(Circulation. 1996;93:704-711.)
© 1996 American Heart Association, Inc.
Articles |
Tumor Necrosis Factor-
and Tumor Necrosis Factor Receptors in the Failing Human Heart
From the Cardiology Section of the Department of Medicine, Veterans Administration Medical Center, and Baylor College of Medicine, Houston, Tex; and the Cardiology Section of the Department of Medicine, University of Colorado, Denver (R.D.B.).
Background Tumor necrosis factor-
(TNF-) is a
proinflammatory cytokine that produces negative inotropic
effects in the heart. Recently, elevated levels of TNF- have been
reported in patients with advanced congestive heart failure. Although
TNF- is thought to exert its deleterious effects by binding to two
cell surface receptors, TNFR1 and TNFR2, the level of expression and
regulation of TNF receptors in the heart in cardiac disease states is
not known.
Methods and Results We examined mRNA and protein levels for
TNFR1, TNFR2, and TNF- in explanted hearts from organ donors as well
as in patients with end-stage dilated
cardiomyopathy (DCM) and ischemic heart
disease (IHD). Northern blot analysis revealed that mRNA for
TNFR1 and TNFR2 was present in nonfailing, DCM, and IHD hearts.
TNFR1 and TNFR2 receptor protein levels, as measured by ELISA, were
decreased 60% in DCM and IHD patients compared with nonfailing hearts
(P<.005). To determine a potential mechanism for the
decrease in TNF receptor expression, we measured levels of circulating
soluble TNF receptors (sTNFRs) in DCM and IHD patients. This
analysis showed that there was a significant
one-and-a-half to threefold increase in sTNFRs in DCM
(P<.03) and IHD patients (P<.001). Another
important finding was that TNF- mRNA and TNF- protein were
present in the explanted hearts from DCM and IHD patients but not
in nonfailing hearts.
Conclusions In summary, the results of this study
constitute the initial demonstration that TNF receptor proteins are
dynamically regulated in patients with advanced congestive heart
failure. Moreover, the observation that failing hearts express elevated
levels of TNF- suggests that overexpression of this cytokine
may be one of several different maladaptive mechanisms responsible for
the progressive cardiac decompensation that occurs in advanced heart
failure.
Key Words: cells, tumor necrosis factor- • receptors • heart failure
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