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  • The principal difference between BrS and


    The principal difference between BrS and ERS is related to the region of the ventricle most affected. Epicardial mapping studies in BrS patients report accentuated J waves and fragmented and/or late potentials in the epicardial region of the RVOT [129–131], whereas in ERS only accentuated J waves, particularly in the inferior wall of LV, are observed [29]. Fractionated electrogram activity and late potentials have been observed in experimental models of ERS [30] but have not yet been reported clinically. Noninvasive mapping electroanatomic studies have reported very steep localized repolarization gradients across the inferior/lateral regions of LV of ERS patients, preceded by normal ventricular activation [132], whereas in BrS both slow discontinuous conduction and steep dispersion of repolarization are present in the RVOT [133]. Another presumed difference is the presence of structural abnormalities in BrS, which have not yet been described in ERS [76]. Although J waves are accentuated or induced by both hypothermia and fever [33,34,134–139], the development of arrhythmias in ERS is much more sensitive to hypothermia, and arrhythmogenesis in BrS appears to be promoted only by fever [33,34,138,139]. Hypothermia has been reported to increase the risk of VF in ERS [33,34,134,135,140], and fever is well recognized as a major risk factor in BrS [138,139]. It is noteworthy that hypothermia can diminish the manifestation of a BrS ECG when already present [141,142]. An ERP is associated with an increased risk for VF in patients with acute myocardial infarction[143] and hypothermia [33,144]. A concomitant ERP in the inferolateral leads has also been reported to be associated with an increased risk of arrhythmic events in patients with BrS. Kawata et al. [145]. reported that the prevalence of ER in inferolateral leads was high (63%) in BrS patients with documented VF.
    Genetics BrS has been associated with variants in 18 CI-1040 (Table 7). To date, more than 300 BrS-related variants in SCN5A have been described [21,146–148]Fig. 2 shows the overlap syndromes attributable to genetic defects in SCN5A. Loss-of- function mutations in SCN5A contribute to the development of both BrS and ERS, as well as to a variety of conduction diseases, Lenegre disease, and sick sinus syndrome. The available evidence suggests that the presence of a prominent Ito determines whether loss-of-function mutations resulting in a reduction in INa will manifest as BrS/ERS or as conduction disease [59,149–151]. Variants in CACNA1C (Cav1.2), CACNB2b (Cavβ2b), and CACNA2D1 (Cavα2δ) have been reported in up to 13% of probands [152–155]. Mutations in glycerol-3-phophate dehydrogenase 1-like enzyme gene (GPD1L), SCN1B (β1 subunit of Na channel), KCNE3 (MiRP2), SCN3B (β3 subunit of Na channel), KCNJ8 (Kir6.1), KCND3 (Kv4.3), RANGRF (MOG1), SLMAP, ABCC9 (SUR2A), (Navβ2), PKP2 (plakophillin-2), FGF12 (FHAF1), HEY2, and SEMA3A (semaphorin) are relatively rare [156–176]. An association of BrS with SCN10A, a neuronal sodium channel, was recently reported [167,177,178]. A wide range of yields of variants was reported by the 2 studies that examined the prevalence of pathogenic SCN10A mutations and rare variants (5–16.7%) [177–179]. Mutations in these genes lead to loss of function in sodium (INa) and calcium (ICa) channel currents, as well as to a gain of function in transient outward potassium current (Ito) or ATP-sensitive potassium current (IK-ATP) [178]. New susceptibility genes recently proposed and awaiting confirmation include the transient receptor potential melastatin protein-4 gene (TRPM4) [180] and the KCND2 gene. The mutation uncovered in KCND2 in a single patient was shown to cause a gain of function in Ito when heterologously expressed [181]. Variants in KCNH2, KCNE5, and SEMA3A, although not causative, have been identified as capable of modulating the substrate for the development of BrS [182–185]. Loss-of-function mutations in HCN4 causing a reduction in the pacemaker current If can unmask BrS by reducing heart rate [186].