Molecular and Cellular Biochemistry

, Volume 242, Issue 1–2, pp 135–144 | Cite as

Gap junction remodeling and altered connexin43 expression in the failing human heart

  • Sawa Kostin
  • Markus Rieger
  • Sebastian Dammer
  • Stefan Hein
  • Manfred Richter
  • Wölf-Peter Klövekorn
  • Erwin P. Bauer
  • Jutta Schaper


Gap junctions (GJ) are important determinants of cardiac conduction and the evidence has recently emerged that altered distribution of these junctions and changes in the expression of their constituent connexins (Cx) may lead to abnormal coupling between cardiomyocytes and likely contribute to arrhythmogenesis. However, it is largely unknown whether changes in the expression and distribution of the major cardiac GJ protein, Cx43, is a general feature of diverse chronic myocardial diseases or is confined to some particular pathophysiological settings. In the present study, we therefore set out to investigate qualitatively and quantitatively the distribution and expression of Cx43 in normal human myocardium and in patients with dilated (DCM), ischemic (ICM), and inflammatory cardiomyopathies (MYO). Left ventricular tissue samples were obtained at the time of cardiac transplantation and investigated with immunoconfocal and electron microscopy. As compared with the control group, Cx43 labeling in myocytes bordering regions of healed myocardial infarction (ICM), small areas of replacement fibrosis (DCM) and myocardial inflammation (MYO) was found to be highly disrupted instead of being confined to the intercalated discs. In all groups, myocardium distant from these regions showed an apparently normal Cx43 distribution at the intercalated discs. Quantitative immunoconfocal analyis of Cx43 in the latter myocytes revealed that the Cx43 area per myocyte area or per myocyte volume is significantly decreased by respectively 30 and 55% in DCM, 23 and 48% in ICM, and by 21 and 40% in MYO as compared with normal human myocardium. In conclusion, focal disorganization of GJ distribution and down-regulation of Cx43 are typical features of myocardial remodeling that may play an important role in the development of an arrhythmogenic substrate in human cardiomyopathies.

human heart ischemic heart disease dilated cardiomyopathy myocarditis gap junctions arrhythmia 


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  1. 1.
    Levy D, Anderson KM, Savage DD, Balkus SA, Kannel WB, Castelli WP: Risk of ventricular arrhythmias in cardiac failure and hypertrophy: The Framingham study. Am J Cardiol 60: 560-565, 1987Google Scholar
  2. 2.
    Janse MJ, Wit AL: Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction. Phisiol Rev 69: 1049-1169, 1989Google Scholar
  3. 3.
    Gardner PI, Ursell PC, Fenoglio JJ, Wit AL: Electrophysiologic and anatomic basis for fractionated electrograms recorded from healed myocardial infarcts. Circulation 72: 596-611, 1985Google Scholar
  4. 4.
    Boyden PA, Gardner PI, Wit AL: Action potentials of cardiac muscle in healing infarcts: Response to norepinephrine and caffeine. J Mol Cell Cardiol 20: 525-537, 1988Google Scholar
  5. 5.
    Saffitz JE, Corr PB, Sobel BE: Arrhythmogenesis and ventricular dysfunction after myocardial infarction. Is anomalous cellular coupling the elusive link? Circulation 87: 1742-1745, 1993Google Scholar
  6. 6.
    Severs NJ: Cardiac muscle cell interaction: From microanatomy to the molecular make-up of the gap junction. Histol Histopathol 10: 481-501, 1995Google Scholar
  7. 7.
    Peters NS, Coromilas J, Severs NJ, Wit AL: Disturbed connexin43 gap junction distribution correlates with the location of reentrant circuits in the epicardial border zone of healing canine infarcts that cause ventricular tachycardia. Circulation 95: 988-996, 1997Google Scholar
  8. 8.
    Peters NS, Wit AL: Myocardial architecture and ventricular arrhythmogenesis. Circulation 97: 1746-1754, 1998Google Scholar
  9. 9.
    Spach MS, Heidlage F, Dolber PC, Barr RC: Electrophysiological effects of remodeling cardiac gap junctions and cell size. Experimental and model studies of normal cardiac growth. Circ Res 86: 302-311, 2000Google Scholar
  10. 10.
    Saffitz JE, Kanter HL, Green KG, Tolley TK, Beyer EC: Tissue-specific determinants of anisotropic conduction velocity in canine atrial and ventricular myocardium. Circ Res 74: 1065-1070, 1994Google Scholar
  11. 11.
    Gros DB, Jongsma HJ: Connexins in mammalian heart function. Bioessays 18: 719-730, 1996Google Scholar
  12. 12.
    Jongsma HJ, Wilders R: Gap junctions in cardiovascular disease. Circ Res 86: 1193-1197, 2000Google Scholar
  13. 13.
    van Veen TAB, van Rijen HVM, Opthof T: Cardiac gap junction channels: Modulation of expression and channel properties. Cardiovasc Res 51: 217-229, 2001Google Scholar
  14. 14.
    Kanno S, Saffitz JE: The role of myocardial gap junctions in electrical conduction and arrythmogenesis. Cardiovasc Pathol 10: 169-177, 2001Google Scholar
  15. 15.
    Severs NJ, Rothery S, Dupont E, Coppen SR, Yeh H-I, Ko Y-S, Matsushita T, Kaba R, Halliday D: Immunohistochemical analysis of connexin expression in the healthy and diseased cardiovascular system. Microsc Res Tech 52: 301-322, 2001Google Scholar
  16. 16.
    Kostin S, Schaper J: Tissue-specific patterns of gap junctions in adult rat atrial and ventricular cardiomyocytes in vivo and in vitro. Circ Res 88: 933-939, 2001Google Scholar
  17. 17.
    Saffitz JE, Davis LM, Darrow BJ, Kanter HL, Laing JG, Beyer EC: The molecular basis of anisotropy: Role of gap junctions. J Cardiovasc Electrophysiol 6: 498-510, 1995Google Scholar
  18. 18.
    Severs NJ, Dupont E, Kaprielian RR, Yeh HI, Rothery S: Gap junctions and connexins in the cardiovascular system. In: M.H. Yacoub, A. Carpentier, J. Pepper, J. N. Fabiani (eds). Annual of Cardiac Surgery 1996, 9th edition. Current Science, London, 1996, pp 31-44Google Scholar
  19. 19.
    Luke RA, Saffitz JE: Remodeling of ventricular conduction pathways in healed canine infarct border zones. J Clin Invest 87: 1594-1602, 1990Google Scholar
  20. 20.
    Smith JH, Green CR, Peters NS, Rothery S, Severs NJ: Altered patterns of gap junction distribution in ischemic heart disease: An immunohistochemical study of human myocardium using laser scanning confocal microscopy. Am J Pathol 139: 801-821, 1991Google Scholar
  21. 21.
    Campos de Carvalho AC, Tanowitz HB, Wittner M, Dermietzel R, Roy C, Hertzberg EL, Spray DC: Gap junction distribution is altered between cardiac myocytes infected with Trypanosoma cruzi. Circ Res 70: 733-742, 1992Google Scholar
  22. 22.
    Peters NS, Green CR, Poole-Wilson PA, Severs NJ: Reduced content of connexin 43 gap junctions in ventricular myocardium from hypertrophied and ischemic human hearts. Circulation 88: 864-875, 1993Google Scholar
  23. 23.
    Bastide B, Neyses L, Ganten D, Paul M, Willecke K, Traub O: Gap junction protein connexin40 is preferentially expressed in vascular endothelium and conductive bundles of rat myocardium and is increased under hypertensive conditions. Circ Res 73: 1138-1149, 1993Google Scholar
  24. 24.
    Sepp R, Severs N, Gourdie R: Altered patterns of cardiac junction distribution in hypertrophic cardiomyopathy. Heart 76: 412-417, 1996Google Scholar
  25. 25.
    Kaprielian RR, Gunning M, Dupont E, Sheppard MN, Rothery SM, Underwood R, Pennel DJ, Fox Kim, Pepper J, Poole-Wilson PA, Severs NJ: Downregulation of immunodetectable connexin43 and decreased gap junction size in the human left ventricle. Circulation 97: 651-660, 1998Google Scholar
  26. 26.
    Matsushita T, Oyamada M, Fujimoto K, Yasuda Y, Masuda S, Wada Y, Oka T, Takamatsu T: Remodeling of cell-cell and cell-extracellular matrix interactions at the border zone of rat myocardial infarcts. Circ Res 85: 1046-1055, 1999Google Scholar
  27. 27.
    Uzzaman M, Honjo H, Takagishi Y, Emdad L, Magee AI, Severs NJ, Kodama I: Remodeling of gap junctional coupling of rats with monocrotaline-induced pulmonary hypertension. Circ Res 86: 871-878, 2000Google Scholar
  28. 28.
    Saffitz JE, Green KG, Kraft WJ, Schechtman KB, Yamada KA: Effects of diminished expression of connexin 43 on gap junction number and size in ventricular myocardium. Am J Physiol 278: H1662-H1670, 2000Google Scholar
  29. 29.
    Dupont E, Matsushita T, Kaba RA, Vozzi C, Coppen SR, Khan N, Kaprelian R, Yacoub MH, Severs NJ: Altered connexin expression in human congestive heart failure. J Mol Cell Cardiol 33: 359-371, 2001Google Scholar
  30. 30.
    Kostin S, Scholz D, Shimada T, Maeno Y, Mollnau H, Hein S, Schaper J: The internal and external protein scaffold of the T-tubular system in cardiomyocytes. Cell Tissue Res 294: 449-460, 1998Google Scholar
  31. 31.
    Kostin S: The structural correlate of reduced cardiac function in failing human hearts. In: N. Takeda, M. Nagano, N.S. Dhalla (eds). The Hypertrophied Heart. Kluwer Academic Publishers, Boston, MA, 2000, pp 423-439Google Scholar
  32. 32.
    Kostin S, Hein S, Bauer EP, Schaper J: Spatio-temporal development and distribution of the intercellular junctions in adult rat cardiomyocytes in culture. Circ Res 85: 154-167, 1999Google Scholar
  33. 33.
    Gourdie RG, Green CR, Severs NJ: Gap junction distribution in mammalian myocardium revealed by an anti-peptide antibody and laser scanning confocal microscopy. J Cell Sci 99: 41-45, 1991Google Scholar
  34. 34.
    Green CR, Peters NS, Gourdie RG, Rothery S, Severs NJ: Validation of immunohistochemical quantification in confocal scanning laser microscopy: A comparative assessment of gap junction size with confocal and ultrastructural techniques. J Histochem Cytochem 41: 1339-1349, 1993Google Scholar
  35. 35.
    Severs NJ, Gourdie RG, Harfst E, Peters NS, Green CR: Intercellular junctions and the application of microscopical techniques: The cardiac gap junction as a case model. J Microsc 169: 299-328, 1993Google Scholar
  36. 36.
    Luke RA, Beyer EC, Hoyt RH, Saffitz JE: Quantitative analysis of intercellular connections by immunohistochemistry of the cardiac gap junction protein connexin43. Circ Res 65: 1450-1457, 1989Google Scholar
  37. 37.
    Severs NJ: Gap junction alteration in the failing human heart. Eur Heart J 15: 53-57, 1994Google Scholar
  38. 38.
    Saffitz JE, Schuessler RB, Yamada KA: Mechanisms of remodeling of gap junction distributions and the development of anatomic substrates of arrhythmias. Cardiovasc Res 42: 309-317, 1999Google Scholar
  39. 39.
    DeBakker MJT, Van Capelle FJL, Janse MJ, Tasserson S, Vermeulen JT, de Jonge N, Lahpor JR: Slow conduction in the infarcted human heart. ‘Zigzag’ course of activation. Circulation 88: 915-926, 1993Google Scholar
  40. 40.
    Factor SM, Sonnenblick EH, Kirk ES: The histologic border zone of acute myocardial infarction — islands or peninsulas? Am J Pathol 92: 111-124, 1978Google Scholar
  41. 41.
    Spach MS, Josephson ME: The role of nonuniform anisotropy in small circuits. J Cardiovasc Electrophysiol 5: 182-209, 1994Google Scholar
  42. 42.
    Spach MS, Boineau JP: Microfibrosis produces electrical load variations due to loss of side-to-side connections: A major mechanism of structural heart disease. Pacing Clin Electrophysiol 20: 397-413, 1997Google Scholar
  43. 43.
    Maron BJ, Anan TJ, Roberts WC: Quantitative analysis of the distribution of cardiac muscle cell disorganization in the left ventricular wall of patients with hypertrophic cardiomyopathy. Circulation 63: 882-894, 1981Google Scholar
  44. 44.
    Kostin S: Morphological and morphometric characteristics of hypertrophic cardiomyopathy. Ark Patol 51: 47-53, 1989Google Scholar
  45. 45.
    McKenna WJ, Camm AJ: Sudden death in hypertrophic cardiomyopathy. Assessment of patients at high risk. Circulation 80: 1489-1492, 1989Google Scholar
  46. 46.
    Kucera JP, Rudy Y: Mechanistic insights into very slow conduction in branching cardiac tissue. Circ Res 89: 799-806, 2001Google Scholar
  47. 47.
    Peters NS: New insights into myocardial arrhythmogenesis: Distribution of gap-junctional coupling in normal, ischaemic and hypertrophied human hearts. Clin Sci 90: 447-452, 1996Google Scholar
  48. 48.
    Wang X, Gerdes AM: Chronic pressure overload cardiac hypertrophy and failure in quinea pigs: III. Intercalated disc remodeling. J Mol Cell Cardiol 31: 333-343, 1999Google Scholar
  49. 49.
    Lerner DL, Chapman Q, Green KG, Saffitz JE: Reversible down-regulation of connexin43 expression in acute cardiac allograft rejection. J Heart Lung Transplant 20: 93-97, 2001Google Scholar
  50. 50.
    Guerrero PA, Schuessler RB, Davis LM, Beyer EC, Johnson CM, Yamada KA, Saffitz JE: Slow ventricular conduction in mice heterogeneous for a connexin43 null mutation. J Clin Invest 99: 1991-1998, 1997Google Scholar
  51. 51.
    Gutstein DE, Morley GE, Tamaddon H, Vaidya D, Schneider MD, Chen J, Chien KR, Stuhlmann H, Fishman GI: Conduction slowing and sudden arrhythmic death in mice with cardiac-restricted inactivation of connexin43. Circ Res 88: 333-339, 2001Google Scholar

Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • Sawa Kostin
    • 1
  • Markus Rieger
    • 2
  • Sebastian Dammer
    • 2
  • Stefan Hein
    • 3
  • Manfred Richter
    • 3
  • Wölf-Peter Klövekorn
    • 3
  • Erwin P. Bauer
    • 3
  • Jutta Schaper
    • 2
  1. 1.Max-Planck-InstituteBad NauheimGermany
  2. 2.Department of Experimental CardiologyMax-Planck-InstituteBad NauheimGermany
  3. 3.Department of Cardiac SurgeryKerckhoff-ClinicBad NauheimGermany

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