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. Conclusion: 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.