Abstract
A variety of clinical and experimental investigations have suggested that tumor necrosis factor alpha (TNF-α) may play a role in the pathophysiology of heart failure. Serum levels of TNF-α are elevated in patients with heart failure, and both cardiac and infiltrating cells of the myocardium can produce this proinflammatory cytokine. Both cardiac myocytes and nonmyocytes also express receptors for TNF-α, and experimental studies on isolated cells, muscles, and transgenic models demonstrate the ability of TNF-α to recapitulate functional and biochemical alterations resembling that observed in human congestive heart failure. The intracellular pathways affected by TNF-α include production of ceramide and an alteration in calcium metabolism. Recent studies in both animal models and clinical investigations suggest that anti-TNF-α therapies may limit the pathophysiologic consequences of congestive heart failure.
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References and Recommended Reading
Bristow MR, Ginsburg R, Umans V, et al.: Beta 1- and beta 2-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective beta 1-receptor down-regulation in heart failure. Circ Res 1986, 59:297–309.
Takahashi T, Allen PD, Izumo S: Expression of A-, B-, and C-type natriuretic peptide genes in failing and developing human ventricles. Correlation with expression of the Ca(2+)-ATPase gene. Circ Res 1992, 71:9–17.
Mercadier JJ, Lompre AM, Duc P, et al.: Altered sarcoplasmic reticulum Ca2(+)-ATPase gene expression in the human ventricle during end-stage heart failure. J Clin Invest 1990, 85:305–309.
Feldman AM, Ray PE, Silan CM, et al.: Selective gene expression in failing human heart. Quantification of steady-state levels of messenger RNA in endomyocardial biopsies using the polymerase chain reaction. Circulation 1991, 83:1866–1872.
Brillantes AM, Allen P, Takahashi T, et al.: Differences in cardiac calcium release channel (ryanodine receptor) dexpression in myocardium from patients with end-stage heart failure caused by ischemic versus dilated cardiomyopathy [published erratum appears in Circ Res 1992, 71:1538]. Circ Res 1992, 71:18–26.
Studer R, Reinecke H, Bilger J, et al.: Gene expression of the cardiac Na(+)-Ca2+ exchanger in end-stage human heart failure. Circ Res 1994, 75:443–453.
Nakao K, Minobe W, Roden R, et al.: Myosin heavy chain gene expression in human heart failure. J Clin Invest 1997, 100:2362–2370.
Lowes BD, Minobe W, Abraham WT, et al.: Changes in gene expression in the intact human heart. Downregulation of alpha-myosin heavy chain in hypertrophied, failing ventricular myocardium. J Clin Invest 1997, 100:2315–2324.
Li YY, Feldman AM, Sun Y, McTiernan CF: Differential expression of tissue inhibitors of metalloproteinases in the failing human heart. Circulation 1998, 98:1728–1734.
de Belder AJ, Radomski MW, Why HJ, et al.: Myocardial calcium-independent nitric oxide synthase activity is present in dilated cardiomyopathy, myocarditis, and postpartum cardiomyopathy but not in ischaemic or valvar heart disease. Br Heart J 1995, 74:426–430.
Haywood GA, Tsao PS, von der Leyen HE, et al.: Expression of inducible nitric oxide synthase in human heart failure [see comments]. Circulation 1996, 93:1087–1094.
Haunstetter A, Izumo S: Apoptosis: basic mechanisms and implications for cardiovascular disease. Circ Res 1998, 82:1111–1129. A thorough review article on the biochemistry of apoptosis and its potential relevance to cardiovascular diseases.
Carswell EA, Old LJ, Kassel RL, et al.: An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A 1975, 72:3666–3670.
Beutler B, Greenwald D, Hulmes JD, et al.: Identity of tumour necrosis factor and the macrophage-secreted factor cachectin. Nature 1985, 316:552–554.
Black RA, Rauch CT, Kozlosky CJ, et al.: A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature 1997, 385:729–733.
Vassalli P: The pathophysiology of tumor necrosis factors. Annu Rev Immunol 1992, 10:411–452.
Dembic Z, Loetscher H, Gubler U, et al.: Two human TNF receptors have similar extracellular, but distinct intracellular, domain sequences. Cytokine 1990, 2:231–237.
Engelmann H, Novick D, Wallach D: Two tumor necrosis factor-binding proteins purified from human urine. Evidence for immunological cross-reactivity with cell surface tumor necrosis factor receptors. J Biol Chem 1990, 265:1531–1536.
Seckinger P, Isaaz S, Dayer JM: A human inhibitor of tumor necrosis factor alpha. J Exp Med 1988, 167:1511–1516.
Levine B, Kalman J, Mayer L, et al.: Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 1990, 323:236–241.
Torre-Amione G, Kapadia S, Benedict C, et al.: Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD). J Am Coll Cardiol 1996, 27:1201–1206.
Testa M, Yeh M, Lee P, et al.: Circulating levels of cytokines and their endogenous modulators in patients with mild to severe congestive heart failure due to coronary artery disease or hypertension. J Am Coll Cardiol 1996, 28:964–971.
Ferrari R, Bachetti T, Confortini R, et al.: Tumor necrosis factor soluble receptors in patients with various degrees of congestive heart failure [see comments]. Circulation 1995, 92:1479–1486.
Torre-Amione G, Kapadia S, Lee J, et al.: Tumor necrosis factoralpha and tumor necrosis factor receptors in the failing human heart. Circulation 1996, 93:704–711.
Badorff C, Noutsias M, Kuhl U, Schultheiss HP: Cell-mediated cytotoxicity in hearts with dilated cardiomyopathy: correlation with interstitial fibrosis and foci of activated T lymphocytes. J Am Coll Cardiol 1997, 29:429–434.
Habib FM, Springall DR, Davies GJ, et al.: Tumour necrosis factor and inducible nitric oxide synthase in dilated cardiomyopathy [see comments]. Lancet 1996, 347:1151–1155.
Kapadia S, Lee J, Torre-Amione G, et al.: Tumor necrosis factor-alpha gene and protein expression in adult feline myocardium after endotoxin administration. J Clin Invest 1995, 96:1042–1052.
Wagner DR, McTiernan C, Sanders VJ, Feldman AM: Adenosine inhibits lipopolysaccharide-induced secretion of tumor necrosis factor-alpha in the failing human heart. Circulation 1998, 97:521–524.
Wagner DR, Combes A, McTiernan C, et al.: Adenosine inhibits lipopolysaccharide-induced cardiac expression of tumor necrosis factor-alpha. Circ Res 1998, 82:47–56.
Kapadia SR, Oral H, Lee J, et al.: Hemodynamic regulation of tumor necrosis factor-alpha gene and protein expression in adult feline myocardium. Circ Res 1997, 81:187–195.
Torre-Amione G, Stetson SJ, Youker KA, et al.: Decreased expression of tumor necrosis factor-alpha in failing human myocardium after mechanical circulatory support: A potential mechanism for cardiac recovery. Circulation 1999, 100:1189–1193.
Irwin MW, Mak S, Mann DL, et al.: Tissue expression and immunolocalization of tumor necrosis factor-alpha in postinfarction dysfunctional myocardium. Circulation 1999, 99:1492–1498.
Grosjean SA, Arstall MA, Mitchell RN, et al.: Inducible nitric oxide synthase and tumor necrosis factor in animal models of myocardial necrosis induced by coronary artery ligation or isoproterenol injection. J Card Fail 1999, 5:236–245.
Krown KA, Yasui K, Brooker MJ, et al.: TNF alpha receptor expression in rat cardiac myocytes: TNF alpha inhibition of L-type Ca2+ current and Ca2+ transients. FEBS Lett 1995, 376:24–30.
Murray DR, Freeman GL: Tumor necrosis factor-alpha induces a biphasic effect on myocardial contractility in conscious dogs. Circ Res 1996, 78:154–160.
Finkel MS, Oddis CV, Jacob TD, et al.: Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 1992, 257:387–389.
Goldhaber JI, Kim KH, Natterson PD, et al.: Effects of TNFalpha on [Ca2+]i and contractility in isolated adult rabbit ventricular myocytes. Am J Physiol 1996, 271:H1449-H1455.
Yokoyama T, Vaca L, Rossen RD, et al.: Cellular basis for the negative inotropic effects of tumor necrosis factor-alpha in the adult mammalian heart. J Clin Invest 1993, 92:2303–2312.
Chung MK, Gulick TS, Rotondo RE, et al.: Mechanism of cytokine inhibition of beta-adrenergic agonist stimulation of cyclic AMP in rat cardiac myocytes. Impairment of signal transduction. Circ Res 1990, 67:753–763.
Stein B, Frank P, Schmitz W, et al.: Endotoxin and cytokines induce direct cardiodepressive effects in mammalian cardiomyocytes via induction of nitric oxide synthase. J Mol Cell Cardiol 1996, 28:1631–1639.
Yokoyama T, Nakano M, Bednarczyk JL, et al.: Tumor necrosis factor-alpha provokes a hypertrophic growth response in adult cardiac myocytes. Circulation 1997, 95:1247–1252.
Li YY, McTiernan CF, Feldman AM: Proinflammatory cytokines regulate tissue inhibitors of metalloproteinases and disintegrin metalloproteinase in cardiac cells. Cardiovasc Res 1999, 42:162–172.
Gulick T, Chung MK, Pieper SJ, et al.: Interleukin 1 and tumor necrosis factor inhibit cardiac myocyte beta-adrenergic responsiveness. Proc Natl Acad Sci U S A 1989, 86:6753–6757.
Krown KA, Page MT, Nguyen C, et al.: Tumor necrosis factor alpha-induced apoptosis in cardiac myocytes. Involvement of the sphingolipid signaling cascade in cardiac cell death. J Clin Invest 1996, 98:2854–2865.
Tracey KJ, Vlassara H, Cerami A: Cachectin/tumour necrosis factor. Lancet 1989, 1:1122–1126.
Kubota T, McTiernan CF, Frye CS, et al.: Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-alpha. Circ Res 1997, 81:627–635.
Kubota T, Bounoutas GS, Miyagishima M, et al.: Soluble Tumor necrosis factor receptor abrogates myocardial inflammation but not hypertrophy in cytokine-induced cardiomyopathy. Circulation 2000, in press. This animal model of congestive heart failure, induced through cardiac-specific overexpression of TNF-a, shows some positive functional and biochemical changes in response to therapy with an adenovirus driving overexpression of a soluble TNF receptor-IgG fusion protein. These results may be compared with studies in patients with congestive heart failure that are treated with Enbrel.
Li YY, Feng YQ, Kadokami T, et al.: Modulation of matrix metalloproteinase activites remodels myocardial extracellular matrix in TNF-alpha transgenic mice. Circulation 1999, 100:I-752.
Kubota T, Bounoutas GS, Miyagishima M, et al.: Development of myocarditis in transgenic mice overexpressing tumor necrosis factor-alpha is mediated in part by the selctive induction of downstream proinflammatory cytokines and beta-chemokines. Circulation 1998, 98:I-345.
Kubota T, Miyagishima M, Bounoutas GS, et al.: Overexpression of tumor necrosis factor-alpha activates the expression of multiple members of the apoptosis pathway in transgenic mice. Circulation 1998, 98:I-462.
Pan X, Baker L, Lee JS, et al.: Atrial and ventricular arrhythmias in transgenic mice with myocardial expression of TNF-alpha. Circulation 1998, 98:I-745.
Dibbs ZL, Kalra D, Abdellatif M, et al.: Different cardiac phenotypes of secreted and membrane-bound TNF in transgenic mouse models of cardiac restricted overexpression of TNF. Circulation 1999, 100:I-16.
Bryant D, Becker L, Richardson J, et al.: Cardiac failure in transgenic mice with myocardial expression of tumor necrosis factor-alpha [see comments]. Circulation 1998, 97:1375–1381.
Bozkurt B, Kribbs SB, Clubb FJ Jr, et al.: Pathophysiologically relevant concentrations of tumor necrosis factor-alpha promote progressive left ventricular dysfunction and remodeling in rats. Circulation 1998, 97:1382–1391. This study confirmed that a prolonged infusion of physiologically relevant levels of TNF-a produced a decrease in contractile function that could be partially reversed through administration of an anti-TNF-a therapy consisting of a soluble TNF receptor-IgG fusion protein.
Oral H, Dorn GW 2nd, Mann DL: Sphingosine mediates the immediate negative inotropic effects of tumor necrosis factor-alpha in the adult mammalian cardiac myocyte. J Biol Chem 1997, 272:4836–4842.
Sabbadini RA, Betto R, Teresi A, et al.: The effects of sphingosine on sarcoplasmic reticulum membrane calcium release. J Biol Chem 1992, 267:15475–15484.
Francis SE, Holden H, Holt CM, Duff GW: Interleukin-1 in myocardium and coronary arteries of patients with dilated cardiomyopathy. J Mol Cell Cardiol 1998, 30:215–223.
Thaik CM, Calderone A, Takahashi N, Colucci WS: Interleukin-1 beta modulates the growth and phenotype of neonatal rat cardiac myocytes. J Clin Invest 1995, 96:1093–1099.
McTiernan CF, Lemster BH, Frye C, et al.: Interleukin-1 beta inhibits phospholamban gene expression in cultured cardiomyocytes. Circ Res 1997, 81:493–503.
Clerk A, Harrison JG, Long CS, Sugden PH: Pro-inflammatory cytokines stimulate mitogen-activated protein kinase subfamilies, increase phosphorylation of c-Jun and ATF2 and upregulate c-Jun protein in neonatal rat ventricular myocytes [In Process Citation]. J Mol Cell Cardiol 1999, 31:2087–2099.
Sugden PH, Clerk A: "Stress-responsive" mitogen-activated protein kinases (c-Jun N-terminal kinases and p38 mitogenactivated protein kinases) in the myocardium. Circ Res 1998, 83:345–352.
Kyriakis JM: Making the connection: coupling of stressactivated ERK/MAPK (extracellular-signal-regulated kinase/ mitogen-activated protein kinase) core signaling modules to extracellular stimuli and biological responses. Biochem Soc Symp 1999, 64:29–48.
Saklatvala J, Dean J, Finch A: Protein kinase cascades in intracellular signalling by interleukin-I and tumour necrosis factor. Biochem Soc Symp 1999, 64:63–77.
Wooley PH, Dutcher J, Widmer MB, Gillis S: Influence of a recombinant human soluble tumor necrosis factor receptor FC fusion protein on type II collagen-induced arthritis in mice. J Immunol 1993, 151:6602–6607.
Moreland LW, Schiff MH, Baumgartner SW, et al.: Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. Ann Intern Med 1999, 130:478–486.
Deswal A, Bozkurt B, Seta Y, et al.: Safety and efficacy of a soluble P75 tumor necrosis factor receptor (Enbrel, etanercept) in patients with advanced heart failure [see comments]. Circulation 1999, 99:3224–3226. The first published report suggesting that Enbrel may improve cardiac function in patients with significant cardiac dysfunction.
Bozkurt B, Torre-Aminoe G, Deswal A, et al.: Regression of left ventricular remodleing in chronic heart failure after treatment with ENBREL (Etanercept, p75 TNF receptor Fc Fusion protein). Circulation 1999, 100:I-645.
Sliwa K, Skudicky D, Candy G, et al.: Randomised investigation of effects of pentoxifylline on left-ventricular performance in idiopathic dilated cardiomyopathy. Lancet 1998, 351:1091–1093. This report presents data from a clinical study indicating that a potential anti-cytokine agent (pentoxifylline) may prove of benefit in improving cardiac function in congestive heart failure.
Oliver SJ, Freeman SL, Corral LG, et al.: Thalidomide analogue CC1069 inhibits development of rat adjuvant arthritis. Clin Exp Immunol 1999, 118:315–321.
Dibbs ZL, Longo T, Muller GW, et al.: Thalidomide and thalidomide analogs suppress TNF alpha secretion by myocytes. Circulation 1998, 98:I-247.
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McTiernan, C.F., Feldman, A.M. The role of tumor necrosis factor alpha in the pathophysiology of congestive heart failure. Curr Cardiol Rep 2, 189–197 (2000). https://doi.org/10.1007/s11886-000-0068-4
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DOI: https://doi.org/10.1007/s11886-000-0068-4