A novel SCN5A mutation associated with drug induced Brugada type ECG

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

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 1 2016

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Electrocardiography
Brugada Syndrome
mutation
myocardial depressants
drugs
Mutation
Sodium
Pharmaceutical Preparations
Drug therapy
Pharmacokinetics
Sodium Channels
Induced currents
Clamping devices
Electric potential
sodium
Screening
Current density
Genes
Chemical activation
Atrial Flutter

ASJC Scopus subject areas

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

Cite this

Isik, T., Takeru, M., Matteo, V., Hideki, I., Takeshi, U., Akihiko, S., ... 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

A novel SCN5A mutation associated with drug induced Brugada type ECG. / Isik, Turker; Takeru, Makiyama; Matteo, Vatta; Hideki, Itoh; Takeshi, Ueyama; Akihiko, Shimizu; Ai, Tomohiko; Minoru, Horie.

In: PLoS One, Vol. 11, No. 8, e0161872, 01.08.2016.

Research output: Contribution to journalArticle

Isik, T, Takeru, M, Matteo, V, Hideki, I, Takeshi, U, Akihiko, S, Ai, T & Minoru, H 2016, 'A novel SCN5A mutation associated with drug induced Brugada type ECG', PLoS One, vol. 11, no. 8, e0161872. https://doi.org/10.1371/journal.pone.0161872
Isik T, Takeru M, Matteo V, Hideki I, Takeshi U, Akihiko S et al. A novel SCN5A mutation associated with drug induced Brugada type ECG. PLoS One. 2016 Aug 1;11(8). e0161872. https://doi.org/10.1371/journal.pone.0161872
Isik, Turker ; Takeru, Makiyama ; Matteo, Vatta ; Hideki, Itoh ; Takeshi, Ueyama ; Akihiko, Shimizu ; Ai, Tomohiko ; Minoru, Horie. / A novel SCN5A mutation associated with drug induced Brugada type ECG. In: PLoS One. 2016 ; Vol. 11, No. 8.
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AB - 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.

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