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. 1997 Apr 15;99(8):1991–1998. doi: 10.1172/JCI119367

Slow ventricular conduction in mice heterozygous for a connexin43 null mutation.

P A Guerrero 1, R B Schuessler 1, L M Davis 1, E C Beyer 1, C M Johnson 1, K A Yamada 1, J E Saffitz 1
PMCID: PMC508024  PMID: 9109444

Abstract

To characterize the role of the gap junction protein connexin43 (Cx43) in ventricular conduction, we studied hearts of mice with targeted deletion of the Cx43 gene. Mice homozygous for the Cx43 null mutation (Cx43 -/-) die shortly after birth. Attempts to record electrical activity in neonatal Cx43 -/- hearts (n = 5) were unsuccessful. Ventricular epicardial conduction of paced beats, however, was 30% slower in heterozygous (Cx43 -/+) neonatal hearts (0.14+/-0.04 m/s, n = 27) than in wild-type (Cx43 +/+) hearts (0.20+/-0.07 m/s, n = 32; P < 0.001). This phenotype was even more severe in adult mice; ventricular epicardial conduction was 44% slower in 6-9 mo-old Cx43 -/+ hearts (0.18+/-0.03 m/s, n = 5) than in wild-type hearts (0.32+/-0.07 m/s, n = 7, P < 0.001). Electrocardiograms revealed significant prolongation of the QRS complex in adult Cx43 -/+ mice (13.4+/-1.8 ms, n = 13) compared with Cx43 +/+ mice (11.5+/-1.4 ms, n = 12, P < 0.01). Whole-cell recordings of action potential parameters in cultured disaggregated neonatal ventricular myocytes from Cx43 -/+ and +/+ hearts showed no differences. Thus, reduction in the abundance of a major cardiac gap junction protein through targeted deletion of a Cx43 allele directly leads to slowed ventricular conduction.

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Selected References

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  1. 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. 1993 Dec;73(6):1138–1149. doi: 10.1161/01.res.73.6.1138. [DOI] [PubMed] [Google Scholar]
  2. Beyer E. C., Paul D. L., Goodenough D. A. Connexin family of gap junction proteins. J Membr Biol. 1990 Jul;116(3):187–194. doi: 10.1007/BF01868459. [DOI] [PubMed] [Google Scholar]
  3. Brugada J., Mont L., Boersma L., Kirchhof C., Allessie M. A. Differential effects of heptanol, potassium, and tetrodotoxin on reentrant ventricular tachycardia around a fixed obstacle in anisotropic myocardium. Circulation. 1991 Sep;84(3):1307–1318. doi: 10.1161/01.cir.84.3.1307. [DOI] [PubMed] [Google Scholar]
  4. Callans D. J., Moore E. N., Spear J. F. Effect of coronary perfusion of heptanol on conduction and ventricular arrhythmias in infarcted canine myocardium. J Cardiovasc Electrophysiol. 1996 Dec;7(12):1159–1171. doi: 10.1111/j.1540-8167.1996.tb00495.x. [DOI] [PubMed] [Google Scholar]
  5. Darrow B. J., Fast V. G., Kléber A. G., Beyer E. C., Saffitz J. E. Functional and structural assessment of intercellular communication. Increased conduction velocity and enhanced connexin expression in dibutyryl cAMP-treated cultured cardiac myocytes. Circ Res. 1996 Aug;79(2):174–183. doi: 10.1161/01.res.79.2.174. [DOI] [PubMed] [Google Scholar]
  6. Davis L. M., Kanter H. L., Beyer E. C., Saffitz J. E. Distinct gap junction protein phenotypes in cardiac tissues with disparate conduction properties. J Am Coll Cardiol. 1994 Oct;24(4):1124–1132. doi: 10.1016/0735-1097(94)90879-6. [DOI] [PubMed] [Google Scholar]
  7. Delmar M., Michaels D. C., Johnson T., Jalife J. Effects of increasing intercellular resistance on transverse and longitudinal propagation in sheep epicardial muscle. Circ Res. 1987 May;60(5):780–785. doi: 10.1161/01.res.60.5.780. [DOI] [PubMed] [Google Scholar]
  8. Dillon S. M., Allessie M. A., Ursell P. C., Wit A. L. Influences of anisotropic tissue structure on reentrant circuits in the epicardial border zone of subacute canine infarcts. Circ Res. 1988 Jul;63(1):182–206. doi: 10.1161/01.res.63.1.182. [DOI] [PubMed] [Google Scholar]
  9. Gourdie R. G., Severs N. J., Green C. R., Rothery S., Germroth P., Thompson R. P. The spatial distribution and relative abundance of gap-junctional connexin40 and connexin43 correlate to functional properties of components of the cardiac atrioventricular conduction system. J Cell Sci. 1993 Aug;105(Pt 4):985–991. doi: 10.1242/jcs.105.4.985. [DOI] [PubMed] [Google Scholar]
  10. Gros D., Jarry-Guichard T., Ten Velde I., de Maziere A., van Kempen M. J., Davoust J., Briand J. P., Moorman A. F., Jongsma H. J. Restricted distribution of connexin40, a gap junctional protein, in mammalian heart. Circ Res. 1994 May;74(5):839–851. doi: 10.1161/01.res.74.5.839. [DOI] [PubMed] [Google Scholar]
  11. Janse M. J., Wit A. L. Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction. Physiol Rev. 1989 Oct;69(4):1049–1169. doi: 10.1152/physrev.1989.69.4.1049. [DOI] [PubMed] [Google Scholar]
  12. Kanter H. L., Laing J. G., Beau S. L., Beyer E. C., Saffitz J. E. Distinct patterns of connexin expression in canine Purkinje fibers and ventricular muscle. Circ Res. 1993 May;72(5):1124–1131. doi: 10.1161/01.res.72.5.1124. [DOI] [PubMed] [Google Scholar]
  13. Kanter H. L., Laing J. G., Beyer E. C., Green K. G., Saffitz J. E. Multiple connexins colocalize in canine ventricular myocyte gap junctions. Circ Res. 1993 Aug;73(2):344–350. doi: 10.1161/01.res.73.2.344. [DOI] [PubMed] [Google Scholar]
  14. Kanter H. L., Saffitz J. E., Beyer E. C. Cardiac myocytes express multiple gap junction proteins. Circ Res. 1992 Feb;70(2):438–444. doi: 10.1161/01.res.70.2.438. [DOI] [PubMed] [Google Scholar]
  15. Luke R. A., Saffitz J. E. Remodeling of ventricular conduction pathways in healed canine infarct border zones. J Clin Invest. 1991 May;87(5):1594–1602. doi: 10.1172/JCI115173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Nelson W. L., Makielski J. C. Block of sodium current by heptanol in voltage-clamped canine cardiac Purkinje cells. Circ Res. 1991 Apr;68(4):977–983. doi: 10.1161/01.res.68.4.977. [DOI] [PubMed] [Google Scholar]
  17. Oosthoek P. W., Virágh S., Lamers W. H., Moorman A. F. Immunohistochemical delineation of the conduction system. II: The atrioventricular node and Purkinje fibers. Circ Res. 1993 Sep;73(3):482–491. doi: 10.1161/01.res.73.3.482. [DOI] [PubMed] [Google Scholar]
  18. Oosthoek P. W., Virágh S., Mayen A. E., van Kempen M. J., Lamers W. H., Moorman A. F. Immunohistochemical delineation of the conduction system. I: The sinoatrial node. Circ Res. 1993 Sep;73(3):473–481. doi: 10.1161/01.res.73.3.473. [DOI] [PubMed] [Google Scholar]
  19. Oxford G. S., Swenson R. P. n-Alkanols potentiate sodium channel inactivation in squid giant axons. Biophys J. 1979 Jun;26(3):585–590. doi: 10.1016/S0006-3495(79)85273-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Reaume A. G., de Sousa P. A., Kulkarni S., Langille B. L., Zhu D., Davies T. C., Juneja S. C., Kidder G. M., Rossant J. Cardiac malformation in neonatal mice lacking connexin43. Science. 1995 Mar 24;267(5205):1831–1834. doi: 10.1126/science.7892609. [DOI] [PubMed] [Google Scholar]
  21. Saffitz J. E., Kanter H. L., Green K. G., Tolley T. K., Beyer E. C. Tissue-specific determinants of anisotropic conduction velocity in canine atrial and ventricular myocardium. Circ Res. 1994 Jun;74(6):1065–1070. doi: 10.1161/01.res.74.6.1065. [DOI] [PubMed] [Google Scholar]
  22. Spach M. S., Heidlage J. F. The stochastic nature of cardiac propagation at a microscopic level. Electrical description of myocardial architecture and its application to conduction. Circ Res. 1995 Mar;76(3):366–380. doi: 10.1161/01.res.76.3.366. [DOI] [PubMed] [Google Scholar]
  23. Spach M. S., Kootsey J. M., Sloan J. D. Active modulation of electrical coupling between cardiac cells of the dog. A mechanism for transient and steady state variations in conduction velocity. Circ Res. 1982 Sep;51(3):347–362. doi: 10.1161/01.res.51.3.347. [DOI] [PubMed] [Google Scholar]
  24. Traub O., Eckert R., Lichtenberg-Fraté H., Elfgang C., Bastide B., Scheidtmann K. H., Hülser D. F., Willecke K. Immunochemical and electrophysiological characterization of murine connexin40 and -43 in mouse tissues and transfected human cells. Eur J Cell Biol. 1994 Jun;64(1):101–112. [PubMed] [Google Scholar]
  25. Veenstra R. D. Size and selectivity of gap junction channels formed from different connexins. J Bioenerg Biomembr. 1996 Aug;28(4):327–337. doi: 10.1007/BF02110109. [DOI] [PubMed] [Google Scholar]
  26. de Bakker J. M., van Capelle F. J., Janse M. J., Tasseron S., Vermeulen J. T., de Jonge N., Lahpor J. R. Slow conduction in the infarcted human heart. 'Zigzag' course of activation. Circulation. 1993 Sep;88(3):915–926. doi: 10.1161/01.cir.88.3.915. [DOI] [PubMed] [Google Scholar]

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