. Journal of Thrombosis and Thrombolysis 28: 50–56.

    Article  PubMed  CAS  Google Scholar 

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ACKNOWLEDGMENT

Dr. Brunetti had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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Correspondence to Natale Daniele Brunetti.

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De Gennaro, L., Brunetti, N.D., Montrone, D. et al. Subacute Inflammatory Activation in Subjects with Acute Coronary Syndrome and Left Ventricular Dysfunction. Inflammation 35, 363–370 (2012). https://doi.org/10.1007/s10753-011-9326-4

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