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  • Our group then carried out


    Our group then carried out a study to determine the substrate sites and arrhythmogenic mechanisms of the BrS [29]. We found that all our BrS patients had abnormal low voltage, fractionated late potentials exclusively clustering in the anterior aspect of the RVOT epicardium and not seen anywhere else, and RVOT endocardium or left ventricular (LV) epicardium. Fig. 2 shows an example of low-voltage fractionated electrograms recorded from the anterior RVOT epicardium of a patient who presented with ES. Ablation at this area normalized the Brugada ECG pattern and prevented recurrent VF episodes. Similar observations were found in all our study patients, and these findings clearly provide the strongest clinical evidence that the delayed depolarization at the anterior aspect of the RVOT is the most likely underlying electrophysiologic mechanism underlying BrS (see more discussion below). Although it is quite apparent that depolarization disorder is likely to be the main mechanism underlying the BrS, one has to be mindful that repolarization abnormality could contribute to the arrhythmogenesis of the BrS patients, along with genetic mutations of ionic channel and other precipitating factors. Genetic mutation in BrS was first described by Chen et al., who reported the first mutation linked to BrS in the SCN5A gene, which encodes for the α-subunit of the sodium channel [30]. Since then, >100 SCN5A mutations have been discovered in BrS patients, and they are the most common type found in 11–28% of BrS probands; however, the increased of BrS have become heterogeneous. In addition to the SCN5A mutations, more mutations are found in gene encoding protein of potassium and calcium channels. These genetic findings in and the pharmacological features of BrS are generally considered favorable evidence for the repolarization theory. However, in structural discontinuous myocardium, AP propagation is determined by the tissue architecture itself which is abnormal in BrS, as evidenced by the late fractionated potential in the anterior RVOT epicardium and by the ionic current available for propagation. The latter is more or less determined by the AP morphology, which in turn is modulated by INa, ICa−L and Ito. A decrease in INa (commonly seen in SCN5A mutations in BrS patients), a decrease in ICa−L, and an increase in Ito or IKATP, modify the action morphology in such a way that safety of conduction is decreased (i.e., potentially leading to conduction slowing or conduction block in structural discontinuous myocardium or at Purkinje-ventricular muscle boundaries). All of these possibilities are linked to genetic variants associated with BrS, and some of them, in particular the amplitude of ICa−L, are sensitive to changes in autonomic tone. Similarly, pharmacologic interventions that block Ito or increase ICa−L, respectively, quinidine and isoproterenol, are expected to exert the opposite effect and improve safety of conduction. Indeed, both drugs are known to attenuate the Brugada ECG pattern and suppress the associated arrhythmias. Fig. 3 shows the possible pathophysiologic mechanisms underlying BrS and their modulating and precipitating factors. BrS patients had arrhythmogenic substrates displaying as late fractionated low-voltage potential in the anterior RVOT epicardium, which causes type I Brugada ECG pattern or could be accentuated or unmasked by sodium channel blocker (i.e., ajmaline, procainamide, flecainide, etc.), febrile illness, vagotonic agents, α-adrenergic agonists, β-adrenergic blockers, tricyclic or tetracyclic antidepressants, or first generation antihistaminies (dimenhydrinate). In the presence of SCN5A mutation that results in loss of INa, BrS patients not only could have more prominent ECG abnormality, but also develop short-coupling PVCs that could trigger VT/VF. In the presence of predisposing factors such as an altered autonomic nervous system, fever, or hypokalemia, VF could become sustained and occur frequently.