SCN5A mutation associated with acute myocardial infarction

Abstract

Ventricular tachycardia and fibrillation (VT/VF) complicating Brugada syndrome, a genetic disorder linked to SCN5A mutations, and VF complicating acute myocardial infarction (AMI) have both been linked to phase 2 reentry. Because of these mechanistic similarities in arrhythmogenesis, we examined the contribution of SCN5A mutations to VT/VF complicating AMI. Nineteen consecutive patients developing VF during AMI were enrolled. Wild-type (WT) and mutant SCN5A genes were co-expressed with SCN1B in TSA201 cells and studied using whole-cell patch-clamp techniques. One missense mutation (G400A) in SCN5A was detected in a conserved region among the cohort of 19 patients. A H558R polymorphism was detected on the same allele. Unlike the other 18 patients who each developed 1-2 VF episodes during acute MI, 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. 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. These results could be very useful for forensic implications regarding genetic screening in relatives.

Fig. 1

Genetic analysis of patient MMRL23. (A) PCR-based sequence of SCN5A exon 10 showing wild-type (WT) and G-to-C transversion at nucleotide 1199 (arrow) in patient MMRL23. The mutation predicts a substitution of Ala (GCG) for Gly (GGG) at position 400 (G400A). (B) Location of the G400A mutation and H558R polymorphism are indicated using the conventional transmembrane topology model. (C) Alignment of the voltage-gated sodium channel α-subunit family amino acid sequence, with related sequence shows that G400 is highly conserved among different sodium channels and different species. Dashes indicate identical residues to human SCN5A channel.