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Cardiac conduction disturbances and differential effects on atrial and ventricular electrophysiological properties in desmin deficient mice

  • Jan Wilko Schrickel
  • Florian Stöckigt
  • Wieslaw Krzyzak
  • Denise Paulin
  • Zhenlin Li
  • Indra Lübkemeier
  • Bernd Fleischmann
  • Philipp Sasse
  • Markus Linhart
  • Thorsten Lewalter
  • Georg Nickenig
  • Lars Lickfett
  • Rolf Schröder
  • Christoph Stephan Clemen
Article

Abstract

Purpose

Desmin mutations in humans cause desmin-related cardiomyopathy, resulting in heart failure, atrial and ventricular arrhythmias, and sudden cardiac death. The intermediate filament desmin is strongly expressed in striated muscle cells and in Purkinje fibers of the ventricular conduction system. The aim of the present study was to characterize electrophysiological cardiac properties in a desmin-deficient mouse model.

Methods

The impact of desmin deficiency on cardiac electrophysiological characteristics was examined in the present study. In vivo electrophysiological studies were carried out in 29 adult desmin deficient (Des−/−) and 19 wild-type (Des+/+) mice. Additionally, epicardial activation mapping was performed in Langendorff-perfused hearts.

Results

Intracardiac electrograms showed no significant differences in AV, AH, and HV intervals. Functional testing revealed equal AV-nodal refractory periods, sinus-node recovery times, and Wenckebach points. However, compared to the wild-type situation, Des−/− mice were found to have a significantly reduced atrial (23.6 ± 10.3 ms vs. 31.8 ± 12.5 ms; p = 0.045), but prolonged ventricular refractory period (33.0 ± 8.7 ms vs. 26.7 ± 6.5 ms; p = 0.009). The probability of induction of atrial fibrillation was significantly higher in Des−/− mice (Des−/−: 38% vs. Des+/+: 27%; p = 0.0255), while ventricular tachycardias significantly were reduced (Des−/−: 7% vs. Des+/+: 21%; p < 0.0001). Epicardial activation mapping showed slowing of conduction in the ventricles of Des−/− mice.

Conclusions

Des−/− mice exhibit reduced atrial but prolonged ventricular refractory periods and ventricular conduction slowing, accompanied by enhanced inducibility of atrial fibrillation and diminished susceptibility to ventricular arrhythmias. Desmin deficiency does not result in electrophysiological changes present in human desminopathies, suggesting that functional alterations rather than loss of desmin cause the cardiac alterations in these patients.

Keywords

Desmin Desmin-related cardiomyopathies Arrhythmias Conduction Desmin knockout mouse Desminopathy Myofibrillar myopathy Connexin 

Notes

Acknowledgements

This work was supported by institutional grants from the University of Bonn (BONFOR O-109.0008 and O-109.0024 awarded to J.W.S.) and by the German Research Foundation (DFG) (SCHR 562/4-1, 4-2 awarded to R.S.). R.S. and C.S.C. are members of the German network on muscular dystrophies (MD-NET2, Project 7) funded by the German ministry of education and research (BMBF) and of the multi-location DFG research group FOR1228. Thanks to H.J.M. van Rijen and C. de Bakker for their technical assistance regarding with the epicardial mapping system. Thanks to D. Axt for technical assistance and H. Begerau for programming and designing the software for the analysis of the epicardial activation maps. There are no financial disclosures or conflicts of interest existing for any of the authors.

References

  1. 1.
    Goldfarb, L. G., Vicart, P., Goebel, H. H., & Dalakas, M. C. (2004). Desmin myopathy. Brain, 127, 723–734.CrossRefPubMedGoogle Scholar
  2. 2.
    Schroder, R., Goudeau, B., Simon, M. C., et al. (2003). On noxious desmin: functional effects of a novel heterozygous desmin insertion mutation on the extrasarcomeric desmin cytoskeleton and mitochondria. Human Molecular Genetics, 12, 657–669.CrossRefPubMedGoogle Scholar
  3. 3.
    Schroder, R., Vrabie, A., & Goebel, H. H. (2007). Primary desminopathies. Journal of Cellular and Molecular Medicine, 11, 416–426.CrossRefPubMedGoogle Scholar
  4. 4.
    Selcen, D., Ohno, K., & Engel, A. G. (2004). Myofibrillar myopathy: clinical, morphological and genetic studies in 63 patients. Brain, 127, 439–451.CrossRefPubMedGoogle Scholar
  5. 5.
    Bar, H., Strelkov, S. V., Sjoberg, G., Aebi, U., & Herrmann, H. (2004). The biology of desmin filaments: how do mutations affect their structure, assembly, and organisation? Journal of Structural Biology, 148, 137–152.CrossRefPubMedGoogle Scholar
  6. 6.
    Price, M. G. (1984). Molecular analysis of intermediate filament cytoskeleton—a putative load-bearing structure. American Journal of Physiology, 246, H566–572.PubMedGoogle Scholar
  7. 7.
    Eriksson, A., & Thornell, L. E. (1979). Intermediate (skeletin) filaments in heart Purkinje fibers. A correlative morphological and biochemical identification with evidence of a cytoskeletal function. Journal of Cell Biology, 80, 231–247.CrossRefPubMedGoogle Scholar
  8. 8.
    Li, Z., Colucci-Guyon, E., Pincon-Raymond, M., et al. (1996). Cardiovascular lesions and skeletal myopathy in mice lacking desmin. Developmental Biology, 175, 362–366.CrossRefPubMedGoogle Scholar
  9. 9.
    Milner, D. J., Weitzer, G., Tran, D., Bradley, A., & Capetanaki, Y. (1996). Disruption of muscle architecture and myocardial degeneration in mice lacking desmin. Journal of Cell Biology, 134, 1255–1270.CrossRefPubMedGoogle Scholar
  10. 10.
    Kreuzberg, M. M., Schrickel, J. W., Ghanem, A., et al. (2006). Connexin30.2 containing gap junction channels decelerate impulse propagation through the atrioventricular node. Proceedings of the National Academy of Sciences of the United States of America, 103, 5959–5964.CrossRefPubMedGoogle Scholar
  11. 11.
    Schrickel, J. W., Brixius, K., Herr, C., et al. (2007). Enhanced heterogeneity of myocardial conduction and severe cardiac electrical instability in annexin A7-deficient mice. Cardiovascular Research, 76, 257–268.CrossRefPubMedGoogle Scholar
  12. 12.
    Schrickel, J. W., Bielik, H., Yang, A., et al. (2002). Induction of atrial fibrillation in mice by rapid transesophageal atrial pacing. Basic Research in Cardiology, 97, 452–460.CrossRefPubMedGoogle Scholar
  13. 13.
    Coronel, R., Wilms-Schopman, F. J., de Groot, J. R., et al. (2000). Laplacian electrograms and the interpretation of complex ventricular activation patterns during ventricular fibrillation. Journal of Cardiovascular Electrophysiology, 11, 1119–1128.CrossRefPubMedGoogle Scholar
  14. 14.
    van Rijen, H. V., Eckardt, D., Degen, J., et al. (2004). Slow conduction and enhanced anisotropy increase the propensity for ventricular tachyarrhythmias in adult mice with induced deletion of connexin43. Circulation, 109, 1048–1055.CrossRefPubMedGoogle Scholar
  15. 15.
    Lammers, W. J., Schalij, M. J., Kirchhof, C. J., & Allessie, M. A. (1990). Quantification of spatial inhomogeneity in conduction and initiation of reentrant atrial arrhythmias. American Journal of Physiology, 259, H1254–1263.PubMedGoogle Scholar
  16. 16.
    Li, D., Fareh, S., Leung, T. K., & Nattel, S. (1999). Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort. Circulation, 100, 87–95.PubMedGoogle Scholar
  17. 17.
    Traub, O., Eckert, R., Lichtenberg-Frate, H., et al. (1994). Immunochemical and electrophysiological characterization of murine connexin40 and -43 in mouse tissues and transfected human cells. European Journal of Cell Biology, 64, 101–112.PubMedGoogle Scholar
  18. 18.
    Schroder, R., & Schoser, B. (2009). Myofibrillar myopathies: a clinical and myopathological guide. Brain Pathology, 19, 483–492.CrossRefPubMedGoogle Scholar
  19. 19.
    Baker, L. C., London, B., Choi, B. R., Koren, G., & Salama, G. (2000). Enhanced dispersion of repolarization and refractoriness in transgenic mouse hearts promotes reentrant ventricular tachycardia. Circulation Research, 86, 396–407.PubMedGoogle Scholar
  20. 20.
    Sabir, I. N., Fraser, J. A., Killeen, M. J., Grace, A. A., & Huang, C. L. (2007). The contribution of refractoriness to arrhythmic substrate in hypokalemic Langendorff-perfused murine hearts. Pflugers Archiv. European Journal of Physiology, 454, 209–222.CrossRefPubMedGoogle Scholar
  21. 21.
    Galou, M., Gao, J., Humbert, J., et al. (1997). The importance of intermediate filaments in the adaptation of tissues to mechanical stress: evidence from gene knockout studies. Biology of the Cell, 89, 85–97.CrossRefPubMedGoogle Scholar
  22. 22.
    Li, J., Patel, V. V., & Radice, G. L. (2006). Dysregulation of cell adhesion proteins and cardiac arrhythmogenesis. Clin Med Res, 4, 42–52.CrossRefPubMedGoogle Scholar
  23. 23.
    Sohl, G., & Willecke, K. (2004). Gap junctions and the connexin protein family. Cardiovascular Research, 62, 228–232.CrossRefPubMedGoogle Scholar
  24. 24.
    Taylor, M. R., Slavov, D., Ku, L., et al. (2007). Prevalence of desmin mutations in dilated cardiomyopathy. Circulation, 115, 1244–1251.CrossRefPubMedGoogle Scholar
  25. 25.
    Gard, J. J., Yamada, K., Green, K. G., et al. (2005). Remodeling of gap junctions and slow conduction in a mouse model of desmin-related cardiomyopathy. Cardiovascular Research, 67, 539–547.CrossRefPubMedGoogle Scholar
  26. 26.
    Danik, S. B., Liu, F., Zhang, J., et al. (2004). Modulation of cardiac gap junction expression and arrhythmic susceptibility. Circulation Research, 95, 1035–1041.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Jan Wilko Schrickel
    • 1
  • Florian Stöckigt
    • 1
  • Wieslaw Krzyzak
    • 2
  • Denise Paulin
    • 2
    • 3
  • Zhenlin Li
    • 2
    • 3
  • Indra Lübkemeier
    • 4
  • Bernd Fleischmann
    • 5
  • Philipp Sasse
    • 5
  • Markus Linhart
    • 1
  • Thorsten Lewalter
    • 6
  • Georg Nickenig
    • 1
  • Lars Lickfett
    • 1
  • Rolf Schröder
    • 7
    • 8
  • Christoph Stephan Clemen
    • 9
  1. 1.Department of Medicine-CardiologyUniversity of BonnBonnGermany
  2. 2.UMR 7079, Physiology and PhysiopathologyUPMC Univ Paris 6ParisFrance
  3. 3.UMR 7079CNRSParisFrance
  4. 4.Institute of GeneticsUniversity of BonnBonnGermany
  5. 5.Department of Physiology 1, Life and Brain CenterUniversity of BonnBonnGermany
  6. 6.St. Marien HospitalBonnGermany
  7. 7.Institute of NeuropathologyUniversity Hospital ErlangenErlangenGermany
  8. 8.Department of NeurologyUniversity Hospital ErlangenErlangenGermany
  9. 9.Institute of Biochemistry IUniversity of CologneCologneGermany

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