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J Am Coll Cardiol, 1996; 28:964-971
© 1996 by the American College of Cardiology Foundation
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Circulating levels of cytokines and their endogenous modulators in patients with mild to severe congestive heart failure due to coronary artery disease or hypertension

M Testa, M Yeh, P Lee, R Fanelli, F Loperfido, JW Berman, and TH LeJemtel

Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

OBJECTIVES: This study sought to determine the circulating levels of cytokines and their respective endogenous modulators in patients with congestive heart failure of variable severity. BACKGROUND: Activation of immune elements localized in the heart or periphery, or both, may promote release of cytokines in patients with congestive heart failure. Although an increased circulating level of tumor necrosis factor-alpha (TNF-alpha) and its soluble receptor type II (sTNF-RII) is well documented, less is known about other cytokines (i.e., interleukin-1-beta [IL-1-beta], interleukin-6 [IL-6] and interleukin-2 [IL-2] and their soluble receptor/receptor antagonists). METHODS: Circulating levels of TNF-alpha and sTNF-RII, IL-1-beta, IL-1 receptor antagonist (IL-1-Ra), IL-6, IL-6 soluble receptor (IL-6-sR), IL-2 and IL-2 soluble receptor-alpha were measured using enzyme-linked immunosorbent assay kits (Quantikine, R&D Systems) in 80 patients with congestive heart failure due to coronary artery disease or hypertension. The severity of their symptoms, which ranged from New York Heart Association functional class I to IV, was confirmed by measurement of peak oxygen consumption. RESULTS: The percentage of patients with elevated levels of cytokines and their corresponding soluble receptor/receptor antagonists significantly increased with functional class. For TNF-alpha and IL-1-beta, the percentage of patients with elevated levels of soluble receptor/receptor antagonists was higher than that of patients with elevated levels of the cytokine itself. For IL-6, the percentage of patients with elevated levels of IL-6-sR tended to be lower than that of patients with elevated levels of IL-6. All but two patients had undetectable levels of IL-2, and all but seven had levels of IL-2-sR within a normal range. CONCLUSIONS: In patients with congestive heart failure, circulating levels of cytokines increased with the severity of symptoms. In these patients, circulating levels of sTNF-RII and IL-1-Ra are more sensitive markers of immune activation than are circulating levels of TNF-alpha and IL-1-beta, respectively. Levels of IL-2 and IL-2-sR are not elevated when congestive heart failure is due to coronary artery disease or hypertension.


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Ann Rheum DisHome page
B. Bozkurt
Activation of cytokines as a mechanism of disease progression in heart failure
Ann Rheum Dis, November 1, 2000; 59(90001): i90 - 93.
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Arterioscler. Thromb. Vasc. Bio.Home page
H. Gierens, M. Nauck, M. Roth, R. Schinker, C. Schurmann, H. Scharnagl, G. Neuhaus, H. Wieland, and W. Marz
Interleukin-6 Stimulates LDL Receptor Gene Expression via Activation of Sterol-Responsive and Sp1 Binding Elements
Arterioscler Thromb Vasc Biol, July 1, 2000; 20(7): 1777 - 1783.
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Am. J. Physiol. Heart Circ. Physiol.Home page
I. Hamanaka, Y. Saito, T. Nishikimi, T. Magaribuchi, S. Kamitani, K. Kuwahara, M. Ishikawa, Y. Miyamoto, M. Harada, E. Ogawa, et al.
Effects of cardiotrophin-1 on hemodynamics and endocrine function of the heart
Am J Physiol Heart Circ Physiol, July 1, 2000; 279(1): H388 - H396.
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CirculationHome page
D. R. Murray, S. D. Prabhu, and B. Chandrasekar
Chronic {beta}-Adrenergic Stimulation Induces Myocardial Proinflammatory Cytokine Expression
Circulation, May 23, 2000; 101(20): 2338 - 2341.
[Abstract] [Full Text] [PDF]


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CirculationHome page
S. D. Prabhu, B. Chandrasekar, D. R. Murray, and G. L. Freeman
{beta}-Adrenergic Blockade in Developing Heart Failure : Effects on Myocardial Inflammatory Cytokines, Nitric Oxide, and Remodeling
Circulation, May 2, 2000; 101(17): 2103 - 2109.
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J Am Coll CardiolHome page
A. M. Feldman, A. Combes, D. Wagner, T. Kadakomi, T. Kubota, Y. You Li, and C. McTiernan
The role of tumor necrosis factor in the pathophysiology of heart failure
J. Am. Coll. Cardiol., March 1, 2000; 35(3): 537 - 544.
[Abstract] [Full Text] [PDF]


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HypertensionHome page
Q. He and M. C. LaPointe
Interleukin-1{beta} Regulates the Human Brain Natriuretic Peptide Promoter via Ca2+-Dependent Protein Kinase Pathways
Hypertension, January 1, 2000; 35(1): 292 - 296.
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J Am Coll CardiolHome page
L. Gullestad, P.a. Aukrust, T. Ueland, T. Espevik, G. Yee, R. Vagelos, S. S. Froland, and M. Fowler
Effect of high- versus low-dose angiotensin converting enzyme inhibition on cytokine levels in chronic heart failure
J. Am. Coll. Cardiol., December 1, 1999; 34(7): 2061 - 2067.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Heart Circ. Physiol.Home page
D. R. Wagner, T. Kubota, V. J. Sanders, C. F. McTiernan, and A. M. Feldman
Differential regulation of cardiac expression of IL-6 and TNF-alpha by A2- and A3-adenosine receptors
Am J Physiol Heart Circ Physiol, June 1, 1999; 276(6): H2141 - H2147.
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Cardiovasc ResHome page
Y. Y. Li, C. F. McTiernan, and A. M. Feldman
Proinflammatory cytokines regulate tissue inhibitors of metalloproteinases and disintegrin metalloproteinase in cardiac cells
Cardiovasc Res, April 1, 1999; 42(1): 162 - 172.
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CirculationHome page
F. Franco, G. D. Thomas, B. Giroir, D. Bryant, M. C. Bullock, M. C. Chwialkowski, R. G. Victor, and R. M. Peshock
Magnetic Resonance Imaging and Invasive Evaluation of Development of Heart Failure in Transgenic Mice With Myocardial Expression of Tumor Necrosis Factor-{alpha}
Circulation, January 26, 1999; 99(3): 448 - 454.
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HypertensionHome page
Q. He and M. C. LaPointe
Interleukin-1 Regulation of the Human Brain Natriuretic Peptide Promoter Involves Ras-, Rac-, and p38 Kinase Dependent Pathways in Cardiac Myocytes
Hypertension, January 1, 1999; 33(1): 283 - 289.
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EndocrinologyHome page
T. Horio, T. Nishikimi, F. Yoshihara, N. Nagaya, H. Matsuo, S. Takishita, and K. Kangawa
Production and Secretion of Adrenomedullin in Cultured Rat Cardiac Myocytes and Nonmyocytes: Stimulation by Interleukin-1{beta} and Tumor Necrosis Factor-{alpha}
Endocrinology, November 1, 1998; 139(11): 4576 - 4580.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Heart Circ. Physiol.Home page
P. Yue, B. M. Massie, P. C. Simpson, and C. S. Long
Cytokine expression increases in nonmyocytes from rats with postinfarction heart failure
Am J Physiol Heart Circ Physiol, July 1, 1998; 275(1): H250 - H258.
[Abstract] [Full Text] [PDF]


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CirculationHome page
P. Aukrust, T. Ueland, F. Muller, A. K. Andreassen, I. Nordoy, H. Aas, J. Kjekshus, S. Simonsen, S. S. Froland, and L. Gullestad
Elevated Circulating Levels of C-C Chemokines in Patients With Congestive Heart Failure
Circulation, March 31, 1998; 97(12): 1136 - 1143.
[Abstract] [Full Text] [PDF]


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Circ. Res.Home page
C. F. McTiernan, B. H. Lemster, C. Frye, S. Brooks, A. Combes, and A. M. Feldman
Interleukin-1 Inhibits Phospholamban Gene Expression in Cultured Cardiomyocytes
Circ. Res., October 19, 1997; 81(4): 493 - 503.
[Abstract] [Full Text]


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Circ. Res.Home page
T. Kubota, C. F. McTiernan, C. S. Frye, S. E. Slawson, B. H. Lemster, A. P. Koretsky, A. J. Demetris, and A. M. Feldman
Dilated Cardiomyopathy in Transgenic Mice With Cardiac-Specific Overexpression of Tumor Necrosis Factor-{alpha}
Circ. Res., October 19, 1997; 81(4): 627 - 635.
[Abstract] [Full Text]



 
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