SCN5A Genetic Polymorphisms Associated With Increased Defibrillator Shocks in Brugada Syndrome

Abstract

BackgroundBrugada syndrome (BrS) is an inherited primary arrhythmia disorder leading to sudden cardiac arrest. SCN5A, encoding the α‐subunit of the cardiac sodium channel (Nav1.5), is the most common pathogenic gene of BrS. An implantable cardioverter defibrillator (ICD) is the standard treatment for secondary prevention. This study aimed to evaluate association of the SCN5A variant with this cardiac conduction disturbance and appropriate ICD shock therapy in Thai symptomatic BrS patients with ICD implants.Methods and ResultsSymptomatic BrS patients diagnosed at university hospital were enrolled from 2008 to 2011. The primary outcome of the study was an appropriate ICD shock defined as having non‐pacing‐associated ICD shock after the occurrence of ventricular tachycardia or ventricular fibrillation. Associations between SCN5A polymorphisms, cardiac conduction disturbance, and potential confounding factors associated with appropriate ICD shock therapy were analyzed. All 40 symptomatic BrS patients (median age, 43 years) with ICD implantations were followed for 24 months. There were 16 patients (40%) who had the appropriate ICD shock therapy after ICD treatment. An independent factor associated with appropriate ICD shock therapy was SCN5A‐R1193Q with an adjusted hazard ratio of 10.550 (95% CI, 1.631–68.232).Conclusions SCN5A‐R1193Q is associated with cardiac conduction disturbances. It may be a genetic marker associated with ventricular arrhythmia leading to appropriate ICD shock therapy in symptomatic BrS patients with ICD treatment. Because of the small sample size of study population and the appropriate ICD shock outcome, further large studies are needed to confirm the results of this study.

SCN5A mutation status increases the risk of major arrhythmic events in Asian populations with Brugada syndrome: systematic review and meta‐analysis

“…These aforementioned factors are thus suggestive of existing heterogeneity interfering with the results from our analyses. The cause of heterogeneity is also noted in the study performed by Makarawate et al () which correlated SCN5A mutation status with cardiac conduction disturbances and resultant appropriate ICD shocks. Their study included a geographically and genetically isolated population: most patients were of northeastern Thai origin; only symptomatic patients were included; and only two polymorphisms were identified (R1193Q and H558R).…”

“…Seven studies from March 2002 to October 2017 were included in this meta‐analysis involving 1,049 subjects with BrS (302 patients with SCN5A mutations and 747 patients without SCN5A mutations). Five studies revealed an increased MAE among BrS patients with SCN5A mutations (Andorin et al, ; Conte et al, ; Makarawate et al, ; Nishii et al, ; Yamagata et al, ) with one of the five studies (Makarawate et al, ) achieving statistical significance. The pooled analysis demonstrated a nonsignificant increased risk of MAE in BrS patients with SCN5A mutations compared to those without the mutation, with a pooled RR of 1.50 (95% CI: 0.93–2.41, p = 0.10, I 2 = 38.0%).…”

“…In subgroup analysis among ethnicities, three studies (two studies from Japan and one study from Thailand) were included in Asian populations (Makarawate et al, ; Nishii et al, ; Yamagata et al, ) involving 486 subjects with BrS (80 patients with SCN5A mutations and 406 patients without SCN5A mutations). All three studies revealed increased MAE among BrS patients with SCN5A mutations (Makarawate et al, ; Nishii et al, ; Yamagata et al, ) with one study (Makarawate et al, ) achieving statistical significance. The pooled analysis demonstrated a significant increased risk of MAE in Asian BrS patients with SCN5A mutations compared to those without the mutation (RR = 1.78, 95% CI: 1.23–2.58, p = 0.002, I 2 = 0%).…”

“…Priori et al demonstrated that the presence of both syncope and spontaneous ST‐segment elevation has a sensitivity of 36% and a high specificity of 94% in predicting the occurrence of cardiac arrest in BrS patients (Priori et al, ). On the contrary, many studies have assessed family history of sudden cardiac death as a predictor for poorer outcomes, and the results were reproducibly unrevealing (Gehi et al, ; Makarawate et al, ; Nishii et al, ; Priori et al, ). Clinicians have long been intrigued by the concept of using SCN5A mutation status to predict MAE in BrS patients.…”

“…The only preventive measure for sudden cardiac death in BrS is ICD implantation; thus, risk stratification to select the patient in whom ICD is appropriate is crucial (Probst et al, ). The use of SCN5A mutation status to prognosticate the risk of MAE in BrS patients has been controversial (Adler et al, ): some studies showed positive results (Makarawate et al, ; Nishii et al, ; Yamagata et al, ), while others failed to correlate the mutation to subsequent MAE (Andorin et al, ; Gehi, Duong, Metz, Gomes, & Mehta, ; Priori et al, ; Probst et al, ). The goal of this systematic review and meta‐analysis was to examine the association of SCN5A mutations and MAE in BrS patients.…”