This Article Extract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bristow, M. R. Search for Related Content PubMed PubMed Citation Articles by Bristow, M. R. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Cardiomyopathy

(Circulation. 1998;97:1340-1341.)
© 1998 American Heart Association, Inc.

Editorial

Tumor Necrosis Factor- and Cardiomyopathy

Michael R. Bristow, MD, PhD

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.)

Key Words: Editorials • TNF- • cytokines • remodeling • heart failure

The 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 ß-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 ß-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- (TNF-),¹ a 17-kD protein that acts through two distinct receptors, TNFR₁ and TNFR₂. TNF- 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- are helpful in combating infection or responding to injury.

TNF-, 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-.⁶ In septic shock, the stimulus for the production and release of TNF- from activated macrophages and other mononuclear cells is lipopolysaccharide, or endotoxin, which is shed from Gram-negative bacterial membranes. TNF- 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- levels were elevated in chronic heart failure. TNF- can increase protein catabolism in certain model systems,⁹ but TNF-¹⁰ 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- production is induced in cardiac myocytes¹² and that chronic infusion of TNF- in rats produces left ventricular contractile dysfunction and dilatation.¹³ Therefore, local myocardial production of TNF- becomes, along with neurotransmitter-derived norepinephrine, autocrine- or paracrine-produced 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- 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 -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- 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- 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- 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- lower than those reported by Bryant et al, which results in a dilated cardiomyopathy phenotype without much inflammation. Therefore, the available data for cardiac transgenic overexpression of TNF- 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- cardiac overexpressor mice provide additional evidence that cardiac inflammation can evolve to a dilated cardiomyopathy, with TNF- 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 20 21}

The one remaining step in the proof of the "TNF- hypothesis" is to demonstrate that treatment with agents that inhibit the production or action of TNF- 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- 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- inhibitors. One such compound, soluble TNF- receptors that bind and inactivate TNF-, 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.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

References

1. 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;223:236–241.

2. Vilcek J, Lee TH. Tumor necrosis factor. J Biol Chem. 1991;266:7313–7316.[Free Full Text]

3. Oliff A, Defeo-Jones D, Boyer M, Martinez D, Kiefer D, Vuocolo G, Wolfe A, Socher SH. Tumors secreting human TNF/cachectin induce cachexia in mice. Cell. 1987;50:555–563.[Medline] [Order article via Infotrieve]

4. Anker SD, Chua TP, Ponikowski P, Harrington D, Swan JW, Kox WJ, Poole-Wilson PA, Coats AJ. Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia. Circulation. 1997;96:526–534.[Abstract/Free Full Text]

5. Parrillo JE, Burch C, Shelhamer JH, Parker MM, Natanson C, Schuette W. A circulating myocardial depressant substance in humans with septic shock. J Clin Invest. 1985;76:1539–1553.

6. Michie HR, Manogue KR, Spriggs DR, Revhaug A, O'Dwyer S, Dinarello CA, Cerami A, Wolff SM, Wilmore DW. Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med. 1988;318:1481–1486.[Abstract]

7. Yokoyama T, Vaca L, Rossen RD, Durante W, Hazarika P, Mann DL. Cellular basis for the negative inotropic effects of tumor necrosis factor-alpha in the adult mammalian heart. J Clin Invest. 1993;92:2303–2312.

8. Finkel MS, Oddis CV, Jacob TD, Watkins SC, Hattler BG, Simmons RL. Negative inotropic effects of cytokines heart mediated by nitric oxide. Science. 1992;257:387–389.[Abstract/Free Full Text]

9. Costelli P, Carbo N, Tessitore L, Bagby GJ, Lopez-Soriano FJ, Argiles JM, Baccino FM. Tumor necrosis factor- mediates changes in tissue protein turnover in a rat cancer cachexia model. J Clin Invest. 1993;92:2783–2789.

10. Yokoyama T, Nakano M, Bednerczyk JL, McIntyre BW, Entman M, Mann DL. Tumor necrosis factor- provokes a hypertrophic growth response in adult cardiac myocytes. Circulation. 1997;95:1247–1252.[Abstract/Free Full Text]

11. Palmer JN, Hartogensis WE, Patten M, Fortuin FD, Long CS. Interleukin-1ß induces cardiac myocyte growth but inhibits fibroblast proliferation in culture. J Clin Invest. 1995;95:2555–2564.

12. Torre-Amione G, Kapadia S, Lee J, Durand J-B, Bies RD, Young JB, Mann DL. Tumor necrosis factor- and tumor necrosis factor receptors in the failing human heart. Circulation. 1996;93:704–711.[Abstract/Free Full Text]

13. Bozkurt B, Kribbs SB, Clubb FJ Jr, Michael LH, Didenko VV, Hornsby PJ, Seta Y, Oral H, Spinale FG, Mann DL. Pathophysiologically relevant concentrations of tumor necrosis factor- promote progressive left ventricular dysfunction and remodeling in rats. Circulation. 1998;97:1382–1391.[Abstract/Free Full Text]

14. Eichhorn EJ, Bristow MR. Medical therapy can improve the biologic properties of the chronically failing heart: a new era in the treatment of heart failure. Circulation. 1996;94:2285–2296.[Abstract/Free Full Text]

15. Subramaniam A, Jones WK, Gulick J, Wert S, Neumann J, Robbins J. Tissue-specific regulation of the -myosin heavy chain gene promoter in transgenic mice. J Biol Chem. 1991;266:24613–24620.[Abstract/Free Full Text]

16. 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-. Circulation. 1998;97:1375–1381.[Abstract/Free Full Text]

17. Kubota T, McTiernan CF, Frye CS, Demetris AJ, Feldman AM. Cardiac-specific overexpression of tumor necrosis factor-alpha causes lethal myocarditis in transgenic mice. J Card Fail. 1997;3:117–124.[Medline] [Order article via Infotrieve]

18. Kubota T, McTiernan CF, Frye CS, Slawson SE, Lemster BH, Koretsky AP, Demetris J, Feldman AM. Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-. Circ Res. 1997;81:627–635.[Abstract/Free Full Text]

19. Port JD, Weinberger HD, Bisognano JD, Knudson OA, Bohlmeyer TJ, Pende A, Bristow MR. Echocardiographic and histopathological characterization of young and old transgenic mice over-expressing the human ß₁-adrenergic receptor. J Am Coll Cardiol. 1998;31(suppl A):177A. Abstract.

20. Iwase M, Bishop SP, Uechi M, Vatner DE, Shannon RP, Kudej RK, Wight DC, Wagner TE, Ishikawa Y, Homcy CJ, Vatner SF. Adverse effects of chronic endogenous sympathetic drive induced by cardiac G_s overexpression. Circ Res. 1996;78:517–524.[Abstract/Free Full Text]

21. D'Angelo DD, Sakata Y, Lorenz JN, Boivin GP, Walsh RA, Liggett SB, Dorn GW II. Transgenic G_q overexpression induces cardiac contractile failure in mice. Proc Natl Acad Sci U S A. 1997;94:8121–8126.[Abstract/Free Full Text]

22. Matsumori A, Shioi T, Yamada T, Matsui S, Sasayama S. Vesnarinone, a new inotropic agent, inhibits cytokine production by stimulated human blood from patients with heart failure. Circulation. 1994;89:955–958.[Abstract/Free Full Text]

23. Feldman A, Young J, Bourge R, Carson P, Jaski B, DeMets D, White BG, Cohn JN, for the VesT Investigators. Mechanism of increased mortality from vesnarinone in the Severe Heart Failure Trial (VesT). J Am Coll Cardiol. 1997;29(suppl A):64A. Abstract.

24. Feldman AM, Bristow MR, Parmley WW, Carson PE, Pepine CJ, Gilbert EM, Strobeck JE, Hendrix GH, Powers ER, Bain RP, White BG, for the Vesnarinone Study Group. Effects of vesnarinone on morbidity and mortality in patients with heart failure. N Engl J Med. 1993;329:149–155.[Abstract/Free Full Text]

25. Bergman MR, Holycross BJ. Pharmacological modulation of myocardial tumor necrosis factor alpha production by phosphodiesterase inhibitors. J Pharmacol Exp Ther. 1996;279:247–254.[Abstract/Free Full Text]

26. Deswal A, Seta Y, Blosch CM, Mann DL. A phase I trial of tumor necrosis factor receptor (p75) fusion protein (TNPR:Fc) in patients with advanced heart failure. Circulation. 1997;96(suppl I):I-323. Abstract.

This article has been cited by other articles:

				O. Zimmermann, M. Kochs, T. P. Zwaka, M. Bienek-Ziolkowski, M. Hoher, V. Hombach, and J. Torzewski Prognostic role of myocardial tumor necrosis factor-alpha and terminal complement complex expression in patients with dilated cardiomyopathy Eur J Heart Fail, January 1, 2007; 9(1): 51 - 54. [Abstract] [Full Text] [PDF]

				R. Nishio, S. Sasayama, and A. Matsumori Left ventricular pressure-volume relationship in a murine model of congestive heart failure due to acute viral myocarditis J. Am. Coll. Cardiol., October 16, 2002; 40(8): 1506 - 1514. [Abstract] [Full Text] [PDF]

				M. Afanasyeva and N. R. Rose Cardiomyopathy Is Linked to Complement Activation Am. J. Pathol., August 1, 2002; 161(2): 351 - 357. [Full Text] [PDF]

				S. Adamopoulos, J. T. Parissis, and D. Th. Kremastinos A glossary of circulating cytokines in chronic heart failure Eur J Heart Fail, October 1, 2001; 3(5): 517 - 526. [Abstract] [Full Text] [PDF]

				H. Wada, K. Saito, T. Kanda, I. Kobayashi, H. Fujii, S. Fujigaki, N. Maekawa, H. Takatsu, H. Fujiwara, K. Sekikawa, et al. Tumor Necrosis Factor-{{alpha}} (TNF-{{alpha}}) Plays a Protective Role in Acute Viral Myocarditis in Mice : A Study Using Mice Lacking TNF-{{alpha}} Circulation, February 6, 2001; 103(5): 743 - 749. [Abstract] [Full Text] [PDF]

				L. Rossig, J. Haendeler, Z. Mallat, B. Hugel, J.-M. Freyssinet, A. Tedgui, S. Dimmeler, and A. M. Zeiher Congestive heart failure induces endothelial cell apoptosis: protective role of carvedilol J. Am. Coll. Cardiol., December 1, 2000; 36(7): 2081 - 2089. [Abstract] [Full Text] [PDF]

				C Berry and A.L Clark Catabolism in chronic heart failure Eur. Heart J., April 1, 2000; 21(7): 521 - 532. [PDF]

				A. M. Feldman, A. Combes, D. Wagner, T. Kadakomi, T. Kubota, Y. You Li, and C. McTiernan The role of tumor necrosis factor in the pathophysiology of heart failure J. Am. Coll. Cardiol., March 1, 2000; 35(3): 537 - 544. [Abstract] [Full Text] [PDF]

				L. Tiret, C. Mallet, O. Poirier, V. Nicaud, A. Millaire, J.-B. Bouhour, G.e. Roizes, M. Desnos, R. Dorent, K. Schwartz, et al. Lack of association between polymorphisms of eight candidate genes and idiopathic dilated cardiomyopathy: The CARDIGENE study J. Am. Coll. Cardiol., January 1, 2000; 35(1): 29 - 35. [Abstract] [Full Text] [PDF]

				M Tendera and H Wysocki TNF-{alpha} in patients with chronic failure is not only a proinflammatory cytokine Eur. Heart J., October 2, 1999; 20(20): 1445 - 1446. [PDF]

				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]

				D. Hamerman Toward an Understanding of Frailty Ann Intern Med, June 1, 1999; 130(11): 945 - 950. [Full Text] [PDF]

				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]

This Article Extract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bristow, M. R. Search for Related Content PubMed PubMed Citation Articles by Bristow, M. R. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Cardiomyopathy