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    • In the management of BrS patients it is

    2019-07-01

    In the management of BrS patients, it is important to avoid or treat certain drugs or circumstances such as a febrile state, electrolyte disturbances (hyperkalemia and hypercalcemia), and the use of class Ia/Ic antiarrhythmic drugs, vagotonic agents, beta-adrenergic antagonists, tricyclic antidepressants, first-generation antihistamines, and cocaine, which can induce ECG aggravation and VF [2]. BrS is sensitive to body temperature. Fever directly aggravates ST-segment elevation and leads to TWA, frequent PVC, and VF. A previous study showed that temperature elevation caused a positive shift of steady-state activation, acceleration of inactivation, and slow recovery from inactivation in both wild type and mutant sodium channels (F1344S in the SCN5A gene), resulting in reduction of sodium currents, deepening of the AP notch, and aggravation of BrS [40]. Another study demonstrated that a single amino KN-93 hydrochloride substitution (H681P) in the SCN5A gene shifted both steady-state activation and inactivation, resulting in a 60% reduction of the sodium window current. Therefore, a febrile state should be avoided in BrS patients [41]. Patients with a history of cardiac arrest/aborted sudden death must be treated with an implantable cardioverter defibrillator (ICD). Drug therapy to prevent VF is not recommended for BrS patients because clinical trials have failed to convincingly prove the effectiveness of drug therapy [2,42]. Therefore, medications should be considered when multiple direct current (DC) shocks (electrical storm or repetitive ventricular tachycardia) are observed. For this purpose, an Ito-specific drug would theoretically be the most appropriate; however, there are no drugs that block Ito selectively. Isoproterenol [43,44], quinidine [20,45,46] cilostazol [47], denopamine [43], disopyramide [48], and bepridil [48,49] are reported to be effective for preventing VF. Acute treatment should be administered by intravenous injection of isoproterenol (1–2μg bolus followed by continuous infusion at 0.15–0.20μg/min) and/or quinidine (1000–2000mg/day). Isoproterenol induces an increase in the inward l-type calcium current and attenuates outward current excess. Quinidine has an anticholinergic effect and also blocks the calcium-independent Ito current, resulting in restoration of the epicardial AP dome, normalization of ST-segment elevation, and prevention of phase 2 reentry, as demonstrated by an experimental model of BrS [20]. Quinidine is the most commonly used drug for preventing VF in BrS patients in the clinical setting, although it is sometimes difficult to use in Japan due to its common side effect (diarrhea). Mizusawa et al. reported the effectiveness of low-dose quinidine (300–600mg/day); however, their results were not sufficient (VF was prevented in only 44% of cases) [50]. The phosphodiesterase III inhibitor cilostazol and the beta-adrenergic stimulator denopamine have been reported to normalize ST-segment elevation by augmenting the calcium and Ito currents secondary to an increase in heart rate [43,47]. Disopyramide has been reported to be clinically useful for preventing VF in some cases, possibly due to its Ito-blocking and anticholinergic effects. However, this drug is a class Ia drug, which causes aggravation of ST-segment elevation, thus careful attention is needed when using it. Bepridil, a blocker of multiple potassium channels including Ito, has been reported to prevent VF in BrS patients. Interestingly, this drug is quite effective in patients with an SCN5A mutation [49]. Recently, chronic long-term exposure of cardiomyocytes to bepridil was shown to inhibit the action of calmodulin, which decreased cardiac sodium alpha-subunit degradation and increased the sodium current [51]. This chronic effect might be related to the clinical effectiveness of bepridil. More recently, the effectiveness of catheter ablation has been reported. Haissaguerre et al. reported endocardial focal ablation of triggered PVC preceding VF [52], and Nademanee et al. showed epicardial arrhythmogenic substrate ablation in the RVOT [53]. While further efficacy and safety studies are needed, these non-pharmacologic therapies should be considered as treatment options.