Lidocaine-induced Brugada syndrome phenotype linked to a novel double mutation in the cardiac sodium channel.
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 I(Na) 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 I(Na) by lidocaine was more pronounced in V232I+L1308F versus wild-type (73.0+/-0.1% versus 18.23+/-0.04% at 10 micromol/L measured at 10 Hz, respectively). A dose of 10 micromol/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.
Barajas-Martínez
Hector M
HM
Masonic Medical Research Laboratory, Utica, New York, USA.
Hu
Dan
D
Cordeiro
Jonathan M
JM
Wu
Yuesheng
Y
Kovacs
Richard J
RJ
Meltser
Henry
H
Kui
Hong
H
Elena
Burashnikov
B
Brugada
Ramon
R
Antzelevitch
Charles
C
Dumaine
Robert
R
D000779:Anesthetics, Local / Q000009:adverse effects*; D053840:Brugada Syndrome / Q000235:genetics* / Q000503:physiopathology; D004562:Electrocardiography; D006801:Humans; D008012:Lidocaine / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010641:Phenotype; D015222:Sodium Channels / Q000235:genetics*
D000779:Anesthetics, Local; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; D008012:Lidocaine