• 2018-07
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  • The principal difference between BrS


    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 ikk pathway (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].