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

Nature Medicine volume 7, pages 1021–1027 (2001)Cite this article

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 (SCN5AΔ/+) 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.

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Figure 1: Prolonged repolarization in Scn5aΔ/+ mice.
Figure 2: Prolonged repolarization and action potentials in Scn5aΔ/+ mice.
Figure 3: Electrophysiological characteristics of the Na+ current in Scn5aΔ/+ mice.
Figure 4: Spontaneous arrhythmias in Scn5aΔ/+ mice.
Figure 5: Pacing-induced ventricular arrhythmias in Scn5aΔ/+ mice.
Figure 6: Anti-arrhythmic effect of isoproterenol (ISO) in Scn5aΔ/+ mice.

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Acknowledgements

We thank D. Boon, K. Bijnens, M. De Mol, B. Hermans, S. Jansen, L. Kieckens, A. Vandenhoeck, S.Wyns and Roel Spatjens for assistance.

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Authors and Affiliations

  1. Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KU Leuven, Leuven, Belgium

    Dieter Nuyens, Tom Rossenbacker, Veerle Compernolle, Lieve Moons, Mieke Dewerchin, Désiré Collen & Peter Carmeliet

  2. Cardiology, Research Institute Maastricht (CARIM), University of Maastricht, Maastricht, The Netherlands

    Milan Stengl & Marc A. Vos

  3. Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, Maastricht, The Netherlands

    Jos F. Smits

  4. Klinikum der Friederich-Schiller-Universität Jena, Institut für Physiologie, Jena, Germany

    Saran Dugarmaa & Klaus Benndorf

  5. Cardiac Bioelectricity Research and Training Center, Case Western Reserve University, Cleveland, Ohio, USA

    Yoram Rudy & Colleen E. Clancy

  6. Laboratory of Experimental Cardiac Surgery, KU Leuven, Leuven, Belgium

    Willem Flameng & Edward Carmeliet

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Correspondence to Peter Carmeliet.

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Nuyens, D., Stengl, M., Dugarmaa, S. et al. Abrupt rate accelerations or premature beats cause life-threatening arrhythmias in mice with long-QT3 syndrome. Nat Med 7, 1021–1027 (2001). https://doi.org/10.1038/nm0901-1021

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