Skip to main content
SpringerLink
Log in

A Targeted Disruption in Connexin40 Leads to Distinct Atrioventricular Conduction Defects

  • Published:
Journal of Interventional Cardiac Electrophysiology Aims and scope Submit manuscript

Abstract

Introduction: Gap junctions consist of connexin (Cx) proteins that enable electrical coupling of adjacent cells and propagation of action potentials. Cx40 is solely expressed in the atrium and His-Purkinje system. The purpose of this study was to evaluate atrioventricular (AV) conduction in mice with a homozygous deletion of Connexin40 (Cx40−/−).

Methods: Surface ECGs, intracardiac electrophysi-ology (EP) studies, and ambulatory telemetry were performed in Cx40−/− mutant mice and wild-type (WT) controls. Atrioventricular (AV) conduction parameters and arrhythmia inducibility were evaluated using programmed stimulation. Analysis of heart rate variability was based on results of ambulatory monitoring.

Results: Significant findings included prolonged measures of AV refractoriness and conduction in connexin40-deficient mice, including longer PR, AH, and HV intervals, increased AV refractory periods, and increased AV Wenckebach and 2:1 block cycle lengths. Connexin40-deficient mice also had an increased incidence of inducible ventricular tachycardia, decreased basal heart rates, and increased heart rate variability.

Conclusion: A homozygous disruption of Cx40 results in prolonged AV conduction parameters due to abnormal electrical coupling in the specialized conduction system, which may also predispose to arrhythmia vulnerability.

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. Simon AM, Goodenough DA, Paul DL. Mice lacking connexin40 have cardiac conduction abnormalities characteristic of first degree atrioventricular block and bundle branch block. Current Biology 1998;8: 295-298.

    Google Scholar 

  2. Kirchoff S, Nelles E, Hagendorff A, et al. Reduced cardiac conduction velocity and predisposition to arrhythmias in connexin40 deficient mice. Current Biology 1998;8:299-302.

    Google Scholar 

  3. Gros D, Jarry-Guichard T, Ten Velde I, et al. Restricted distribution of Connexin40, a gap junctional protein, in mammalian heart. Circ Res 1994;4: 839-851.

    Google Scholar 

  4. Davis LM, Kanter HL, Beyer EC, et al. Distinct gap junction protein phenotypes in cardiac tissues with disparate conduction properties. J Am Coll Cardiol 1994;24:1124-1132.

    Google Scholar 

  5. Darrow BJ, Laing JG, Lampe PD, et al. Expression of multiple connexins in cultured neonatal rat ventricular myocytes. Circ Res 1995;76:381-387.

    Google Scholar 

  6. van der Velden HMW, van Kempen MJA, Wijffells MCEF, et al. Altered pattern of connexin40 distribution in persistent atrial fibrillation in the goat. J Cardiovasc Electrophysiol 1998;9:596-607.

    Google Scholar 

  7. Saffitz J, Davis LM, Darrow BJ, et al. The molecular basis of anisotropy: role of gap junctions. J Cardiovasc Electrophysiol 1995;6:498-510.

    Google Scholar 

  8. Thomas SA, Schuessler RB, Berul CI, et al. Disparate effects of deficient connexin43 on a trial and ventricular conduction. Circulation 1998;97: 686-691.

    Google Scholar 

  9. Thomas SA, Schuessler RB, Saffitz JA. Connexins, conduction, and atrial fibrillation. J Cardiovasc Electrophysiol 1998;9:608-611.

    Google Scholar 

  10. Coppen SR, Severs NJ, Gourdie RG. Connexin45 (alpha 6) expression delineates an extended conduction system in the embryonic and mature rodent heart. Dev Genetics 1999;24:82-90.

    Google Scholar 

  11. Berul CI, Aronovitz MJ, Wang PJ, et al. In vivo cardiac electrophysiology studies in the mouse. Circulation 1996;94:2641-2648.

    Google Scholar 

  12. Berul CI, Christe ME, Aronovitz MJ, et al. Familial hypertrophic cardiomyopathy mice display gender differences in electrophysiological abnormalities. Journal of Interventional Cardiac Electrophysiology 1998;2:7-14.

    Google Scholar 

  13. Berul CI, Mendelsohn ME. Molecular biology and genetics of cardiac disease associated with sudden death: electrophysiologic studies in mouse models of inherited human diseases. In: Estes NAM, Salem DN, Wang PJ, eds. Sudden Cardiac Death in the Athlete. New York: Futura, 1998:465-482.

    Google Scholar 

  14. HRV Standards of Measurement, Task Force of ESC and NASPE. Circulation 1996;93:1043-1065.

    Google Scholar 

  15. Mitchell GF, Jeron A, Koren G. Measurement of heart rate and Q-T interval in the conscious mouse. Am J Physiol 1998;274:H747-751.

    Google Scholar 

  16. Hagendorff A, Schumacher B, Kirchoff S, et al. Conduction disturbances and increased atrial vulnerability in connexin40-deficient mice analyzed by transesophageal stimulation. Circulation 1999;99:1508-1515.

    Google Scholar 

  17. Mehdirad AA, Keim S, Rist K, et al. Asymmetry of retrograde conduction and reentry within the His-Purkinje system: a comparative analysis of left and right ventricular stimulation. J Am Coll Cardiol 1994;24:177-184.

    Google Scholar 

  18. Kwong KF, Schuessler KG, Green JG, et al. Differential expression of gap junction proteins in the canine sinus node. Circ Res 1998;82:604-612.

    Google Scholar 

  19. De Wit C, Roos F, Bolz SS, et al. Impaired conduction of vasodilation along arterioles in connexin 40-deficient mice. Circ Res 2000;86:649-655.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cardiology, Children's Hospital, Harvard Medical School Boston, Massachusetts, 02115

    Laura M. Bevilacqua, Colin T. Maguire, Josef Gehrmann, Hiroko Wakimoto & Charles I. Berul

  2. Department of Neurobiology, Harvard Medical School, Boston, Massachusetts

    Alexander M. Simon & David L. Paul

Authors
  1. Laura M. Bevilacqua
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alexander M. Simon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Colin T. Maguire
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Josef Gehrmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hiroko Wakimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. David L. Paul
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Charles I. Berul
    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

Bevilacqua, L.M., Simon, A.M., Maguire, C.T. et al. A Targeted Disruption in Connexin40 Leads to Distinct Atrioventricular Conduction Defects. J Interv Card Electrophysiol 4, 459–567 (2000). https://doi.org/10.1023/A:1009800328836

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1009800328836

Search

Navigation