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European Heart Journal 2002 23(1):70-78; doi:10.1053/euhj.2001.2780
Copyright © 2002 by the European Society of Cardiology.
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Do cytokines enable risk stratification to be improved in NYHA functional class III patients?. Comparison with other potential predictors of prognosis

R. Kell, A. Haunstetter, T.J. Dengler, C. Zugck, W. Kübler and M. Haassf1

Department of Cardiology, University of Heidelberg, Heidelberg, Germany

Received February 13, 2001; accepted April 25, 2001

Abstract

Aims Elevated plasma levels of proinflammatory cytokines have been reported in patients with congestive heart failure. The purpose of this study was to assess whether cytokines improve risk stratification in a homogenous group of NYHA class III patients with a left ventricular ejection fraction <40%.

Methods and Results Plasma concentrations of big endothelin, tumour necrosis factor alpha, interleukins -1, -6, -10 and -12, sCD14 and GM-CSF were measured by ELISA in 91 NYHA III patients [mean (SD) age: 55 (10) years, 69% male, 34% coronary artery disease, 66% dilated cardiomyopathy] with a left ventricular ejection fraction and a peak oxygen uptake (peak VO2) of 19 (9)% and 12·1 (3·6)ml min–1.kg–1, respectively. During follow-up [22 (13) months], 31 patients (34%) died due to cardiovascular causes. In non-survivors, interleukin-6 was twice as high as in survivors [12·8 (16·9)pg.ml–1vs 5·6(5·3)pg.ml–1,P <0·003], whereas plasma concentrations of the other cytokines showed no significant differences. Concerning long-term survival (≥1 year), multivariate Cox regression analysis revealed an independent prognostic power for interleukin-6, which was further improved by combining with left ventricular ejection fraction and peak VO2, while for short-term survival (up to 6 months) interleukin-6 did not allow risk stratification.

Conclusion In NYHA class III patients, plasma concentrations of interleukin-6 are predictive of long-term survival. However, its value may be limited for clinical decision-making for cardiac transplantation (short-term survival).

Key Words: Cytokines, heart failure, interleukin-6, risk stratification

f1 Correspondence: Markus Haass, MD, Department of Cardiology, University of Heidelberg, Bergheimer Str. 58, D-69115 Heidelberg, Germany.

References

  1. Ghali JK, Cooper R, Ford E. Trends in hospitalization rates for heart failure in the United States 1973–1986. Arch Intern Med. 1990;150:769–773[Abstract]
  2. Cowie MR, Mosterd A, Wood DA. The epidemiology of heart failure. Eur Heart J. 1997;18:208–225[Free Full Text]
  3. Cohn JN, Johnson G, Ziesche S. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med. 1991;325:303–310[Abstract]
  4. N Engl J Med. 1987;316:1429–1435[Abstract]
  5. Dargie HJ, Lechat P. The cardiac insufficiency bisoprolol study II (CIBIS II). Lancet. 1999;353:9–13[CrossRef][ISI][Medline]
  6. Hosenpud JD, Bennett LE, Keck BM, Boucek MM, Novick RJ. The registry of the International Society of Heart and Lung Transplantation: seventeenth official report—2000. J Heart Lung Transplant. 2000;19:909–931[CrossRef][ISI][Medline]
  7. Cohn JN, Johnson G, Shabetai R. Ejection fraction, peak exercise oxygen consumption, cardiothoracic ratio, ventricular arrhythmias and plasma norepinephrine as determinants of prognosis in heart failure. Circulation. 1993;87:VI5–16
  8. Stevenson LW, Steimle AE, Fonarow G. Improvement in exercise capacity of candidates awaiting heart transplantation. J Am Coll Cardiol. 1995;25:163–170[Abstract]
  9. Cohn JN, Levine TB, Olivari MT. Plasma norepinephrine as a guide to prognosis in patients with congestive heart failure. N Engl J Med. 1984;311:819–823[Abstract]
  10. Tsutamoto T, Wada A, Maeda K. Attenuation of compensation of endogenous cardiac natriuretic peptide system in chronic heart failure—Prognostic role of plasma brain natriuretic peptide concentration in patients with symptomatic left ventricular dysfunction. Circulation. 1997;97:1921–1929
  11. Pacher R, Stanek B, Hülsmann M. Prognostic impact of big endothelin-1 plasma concentrations compared with invasive hemodynamic evaluation in severe heart failure. J Am Coll Cardiol. 1996;27:633–641[Abstract]
  12. Koller-Strametz J, Pacher R, Frey B, Kos T, Woloszuk W, Stanek B. Circulating tumor necrosis factor-alpha levels in chronic heart failure: relation to its soluble receptor II, interleukin-6, and neurohumoral variables. J Heart Lung Transplant. 1998;17:356–362[ISI][Medline]
  13. Maury CPJ, Teppo AM. Circulating tumor necrosis factor-{alpha} (cachectin) in myocardial infarction. J Intern Med. 1989;225:333–336[ISI][Medline]
  14. Miyao Y, Yasue H, Ogawa H. Elevated plasma interleukin-6 levels in patients with acute myocardial infarction. Am Heart J. 1993;126:1299–1304[CrossRef][ISI][Medline]
  15. Neumann F-J, Ott I, Gawaz M. Cardiac release of cytokines and inflammatory responses in acute myocardial infarction. Circulation. 1995;92:748–755[Abstract/Free Full Text]
  16. Han RO, Ray PE, Baughman KL, Feldmann AM. Detection of interleukin-1 and interleukin-1-receptor mRNA in human heart by polymerase chain reaction. Biochem Biophys Res Commun. 1991;181:520–523[CrossRef][ISI][Medline]
  17. Biasucci LM, Vitelli A, Liuzzi G. Elevated plasma levels of interleukin-6 in unstable angina. Circulation. 1996;94:874–877[Abstract/Free Full Text]
  18. Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med. 1990;323:236–241[Abstract]
  19. McMurry J, Abdullah I, Dargie HJ, Shapiro D. Increased concentrations of tumor necrosis factor in cachectic patients with severe chronic heart failure. Br Heart J. 1991;66:356–358[Abstract/Free Full Text]
  20. Dutka DP, Elborn JS, Delamere F, Shale DJ, Morris GK. Tumor necrosis factor {alpha} in severe congestive cardiac failure. Br Heart J. 1993;70:141–143[Abstract/Free Full Text]
  21. Wiedermann CJ, Bermpold H, Manfred H, Knapp E, Braunstein H. Increased levels of serum neopterin and decreased production of neutrophil superoxide anions in chronic heart failure with elevated levels of tumor necrosis factor alpha. J Am Coll Cardiol. 1993;22:1897–1901[Abstract]
  22. Torre-Amione G, Kapadia S, Lee J. Tumor necrosis factor-{alpha} and tumor necrosis factor receptors in the failing human heart. Circulation. 1996;93:704–711[Abstract/Free Full Text]
  23. Torre-Amione G, Kapadia S, Benedict C, Oral C, Young JB, Mann DL. Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the studies of left ventricular dysfunction (SOLVD). J Am Coll Cardiol. 1996;27:1201–1206[Abstract]
  24. Munger MA, Johnson B, Amber IJ, Callahan KS, Gilbert EM. Circulating concentrations of proinflammatory cytokines in mild or moderate heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol. 1996;77:723–727[CrossRef][ISI][Medline]
  25. Deng MC, Erren M, Lüttgen A. Interleukin-6 correlates with hemodynamic impairment during dobutamine administration in chronic heart failure. Int J Cardiol. 1996;57:129–134[CrossRef][ISI][Medline]
  26. Anker SD, Egerer KR, Volk H-D, Kox WJ, Poole-Wilson PA, Coats AJS. Elevated soluble CD14 receptors and altered cytokines in chronic heart failure. Am J Cardiol. 1997;79:1426–1430[CrossRef][ISI][Medline]
  27. Lommi J, Pulkki K, Koskinen P. Haemodynamic, neuroendocrine and metabolic correlates of circulating cytokine concentrations in congestive heart failure. Eur Heart J. 1997;18:1620–1625[Abstract/Free Full Text]
  28. Rauchhaus M, Doehner W, Francis DP. Plasma cytokine parameters and mortality in patients with chronic heart failure. Circulation. 2000;102:3060–3067[Abstract/Free Full Text]
  29. Haass M. Neuropeptide Y: A cardiac sympathetic cotransmitter? Adv Pharmacol. 1989;42:129–132
  30. Whicher JT, Ritchie RF, Johnson AM. New international reference preparation for proteins in human serum (RPPHS). Clin Chem. 1994;40:934–938[Abstract/Free Full Text]
  31. Zugck C, Krüger C, Dürr S. Is the six minute walk test a reliable substitute of peak oxygen uptake in patients with dilated cardiomyopathy? Eur Heart J. 2000;21:540–549[Abstract/Free Full Text]
  32. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. Am J Stat Assoc. 1958;53:457–481[CrossRef]
  33. Peto R, Peto L. Asymptomatically efficant rank invariant procedures. J Roy Stat Soc. 1972;135:185–207
  34. Cox D. Regression models and life tables with discussion. J Roy Stat Soc. 1972;34:187–202
  35. Lee E. Statistical methods for survival data analysis. New York: John Wiley & Sons Inc; 1992. p. 250–63
  36. Metz C, Wang P, Kronman H. A new apporach for testing the significance of differences between ROC curves measured from correlated data. Deconinck F. Information processing in medical imaging. The Hague: Martinus Nijhoff; 1984. p. 432–445
  37. Metz C, Herman B, Roe C. Statistical comparison of two ROC curves estimates obtained from partially paired datasets. Med Decis Making. 1998;18:110–121[Abstract/Free Full Text]
  38. Delong E, Delong D, Clarke-Pearson D. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics. 1988;44:837–845[CrossRef][ISI][Medline]
  39. Tsutamoto T, Hisanaga T, Wada A. 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. J Am Coll Cardiol. 1998;31:391–398[Abstract/Free Full Text]
  40. Orus J, Roig E, Perez-Villa F. Prognostic value of serum cytokines in patients with congestive heart failure. J Heart Lung Transplant. 2000;19:419–425[CrossRef][ISI][Medline]
  41. Cowburn PJ, Cleland JGF, Coats AJS, Komajda M. Risk stratification in chronic heart failure. Eur Heart J. 1998;19:696–710[Free Full Text]
  42. Keogh AM, Baron DW, Hickie JB. Prognostic guides in patients with idiopathic or ischemic dilated cardiomyopathy assessed for cardiac transplantation. Am J Cardiol. 1990;65:903–908[CrossRef][ISI][Medline]
  43. Mancini DM, Eisen H, Kussmaul W, Mull R, Edmunds LH Jr, Wilson JR. Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation. 1991;83:778–786[Abstract/Free Full Text]
  44. Horii Y, Muraguchi A, Suematsu S. Regulation of BSF-2/IL-6 production by human mononuclear cells: macrophage-dependent synthesis of BSF-2/IL-6 by T cells. J Immunol. 1988;141:1529–1535[Abstract]
  45. Jirik FR, Podor TJ, Hirano T. Bacterial lipopolysaccharide and inflammatory mediators augment IL-6 production secretion by human endothelial cells. J Immunol. 1989;142:144–147[Abstract]
  46. Lippnow H, Libby P. Proliferating or interleukin 1-activated human vascular smooth muscle cells secrete copious interleukin 6. J Clin Invest. 1990;85:731–738[ISI][Medline]
  47. Finkel MS, Oddis CV, Jacob TD. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science. 1992;257:387–389[Abstract/Free Full Text]
  48. Hirota H, Chen J, Betz U. Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stress. Cell. 1999;97:189–198[CrossRef][ISI][Medline]
  49. Dibbs Z, Thornby T, White BG. Natural variability of circulating levels of cytokines and cytokine receptors in patients with heart failure: Implications for clinical trials. J Am Coll Cardiol. 1999;33:1935–1942[Abstract/Free Full Text]
  50. Sothern RB, Roitman-Johnson B, Kanabrocki EL. Circadian characteristics of circulating interleukin-6 in men. J Allergy Clin Immunol. 1995;95:1029–1035[CrossRef][ISI][Medline]
  51. Ikonimidis I, Andreotti F, Economou E. Increased proinflammatory cytokines in patients with chronic stable angina and their reduction by aspirin. Circulation. 1999;100:793–798[Abstract/Free Full Text]
  52. Gullestad L, Aukrust P, Ueland T. Effect of high- versus low-dose angiotensin converting enzyme inhibition on cytokine levels in chronic heart failure. J Am Coll Cardiol. 1999;34:2061–2067[Abstract/Free Full Text]
  53. Müller-Werdan U, Jacoby J, Loppnow H, Werdan K. Noradrenalin stimulates cardiomyocytes to produce interleukin-6 indicative of a proinflammatory action, which is surpressed by carvedilol (Abstr). Eur Heart J. 1999;20:P1721
  54. Chrousos GP. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med. 1995;332:1351–1361[Free Full Text]

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