R. Ferrari et al., TUMOR-NECROSIS-FACTOR SOLUBLE RECEPTORS IN PATIENTS WITH VARIOUS DEGREES OF CONGESTIVE-HEART-FAILURE, Circulation, 92(6), 1995, pp. 1479-1486
Background Tumor necrosis factor alpha (TNF-alpha) increases in patien
ts with severe congestive heart failure (CHF) and cachexia. Two natura
lly 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 determ
ination of circulating sTNF-Rs could provide us with some additional i
nformation about the activation of this cytokine in CHF. Methods and R
esults 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 heal
thy 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 Yor
k 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 c
ytolytic bioassay, TNF-alpha was undetectable (<100 pg/mL). Addition o
f 625 pg/mL recombinant human TNF-alpha (rhTNF-alpha), corresponding i
n the bioassay to 60% of the lethal dose, to the serum of healthy subj
ects resulted in a significant increase of the expected cytotoxicity (
from 625 to 1290+/-411 pg/mL, P<.001). Addition of the same dose of rh
TNF-alpha to the serum of patients with mild to moderate CHF (NYHA cla
sses II and III) increased the cytotoxicity from 625 to 877+/-132 pg/m
L, P<.001. In 4 patients with severe CHF (class IV), the expected cyto
toxicity was completely inhibited, whereas it was reduced from 625 to
263+/-198 pg/mL, P<.001, in the remaining 8 patients. Ten patients die
d within 1 month of entry into the study. They had the highest level o
f sTNF-RII (8.18+/-1.92 ng/mL). sTNF-RII was a more powerful independe
nt indicator of mortality than TNF-alpha, sTNF-RI, NYHA class, norepin
ephrine, and atrial natriuretic peptide. Conclusions Measurement of sT
NF-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 th
e in vitro cytotoxicity of TNF-alpha. Antigenic TNF-alpha also increas
es in severe CHF. The increased levels of sTNF-RII independently corre
late with poor short-term prognosis.