Tumor Necrosis Factor Soluble Receptors in Patients With Various Degrees of Congestive Heart Failure

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Abstract
BackgroundTumor necrosis factor alpha (TNF-α) increases in patients with severe congestive heart failure (CHF) and cachexia. Two naturally occurring modulators of TNF-α activity have been identified in human serum. These two soluble proteins are the extracellular domains of the TNF receptors (sTNF-RI and sTNF-RII, respectively). The determination of circulating sTNF-Rs could provide us with some additional information about the activation of this cytokine in CHF.Methods and ResultsThis study was undertaken to examine the concentration of sTNF-Rs and of bioactive and antigenic TNF-α in 37 consecutive patients with various degrees of CHF compared with that of 26 age-matched healthy subjects. Antigenic TNF-α increased (from 14.3±7.08 to 33.5±13.1 pg/mL,P<.001) in preterminal patients with severe CHF (New York Heart Association [NYHA] class IV). In these patients, sTNF-Rs were also increased (sTNF-RI from 1.17±0.43 to 4.43±2.14 ng/mL and sTNF-RII from 2.2±0.44 to 7.55±2.28 ng/mL,P<.001). When measured by cytolytic bioassay, TNF-α was undetectable (P<.001). Addition of the same dose of rhTNF-α to the serum of patients with mild to moderate CHF (NYHA classes II and III) increased the cytotoxicity from 625 to 877±132 pg/mL,P<.001. In 4 patients with severe CHF (class IV), the expected cytotoxicity was completely inhibited, whereas it was reduced from 625 to 263±198 pg/mL,P<.001, in the remaining 8 patients. Ten patients died within 1 month of entry into the study. They had the highest level of sTNF-RII (8.18±1.92 ng/mL). sTNF-RII was a more powerful independent indicator of mortality than TNF-α, sTNF-RI, NYHA class, norepinephrine, and atrial natriuretic peptide.ConclusionsMeasurement of sTNF-Rs, in addition to antigenic and bioactive TNF-α, is essential for evaluation of the activation of this cytokine in CHF. Both sTNF-Rs increase in preterminal patients with severe CHF and might inhibit the in vitro cytotoxicity of TNF-α. Antigenic TNF-α also increases in severe CHF. The increased levels of sTNF-RII independently correlate with poor short-term prognosis.