(Circulation. 1995;92:1379-1382.)
© 1995 American Heart Association, Inc.
Articles |
Is Tumor Necrosis Factor an Important Neurohormonal Mechanism in Chronic Heart Failure?
From the Division of Circulatory Physiology and Center for Heart Failure Research, Columbia University, College of Physicians and Surgeons, New York, NY.
Key Words: Editorials • tumor necrosis factor • heart failure • hormones
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Introduction |
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 Top Introduction References |
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Although heart failure has traditionally been regarded as a circulatory disorder, physicians have recognized for more than 2500 years that patients with heart failure share many of the clinical features of those afflicted with chronic inflammatory or neoplastic diseases.1 2 As heart failure advances, many patients develop a syndrome known as cardiac cachexia, which is characterized by a profound loss of lean body mass and anorexia and is accompanied by many of the biochemical changes of malnutrition (anemia, hypoalbuminemia, leukopenia, and hypocholesterolemia) and inflammation (increased erythrocyte sedimentation rate, fibrinogen, and acute-phase reactants).3 4 The pathogenesis of cardiac cachexia remained obscure for many years, until it was recognized that patients with cardiac cachexia have high circulating levels of tumor necrosis factor (TNF).5 This pluripotent cytokine causes cachexia, anorexia, and inflammation during long-term administration to experimental animals,6 and high circulating levels of TNF have been reported in patients with a variety of neoplastic, infectious, and collagen vascular disorders characterized by muscle wasting and malnutrition.7 8 9
The first study of elevated circulating levels of tumor necrosis factor in heart failure used a cytotoxicity assay to measure concentrations of the cytokine.5 In that study, we noted that circulating levels of the cytokine were increased primarily in patients with the most advanced symptoms, peripheral hypoperfusion and cachexia. Subsequent investigators, using immunologic assays to measure TNF, confirmed that levels of the cytokine were increased in patients with heart failure and that there was a relation between circulating levels of TNF and clinical features of the disease; furthermore, interventions that improved heart failure were accompanied by a decrease in circulating TNF.10 11 12 13 14 15 Because of the parallel findings of these reports, many assumed that the assessment of circulating TNF by the cytotoxicity assays would be highly correlated with its measurement by the immunologic assays, since the results of these assays are highly correlated in vitro when known quantities of recombinant TNF are added to culture media. However, we found no relation between circulating levels of the cytokine measured by one assay and those measured by the other (unpublished observations). This discrepancy is a common occurrence when TNF is measured in biological fluids and has three possible explanations.16 First, the immunoassay might detect precursor or denatured forms of TNF that are biologically inactive but retain important antigenic determinants. Second, the cytotoxicity assay might measure substances that share the cytotoxic properties of TNF but are antigenically distinct. Third, the secretion of TNF in vivo might be accompanied by the release of endogenously produced antagonists, which would interfere with the in vitro cytotoxicity but not the antigenicity of the cytokine.16 Increased circulating levels of such TNF antagonists were subsequently reported in patients with heart failure,17 but the importance of this observation remained uncertain. The article by Ferrari et al18 in this issue of Circulation sheds considerable light on the identity and potential importance of circulating TNF antagonists in patients with chronic heart failure. These authors note that patients with heart failure had elevated levels of antigenic TNF (measured by ELISA) and that the magnitude of these levels was related to the severity of the disease, assessed by either clinical, hemodynamic, or neurohormonal variables. However, none of the patients with elevated levels of antigenic TNF showed elevated levels of biologically active TNF (as assessed by a cytotoxicity assay). This discrepancy was related to the presence of high levels of circulating antagonists in the patients with high levels of antigenic TNF; these antagonists acted to block the cytotoxicity but not the immunogenicity of TNF. Interestingly, these circulating antagonists were identified as soluble forms of the TNF receptor, which are known to be shed from target cells upon interaction with cytokine and to circulate in the blood stream. Ferrari et al18 noted that the level of soluble receptors was closely correlated with serum levels of TNF, and high levels of soluble receptors were measured primarily in patients with the most advanced disease, assessed either by specific clinical, hemodynamic, and neurohormonal variables or by the patient's prognosis.
The finding of high levels of circulating TNF antagonists in heart failure raises questions far beyond their ability to impair the interpretation of conventional bioassays. Their presence suggests the possibility that the shedding of TNF receptors in patients with high circulating levels of the cytokine functions as an adaptive response that effectively neutralizes the biological actions of TNF in heart failure.17 18 20 Not only does the shedding of TNF receptors reduce the number of active receptors that are necessary for TNF action,21 but circulating receptors also can block the actions of TNF on target cells.20 22 Indeed, some investigators have raised doubts that TNF exerts any important biological actions in heart failure and have suggested that the finding of increased levels of TNF in heart failure has little clinical relevance.17 However, although TNF receptors are required for the action of TNF on cells, a reduction in TNF receptor density as a result of shedding does not necessarily blunt its actions.23 Furthermore, neutralization of the actions of TNF as a result of the formation of soluble receptor-TNF complexes is likely only if soluble receptors circulate at extremely high levels.20 22
Indeed, some investigators have suggested that soluble TNF receptors may enhance, rather than attenuate, the biological actions of TNF in both the experimental and clinical settings. By binding to TNF, soluble TNF receptors appear to stabilize the cytokine and thereby prolong its half-life and biological functions.22 24 In effect, the release of soluble receptors acts to establish a circulating reservoir for TNF, which can then slowly release TNF to target cells. Since the effects of TNF may be related more to the persistence of the cytokine rather than to its peak levels,25 such a reservoir may markedly potentiate the actions of TNF on target cells. This concept may explain why the administration of soluble TNF receptors to experimental animals does not prevent and may enhance the actions of TNF in target organs,26 although such receptors inhibit the detection of the cytokine by conventional cytotoxicity assays.
Finally, it is possible that circulating receptors act neither to enhance nor to neutralize the actions of TNF in vivo but may simply provide a sensitive marker for the interaction of the cytokine with its target cells.27 If so, the role of soluble TNF receptors would be similar to that reported for other soluble cytokine receptors; eg, high levels of soluble interleukin-2 receptors do not neutralize the actions of interleukin-2 but are a sensitive marker of immune activation.28 Viewed from this perspective, the observation by Ferrari et al that soluble TNF receptor levels are increased in heart failure indicates that the elevation of TNF is not simply an epiphenomenon but rather that the cytokine is activating its target receptors in patients with this disorder. Further evidence that TNF is exerting biological effects comes from the measurement of circulating neopterin. After TNF receptor activation, a major action of TNF is to augment intracellular levels of tetrahydrobiopterin (an important cofactor for nitric oxide biosynthesis) and its inactive metabolite, neopterin.29 Whereas the measurement of soluble receptors reflects early events in the action of TNF on target cells, the measurement of neopterin reflects later effects of the cytokine (eg, beyond the receptor). Levels of both soluble TNF receptors and neopterin are increased in patients with neoplastic and chronic inflammatory disorders characterized by cachexia and high levels of TNF.30 Similarly, circulating levels of soluble TNF receptors as well as neopterin are increased in patients with heart failure, are closely correlated with circulating levels of TNF as well as the presence of cardiac cachexia, and carry a poor prognosis.13 31 Indeed, both the level of soluble TNF receptors and that of neopterin may be more sensitive and specific markers of the actions of TNF in clinical disorders than the measurement of TNF itself.
What are the biological effects of TNF in patients with heart failure? Although TNF may cause many of the clinical features of cardiac cachexia, it is more intriguing to postulate that TNF may contribute directly to the syndrome of heart failure. The most fundamental clinical feature of patients with heart failure is their exercise intolerance. Interestingly, this impairment in functional capacity is related not only to a reduced ability of the heart to eject blood but also to a defect in the periphery,32 due in part to an impairment in the ability of peripheral blood vessels to dilate in response to increased flow and in part to a decrease in the strength and endurance of skeletal muscles.33 The deficit in peripheral vasodilator capacity is the result of attenuation of the normal functions of the vascular endothelium due to a loss of the ability of the endothelium to release nitric oxide in response to physiological stimuli.34 35 The skeletal muscle defect appears to be related to the atrophy of specific muscle fibers, which impairs the ability of the muscle to generate and sustain its contraction.33 Interestingly, both abnormalities might be explained by the known biological effects of TNF. Specifically, TNF may cause endothelial dysfunction36 by decreasing the levels of mRNA for the enzyme responsible for endothelial nitric oxide synthesis37 or by increasing the production of reactive oxygen intermediates by vascular smooth muscle, which can destroy the nitric oxide produced by the endothelium.38 In addition, TNF can impair the synthesis and accelerate the catabolism of protein in skeletal muscle.39 Hence, the increase in TNF observed in patients with New York Heart Association functional class IV symptoms may contribute importantly to the severe limitation of exercise tolerance that is so characteristic of these patients.
Even more intriguing is the possibility that TNF may contribute to the progression of heart failure by exerting direct effects on the impaired left ventricle. The possibility that the failing heart itself may be a target organ for TNF is strongly supported by recent evidence that the density of cardiac receptors for TNF are decreased in patients with heart failure (D. Mann, personal communication), presumably as a result of the shedding of these receptors as the cytokine attaches to cardiac cells. As a consequence of the interaction with its cardiac receptors, TNF acts to increase intracellular levels of tetrahydrobiopterin, which acts as a cofactor to enhance the expression of the enzyme, inducible nitric oxide synthase.29 The resulting increase in nitric oxide within the heart not only may inhibit the contractility of myocardial cells40 but also may be cytotoxic by virtue of its ability to trigger apoptosis, a type of programmed cell death.41 42 The risk of cell death may also be increased by the ability of TNF to enhance the expression of proto-oncogenes,43 which are important cofactors to the apoptotic process.44 Hence, TNF may contribute importantly to the increased expression of inducible nitric oxide synthase and proto-oncogenes as well as the occurrence of apoptosis reported in failing hearts.45 46 47
Could these deleterious effects of TNF on the heart be blocked to the advantage of patients with heart failure? It is provocative to suggest that the development of pharmacological agents that suppress the synthesis or block the actions of TNF would be useful in preventing or delaying the progression of heart failure, but the utility of specific TNF inhibitors in this disorder has not yet been explored. Although some drugs (eg, vesnarinone) that have been reported to prolong life in patients with chronic heart failure48 may act to block the synthesis or release of TNF,49 any relation between the inhibitory effects of vesnarinone on cytokines and its effects on survival remains speculative at the present time. Such caution seems particularly warranted since some drugs that are known to increase the risk of death in patients with chronic heart failure50 (ie, milrinone and other phosphodiesterase inhibitors) can also suppress the synthesis and release of tumor necrosis factor.51
What is the stimulus to the increased TNF production in patients with heart failure? Since the major source of TNF in many disease states is the activated macrophage, this cell has also been postulated to be the major source of TNF in heart failure. This possibility was supported by early reports that serum levels of neopterin were increased in heart failure associated with myocardial inflammation.52 However, subsequent work has demonstrated that the increased levels of TNF, soluble TNF receptors, and neopterin are not dependent on the cause of heart failure and that levels are increased to a similar extent in both ischemic and dilated cardiomyopathy.5 53 This observation has led investigators to conclude that the increase in TNF in heart failure is related to the presence of heart failure rather than the cause of heart failure. What hemodynamic or neurohormonal abnormality of heart failure could stimulate the production of TNF? The increase in prostaglandin E seen in patients with class IV symptoms could stimulate circulating macrophages to produce TNF54 55 ; this hypothesis suggests that TNF might affect the heart primarily by acting as a circulating hormone. However, the fact that most cytokines act at an autocrine or paracrine level raises the possibility that the major source of TNF in heart failure may be the heart itself. Indeed, the expression of TNF is enhanced in failing hearts,56 57 although the precise stimulus for such increased myocardial expression remains to be elucidated.
These insights into the mechanisms of TNF action give special meaning to the venerable term "cardiac cachexia." For centuries, physicians marveled at the clinical wasting that characterized patients with advanced heart failure. To many observers, it seemed that the body was consuming itself, adding enormously to the disability imposed by the cardiac disorder. Yet, we have learned in the past few years that this process of self-destruction may not be confined to the peripheral organs but may also characterize the process occurring within the heart itself. It now seems possible that the failing heart synthesizes a locally active cytokine that induces the heart to commit suicide, literally, at the most fundamental molecular level. The possibility that heart failure leads to the excessive endogenous elaboration of deleterious substances is not new; several cardiovascular hormones have been postulated to exert detrimental effects in this syndrome.58 However, cytokines are not generally classified as cardiovascular hormones, since they neither are specifically produced by nor specifically act on the cardiovascular system. The observation that TNF is activated in patients with heart failure and can adversely affect myocardial and vascular function suggests that we may need to greatly expand our current perspective of neurohormonal activation as a pathogenetic factor in the development and progression of this disorder.
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Footnotes |
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Reprint requests to Milton Packer, MD, Division of Circulatory Physiology, Columbia-Presbyterian Medical Center, 630 W 168th Street, New York, NY 10032.
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References |
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A. Deswal, N. J. Petersen, A. M. Feldman, B. G. White, and D. L. Mann Effects of Vesnarinone on Peripheral Circulating Levels of Cytokines and Cytokine Receptors in Patients With Heart Failure : A Report From the Vesnarinone Trial Chest, August 1, 2001; 120(2): 453 - 459. [Abstract] [Full Text] [PDF]
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T. M. Behr, X. Wang, N. Aiyar, R. W. Coatney, X. Li, P. Koster, C. E. Angermann, E. Ohlstein, G. Z. Feuerstein, and J. Winaver Monocyte Chemoattractant Protein-1 is Upregulated in Rats With Volume-Overload Congestive Heart Failure Circulation, September 12, 2000; 102(11): 1315 - 1322. [Abstract] [Full Text] [PDF]
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C. Piper, J. Bilger, E.-M. Henrichs, H.-P. Schultheiss, D. Horstkotte, and A. Doerner Is myocardial Na+/Ca2+ exchanger transcription a marker for different stages of myocardial dysfunction? Quantitative polymerase chain reaction of the messenger RNA in endomyocardial biopsies of patients with heart failure J. Am. Coll. Cardiol., July 1, 2000; 36(1): 233 - 241. [Abstract] [Full Text] [PDF]
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K. C. Wollert, J. Heineke, J. Westermann, M. Ludde, B. Fiedler, W. Zierhut, D. Laurent, M. K. A. Bauer, K. Schulze-Osthoff, and H. Drexler The Cardiac Fas (APO-1/CD95) Receptor/Fas Ligand System : Relation to Diastolic Wall Stress in Volume-Overload Hypertrophy In Vivo and Activation of the Transcription Factor AP-1 in Cardiac Myocytes Circulation, March 14, 2000; 101(10): 1172 - 1178. [Abstract] [Full Text] [PDF]
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L. Agnoletti, S. Curello, T. Bachetti, F. Malacarne, G. Gaia, L. Comini, M. Volterrani, P. Bonetti, G. Parrinello, M. Cadei, et al. Serum From Patients With Severe Heart Failure Downregulates eNOS and Is Proapoptotic : Role of Tumor Necrosis Factor-{alpha} Circulation, November 9, 1999; 100(19): 1983 - 1991. [Abstract] [Full Text] [PDF]
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L. Comini, T. Bachetti, L. Agnoletti, G. Gaia, S. Curello, B. Milanesi, M. Volterrani, G. Parrinello, C. Ceconi, A. Giordano, et al. Induction of functional inducible nitric oxide synthase in monocytes of patients with congestive heart failure. Link with tumour necrosis factor-{alpha} Eur. Heart J., October 2, 1999; 20(20): 1503 - 1513. [Abstract] [PDF]
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R. Nishio, A. Matsumori, T. Shioi, H. Ishida, and S. Sasayama Treatment of Experimental Viral Myocarditis With Interleukin-10 Circulation, September 7, 1999; 100(10): 1102 - 1108. [Abstract] [Full Text] [PDF]
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M. R. Bergman, R. H. Kao, S. A. McCune, and B. J. Holycross Myocardial tumor necrosis factor-alpha secretion in hypertensive and heart failure-prone rats Am J Physiol Heart Circ Physiol, August 1, 1999; 277(2): H543 - H550. [Abstract] [Full Text] [PDF]
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G. W Moe and P. Armstrong Pacing-induced heart failure: a model to study the mechanism of disease progression and novel therapy in heart failure Cardiovasc Res, June 1, 1999; 42(3): 591 - 599. [Full Text] [PDF]
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S.D. Anker, P.P. Ponikowski, A.L. Clark, F. Leyva, M. Rauchhaus, M. Kemp, M.M. Teixeira, P.G. Hellewell, J. Hooper, P.A. Poole-Wilson, et al. Cytokines and neurohormones relating to body composition alterations in the wasting syndrome of chronic heart failure Eur. Heart J., May 1, 1999; 20(9): 683 - 693. [Abstract] [PDF]
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R. Nishio, A. Matsumori, T. Shioi, W. Wang, T. Yamada, K. Ono, and S. Sasayama Denopamine, a {beta}1-adrenergic agonist, prolongs survival in a murine model of congestive heart failure induced by viral myocarditis: suppression of tumor necrosis factor-{alpha} production in the heart J. Am. Coll. Cardiol., September 1, 1998; 32(3): 808 - 815. [Abstract] [Full Text] [PDF]
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W. H. Barry Load-Dependent Myocyte Dysfunction Circulation, June 16, 1998; 97(23): 2297 - 2298. [Full Text] [PDF]
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B. Bozkurt, S. B. Kribbs, F. J. Clubb Jr, L. H. Michael, V. V. Didenko, P. J. Hornsby, Y. Seta, H. Oral, F. G. Spinale, and D. L. Mann Pathophysiologically Relevant Concentrations of Tumor Necrosis Factor-{alpha} Promote Progressive Left Ventricular Dysfunction and Remodeling in Rats Circulation, April 14, 1998; 97(14): 1382 - 1391. [Abstract] [Full Text] [PDF]
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 D. R. Meldrum Tumor necrosis factor in the heart Am J Physiol Regulatory Integrative Comp Physiol, March 1, 1998; 274(3): R577 - R595. [Abstract] [Full Text] [PDF]
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R. Ferrari Tumor necrosis factor in CHF: a double facet cytokine Cardiovasc Res, March 1, 1998; 37(3): 554 - 559. [Full Text] [PDF]
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 C. Oakley Aetiology, diagnosis, investigation, and management of the cardiomyopathies BMJ, December 6, 1997; 315(7121): 1520 - 1524. [Full Text]
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T. De Marco and L. Goldman Predicting Outcomes in Severe Heart Failure Circulation, June 17, 1997; 95(12): 2597 - 2599. [Full Text]
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T. Yokoyama, M. Nakano, J. L. Bednarczyk, B. W. McIntyre, M. Entman, and D. L. Mann Tumor Necrosis Factor-{alpha} Provokes a Hypertrophic Growth Response in Adult Cardiac Myocytes Circulation, March 4, 1997; 95(5): 1247 - 1252. [Abstract] [Full Text]
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