From the Departments of Pediatrics (D.B., L.B., M.T., B.G.), Pathology
(J.R., J.S.), and Radiology (F.F., R.P.), The University of Texas Southwestern
Medical Center, Dallas.
Correspondence to Brett P. Giroir, MD, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75235-9063. E-mail bgiroi{at}mednet.swmed.edu
Background—Tumor necrosis factor-
Methods and Results—To determine the consequences of TNF-
Conclusions—This is the first report detailing the effects of
tissue-specific production of TNF-
© 1998 American Heart Association, Inc.
Basic Science Reports
Cardiac Failure in Transgenic Mice With Myocardial Expression of Tumor Necrosis Factor-
(TNF-) is a multifunctional cytokine that has been detected
in several human cardiac-related conditions, including congestive heart
failure and septic cardiomyopathy. In these
conditions, the origin of TNF- secretion is, at least in part,
cardiac myocytes.
production by cardiac myocytes in vivo, we developed transgenic
mice in which expression of a murine TNF- coding sequence was driven
by the murine -myosin heavy chain promoter. Four transgenic founders
developed an identical illness consisting of tachypnea, decreased
activity, and hunched posture. In vivo, ECG-gated MRI of
symptomatic transgenic mice documented a severe impairment
of cardiac function evidenced by biventricular dilatation
and depressed ejection fractions. All transgenic mice died prematurely.
Pathological examination of affected animals revealed a globular
dilated heart, bilateral pleural effusions, myocyte apoptosis,
and transmural myocarditis in both the right and left
ventricular free walls, septum, and atrial chambers. In all
terminally ill animals, there was significant biventricular
fibrosis and atrial thrombosis. by cardiac myocytes in
vivo. These findings indicate that production of TNF- by
cardiac myocytes is sufficient to cause severe cardiac disease and
support a causal role for this cytokine in the pathogenesis of
human cardiac disease.
Key Words: apoptosis • magnetic resonance imaging • heart failure • cardiomyopathy • myocarditis
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J. Stypmann, K. Glaser, W. Roth, D. J. Tobin, I. Petermann, R. Matthias, G. Monnig, W. Haverkamp, G. Breithardt, W. Schmahl, et al. Dilated cardiomyopathy in mice deficient for the lysosomal cysteine peptidase cathepsin L PNAS, April 18, 2002; (2002) 92637699. [Abstract] [Full Text] [PDF]
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D. B. Sawyer and J. Loscalzo Myocardial Hibernation: Restorative or Preterminal Sleep? Circulation, April 2, 2002; 105(13): 1517 - 1519. [Full Text] [PDF]
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A. Yndestad, J. Kristian Damas, H. Geir Eiken, T. Holm, T. Haug, S. Simonsen, S. S. Froland, L. Gullestad, and P. Aukrust Increased gene expression of tumor necrosis factor superfamily ligands in peripheral blood mononuclear cells during chronic heart failure Cardiovasc Res, April 1, 2002; 54(1): 175 - 182. [Abstract] [Full Text] [PDF]
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G. Wright, I. S. Singh, J. D. Hasday, I. K. Farrance, G. Hall, A. S. Cross, and T. B. Rogers Endotoxin stress-response in cardiomyocytes: NF-kappa B activation and tumor necrosis factor-alpha expression Am J Physiol Heart Circ Physiol, March 1, 2002; 282(3): H872 - H879. [Abstract] [Full Text] [PDF]
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W. S. Bradham, B. Bozkurt, H. Gunasinghe, D. Mann, and F. G. Spinale Tumor necrosis factor-alpha and myocardial remodeling in progression of heart failure: a current perspective Cardiovasc Res, March 1, 2002; 53(4): 822 - 830. [Abstract] [Full Text] [PDF]
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C G Densem, I V Hutchinson, N Yonan, and N H Brooks Tumour necrosis factor {alpha} gene polymorphism: a predisposing factor to non-ischaemic myocardial dysfunction? Heart, February 1, 2002; 87(2): 153 - 155. [Abstract] [Full Text] [PDF]
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D. Hilfiker-Kleiner, A. Hilfiker, B. Schieffer, D. Engel, D. L Mann, K. C Wollert, and H. Drexler TNF{alpha} decreases {alpha}MHC expression by a NO mediated pathway: role of E-box transcription factors for cardiomyocyte specific gene regulation Cardiovasc Res, February 1, 2002; 53(2): 460 - 469. [Abstract] [Full Text] [PDF]
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A.L. Clark, M. Loebe, E.V. Potapov, K. Egerer, C. Knosalla, R. Hetzer, and S.D. Anker Ventricular assist device in severe heart failure. Effects on cytokines, complement and body weight Eur. Heart J., December 2, 2001; 22(24): 2275 - 2283. [Abstract] [PDF]
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 A. L. Farre and S. Casado Heart Failure, Redox Alterations, and Endothelial Dysfunction Hypertension, December 1, 2001; 38(6): 1400 - 1405. [Abstract] [Full Text] [PDF]
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C. Stamm, I. Friehs, D. B. Cowan, A. M. Moran, H. Cao-Danh, L. F. Duebener, P. J. del Nido, and F. X. McGowan Jr Inhibition of Tumor Necrosis Factor-{alpha} Improves Postischemic Recovery of Hypertrophied Hearts Circulation, September 18, 2001; 104 (2009): I-350 - I-355. [Abstract] [Full Text] [PDF]
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N. Sivasubramanian, M. L. Coker, K. M. Kurrelmeyer, W. R. MacLellan, F. J. DeMayo, F. G. Spinale, and D. L. Mann Left Ventricular Remodeling in Transgenic Mice With Cardiac Restricted Overexpression of Tumor Necrosis Factor Circulation, August 14, 2001; 104(7): 826 - 831. [Abstract] [Full Text] [PDF]
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S. J. Stetson, A. Perez-Verdia, W. Mazur, J. A. Farmer, M. M. Koerner, D. G. Weilbaecher, M. L. Entman, M. A. Quinones, G. P. Noon, and G. Torre-Amione Cardiac Hypertrophy After Transplantation Is Associated With Persistent Expression of Tumor Necrosis Factor-{alpha} Circulation, August 7, 2001; 104(6): 676 - 681. [Abstract] [Full Text] [PDF]
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E. Braunwald Congestive heart failure: a half century perspective Eur. Heart J., May 2, 2001; 22(10): 825 - 836. [PDF]
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C. Ballard-Croft, D. J. White, D. L. Maass, D. P. Hybki, and J. W. Horton Role of p38 mitogen-activated protein kinase in cardiac myocyte secretion of the inflammatory cytokine TNF-{alpha} Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H1970 - H1981. [Abstract] [Full Text] [PDF]
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F. J. Giordano, H.-P. Gerber, S.-P. Williams, N. VanBruggen, S. Bunting, P. Ruiz-Lozano, Y. Gu, A. K. Nath, Y. Huang, R. Hickey, et al. A cardiac myocyte vascular endothelial growth factor paracrine pathway is required to maintain cardiac function PNAS, April 25, 2001; (2001) 91415198. [Abstract] [Full Text]
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S. F. Nagueh, S. J. Stetson, N. M. Lakkis, D. Killip, A. Perez-Verdia, M. L. Entman, W. H. Spencer III, and G. Torre-Amione Decreased Expression of Tumor Necrosis Factor-{{alpha}} and Regression of Hypertrophy After Nonsurgical Septal Reduction Therapy for Patients With Hypertrophic Obstructive Cardiomyopathy Circulation, April 10, 2001; 103(14): 1844 - 1850. [Abstract] [Full Text] [PDF]
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A. L. Graciano, D. D. Bryant, D. J. White, J. Horton, N. E. Bowles, and B. P. Giroir Targeted disruption of ICAM-1, P-selectin genes improves cardiac function and survival in TNF-{alpha} transgenic mice Am J Physiol Heart Circ Physiol, April 1, 2001; 280(4): H1464 - H1471. [Abstract] [Full Text] [PDF]
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R. G. Weiss Imaging the Murine Cardiovascular System With Magnetic Resonance Circ. Res., March 30, 2001; 88(6): 550 - 551. [Full Text] [PDF]
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F. Wiesmann, J. Ruff, S. Engelhardt, L. Hein, C. Dienesch, A. Leupold, R. Illinger, A. Frydrychowicz, K.-H. Hiller, E. Rommel, et al. Dobutamine-Stress Magnetic Resonance Microimaging in Mice : Acute Changes of Cardiac Geometry and Function in Normal and Failing Murine Hearts Circ. Res., March 30, 2001; 88(6): 563 - 569. [Abstract] [Full Text] [PDF]
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W. W. Parmley How Many Medicines Do Patients With Heart Failure Need? Circulation, March 27, 2001; 103(12): 1611 - 1612. [Full Text] [PDF]
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S. B. Haudek, E. Spencer, D. D. Bryant, D. J. White, D. Maass, J. W. Horton, Z. J. Chen, and B. P. Giroir Overexpression of cardiac I-{kappa}B{alpha} prevents endotoxin-induced myocardial dysfunction Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H962 - H968. [Abstract] [Full Text] [PDF]
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C. Li, R. L. Kao, T. Ha, J. Kelley, I. W. Browder, and D. L. Williams Early activation of IKK{beta} during in vivo myocardial ischemia Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H1264 - H1271. [Abstract] [Full Text] [PDF]
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D. L. Mann Tumor Necrosis Factor and Viral Myocarditis: The Fine Line Between Innate and Inappropriate Immune Responses in the Heart Circulation, February 6, 2001; 103(5): 626 - 629. [Full Text] [PDF]
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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]
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T. Ohtsuka, M. Hamada, G. Hiasa, O. Sasaki, M. Suzuki, Y. Hara, Y. Shigematsu, and K. Hiwada Effect of beta-blockers on circulating levels of inflammatory and anti-inflammatory cytokines in patients with dilated cardiomyopathy J. Am. Coll. Cardiol., February 1, 2001; 37(2): 412 - 417. [Abstract] [Full Text] [PDF]
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X. Li, M. R. Moody, D. Engel, S. Walker, F. J. Clubb Jr, N. Sivasubramanian, D. L. Mann, and M. B. Reid Cardiac-Specific Overexpression of Tumor Necrosis Factor-{alpha} Causes Oxidative Stress and Contractile Dysfunction in Mouse Diaphragm Circulation, October 3, 2000; 102(14): 1690 - 1696. [Abstract] [Full Text] [PDF]
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M. Satoh, M. Nakamura, H. Satoh, H. Saitoh, I. Segawa, and K. Hiramori Expression of tumor necrosis factor-alpha-converting enzyme and tumor necrosis factor-alpha in human myocarditis J. Am. Coll. Cardiol., October 1, 2000; 36(4): 1288 - 1294. [Abstract] [Full Text] [PDF]
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