(Circulation. 1999;99:3213-3214.)
© 1999 American Heart Association, Inc.
Editorial |
TNF-
and Heart Failure
The Difference Between Proof of Principle and Hypothesis Testing
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{at}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
signal transduction. There is the possibility that shedding of surface
membrane TNF- receptors in patients with heart failure and increased
circulating levels of TNF- may combine to neutralize the biological
actions of TNF- in heart failure.6 Soluble circulating
TNF- receptors may bind to circulating TNF-, rendering the
cytokine less active. Alternatively, a protein can be
genetically engineered that couples, or fuses, the Fc portion of
heavy-chain IgG to the extracellular domain of the TNF- receptor,
rendering the TNF- molecule less active. Chimeric
inhibitors of TNF- are now beginning to emerge as
potential new anti-inflammatory drugs, and it is natural that they be
considered for heart failure.
It has been nearly a decade since Levine et al,7
using a bioassay system, provided evidence demonstrating that
circulating levels of TNF- are elevated in patients with severe
chronic heart failure. Because of repeated observations that TNF- is
increased in the blood of patients with cardiac injury, including
inflammatory myocarditis,8 9 acute myocardial
infarction,10 and unstable angina pectoris,11
it is reasonable to assume that it evolved as one of many
protective responses to cellular injury. Over the past decade, Mann and
his group have performed a series of experiments examining the role of
TNF- in both experimental and clinical heart failure. Among the
findings are data demonstrating that TNF- production is
induced in cardiac myocytes12 and that chronic infusion of
TNF- in rats produces left ventricular contractile
dysfunction and dilatation.13 Supporting evidence that
overproduction of TNF- by cardiac myocytes is sufficient to
cause severe cardiac disease has been provided by Bryant and
colleagues,14 who overexpressed the protein in hearts of
transgenic mice, leading to a phenotype characterized by
systolic dysfunction, cardiac inflammation,
ventricular dilatation, congested tissue, and increased
mortality. Another transgenic line of mice from Feldman's laboratory
also overexpressed TNF-, albeit at a lower level, producing a
phenotype with dilated cardiomyopathy
without much inflammation.15 The Feldman experiments used
a single transgenic line, and the gene dose effect is not clear. Yet,
the accumulated evidence supports the concept that this
cytokine, like the neurotransmitter norepinephrine
and the peptides angiotensin II and endothelin, helps to
orchestrate a response to injury that ultimately leads to cardiac
dysfunction and progressive heart failure. There is now proof of
principle for this important concept. In the aggregate, these findings
also support the broader hypothesis that neurohumoral activation and
cytokine production contribute importantly to the
pathogenesis of progressive heart failure.
An experiment of nature further supports the possible role of TNF-
in the genesis of progressive heart failure. The recently described
mutation of a gene that normally encodes for AMP deaminase 1 (AMPD1)
may be associated with delayed progression of heart
failure.16 As a consequence of diminished
adenosine deamination, patients having a mutation in 
1
allele of the AMPD1 gene may develop heightened intracellular
cardiac myocyte adenosine levels. High levels of cardiac
myocyte adenosine would then be expected to attenuate TNF-
expression,17 thus retarding progression of heart failure
and providing a potential mechanism whereby a point mutation may
benefit patients.
In the case of the sympathetic nervous system and the renin-angiotensin-aldosterone system, the neurohumoral hypothesis has been tested beyond proof of principle. There is now abundant clinical evidence that ACE inhibitors18 19 and ß-adrenergic blocking agents20 21 favorably alter the natural history of patients with heart failure. Recently published guidelines recommend the use of ACE inhibitors and ß-adrenergic blockers for the treatment of chronic heart failure,22 although additional data regarding the use of ß-adrenergic blockers in patients in NYHA classes I and IV are eagerly awaited. In the case of TNF, we also have proof of principle, but hypothesis testing remains incomplete.
In the current issue of Circulation, Deswal et
al23 report on the use of a soluble p75 TNF receptor
fusion protein that essentially blocks the effects of TNF in a small
group of patients with NYHA class III heart failure and elevated
TNF- levels. Patients were randomly allocated to treatment or
vehicle in a double-blind dose-escalation study to examine the safety
and potential efficacy of a single intravenous infusion of
etanercept, a TNF fusion protein antagonist. The results
indicate no significant side effects, a decrease in the biologically
active levels of TNF-, and an increase in quality-of-life scores,
6-minute walk distance, and ejection fraction. The study offers further
proof of principle and suggests a green light to proceed with a
large-scale clinical trial to further test the cytokine
hypothesis. Such a trial is about to be launched with the p75 TNF
receptor fusion protein in patients with heart failure.
As with all preliminary phase I and II trials, caveats are in order. The numbers of patients receiving the full dose are very small. Absolute values for the end points are not provided; rather, the authors elected to provide only percent change from baseline and did not make comparisons against placebo. The dose of etanercept that will prove both safe and most effective must be carefully determined. Recent data suggest that 12 mg/m2, slightly higher than the maximum dose of 10 mg/m2 used by Deswal et al, may be more effective.24 The time course over which the fusion protein must be given is not clear. Why did the investigators choose to block the TNF-R2, when the preponderance of TNF biological activity, including apoptosis, is mediated by TNF-R1? Is there rebound hemodynamic deterioration if the fusion protein dose is reduced or stopped? As with all immunomodulators, will such patients be at risk for infection? Unlike rheumatoid arthritis and inflammatory bowel disease, for which TNF inhibitors show great promise, heart failure is not generally considered to be a purely inflammatory condition. It is a highly complex syndrome that incorporates many noninflammatory features, such as growth, apoptosis, heightened matrix metalloproteinase activity, protein isoform switches, altered Ca2+ transients, and unusual mechanical forces on integrins that signal the nucleus through a variety of pathways. The quantitative contribution that cytokines make toward the pathophysiology of heart failure is still not clear. Despite these caveats, the Mann laboratory is to be congratulated for fulfilling Koch's postulates with a highly innovative treatment strategy. We have proof of principle. The cytokine hypothesis, however, remains to be tested, and only a large randomized clinical trial can provide this forum.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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