REVIEW ARTICLES
The role of tumor necrosis factor in the pathophysiology of heart failure
Arthur M. Feldman, MD, PhD, FACCa,
Alain Combes, MDa,
Daniel Wagner, MDa,
Toshiaki Kadakomi, MDa,
Toru Kubota, MD, PhDa,
Yun You Li, PhDa and
Charles McTiernan, PhDa
a Cardiovascular Institute of the UPMC Health System, Pittsburgh, Pennsylvania, USA
Manuscript received July 2, 1999;
revised manuscript received October 5, 1999,
accepted November 18, 1999.
Reprint requests and correspondence: Dr. Arthur M. Feldman, Cardiovascular Institute of the UPMC Health System, 200 Lothrop Street, S-572 Scaife Hall, Pittsburgh, Pennsylvania 15213
feldmanam{at}msx.upmc.edu
Recent studies have focused their attention on the role of the proinflammatory cytokine tumor necrosis factor (TNF) in the development of heart failure. First recognized as an endotoxin-induced serum factor that caused necrosis of tumors and cachexia, it is now recognized that TNF participates in the pathophysiology of a group of inflammatory diseases including rheumatoid arthritis and Crohn’s disease. The normal heart does not express TNF; however, the failing heart produces robust quantities. Furthermore, there is a direct relationship between the level of TNF expression and the severity of disease. In addition, both in vivo and in vitro studies demonstrate that TNF effects cellular and biochemical changes that mirror those seen in patients with congestive heart failure. Furthermore, in animal models, the development of the heart failure phenotype can be abrogated at least in part by anticytokine therapy. Based on information from experimental studies, investigators are now evaluating the clinical efficacy of novel anticytokine and anti-TNF strategies in patients with heart failure; one such strategy is the use of a recombinantly produced chimeric TNF alpha soluble receptor. Thus, in view of the emerging importance of proinflammatory cytokines in the pathogenesis of heart disease, we review the biology of TNF, its role in inflammatory diseases, the effects of TNF on the physiology of the heart and the development of clinical strategies that target the cytokine pathways.
|
Abbreviations and Acronyms
| | alpha-MHC | = alpha myosin heavy chain | | AMP | = adenosine monophosphate | | beta-MHC | = beta myosin heavy chain | | CHF | = congestive heart failure | | ELAMS | = endothelial leukocyte adhesion molecules | | ICAMS | = intracellular adhesion molecules | | IL-1 | = interleukin-1 | | LPS | = lipopolysaccharide | | MCP | = monocyte chemoattractant protein | | mRNA | = messenger RNA | | NYHA | = New York Heart Association | | SERCA | = sarcoplasmic reticulum Ca2+ ATPase | | TNF | = tumor necrosis factor | | TNFR | = soluble tumor necrosis factor receptor |
|
This article has been cited by other articles:
|
|
|
|
 
E. M. Hylek, L. Frison, L. E. Henault, and A. Cupples
Disparate Stroke Rates on Warfarin Among Contemporaneous Cohorts With Atrial Fibrillation: Potential Insights Into Risk From a Comparative Analysis of SPORTIF III Versus SPORTIF V
Stroke,
November 1, 2008;
39(11):
3009 - 3014.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Panagopoulou, C. H. Davos, D. J. Milner, E. Varela, J. Cameron, D. L. Mann, and Y. Capetanaki
Desmin mediates TNF-{alpha}-induced aggregate formation and intercalated disk reorganization in heart failure
J. Cell Biol.,
October 20, 2008;
181(5):
761 - 775.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Elliott
Relevance of platelet activation in obstructive hypertrophic cardiomyopathy
Heart,
June 1, 2008;
94(6):
688 - 689.
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Knuefermann, M. Schwederski, M. Velten, P. Krings, H. Ehrentraut, M. Rudiger, O. Boehm, K. Fink, U. Dreiner, C. Grohe, et al.
Bacterial DNA induces myocardial inflammation and reduces cardiomyocyte contractility: role of Toll-like receptor 9
Cardiovasc Res,
April 1, 2008;
78(1):
26 - 35.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Chakir, S. K. Daya, R. S. Tunin, R. H. Helm, M. J. Byrne, V. L. Dimaano, A. C. Lardo, T. P. Abraham, G. F. Tomaselli, and D. A. Kass
Reversal of Global Apoptosis and Regional Stress Kinase Activation by Cardiac Resynchronization
Circulation,
March 18, 2008;
117(11):
1369 - 1377.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. Schoner and G. Scheiner-Bobis
Endogenous and exogenous cardiac glycosides: their roles in hypertension, salt metabolism, and cell growth
Am J Physiol Cell Physiol,
August 1, 2007;
293(2):
C509 - C536.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Monden, T. Kubota, T. Inoue, T. Tsutsumi, S. Kawano, T. Ide, H. Tsutsui, and K. Sunagawa
Tumor necrosis factor-{alpha} is toxic via receptor 1 and protective via receptor 2 in a murine model of myocardial infarction
Am J Physiol Heart Circ Physiol,
July 1, 2007;
293(1):
H743 - H753.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Smith, N. W. Wilson, A. Louw, and K. H. Myburgh
Illuminating the interrelated immune and endocrine adaptations after multiple exposures to short immobilization stress by in vivo blocking of IL-6
Am J Physiol Regulatory Integrative Comp Physiol,
April 1, 2007;
292(4):
R1439 - R1447.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Westermann, S. Rutschow, S. Jager, A. Linderer, S. Anker, A. Riad, T. Unger, H.-P. Schultheiss, M. Pauschinger, and C. Tschope
Contributions of Inflammation and Cardiac Matrix Metalloproteinase Activity to Cardiac Failure in Diabetic Cardiomyopathy: The Role of Angiotensin Type 1 Receptor Antagonism
Diabetes,
March 1, 2007;
56(3):
641 - 646.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Monden, T. Kubota, T. Tsutsumi, T. Inoue, S. Kawano, N. Kawamura, T. Ide, K. Egashira, H. Tsutsui, and K. Sunagawa
Soluble TNF receptors prevent apoptosis in infiltrating cells and promote ventricular rupture and remodeling after myocardial infarction
Cardiovasc Res,
March 1, 2007;
73(4):
794 - 805.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Roig
Usefulness of neurohormonal markers in the diagnosis and prognosis of heart failure
Eur. Heart J. Suppl.,
September 1, 2006;
8(suppl_E):
E12 - E17.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. van der Harst, A. A. Voors, W. H. van Gilst, M. Bohm, and D. J. van Veldhuisen
Statins in the treatment of chronic heart failure: Biological and clinical considerations
Cardiovasc Res,
August 1, 2006;
71(3):
443 - 454.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. S. Petkova-Kirova, E. Gursoy, H. Mehdi, C. F. McTiernan, B. London, and G. Salama
Electrical remodeling of cardiac myocytes from mice with heart failure due to the overexpression of tumor necrosis factor-{alpha}
Am J Physiol Heart Circ Physiol,
May 1, 2006;
290(5):
H2098 - H2107.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Anand, A. N Mooss, and S. M Mohiuddin
Review: Aldosterone Inhibition Reduces the Risk of Sudden Cardiac Death in Patients with Heart Failure
Journal of Renin-Angiotensin-Aldosterone System,
March 1, 2006;
7(1):
15 - 19.
[Abstract]
[PDF]
|
|
|
|
|
|
|
Y. Higuchi, T. O. Chan, M. A. Brown, J. Zhang, B. R. DeGeorge Jr., H. Funakoshi, G. Gibson, C. F. McTiernan, T. Kubota, W. K. Jones, et al.
Cardioprotection afforded by NF-{kappa}B ablation is associated with activation of Akt in mice overexpressing TNF-{alpha}
Am J Physiol Heart Circ Physiol,
February 1, 2006;
290(2):
H590 - H598.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Matsusaka, M. Ikeuchi, S. Matsushima, T. Ide, T. Kubota, A. M. Feldman, A. Takeshita, K. Sunagawa, and H. Tsutsui
Selective disruption of MMP-2 gene exacerbates myocardial inflammation and dysfunction in mice with cytokine-induced cardiomyopathy
Am J Physiol Heart Circ Physiol,
November 1, 2005;
289(5):
H1858 - H1864.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Hall, I. S. Singh, L. Hester, J. D. Hasday, and T. B. Rogers
Inhibitor-{kappa}B kinase-{beta} regulates LPS-induced TNF-{alpha} production in cardiac myocytes through modulation of NF-{kappa}B p65 subunit phosphorylation
Am J Physiol Heart Circ Physiol,
November 1, 2005;
289(5):
H2103 - H2111.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-P. Quenot, G. Le Teuff, C. Quantin, J.-M. Doise, M. Abrahamowicz, D. Masson, and B. Blettery
Myocardial Injury in Critically Ill Patients: Relation to Increased Cardiac Troponin I and Hospital Mortality
Chest,
October 1, 2005;
128(4):
2758 - 2764.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z. Kassiri, G. Y. Oudit, O. Sanchez, F. Dawood, F. F. Mohammed, R. K. Nuttall, D. R. Edwards, P. P. Liu, P. H. Backx, and R. Khokha
Combination of Tumor Necrosis Factor-{alpha} Ablation and Matrix Metalloproteinase Inhibition Prevents Heart Failure After Pressure Overload in Tissue Inhibitor of Metalloproteinase-3 Knock-Out Mice
Circ. Res.,
August 19, 2005;
97(4):
380 - 390.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Li, D. Georgakopoulos, G. Lu, L. Hester, D. A. Kass, J. Hasday, and Y. Wang
p38 MAP Kinase Mediates Inflammatory Cytokine Induction in Cardiomyocytes and Extracellular Matrix Remodeling in Heart
Circulation,
May 17, 2005;
111(19):
2494 - 2502.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Kalantar-Zadeh, K. C Abbott, A. K Salahudeen, R. D Kilpatrick, and T. B Horwich
Survival advantages of obesity in dialysis patients
Am. J. Clinical Nutrition,
March 1, 2005;
81(3):
543 - 554.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. E. Munroe and G. A. Bishop
Role of Tumor Necrosis Factor (TNF) Receptor-associated Factor 2 (TRAF2) in Distinct and Overlapping CD40 and TNF Receptor 2/CD120b-mediated B Lymphocyte Activation
J. Biol. Chem.,
December 17, 2004;
279(51):
53222 - 53231.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. W. Moe, J. Marin-Garcia, A. Konig, M. Goldenthal, X. Lu, and Q. Feng
In vivo TNF-{alpha} inhibition ameliorates cardiac mitochondrial dysfunction, oxidative stress, and apoptosis in experimental heart failure
Am J Physiol Heart Circ Physiol,
October 1, 2004;
287(4):
H1813 - H1820.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. E. Morley and R. N. Baumgartner
Cytokine-Related Aging Process
J. Gerontol. A Biol. Sci. Med. Sci.,
September 1, 2004;
59(9):
M924 - M929.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Morita, G. Stamp, P. Robins, A. Dulic, I. Rosewell, G. Hrivnak, G. Daly, T. Lindahl, and D. E. Barnes
Gene-Targeted Mice Lacking the Trex1 (DNase III) 3'->5' DNA Exonuclease Develop Inflammatory Myocarditis
Mol. Cell. Biol.,
August 1, 2004;
24(15):
6719 - 6727.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. M Janczewski, M. Zahid, B. H Lemster, C. S Frye, G. Gibson, Y. Higuchi, E. G Kranias, A. M Feldman, and C. F McTiernan
Phospholamban gene ablation improves calcium transients but not cardiac function in a heart failure model
Cardiovasc Res,
June 1, 2004;
62(3):
468 - 480.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Higuchi, C. F. McTiernan, C. B. Frye, B. S. McGowan, T. O. Chan, and A. M. Feldman
Tumor Necrosis Factor Receptors 1 and 2 Differentially Regulate Survival, Cardiac Dysfunction, and Remodeling in Transgenic Mice With Tumor Necrosis Factor-{alpha}-Induced Cardiomyopathy
Circulation,
April 20, 2004;
109(15):
1892 - 1897.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. B. Horwich, W. R. MacLellan, and G. C. Fonarow
Statin therapy is associated with improved survival in ischemic and non-ischemic heart failure
J. Am. Coll. Cardiol.,
February 18, 2004;
43(4):
642 - 648.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. A. Jortani, S. D. Prabhu, and R. Valdes Jr
Strategies for Developing Biomarkers of Heart Failure
Clin. Chem.,
February 1, 2004;
50(2):
265 - 278.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F.-X. Blanc, O. Langeron, C. Coirault, S. Salmeron, F. Lambert, B. Riou, and Y. Lecarpentier
Mechanical Properties of Tracheal Smooth Muscle Are Impaired in the Rabbit With Experimental Cardiac Pressure Overload
Chest,
January 1, 2004;
125(1):
236 - 242.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. C. Fonarow and T. B. Horwich
Cholesterol and mortality in heart failure: the bad gone good?
J. Am. Coll. Cardiol.,
December 3, 2003;
42(11):
1941 - 1943.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Adamopoulos, J. T. Parissis, I. Paraskevaidis, D. Karatzas, E. Livanis, M. Georgiadis, G. Karavolias, D. Mitropoulos, D. Degiannis, and D. Th. Kremastinos
Effects of growth hormone on circulating cytokine network, and left ventricular contractile performance and geometry in patients with idiopathic dilated cardiomyopathy
Eur. Heart J.,
December 2, 2003;
24(24):
2186 - 2196.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. A. Ahokas, K. J. Warrington, I. C. Gerling, Y. Sun, L. A. Wodi, P. A. Herring, L. Lu, S. K. Bhattacharya, A. E. Postlethwaite, and K. T. Weber
Aldosteronism and Peripheral Blood Mononuclear Cell Activation: A Neuroendocrine-Immune Interface
Circ. Res.,
November 14, 2003;
93
(10):
e124 - e135.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D B McKenzie and A J Cowley
Drug therapy in chronic heart failure
Postgrad. Med. J.,
November 1, 2003;
79(937):
634 - 642.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. B. Horwich, J. Patel, W. R. MacLellan, and G. C. Fonarow
Cardiac Troponin I Is Associated With Impaired Hemodynamics, Progressive Left Ventricular Dysfunction, and Increased Mortality Rates in Advanced Heart Failure
Circulation,
August 19, 2003;
108(7):
833 - 838.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Nakamura, S. Umemoto, G. Naik, G. Moe, S. Takata, P. Liu, and M. Matsuzaki
Induction of left ventricular remodeling and dysfunction in the recipient heart after donor heart myocardial infarction: new insights into the pathologic role of tumor necrosis factor-alpha from a novel heterotopic transplant-coronary ligation rat model
J. Am. Coll. Cardiol.,
July 2, 2003;
42(1):
173 - 181.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Stenvinkel, R. Pecoits-Filho, and B. Lindholm
Coronary Artery Disease in End-Stage Renal Disease: No Longer a Simple Plumbing Problem
J. Am. Soc. Nephrol.,
July 1, 2003;
14(7):
1927 - 1939.
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. He, Y. Liu, V. Sharma, R. T. Dirksen, R. Waugh, S.-S. Sheu, and W. Min
ASK1 Associates with Troponin T and Induces Troponin T Phosphorylation and Contractile Dysfunction in Cardiomyocytes
Am. J. Pathol.,
July 1, 2003;
163(1):
243 - 251.
[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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
E. Page, D. Assouline, O. Brun, D. Coeffic, D. Fric, P. Winckel, A. D. Seidman, M. K. Pierri, and C. Hudis
Cardiac Dysfunction in Clinical Trials of Trastuzumab
J. Clin. Oncol.,
October 1, 2002;
20(19):
4119 - 4120.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J J V McMurray
Heart failure in 10 years time: focus on pharmacological treatment
Heart,
October 1, 2002;
88(90002):
ii40 - 46.
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. N. Witherow, P. Dawson, C. A. Ludlam, K. A. A. Fox, and D. E. Newby
Marked bradykinin-induced tissue plasminogen activator release in patients with heart failure maintained on long-term angiotensin-converting enzyme inhibitor therapy
J. Am. Coll. Cardiol.,
September 4, 2002;
40(5):
961 - 966.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Funakoshi, T. Kubota, Y. Machida, N. Kawamura, A. M. Feldman, H. Tsutsui, H. Shimokawa, and A. Takeshita
Involvement of inducible nitric oxide synthase in cardiac dysfunction with tumor necrosis factor-alpha
Am J Physiol Heart Circ Physiol,
June 1, 2002;
282(6):
H2159 - H2166.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Funakoshi, T. Kubota, N. Kawamura, Y. Machida, A. M. Feldman, H. Tsutsui, H. Shimokawa, and A. Takeshita
Disruption of Inducible Nitric Oxide Synthase Improves {beta}-Adrenergic Inotropic Responsiveness but Not the Survival of Mice With Cytokine-Induced Cardiomyopathy
Circ. Res.,
May 17, 2002;
90(9):
959 - 965.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Yndestad, J. Kristian Damas, H. Geir Eiken, T. Holm, T. Haug, S. Simonsen, S. S. Froland, L. Gullestad, and P. Aukrust
Increased gene expression of tumor necrosis factor superfamily ligands in peripheral blood mononuclear cells during chronic heart failure
Cardiovasc Res,
April 1, 2002;
54(1):
175 - 182.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. B. Horwich, G. C. Fonarow, M. A. Hamilton, W. R. MacLellan, M. A. Woo, and J. H. Tillisch
The relationship between obesity and mortality in patients with heart failure
J. Am. Coll. Cardiol.,
September 1, 2001;
38(3):
789 - 795.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K S Channer and P J Pugh
Interfering with healing: the benefits of intervention during acute myocardial infarction
Heart,
June 1, 2001;
85(6):
620 - 622.
[Full Text]
|
|
|
|
|
|
|
W. W. Parmley
How Many Medicines Do Patients With Heart Failure Need?
Circulation,
March 27, 2001;
103(12):
1611 - 1612.
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. L. Clark
Perioperative Treatment of Congestive Heart Failure
Seminars in Cardiothoracic and Vascular Anesthesia,
November 1, 2000;
4(4):
223 - 235.
[Abstract]
[PDF]
|
|
|
|
<