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
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.
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.
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.
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.
Packer, M. 1992. Pathophysiology of chronic heart failure. Lancet 340: 88–92.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Heinrich, P.C., J.V. Castell, and T. Andus. 1990. Interleukin-6 and the acute phase response. The Biochemical Journal 265: 621–636.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Romagnani, S. 1994. Lymphokine production by human T cells in disease states. Annual Review of Immunology 12: 227–257.
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.
Kelly, R.A., and T.W. Smith. 1997. Cytokines and cardiac contractile function. Circulation 95: 778–781.
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.
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.
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.
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.
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.
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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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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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DOI: https://doi.org/10.1007/s10753-011-9326-4