Pathophysiologically Relevant Concentrations of Tumor Necrosis Factor-α Promote Progressive Left Ventricular Dysfunction and Remodeling in Rats
Abstract
Background —Although patients with heart failure express elevated circulating levels of tumor necrosis factor-α (TNF-α) in their peripheral circulation, the structural and functional effects of circulating levels of pathophysiologically relevant concentrations of TNF-α on the heart are not known. Methods and Results —Osmotic infusion pumps containing either diluent or TNF-α were implanted into the peritoneal cavity of rats. The rate of TNF-α infusion was titrated to obtain systemic levels of biologically active TNF-α comparable to those reported in patients with heart failure (≈80 to 100 U/mL), and the animals were examined serially for 15 days. Two-dimensional echocardiography was used to assess changes in left ventricular (LV) structure (remodeling) and LV function. Video edge detection was used to assess isolated cell mechanics, and standard histological techniques were used to assess changes in the volume composition of LV cardiac myocytes and the extracellular matrix. The reversibility of cytokine-induced effects was determined either by removal of the osmotic infusion pumps on day 15 or by treatment of the animals with a soluble TNF-α antagonist (TNFR:Fc). The results of this study show that a continuous infusion of TNF-α led to a time-dependent depression in LV function, cardiac myocyte shortening, and LV dilation that were at least partially reversible by removal of the osmotic infusion pumps or treatment of the animals with TNFR:Fc. Conclusions —These studies suggest that pathophysiologically relevant concentrations of TNF-α are sufficient to mimic certain aspects of the phenotype observed in experimental and clinical models of heart failure.
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In mice, administration of TNF at pathologic concentrations results in a dilated cardiomyopathy phenotype.
“For example, in mice, administration of TNF at pathologic concentrations is reported to result in a dilated cardiomyopathy phenotype48.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [48]
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Cites
Recommendations for Quantitation of the Left Ventricle by Two-Dimensional Echocardiography
Schiller, N. B., Shah, P. M., Crawford, M., DeMaria, A. N., Devereux, R. B., Feigenbaum, H., Gutgesell, H. P., Reichek, N., Sahn, D. J., Schnittger, I., et al. (1989) · Journal of the American Society of Echocardiography · doi:10.1016/s0894-7317(89)80014-8 · Cited by 8,110 · see citing works
Elevated Circulating Levels of Tumor Necrosis Factor in Severe Chronic Heart Failure
Levine, B., Kalman, J., Mayer, L., Fillit, H. M., & Packer, M. (1990) · New England Journal of Medicine · doi:10.1056/nejm199007263230405 · Cited by 2,582 · cited 2× · see citing works
“In preliminary control experiments using TNF-a infusion rates of 0.125 to 7.5mg z kg21 z min21, we established that an infusion rate of 2.5 mg z kg21 z min21 resulted in systemic levels of biologically active TNF-a comparable to those reported in patients with heart failure, that is,'80 to 100 U/mL.1 Accordingly, this…”
ResultInfluentialNegative Inotropic Effects of Cytokines on the Heart Mediated by Nitric Oxide
Finkel, M. S., Oddis, C. V., Jacob, T. D., Watkins, S. C., Hattler, B. G. J., & Simmons, R. L. (1992) · Science · doi:10.1126/science.1631560 · Cited by 1,626 · see citing works
Torre-Amione, G., Kapadia, S., Benedict, C., Oral, H., Young, J. B., & Mann, D. L. (1996) · Journal of the American College of Cardiology · doi:10.1016/0735-1097(95)00589-7 · Cited by 1,211 · see citing works
Self-citationThe cardiovascular response of normal humans to the administration of endotoxin.
Suffredini, A., Fromm, R., Parker, M., Brenner, M., Kovacs, J., Wesley, R., & Parrillo, J. (1989) · New England Journal of Medicine · doi:10.1056/nejm198908033210503 · Cited by 1,133 · see citing works
Packer, M. (1992) · Journal of the American College of Cardiology · doi:10.1016/0735-1097(92)90167-l · Cited by 1,056 · see citing works
Tumor Necrosis Factor-α and Tumor Necrosis Factor Receptors in the Failing Human Heart
Torre‐Amione, G., Kapadia, S. R., Lee, J. J., Durand, J., Bies, R. D., Young, J. B., & Mann, D. L. (1996) · Circulation · doi:10.1161/01.cir.93.4.704 · Cited by 991 · see citing works
Self-citationTumor necrosis factor can induce both apoptic and necrotic forms of cell lysis.
Laster, S. M., Wood, J. G., & Gooding, L. R. (1988) · The Journal of Immunology · doi:10.4049/jimmunol.141.8.2629 · Cited by 909 · see citing works
Adrenergic effects on the biology of the adult mammalian cardiocyte.
Mann, D. L., Kent, R. L., Parsons, B., & Cooper, G. (1992) · Circulation · doi:10.1161/01.cir.85.2.790 · Cited by 865 · see citing works
Self-citationMatrix Metalloproteinases and Cardiovascular Disease
DOLLERY, C. M., McEwan, J. R., & HENNEY, A. M. (1995) · Circulation Research · doi:10.1161/01.res.77.5.863 · Cited by 864 · see citing works
Mohler, K. M., Torrance, D., Smith, C., Goodwin, R., Stremler, K. E., Fung, V., Madani, H., & Widmer, M. B. (1993) · The Journal of Immunology · doi:10.4049/jimmunol.151.3.1548 · Cited by 832 · see citing works
Density and composition of mammalian muscle
Méndez, J., & Keys, A. (1960) · Metabolism · Cited by 813 · see citing works
Krown, K. A., Pagé, M., Nguyen, C., Zechner, D., Gutierrez, V., Comstock, K. L., Glembotski, C. C., Quintana, P. J. E., & Sabbadini, R. A. (1996) · Journal of Clinical Investigation · doi:10.1172/jci119114 · Cited by 728 · see citing works
Yokoyama, T., Vaca, L. A., Rossen, R. D., Durante, W., Hazarika, P., & Mann, D. L. (1993) · Journal of Clinical Investigation · doi:10.1172/jci116834 · Cited by 714 · see citing works
Self-citationInhibition of myocardial endothelin pathway improves long-term survival in heart failure
Sakai, S., Miyauchi, T., Kobayashi, M., Yamaguchi, I., Goto, K., & Sugishita, Y. (1996) · Nature · doi:10.1038/384353a0 · Cited by 622 · see citing works
Endothelin in human congestive heart failure.
Wei, C., Lerman, A., Rodeheffer, R. J., McGregor, C. G. A., Brandt, R. R., Wright, S., Heublein, D. M., Kao, P.-C., Edwards, W. D., & Burnett, J. C. J. (1994) · Circulation · doi:10.1161/01.cir.89.4.1580 · Cited by 585 · see citing works
Evidence for endothelin-1-mediated vasoconstriction in severe chronic heart failure
Kiowski, W., Kim, J., Oechslin, E. N., et al. (1995) · The Lancet · doi:10.1016/s0140-6736(95)91504-4 · Cited by 574 · see citing works
Natanson, C., Eichenholz, P. W., Danner, R. L., Eichacker, P. Q., Hoffman, W. D., Kuo, G. C., Banks, S. M., MacVittie, T. J., & Parrillo, J. E. (1989) · The Journal of Experimental Medicine · doi:10.1084/jem.169.3.823 · Cited by 566 · see citing works
Tumor Necrosis Factor Soluble Receptors in Patients With Various Degrees of Congestive Heart Failure
Ferrari, R., Bachetti, T., Confortini, R., Opasich, C., Febo, O., Corti, A., Cassani, G., & Visioli, O. (1995) · Circulation · doi:10.1161/01.cir.92.6.1479 · Cited by 535 · see citing works
Lang, C. H., Dobrescu, C., & Bagby, G. J. (1992) · Endocrinology · doi:10.1210/endo.130.1.1727716 · Cited by 535 · see citing works
Whittaker, P., Kloner, R. A., Boughner, D. R., & Pickering, J. G. (1994) · Basic Research in Cardiology · doi:10.1007/bf00788278 · Cited by 496 · see citing works
Interleukin 1 and tumor necrosis factor inhibit cardiac myocyte beta-adrenergic responsiveness.
Gulick, T., Chung, M. K., Pieper, S. J., Lange, L. G., & Schreiner, G. F. (1989) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.86.17.6753 · Cited by 495 · see citing works
Balligand, J., Longrois, D., Kelly, R. A., Kobzik, L., Pimental, D. R., Michel, T. M., & Smith, T. W. (1993) · Journal of Clinical Investigation · doi:10.1172/jci116461 · Cited by 452 · see citing works
Basic mechanisms in heart failure: The cytokine hypothesis
Seta, Y., Shan, K., Bozkurt, B., Oral, H., & Mann, D. L. (1996) · Journal of Cardiac Failure · doi:10.1016/s1071-9164(96)80047-9 · Cited by 444 · see citing works
Self-citationKapadia, S. R., Lee, J., Torre‐Amione, G., Birdsall, H. H., Ma, T. S., & Mann, D. L. (1995) · Journal of Clinical Investigation · doi:10.1172/jci118090 · Cited by 437 · see citing works
Self-citationBasic Mechanisms in Congestive Heart Failure
Mann, D. L., & Young, J. B. (1994) · CHEST Journal · doi:10.1378/chest.105.3.897 · Cited by 365 · see citing works
Self-citationMcMurray, J. J. V., Abdullah, I., Dargie, H. J., & Shapiro, D. (1991) · Heart · doi:10.1136/hrt.66.5.356 · Cited by 344 · see citing works
Oral, H., Dorn, G. W., & Mann, D. L. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.8.4836 · Cited by 323 · see citing works
Self-citationTumor necrosis factor provokes superoxide anion generation from neutrophils
Tsujimoto, M., Yokota, S., Vilček, J., & Weissmann, G. (1986) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(86)90337-2 · Cited by 301 · see citing works
Pagani, F. D., Baker, L. S., Hsi, C. C., Knox, M. A., Fink, M. P., & Visner, M. S. (1992) · Journal of Clinical Investigation · doi:10.1172/jci115873 · Cited by 277 · see citing works
Itoh, G., Tamura, J., Suzuki, M., et al. (1995) · PubMed · Cited by 267 · see citing works
Coroneos, E., Martinez, M., McKenna, S. M., et al. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.40.23305 · Cited by 221 · see citing works
Echocardiographic Assessment of Left Ventricular Mass and Systolic Function in Mice
Gardin, J. M., Siri, F. M., Kitsis, R. N., Edwards, J. G., & Leinwand, L. A. (1995) · Circulation Research · doi:10.1161/01.res.76.5.907 · Cited by 220 · see citing works
Millar, A., Singer, M., Meager, A., Foley, N. M., Johnson, N. M., & Rook, G. A. W. (1989) · The Lancet · doi:10.1016/s0140-6736(89)90772-1 · Cited by 198 · see citing works
Endothelin has biological actions at pathophysiological concentrations.
Lerman, A., Hildebrand, F. L., Aarhus, L. L., et al. (1991) · Circulation · doi:10.1161/01.cir.83.5.1808 · Cited by 189 · see citing works
Didenko, V. V., & Hornsby, P. J. (1996) · The Journal of Cell Biology · doi:10.1083/jcb.135.5.1369 · Cited by 189 · see citing works
Self-citationHegewisch, S. (1990) · The Lancet · doi:10.1016/0140-6736(90)90115-l · Cited by 187 · see citing works
Spinale, F. G., Tomita, M., Zellner, J. L., Cook, J., Crawford, F. A., & Zile, M. R. (1991) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.1991.261.2.h308 · Cited by 176 · see citing works
Self-citationInadequate collagen tethers in dilated cardiopathy
Weber, K. T., Pick, R. L., Janicki, J. S., et al. (1988) · American Heart Journal · doi:10.1016/0002-8703(88)90763-6 · Cited by 143 · see citing works
c‐Myc induces cellular susceptibility to the cytotoxic action of TNF‐alpha.
Klefström, J. T., Västrik, I., SAKSELA, E., Valle, J., Eilers, M., & Alitalo, K. K. (1994) · The EMBO Journal · doi:10.1002/j.1460-2075.1994.tb06879.x · Cited by 138 · see citing works
Tumor Necrosis Factor-α Induces a Biphasic Effect on Myocardial Contractility in Conscious Dogs
Murray, D. R. P., & Freeman, G. L. (1996) · Circulation Research · doi:10.1161/01.res.78.1.154 · Cited by 137 · see citing works
Is Tumor Necrosis Factor an Important Neurohormonal Mechanism in Chronic Heart Failure?
Packer, M. (1995) · Circulation · doi:10.1161/01.cir.92.6.1379 · Cited by 135 · see citing works
Spinale, F. G., Zellner, J. L., Tomita, M., Crawford, F. A., & Zile, M. R. (1991) · Circulation Research · doi:10.1161/01.res.69.4.1058 · Cited by 124 · see citing works
Self-citationSocher, S. H., Friedman, A., & Martínez, D. (1988) · The Journal of Experimental Medicine · doi:10.1084/jem.167.6.1957 · Cited by 121 · see citing works
Morphometric analysis of biologic processes.
Loud, A. V., & Anversa, P. (1984) · PubMed · Cited by 118 · see citing works
Tumor necrosis factor challenges in canines: patterns of cardiovascular dysfunction
Eichenholz, P. W., Eichacker, P. Q., Hoffman, W. D., et al. (1992) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.1992.263.3.h668 · Cited by 112 · see citing works
Spinale, F. G., Ishihra, K., Zile, M. R., DeFryte, G., Crawford, F. A., & Carabello, B. A. (1993) · Journal of Thoracic and Cardiovascular Surgery · doi:10.1016/s0022-5223(19)33992-3 · Cited by 111 · see citing works
Self-citationDecrease in left ventricular contractility after tumor necrosis factor-alpha infusion in dogs
Walley, K. R., Hébert, P. C., Wakai, Y., et al. (1994) · Journal of Applied Physiology · doi:10.1152/jappl.1994.76.3.1060 · Cited by 97 · see citing works
Chronic TNF Infusion Causes Anorexia But Not Accelerated Nitrogen Loss
MICHIE, H. R., Sherman, M. L., Spriggs, D. R., CHRISTIE, M., Wilmore, D. W., & Rounds, J. D. (1989) · Annals of Surgery · doi:10.1097/00000658-198901000-00002 · Cited by 87 · see citing works
Wiedermann, C. J., Beimpold, H., Herold, M., Knapp, E., & Braunsteiner, H. (1993) · Journal of the American College of Cardiology · doi:10.1016/0735-1097(93)90776-w · Cited by 87 · see citing works
Regional myocyte size in normotensive and spontaneously hypertensive rats.
Bishop, S. P., Oparil, S., Reynolds, R. H., et al. (1979) · Hypertension · doi:10.1161/01.hyp.1.4.378 · Cited by 60 · see citing works
Continuous infusion of tumor necrosis factor: Mechanisms of toxicity in the rat
Gaskill, H. V. (1988) · Journal of Surgical Research · doi:10.1016/0022-4804(88)90098-4 · Cited by 37 · see citing works
Molecular phenotype of the hypertrophied and failing myocardium
Schwartz, K. S., Mercadier, J.-J., Lompré, A., et al. (1993) · Cited by 34 · see citing works
Westermarck, J. K., Häkkinen, L., Fiers, W., et al. (1995) · Journal of Investigative Dermatology · doi:10.1111/1523-1747.ep12317114 · Cited by 24 · see citing works
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- Kapadia S, Torre-Amione G, Yokoyama T, Mann DL. Soluble tumor necrosis factor binding proteins modulate the negative inotropic effects of TNF-␣ in vitro. Am J Physiol. 1995;37:H517-H525.
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Chung, E. S., Packer, M., Lo, K. H., Fasanmade, A. A., & Willerson, J. T. (2003) · Circulation · doi:10.1161/01.cir.0000077913.60364.d2 · Cited by 1,644 · see citing works
Mann, D. L., McMurray, J. J. V., Packer, M., Swedberg, K., Borer, J. S., Colucci, W. S., Djian, J., Drexler, H., Feldman, A., Kober, L., et al. (2004) · Circulation · doi:10.1161/01.cir.0000124490.27666.b2 · Cited by 1,240 · see citing works
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Tang, W. H. W., Li, D. Y., & Hazen, S. L. (2019) · Nature Reviews Cardiology · doi:10.1038/s41569-018-0108-7 · Cited by 789 · see citing works
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Everett, B. M., Cornel, J. H., Lainscak, M., Anker, S. D., Abbate, A., Thuren, T., Libby, P., Glynn, R. J., & Ridker, P. M. (2019) · Circulation · doi:10.1161/circulationaha.118.038010 · Cited by 658 · see citing works
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Pedersen, B. K. (2017) · European Journal of Clinical Investigation · doi:10.1111/eci.12781 · Cited by 617 · see citing works
Pharmacological stimulation of the cholinergic antiinflammatory pathway
Bernik, T. R., Friedman, S. G., Ochani, M., DiRaimo, R., Ulloa, L., Yang, H., Sudan, S., Czura, C. J., Ivanova, S. M., & Tracey, K. J. (2002) · The Journal of Experimental Medicine · doi:10.1084/jem.20011714 · Cited by 529 · see citing works
Inflammatory Markers and Incident Heart Failure Risk in Older Adults
Kalogeropoulos, A., Georgiopoulou, V., Psaty, B. M., Rodondi, N., Smith, A. L., Harrison, D. G., Liu, Y., Hoffmann, U., Bauer, D. C., Newman, A. B., et al. (2010) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2009.12.045 · Cited by 478 · see citing works
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“cal place to start because patients with acute and chronic heart failure have elevated circulating levels of TNF,(54) and TNF promotes left ventricular dysfunction and remodeling.(55) Further,”
BackgroundPORTER, K., TURNER, N., OREGAN, D., & BALL, S. (2004) · Cardiovascular Research · doi:10.1016/j.cardiores.2004.07.020 · Cited by 123 · see citing works
Korf-Klingebiel, M., Reboll, M. R., Polten, F., Weber, N., Jäckle, F., Wu, X., Kallikourdis, M., Kunderfranco, P., Condorelli, G., Giannitsis, E., et al. (2021) · Circulation · doi:10.1161/circulationaha.120.053365 · Cited by 71 · see citing works
- Authors
- Bozkurt, B., Kribbs, S. B., Clubb, F. J., Michael, L. H., Didenko, V. V., Hornsby, P. J., Seta, Y., Oral, H., Spinale, F. G., & Mann, D. L.
- Affiliations
- United States Department of Veterans Affairs (US)
- Venue
- Circulation
- Published
- 1998-04-14
- Volume
- 97
- Issue
- 14
- Pages
- 1382-1391
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2016677731
- Cited by
- 821
- References
- 54
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 15 · 2023: 10 · 2022: 17 · 2021: 25 · 2020: 23 · 2019: 25 · 2018: 22 · 2017: 24 · 2016: 21 · 2015: 30 · 2014: 24 · 2013: 29 · 2012: 31
- FWCI
- 35.59
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs
- American Heart Association
- National Institutes of Health (5r29hl052910-04)
- National Heart, Lung, and Blood Institute (R29-HL-52910, P50HL-06H)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Keywords
- TNF-α, heart failure, left ventricular dysfunction, left ventricular remodeling, peritoneal infusion, TNF-alpha inhibitors, soluble TNF receptors, extracellular matrix
- MeSH terms
- Animals, Cardiac Output, Low, Disease Models, Animal, DNA Damage, Female, Heart, Hemodynamics, Male, Tumor Necrosis Factor-alpha, Ultrasonography, Infusion Pumps, Implantable, Rats, Sprague-Dawley, Disease Progression, Ventricular Dysfunction, Left, Dimerization, Rats
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