br Epidemiology Electrophysiological BrS phenotypes occur

Epidemiology Electrophysiological BrS phenotypes occur predominantly in young male adults (<40 to 45 years of age; BrS is 8–10 times more prevalent in men than women) and are dynamically altered by corticotropin releasing factor rate, autonomic nervous system activity, some types of drugs, and a febrile state. Therefore, the true prevalence of BrS in the general population is difficult to estimate. However, the BrS prevalence of the general population is thought to be much higher in East/Southeast Asia than in Europe and the USA. The reason for this is not clear, but might be due to an Asian-specific haplotype of the promoter region of the SCN5A gene [12], which encodes the alpha subunit of the cardiac sodium channel. Supraventricular arrhythmias are more prevalent in BrS. Atrial fibrillation is observed in 10–20% of cases [13], and atrial arrhythmias may be associated with higher BrS risk and more advanced disease [14]. Infrahisian conduction disturbance [1] and sick sinus syndrome [15] have also been reported to be prevalent in this syndrome.
Gene mutations in BrS Approximately 20% of BrS patients have been shown to have sodium channel gene mutations (BrS 1, 5, 7, and 11) and about 10% of patients have been shown to have l-type calcium channel gene mutations (BrS 3, 4, and 9) (Table 1). In rare cases (<1%), mutations of glycerol-3-phosphate dehydrogenase-like peptide (GPD1-L: BrS 2), transient outward potassium current (BrS 6 and 10), and ATP-sensitive potassium channel (BrS 8 and 12) have been reported. Genotype–phenotype correlations have been reported in BrS. For example, patients with an SCN5A mutation had longer and progressive conduction delays (PQ, QRS, and HV intervals) [16,17], frequent occurrence of fragmented QRS complex (f-QRS: defined as an abnormal fragmentation within the QRS complex as ≥4 spikes in 1 or ≥8 spikes in all of the V1, V2, and V3 leads) [6], and ventricular arrhythmias of extra-RVOT origin [18]. Patients with calcium channel gene mutations have a short QT interval [19].
Mechanism of ST-T segment abnormality In an experimental study using perfused right ventricular wedge preparations from dogs, Yan et al. revealed that the mechanism of ST-T abnormality in the right precordial leads is an outward shift of ionic currents during early repolarization (transmural voltage gradient), causing a marked accentuation of the action potential (AP) notch and prolongation of repolarization in the right ventricular epicardial (spike-and-dome), but not endocardial, cells in the RVOT (Fig. 3) [20]. This process is thought to be due to an increased contribution of the transient outward current (Ito) in this area. This discriminating electrophysiological mechanism has been thought to be associated with ST-segment elevation (J wave) and T wave inversion in BrS. In a human study using the activation recovery interval (ARI) method, Nagase et al. demonstrated that an inverted T wave associated with a type 1 ECG pattern is due to preferential epicardial ARI prolongation secondary to accentuation of the AP notch in the RVOT [21]. Another human study using monophasic action potential (MAP) recordings during open chest surgery in BrS patients revealed that “spike-and-dome” AP shapes were recorded in the RVOT epicardium but not in the endocardium or in control subjects, consistent with the results of the previously described experimental study.
Mechanism of VF Experimental studies [22–24] have suggested that the aforementioned excessive repolarization heterogeneity within the RVOT epicardium, (repolarization abnormality) triggers premature ventricular contractions (PVCs), maintains a polymorphic ventricular tachycardia, and contributes to VF development in BrS patients. Traveling (by both electrotonic and induced ionic currents) of the dome caused phase 2 reentry (Fig. 4) [20,24] that, after initial conduction within the epicardium (from the region with a prominent dome to regions without a dome and then reentering the region of origin), was conducted into the mid- and endo-cardium after recovery of local excitability. Local or global RVOT conduction delay (depolarization abnormality) exacerbates repolarization heterogeneity by increasing the transmural gradient of the membrane potential and contributes to VF development [25]. Numerous clinical observations have supported the presence of depolarization abnormality in high-risk BrS. For example, sodium channel blockers exacerbate/provoke ST-segment elevation and VF development [26], late potential indicates high-risk BrS [27,28], longer HV interval predicts VF inducibility [29], VF patients without a SCN5A gene mutation have more histological abnormalities, including myocarditis [30] and oxidative stress [31], and fragmented QRS (f-QRS) indicates high-risk BrS (Fig. 5) [6].