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  • neurokinin receptor antagonist The BrS ECG is often

    2019-04-15

    The BrS ECG is often widely dynamic, with ST segment elevations that fluctuate from hour to hour, day to day, and month to month. Diurnal variation shows that events occur more frequently at night during periods of high vagal tone [2]. In some patients, the use of frequent ECGs or 12-lead ambulatory Holter monitoring is useful for diagnosing BrS. The concealed BrS phenotype can be unmasked using class IA and IC antiarrhythmic drugs, which possess potent use-dependent sodium channel blocking activity [3]. These drugs induce or exaggerate the appearance of a coved-type ST with J point elevation (type 1 BrS ECG) and can convert type 2 to type 3 ST segment elevations to type 1 (coved-type) elevations. Pilsicainide (Japan), procainamide (USA), ajmaline (Europe), and flecainide (Europe) have all demonstrated good efficacy in unmasking BrS and have become valuable tools for the diagnosis of BrS [4,5]. In addition to antiarrhythmic drugs, a wide variety of other drugs have been reported to unmask or induce the ECG and arrhythmic manifestations of BrS, including antianginals, antidepressants, antipsychotics, and antihistamines (Table 1). Postema et al. recently created a website that tracks drugs that are capable of causing adverse events in patients with BrS (www.brugadadrugs.org) [6]. BrS has been associated with mutations in 12 different genes. More than 300 mutations in SCN5A (Nav1.5, BrS1) have been reported in 11–28% of BrS probands [7–9]. Mutations in CACNA1C (Cav1.2, BrS3), CACNB2b (Cavβ2b, BrS4), and CACNA2D1 (Cavα2δ, BrS9) are found in approximately 13% of probands [10,11]. Mutations in the glycerol-3-phosphate dehydrogenase 1-like enzyme gene (GPD1L, BrS2), the β1-subunit of Na channel (SCN1B, BrS5) KCNE3 (MiRP2, BrS6), the β3-subunit of Na channel (SCN3B, BrS7) KCNJ8 (BrS8), KCND3 (BrS10), MOG1 (BrS11), and SLMAP (BrS12) are more rare [12–19]. Mutations in these neurokinin receptor antagonist lead to a loss of function in sodium channel current (INa) and calcium channel current (ICa) as well as a gain of function in the transient outward potassium current (Ito) or adenosine triphosphate (ATP)-sensitive potassium current (IK-ATP). Acquired forms of the BrS mimic some forms of the congenital syndrome by reducing INa and ICa and by augmenting Ito and IK-ATP.
    Antiarrhythmic drugs
    Antianginal drugs
    Psychotropic drugs
    Lithium Lithium is widely used to treat depression and bipolar disorder. The lithium-induced BrS phenotype is not common, but it can be observed even with use of therapeutic dosages [49]. Lithium also causes other conduction dysfunctions such as sinus node dysfunction, conduction block, and ventricular arrhythmias. Lithium has also been shown to block INa in a dose-dependent manner [50].
    Selective serotonin reuptake inhibitors Data regarding the selective serotonin reuptake inhibitor (SSRI)-induced BrS phenotype are scarce. Paroxetine and fluvoxamine have been shown to lead to a BrS pattern in the ECG via a reduction in INa[51,52].
    Anticonvulsant and antipsychotics Phenytoin is an antiepileptic agent. There are case reports of BrS caused by supratherapeutic phenytoin levels in a patient with a seizure disorder [53]. There are several reports of ECG signs of BrS in cases of hyperkalemia in conjunction with psychotropic drug overdoses, notably phenothiazines [54].
    Anesthesia Anesthetics such as propofol and bupivacaine are commonly used in clinical settings. Bupivacaine was reported to induce the BrS phenotype in silent carriers of an SCN5A mutation [55]. Another report also demonstrated a bupivacaine-induced BrS phenotype that normalized following drug withdrawal. Propofol has been reported to cause sudden cardiac death in one non-genetic and 6 unclear cases [56]. Propofol has been shown to inhibit neuronal sodium channels [57], but there are no data relative to cardiac sodium channels. It is unclear whether a genetic predisposition is present in those who display a BrS phenotype after propofol administration.