Background Tumor necrosis factor alpha (TNF-alpha) increases in patients with severe congestive heart failure (CHF) and cachexia. Two naturally occurring modulators of TNF-alpha 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 Results This study was undertaken to examine the concentration of sTNF-Rs and of bioactive and antigenic TNF-alpha in 37 consecutive patients with various degrees of CHF compared with that of 26 age-matched healthy subjects. Antigenic TNF-alpha 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-alpha was undetectable (<100 pg/mL). Addition of 625 pg/mL recombinant human TNF-alpha (rhTNF-alpha), corresponding in the bioassay to 60% of the lethal dose, to the serum of healthy subjects resulted in a significant increase of the expected cytotoxicity (from 625 to 1290+/-411 pg/mL, P<.001). Addition of the same dose of rhTNF-alpha 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-alpha, sTNF-RI, NYHA class, norepinephrine, and atrial natriuretic peptide. Conclusions Measurement of sTNF-Rs, in addition to antigenic and bioactive TNF-alpha, 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-alpha. Antigenic TNF-alpha also increases in severe CHF. The increased levels of sTNF-RII independently correlate with poor short-term prognosis.
Tumor-necrosis-factor soluble receptors in patients with various degrees of congestive-heart-failure
CORTI , ANGELO;
1995-01-01
Abstract
Background Tumor necrosis factor alpha (TNF-alpha) increases in patients with severe congestive heart failure (CHF) and cachexia. Two naturally occurring modulators of TNF-alpha 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 Results This study was undertaken to examine the concentration of sTNF-Rs and of bioactive and antigenic TNF-alpha in 37 consecutive patients with various degrees of CHF compared with that of 26 age-matched healthy subjects. Antigenic TNF-alpha 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-alpha was undetectable (<100 pg/mL). Addition of 625 pg/mL recombinant human TNF-alpha (rhTNF-alpha), corresponding in the bioassay to 60% of the lethal dose, to the serum of healthy subjects resulted in a significant increase of the expected cytotoxicity (from 625 to 1290+/-411 pg/mL, P<.001). Addition of the same dose of rhTNF-alpha 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-alpha, sTNF-RI, NYHA class, norepinephrine, and atrial natriuretic peptide. Conclusions Measurement of sTNF-Rs, in addition to antigenic and bioactive TNF-alpha, 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-alpha. Antigenic TNF-alpha also increases in severe CHF. The increased levels of sTNF-RII independently correlate with poor short-term prognosis.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
