Novel SCN5A mutation in amiodarone-responsive multifocal ventricular ectopy-associated cardiomyopathy

Thomas M. Beckermann, Karen McLeod, Victoria Murday, Franck Potet, Alfred L. George*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

39 Scopus citations


Background Mutations in SCN5A, which encodes the cardiac sodium channel NaV1.5, typically cause ventricular arrhythmia or conduction slowing. Recently, SCN5A mutations have been associated with heart failure combined with variable atrial and ventricular arrhythmia. Objective The purpose of this study was to determine the clinical, genetic, and functional features of an amiodarone-responsive multifocal ventricular ectopy-related cardiomyopathy associated with a novel mutation in a NaV1.5 voltage sensor domain. Methods A novel, de novo SCN5A mutation (NaV1.5-R225P) was identified in a boy with prenatal arrhythmia and impaired cardiac contractility followed by postnatal multifocal ventricular ectopy suppressible by amiodarone. We investigated the functional consequences of NaV1.5-R225P expressed heterologously in tsA201 cells. Results Mutant channels exhibited significant abnormalities in both activation and inactivation leading to large, hyperpolarized window and ramp currents that predict aberrant sodium influx at potentials near the cardiomyocyte resting membrane potential. Mutant channels also exhibited significantly increased persistent (late) sodium current. This profile of channel dysfunction shares features with other SCN5A voltage sensor mutations associated with cardiomyopathy and overlapped that of congenital long QT syndrome. Amiodarone stabilized fast inactivation, suppressed persistent sodium current, and caused frequency-dependent inhibition of channel availability. Conclusion We determined the functional consequences and pharmacologic responses of a novel SCN5A mutation associated with an arrhythmia-associated cardiomyopathy. Comparisons with other cardiomyopathy-associated NaV1.5 voltage sensor mutations revealed a pattern of abnormal voltage dependence of activation as a shared biophysical mechanism of the syndrome.

Original languageEnglish (US)
Pages (from-to)1446-1453
Number of pages8
JournalHeart rhythm
Issue number8
StatePublished - Aug 2014


  • Amiodarone
  • Cardiomyopathy
  • Electrophysiology
  • SCN5A mutation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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