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Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans

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Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal inherited arrhythmia syndrome in which drug therapy is often ineffective. We discovered that flecainide prevents arrhythmias in a mouse model of CPVT by inhibiting cardiac ryanodine receptor–mediated Ca2+ release and thereby directly targeting the underlying molecular defect. Flecainide completely prevented CPVT in two human subjects who had remained highly symptomatic on conventional drug therapy, indicating that this currently available drug is a promising mechanism-based therapy for CPVT.

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Figure 1: Flecainide inhibits RyR2 Ca2+ release channels, reduces spontaneous Ca2+ release events and triggered beats and prevents ventricular tachycardia in a CPVT mouse model.
Figure 2: Flecainide treatment prevents exercise-induced ventricular arrhythmia in two subjects with CPVT refractory to conventional drug therapy.

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Acknowledgements

We thank S. Huke and S. Kim for their assistance with the data analysis and the preparation of figures, P. Johnson for his assistance with the single-channel recording and N. Masalha and S.A. Clur for their assistance in patient care and management. This work was supported in part by the US National Institutes of Health grants HL88635 and HL71670 (to B.C.K.) and HL49989 (to D.M.R.), by the American Heart Association Established Investigator Award 0840071N (to B.C.K.), by the Australian Research Council grant DP0557780 (to D.R.L.), by an infrastructure grant from New South Wales Health through Hunter Medical Research Institute (to D.R.L.), by the Leducq Foundation grant 05CVD01 (to A.A.M.W. and D.M.R.) and by the Alberta Heart and Stroke Foundation Chair in Cardiovascular Medicine (to H.J.D.).

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Author notes

  1. Hiroshi Watanabe

    Present address: Current address: Division of Cardiology, Niigata University School of Medical and Dental Sciences, Niigata, Japan.,

  2. Hiroshi Watanabe, Nagesh Chopra and Derek Laver: These authors contributed equally to this work.

Authors and Affiliations

  1. Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

    Hiroshi Watanabe, Nagesh Chopra, Hyun Seok Hwang, Sean S Davies, Dan M Roden & Björn C Knollmann

  2. School of Biomedical Sciences, University of Newcastle and Hunter Medical Research Institute, Callaghan, Australia

    Derek Laver

  3. Libin Cardiovascular Institute, University of Calgary, Calgary, Alberta, Canada

    Daniel E Roach & Henry J Duff

  4. Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    Arthur A M Wilde

Authors
  1. Hiroshi Watanabe
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  2. Nagesh Chopra
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  3. Derek Laver
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  4. Hyun Seok Hwang
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  5. Sean S Davies
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  6. Daniel E Roach
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  7. Henry J Duff
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  8. Dan M Roden
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  9. Arthur A M Wilde
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  10. Björn C Knollmann
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Contributions

H.W. and H.S.H. conducted and analyzed the in vivo mouse ECG experiments, N.C. and H.S.H. conducted and analyzed the isolated myocyte experiments, D.L. conducted and analyzed the RyR2 single-channel experiments, A.A.M.W. conducted and analyzed the human studies, S.S.D. analyzed the flecainide concentrations, D.E.R. and H.J.D. provided the ECG telemetry analysis software, H.W. and N.C. wrote the initial draft of the manuscript, D.M.R. edited the manuscript, and B.C.K. designed and supervised the overall project, and prepared the final manuscript and figures.

Corresponding author

Correspondence to Björn C Knollmann.

Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1–5 and Supplementary Methods (PDF 495 kb)

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Watanabe, H., Chopra, N., Laver, D. et al. Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans. Nat Med 15, 380–383 (2009). https://doi.org/10.1038/nm.1942

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