The role of tumor necrosis factor in the pathophysiology of heart failure.
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.
Feldman
A M
AM
Cardiovascular Institute of the UPMC Health System, Pittsburgh, Pennsylvania 15213, USA. feldmanam@msx.upmc.edu
Combes
A
A
Wagner
D
D
Kadakomi
T
T
Kubota
T
T
Li
Y Y
YY
McTiernan
C
C
D000818:Animals; D015415:Biomarkers; D006321:Heart / Q000503:physiopathology; D006333:Heart Failure / Q000503:physiopathology*; D006801:Humans; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D015415:Biomarkers; D014409:Tumor Necrosis Factor-alpha