title: Mutation-specific effects of lidocaine in Brugada syndrome.
abstract: Brugada syndrome (BrS) is a hereditary cardiac disease characterized by right bundle-branch block, an elevation of the ST-segment in leads V1 through V3 on the electrocardiogram, and ventricular fibrillation that can lead to sudden cardiac death. Mutations in the cardiac sodium channel gene SCN5A, which encodes the alpha-subunit of the human cardiac voltage-dependent Na+ channel (Na(v)1.5), are identified in 15-30% of patients with BrS. Most SCN5A mutations lead to a 'loss-of-function' phenotype, reducing the Na+ current during the early phases of the action potential. Anti-arrhythmic drugs that affect Na+ channels typically block these Na+ channels, thereby exaggerating the ECG abnormalities and arrhythmogenicity in the BrS. However, the N406S mutation in SCN5A causes distinct gating defects and enhanced intermediate inactivation of Na+ channels, which led to unexpected pharmacological effects of lidocaine in a patient carrying this mutation. In the presence of the N406S mutation, use-dependent block by lidocaine is reduced and recovery from intermediate inactivation is hastened by lidocaine. These findings suggest that lidocaine may improve the Brugada phenotype in patients with N406S by increasing the availability of Na+ channels.
authors.forename: Colleen E
authors.initials: CE
authors.lastname: Clancy
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
mesh_terms: D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D053840:Brugada Syndrome / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D020022:Genetic Predisposition to Disease; D006801:Humans; D008012:Lidocaine / Q000494:pharmacology*; D009124:Muscle Proteins / Q000235:genetics*; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010641:Phenotype; D015222:Sodium Channels / Q000187:drug effects* / Q000235:genetics
chemical_list: D000889:Anti-Arrhythmia Agents; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; D008012:Lidocaine