Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD)

Department of Medicine, Veterans Administration Medical Center and Baylor College of Medicine, Houston, Texas, USA.

OBJECTIVES. This study sought to assess proinflammatory cytokine levels in patients in the studies of left ventricular dysfunction trial (SOLVD) in relation to both their New York Heart Association functional classification and their neurohormonal status before randomization. BACKGROUND. Elevated levels of tumor necrosis factor-alpha have been identified in 30% to 40% of patients with heart failure. However, it is unclear which subsets of patients with heart failure elaborate tumor necrosis factor-alpha. It is also unclear what the mechanism for the increased expression of proinflammatory cytokines is. METHODS. Tumor necrosis factor-alpha and interleukin-6 levels were analyzed by enzymes-linked immunoassay using randomly selected plasma samples from patients in functional classes I to III who were enrolled in neurohormonal substudies of the SOLVD trial; age-matched healthy subjects served as the control group. RESULTS. Plasma levels of tumor necrosis factor-alpha (p < 0.001) were elevated in patients in functional classes I to III ([mean +/- SD] 1.95 +/- 0.54, 2.63 +/- 0.48, 6.4 +/- 1.9 pg/ml, respectively) compared with age-matched control subjects (0.75 +/- 0.05 pg/ml) and were progressively elevated in relation to decreasing functional status of the patient. Plasma levels of interleukin-6 (p < 0.001) were elevated in patients in functional classes I to III (3.3 +/- 0.55, 6.2 +/- 1.1, 5.22 +/- 0.9 pg/ml, respectively) compared with age-matched control subjects (1.8 +/- 0.5 pg/ml and were progressively elevated in relation to decreasing functional status of the patient. Cox proportional-hazards analysis showed that there was a trend toward significance between plasma tumor necrosis factor-alpha (p < 0.07) and survival, whereas there was no significant relation for plasma interleukin-6 (p < 0.72). Except for atrial natriuretic factor, which correlated weakly (r = 0.23, p = 0.04) with circulating tumor necrosis factor-alpha levels, there was no significance correlation between neurohormonal and proinflammatory cytokine levels. CONCLUSIONS. Circulating levels of proinflammatory cytokines increase in patients as their functional heart failure classification deteriorates. Moreover, activation of the neurohumoral axis is unlikely to completely explain the elaboration of proinflammatory cytokines in heart failure.

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				J. A. Thomas, S. B. Haudek, T. Koroglu, M. F. Tsen, D. D. Bryant, D. J. White, D. F. Kusewitt, J. W. Horton, and B. P. Giroir IRAK1 deletion disrupts cardiac Toll/IL-1 signaling and protects against contractile dysfunction Am J Physiol Heart Circ Physiol, August 1, 2003; 285(2): H597 - H606. [Abstract] [Full Text] [PDF]

				I. C. Gerling, Y. Sun, R. A. Ahokas, L. A. Wodi, S. K. Bhattacharya, K. J. Warrington, A. E. Postlethwaite, and K. T. Weber Aldosteronism: an immunostimulatory state precedes proinflammatory/fibrogenic cardiac phenotype Am J Physiol Heart Circ Physiol, July 11, 2003; 285(2): H813 - H821. [Abstract] [Full Text] [PDF]

				E. S. Chung, M. Packer, K. H. Lo, A. A. Fasanmade, and J. T. Willerson Randomized, Double-Blind, Placebo-Controlled, Pilot Trial of Infliximab, a Chimeric Monoclonal Antibody to Tumor Necrosis Factor-{alpha}, in Patients With Moderate-to-Severe Heart Failure: Results of the Anti-TNF Therapy Against Congestive Heart failure (ATTACH) Trial Circulation, July 1, 2003; 107(25): 3133 - 3140. [Abstract] [Full Text] [PDF]

				C. Wunderlich, U. Flogel, A. Godecke, J. Heger, and J. Schrader Acute Inhibition of Myoglobin Impairs Contractility and Energy State of iNOS-Overexpressing Hearts Circ. Res., June 27, 2003; 92(12): 1352 - 1358. [Abstract] [Full Text] [PDF]

				H. J. Kwon, T. R. Cote, M. S. Cuffe, J. M. Kramer, and M M. Braun Case Reports of Heart Failure after Therapy with a Tumor Necrosis Factor Antagonist Ann Intern Med, May 20, 2003; 138(10): 807 - 811. [Abstract] [Full Text] [PDF]

				D. R. Murray and G. L. Freeman Proinflammatory Cytokines: Predictors of a Failing Heart? Circulation, March 25, 2003; 107(11): 1460 - 1462. [Full Text] [PDF]

				R. S. Vasan, L. M. Sullivan, R. Roubenoff, C. A. Dinarello, T. Harris, E. J. Benjamin, D. B. Sawyer, D. Levy, P. W.F. Wilson, and R. B. D'Agostino Inflammatory Markers and Risk of Heart Failure in Elderly Subjects Without Prior Myocardial Infarction: The Framingham Heart Study Circulation, March 25, 2003; 107(11): 1486 - 1491. [Abstract] [Full Text] [PDF]

				D. R. Murray What Is "Heart Rate Variability" and Is It Blunted by Tumor Necrosis Factor? Chest, March 1, 2003; 123(3): 664 - 667. [Full Text] [PDF]

				H. A. Malave, A. A. Taylor, J. Nattama, A. Deswal, and D. L. Mann Circulating Levels of Tumor Necrosis Factor Correlate With Indexes of Depressed Heart Rate Variability: A Study in Patients With Mild-to-Moderate Heart Failure Chest, March 1, 2003; 123(3): 716 - 724. [Abstract] [Full Text] [PDF]

				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]

				H. Oral, N. Sivasubramanian, D. B. Dyke, R. H. Mehta, P. M. Grossman, K. Briesmiester, W. P. Fay, F. D. Pagani, S. F. Bolling, D. L. Mann, et al. Myocardial Proinflammatory Cytokine Expression and Left Ventricular Remodeling in Patients With Chronic Mitral Regurgitation Circulation, February 18, 2003; 107(6): 831 - 837. [Abstract] [Full Text] [PDF]

				B. London, L. C. Baker, J. S. Lee, V. Shusterman, B.-R. Choi, T. Kubota, C. F. McTiernan, A. M. Feldman, and G. Salama Calcium-dependent arrhythmias in transgenic mice with heart failure Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H431 - H441. [Abstract] [Full Text] [PDF]

				P A Henriksen and D E Newby Therapeutic inhibition of tumour necrosis factor {alpha} in patients with heart failure: cooling an inflamed heart Heart, January 1, 2003; 89(1): 14 - 18. [Abstract] [Full Text] [PDF]

				C Seiler, T Pohl, M Billinger, and B Meier Tumour necrosis factor {alpha} concentration and collateral flow in patients with coronary artery disease and normal systolic left ventricular function Heart, January 1, 2003; 89(1): 96 - 97. [Full Text] [PDF]