• 2018-07
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  • Common and rare SCN A variants may


    Common and rare SCN10A variants may contribute to AF susceptibility [59,60]. SCN10A mutations (R14L and R1268Q) cause a loss of function of Nav1.5 current, which is expected to reduce excitability and lead to the development of the arrhythmogenic substrate responsible for BrS and AF. A common variant in SCN10A (A1073) is associated with increased susceptibility to AF [60]. Genetic mutations, particularly, loss-of-function mutations and/or deletions in INa channel α-subunit (SCN5A), have been identified in patients with both BrS and AFL [37–45]. Genetic screening in the group of patients studied (n=17) with both AVNRT and drug-induced type 1 Brugada pattern identified 19 mutations or rare variants in 13 different genes in 13 of 17 patients (yield=76.5%). Ten of these 13 genotype-positive patients (76.9%) harbored genetic variants known or suspected to cause a loss of function of cardiac sodium channel current (INa) (SCN5A, SCN10A, SCN1B, GPD1L, PKP2, and HEY2) [17]. In SQTS, gain-of-function mutations in potassium channels (IKr [KCNH2], IKs [KCNQ1], and IK1 [KCNJ2]) and loss-of-function mutations in ICa,L channel α- and β-subunits (CACNA1C, CACNB2, and CACNA2D1) cause shortening of the Phenyl sulfate manufacturer duration and QT interval [55,61,62]. In CPVT, loss-of-function mutations in the gene encoding the sarcoplasmic reticulum calcium release channel (RyR2), or in genes encoding the RyR2-binding proteins, such as cardiac calsequestrin (CASQ2), triadin, and calmodulin, cause dysregulation in intracellular calcium handling [46].
    Mechanistic link between atrial arrhythmias and inherited arrhythmogenic disorders Atrial arrhythmias can be maintained by reentry (AF, AFL, and AVNRT) and/or rapid focal ectopic firing (AF) [63]. AF requires triggers (most commonly pulmonary veins) for the initiation of reentrant circuits and a vulnerable substrate that enables reentrant circuits to remain in the atria. Both triggers and the atrial substrate are modulated by electrical, structural/anatomical remodeling, and the autonomic nervous system. Prolonged intra-atrial conduction time determined by surface ECG (P-wave duration and PR interval) or intra-cardiac electrograms (time interval from the stimulus at the high right atrium to atrial deflection at the distal coronary sinus) has been demonstrated in patients with BrS with or without AF [11,12]. Signal-averaged ECG has been used to assess the vulnerability to AF [64]. The filtered P-wave duration is prolonged in patients with BrS. Atrial structural remodeling (increased left atrial volume index) assessed by transthoracic echocardiography has been also demonstrated in these patients [11]. The onset of AF is often preceded by fluctuations in autonomic tone, consistent with most AF cases occurring at night in patients with BrS [9]. Vagal stimulation reduces atrial conduction velocities and shortens the effective refractory period facilitating the induction of AF. Previous studies demonstrated the expression of SCN5A and SCN10A in intracardiac ganglia [65,66]. Therefore, genetic variants SCN5A and/or SCN10A may generate an imbalance in the intracardiac ganglia activity and increase vagal tone. Genetic variants impairing the INa channel function along with structural remodeling promote AF by prolonging refractoriness and slowing conduction velocity. Reduced levels of INa are known to depress INa-dependent parameters such as excitability and conduction leading to heterogeneous prolongation of refractoriness, thus facilitating the development of unidirectional block and reentry, giving rise to AF, AFL, and AVNRT. Loss of function of INa is also known to cause an outward shift in the balance of currents in the right ventricular epicardium. This shift can accentuate the epicardial action potential notch, thus giving rise to repolarization and depolarization abnormalities that result in the BrS phenotype, including the development of phase-2 reentry and polymorphic ventricular tachycardia [67].