Abrupt rate accelerations or premature beats cause life-threatening arrhythmias in mice with long-QT3 syndrome

D. Nuyens, M. Stengl, S. Dugarmaa, T. Rossenbacker, V. Compernolle, Y. Rudy, J. F. Smits, W. Flameng, Colleen E Clancy, L. Moons, M. A. Vos, M. Dewerchin, K. Benndorf, D. Collen, E. Carmeliet, P. Carmeliet

Research output: Contribution to journalArticle

204 Scopus citations

Abstract

Deletion of amino-acid residues 1505-1507 (KPQ) in the cardiac SCN5A Na+ channel causes autosomal dominant prolongation of the electrocardiographic QT interval (long-QT syndrome type 3 or LQT3). Excessive prolongation of the action potential at low heart rates predisposes individuals with LQT3 to fatal arrhythmias, typically at rest or during sleep. Here we report that mice heterozygous for a knock-in KPQ-deletion (SCN5A Δ/+) show the essential LQT3 features and spontaneously develop life-threatening polymorphous ventricular arrhythmias. Unexpectedly, sudden accelerations in heart rate or premature beats caused lengthening of the action potential with early afterdepolarization and triggered arrhythmias in Scn5aΔ/+ mice. Adrenergic agonists normalized the response to rate acceleration in vitro and suppressed arrhythmias upon premature stimulation in vivo. These results show the possible risk of sudden heart-rate accelerations. The Scn5aΔ/+ mouse with its predisposition for pacing-induced arrhythmia might be useful for the development of new treatments for the LQT3 syndrome.

Original languageEnglish (US)
Pages (from-to)1021-1027
Number of pages7
JournalNature Medicine
Volume7
Issue number9
DOIs
StatePublished - 2001
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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    Nuyens, D., Stengl, M., Dugarmaa, S., Rossenbacker, T., Compernolle, V., Rudy, Y., Smits, J. F., Flameng, W., Clancy, C. E., Moons, L., Vos, M. A., Dewerchin, M., Benndorf, K., Collen, D., Carmeliet, E., & Carmeliet, P. (2001). Abrupt rate accelerations or premature beats cause life-threatening arrhythmias in mice with long-QT3 syndrome. Nature Medicine, 7(9), 1021-1027. https://doi.org/10.1038/nm0901-1021