Skip to main content
SpringerLink
Log in

Insights into pathogenesis and treatment of cytokines in cardiomyopathy

  • Published:
Current Cardiology Reports Aims and scope Submit manuscript

Abstract

Our understanding of the pathophysiology of chronic heart failure is rapidly expanding. recent investigations suggest a role for various proinflammatory and vasoconstrictive cytokines in the development and progression of the disease. In particular, tumor necrosis factor-α, interlukin-6, and endothelin have all been implicated in heart failure desease progression. These cytokines appear to be activated in response to a remodeling, induction of programmed cell death, neurohormonal activation, and hemodynamics, these agents cause a variety of deleterious effects in the setting of ventricular dysfunction. Investigational inhibitors and antagonists of these substances show promise for the future treatment of heart failure.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Mann DL, Young JB: Basic mechanisms in congestive heart failure: understanding the role of proinflammatory cytokines. Chest 1994, 105:897–904.

    PubMed  CAS  Google Scholar 

  2. Neta R, Oppenheim JJ, Durum SK: The cytokine concept: historical perspectives and current status of the clonal cytokines. In Lymphokines and the immune response. Edited by Stanley C. Boca Raton: CRC Press; 1990:29–42.

    Google Scholar 

  3. Carswell EA, Old LJ, Kassell RL, et al.: An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A 1975, 72:3666–3670.

    Article  PubMed  CAS  Google Scholar 

  4. Beutler B, Milsark IW, Cerami AC: Purification of cachectin, a lipoprotein lipase-suppressing hormone secreted by endotoxin-induced RAW 264.7 cells. J Exp Med 1985, 161:984–995.

    Article  PubMed  CAS  Google Scholar 

  5. Beutler B, Cerami AC: Cachectin and tumor necrosis factor as two sides of the same biological coin. Nature 1986, 320:584–588.

    Article  PubMed  CAS  Google Scholar 

  6. Beutler B, Milsark IW, Cerami AC: Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science 1985, 229:869–871.

    Article  PubMed  CAS  Google Scholar 

  7. Finkel MS, Oddis CV, Jacob TD, et al.: Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 1992, 257:387–389.

    Article  PubMed  CAS  Google Scholar 

  8. Murray DR, Freeman GL: Tumor necrosis factor-α induces a biphasic effect on myocardial contractility in conscious dogs. Circ Res 1996, 78:154–160.

    PubMed  CAS  Google Scholar 

  9. Levine B, Kalman J, Mayer L, et al.: Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 1990, 323:236–241.

    Article  PubMed  CAS  Google Scholar 

  10. McMurray J, Abdullah I, Dargie HJ, Shapiro D: Increased concentrations of tumor necrosis factor in "cachectic" patients with severe chronic heart failure. Br Heart J 1991, 66:356–358.

    PubMed  CAS  Google Scholar 

  11. Milani RV, Mehra MR, Endres S, et al.: The clinical relevance of circulating tumor necrosis factor-α in acute decompensated heart failure without cachexia. Chest 1996, 110:992–995.

    PubMed  CAS  Google Scholar 

  12. Torre-Amione G, Kapadia S, Benedict C, et al.: Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD). J Am Coll Cardiol 1996, 27:1201–1206.

    Article  PubMed  CAS  Google Scholar 

  13. Doyama K, Fujiwara H, Fukumoto M, et al.: Tumour necrosis factor is expressed in cardiac tissues of patients with heart failure. Intl J Cardiol 1996, 54:217–225.

    Article  CAS  Google Scholar 

  14. Nozaki N, Yamaguchi S, Shirakabe M, et al.: Soluble tumor necrosis factor receptors are elevated in relation to severity of congestive heart failure. Jpn Circulation J 1997, 61:657–664.

    Article  CAS  Google Scholar 

  15. Torre-Amione G, Kapadia S, Lee J, et al.: Expression and functional significance of tumor necrosis factor receptors in human myocardium. Circulation 1995, 92:1487–1493.

    PubMed  CAS  Google Scholar 

  16. Torre-Amione G, Kapadia S, Lee J, et al.: Tumor necrosis factor and tumor necrosis factor receptors in the failing human heart. Circulation 1996, 93:704–711.

    PubMed  CAS  Google Scholar 

  17. Yokoyama T, Vaca L, Rossen RD, et al.: Cellular basis for the negative inotropic effects of tumor necrosis factor-α in the adult mammalian heart. J Clin Invest 1993, 92:2303–2312.

    PubMed  CAS  Google Scholar 

  18. Goldhaber JL, Kim KH, Nateerson PD, et al.: Effects of TNF-alpha on [Ca] and contractility in isolated adult rabbit ventricular myocytes. Am J Physiol 1996, 271:H1449-H1455.

    PubMed  CAS  Google Scholar 

  19. Kumar A, Brar R, Wang P, et al.: Role of nitric oxide and cGMP in human septic serum-induced depression of cardiac myocyte contractility. Am J Physiol 1992, 276:R265-R276.

    Google Scholar 

  20. Ikeda U, Maeda Y, Kawahara Y, et al.: Angiotensin II augments cytokine-stimulated nitric oxide synthesis in rat cardiac myocytes. Circulation 1995, 92:2683–2689.

    PubMed  CAS  Google Scholar 

  21. Ikead U, Murakami Y, Kambe T, Shimada K: Alpha-adrenergic stimulation enhances inducible nitric oxide synthase expression in rat cardiac myocytes. J Mol Cell Cardiol 1996, 28:789–795.

    Article  Google Scholar 

  22. Gross WL, Bak MI, Ingwall JS, et al.: Nitric oxide regulates rat heart contractile reserve and inhibits creatine kinase. Proc Natl Acad Sci USA 1996, 93:5604–5609.

    Article  PubMed  CAS  Google Scholar 

  23. Campbell DL, Stamler JS, Strauss HC: Redox modualtion of L-type calcium channels in ferret ventricular myocytes: mechanisms of dual indirect and direct modulation by nitric oxide and S-nitrosthiols. J Gen Physiol 1996, 108:277–293.

    Article  PubMed  CAS  Google Scholar 

  24. Pinsky DJ, Cai B, Yang X, et al.: The lethal effects of cytokineinduced nitric oxide on cardiac myocytes is blocked by nitric oxide synthase antagonism or transforming growth factorbeta. J Clin Invest 1995, 95:677–685.

    PubMed  CAS  Google Scholar 

  25. Krown KA, Page MT, Nguyen C, et al.: Tumor necrosis factoralpha induced apoptosis in cardiac myocytes: Involvement of the sphingolipid signaling cascade in cardiac cell death. J Clin Invest 1996, 98:2854–2865.

    PubMed  CAS  Google Scholar 

  26. Ohta H, Yatomi Y, Sweeney EA, et al.: A possible role of sphingosine in induction of apoptosis by tumor necrosis factoralpha in human neutrophils. FEBS Lett 1994, 355:267–270.

    Article  PubMed  CAS  Google Scholar 

  27. Ing DJ, Zang J, Dzau VJ, et al.: Modulation of cytokine-induced cardiac myocyte apoptosis by nitric oxide, Bak and Bcl-x. Circ Res 1999, 84:21–33.

    PubMed  CAS  Google Scholar 

  28. Kapadia S, Lee J, Torre-Amione G, et al.: Tumor necrosis factoralpha gene and protein expression in adult feline myocardium after endotoxin administration. J Clin Invest 1995, 11:166–176.

    Google Scholar 

  29. Testa M, Yeh M, Lee P, et al.: Circulating levels of cytokines and their endogenous modulators in patients with mild to severe congestive heart failure due to coronary artery disease or hypertension. J Am Coll Card 1996, 28:964–971.

    Article  CAS  Google Scholar 

  30. Sasayama S, Matsumori A: Vesnarinone: a potential cytokine inhibitor [review]. J Cardiac Failure 1996, 2:251–258.

    Article  CAS  Google Scholar 

  31. Sasayama S, Matsumori A, Matoba Y, et al.: Immunomodulation: a new horizon for medical treatment of heart failure. J Cardiac Failure 1996, 2:S287-S294.

    Article  CAS  Google Scholar 

  32. Matsumori A, Ono K, Nishio R, et al.: Amiodarone inhibits the Production of tumor necrosis factor-α by human mononuclear cells: a possible mechanism for its effect in heart failure. Circulation 1997, 96:1386–1389.

    PubMed  CAS  Google Scholar 

  33. Deswal A, Bozkurt B, Seta Y, et al.: Safety and efficacy of a soluble p75 tunor necrosis factor receptor (Enbrel, etanercept) in patients with advanced heart failure. Circulation 1999, 99:3224–3226.

    PubMed  CAS  Google Scholar 

  34. Jourdan M, Bataille R, Seguin J, et al.: Constitutive production of interleukin-6 and immunologic features in cardiac myxoma. Arthritis Rheum 1990, 33:398–402.

    Article  PubMed  CAS  Google Scholar 

  35. Takahara H, Mori A, Tabata R, et al.: Left atrial myxoma with the production of interleukin-6. Nippon Kyobu Geka Gakkai Zasshi 1992, 40:326–329.

    PubMed  CAS  Google Scholar 

  36. Deng MC, Erren M, Lutgen A, et al.: Interleukin-6 correlates with the hemodynamic impairment during dobutamine administration in chronic heart failure. Int J Cardiol 1996, 57:129–134.

    Article  PubMed  CAS  Google Scholar 

  37. Plenz G, Song ZF, Reichenberg S, et al.: Left-ventricular expression of interleukin-6 messenger-RNA is higher in idiopathic dilated than in ischemic cardiomyopathy. Thorac Cardiovasc Surg 1998, 46:213–216.

    PubMed  CAS  Google Scholar 

  38. Roig E, Orus J, Pare C, et al.: Serum interleukin-6 in congestive heart failure secondary to idiopathic cardiomyopathy. Am J Cardiol 1998, 82:688–690.

    Article  PubMed  CAS  Google Scholar 

  39. Aukrust P, Ueland T, Lien E, et al.: Cytokine network in congestive heart failure secondary to ischemic or idiopathic dilated cardioyopathy. Am J Cardiol 1999, 83:376–382.

    Article  PubMed  CAS  Google Scholar 

  40. Ikeda U, Yamamoto K, Akazawa H, et al.: Plasma cytokine levels in cardiac chambers of patients with mitral stenosis with congestive heart failure. Cardiology 1996, 87:476–480.

    Article  PubMed  CAS  Google Scholar 

  41. Ferrari R, Bachetti T, Confortini R, et al.: Tumor necrosis factorsoluble receptors in patients with various degrees of congestive heart faiulre. Circulation 1995, 92:1479–1486.

    PubMed  CAS  Google Scholar 

  42. MacGowan GA, Mann DL Kormos RL, et al.: Circulating interleukin-6 in severe heart failure. Am J Cardiol 1997, 79:1128–1131.

    Article  PubMed  CAS  Google Scholar 

  43. Kishimoto T, Akira S, Narazaki M, Taga T: Interleukin-6 family of cytokines and gp130. Blood 1995:1243–1254.

  44. Pennica D, Shaw KJ, Swanson TA, et al.: Cardiotropin -1. Biological activities and binding to the leukemia inhibitory factor receptor/gp130 signaling complex. J Biol Chem 1995, 275:10915–10922.

    Google Scholar 

  45. Kunisada K, Hirota H, Fujio Y, et al.: Activation of JAK-STAT and MAP kinases by leukemia inihibitory factor through gp130 in cardiac myocytes. Circulation 1996, 94:2626–2632.

    PubMed  CAS  Google Scholar 

  46. Tsujikawa T, Ebisui C, Fujita J, et al.: Interleukin-6 receptor antibody inhibits muscle atrophy and modulates proteolytic systems in interleukin-6 transgenic mice. J Clin Invest 1996, 97:244–249.

    Google Scholar 

  47. Wiedermann CJ, Beimpold H, Herold M, et al.: Increased levels of serum neopterin and decreased production of neutrophil superoxide anions in chronic heart failure with elevated levels of tumor necrosis factor-alpha. J Am Coll Cardiol 1993, 22:1897–1901.

    Article  PubMed  CAS  Google Scholar 

  48. Kishimoto T: The biology of interleukin-6. Blood 1989, 74:1–10.

    PubMed  CAS  Google Scholar 

  49. Hirano T, Yasukawa K, Harada H: Complementary DNA for novel human interleukin (BSF-2) that induces B cell lymphocytes to produce immunoglobulin. Nature 1996, 324:73–76.

    Article  Google Scholar 

  50. Jirik FR, Podor TJ, Hirano T: Bacterial lipopolysaccharide ad inflammation mediators augment IL-6 production secretion by human endothelial cells. J Immunol 1989, 142:1529–1535.

    Google Scholar 

  51. Yamauchi-Takihara K, Ihara Y, Ogata A, et al.: Hypoxic stress induces cardiac myocyte-derived interleukin-6. Circulation 1995, 91:1520–1524.

    PubMed  CAS  Google Scholar 

  52. Tsutomoto T, Misanaga T, Wada A, et al.: Interleukin-6 spillover in the peripheral circulation increases with severity of heart failure, and the high plasma level of Interleukin-6 is an important prognostic predictor in patients with congestive heart failure. J Am Coll Cardiol 1998, 31:391–398.

    Article  Google Scholar 

  53. Iwasaki A, Matsumori A, Yamada T, et al.: Pimobendan inhibits the production of proinflammatory cytokines and gene expression of inducible nitric oxide synthase in a murine model of myocarditis. J Am Coll Card 1999, 33:1400–1407.

    Article  CAS  Google Scholar 

  54. Mohler ER 3rd,Sorensen LC, Ghali JK, et al.: Role of cytokines in the mechanism of action of amlodipine: the PRAISE Heart Failure Trial. Prospective Randomized Amlodipine Survival Evaluation. J Am Coll Cardiol 1997, 30:35–41.

    Article  PubMed  CAS  Google Scholar 

  55. Hickey KA, Rubanyi G, Paul RJ, Highsmith RF: Characterization of a coronary vasoconstrictor produced by cultured endothelial cells. Am J Physiol 1985, 248:C550-C556.

    PubMed  CAS  Google Scholar 

  56. Gillespie MN, Owasoyo JO, McMurtry IF, O'Brien RF: Sustained coronary vasoconstriction provoked by a peptidergic substance released from endothelial cells in culture. J Pharmacol Exp Therap 1986, 236:339–343.

    CAS  Google Scholar 

  57. Yanagisawa M, Kurihara H, Kimura S, et al.: A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988, 332:411–415.

    Article  PubMed  CAS  Google Scholar 

  58. Biebuyck JF: Endothelins: biochemistry and pathophysiologic actions. Anesthesiology 1994, 80:892–905.

    Article  Google Scholar 

  59. Ikegawa R, Matsumura Y, Tsukahara Y, et al.: Phosphoramidon, a metalloproteinase inhibitor, suppresses the secretion of endothelin-1 from cultured vascular endothelial cells by inhibiting a big endothelin-1 converting enzyme. Biochem Biophys Res Comm 1990, 171:669–675.

    Article  PubMed  CAS  Google Scholar 

  60. Ikegawa R, Matsumura Y, Tsukahara Y, et al.: Phosphoramidon inhibits the generation of endothelin-1 from exogenously applied big endothelin-1 in cultured vascular endothelial cells and smooth muscle cells. FEBS Letter 1991, 293:45–48.

    Article  CAS  Google Scholar 

  61. Schini VB, Hendrickson H, Heublein DM, et al.: Thrombin enhances the release of endothelin from cultured porcine aortic endothelial cells. Eur J Pharmacol 1989, 165:333–334.

    Article  PubMed  CAS  Google Scholar 

  62. Kurihara H, Yoshizumi M, Sugiyama T, et al.: Transforming growth factor beta stimulates expression of endothelin mRNA by vasculsar endothelial cells. Biochem Biophys Res Comm 1989, 159:1435–1440.

    Article  PubMed  CAS  Google Scholar 

  63. Emori T, Hirata Y, Ohta K, et al.: Secretory mechanism of immunoreactive endothelin in cultured bovine endothelial cells. Biophys Biophys Res Comm 1989, 160:93–100.

    Article  CAS  Google Scholar 

  64. Morel DR, Lacroix JS, Hemsen A, et al.: Increased plasma and pulmonary lymph levels of endothelin during endotoxic shock. Eur J Pharmacol 1989, 167:427–428.

    Article  PubMed  CAS  Google Scholar 

  65. Sugiura M, Inagami T, Kon V: Endotoxin stimulates endothelin release in vivo and in vitro as determined by radioimmunoassay. Biochem Biophys Res Comm 1989, 161:1220–1227.

    Article  PubMed  CAS  Google Scholar 

  66. Kourembanas S, Marsden PA, McQuillan LP, Faller DV: Hypoxia induces endothelin gene expression and secretion in cultured human endothelium. J Clin Invest 1991, 88:1054–1057.

    Article  PubMed  CAS  Google Scholar 

  67. Cade C, Ilozue CV, Rubanyi GM, et al.: Smooth muscle cells contain a factor responsible for decreasing big endothelin and endothelin-1 production by cultured endothelial cells. J Cardiovasc Pharmacol 1991, 17:S71-S75.

    Article  PubMed  CAS  Google Scholar 

  68. Goto K, Kasuya Y, Matsuki N, et al.: Endothelin activated the di-hydropyridine-sensitive, voltage-dependent Ca channel in vascular smooth muscle. Proc Natl Acad Sci U S A 1989, 86:3915–3918.

    Article  PubMed  CAS  Google Scholar 

  69. Sugiura M, Inagami T, Hare GMT, Johns JA: Endothelin action: Inhibition by a protein kinase C inhibitor and involvement of phosphoinositols. Biochem Biophys Res Comm 1989, 158:170–176.

    Article  PubMed  CAS  Google Scholar 

  70. de Nucci G, Thomas R, D'Orleans-Juste P, et al.: effects of circulating endothelin are limited by its removal in the pulmonary circulation and by the release of prostacyclin and endothelium-derived relaxing factor. Proc Natl Acad Sci U S A 1988, 85:9797–9800.

    Article  PubMed  Google Scholar 

  71. Mortensen LH, Fink GD: Hemodynamic effect of human and rat endothelin administration into conscious rats. Am J Physiol 1990, 258:H362-H368.

    PubMed  CAS  Google Scholar 

  72. Hiley CR, Douglas SA, Randall MD: Pressor effects of endothelin- 1 and some analogs in the perfused mesenteric arterial bed of the rat. J Cardiovasc Pharmacol 1989, 13:S197-S199.

    Article  PubMed  CAS  Google Scholar 

  73. Marguiles KB, Hildebrand FL, Lerman A, et al.: Increased endothelin in experimental heart failure. Circulation 1990, 82:2226–2230.

    Google Scholar 

  74. Cavero PG, Miller WL, Heublein DM, et al.: Endothelin in experimental congestive heart failure in the anesthetized dog. Am J Physiol 1990, 259:F312-F317.

    PubMed  CAS  Google Scholar 

  75. McMurray JJ, Ray SG, Abdullah I, et al.: Plasma endothelin in chronic heart failure. Circulation 1992, 85:1374–1379.

    PubMed  CAS  Google Scholar 

  76. Rodeheffer RJ, Heublein DM, McKinley L, BurnettJC, Jr: Plasma endothelin concentrations are increased in humans with congestive heart failure [abstract]. J Am Coll Cardiol 1991,17:281A.

    Article  Google Scholar 

  77. Lerman A, Kubo SH, Tschumperlin LK, Burnett JC, Jr: Plasma endothelin concentration in humans with end-stage failure and after heart transplantation. J Am Coll Cardiol 1992, 20:849–853.

    Article  PubMed  CAS  Google Scholar 

  78. Saito T, Yanagisawa M, Miyauchi et al.: Endothelin in human circulating blood: effect of major surgical stress [abstract]. Jpn J Pharmacol 1989, 49:215.

    Google Scholar 

  79. Lerman A, Click RL, Narr BJ, et al.: Elevation of plasma endothelin with systemic hypertension following orthotopic liver transplantation. Transplantation 1991, 51:646–650.

    Article  PubMed  CAS  Google Scholar 

  80. Edwards BS, Hunt SA, Fowler MB, et al.: Effect of cyclosporine on plasma endothelin levels in humans after cardiac transplantation. Am J Cardiol 1991, 67:82–84.

    Article  Google Scholar 

  81. Wei CM, Lerman A, Rodeheffer RJ, et al.: Endothelin in human congestive heart failure. Circulation 1994, 89:1580–1586.

    PubMed  CAS  Google Scholar 

  82. Kobayashi T, Miyauchi T, Sakai S, et al.: Endothelin converting enzyme and angiotensin converting enzyme in failing hearts of rats with myocardial infarction. J Cardiovasc Pharmacol 1998, 31l:S417-S420.

    Article  Google Scholar 

  83. Galtius-Jensen S, Wroblewski H, Emmeluth C, et al.: Plasma endothelin in congestive heart failure: a predictor of cardiac death? J Card Failure 1996, 2:71–76.

    Article  Google Scholar 

  84. Shubeita HE, McDonough PM, Harris AN, et al.: Endothelin induction of inositol phospholipid hydrolysis, sarcomere assembly, and cardiac gene expression in ventricular myocytes: a paracrine mechanism for myocardial cell hypertrophy. J Biol Chem 1990, 265:20555–20562.

    PubMed  CAS  Google Scholar 

  85. Sakai S, Miyauchi T, Sakurai T, et al.: Endogenous endothelin-1 participates in the maintenance of cardiac function in rats with congestive heart failure: marked increase in endothelin- 1 production in the failing heart. Circulation 1996, 93:1214–1222.

    PubMed  CAS  Google Scholar 

  86. Mulder P, Vincent R, Derumeauzx G, et al.: Role of endogenous endothelin in chronic heart failure. Circulation 1997, 96:1976–1982.

    PubMed  CAS  Google Scholar 

  87. Otsuka A, Mikami H, Katahira K, et al.: Haemodynamic effect of endothelin, a novel potent vasoconstrictor in dogs. Clin Exp Pharmacol Physiol 1990, 17:351–360.

    PubMed  CAS  Google Scholar 

  88. Sakai S, Miyauchi T, Sakurai T, et al.: Pulmonary hypertension caused by congestive heart failure is ameliorated by long-term application of an endothelin receptor antagonist: increased expression of endothelin-1 messenger ribonucleic acid and endothelin-1 like immunoreactivity in the lung in congestive heart failure. J Am Coll Cardiol 1996, 28:1580–1588.

    Article  PubMed  CAS  Google Scholar 

  89. Fukuroda T, Nishikibe M, Ohta Y, et al.: Analysis of responses to endothelins in isolated porcine blood vessels by using a novel endothelin antagonist, BQ-153. Life Sci 1992, 50:P1107-P1112.

    Article  Google Scholar 

  90. Galatius-Jensen S, Wroblewski H, Emmeluth C, et al.: Plasma endothelin in congestive heart failure: effect of the ACE inhibitor, fosinopril. Cardiovasc Res 1996, 32:1148–1154.

    Article  PubMed  CAS  Google Scholar 

  91. Townend J, Doran J, Jones S, Davies M: Effect of angiotensin inhibition on plasma endothelin in congestive heart failure. Int J Cardiol 1994, 43:299–304.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Section of Heart Failure and Cardiac Transplantation, University of Cincinnati College of Medicine, 231 Bethesda Avenue, 45267-0542, Cincinnati, OH, USA

    Lou Vadlamani MD & William T. Abraham MD, FACP, FACC

Authors
  1. Lou Vadlamani MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. William T. Abraham MD, FACP, FACC
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vadlamani, L., Abraham, W.T. Insights into pathogenesis and treatment of cytokines in cardiomyopathy. Curr Cardiol Rep 2, 120–128 (2000). https://doi.org/10.1007/s11886-000-0008-3

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11886-000-0008-3

Keywords

Search

Navigation