BackgroundA common SCN5A polymorphism H558R (c.1673 A > G, rs1805124) improves sodium channel activity in mutated channels and known to be a genetic modifier of Brugada syndrome patients (BrS). We investigated clinical manifestations and underlying mechanisms of H558R in BrS.Methods and resultsWe genotyped H558R in 100 BrS (mean age 45 ± 14 years; 91 men) and 1875 controls (mean age 54 ± 18 years; 1546 men). We compared clinical parameters in BrS with and without H558R (H558R+ vs. H558R- group, N = 9 vs. 91). We also obtained right atrial sections from 30 patients during aortic aneurysm operations and compared SCN5A expression and methylation with or without H558R. H558R was less frequent in BrS than controls (9.0% vs. 19.2%, P = 0.028). The VF occurrence ratio was significantly lower (0% vs. 29.7%, P = 0.03) and spontaneous type 1 ECG was less observed in H558R+ than H558R- group (33.3% vs. 74.7%, P = 0.01). The SCN5A expression level was significantly higher and the methylation rate was significantly lower in sections with H558R (N = 10) than those without (0.98 ± 0.14 vs. 0.83 ± 0.19, P = 0.04; 0.7 ± 0.2% vs. 1.6 ± 0.1%, P = 0.004, respectively). In BrS with heterozygous H558R, the A allele mRNA expression was 1.38 fold higher than G allele expression.ConclusionThe SCN5A polymorphism H558R may be a modifier that protects against VF occurrence in BrS. The H558R decreased the SCN5A promoter methylation and increased the expression level in cardiac tissue. An allelic expression imbalance in BrS with a heterozygous H558R may also contribute to the protective effects in heterozygous mutations.Electronic supplementary materialThe online version of this article (doi: 10.1186/s12929-017-0397-x) contains supplementary material, which is available to authorized users.

rugada syndrome (BS) is characterized by ST-segment elevation in leads V1-3 with a right bundle branch block pattern and nocturnal sudden cardiac death caused by ventricular fibrillation (VF). 1,2 Patients with this syndrome who have experienced syncopal episodes or have been resuscitated from cardiac arrest have a poor prognosis if they do not receive an implantable cardioverter defibrillator (ICD). Although the prevalence of Brugada-type ECG change in healthy subjects is approximately 0.1-1%, their prognosis of is relatively good compared with symptomatic patients. 3-10 However, some asymptomatic patients become symptomatic and sudden cardiac death can occur with the first VF attack, so it is a problem in Japan of how to treat asymptomatic patients with a typical Brugada-type ECG who are detected by daily medical checkup. The results of some recent studies regarding the prognostic value of programmed electrical stimulation (PES) for patients with BS are conflicting; 6-9 Priori et al reported that the factors that predicted cardiac events were spontaneous ST elevation in leads V1-3 and episodes of syncope, but that VF inducible by PES did not indicate an increased risk of cardiac arrest, 7 whereas Brugada et al reported that induci-bility of ventricular arrhythmia and an abnormal ECG without provocation were predictors of arrhythmic events. 8,9 However, an electrophysiological study (EPS) is expensive and invasive, and sometimes results in complications, so it should not be carried out for all asymptomatic patients who show a Brugada-type ECG, but only for those patients for whom there is a high risk for a cardiac event. Because it is currently impossible to accurately predict the occurrence of cardiac events in asymptomatic patients, the present study was designed to determine noninvasive methods that could predict induction of VF by PES in asymptomatic patients with Brugada syndrome. For this purpose, the clinical characteristics of asymptomatic patients in whom VF was induced by PES were assessed, and the differences between the clinical values in asymptomatic patients with PES-induced VF and those without PES-induced VF were studied using noninvasive methods (a sodium channel blocker [pilsicainide] challenge test and a signal averaged electro-gram). Methods Patients The subjects of this study were 41 male asymptomatic patients with BS (age 27-66 years; mean age, 45±10 years). A Brugada-type ECG was defined as late r' wave (>0.2 mV) and ST segment elevation (>0.1 mV). 3 All of the subjects Circ J 2003; 67: 312-316 Ventricular fibrillation (VF) is induced in some asymptomatic patients with Brugada syndrome (BS), but the pro-gnostic value of programmed electrical stimulation (PES) in such patients is controversial. The clinical characteristics of 41 asymptomatic BS patients, divided into 2 groups according to whether VF was induced by PES (inducible VF group: n=13, non-inducible VF group: n=28) were evaluated. ST levels in the right precordial leads were measured before and after administration of pilsicainide...

IntroductionThe single nucleotide polymorphism (SNP) rs2106261 in the transcription factor gene ZFHX3 (16q22), a major regulator of inflammation, has been reported linking to atrial fibrillation (AF) by genome-wide association studies. Inflammation is known to be a strong predictor of atrial fibrillation recurrence after ablation, so we examined the association of the ZFHX3 SNP rs2106261 to inflammation marker expression and recurrence after AF ablation.MethodsWe genotyped ZFHX3 SNP rs2106261 and compared the minor (T) allele frequency between 362 paroxysmal AF (PAF) patients underwent pulmonary vein isolation (PVI) and 627 non-AF controls. We also analyzed associations between ZFHX3 SNP rs2106261 genotype and recurrence rate after pulmonary vein isolation and the inflammation markers.ResultsThe minor (T) allele frequency of the ZFHX3 SNP rs2106261 was significantly higher in AF patients than non-AF controls (odds ratio 1.52, p = 2.2×10−5). Multivariable analysis revealed that the minor allele (T) decreased AF recurrence rate after pulmonary vein isolation (hazard ratio 0.53, p = 0.04). Further, neutrophil/lymphocyte (N/L) ratio, C-reactive protein (CRP), and interleukin-6 (IL-6) expression levels were lower in PAF patients with the ZFHX3 SNP rs2106261 minor allele (TT+TC) than in CC patients (N/L ratio: CC 2.22 ± 0.08, TT+TC 1.98 ± 0.06, p = 0.018; CRP: CC 0.103 ± 0.009 mg/dl, TT+TC 0.076 ±0.007 mg/dl, p = 0.016; IL-6: CC 60.3 ± 3.0 pg/ml, TT+TC 52.8 ± 2.3 pg/ml, p = 0.04).ConclusionsThe ZFHX3 SNP rs2106261 minor allele is associated with lower AF recurrence rate after pulmonary vein isolation. Low baseline inflammation conferred by this allele may reduce AF recurrence risk.

BackgroundAlcohol consumption and oxidative stress are well-known risk factors for developing atrial fibrillation (AF). Single nucleotide polymorphisms (SNPs) of alcohol dehydrogenase (ADH1B) and aldehyde dehydrogenase 2 (ALDH2) genes encoding enzymes of alcohol and reactive aldehyde metabolism, respectively, are prevalent among East Asians. Here, we examined whether these SNPs were associated with AF in Japanese patients.Methods and resultsFive hundred seventy-seven Japanese patients with AF undergoing catheter ablation and 1935 controls at Hiroshima University Hospital were studied. Alcohol consumption habits, medical history, electrocardiogram (EKG), electrophysiology and cardiac echocardiography were reviewed. Patients were also genotyped for ALDH2 (rs671) and ADH1B (rs1229984). A significant linear correlation was found between ALDH2 genotype and mean alcohol intake (P = 1.7 × 10−6). Further, ALDH2 (rs671) was associated with AF (P = 7.6 × 10−4, odds ratio [OR] = 0.6). Frequency of the ALDH2 SNP allele A which limits acetaldehyde metabolism was lower in patients with AF (18.8%) than in controls (23.5%). In contrast, we found that the frequencies of the ADH1B SNP genotypes were similar in patients with AF and in controls. Subset analysis among the 182 patients with lone AF and 914 controls (control II) (<60 years of age and without hypertension), both ALDH2 and ADH1B SNPs were significantly associated with AF (P = 0.013, OR = 0.7; P = 0.0007, OR = 1.4, respectively). The frequency of the dysfunctional allele A of ALDH2 was significantly lower and the dysfunctional allele G of ADH1B was significantly higher in patients with lone AF than in control II (ALDH2 A allele frequency = 0.176 vs 0.235, OR = 1.3, P = 0.013, ADH1B SNP G allele frequency = 0.286 vs 0.220, OR = 1.4, P = 0.0007).ConclusionsWhen considering all patients enrolled, the dysfunctional ALDH2 allele was negatively associated with AF. When examining a subset of patients with lone AF, the dysfunctional ALDH2 allele was negatively associated with AF and the slower metabolizing ADH1B allele was positively associated with AF. Hence, prolonged metabolic conversion of alcohol to acetaldehyde may be associated with the occurrence of AF in the Japanese and other East Asian populations.

B rugada syndrome (BrS) is characterized by right precordial ST elevation, susceptibility to ventricular arrhythmias, and sudden cardiac death.1,2 Because the SCN5A gene, which codes for cardiac voltage-gated sodium channels, was reported to be a causative gene of BrS, 3 many other susceptibility genes have been identified. 4 Among them, the SCN5A gene accounts for the vast majority of cases.In 2009, Kapplinger et al 5 reported that 300 distinct SCN5A mutations were detected in 438 (21%) of 2111 unrelated, clinically diagnosed patients with BrS, with the mutation detection yield ranging from 11% to 28% across the 9 testing centers. Mutations in calcium channel genes, including CACNA1C (Cav1.2, BrS3), CACNB2b (Cav b2b, BrS4), and CACNA2D1 (Cav a2δ1, BrS9), have been found in ≈12%© 2016 American Heart Association, Inc. ; odds ratio, 1.7, respectively). Interestingly, the HEY2 risk allele C was less frequent in BrS patients with ventricular fibrillation than in those without (59% versus 74%; P=4.1×10 ). The HEY2 mRNA expression level in the right ventricular specimens from patients with BrS (n=20) was significantly lower in patients with CC genotype than the other genotypes (P=0.04). Additionally, during 63±28 months follow-up periods after implantable cardioverter defibrillator implantation (n=90), Kaplan-Meier event-free survival curves revealed that the cumulative rate of ventricular fibrillation events was significantly lower in cases with HEY2 CC genotype (P=0.04). Conclusions-Our findings suggest that HEY2 CC genotype may be a favorable prognostic marker for BrS, protectively acting to prevent ventricular fibrillation presumably by regulating the repolarization current. (Circ Arrhythm Electrophysiol. 2016;9:e003436. Circ Arrhythm Electrophysiol