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(Circulation. 1999;99:3213-3214.)
© 1999 American Heart Association, Inc.

Editorial

TNF- and Heart Failure

The Difference Between Proof of Principle and Hypothesis Testing

Gary S. Francis, MD

From the George M. and Linda H. Kaufman Center for Heart Failure, The Cleveland Clinic Foundation, Cardiology Department, Cleveland, Ohio.

Correspondence to Gary S. Francis, MD, The George M. and Linda H. Kaufman Center for Heart Failure, The Cleveland Clinic Foundation, Cardiology Department, Desk F25, 9500 Euclid Ave, Cleveland, OH 44195. E-mail francig@cesmtp.ccf.org

Key Words: Editorials • heart failure • tumor necrosis factor

Cachexia (from the Greek kakos, meaning bad, and hexis, a state of being) has both fascinated and challenged clinicians and scientists for many years. It has been known since the earliest descriptions of heart failure that cachexia can be associated with the late stages of the syndrome. Cachectin, a hormone that suppresses the expression of lipoprotein lipase and other anabolic enzymes in fat, was purified in 1985.¹ Tumor necrosis factor (TNF) had been isolated much earlier, in the 1970s.² After the purification of cachectin, the complementary DNAs and genes encoding each protein were cloned almost immediately and were shown to be identical.³ Cachectin and TNF were one and the same. Since then, considerable evidence has accumulated suggesting a role of TNF in various inflammatory conditions,⁴ and TNF- is now known to be one of the most pleiotropic of all cytokines. Among a large number of cellular responses to TNF- are immunoregulation, transcriptional regulation, cytotoxicity, and antiviral activity.⁵ Two distinct TNF- receptors occur on multiple cell surfaces: a 55-kDa (TNF-R1) and a 75-kDa (TNF-R2) protein, with the TNF-R1 receptor subserving most of the activity of TNF, including cytotoxicity, fibroblast proliferation, bacterial resistance, prostaglandin E₂ synthesis, antiviral activity, and induction of superoxide dismutase.⁵ The TNF-R2 receptor subserves T-cell proliferation, dermal necrosis, and insulin resistance, although there are overlapping activities between TNF-R1 and TNF-R2. The cytoplasmic domains of the 2 receptors are structurally different, suggesting distinctive evolutionary signal transduction pathways.

Trimeric TNF- binds to several cell-surface receptors simultaneously, crosslinking the receptors to initiate . . . [Full Text of this Article]

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