Experimental Heart Failure Models of Cytokine Overexpression

  • Charles F. McTiernan
  • Toshi Kadokami
  • Yun You Li
  • Arthur M. Feldman
Part of the Developments in Cardiovascular Medicine book series (DICM, volume 236)


Heart failure secondary to systolic dysfunction is a progressive cardiovascular disease that affects over 5 million people in the U.S. While the initial cause of heart failure in most patients is myocardial damage, the heart usually accommodates to the damage. However, over time, the heart remodels with the development of cardiac dilatation, cellular hypertrophy, cell slippage, diminished adrenergic responsiveness, apoptosis and extracellular matrix fibrosis and restructuring. Over the past decade, there has been a substantive increase in our knowledge of the pathobiology of the development of the heart failure phenotype. This increased knowledge has in part been attributable to advances in the sciences of cell and molecular biology and their application to studies of the failing human heart. However, our improved understanding of the molecular and cellular events leading to the development of heart failure and in particular the transition from compensated to de-compensated myocardial function can also be attributed to studies of new and novel animal models. Indeed, it is studies in animal models that have contributed seminal information regarding the fundamental role of the pro-inflammatory cytokines in the development of the heart failure phenotype. This Chapter will review in detail the observations from animal models that have supported the “Cytokine Hypothesis” of heart failure and will detail how animal models of cytokine over-expression have provided novel experimental platforms for evaluating the efficacy of anti-cytokine pharmacotherapy.


Heart Failure Extracellular Matrix Remodel Soluble Tumor Necrosis Factor Receptor Heart Failure Model Adrenergic Responsiveness 
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  1. 1.
    Natanson C, Eichenholz PW, Danner RL, Eichacker W, Hoffman D, Kuo SM, Banks TJ, MacViottie TJ, Parrillo JE. Endotoxin and tumor necrosis factor challenges in dogs simulate the cardiovascular profile of human septic shock. J Exp Med 1989;169:823–832.PubMedCrossRefGoogle Scholar
  2. 2.
    McMurray JJ, Abdullah I, Dargie HJ, Shapiro D. Increased concentrations of tumour necrosis factor in `cachectic’ patients with severe chronic heart failure. Br Heart J 1991;66:356–358.PubMedCrossRefGoogle Scholar
  3. 3.
    Eichenholz PW, Eichacker PQ, Hoffman WD, Banks SM, Parrillo JEDR, Natanson C. Tumor necrosis factor challenges in canines: patterns of cardiovascular dysfunction. Am J Physiol 1992;263: H668–H675.PubMedGoogle Scholar
  4. 4.
    Walley KR, Hebert PC, Wakai Y, Wilcox PG, Road JD, Cooper DJ. Decrease in left ventricular contractility after tumor necrosis factor-a infusion in dogs. J Appl Physiol 1994;76:1060–1067.PubMedGoogle Scholar
  5. 5.
    Murray DR, Freeman GL. Tumor necrosis factor-a induces a biphasic effect on myocardial contractility in conscious dogs. Circ Res 1996;78:154–160.PubMedCrossRefGoogle Scholar
  6. 6.
    Pagani FD, Baker LS, Hsi C, Knox M, Fink MP, Visner MS. Left ventricular systolic and diastolic dysfunction after infusion of tumor necrosis factor-a in conscious dogs. J Clin Invest 1992;90:389–398.PubMedCrossRefGoogle Scholar
  7. 7.
    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-alpha promote progressive left ventricular dysfunction and remodeling in rats. Circulation 1998;97:1382–1391.PubMedCrossRefGoogle Scholar
  8. 8.
    Kubota T, McTiernan CF, Frye CS, Demetris AJ, Feldman AM. Cardiac-Specific Overexpression of tumor necrosis factor-Alpha Causes lethal myocarditis in transgenic mice. Journal of Cardiac Failure 1997;3:117–124.PubMedCrossRefGoogle Scholar
  9. 9.
    Kubota T, McTiernan CF, Frye CS, Slawson SE, Koretsky AP, Demetris AJ, Feldman AM. Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-alpha. Circ Res 1997;81:627–635.PubMedCrossRefGoogle Scholar
  10. 10.
    Bryant D, Becker L, Richardson J, Shelton J, Franco F, Peschock R, Thompson M, Giroir B. Cardiac failure in transgenic mice with myocardial expression of tumor necrosis factor-a. Circulation 1998;97:1375–1381.PubMedCrossRefGoogle Scholar
  11. 11.
    Kubota T, Miyagishima M, Bounoutas GS, Kadokami T, Watkins SC, McTiernan CF, Feldman AM. Over-expression of tumor necrosis factor-a activates both anti-and pro-apoptotic pathways in the myocardium. J Mol Cell Cardiol 2000;in pressGoogle Scholar
  12. 12.
    Shusterman V, Usiene I, Aysin B, Feldman AM, London B. Slow rhythm destabilization precedes initiation of ventricular arrhythmias in a TNF-? Mouse model of congestive heart failure. NASPE in press: (Abstract)Google Scholar
  13. 13.
    Weber KT. Cardiac interstitium in health and disease: The Fibrillar Collagen Network. J Am Coll Cardiol 1989;13:1637–1652.PubMedCrossRefGoogle Scholar
  14. 14.
    Dollery CM, McEwan JR, Henney AM. Matrix metalloproteinases and cardiovascular disease. Circulation Research 1995;77:863–868.PubMedCrossRefGoogle Scholar
  15. 15.
    Spinale FG, Tomita M, Thomas CV, Walker JD, Mukherjee R, Hebbar L. Time-dependent changes in matrix metalloproteinase activity and selective up-regulation in LV myocardium from patients with end-stage dilated cardiomyopathy. Circulation Research 1998;82:482–495.PubMedCrossRefGoogle Scholar
  16. 16.
    Li YY, McTiernan CF, Feldman AM. Interplay of matrix metalloproteinases, tissue inhibitors of metalloproteinases and their regulators in cardiac matrix remodeling. Cardiovascular Research 2000;46:214–224.PubMedCrossRefGoogle Scholar
  17. 17.
    Maquart FX, Pickart L, Laurent M, Gillery P, Monboisse JC, Borel JP. Stimulation of collagen synthesis in fibroblast cultures by the tripeptidecopper complex glycl-L-histidyl-L-lysine-Cu2 +. FEBS Lett 1988;238:343–346.PubMedCrossRefGoogle Scholar
  18. 18.
    Kim HE, Dalal SS, Young E, Legato MJ, Weisfeldt ML, D’Armiento J. Disruption of the myocardial extracellular matrix leads to cardiac dysfunction. J Clin Invest 2000;106:857–866.PubMedCrossRefGoogle Scholar
  19. 19.
    Li YY, Feng Q, Kadokami T, McTiernan CF, Watkins SC, Feldman AM. Myocardial extracellular matrix remodeling in transgenic mice overexpressing tumor necrosis factor-a can be modulated by antitumor necrosis factor-a therapy. Proc Natl Acad Sci USA 2000;97:12746–12751.PubMedCrossRefGoogle Scholar
  20. 20.
    Li YY, McTiernan CF, Feldman AM. Proinflammatory cytokines regulate tissue inhibitors of metalloproteinases and disintegrin metalloproteinase in cardiac cells. Cardiovascular Research 1999;42:162–172.PubMedCrossRefGoogle Scholar
  21. 21.
    Galis ZS, Muszynski M, Sukhova GK, Simon-Morrissey E, Libby P. Enhanced expression of vascular matrix metalloproteinases induced in vitro by cytokines and in regions of human atherosclerotic lesions. Ann NYAcad Sci 1995;748:501–507.CrossRefGoogle Scholar
  22. 22.
    Lefebvre V, Peeters-Joris C, Vaees G. Production of gelatin-degrading matrix metalloproteinases (`type IV collagenases’) and inhibitors by articular chondrocytes during their dedifferentiation by serial subcultures and under stimulation by interleukin-1 and tumor necrosis factor alpha. Biochim Biophys Acta 1991;1094:8–18.PubMedCrossRefGoogle Scholar
  23. 23.
    Lee E, Vaughan DE, Parikh S, Grodzinsky AJ, Libby P, Lark MW, Lee RT. Regulation of matrix metallopro-teinases and plasminogen activator inhibitor-1 synthesis by plasminogen in cultured human vascular smooth muscle cells. Circ Res 1996;78:44–49.PubMedCrossRefGoogle Scholar
  24. 24.
    Kadokami T, McTiernan CF, Frye CS, Feldman AM. Sex-related survival differences in murine cardiomyopathy are associated with differences in TNF-receptor expression. J Clin Invest 2000;106:589–597.PubMedCrossRefGoogle Scholar
  25. 25.
    Kadokami T, McTiernan CF, Kubota T, Feldman AM. Long term estradiol treatment improves survival in male mice with heart failure induced by cardiac specific TNF-expression. Circulation 102:II-72 (Abstract)Google Scholar
  26. 26.
    Li X, Moody MR, Engel D, Walker S, Clubb FJ, Jr., Sivasubramanian N, Mann DL, Reid MB. Cardiac-specific overexpression of tumor necrosis factor-a causes oxidative stress and contractile dysfunction in mouse diaphragm. Circulation 2000;102:1690–1696.PubMedCrossRefGoogle Scholar
  27. 27.
    Feldman AM, McNamara DM. Medical Progress: Myocarditis. N Eng J Med 2000;343:1388–1398.CrossRefGoogle Scholar
  28. 28.
    Guerra S, Len A, Wang X, Finato N, DiLoreto C, Beltrami CA, Kajstura J, Anversa P. Myoctye death in the failing human heart is gender dependent. Circ Res 1999;85:856–866.PubMedCrossRefGoogle Scholar
  29. 29.
    Adams KF, Dunlap S, Sueta CA, Clarke SW, Patterson JH, Blauwet MB, Jensen LR, Tomasko L, Koch GG. Relation between gender, etiology and survival in patients with symptomatic heart failure. J Am Coll Cardiol 1996;28:1781–1788.PubMedCrossRefGoogle Scholar
  30. 30.
    Shioi T, Matsumori A, Sasayama S. Persistent expression of cytokine in the chronic stage of viral myocarditis in mice. Circulation 1996;94:2930–2937.PubMedCrossRefGoogle Scholar
  31. 31.
    Lowry RP, Blais D. Tumor necrosis factor-alpha in rejecting rat cardiac allografts. Transplant Proc 1988;20:245–247.PubMedGoogle Scholar
  32. 32.
    Maury CPJ, Teppo AM. Raised serum levels of cachectin/tumor necrosis factor in renal allograft rejection. J Exp Med 1987;166:1132–1137.PubMedCrossRefGoogle Scholar
  33. 33.
    Bolling SF, Kunkel SL, Lin H. Prolongation of cardiac allograft survival in rats by anti-TNF and cyclosporine combination therapy. Transplantation 1992;53:283–286.PubMedCrossRefGoogle Scholar
  34. 34.
    Lin H, Chensue SW, Strieter RM, Remick DG, Gallagher KP, Bolling, SF, Kunkel SL. Antibodies against tumor necrosis factor prolong cardiac allograft survival in the rat. Journal of Heart & Lung Transplantation 1992;11:330–335.Google Scholar
  35. 35.
    Ono K, Matsumori A, Shioi T, Furukawa Y, Sasayama S. Cytokine gene expression after myocardial infarction in rat hearts: possible implication in left ventricular remodeling. Circulation 1998;98:149–156.PubMedCrossRefGoogle Scholar
  36. 36.
    Yue P. Massie BM, Simpson PC, Long CS. Cytokine expression increases in nonmyocytes from rats with postinfarction heart failure. American Journal of Physiology 1998;275:H250–H258.PubMedGoogle Scholar
  37. 37.
    Kurrelmeyer KM, Michael LH, Baumgarten G, Taffett GE, Peschon JJ, Sivasubramanian N, Entman ML, Mann DL. Endogenous tumor necrosis factor protects the adult cardiac myocyte against ischemic-induced apoptosis in a murine model of acute myocardial infarction. Proc Natl Acad Sci USA 2000;97:5456–5461.PubMedCrossRefGoogle Scholar
  38. 38.
    Amiot F, Fitting C, Tracey KJ, Cavaillon JM, Dautry F. Lipopolysaccharide-induced cytokine cascade and lethality in LTa/TNFa-deficient mice. Mol Med 1997;3:864–875.PubMedGoogle Scholar
  39. 39.
    Kadokami T, Kubota T, Bounoutas GS, McTiernan CF, Feldman AM. Soluble tumor necrosis factor receptor differentially regulates cardiac cytokine gene expression in mice with lipopolysaccharide-induced endotoxemia. Circulation 1999;100:I-16 (Abstract)Google Scholar
  40. 40.
    Kapadia S, Torre-Amione G, Yokoyama T, Mann DL. Soluble TNF binding proteins modulate the negative inotropic properties of TNF-alpha in vitro. American Journal of Physiology 1995;268:H517–25.PubMedGoogle Scholar
  41. 41.
    Kubota T, Bounoutas GS, Miyagishima M, Kadokami T, Sanders VJ, Bruton C, Robbins PD, McTiernan CF, Feldman AM. Soluble tumor necrosis factor receptor abrogates myocardial inflammation but not hypertrophy in cytokine-induced cardiomyopathy. Circulation 2000;101:2518–2525.PubMedCrossRefGoogle Scholar
  42. 42.
    McTiernan CF, Kadokami T, Lemster BH, Frye CS, Wagner CL, Feldman AM. Anti-TNF antibody limits progression of heart failure in a murine transgenic model. Circulation 2000;102:11–265 (Abstract)CrossRefGoogle Scholar
  43. 43.
    Rohde LE, Ducharme A, Arroyo LH, et al. Matrix metalloproteinase inhibition attenuates early left ventricular enlargement after experimental myocardial infarction in mice. Circulation 1999;99:3063–3070.PubMedCrossRefGoogle Scholar
  44. 44.
    Spinale FG, Coker ML, Krombach SR, Mukherjee R, Hallak H, Houck WV, Clair MJ, Kribbs SB, Johnson LL, Peterson JT, Zile MR. Matrix metalloproteinase inhibition during the development of congestive heart failure. Effects on left ventricular dimensions and function. Circ Res 1999;85:364–376.PubMedCrossRefGoogle Scholar
  45. 45.
    Li YY, Feng YQ, Kadokami T, McTiernan CF, Feldman AM. Modulation of matrix metalloproteinase activities remodels myocardial extracellular matrix in TNFs transgenic mice. Circulation 1999; 100:I-752 (Abstract)Google Scholar
  46. 46.
    Gunja-Smith Z, Morales AR, Romanelli R, Woessner JF. Remodeling of human myocardial collagen in idiopathic dilated cardiomyopathy: role of metalloproteinases and pyridinoline cross links. American Journal of Physiology 1996;148:1639–1648.Google Scholar
  47. 47.
    Rectenwald JE, Moldawer LL, Huber TS, Seeger JM, Ozaki CK. Direct evidence for cytokine involvement in neointimal hyperplasia. Circulation 2000;102:1697–1702.PubMedCrossRefGoogle Scholar
  48. 48.
    Tinut Y, Patel J, Parhami F, Demer LL. Tumor necrosis factor-x promotes in vitro calcification of vascular cells via the cAMP pathyway. Circulation 2000;102:2636–2642.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Charles F. McTiernan
    • 1
  • Toshi Kadokami
    • 1
  • Yun You Li
    • 1
  • Arthur M. Feldman
    • 1
  1. 1.The Cardiovascular Institute of the UPMC Health SystemPittsburghUSA

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