A novel SCN5A mutation associated with drug induced Brugada type ECG

Turker Isik, Makiyama Takeru, Vatta Matteo, Itoh Hideki, Ueyama Takeshi, Shimizu Akihiko, Ai Tomohiko, Horie Minoru

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Abstract

Background: Class IC antiarrhythmic agents may induce acquired forms of Brugada Syndrome. We have identified a novel mutation in SCN5A, the gene that encodes the α-subunit of the human cardiac sodium channel (hNav1.5), in a patient who exhibited Brugada- type ECG changes during pharmacotherapy of atrial arrhythmias. Objective: To assess whether the novel mutation p.V1328M can cause drug induced Brugada Syndrome. Methods: Administration of pilsicainide, a class IC antiarrhythmic agent, caused Brugada- type ST elevation in a 66-year-old Japanese male who presented with paroxysmal atrial fibrillation (PAF), type I atrial flutter and inducible ventricular fibrillation (VF) during electrophysiological study. Genetic screening using direct sequencing identified a novel SCN5A variant, p. V1328M. Electrophysiological parameters of WT and p.V1328M and their effects on drug pharmacokinetics were studied using the patch-clamp method. Results: Whole-cell sodium current densities were similar for WT and p.V1328M channels. While p. V1328M mutation did not affect the voltage-dependence of the activation kinetics, it caused a positive shift of voltage-dependent steady-state inactivation by 7 mV. The tonic block in the presence of pilsicainide was similar in WT and p.V1328M, when sodium currents were induced by a low frequency pulse protocol (q15s). On the contrary, p.V1328M mutation enhanced pilsicainide induced use-dependent block at 2 Hz. (Ki: WT, 35.8 μM; V1328M, 19.3 μM). Conclusion: Our study suggests that a subclinical SCN5A mutation, p.V1328M, might predispose individuals harboring it to drug-induced Brugada Syndrome.

Original languageEnglish (US)
Article numbere0161872
JournalPloS one
Volume11
Issue number8
DOIs
StatePublished - Aug 2016

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Isik, T., Takeru, M., Matteo, V., Hideki, I., Takeshi, U., Akihiko, S., Tomohiko, A., & Minoru, H. (2016). A novel SCN5A mutation associated with drug induced Brugada type ECG. PloS one, 11(8), [e0161872]. https://doi.org/10.1371/journal.pone.0161872