Interactions Between Cytokines and Neurohormonal Systems in the Failing Heart

  • Hong Kan
  • Mitchell S. Finkel
Part of the Developments in Cardiovascular Medicine book series (DICM, volume 236)


Congestive heart failure (CHF) remains an enormous health care problem in the United States, as well as other industrialized countries [1, 2, 3]. Millions of Americans are currently being treated for CHF and hundreds of thousands of others are expected to join their ranks annually. The prognosis for CHF patients has been improved as a result of the use of angiotensin converting enzyme inhibitors (ACEI) and β-adrenergic receptor blockers (β-blockers) [1, 2, 3, 4]. The success of these therapies underscores the pathogenic role of neurohormonal activation in CHF. It is now widely appreciated that norepinephrine (NE) and angiotensin II (AII) directly contribute to progressive deterioration in myocardial function and are not merely markers of disease severity or epiphenomenae [5, 6, 7].


Nitric Oxide Cardiac Myocytes Congestive Heart Failure Patient Calcium Release Channel Neurohormonal System 
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  1. 1.
    The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survial Study (CONSENSUS). N Engl J Med 1987;316:1429–1435.CrossRefGoogle Scholar
  2. 2.
    Ho KK, Anderson KM, Kannel WB, et al. Survival after the onset of congestive heart failure in Framingham Heart Study subjects. Circulation 1993;88:107–115.PubMedCrossRefGoogle Scholar
  3. 3.
    Packer M, Bristow MR, Cohn JN, et al. for the U.S. Carvedilol Heart Failure Study Group. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. NEngl JMed 1996;334:1349–1355.CrossRefGoogle Scholar
  4. 4.
    Swedberg K, Hjalmarson A, Waagstein F, Wallentin I. Prolongation of survival in congestive cardiomyopathy by beta-receptor blockade. Lancet 1979;2:1374–1376.CrossRefGoogle Scholar
  5. 5.
    Cohn JN, Levine TB, Olivari MT, et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Eng J Med 1984;311:819.CrossRefGoogle Scholar
  6. 6.
    Oddis CV, Finkel MS. Cytokine-stimulated nitric oxide production inhibits mitochondrial activity in cardiac myocytes. Biochem and Biophys Res Comm 1995;213(3):1002–1009.CrossRefGoogle Scholar
  7. 7.
    Sadoshima J, Izumo S. Signal transduction pathways of angiotension II-induced c-fos gene expression in cardiac myocytes in vitro. Circ Res 1993;73:424–438.PubMedCrossRefGoogle Scholar
  8. 8.
    Mann DL, Young JB. Basic mechanisms in congestive heart failure. Recognizing the role of proinflammatory cytokines. Chest 1994;105:897–904.PubMedCrossRefGoogle Scholar
  9. 9.
    Reilly JM, Cunnion RE, Burch-Whitman C, Parker MM, Shelhamer JH, Parrillo JE. A circulating myocardial depressant substance is associated with cardiac dysfunction and peripheral hypoperfusion (lactic acidemia) in patients with septic shock. Chest 1989;95:1072–1080.PubMedCrossRefGoogle Scholar
  10. 10.
    Parillo JE. Mechanisms of disease: pathogenic mechanisms of septic shock. N Eng J Med 1993;328:1471–1477.CrossRefGoogle Scholar
  11. 11.
    Parker MM, Shelhamer JH, Bacharach SL, Green MV, Natanson C, Frederick TM, Damske BA, Parrillo JE. Profound but reversible myocardial depression in patients with septic shock. Annals of Internal Medicine 1985;100:483–490.Google Scholar
  12. 12.
    Vincent JL, Bakker J, Marecaux G, Schandene L, Kahn RJ, Dupont E. Administration of anti-TNF antibody improves left ventricular function in septic shock patients. Chest 1992;101:810–815.PubMedCrossRefGoogle Scholar
  13. 13.
    Levine B, Kalman J, Mayer L, Filit HM, Packer M. Elevated circulating levels of tumor necrosis factor inGoogle Scholar
  14. The Role of Inflammatory Mediators in the Failing Heart severe chronic heart failure. N Eng J Med 1990;323(4):236–241.Google Scholar
  15. 14.
    Feldman AM, Combes A, Wagner D, Kadakomi T, Kubota T, Li YY, McTiernan C. The role of tumor necrosis factor in the pathophysiology of heart failure. J Am Coll Cardiol 2000;35:537–544.PubMedCrossRefGoogle Scholar
  16. 15.
    Braunwald E, Kloner RA. The stunned myocardium: Prolonged, postischemic ventricular dysfunction. Circulation 1982;66:1146–1149.PubMedCrossRefGoogle Scholar
  17. 16.
    Kumar AR, Brar R, Wang P, Dee L, Skorupa G, Khadour F, Schulz R, Parrillo JE. Role of nitric oxide and cAMP in human septic serum-induced depression of cardiac myocyte contractility. Am J Physiol 1999;276:R265–R276.PubMedGoogle Scholar
  18. 17.
    Smith LW, McDonough KH. Inotropic sensitivity to adrenergic stimulation in early sepsis. Am J Physiol 1988;255 (Heart Circ. Physiol. 24):H699–H703.PubMedGoogle Scholar
  19. 18.
    Balligand JL, Ungureanu-Longrois D, Simmons WW, Pimental D, Malinski TA, Kapturczak M, Taha Z, Lowenstein CJ, Davidoff AJ, Kelly RA, Smith TW, Michel T. Cytokine-inducible nitric oxide synthase (iNOS) expression in cardiac myocytes. J Biol Chem 1994;269:27580–27588.PubMedGoogle Scholar
  20. 19.
    Balligand JL, Ungureann D, Kelly RA, Kobzik L, Pimental D, Michael T, Smith TW. Abnormal contractile function due to induction of nitric oxide synthesis in rat cardiac myocytes follows exposure to activated macrophage-conditioned medium. J Clin Invest 1993;91:2314–2319.PubMedCrossRefGoogle Scholar
  21. 20.
    Balligand JL, Kobzik L, Han X, Kaye DM, Belhassen L, O’Hara DS, Kelly RA, Smith TW, Michel T. Nitric oxide-dependent parasympathetic signaling is due to activation of constitutive endothelial (Type III) nitric oxide synthase in cardiac myocytes. J Biol Chem 1995;270(4):14582–14586.PubMedCrossRefGoogle Scholar
  22. 21.
    Bers DM. Excitation-contraction coupling and cardiac contractile force. Norwell: Kluwer Academic Publishers, 1991:119–145.Google Scholar
  23. 22.
    Brady AJB, Warren JB, Poole-Wilson PA, Williams TJ, Harding SE. Nitric oxide attenuates cardiac myocyte contraction. Am J Physiol 1993;265:H176–H182.PubMedGoogle Scholar
  24. 23.
    Drexler H, Kastner S, Strobel A, Studer R, Brodde 0E, Hasenfub G. Expression, activity and functional significance of inducible nitric oxide synthase in the failing human heart. J Am Coll Cardiol 1998;32:955–963.PubMedCrossRefGoogle Scholar
  25. 24.
    Finkel MS, Oddis CV, Jacobs TD, Watkins SC, Hattler BG, Simmons RL. Inotropic effects of cytokines on the heart mediated by nitric oxide. Science 1992;257:387–389.PubMedCrossRefGoogle Scholar
  26. 25.
    Finkel MS, Oddis CV, Mayer OH, Hattler BG, Simmons RL. Nitric oxide synthase inhibitor alters papillary muscle force-frequency relationship. J Pharm Exp Ther 1995;272(2):945–952.Google Scholar
  27. 26.
    Finkel MS, Shen L, Oddis CV, Hoffman RA, Romeo RC, Simmons RL, Hattler BG. IL-6 as a mediator of stunned myocardium. Am J Cardiol 1993;71:1231–1232.PubMedCrossRefGoogle Scholar
  28. 27.
    Gulick T, Chung MK, Peiper SJ, Lange LG, Schreiner GF. Interleukin-1 and tumor necrosis factor inhibit cardiac myocytes-adrenergic responsiveness. Proc Natl Acad Sci USA 1989;86:6753–6757.PubMedCrossRefGoogle Scholar
  29. 28.
    Habib FM, Spingall DR, Davies GJ, Oakley CM, Yacoub MH, Polak JM. Tumor necrosis factor and inducible nitric oxide synthase in dilated cardiomyopathy. Lancet 1996;347:1151–1155.PubMedCrossRefGoogle Scholar
  30. 29.
    Hattler BG, Gorcsan JIII, Shah N, Oddis CV, Billiar TR, Simmons RL, Finkel MS. A potential role for nitric oxide (NO) in myocardial stunning. J Card Surg 1994;9:425–429.PubMedGoogle Scholar
  31. 30.
    Hattler BG, Oddis CV, Zeevi A, Luss H, Shah N, Geller DA, Billiar TR, Simmons RL, Finkel MS. Regulation of constitutive nitric oxide synthase activity by the human heart. Am J Cardiol 1995;76:957959.Google Scholar
  32. 31.
    Kanai AJ, Mesaros S, Finkel MS, Oddis CV, Strauss HC, Malinski T. Nitric oxide release measured directly with a porphyrinic microsensor reveals adrenergic control of constitutive nitric oxide synthase in cardiac myocytes. Am J Physiol 1997;273(42):C1371-C 1377.PubMedGoogle Scholar
  33. 32.
    Kan H, Xie Z, Finkel MS. Norepinephrine stimulated MAP kinase activity enhances cytokine induced nitric oxide production by neonatal rat cardiac myocytes. Am J Physiol 1999;276:H47–H52.PubMedGoogle Scholar
  34. 33.
    Kan H, Xie Z, Finkel MS. TNF enhances NO production by neonatal rat cardiac myocytes through MAP kinase mediated activation of NF-KB. Am J Physiol 1999;277:H1646–H1646.Google Scholar
  35. 34.
    Liu S, Schreur KD. G protein-mediated suppression of L-type Cat+ current by interleukin-1 beta in cultured rat ventricular myocytes. Am J Physiol 1995;268(2Pt1):C339–C349.PubMedGoogle Scholar
  36. 35.
    Mery PF, Pavoine C, Belhassen L, Pecker F, Fishmeister R. Nitric oxide regulates cardiac Cat current. J Biol Chem 1993;268:26286–26295.PubMedGoogle Scholar
  37. 36.
    Oddis CV, Simmons RL, Hattler BG, Finkel MS. cAMP enhances inducible nitric oxide synthase mRNA stability in cardiac myocytes. Am J Physiol 1995;H38(6):2044–2050.Google Scholar
  38. 37.
    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
  39. 38.
    Rozanski GJ, Witt RC. IL-1 inhibits beta-adrenergic control of cardiac calcium current: role of L-arginine/ nitric oxide pathyway. Am J Phys 1994;267(5Pt2): H1753–H1758.Google Scholar
  40. 39.
    Shinke T, Takaoka H, Takeuchi M, Hata K, Kawai H, Okubo H, Kijima Y, Murata T, Yokoyama M. Nitric oxide spares myocardial oxygen consumption through attenuation of contractile response to β-adrenergic stimulation in patients with idiopathic dilated cardiomyopathy. Circulation 2000;101:1925–1930.PubMedCrossRefGoogle Scholar
  41. 40.
    Tatsumi T, Matoba S, Kawahara A, Keira N, Shiraishi J, Akashi K, Kobara M, Tanaka T, Katamura M, Nakagawa C, Ohta B, Shirayama T, Takeda K, Asayama J, Fliss H, Nakagawa M. Cytokine-induced nitric oxide production inhibits mitochondrial energy production and impairs contractile function in rat cardiac myocytes. J Am Coll Cardiol 2000;35:1338–1346.PubMedCrossRefGoogle Scholar
  42. 41.
    Xu L, Eu JP, Meissner G, Stamler JS. Activation of the cardiac calcium release channel (ryanodine receptor) by poly-s-nitrosylation. Science 1998;27(9):234–236.CrossRefGoogle Scholar
  43. 42.
    Katz AM, ed. Physiology of the heart, 2nd ed. New York: Raven Press, 1992.Google Scholar
  44. 43.
    Abramson JJ, Trimm JL, Weden L, Salama G. Heavy metals induce rapid calcium release from sarcoplasmic reticulum vesicles isolated from skeletal muscle. Proc Natl Acad Sci USA 1983;80:1526–1530.PubMedCrossRefGoogle Scholar
  45. 44.
    Finkel MS, Oddis CV, Romeo RC, Salama G. Positive inotropic effect of acetylcysteine in the cardiomyopathic Syrian hamster. J Card Pharm 1993;21:29–34.CrossRefGoogle Scholar
  46. 45.
    Kelly RA, Balligand JL, Smith TW. Nitric oxide and cardiac function. Circ Res 1996;79:363–380.Google Scholar
  47. 46.
    Bredt DS, Hwang PM, Glatt CE, Lowenstein C, Reed RR, Snyder SH. Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase. Nature 1991;351:714–718.PubMedCrossRefGoogle Scholar
  48. 47.
    Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci USA 1987;84:9265–9269.PubMedCrossRefGoogle Scholar
  49. 48.
    Janssens SP, Shimouchi A, Quertermous T, Bloch DB, Bloch KD. Cloning and expression of cDNA encoding human endothelium-derived relaxing factor/nitric oxide synthase. J Biol Chem 1992;267:14519–14522.PubMedGoogle Scholar
  50. 49.
    Lyons C, Orloff B, Cunningham J. Molecular cloning and functional expression of an inducible nitric oxide synthase from a murine macrophage cell line. J Biol Chem 1992;267:6370–6374.PubMedGoogle Scholar
  51. 50.
    Xie QW, Cho HJ, Calaycay J, Mumford RA, Swiderek KM, Lee TD, Ding A, Troso T, Nathan C. Cloning and characterization of inducible nitric oxide synthase from mouse macrophages. Science 1992;256:225–228.PubMedCrossRefGoogle Scholar
  52. 51.
    Abbas AK, Lichtman AH, Pober JS. Cellular and molecular immunology. Philadelphia: W. B. Saunders Company, 1991:226–242.Google Scholar
  53. 52.
    Ognibene FP, Rosenberg SA, Lotze MT, Skibber J, Parker MM, Shelhamer JH, Parillo JE. Interleukin2 administration causes reversible hemodynamic changes and left ventricular dysfunction similar to those seen in septic shock. Chest 1988;94:750–754.PubMedCrossRefGoogle Scholar
  54. 53.
    Oddis CV, Finkel MS. Cytokines and nitric oxide synthase inhibitor as mediators of adrenergic refractoriness in cardiac myocytes. Eur J Pharmacol 1997;320:167–174.PubMedCrossRefGoogle Scholar
  55. 54.
    Frering B, Philip I, Dehoux M, Rolland C, Langlois JM, Desmonts JM. Circulating cytokines in patients undergoing normothermic cardiopulmonary bypass. J Thorac Cardiouasc Sur 1994;108:636–641.Google Scholar
  56. 55.
    Steinberg JB, Kapelanski DP, Olson JD, Weiler JM. Cytokine and complement levels in patients undergoing cardiopulmonary bypass. J Thorac Cardiovasc Surg 1993;106:1008–1016.PubMedGoogle Scholar
  57. 56.
    Guillen I, Blanes M, Gomez-Lechon MJ, Castell JV. Cytokine signaling during myocardial infarction: sequential appearance of IL-1# and IL-6. Am J Physiol 1995;269 (Regulatory Integrative Comp. Physiol 38):R229–R235.PubMedGoogle Scholar
  58. 57.
    Ikeda U, Ohkawa F, Seino Y, Yamamotor K, Hidaka Y, Kasahara T, Kawai T, Shimada K. Serum interleukin 6 levels become elevated in acute myocardial infarction. J Mol Cell Cardiol 1992;24:579–584.PubMedCrossRefGoogle Scholar
  59. 58.
    Ikeda U, Maeda Y, Kawahara Y, Yokoyama M, Shimada K. Angiotensin II augments cytokine-stimulated nitric oxide synthesis in rat cardiac myocytes. Circulation 1995;92:2683–2689.PubMedCrossRefGoogle Scholar
  60. 59.
    Feldman MC, Gwarthmey JC, Phillips P, Schoen F, Morgan JP. Reversal of the force-frequency relationship in working myocardium from patients with end-stage heart failure. J Appl Cardiol 1988;3:273–283.Google Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Hong Kan
    • 1
  • Mitchell S. Finkel
    • 1
    • 2
  1. 1.Departments of Medicine (Cardiology)Robert C. Byrd Health Sciences Center, Louis A. Johnson V.A. Medical CenterMorgantownUSA
  2. 2.Pharmacology and ToxicologyWest Virginia University School of Medicine, Robert C. Byrd Health Sciences Center, Louis A. Johnson V.A. Medical CenterMorgantownUSA

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