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Molekulare Grundlagen primär elektrischer Herzerkrankungen

Molecular basis of primary electrical heart diseases

  • BEITRAG ZUM THEMENSCHWERPUNKT
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Summary

The last decade has seen rapid progress in our understanding of the molecular basis of arrhythmias, particularly concerning hereditary arrhythmia syndromes. This has led to significant improvement regarding differentiation, risk stratification and therapy in these patients and their families. However, there is mounting evidence that the knowledge obtained by studying these rare monogenic disorders will also enable us to dissect the molecular mechanisms underlying polygenetic and multi-factorial arrhythmias that are by far more common in clinical practice. The goal of this review is to give a brief overview of current knowledge on the molecular basis of primary electrical heart diseases. A focus is on the long QT syndrome.

Zusammenfassung

Seit Mitte der 1990er Jahre sind auf dem Gebiet der kardialen molekularen Elektrophysiologie faszinierende Fortschritte erzielt worden. Heute ist ein detailliertes Verständnis vieler genetischer und pathophysiologischer Grundlagen primär elektrischer Herzerkrankungen möglich, das einer besseren Differenzierung, Risikostratifizierung und Therapie den Weg bereitet hat. Gleichzeitig zeichnet sich zunehmend ab, dass die an seltenen monogenen Krankheitsbildern gewonnenen Erkenntnisse auch zu einem besseren Verständnis der epidemiologisch häufigeren polygenetischen und multifaktoriell bedingten Rhythmusstörungen führen werden.

Ziel dieses Übersichtsartikels ist es, in der gebotenen Kürze einen Überblick über den aktuellen Stand des Wissens über molekulare Grundlagen primär elektrischer Herzerkrankungen zu geben. Ein Schwerpunkt wird hierbei auf das Long-QT-Syndrom gelegt.

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References

  1. Anderson ME, Al-Khatib SM, Roden DM, Califf RM (2002) Cardiac repolarization: Current knowledge, critical gaps, and new approaches to drug development and patient management. Am Heart J 144:769–781

    PubMed  CAS  Google Scholar 

  2. Antzelevich C (2001) The Brugada syndrome: ionic basis and arrhythmia mechanism. J Cardiovasc Electrophysiol 12:268–272

    Google Scholar 

  3. El-Sherif N (2001) Mechanism of ventricular arrythmias in the long QT syndrome: on hermeneutics. J Cardiovasc Electrophysiol 12:973–976

    PubMed  CAS  Google Scholar 

  4. El-Sherif N, Turitto G (2003) Torsade de pointes. Curr Opin Cardiol 18:6–13

    Article  PubMed  Google Scholar 

  5. Farzaneh-Far A, Lerman BB (2005) Idiopathic right ventrikular outflow tract tachycardia. Heart 91:136-138

    Article  PubMed  CAS  Google Scholar 

  6. January CT, Gong Q, Zhou Z (2000) Long QT syndrome: cellular basis and arrythmia mechanism in LQT2. J Cardiovasc Electrophysiol 11:1413–1418

    Article  PubMed  CAS  Google Scholar 

  7. Kääb S, Schulze-Bahr E (2005) Susceptibility genes and modifiers for cardiac arrhythmias. Cardiovasc Res 67:397–413

    PubMed  Google Scholar 

  8. Karle CA, Zitron E, Zhang W, et al. (2002) Human cardiac inwardly-rectifying K+ channel Kir2.1b is inhibited by direct protein kinase C-dependent regulation in human isolated cardiomyocytes and in an expression system. Circulation 106:1493–1499

    Article  PubMed  CAS  Google Scholar 

  9. Karle CA, Zitron E, Zhang W, Kathöfer S, Schöls W, Kiehn J (2002) Rapid component IKr of the guinea-pig cardiac delayed rectifier K+ current is inhibited by beta1-adrenoceptor activation, via cAMP/protein kinase A—dependent pathways. Cardiovasc Res 53:355–362

    PubMed  CAS  Google Scholar 

  10. Marx SO, Kurokawa J, Reiken S, Motoike H, D‘Armiento J, Marks AR, Kass RS (2002) Requirement of a macromolecular signalling complex for β adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel. Science 295:496–499

    PubMed  CAS  Google Scholar 

  11. Meregalli PG, Wilde AM, Tan HL (2005) Pathophysiological mechanisms of Brugada syndrome: Depolarization disorder, repolarization disorder, or more? Cardiovasc Res 67:367–378

    Article  PubMed  CAS  Google Scholar 

  12. Mitcheson JS, Chen J, Lin M, Culberson C, Sanguinetti MC (2000 a) A structural basis for drug-induced long QT syndrome. Proc Natl Acad Sci USA 97:12329–12333

    Article  CAS  Google Scholar 

  13. Mitcheson JS, Chen J, Sanguinetti MC (2000 b) Trapping of a methanesulfonanilide by closure of the HERG potassium channel activation gate. J Gen Physiol 115:229–240

    Article  CAS  Google Scholar 

  14. Mohler PJ, Schott JJ, Gramolini AO, et al (2003) Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature 421:634–639

    Article  PubMed  CAS  Google Scholar 

  15. Moss AJ, Kass RS (2005) Long QT syndrome: from channels to cardiac arrhythmias. J Clin Invest 115:2018–2024

    Article  PubMed  CAS  Google Scholar 

  16. Plaster NM, Tawil R, Tristani-Firouzi M, et al. (2001) Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen’s syndrome. Cell 105:511–519

    Article  PubMed  CAS  Google Scholar 

  17. Priori SG, Napolitano C (2004) Genetics of cardiac arrhythmias and sudden death. Ann NY Acad Sci 1015:96–110

    PubMed  CAS  Google Scholar 

  18. Redfern WS, Carlsson L, Davis AS et al (2003) Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc Res 58:32–45

    Article  PubMed  CAS  Google Scholar 

  19. Roden DM (2005) Proarrhythmia as a pharmacogenomic entity: A critical review and formulation of a unifying hypothesis. Cardiovasc Res 67:419–425

    Article  PubMed  CAS  Google Scholar 

  20. Roden DM, Balser JR, George AL, Anderson ME (2002) Cardiac Ion Channels. Annu Rev Physiol 64:431–475

    Article  PubMed  CAS  Google Scholar 

  21. Roden DM, Viswanathan PC (2005) Genetics of acquired long QT syndrome. J Clin Invest 115:2025-2032

    Article  PubMed  CAS  Google Scholar 

  22. Schimpf R, Wolpert C, Gaita F, Giustetto C, Borggrefe M (2005) Short QT syndrome. Cardiovasc Res 67:357–366

    Article  PubMed  CAS  Google Scholar 

  23. Scholz EP, Zitron E, Kiesecker C (2003) Drug binding to aromatic residues in the HERG channel pore cavity as possible explanation for acquired long QT syndrome by antiparkinsonian drug budipine. Naunyn Schmiedeberg’s Arch Pharmacol 368:404–414

    CAS  Google Scholar 

  24. Schulze-Bahr E (2005) Short QT syndrome or Andersen syndrome: Yin and Yang of Kir2.1 channel dysfunction. Circ Res 96:703–704

    Article  PubMed  CAS  Google Scholar 

  25. Schulze-Bahr E, Neu A, Friederich P, et al. (2003) Pacemaker channel dysfunction in a patient with sinus node disease. J Clin Invest 111:1537–1545

    Article  PubMed  CAS  Google Scholar 

  26. Splawski I, Timothy KW, Sharpe LM et al (2004) Cav1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 119:19–31

    Article  PubMed  CAS  Google Scholar 

  27. Thomas D, Zhang W, Karle CA et al (1999) Deletion of protein kinase A phosphorylation sites in the HERG potassium channel inhibits activation shift by protein kinase A. J Biol Chem 274:27457–27462

    PubMed  CAS  Google Scholar 

  28. Tristani-Firouzi M, Jensen JL, Donaldson MR et al (2002) Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome). J Clin Invest 110:381–388

    Article  PubMed  CAS  Google Scholar 

  29. Viskin (1999) Long QT syndrome and torsade de pointes. Lancet 354:1625–1633

    Article  PubMed  CAS  Google Scholar 

  30. Wichter T, Schulze-Bahr E, Eckardt L et al (2002) Molecular mechanisms of inherited ventricular arrhythmias. Herz 27:712–739

    Article  PubMed  Google Scholar 

  31. Zitron E, Scholz EP, Owen R et al (2005) QTc prolongation by grapefruit juice and its potential pharmacologic basis: HERG channel blockade by flavonoids. Circulation 111:835–838

    Article  PubMed  CAS  Google Scholar 

  32. Zitron E, Kiesecker C, Lück S et al (2004) Human cardiac inwardly rectifying current I(Kir2.2) is upregulated by activation of protein kinase A. Cardiovasc Res 63:520–527

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. AG Molekulare Elektrophysiologie (Leiter), Medizinische Universitätsklinik Heidelberg, Innere Medizin III, 69120, Heidelberg

    C. A. Karle

Authors
  1. E. Zitron
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  2. E. P. Scholz
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  3. C. Kiesecker
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  4. M. Pirot
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  5. S. Kathöfer
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  6. D. Thomas
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  7. J. Kiehn
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  8. H. A. Katus
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  9. R. Becker
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  10. C. A. Karle
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Correspondence to C. A. Karle.

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Zitron, E., Scholz, E.P., Kiesecker, C. et al. Molekulare Grundlagen primär elektrischer Herzerkrankungen. Herzschr. Elektrophys. 16, 229–238 (2005). https://doi.org/10.1007/s00399-005-0490-9

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  • DOI: https://doi.org/10.1007/s00399-005-0490-9

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