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Gap Junctions and Cardiac Impulse Propagation. New Aspects of Arrhythmogenesis and Antiarrhythmic Agents Targeting Gap Junctions

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Heart Rate and Rhythm

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Abstract

A basic phenomenon of the heart is its regular beating and a directed propagation of the electrical impulse which, during the plateau phase of the action potential, initiates contraction. The heart is a network of inter-communicating cells, allowing such a directed spread of activation. Cardiomyocytes communicate among each other and to a certain degree with non-cardiomyocytes such as fibroblasts. Action potentials are transferred from one cell to the next by intercellular communication channels, the gap junction channels, formed as dodecameric channels from protein subunits called connexins. In the heart, the main connexin isoforms are Cx43 (the 43 kDa connexin; ubiquitous), Cx40 (mostly in the atrium and specific conduction system) and Cx45 (in early developmental states and between fibroblasts and cardiomyocytes). Gap junction channels allow the intercellular transfer of current and small molecules (<1000 Da). Regarding arrhythmia, a specific feature of gap junctions is that they are normally found at the cell poles, thereby contributing to the heart’s anisotropic properties, while in cardiac disease, these channels are often found at the lateral borders of the cells. Moreover, a broad number of stimuli can regulate the channels. Thus, ions like H+, Ca++ and Na+, as well as ATP-loss, acylcarnitines, and lysophosphoglycerides, among others, can close the channels. Since these factors occur during cardiac ischemia, they lead to electrical isolation and silencing of the ischemic area. This alters the current source/sink ratio at the border, which will affect successive conduction.

Antiarrhythmic peptides, such as AAP10 enhance the Cx43-gap junction current by preventing the channels from uncoupling. This effect of AAPs is mediated via PKCα-activation and PKC-dependent phosphorylation of Cx43. The effect of AAP10 is pronounced in areas of increased de-phosphorylation and thereby shows a preference for ischemic tissue. These new agents open novel pharmacological options for prevention of ischemia-associated ventricular fibrillation.

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References

  1. Bedner P, Niessen H, Odermatt B, Willecke K, Harz H. A method to determine the relative cAMP permeability of connexin channels. Exp Cell Res. 2003;291:25–35.

    Article  CAS  PubMed  Google Scholar 

  2. Noma A, Tsuboi N. Dependence of junctional conductance on proton, calcium and magnesium ions in cardiac paired cells of Guinea pig. J Physiol Lond. 1987;382:193–211.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Spray DC, Harris AL, Bennett MVL. Equilibrium properties of a voltage dependent junctional conductance. J Gen Physiol. 1981;77:77–93.

    Article  CAS  PubMed  Google Scholar 

  4. Spray DC, White RL, Mazet F, Bennett MVL. Regulation of gap junction conductance. Am J Phys. 1985;248:H753–64.

    CAS  Google Scholar 

  5. Weingart R, Maurer P. Cell-to-cell coupling studied in isolated ventricular cell pairs. Experientia. 1987;43:1091–4.

    Article  CAS  PubMed  Google Scholar 

  6. Dhein S. Pharmacology of gap junctions in the cardiovascular system. Cardiovasc Res. 2004;62:287–98.

    Article  CAS  PubMed  Google Scholar 

  7. Salameh A, Dhein S. Pharmacology of gap junctions. New pharmacological targets for treatment of arrhythmia, seizure and cancer? Biochim Biophys Acta. 2005;1719(1–2):36–58.

    Article  CAS  PubMed  Google Scholar 

  8. Salameh A. Life cycle of connexins: regulation of connexin synthesis and degradation. Adv Cardiol. 2006;42:57–70.

    Article  CAS  PubMed  Google Scholar 

  9. Fallon RF, Goodenough DA. Five hour half-life of mouse liver gap junction protein. J Cell Biol. 1981;127:343–55.

    Google Scholar 

  10. Darrow BJ, Laing JG, Lampe PD, Saffitz JE, Beyer EC. Expression of multiple connexins in cultured neonatal rat ventricular myocytes. Circ Res. 1995;76:381–7.

    Article  CAS  PubMed  Google Scholar 

  11. Beardslee AMA, Laing JG, Beyer EC, Saffitz JE. Rapid turnover of connexin43 in the adult rat heart. Circ Res. 1998;83:629–35.

    Article  CAS  PubMed  Google Scholar 

  12. Severs NJ. Pathophysiology of gap junctions in heart disease. J Cardiovasc Electrophysiol. 1994;5:462–75.

    Article  CAS  PubMed  Google Scholar 

  13. Severs NJ, Dupont E, Thomas N, Kaba R, Rothery S, Jain R, Sharpey K, Fry CH. Alterations in cardiac connexin expression in cardiomyopathies. Adv Cardiol. 2006;42:228–42.

    Article  CAS  PubMed  Google Scholar 

  14. Polontchouk L, Haefliger J-A, Ebelt B, Schaefer T, Stuhlmann D, Mehlhorn U, Kuhn-Reignier F, DeVivie ER, Dhein S. Effects of chronic atrial fibrillation on gap junction distribution in human and rat atria. J Am Coll Cardiol. 2001;38:883–91.

    Article  CAS  PubMed  Google Scholar 

  15. Kostin S, Klein G, Szalay Z, Hein S, Bauer EP, Schaper J. Structural correlate of atrial fibrillation in human patients. Cardiovasc Res. 2002;54:361–79.

    Article  CAS  PubMed  Google Scholar 

  16. Salameh A, Wustmann A, Karl S, Blanke K, Apel D, Rojas-Gomez D, Franke H, Mohr FW, Janousek J, Dhein S. Cyclic mechanical stretch induces cardiomyocyte orientation and polarization of the gap junction protein connexin43. Circ Res. 2010;106:1592–602.

    Article  CAS  PubMed  Google Scholar 

  17. Dhein S, Schreiber A, Steinbach S, Apel D, Salameh A, Schlegel F, Kostelka M, Dohmen PM, Mohr FW. Mechanical control of cell biology. Effects of cyclic mechanical stretch on cardiomyocyte cellular organization. Prog Biophys Mol Biol. 2014;115:93–102.

    Article  CAS  PubMed  Google Scholar 

  18. Buchanan JW, Saito T, Gettes LS. The effect of antiarrhythmic drugs, stimulation frequency and potassium induced resting membrane potential changes on conduction velocity and dV/dtmax in Guinea pig myocardium. Circ Res. 1985;56:696–703.

    Article  CAS  PubMed  Google Scholar 

  19. Weingart R, Maurer P. Action potential transfer in cell pairs isolated from adult rat and Guinea pig ventricles. Circ Res. 1988;63:72–80.

    Article  CAS  PubMed  Google Scholar 

  20. Jozwiak J, Dhein S. Local effects and mechanisms of antiarrhythmic peptide AAP10 in acute regional myocardial ischemia: electrophysiological and molecular findings. Naunyn Schmiedebergs Arch Pharmacol. 2008;378:459–70.

    Article  CAS  PubMed  Google Scholar 

  21. Dhein S, Krüsemann K, Schaefer T. Effects of the gap junction uncoupler palmitoleic acid on activation and repolarization pattern in isolated rabbit hearts. A mapping study. Br J Pharmacol. 1999;128:1375–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Delmar M, Michaels DC, Johnson T, Jalife J. Effects of increasing intercellular resistance on transverse and longitudinal propagation in sheep epicardial muscle. Circ Res. 1987;60:780–5.

    Article  CAS  PubMed  Google Scholar 

  23. Unger VM, Kumar NM, Gilula NB, Yeager M. Three-dimensional structure of a recombinant gap junction membrane channel. Science. 1999;283(5405):1176–80.

    Article  CAS  PubMed  Google Scholar 

  24. Cruciani V, Mikalsen SO. Evolutionary selection pressure and family relationships among connexin genes. Biol Chem. 2007;388:253–64.

    Article  CAS  PubMed  Google Scholar 

  25. Söhl G, Willecke K. Gap junctions and the connexion protein family. Cardiovasc Res. 2004;62:228–32.

    Article  PubMed  Google Scholar 

  26. Kwak BR, Jongsma HJ. Regulation of cardiac gap junction channel permeability and conductance by several phosphorylating conditions. Mol Cell Biochem. 1996;157:93–9.

    Article  CAS  PubMed  Google Scholar 

  27. Jongsma HJ, Wilders R. Gap junctions in cardiovascular disease. Circ Res. 2000;86:1193–7.

    Article  CAS  PubMed  Google Scholar 

  28. Kwak BR, Hermanns MMP, De Jonge HR, Lohmann SM, Jongsma HJ, Chanson M. Differential regulation of distinct types of gap junction channels by similar phosphorylating conditions. Mol Biol Cell. 1995;6:1707–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Christ GJ, Brink PR. Analysis of the presence and physiological relevance of subconducting states of connxin43-derived gap junction channels in cultured human corporal vascular smooth muscle cells. Circ Res. 1999;85:797–803.

    Article  Google Scholar 

  30. Dekker LRC, Fiolet JWT, VanBavel E, Coronel R, Opthof T, Spaan JAE, Janse MJ. Intracellular Ca2+, intercellular electrical coupling and mechanical activity in ischemic rabbit papillary muscle. Effects of preconditioning and metabolic blockade. Circ Res. 1996;79:237–46.

    Article  CAS  PubMed  Google Scholar 

  31. Li J, Li C, Liang D, Lv F, Yuan T, The E, Ma X, Wu Y, Zhen L, Xie D, Wang S, Liu Y, Huang J, Shi J, Liu Y, Shi D, Xu L, Lin L, Peng L, Cui J, Zhu W, Chen YH. LRP6 acts as a scaffold protein in cardiac gap junction assembly. Nat Commun. 2016;7:11775. https://doi.org/10.1038/ncomms11775.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Musil LS, Goodenough DA. Multisubunit assembly of an integral plasma membrane channel protein, gap junction connexin43, occurs after exit from the ER. Cell. 1993;74:1065–77.

    Article  CAS  PubMed  Google Scholar 

  33. Musil LS, Goodenough DA. Biochemical analysis of connexon assembly. In: Kanno Y, Kataoka K, Shiba Y, Shibata Y, Shimazu T, editors. Intercellular communication through gap junctions. Progress in Cell Research Vol.4. Amsterdam: Elesvier Science Publ.; 1995. p. 327–30.

    Chapter  Google Scholar 

  34. Falk MM. Connexin-specific distribution within gap junctions revealed in living cells. J Cell Sci. 2000;113:4109–20.

    Article  CAS  PubMed  Google Scholar 

  35. Giepmans BN. Gap junctions and connexin-interacting proteins. Cardiovasc Res. 2004;62:233–45.

    Article  CAS  PubMed  Google Scholar 

  36. Berthoud VM, Minogue PJ, Laing JG, Beyer EC. Pathways for degradation of connexins and gap junctions. Cardiovasc Res. 2004;62:256–67.

    Article  CAS  PubMed  Google Scholar 

  37. Kam CY, Dubash AD, Magistrati E, Polo S, Satchell KJF, Sheikh F, Lampe PD, Green KJ. Desmoplakin maintains gap junctions by inhibiting Ras/MAPK and lysosomal degradation of connexin-43. J Cell Biol. 2018;217:3219–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Salameh A, Dhein S. Effects of mechanical forces and stretch on intercellular gap junction coupling. Biochim Biophys Acta. 2013;1828:147–56.

    Article  CAS  PubMed  Google Scholar 

  39. Weidmann S. Passive properties of cardiac fibers. In: Rosen MR, Janse MJ, Wit AL, editors. Cardiac electrophysiology. A textbook. Mount Kisco, New York: Futura Publishing Company Inc.; 1990. p. 29–35.

    Google Scholar 

  40. Hodgkin AL, Rushton WAH. The electrical constants of a crustacean nerve fibre. Proc R Soc London Ser B. 1946;133:444–79.

    Article  Google Scholar 

  41. Weidmann S. The electrical constants of Purkinje fibers. J Physiol Lond. 1952;118:348–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kucera J, Rohr S, Rudy Y. Localization of sodium channels in intercalated disks odulates cardiac conduction. Circulation. 2002;91:1176–82.

    Article  CAS  Google Scholar 

  43. Maier SKG, Westenbroek RE, McCormick KA, Curtis R, Scheuer T, Catterall WA. Distinct subcellular localization of different Sodium Channel α and β subunits in single ventricular myocytes from mouse heart. Circulation. 2004;109:1421–7.

    Article  CAS  PubMed  Google Scholar 

  44. Sperelakis N. Propagation mechanisms in the heart. Annu Rev Physiol. 1979;41:441–57.

    Article  CAS  PubMed  Google Scholar 

  45. Lin J, Keener JP. Modeling electrical activity of myocardial cells incorporating the effects of ephaptic coupling. Proc Natl Acad Sci U S A. 2010;107:20935–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Sperelakis N, Mann JE. Evaluation of electric field changes in the cleft between excitable cells. J Theor Biol. 1977;64:71–96.

    Article  CAS  PubMed  Google Scholar 

  47. Mori Y, Fishman GI, Peskin CS. Ephaptic conductin in a cardiac strand model with 3D electrodiffusion. Proc Natl Acad Sci U S A. 2008;105:6463–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Gourdie RG. The cardiac gap junction has discrete functions in Electrotonic and Ephaptic coupling. Anat Rec (Hoboken). 2019;302:93–100.

    Article  CAS  PubMed  Google Scholar 

  49. Veeraraghavan R, Hoeker GS, Alvarez-Laviada A, Hoagland D, Wan X, King DR, Sanchez-Alonso J, Chen C, Jourdan J, Isom LL, Deschenes I, Smyth JW, Gorelik J, Poelzing S, Gourdie RG. The adhesion function of the sodium channel beta subunit (β1) contributes to cardiac action potential propagation. elife. 2018;7:e37610. https://doi.org/10.7554/eLife.37610.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Veeraraghavan R, Lin J, Keener JP, Gourdie R, Poelzing S. Potassium channels in the Cx43 gap junction perinexus modulate ephaptic coupling: an experimental and modeling study. Pflugers Arch. 2016;468:1651–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hubbard ML, Ying W, Henriquez CS. Effect of gap junction distribution on impulse propagation in a monolayer of myocytes: a model study. Europace. 2007;9(Suppl 6):vi20-8.

    PubMed  Google Scholar 

  52. Spach MS, Dolber PC. Discontinuous anisotropic propagation. In: Rosen MR, Janse MJ, editors. Wit AL: cardiac electrophysiology: a textbook. Futura Publishing Company Inc, Mount Kisco: New York; 1990. p. 517–34.

    Google Scholar 

  53. Dupont E, Ko Y-S, Rothery S, Coppen SR, Bagha M, Haw M, Severs NJ. The gap junctional protein connexin40 is elevated in patients susceptible to postoperative atrial fibrillation. Circulation. 2001;103:842–9.

    Article  CAS  PubMed  Google Scholar 

  54. Boldt A, Wetzel U, Weigl J, Garbade J, Lauschke J, Hindricks G, Kottkamp H, Gummert JF, Dhein S. Expression of angiotensin II receptors in human left and right atrial tissue in atrial fibrillation with and without underlying mitral valve disease. J Am Coll Cardiol. 2003;42:1785–92.

    Article  CAS  PubMed  Google Scholar 

  55. Spach MS, Dolber PC. Relating extracellular potentials and their derivatives to anisotropic propagation at a microscopic level in human cardiac muscle. Evidence for electrical uncoupling of side-to-side fiber connections with increasing age. Circ Res. 1986;58:356–71.

    Article  CAS  PubMed  Google Scholar 

  56. Dhein S, Hammerrath SB. Aspects of the intercellular communication in aged hearts. Effects of the gap junction uncopler palmitoleic acid. Naunyn Schmiedeberg's Arch Pharmacol. 2001;364:397–408.

    Article  CAS  Google Scholar 

  57. Rohr S, Kucera JP, Fast VG, Kleber AG. Paradoxical improvement of impulse conduction in cardiac tissue by partial cellular uncoupling. Science. 1997;275(5301):841–4.

    Article  CAS  PubMed  Google Scholar 

  58. Rohr S. Role of gap junctions in the propagation of the cardiac action potential. Cardiovasc Res. 2004;62:309–22.

    Article  CAS  PubMed  Google Scholar 

  59. Shaw RM, Rudy Y. (1997a). Electrophysiologic effects of acute myocardial ischemia. A mechanistic investigation of action potential conduction and conduction failure. Circ Res. 1997;80:124–38.

    Article  CAS  PubMed  Google Scholar 

  60. Shaw RM, Rudy Y. Ionic mechanisms of propagation in cardiac tissue: roles of the sodium and L-type calcium currents during reduced excitability and decreased gap-junction coupling. Circ Res. 1997;81:727–41.

    Article  CAS  PubMed  Google Scholar 

  61. Beardslee MA, Lerner DL, Tadros PN, Laing JG, Beyer EC, Yamada KA, Kléber AG, Schuessler RB, Saffitz JE. Dephosphorylation and intracellular redistribution of ventricular connexin43 during electrical uncoupling induced by ischemia. Circ Res. 2000;87:656–62.

    Article  CAS  PubMed  Google Scholar 

  62. Schulz R, Gres P, Skyschally A, et al. Ischemic preconditioning preserves connexin43 phosphorylation during sustained ischemia in pig hearts in vivo. FASEB J. 2003;17:1355–7.

    Article  CAS  PubMed  Google Scholar 

  63. Jain SK, Schuessler RB, Saffitz JE. Mechanisms of delayed electrical uncoupling induced ischemic preconditioning. Circ Res. 2003;92:1138–44.

    Article  CAS  PubMed  Google Scholar 

  64. Verecchia F, Duthe F, Duval S, Duchatelle I, Sarrouilhe D, Hervé JC. ATP counteracts the rundown of gap juntional channels of rat ventricular myocytes by promoting protein phosphorylation. J Physiol Lond. 1999;516:447–59.

    Article  Google Scholar 

  65. Burt JM. Block of intercellular communication: interaction of intracellular H+ and Ca2+. Am J Phys. 1987;253:C607–9.

    Article  CAS  Google Scholar 

  66. White RL, Doeller JE, Verselis VK, Wittenberg BA. Gap junctional conductance between pairs of ventricular myocytes is modulated synergistically by H+ and Ca++. J Gen Physiol. 1990;95:1061–75.

    Article  CAS  PubMed  Google Scholar 

  67. Yan GX, Kléber AG. Changes in extracellular and intracellular pH in ischemic rabbit papillary muscle. Circ Res. 1992;71:460–70.

    Article  CAS  PubMed  Google Scholar 

  68. Massey KD, Minnich BN, Burt JM. Arachidonic acid and lipoxygenase metabolites uncouple neonatal rat cardiac myocyte pairs. Am J Phys. 1992;263:C494–501.

    Article  CAS  Google Scholar 

  69. Wu J, McHowat J, Saffitz JE, Yamada KA, Corr PB. Inhibition of gap junctional conductance by long-chain acylcarnitines and their preferential accumulation in junctional sarcolemma during hypoxia. Circ Res. 1993;72:879–89.

    Article  CAS  PubMed  Google Scholar 

  70. Maurer P, Weingart R. Cell pairs isolated from Guinea pig and rat hearts: effects of [Ca++]i on nexal membrane resistance. Pflüger's Arch. 1987;409:394–402.

    Article  CAS  Google Scholar 

  71. Reber WR, Weingart R. Ungulate cardiac Purkinje fibers: the influence of intracellular pH on the electrical cell-to-cell coupling. J Physiol Lond. 1982;328:87–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Morley GE, Taffet SM, Delmar M. Intramolecular interactions mediate pH regulation of connexin 43 channels. Biophys J. 1996;701294-1302:1294.

    Article  Google Scholar 

  73. De Mello WC. Influence of the sodium pump on intercellular communication in heart fibers: effect of intracellular injection of sodium ion on electrical coupling. J Physiol Lond. 1976;263:171–97.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Hatanaka K, Kawata H, Toyofuku T, Yoshida K. Down-regulation of Connexin43 in early myocardial ischemia and protective effect by ischemic preconditioning in rat heart in vivo. Jpn Heart J. 2004;45:1007–19.

    Article  CAS  PubMed  Google Scholar 

  75. Ek-Vitorín JF, Pontifex TK, Burt JM. Cx43 channel gating and permeation: multiple phosphorylation-dependent roles of the carboxyl terminus. Int J Mol Sci. 2018;19(6):E1659. https://doi.org/10.3390/ijms19061659.

    Article  CAS  Google Scholar 

  76. Smith WT 4th, Fleet WF, Johnson TA, Engle CL, Cascio WE. The Ib phase of ventricular arrhythmias in ischemic in situ porcine heart is related to changes in cell-to-cell electrical coupling. Experimental Cardiology Group, University of North Carolina. Circulation. 1995;92:3051–60.

    Article  PubMed  Google Scholar 

  77. de Groot JR, Wilms-Schopman FJ, Opthof T, Remme CA, Coronel R. Late ventricular arrhythmias during acute regional ischemia in the isolated blood perfused pig heart. Role of electrical cellular coupling. Cardiovasc Res. 2001;50:362–72.

    Article  PubMed  Google Scholar 

  78. Morley GE, Vaidya D, Samie FH, Lo C, Delmar M, Jalife J. Characterization of conduction in the ventricles of normal and heterozygous Cx43 knockout mice using optical mapping. J Cardiovasc Electrophysiol. 1999;10:1361–75.

    Article  CAS  PubMed  Google Scholar 

  79. Lerner DL, Yamada KA, Schuessler RB, Saffitz JE. Accelerated onset and increased incidence of ventricular arrhythmias induced by ischemia in Cx43-deficient mice. Circulation. 2000;101:547–52.

    Article  CAS  PubMed  Google Scholar 

  80. Thomas SP, Kucera JP, Bircher-Lehmann L, Rudy Y, Saffitz JE, Kleber AG. Impulse propagation in synthetic strands of neonatal cardiac myocytes with genetically reduced levels of connexin43. Circ Res. 2003;92:1209–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. De Groot JR, Schumacher CA, Verkerk AO, Baartscheer A, Fiolet JWT, Coronel R. Intrinsic heterogeneity in repolarization is increased in isolated failing rabbit cardiomyocytes during simulated ischemia. Cardiovasc Res. 2003;59:705–14.

    Article  PubMed  Google Scholar 

  82. Dhein S, Manicone N, Müller A, Gerwin R, Ziskoven U, Irankhahi A, Minke C, Klaus W. A new synthetic antiarrhythmic peptide reduces dispersion of epicardial activation recovery interval and enhances cellular communication. Antiarrhythmic properties in regional ischemia. Naunyn Schmiedeberg’s Arch Pharmacol. 1994;350:174–84.

    Article  CAS  Google Scholar 

  83. Dhein S, Weng S, Grover R, Tudyka T, Gottwald M, Schaefer T, Polontchouk L. Protein kinase Cα mediates the effect of antiarrhythmic peptide on gap junction conductance. Cell Adh Commun. 2001;8:257–64.

    Article  CAS  Google Scholar 

  84. Müller A, Gottwald M, Tudyka T, Linke W, Klaus W, Dhein S. Increase in gap junction conductance by an antiarrhythmic peptide. Eur J Pharmacol. 1997;327:65–72.

    Article  PubMed  Google Scholar 

  85. Hagen A, Dietze A, Dhein S. Human cardiac gap junction coupling: effects of antiarrhythmic peptide AAP10. Cardiovasc Res. 2009;83(2):405–15.

    Article  CAS  PubMed  Google Scholar 

  86. Grover R, Dhein S. Structure-activity relationships of novel peptides related to the antiarrhythmic peptide AAP10 which reduce the dispersion of epicardial action potential duration. Peptides. 2001;22:1011–21.

    Article  CAS  PubMed  Google Scholar 

  87. Xing D, Kjolbye AL, Nielsen MS, Petersen JS, Harlow KW, Holstein-Rathlou N-H, Martins JB. ZP123 increases gap junctional conductance and prevents reentrant ventricular tachycardia during myocardial ischemia in open chest dogs. J Cardiovasc Electrophysiol. 2003;14:510–20.

    Article  PubMed  Google Scholar 

  88. Dhein S. Cardiac ischemia and uncoupling: gap junctions in ischemia and infarction. Adv Cardiol. 2006;42:198–212.

    Article  CAS  PubMed  Google Scholar 

  89. Firek L, Weingart R. Modification of gap junction conductance by divalent cations and protons in neonatal rat heart cells. J Mol Cell Cardiol. 1995;27:1633–43.

    Article  CAS  PubMed  Google Scholar 

  90. Ek JF, Delmar M, Perzova R, Taffet SM. Role of histidine 95 on pH gating of the cardiac gap junction protein connexin43. Circ Res. 1994;74:1058–64.

    Article  CAS  PubMed  Google Scholar 

  91. Hermans MMP, Kortekaas P, Jongsma HJ, Rook MB. pH sensitivity of the cardiac gap junction proteins, connexin 45 and 43. Pflüger’s Arch. 1995;431:138–40.

    Article  CAS  Google Scholar 

  92. Liu S, Taffet S, Stoner L, Delmar M, Vallano ML, Jalife J. A structural basis for the unequal sensitivity of the major cardiac and liver gap junctions to intracellular acidification: the carboxy tail length. Biophys J. 1993;64:1422–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Doble BW, Kardami E. Basic fibroblast growth factor stimulates connexin-43 expression and intercellular communication of cardiac fibroblasts. Mol Cell Biochem. 1995;143:81–7.

    Article  CAS  PubMed  Google Scholar 

  94. Doble BW, Chen Y, Bosc DG, Litchfield DW, Kardami E. Fibroblast growth factor-2 decreases metabolic coupling and stimulates phosphorylation as well as masking of connexin43 epitopes in cardiac myocytes. Circ Res. 1996;79:647–58.

    Article  CAS  PubMed  Google Scholar 

  95. Saffitz JE, Hoyt RH, Luke RA, Kanter HL, Beyer EC. Cardiac myocyte interconnections at gap junctions: role in normal and abnormal electrical conduction. Trends Cardiovasc Med. 1992;2:56–60.

    Article  CAS  PubMed  Google Scholar 

  96. Dillon SM, Allessie MA, Ursell PC, Wit AL. Influences of anisotropic tissue structure on reentrant circuits in the epicardial border zone of subacute canine infarcts. Circ Res. 1988;63:182–206.

    Article  CAS  PubMed  Google Scholar 

  97. Spach MS, Dolber PC, Heidlage JF. Influence of the passive anisotropic properties on directional differences in propagation following modification of the sodium conductance in human atrial muscle. A model of reentry based on anisotropic discontinuous propagation. Circ Res. 1988;62:811–32.

    Article  CAS  PubMed  Google Scholar 

  98. Ursell PC, Gardner PI, Albala A, Fenoglio JJ, Wit AL. Structural and electrophysiological changes in the epicardial border zone of canine myocardial infarcts during infarct healing. Circ Res. 1985;56:436–51.

    Article  CAS  PubMed  Google Scholar 

  99. Peters NS, Green CR, Poole-Wilson PA, Severs NJ. Reduced content of connexin43 gap junctions in ventricular myocardium from hypertrophied and ischaemic human hearts. Circulation. 1993;88:864–75.

    Article  CAS  PubMed  Google Scholar 

  100. Camelliti P, Green CR, Kohl P. Structural and functional coupling of cardiac myocytes and fibroblasts. Adv Cardiol. 2006;42:132–49.

    Article  CAS  PubMed  Google Scholar 

  101. Van der Velden HMW, Ausma J, Rook MB, Hellemous AJCGM, Van Veen TAAB, Allessie MA, Jongsma HJ. Gap junctional remodeling in relation to stabilization of atrial fibrillation in the goat. Cardiovasc Res. 2000;46:476–86.

    Article  PubMed  Google Scholar 

  102. Van der Velden HMW, van Kempen MJA, Wijffels MCEF, van Zijverden M, Groenewegen WA, Allessie MA, Jongsma HJ. Altered pattern of connexin40 distribution in persistent atrial fibrillation in the goat. J Cardiovasc Electrophysiol. 1998;9:596–607.

    Article  PubMed  Google Scholar 

  103. Verheule S, Wilson EE, Arora R, Engle SK, Scott LR, Olgin JE. Tissue structure and connexion expression of canine pulmonary veins. Cardiovasc Res. 2002;55:727–38.

    Article  CAS  PubMed  Google Scholar 

  104. Noureldin M, Chen H, Bai D. Functional characterization of novel atrial fibrillation-linked GJA5 (Cx40) mutants. Int J Mol Sci. 2018;19(4):E977. https://doi.org/10.3390/ijms19040977.

    Article  CAS  Google Scholar 

  105. Carballo S, Pfenniger A, Carballo D, Garin N, James RW, Mach F, Shah D, Kwak BR. Differential association of Cx37 and Cx40 genetic variants in atrial fibrillation with and without underlying structural heart disease. Int J Mol Sci. 2018;19(1):E295. https://doi.org/10.3390/ijms19010295.

    Article  CAS  Google Scholar 

  106. Kanthan A, Fahmy P, Rao R, Pouliopoulos J, Alexander IE, Thomas SP, Kizana E. Human Connexin40 mutations slow conduction and increase propensity for atrial fibrillation. Heart Lung Circ. 2018;27:114–21.

    Article  PubMed  Google Scholar 

  107. Wetzel U, Boldt A, Lauschke J, Weigl J, Schirdewahn P, Dorszewski A, Doll N, Hindricks G, Dhein S, Kottkamp H. Expression of connexins40 and 43 in human left atrium in atrial fibrillation of different aetiologies. Heart. 2005;91:166–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Yan H, Chen JZ, Zhu JH, Ni YM, Yu GW, Hu SJ, Tao QM. Expression of connexin in atrium of patients with atrial fibrillation and its signal transduction pathway. Zhonghua Yi Xue Za Zhi. 2004;84:209–13.

    CAS  PubMed  Google Scholar 

  109. Polontchouk L, Ebelt B, Jackels M, Dhein S. MAP kinases mediate the effects of endothelin-1 and angiotensin-II on the cardiac connexin expression. FASEB J. 2002;16:87–9.

    CAS  PubMed  Google Scholar 

  110. Raisch TB, Yanoff MS, Larsen TR, Farooqui MA, King DR, Veeraraghavan R, Gourdie RG, Baker JW, Arnold WS, AlMahameed ST, Poelzing S. Intercalated disk extracellular Nanodomain expansion in patients with atrial fibrillation. Front Physiol. 2018;9:398. https://doi.org/10.3389/fphys.2018.00398.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Schotten U, Blaauw Y, Allessie MA. In-vivo models of atrial fibrillation. In: Dhein S, Mohr FW, Delmar M, editors. Practical methods in cardiovascular research. Heidelberg: Springer Verlag; 2005. p. 129–49.

    Chapter  Google Scholar 

  112. Ausma J, Van der Velden HMW, Lenders M-H, van Ankeren EP, Jongsma HJ, Ramaekers FCS, Borgers M, Allessie MA. Reverse structural and gap-junctional remodeling after prolonged atrial fibrillation in the goat. Circulation. 2003;107:2051–8.

    Article  PubMed  Google Scholar 

  113. Elvan A, Huang X-D, Pressler ML, Zipes DP. Radiofrequency catheter ablation of the atria eliminates pacing-induced sustained atrial fibrillation and reduces connexin 43 in dogs. Circulation. 1997;96:1675–85.

    Article  CAS  PubMed  Google Scholar 

  114. Dhein S. Role of connexins in atrial fibrillation. Adv Cardiol. 2006;42:161–74.

    Article  CAS  PubMed  Google Scholar 

  115. Salameh A, Frenzel C, Boldt A, Rassler B, Glawe I, Schulte J, Muhlberg K, Zimmer HG, Pfeiffer D, Dhein S. Subchronic alpha- and beta-adrenergic regulation of cardiac gap junction protein expression. FASEB J. 2006;20(2):365–7.

    Article  CAS  PubMed  Google Scholar 

  116. Kostin S, Dammer S, Hein S, Klövekorn WP, Bauer EP, Schaper J. Connexin 43 expression and distribution in compensated and decompensated cardiac hypertrophy in patients with aortic stenosis. Cardiovasc Res. 2004;62:426–36.

    Article  CAS  PubMed  Google Scholar 

  117. Kostin S, Rieger M, Dammer S, Hein S, Richter M, Klövekorn WP, Bauer EP, Schaper J. Gap junction remodeling and altered connexin43 expression in the failing human heart. Mol Cell Biochem. 2003;242:135–44.

    Article  CAS  PubMed  Google Scholar 

  118. Salameh A, Mühlberg K, Rahmel A, Dhein S, Pfeiffer D. Änderungen der Connexin expression bei humanen dilatativen und hypertrophen Kardiomyopathien. Z Kardiol. 2005;94(Suppl. 1):V1186.

    Google Scholar 

  119. Dupont E, Matsushita T, Kaba RA, et al. Altered connexin expression in human congestive heart failure. J Mol Cell Cardiol. 2001;33:359–71.

    Article  CAS  PubMed  Google Scholar 

  120. Kitamura H, Ohnishi Y, Yoshida A, Okajima K, Azumi H, Ishida A, Galeano EJ, Kubo S, Hayashi Y, Itoh H, Yokoyama M. Heterogeneous loss of connexin43 protein in nonischemic dilated cardiomyopathy with ventricular tachycardia. J Cardiovasc Electrophysiol. 2002;13:865–70.

    Article  PubMed  Google Scholar 

  121. Peters NS. New insights into myocardial arrhythmogenesis: distribution of gap junctional coupling in normal, ischaemic and hypertrophied hearts. Clin Sci. 1996;90:447–52.

    Article  CAS  Google Scholar 

  122. Yamada KA, Rogers JG, Sundset R, Steinberg TH, Saffitz JE. Up-regulation of connexin45 in heart failure. J Cardiovasc Electrophysiol. 2003;14:1205–12.

    Article  PubMed  Google Scholar 

  123. Severs NJ, Coppen SR, Dupont E, Yeh H-I, Ko Y-S, Matsushita T. Gap junction alterations in human cardiac disease. Cardiovasc Res. 2004;62:368–77.

    Article  CAS  PubMed  Google Scholar 

  124. Crassous PA, Shu P, Huang C, Gordan R, Brouckaert P, Lampe PD, Xie LH, Beuve A. Newly identified NO-sensor guanylyl cyclase/Connexin 43 association is involved in cardiac electrical function. J Am Heart Assoc. 2017;6(12):e006397. https://doi.org/10.1161/JAHA.117.006397.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Ren Y, Zhang CT, Wu J, Ruan YF, Pu J, He L, Wu W, Chen BD, Wang WG, Wang L. The effects of antiarrhythmic peptide AAP10 on ventricular arrhythmias in rabbits with healed myocardial infarction. Zhonghua Xin Xue Guan Bing Za Zhi. 2006;34:825–8.

    CAS  PubMed  Google Scholar 

  126. Grover R, Dhein S. Spatial structure determination of antiarrhythmic peptide using nuclear magnetic resonance spectroscopy. Peptides. 1998;19:1725–9.

    Article  CAS  PubMed  Google Scholar 

  127. Hennan JK, Swillo RE, Morgan GA, Keith JC Jr, Schaub RG, Smith RP, Feldman HS, Haugan K, Kantrowitz J, Wang PJ, Abu-Qare A, Butera J, Larsen BD, Crandall DL. Rotigaptide (ZP123) prevents spontaneous ventricular arrhythmias and reduces infarct size during myocardial ischemia/reperfusion injury in open-chest dogs. J Pharmacol Exp Ther. 2006;317:236–43.

    Article  CAS  PubMed  Google Scholar 

  128. Ng FS, Kalindjian JM, Cooper SA, Chowdhury RA, Patel PM, Dupont E, Lyon AR, Peters NS. Enhancement of gap junction function during acute myocardial infarction modifies healing and reduces late ventricular arrhythmia susceptibility. JACC Clin Electrophysiol. 2016;2:574–82.

    Article  PubMed  PubMed Central  Google Scholar 

  129. Skyschally A, Walter B, Schultz Hansen R, Heusch G. The antiarrhythmic dipeptide ZP1609 (danegaptide) when given at reperfusion reduces myocardial infarct size in pigs. Naunyn Schmiedeberg's Arch Pharmacol. 2013;386:383–91.

    Article  CAS  Google Scholar 

  130. Boengler K, Bulic M, Schreckenberg R, Schlüter KD, Schulz R. The gap junction modifier ZP1609 decreases cardiomyocyte hypercontracture following ischaemia/reperfusion independent from mitochondrial connexin 43. Br J Pharmacol. 2017;174:2060–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Engstrøm T, Nepper-Christensen L, Helqvist S, Kløvgaard L, Holmvang L, Jørgensen E, Pedersen F, Saunamaki K, Tilsted HH, Steensberg A, Fabricius S, Mouritzen U, Vejlstrup N, Ahtarovski KA, Göransson C, Bertelsen L, Kyhl K, Olivecrona G, Kelbæk H, Lassen JF, Køber L, Lønborg J. Danegaptide for primary percutaneous coronary intervention in acute myocardial infarction patients: a phase 2 randomised clinical trial. Heart. 2018;104:1593–9.

    Article  PubMed  Google Scholar 

  132. Weng S, Lauven M, Schaefer T, Polontchouk L, Grover R, Dhein S. Pharmacological modulation of gap junction coupling by an antiarrhythmic peptide via protein kinase C activation. FASEB J. 2002;16:1114–6.

    Article  CAS  PubMed  Google Scholar 

  133. Kaprielian RR, Gunning M, Dupont E, Sheppard MN, Rothery SM, Underwood R, Pennell DJ, Fox K, Pepper J, Poole-Wilson PA, Severs NJ. Down-regulation of immunodetectable connexin43 and decreased gap junction size in the pathogenesis of chronic hibernation in the human left ventricle. Circulation. 1998;97:651–60.

    Article  CAS  PubMed  Google Scholar 

  134. Dhein S, Tudyka T. The therapeutic potential of antiarrhythmic peptides. Cellular coupling as a new antiarrhythmic target. Drugs. 1995;49:851–5.

    Article  CAS  PubMed  Google Scholar 

  135. Chang CJ, Cheng CC, Chen YC, Kao YH, Chen SA, Chen YJ. Gap junction modifiers regulate electrical activities of the sinoatrial node and pulmonary vein: therapeutic implications in atrial arrhythmogenesis. Int J Cardiol. 2016;221:529–36.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Institute of Pharmacology and Toxicology, University of Leipzig, Leipzig, Germany

    Stefan Dhein

  2. Clinic of Pediatric Cardiology, Heart Centre Leipzig, University of Leipzig, Leipzig, Germany

    Aida Salameh

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  1. Stefan Dhein
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  2. Aida Salameh
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Correspondence to Stefan Dhein .

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Editors and Affiliations

  1. Cardiac Electrophysiology Division, Ion Channel Study Center, Life Science Academy, Lucknow, India

    Onkar N. Tripathi

  2. Department of Physiology and Biophysics, Dalhousie University, Halifax, Canada

    T. Alexander Quinn

  3. Institute for Experimental Cardiovascular Medicine, University Heart Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Ursula Ravens

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Dhein, S., Salameh, A. (2023). Gap Junctions and Cardiac Impulse Propagation. New Aspects of Arrhythmogenesis and Antiarrhythmic Agents Targeting Gap Junctions. In: Tripathi, O.N., Quinn, T.A., Ravens, U. (eds) Heart Rate and Rhythm. Springer, Cham. https://doi.org/10.1007/978-3-031-33588-4_14

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