Novel mutation in the SCN5A gene associated with arrhythmic storm development during acute myocardial infarction.
BACKGROUND
Ventricular tachycardia (VT) and ventricular fibrillation (VF) complicating Brugada syndrome, a genetic disorder linked to SCN5A mutations, and VF complicating acute myocardial infarction (AMI) both have been linked to phase 2 reentry.


OBJECTIVE
Given the mechanistic similarities in arrhythmogenesis, the purpose of this study was to examine the contribution of SCN5A mutations to VT/VF complicating AMI.


METHODS
Nineteen consecutive patients developing VF during AMI were enrolled in the study. Wild-type (WT) and mutant SCN5A genes were coexpressed with SCN1B in TSA201 cells and studied using whole-cell patch clamp techniques.


RESULTS
Among the cohort of 19 patients, one missense mutation (G400A) in SCN5A was detected in a conserved region. An H558R polymorphism was detected on the same allele. Unlike the other 18 patients, who each developed 1-2 VF episodes during AMI, the mutation carrier developed six episodes of VT/VF within the first 12 hours. All VT/VF episodes were associated with ST-segment changes and were initiated by short-coupled extrasystoles. Flecainide and adenosine challenge performed to unmask Brugada and long QT syndromes both were negative. Peak G400A and G400A+H558R current were 70.7% and 88.4% less than WT current at -35 mV (P </=.001). G400A current decay was accelerated and steady-state inactivation was shifted -6.39 mV (V(1/2) = -98.9 +/- 0.1 mV vs -92.5 +/- 0.1 mV, P </=.001). No mutations were detected in KCNH2, KCNQ1, KCNE1, or KCNE2 in the G400A patient.


CONCLUSIONS
We describe the first sodium channel mutation to be associated with the development of an arrhythmic storm during acute ischemia. These findings suggest that a loss of function in SCN5A may predispose to ischemia-induced arrhythmic storm.
Hu
Dan
D
Masonic Medical Research Laboratory, Utica, New York, USA.
Viskin
Sami
S
Oliva
Antonio
A
Carrier
Tabitha
T
Cordeiro
Jonathan M
JM
Barajas-Martinez
Hector
H
Wu
Yuesheng
Y
Burashnikov
Elena
E
Sicouri
Serge
S
Brugada
Ramon
R
Rosso
Rafael
R
Guerchicoff
Alejandra
A
Pollevick
Guido D
GD
Antzelevitch
Charles
C
D000200:Action Potentials; D000328:Adult; D000368:Aged; D004562:Electrocardiography; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D020125:Mutation, Missense; D009203:Myocardial Infarction / Q000150:complications / Q000235:genetics*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D015222:Sodium Channels / Q000235:genetics*; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000235:genetics*; D014162:Transfection; D014693:Ventricular Fibrillation / Q000209:etiology / Q000235:genetics*
D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels