(Circulation. 2001;103:2055.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Cytokines and Cytokine Receptors in Advanced Heart Failure
An Analysis of the Cytokine Database from the Vesnarinone Trial (VEST)
From the Winters Center for Heart Failure Research, Cardiology Section, Department of Medicine, Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Tex (A.D., D.L.M.); the Veterans Affairs Health Services Research and Development Center of Excellence, Houston, Tex (N.J.P.); the Cardiovascular Institute, University of Pittsburgh, Pittsburgh, Pa (A.M.F.); the Kaufman Center for Heart Failure, The Cleveland Clinic Foundation, Cleveland, Ohio (J.B.Y.); and Clinical Cardiovascular Research, Gaithersburg, Md (B.G.W.).
Correspondence and reprint requests to Douglas L. Mann, MD, Cardiology Research (151C), Houston VAMC, 2002 Holcombe Blvd, Houston, TX 77030. E-mail dmann{at}bcm.tmc.edu
Background—Previous reports have shown that elevated circulating levels of cytokines and/or cytokine receptors predict adverse outcomes in patients with heart failure. However, these studies were limited by small numbers of patients and/or they were performed in a single center. In addition, these studies did not have sufficient size to address the influence of age, race, sex, and cause of heart failure on the circulating levels of these inflammatory mediators in patients with heart failure.
Methods and
Results—We analyzed circulating levels
of cytokines (tumor necrosis factor [TNF] and interleukin-6)
and their cognate receptors in 1200 consecutive patients who were
enrolled in a multicenter clinical trial of patients with advanced
heart failure. This analysis constitutes the largest
analysis of cytokines and cytokine receptors to
date. Analysis of the patients receiving placebo showed that
increasing circulating levels of TNF, interleukin-6, and the soluble
TNF receptors were associated with increased mortality. In men, there
was a linear increase in circulating levels of TNF with advancing age.
Women 
50 years of age had relatively low levels of TNF, but TNF
levels were disproportionately higher in women >50 years of
age. No differences existed in cytokines and/or
cytokine receptors in whites versus nonwhites, and circulating
levels of cytokines and cytokine receptors were
significantly greater in patients with ischemic heart
disease.
Conclusions—Cytokines and cytokine receptors are independent predictors of mortality in patients with advanced heart failure. Moreover, circulating levels of cytokines are modified by age, sex, and cause of heart failure.
Key Words: heart failure • cytokines • tumor necrosis factor
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 J. Pasic, W. C. Levy, and M. D. Sullivan Cytokines in Depression and Heart Failure Psychosom Med, March 1, 2003; 65(2): 181 - 193. [Abstract] [Full Text] [PDF]
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R. B. Felder, J. Francis, Z.-H. Zhang, S.-G. Wei, R. M. Weiss, and A. K. Johnson Heart failure and the brain: new perspectives Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2003; 284(2): R259 - R276. [Abstract] [Full Text] [PDF]
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J. Francis, R. M. Weiss, A. K. Johnson, and R. B. Felder Central mineralocorticoid receptor blockade decreases plasma TNF-alpha after coronary artery ligation in rats Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2003; 284(2): R328 - R335. [Abstract] [Full Text] [PDF]
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V.M. Conraads, P. Beckers, J. Bosmans, L.S. De Clerck, W.J. Stevens, C.J. Vrints, and D.L. Brutsaert Combined endurance/resistance training reduces plasma TNF-{alpha} receptor levels in patients with chronic heart failure and coronary artery disease Eur. Heart J., December 1, 2002; 23(23): 1854 - 1860. [Abstract] [Full Text] [PDF]
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D. L. Mann Inflammatory Mediators and the Failing Heart: Past, Present, and the Foreseeable Future Circ. Res., November 29, 2002; 91(11): 988 - 998. [Abstract] [Full Text] [PDF]
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 Y. Sun, J. Zhang, L. Lu, S. S. Chen, M. T. Quinn, and K. T. Weber Aldosterone-Induced Inflammation in the Rat Heart : Role of Oxidative Stress Am. J. Pathol., November 1, 2002; 161(5): 1773 - 1781. [Abstract] [Full Text] [PDF]
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J. R. R. Heyen, E. R. Blasi, K. Nikula, R. Rocha, H. A. Daust, G. Frierdich, J. F. Van Vleet, P. De Ciechi, E. G. McMahon, and A. E. Rudolph Structural, functional, and molecular characterization of the SHHF model of heart failure Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H1775 - H1784. [Abstract] [Full Text] [PDF]
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 J. Zhang, Y. Liu, J. Shi, D. F. Larson, and R. R. Watson Side-Stream Cigarette Smoke Induces Dose-Response in Systemic Inflammatory Cytokine Production and Oxidative Stress Experimental Biology and Medicine, October 1, 2002; 227(9): 823 - 829. [Abstract] [Full Text] [PDF]
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W. Schillinger, H. Schneider, K. Minami, R. Ferrari, and G. Hasenfuss Importance of sympathetic activation for the expression of Na+-Ca2+ exchanger in end-stage failing human myocardium Eur. Heart J., July 2, 2002; 23(14): 1118 - 1124. [Abstract] [Full Text] [PDF]
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T. B. Horwich, G. C. Fonarow, M. A. Hamilton, W. R. MacLellan, and J. Borenstein Anemia is associated with worse symptoms, greater impairment in functional capacity and a significant increase in mortality in patients with advanced heart failure J. Am. Coll. Cardiol., June 5, 2002; 39(11): 1780 - 1786. [Abstract] [Full Text] [PDF]
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C. M. Albert, J. Ma, N. Rifai, M. J. Stampfer, and P. M. Ridker Prospective Study of C-Reactive Protein, Homocysteine, and Plasma Lipid Levels as Predictors of Sudden Cardiac Death Circulation, June 4, 2002; 105(22): 2595 - 2599. [Abstract] [Full Text] [PDF]
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W. S. Bradham, G. Moe, K. A. Wendt, A. A. Scott, A. Konig, M. Romanova, G. Naik, and F. G. Spinale TNF-alpha and myocardial matrix metalloproteinases in heart failure: relationship to LV remodeling Am J Physiol Heart Circ Physiol, April 1, 2002; 282(4): H1288 - H1295. [Abstract] [Full Text] [PDF]
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W. S. Bradham, B. Bozkurt, H. Gunasinghe, D. Mann, and F. G. Spinale Tumor necrosis factor-alpha and myocardial remodeling in progression of heart failure: a current perspective Cardiovasc Res, March 1, 2002; 53(4): 822 - 830. [Abstract] [Full Text] [PDF]
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S. Adamopoulos, J. Parissis, D. Karatzas, C. Kroupis, M. Georgiadis, G. Karavolias, J. Paraskevaidis, K. Koniavitou, A. J. S. Coats, and D. T. Kremastinos Physical training modulates proinflammatory cytokines and the soluble Fas/soluble Fasligand system in patients with chronic heart failure J. Am. Coll. Cardiol., February 20, 2002; 39(4): 653 - 663. [Abstract] [Full Text] [PDF]
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 J. Pfeilschifter, R. Koditz, M. Pfohl, and H. Schatz Changes in Proinflammatory Cytokine Activity after Menopause Endocr. Rev., February 1, 2002; 23(1): 90 - 119. [Abstract] [Full Text] [PDF]
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A. L. Farre and S. Casado Heart Failure, Redox Alterations, and Endothelial Dysfunction Hypertension, December 1, 2001; 38(6): 1400 - 1405. [Abstract] [Full Text] [PDF]
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K. Krasinski, I. Spyridopoulos, M. Kearney, and D. W. Losordo In Vivo Blockade of Tumor Necrosis Factor-{alpha} Accelerates Functional Endothelial Recovery After Balloon Angioplasty Circulation, October 9, 2001; 104(15): 1754 - 1756. [Abstract] [Full Text] [PDF]
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