Article

High Risk for Bradyarrhythmic Complications in Patients With Brugada Syndrome Caused by SCN5A Gene Mutations

Showa University, Shinagawa, Tōkyō, Japan
Journal of the American College of Cardiology (Impact Factor: 15.34). 01/2006; 46(11):2100-6. DOI: 10.1016/j.jacc.2005.08.043
Source: PubMed

ABSTRACT We carried out a complete screening of the SCN5A gene in 38 Japanese patients with Brugada syndrome to investigate the genotype-phenotype relationship.
The gene SCN5A encodes the pore-forming alpha-subunit of voltage-gated cardiac sodium (Na) channel, which plays an important role in heart excitation/contraction. Mutations of SCN5A have been identified in 15% of patients with Brugada syndrome.
In 38 unrelated patients with clinically diagnosed Brugada syndrome, we screened for SCN5A gene mutations using denaturing high-performance liquid chromatography and direct sequencing, and conducted a functional assay for identified mutations using whole-cell patch-clamp in heterologous expression system.
Four heterozygous mutations were identified (T187I, D356N, K1578fs/52, and R1623X) in 4 of the 38 patients. All of them had bradyarrhythmic complications: three with sick sinus syndrome (SSS) and the other (D356N) with paroxysmal complete atrioventricular block. SCN5A-linked Brugada patients were associated with a higher incidence of bradyarrhythmia (4 of 4) than non-SCN5A-linked Brugada patients (2 of 34). Families with T187I and K1578fs/52 had widespread penetrance of SSS. Notably, the patient with K1578fs/52, who had been diagnosed as having familial SSS without any clinical signs of Brugada syndrome, showed a Brugada-type ST-segment elevation after intravenous administration of pilsicainide and programmed electrical stimulation-induced ventricular tachycardia. All of the mutations encoded non-functional Na channels, and thus were suggested to cause impulse propagation defect underlying bradyarrhythmias.
Our findings suggest that loss-of-function SCN5A mutations resulting in Brugada syndrome are distinguished by profound bradyarrhythmias.

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Available from: Minoru Horie, Dec 16, 2013
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    • "This hypothesis could seem counterintuitive since pacemaker activity in sinus nodal cells is mainly regulated by Ca2+ and K+ channels. However, bradyarrhythmic complications have been associated with other Nav1.5 loss-of-function mutations [24,25]. Indeed, it has been described that Nav1.5 channels are distributed in the periphery of the sinus node [26], and thus, it is possible that a functional defect of Nav1.5 channel activity would lead to reduced impulse propagation from the sinoatrial node to the surrounding atrial muscle and, thus, to a decrease in heart rhythm [24,25]. "
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    ABSTRACT: We functionally analyzed a frameshift mutation in the SCN5A gene encoding cardiac Na(+) channels (Nav1.5) found in a proband with repeated episodes of ventricular fibrillation who presented bradycardia and paroxysmal atrial fibrillation. Seven relatives also carry the mutation and showed a Brugada syndrome with an incomplete and variable expression. The mutation (p.D1816VfsX7) resulted in a severe truncation (201 residues) of the Nav1.5 C-terminus. Wild-type (WT) and mutated Nav1.5 channels together with hNavβ1 were expressed in CHO cells and currents were recorded at room temperature using the whole-cell patch-clamp. Expression of p.D1816VfsX7 alone resulted in a marked reduction (≈90%) in peak Na(+) current density compared with WT channels. Peak current density generated by p.D1816VfsX7+WT was ≈50% of that generated by WT channels. p.D1816VfsX7 positively shifted activation and inactivation curves, leading to a significant reduction of the window current. The mutation accelerated current activation and reactivation kinetics and increased the fraction of channels developing slow inactivation with prolonged depolarizations. However, late INa was not modified by the mutation. p.D1816VfsX7 produced a marked reduction of channel trafficking toward the membrane that was not restored by decreasing incubation temperature during cell culture or by incubation with 300 μM mexiletine and 5 mM 4-phenylbutirate. Despite a severe truncation of the C-terminus, the resulting mutated channels generate currents, albeit with reduced amplitude and altered biophysical properties, confirming the key role of the C-terminal domain in the expression and function of the cardiac Na(+) channel.
    PLoS ONE 11/2013; 8(11):e81493. DOI:10.1371/journal.pone.0081493 · 3.23 Impact Factor
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    • "All of them had bradyarrhythmic complications including three with SND and one with paroxysmal complete atrioventricular block. None of these probands had additional SCN5A mutations, suggesting that this type of " loss of function " overlap syndrome (BS plus SND/atrioventricular block) may result from a single SCN5A mutation [9]. Morita et al. have shown that sinus node function is impaired in patients with Brugada ECG pattern and inducible ventricular fibrillation at EPS compared with those without inducible arrhythmias. "
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    ABSTRACT: BACKGROUND: The spectrum of phenotypes related to mutations of the SCN5A gene include Brugada syndrome (BS), long QT syndrome, progressive cardiac conduction defect, and sinus node disease (SND). The present study investigated the incidence of SND in subjects with type 1 electrocardiogram (ECG) pattern of BS. METHODS AND RESULTS: The study population consisted of 68 individuals (55 males, mean age 44.8±12.8 years) with spontaneous (n=27) or drug-induced (n=41) type 1 ECG pattern of BS. Twenty-eight subjects were symptomatic with a history of syncope (41.2%). SND was observed in 6 symptomatic subjects (8.8%), and was mainly attributed to sino-atrial block with sinus pauses. Two patients were initially diagnosed with SND, and received a pacemaker. Patients with SND displayed an increased P-wave duration in leads II and V2, PR interval in leads II and V2, QRS duration in leads II and V2, and increased QTc interval in lead V2 (p<0.05). AH and HV intervals as well as corrected sinus node recovery time (cSNRT) were significantly prolonged in subjects with SND (p<0.05). During a mean follow-up period of 5.0±3.6 years, five subjects with a history of syncope suffered appropriate implantable cardioverter defibrillator (ICD) discharges due to ventricular arrhythmias (7.4%). None of those diagnosed with SND suffered syncope or ICD therapies. CONCLUSION: SND is not an uncommon finding in subjects with type 1 ECG pattern of BS. The occurrence of SND in relatively young patients may deserve meticulous investigation including sodium channel blocking test.
    Journal of Cardiology 02/2013; 61(3-4). DOI:10.1016/j.jjcc.2012.12.006 · 2.57 Impact Factor
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    • "Voltage-gated Na + channels are responsible for generating the main current for excitation propagation in the membrane of most excitable cells, such as cardiomyocytes and neurons [32] [33]. Cardiac Na + channel changes have been implicated in the increased risk of sudden death in heart failure [34] [35] [36]. In our previous studies on the mechanism by which mutations in glycerol-3-phosphate dehydrogenase 1 like (GPD1L) protein cause reduced I Na and Brugada Syndrome, we have shown that increased cytosolic NADH can downregulate the cardiac Na + channel through PKC activation and mitochondrial ROS overproduction [9] [10]. "
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    ABSTRACT: Cardiomyopathy is associated with cardiac Na(+) channel downregulation that may contribute to arrhythmias. Previously, we have shown that elevated intracellular NADH causes a decrease in cardiac Na(+) current (I(Na)) signaled by an increase in mitochondrial reactive oxygen species (ROS). In this study, we tested whether the NADH-mitochondria ROS pathway was involved in the reduction of I(Na) in a nonischemic cardiomyopathic model and correlated the findings with myopathic human hearts. Nonischemic cardiomyopathy was induced in C57BL/6 mice by hypertension after unilateral nephrectomy, deoxycorticosterone acetate (DOCA) pellet implantation, and salt-water substitution. Sham operated mice were used as controls. After six weeks, heart tissue and ventricular myocytes isolated from mice were utilized for whole-cell patch clamp recording, NADH/NAD(+) level measurements, and mitochondrial ROS monitoring with confocal microscopy. Human explanted hearts were studied using optical mapping. Compared to the sham mice, the arterial blood pressure was higher, the left ventricular volume was significantly enlarged (104.7±3.9 vs. 87.9±6.1 μL, P<0.05), and the ejection fraction was reduced (37.1±1.8% vs. 49.4±3.7%, P<0.05) in DOCA mice. Both the whole cell and cytosolic NADH level were increased (279±70% and 123±2% of sham, respectively, P<0.01), I(Na) was decreased (60±10% of sham, P<0.01), and mitochondrial ROS overproduction was observed (2.9±0.3-fold of sham, P<0.01) in heart tissue and myocytes of myopathic mice vs. sham. Treatment of myocytes with NAD(+) (500μM), mitoTEMPO (10μM), chelerythrine (50μM), or forskolin (5μM) restored I(Na) back to the level of sham. Injection of NAD(+) (100mg/kg) or mitoTEMPO (0.7mg/kg) twice (at 24h and 1h before myocyte isolation) to animals also restored I(Na). All treatments simultaneously reduced mitochondrial ROS levels to that of controls. CD38 was found to transduce the extracellular NAD(+) signal. Correlating with the mouse model, failing human hearts showed a reduction in conduction velocity that improved with NAD(+). Nonischemic cardiomyopathy was associated with elevated NADH level, PKC activation, mitochondrial ROS overproduction, and a concomitant decrease in I(Na). Reducing mitochondrial ROS by application of NAD(+), mitoTEMPO, PKC inhibitors, or PKA activators, restored I(Na). NAD(+) improved conduction velocity in human myopathic hearts.
    Journal of Molecular and Cellular Cardiology 10/2012; 54. DOI:10.1016/j.yjmcc.2012.10.011 · 5.22 Impact Factor
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