TNF-α and Heart Failure
1999; Lippincott Williams & Wilkins; Volume: 99; Issue: 25 Linguagem: Inglês
10.1161/01.cir.99.25.3213
ISSN1524-4539
Autores Tópico(s)Adipokines, Inflammation, and Metabolic Diseases
ResumoHomeCirculationVol. 99, No. 25TNF-α and Heart Failure Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBTNF-α and Heart Failure The Difference Between Proof of Principle and Hypothesis Testing Gary S. Francis Gary S. FrancisGary S. Francis From the George M. and Linda H. Kaufman Center for Heart Failure, The Cleveland Clinic Foundation, Cardiology Department, Cleveland, Ohio. Originally published29 Jun 1999https://doi.org/10.1161/01.CIR.99.25.3213Circulation. 1999;99:3213–3214Cachexia (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-α is now known to be one of the most pleiotropic of all cytokines. Among a large number of cellular responses to TNF-α are immunoregulation, transcriptional regulation, cytotoxicity, and antiviral activity.5 Two distinct TNF-α 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-α binds to several cell-surface receptors simultaneously, crosslinking the receptors to initiate signal transduction. There is the possibility that shedding of surface membrane TNF-α receptors in patients with heart failure and increased circulating levels of TNF-α may combine to neutralize the biological actions of TNF-α in heart failure.6 Soluble circulating TNF-α receptors may bind to circulating TNF-α, 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-α receptor, rendering the TNF-α molecule less active. Chimeric inhibitors of TNF-α 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-α are elevated in patients with severe chronic heart failure. Because of repeated observations that TNF-α is increased in the blood of patients with cardiac injury, including inflammatory myocarditis,89 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-α in both experimental and clinical heart failure. Among the findings are data demonstrating that TNF-α production is induced in cardiac myocytes12 and that chronic infusion of TNF-α in rats produces left ventricular contractile dysfunction and dilatation.13 Supporting evidence that overproduction of TNF-α 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-α, 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-α 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-α 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 inhibitors1819 and β-adrenergic blocking agents2021 favorably alter the natural history of patients with heart failure. Recently published guidelines recommend the use of ACE inhibitors and β-adrenergic blockers for the treatment of chronic heart failure,22 although additional data regarding the use of β-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-α 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-α, 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.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.FootnotesCorrespondence 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 [email protected] References 1 Beutler B, Mahoney J, Le Trang N, Pekala P, Cerami A. Purification of cachectin, a lipoprotein lipase-suppressing hormone secreted by endotoxin-induced RAW 264.7 cells. J ExpMed.1985; 161:984–995.Google Scholar2 Carswell EA, Old LJ, Kassell RL, Green S, Fiore N, Williamson B. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A.1975; 72:3666–3670.CrossrefMedlineGoogle Scholar3 Beutler B, Greenwald D, Hulmes JD, Chang M, Pan YC, Mathison J, Ulevitch R, Cerami A. Identity of tumour necrosis factor and the macrophage-secreted factor cachectin. Nature.1985; 316:552–554.CrossrefMedlineGoogle Scholar4 Bazzoni F, Beutler B. The tumor necrosis factor ligand and receptor families. N Engl J Med.1996; 334:1717–1725.CrossrefMedlineGoogle Scholar5 Tartaglia LA, Ayres TM, Wong GHW, Goeddel DV. A novel domain within the 55 kd TNF receptor signals cell death. Cell.1993; 74:845–853.CrossrefMedlineGoogle Scholar6 Ferrari R, Bachetti T, Confortini R, Opasich C, Febo O, Corti A, Cassani G, Visioli O. Tumor necrosis factor soluble receptors in patients with various degrees of chronic heart failure. Circulation.1995; 92:1479–1486.CrossrefMedlineGoogle Scholar7 Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med.1990; 323:236–241.CrossrefMedlineGoogle Scholar8 Smith SC, Allen PM. 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Circulation.1995; 92:1487–1493.CrossrefMedlineGoogle Scholar13 Yokoyama T, Vaca L, Rossen RD, Durante W, Hazarik P, Mann DL. Cellular basis for the negative inotropic effects of tumor necrosis factor-αin the adult mammalian heart. J Clin Invest.1993; 92:2303–2312.CrossrefMedlineGoogle Scholar14 Bryant D, Becker L, Richardson J, Shelton J, Franco F, Peshock R, Thompson M, Giroir B. Cardiac failure in transgenic mice with myocardial expression of tumor necrosis factor-α. Circulation.1998; 97:1375–1381.CrossrefMedlineGoogle Scholar15 Kubota T, McTiernan CF, Frye CS, Slawson SE, Lemester BH, Koretsky AP, Demetris J, Feldman AM. Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-α. Circ Res.1997; 81:627–635.CrossrefMedlineGoogle Scholar16 Loh E, Rebbeck TR, Mahoney PD, NeNofrio D, Swain JL, Holmes EW. Common variant in AMPD1 gene predicts improved clinical outcome in patients with heart failure. Circulation.1999; 99:1422–1425.CrossrefMedlineGoogle Scholar17 Wagner DR, Combes A, McTiernan C, Sanders VJ, Lemster B, Feldman AM. Adenosine inhibits lipopolysaccharide-induced cardiac expression of tumor necrosis factor-α. Circ Res.1998; 82:47–56.CrossrefMedlineGoogle Scholar18 The CONSENSUS trial study group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med.1987; 316:1429–1435.CrossrefMedlineGoogle Scholar19 The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med.1991; 325:293–302.CrossrefMedlineGoogle Scholar20 Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, Shusterman NH. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med.1996; 334:1349–1355.CrossrefMedlineGoogle Scholar21 CIBIS-II Investigators, and Committees. The cardiac insufficiency bisoprolol study II (CIBIS-II): a randomised trial. Lancet.1999; 353:9–13.CrossrefMedlineGoogle Scholar22 Packer M, Cohn JN. Consensus recommendations for the management of chronic heart failure. Am J Cardiol.1999; 83:2A–38A.Google Scholar23 Deswal A, Bozkurt B, Seta Y, Parilti-Eiswirth S, Hayes FA, Blosch C, Mann DL. Safety and efficacy of a soluble p75 tumor necrosis factor receptor (enbrel, etanercept) in patients with advanced heart failure. 1999;99:3224–3226.Google Scholar24 Bozkurt B, Torre-Amione G, Soran OZ, Feldman AM, Blosch C, Warren M, Mann DL. Results of multidose phase I trial with tumor necrosis factor receptor (p. 75) fusion protein (etanercept) in patients with heart failure. J Am Coll Cardiol.1999; 33:184A. 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