Lidocaine-induced brugada syndrome phenotype linked to a novel double mutation in the cardiac sodium channel

Hector M. Barajas-Martínez, Dan Hu, Jonathan M. Cordeiro, Yuesheng Wu, Richard J. Kovacs, Henry Meltser, Hong Kui, Burashnikov Elena, Ramon Brugada, Charles Antzelevitch, Robert Dumaine

Research output: Contribution to journalArticle

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Abstract

Brugada syndrome has been linked to mutations in SCN5A. Agents that dissociate slowly from the sodium channel such as flecainide and ajmaline unmask the Brugada syndrome electrocardiogram and precipitate ventricular tachycardia/fibrillation. Lidocaine, an agent with rapid dissociation kinetics, has previously been shown to exert no effect in patients with Brugada syndrome. We characterized a novel double mutation of SCN5A (V232I in DI-S4+L1308F in DIII-S4) identified in a rare case of lidocaine (1 mg/kg)-induced Brugada syndrome. We studied lidocaine blockade of INa generated by wild-type and V232I+L1308F mutant cardiac sodium channels expressed in mammalian TSA201 cells using patch clamp techniques. Despite no significant difference in steady-state gating parameters between V232I+L1308F and wild-type sodium currents at baseline, use-dependent inhibition of INa by lidocaine was more pronounced in V232I+L1308F versus wild-type (73.0±0.1% versus 18.23±0.04% at 10 μmol/L measured at 10 Hz, respectively). A dose of 10 μmol/L lidocaine also caused a more negative shift of steady-state inactivation in V232I+L1308F versus wild-type (-14.1±0.3 mV and -4.8±0.3 mV, respectively). The individual mutations produced a much less accentuated effect. We report the first case of lidocaine-induced Brugada electrocardiogram phenotype. The double mutation in SCN5A, V232I, and L1308F alters the affinity of the cardiac sodium channel for lidocaine such that the drug assumes Class IC characteristics with potent use-dependent block of the sodium channel. Our results demonstrate an additive effect of the 2 missense mutations to sensitize the sodium channel to lidocaine. These findings suggest caution when treating patients carrying such genetic variations with Class I antiarrhythmic drugs.

Original languageEnglish (US)
Pages (from-to)396-404
Number of pages9
JournalCirculation research
Volume103
Issue number4
DOIs
StatePublished - Aug 15 2008

Fingerprint

Brugada Syndrome
Sodium Channels
Lidocaine
Phenotype
Mutation
Electrocardiography
Ajmaline
Flecainide
Anti-Arrhythmia Agents
Patch-Clamp Techniques
Ventricular Fibrillation
Missense Mutation
Ventricular Tachycardia
Sodium

Keywords

  • Arrhythmia (mechanisms)
  • Brugada syndrome
  • Ion channels
  • Na channels
  • Sudden death

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Lidocaine-induced brugada syndrome phenotype linked to a novel double mutation in the cardiac sodium channel. / Barajas-Martínez, Hector M.; Hu, Dan; Cordeiro, Jonathan M.; Wu, Yuesheng; Kovacs, Richard J.; Meltser, Henry; Kui, Hong; Elena, Burashnikov; Brugada, Ramon; Antzelevitch, Charles; Dumaine, Robert.

In: Circulation research, Vol. 103, No. 4, 15.08.2008, p. 396-404.

Research output: Contribution to journalArticle

Barajas-Martínez, HM, Hu, D, Cordeiro, JM, Wu, Y, Kovacs, RJ, Meltser, H, Kui, H, Elena, B, Brugada, R, Antzelevitch, C & Dumaine, R 2008, 'Lidocaine-induced brugada syndrome phenotype linked to a novel double mutation in the cardiac sodium channel', Circulation research, vol. 103, no. 4, pp. 396-404. https://doi.org/10.1161/CIRCRESAHA.108.172619
Barajas-Martínez, Hector M. ; Hu, Dan ; Cordeiro, Jonathan M. ; Wu, Yuesheng ; Kovacs, Richard J. ; Meltser, Henry ; Kui, Hong ; Elena, Burashnikov ; Brugada, Ramon ; Antzelevitch, Charles ; Dumaine, Robert. / Lidocaine-induced brugada syndrome phenotype linked to a novel double mutation in the cardiac sodium channel. In: Circulation research. 2008 ; Vol. 103, No. 4. pp. 396-404.
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AU - Barajas-Martínez, Hector M.

AU - Hu, Dan

AU - Cordeiro, Jonathan M.

AU - Wu, Yuesheng

AU - Kovacs, Richard J.

AU - Meltser, Henry

AU - Kui, Hong

AU - Elena, Burashnikov

AU - Brugada, Ramon

AU - Antzelevitch, Charles

AU - Dumaine, Robert

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N2 - Brugada syndrome has been linked to mutations in SCN5A. Agents that dissociate slowly from the sodium channel such as flecainide and ajmaline unmask the Brugada syndrome electrocardiogram and precipitate ventricular tachycardia/fibrillation. Lidocaine, an agent with rapid dissociation kinetics, has previously been shown to exert no effect in patients with Brugada syndrome. We characterized a novel double mutation of SCN5A (V232I in DI-S4+L1308F in DIII-S4) identified in a rare case of lidocaine (1 mg/kg)-induced Brugada syndrome. We studied lidocaine blockade of INa generated by wild-type and V232I+L1308F mutant cardiac sodium channels expressed in mammalian TSA201 cells using patch clamp techniques. Despite no significant difference in steady-state gating parameters between V232I+L1308F and wild-type sodium currents at baseline, use-dependent inhibition of INa by lidocaine was more pronounced in V232I+L1308F versus wild-type (73.0±0.1% versus 18.23±0.04% at 10 μmol/L measured at 10 Hz, respectively). A dose of 10 μmol/L lidocaine also caused a more negative shift of steady-state inactivation in V232I+L1308F versus wild-type (-14.1±0.3 mV and -4.8±0.3 mV, respectively). The individual mutations produced a much less accentuated effect. We report the first case of lidocaine-induced Brugada electrocardiogram phenotype. The double mutation in SCN5A, V232I, and L1308F alters the affinity of the cardiac sodium channel for lidocaine such that the drug assumes Class IC characteristics with potent use-dependent block of the sodium channel. Our results demonstrate an additive effect of the 2 missense mutations to sensitize the sodium channel to lidocaine. These findings suggest caution when treating patients carrying such genetic variations with Class I antiarrhythmic drugs.

AB - Brugada syndrome has been linked to mutations in SCN5A. Agents that dissociate slowly from the sodium channel such as flecainide and ajmaline unmask the Brugada syndrome electrocardiogram and precipitate ventricular tachycardia/fibrillation. Lidocaine, an agent with rapid dissociation kinetics, has previously been shown to exert no effect in patients with Brugada syndrome. We characterized a novel double mutation of SCN5A (V232I in DI-S4+L1308F in DIII-S4) identified in a rare case of lidocaine (1 mg/kg)-induced Brugada syndrome. We studied lidocaine blockade of INa generated by wild-type and V232I+L1308F mutant cardiac sodium channels expressed in mammalian TSA201 cells using patch clamp techniques. Despite no significant difference in steady-state gating parameters between V232I+L1308F and wild-type sodium currents at baseline, use-dependent inhibition of INa by lidocaine was more pronounced in V232I+L1308F versus wild-type (73.0±0.1% versus 18.23±0.04% at 10 μmol/L measured at 10 Hz, respectively). A dose of 10 μmol/L lidocaine also caused a more negative shift of steady-state inactivation in V232I+L1308F versus wild-type (-14.1±0.3 mV and -4.8±0.3 mV, respectively). The individual mutations produced a much less accentuated effect. We report the first case of lidocaine-induced Brugada electrocardiogram phenotype. The double mutation in SCN5A, V232I, and L1308F alters the affinity of the cardiac sodium channel for lidocaine such that the drug assumes Class IC characteristics with potent use-dependent block of the sodium channel. Our results demonstrate an additive effect of the 2 missense mutations to sensitize the sodium channel to lidocaine. These findings suggest caution when treating patients carrying such genetic variations with Class I antiarrhythmic drugs.

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