This Article Figures Only Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kapadia, S. R. Articles by Griffin, B. P. Search for Related Content PubMed PubMed Citation Articles by Kapadia, S. R. Articles by Griffin, B. P.

CLINICAL STUDIES: VALVE DISEASE

Elevated circulating levels of serum tumor necrosis factor-alpha in patients with hemodynamically significant pressure and volume overload

^a Cleveland Clinic Foundation, Cleveland, Ohio, USA
^* Winters Center for Heart Failure Research, Baylor College of Medicine and Veterans Affairs Medical Center, Houston, Texas, USA

Manuscript received July 22, 1999; revised manuscript received January 20, 2000, accepted March 27, 2000.

Reprint requests and correspondence: Dr. Brian P. Griffin, The Cleveland Clinic Foundation, 9500 Euclid Avenue, F15, Cleveland, Ohio 44195
Griffib{at}ccf.org

OBJECTIVES

We sought to determine whether serum tumor necrosis factor-alpha (TNF-alpha) levels are elevated in patients with hemodynamically significant pressure and volume overload.

BACKGROUND

It has been previously shown that TNF-alpha messenger ribonucleic acid (mRNA) and protein are rapidly expressed in the hearts of animal models subjected to abrupt hemodynamic overloading. The clinical significance of these experimental findings has not been tested in pathophysiologically relevant clinical models in human subjects.

METHODS

We prospectively measured serum TNF-alpha levels and serum TNF receptor 1 and 2 levels in 21 patients with severe aortic stenosis (AS), in 26 patients with 3+ to 4+ mitral regurgitation (MR) and in normal age- and gender-matched control subjects. Patients with AS and MR were either in New York Heart Association (NYHA) functional class I or II and had no significant coronary disease. We compared the cytokine levels among the groups using analysis of variance. We related cytokine levels to the severity of AS using simple regression analysis.

RESULTS

Serum TNF-alpha levels in patients with AS (2.1 ± 1.6 pg/ml, n = 21) and MR (1.3 ± 0.7 pg/ml, n = 26) were significantly higher than those in the control subjects (0.7 ± 0.2 pg/ml, n = 28). Serum TNF receptor 1 and 2 levels were also higher in patients with AS and MR than in control subjects. Cytokine levels were higher in patients in NYHA class II than in those in class I. In patients with a normal ejection fraction (>50%, n = 16), there was a mild positive correlation (r = 0.56, p = 0.025) between serum TNF-alpha levels and the mean gradient across the aortic valve.

CONCLUSIONS

This study demonstrates that serum TNF-alpha is elevated in patients with chronic hemodynamic overloading and early cardiac decompensation. Furthermore, these findings suggest not only that peripheral TNF-alpha levels correlate with the severity of the hemodynamic pressure overload, but also that peripheral TNF-alpha and TNF receptor levels increase in direct relation to deteriorating NYHA functional class.

Abbreviations and Acronyms   AS = aortic stenosis   AVA = aortic valve area   CI = confidence interval   EF = ejection fraction   LV = left ventricular   mRNA = messenger ribonucleic acid   MR = mitral regurgitation   NYHA = New York Heart Association   OR = odds ratio   TNF-alpha = tumor necrosis factor-alpha

This article has been cited by other articles:

				A. E. Awad, V. Kandalam, S. Chakrabarti, X. Wang, J. M. Penninger, S. T. Davidge, G. Y. Oudit, and Z. Kassiri Tumor necrosis factor induces matrix metalloproteinases in cardiomyocytes and cardiofibroblasts differentially via superoxide production in a PI3K{gamma}-dependent manner Am J Physiol Cell Physiol, March 1, 2010; 298(3): C679 - C692. [Abstract] [Full Text] [PDF]

				R. Beeri, C. Yosefy, J. L. Guerrero, F. Nesta, S. Abedat, M. Chaput, F. del Monte, M. D. Handschumacher, R. Stroud, S. Sullivan, et al. Mitral Regurgitation Augments Post-Myocardial Infarction Remodeling: Failure of Hypertrophic Compensation J. Am. Coll. Cardiol., January 29, 2008; 51(4): 476 - 486. [Abstract] [Full Text] [PDF]

				B. P. Griffin Timing of Surgical Intervention in Chronic Mitral Regurgitation: Is Vigilance Enough? Circulation, May 9, 2006; 113(18): 2169 - 2172. [Full Text] [PDF]

				M Vanderheyden, W J Paulus, M Voss, P Knuefermann, N Sivasubramanian, D Mann, and G Baumgarten Myocardial cytokine gene expression is higher in aortic stenosis than in idiopathic dilated cardiomyopathy Heart, July 1, 2005; 91(7): 926 - 931. [Abstract] [Full Text] [PDF]

				A. P. Patrianakos, F. I. Parthenakis, E. A. Papadimitriou, G. F. Diakakis, P. G. Tzerakis, D. Nikitovic, and P. E. Vardas Restrictive filling pattern is associated with increased humoral activation and impaired exercise capacity in dilated cardiomyopathy Eur J Heart Fail, October 1, 2004; 6(6): 735 - 743. [Abstract] [Full Text] [PDF]

				V. Palmieri, R. P. Tracy, M. J. Roman, J. E. Liu, L. G. Best, J. N. Bella, D. C. Robbins, B. V. Howard, and R. B. Devereux Relation of Left Ventricular Hypertrophy to Inflammation and Albuminuria in Adults With Type 2 Diabetes: The Strong Heart Study Diabetes Care, October 1, 2003; 26(10): 2764 - 2769. [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]

				M. F. Bellamy, P. A. Pellikka, K. W. Klarich, A. J. Tajik, and M. Enriquez-Sarano Association of cholesterol levels, hydroxymethylglutaryl coenzyme-a reductase inhibitor treatment, and progression of aortic stenosis in the community J. Am. Coll. Cardiol., November 20, 2002; 40(10): 1723 - 1730. [Abstract] [Full Text] [PDF]

				C. Stamm, I. Friehs, D. B. Cowan, A. M. Moran, H. Cao-Danh, L. F. Duebener, P. J. del Nido, and F. X. McGowan Jr Inhibition of Tumor Necrosis Factor-{alpha} Improves Postischemic Recovery of Hypertrophied Hearts Circulation, September 18, 2001; 104(2009): I-350 - I-355. [Abstract] [Full Text] [PDF]

				D. Kalra, N. Sivasubramanian, and D. L. Mann Angiotensin II Induces Tumor Necrosis Factor Biosynthesis in the Adult Mammalian Heart Through a Protein Kinase C-Dependent Pathway Circulation, May 7, 2002; 105(18): 2198 - 2205. [Abstract] [Full Text] [PDF]