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  • The most compelling apparent evidence in

    2019-05-15

    The most compelling apparent evidence in support of the depolarization hypothesis derives from the seminal studies of Nademanee et al. [129]. showing that radiofrequency ablation (RFA) of epicardial sites displaying late potentials and fractionated bipolar electrograms in the RVOT of patients with BrS significantly reduced the arrhythmia vulnerability as well as the ECG manifestation of the syndrome. Similar results were reported by Brugada et al. [131]. and by Sacher et al. [130] who also observed in an isolated case that accentuation of the Brugada ECG by ajmaline was associated with an increased area of low-voltage and fragmented electrogram activity. A wider area of low-voltage activity was associated with a more prominent ST-segment elevation [131]. These authors concluded that the late potentials and fractionated electrogram activity are due to conduction delays within the RVOT/RV anterior wall and that ablation of the sites of slow conduction is the basis for the ameliorative effect of ablation therapy [129–131]. In a direct test of this hypothesis, Szel and Antzelevitch [150] provided evidence for an alternative mechanism using an experimental model of BrS. The low-voltage fractionated electrogram activity was shown to develop as a result of regional desynchronization in the appearance of the second AP upstroke, secondary to accentuation of the epicardial AP notch, and high-frequency late potentials to develop in the RV epicardium secondary to concealed phase 2 reentry. Delayed conduction of the primary beat was never observed in a wide variety of BrS models created by exposing canine RV wedge preparations to drugs mimicking the different genetic defects known to give rise to BrS [150]. In more recent studies, ablation of the RV epicardium was shown to diminish the manifestation of J waves and ST-segment elevation and to abolish all arrhythmic activity by destroying the GSK461364 manufacturer with the most prominent AP notch, thus eliminating the cells responsible for the repolarization abnormalities that give rise to phase 2 reentry and VT/VF [15,218]. Confirmation of all of these results in in vivo animal models is desirable. In an attempt to create such a model, Park et al. [149]. recently genetically engineered Yucatan minipigs to heterozygously express a nonsense mutation in SCN5A (E558X) originally identified in a child with BrS. Patch clamp analysis of atrial myocytes isolated from the SCN5AE558X/þ pigs showed a loss of function of INa. Conduction abnormalities consisting of prolongation of P wave, QRS complex, and PR interval were observed, but a BrS phenotype was not observed, not even after administration of flecainide. These observations are expected because of the lack of Ito in the pig, which is a prerequisite for the development of the repolarization abnormalities associated with BrS. Some have argued that the absence of a BrS phenotype is due to the young age of the minipigs (22 months) [219]. However, it is difficult to reconcile why the minipigs manifest major conduction delays at this age but not a BrS phenotype, if indeed the latter depends on the former. Finally, it is noteworthy that monophasic APs recorded from the epicardial and endocardial surfaces of the RVOT of a patient with BrS are nearly identical to transmembrane APs recorded from the epicardial and endocardial surfaces of the wedge model of BrS [220,221]. These differences were not observed in an isolated heart explanted from a BrS patient after transplantation of a new heart. However, the epicardium of this heart was very depressed, GSK461364 manufacturer perhaps as a result of the 129 shocks delivered by the implantable cardioverter-defibrillator (ICD) in an attempt to control the multiple electrical storms [32]. Zhang et al. [133]. recently performed noninvasive electrocardiographic imaging (ECGI) on 25 BrS and 6 RBBB patients. The authors concluded that both slow discontinuous conduction and steep dispersion of repolarization are present in the RVOT of patients with BrS. ECGI was able to differentiate between BrS and RBBB. Unlike BrS, RBBB showed delayed activation in the entire RV, without ST- segment elevation, fractionation, or repolarization abnormalities showing on the electrograms. Importantly, the response to an increase in rate was studied in 6 BrS patients. Increasing rate increased fractionation of the electrogram but reduced ST-segment elevation, indicating that the conduction impairment was not the principal cause of the BrS ECG.