Editorial
Tumor Necrosis Factor-a and Cardiomyopathy
Michael R. Bristow, MD, PhD
T
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he myocardium has limited options for responding to
an injury sufficient to cause decreased global contractile function. Myocardial pump performance can be
quickly stabilized by increased adrenergic drive, which
through b-adrenergic mechanisms increases cardiac output
via positive chronotropic and inotropic effects. In a kinetic
sense, the next available option for stabilizing pump function
is the Frank-Starling mechanism, whereby volume expansion
places the ventricles at a higher position in the preload-performance relationship. The renin-angiotensin and b-adrenergic systems appear to exert most of the signaling in this
regard. The third and slowest-to-develop option is to create
more contractile elements through a hypertrophic response
involving new synthesis of sarcomeres in individual cardiac
myocytes. The first two compensatory adjustments are very
powerful in humans and have probably evolved as protective
responses to trauma and blood loss. The hypertrophic response may also be considered in this context but in more of
a wound-healing paradigm that incorporates features of a
generalized inflammatory response. As such, a host of proinflammatory cytokines have been shown to be increased
systemically or in the myocardium of subjects with heart
failure. The first of these was tumor necrosis factor-a
(TNF-a),1 a 17-kD protein that acts through two distinct
receptors, TNFR1 and TNFR2. TNF-a produces a series of
powerful biological effects that include immunostimulation,
mediation of host resistance to bacteria, activation of protein
kinase C, and activation of the expression of a wide variety of
genes generally involved in inflammation or cell growth.2 In
an acute or subacute setting, most of these biological effects
of TNF-a are helpful in combating infection or responding to
injury.
mononuclear cells is lipopolysaccharide, or endotoxin, which
is shed from Gram-negative bacterial membranes. TNF-a
produces myocardial depression through a direct effect on
calcium handling7 and/or through nitric oxide production.8
Levine et al,1 in an attempt to identify factors responsible
for cardiac cachexia, first reported that TNF-a levels were
elevated in chronic heart failure. TNF-a can increase protein
catabolism in certain model systems,9 but TNF-a10 as well as
other lymphokines11 can also produce an increase in cardiac
protein synthesis and cardiac myocyte hypertrophy. Moreover, Mann’s laboratory has shown that in the failing human
heart, TNF-a production is induced in cardiac myocytes12 and
that chronic infusion of TNF-a in rats produces left ventricular contractile dysfunction and dilatation.13 Therefore, local
myocardial production of TNF-a becomes, along with neurotransmitter-derived norepinephrine, autocrine- or paracrineproduced endothelin, and hormonally or cytokine-derived
angiotensin II, a serious candidate for mediation of the
progression in myocardial dysfunction and remodeling that is
part of the natural history of chronic heart failure.14 As is the
case for angiotensin II and norepinephrine, the maladaptive
aspect of TNF-a in the failing heart is sustained production
and chronic cell signaling.
One approach to the evaluation of a myocardial pathophysiological candidate is transgenic manipulation of protein
expression. As developed by Robbins’ laboratory,15 proteins
can be selectively overexpressed in the myocardium of
transgenic animals, usually mice, by coupling of the coding
region of a gene to the cardiac-specific a-myosin heavy chain
promoter. Because of developmental and cardiac tissue–
specific regulation of transcription, this promoter becomes
progressively activated in adult development and is not active
during embryogenesis or the neonatal period. Thus, a protein
of interest can be expressed only in the adult heart, often at
very high levels. When a protein such as TNF-a is a
candidate for the production of myocardial disease, transgenic overexpression of it in the heart is a relatively straightforward approach to testing the hypothesis that the substance
is pathogenetically important. In the current issue of Circulation, Bryant et al16 overexpressed TNF-a in the hearts of
transgenic mice and report a phenotype of systolic dysfunction, myocarditis, and ventricular dilatation. These mice also
developed a heart failure syndrome consisting of lung and
liver congestion and increased mortality.16 The myocarditis
and increased mortality are similar to results recently reported
by Feldman’s laboratory,17 in which cardiac transgenic expression of TNF-a and mortality were higher than in the two
transgenic lines reported by Bryant et al. Feldman’s laboratory also recently reported18 another transgenic line expressing levels of cardiac TNF-a lower than those reported by
Bryant et al, which results in a dilated cardiomyopathy
phenotype without much inflammation. Therefore, the avail-
See p 1375
TNF-a, also known in the literature as cachectin, inasmuch
as the cytokine produces weight loss in cancer patients3 and
perhaps in end-stage heart failure patients,1,4 has a rich history
in cardiovascular pathophysiology. In 1985, Parrillo et al5
discovered that subjects afflicted with septic shock appeared
to have circulating in their bloodstream a “myocardial depressant substance,” among other cytokines, that later proved
to be TNF-a.6 In septic shock, the stimulus for the production
and release of TNF-a from activated macrophages and other
The opinions expressed in this editorial are not necessarily those of the
editors or of the American Heart Association.
From the Division of Cardiology, University of Colorado HSC,
Denver.
Correspondence to Michael R. Bristow, MD, PhD, Division of
Cardiology, University of Colorado HSC, 4200 E 9th Ave, Denver, CO
80262. (Circulation. 1998;97:1340-1341.)
© 1998 American Heart Association, Inc.
1340
Bristow
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able data for cardiac transgenic overexpression of TNF-a
indicate a direct relation between cytokine concentration and
inflammatory response or mortality.
What are the implications of these findings? For one thing,
the results in TNF-a cardiac overexpressor mice provide
additional evidence that cardiac inflammation can evolve to a
dilated cardiomyopathy, with TNF-a being an important
mediator of both processes. Second, even in the absence of
much overt cellular inflammation, an increase in the cardiac
expression of cytokine inflammatory mediators may contribute to myocardial dysfunction and remodeling,18 as has been
shown for the adrenergic and renin-angiotensin systems.1,19 –21
The one remaining step in the proof of the “TNF-a
hypothesis” is to demonstrate that treatment with agents that
inhibit the production or action of TNF-a prevent or reverse
myocardial dysfunction and remodeling in the failing human
heart. As a cautionary note, one such agent, vesnarinone,22
after encouraging results in smaller trials,24 recently increased
mortality in a large clinical trial.23 However, the mechanism
of action for lowering of TNF-a production by vesnarinone
probably involves phosphodiesterase inhibition,25 and
vesnarinone is also a potassium channel antagonist. One or
both of these effects may have been responsible for the
increase in mortality, and what is required for further hypothesis testing is more selective TNF-a inhibitors. One such
compound, soluble TNF-a receptors that bind and inactivate
TNF-a, was recently reported to transiently improve LV
function and to ameliorate symptoms and exercise intolerance
in subjects with chronic heart failure.26 However, large-scale
clinical trials will require a compound, presumably a small
molecule, that can inhibit production or biological action over
a long period of time. These compounds should be available
for clinical testing in the near future.
References
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KEY WORDS: Editorials
n TNF-a n cytokines n remodeling n heart failure
Tumor Necrosis Factor-α and Cardiomyopathy
Michael R. Bristow
Circulation. 1998;97:1340-1341
doi: 10.1161/01.CIR.97.14.1340
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