Electrocardiographic Characteristics and SCN5A Mutations in Idiopathic Ventricular Fibrillation Associated With Early Repolarization

Division of Cardiology, Niigata University School of Medicine, Niigata, Japan.
Circulation Arrhythmia and Electrophysiology (Impact Factor: 4.51). 12/2011; 4(6):874-81. DOI: 10.1161/CIRCEP.111.963983
Source: PubMed


Recently, we and others reported that early repolarization (J wave) is associated with idiopathic ventricular fibrillation. However, its clinical and genetic characteristics are unclear.
This study included 50 patients (44 men; age, 45 ± 17 years) with idiopathic ventricular fibrillation associated with early repolarization, and 250 age- and sex-matched healthy controls. All of the patients had experienced arrhythmia events, and 8 (16%) had a family history of sudden death. Ventricular fibrillation was inducible by programmed electric stimulation in 15 of 29 patients (52%). The heart rate was slower and the PR interval and QRS duration were longer in patients with idiopathic ventricular fibrillation than in controls. We identified nonsynonymous variants in SCN5A (resulting in A226D, L846R, and R367H) in 3 unrelated patients. These variants occur at residues that are highly conserved across mammals. His-ventricular interval was prolonged in all of the patients carrying an SCN5A mutation. Sodium channel blocker challenge resulted in an augmentation of early repolarization or development of ventricular fibrillation in all of 3 patients, but none was diagnosed with Brugada syndrome. In heterologous expression studies, all of the mutant channels failed to generate any currents. Immunostaining revealed a trafficking defect in A226D channels and normal trafficking in R367H and L846R channels.
We found reductions in heart rate and cardiac conduction and loss-of-function mutations in SCN5A in patients with idiopathic ventricular fibrillation associated with early repolarization. These findings support the hypothesis that decreased sodium current enhances ventricular fibrillation susceptibility.

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    • "Genetic mutations in KCNJ8 leading to a gain of function in ATPsensitive potassium channel current (I K-ATP ) [9] [10] [11] or in CACNA1C, CACNA2D1 and CACNB2 leading to a loss of function I Ca [12], or in SCN5A, leading to a loss of function of I Na [13] [14], have been shown to underlie both ERS and BrS. Here, we report, for the first time, an association of a gain of function in I K-ATP secondary to mutations in ABCC9 with ERS and BrS. "
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    ABSTRACT: Genetic defects in KCNJ8, encoding the Kir6.1 subunit of the ATP-sensitive K(+) channel (IK-ATP), have previously been associated with early repolarization (ERS) and Brugada (BrS) syndromes. Here we test the hypothesis that genetic variants in ABCC9, encoding the ATP-binding cassette transporter of IK-ATP (SUR2A), are also associated with both BrS and ERS. Direct sequencing of all ERS/BrS susceptibility genes was performed on 150 probands and family members. Whole-cell and inside-out patch-clamp methods were used to characterize mutant channels expressed in TSA201-cells. Eight ABCC9 mutations were uncovered in 11 male BrS probands. Four probands, diagnosed with ERS, carried a highly-conserved mutation, V734I-ABCC9. Functional expression of the V734I variant yielded a Mg-ATP IC50 that was 5-fold that of wild-type (WT). An 18-y/o male with global ERS inherited an SCN5A-E1784K mutation from his mother, who displayed long QT intervals, and S1402C-ABCC9 mutation from his father, who displayed an ER pattern. ABCC9-S1402C likewise caused a gain of function of IK-ATP with a shift of ATP IC50 from 8.5±2mM to 13.4±5μM (p<0.05). The SCN5A mutation reduced peak INa to 39% of WT (p<0.01), shifted steady-state inactivation by -18.0mV (p<0.01) and increased late INa from 0.14% to 2.01% of peak INa (p<0.01). Our study is the first to identify ABCC9 as a susceptibility gene for ERS and BrS. Our findings also suggest that a gain-of-function in IK-ATP when coupled with a loss-of-function in SCN5A may underlie type 3 ERS, which is associated with a severe arrhythmic phenotype.
    Full-text · Article · Jan 2014 · International journal of cardiology
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    • "Gain-of-function mutations leading to an increased late INa (INa,L) cause long QT syndrome type 3 (LQT3), whereas loss-of-function mutations resulting in a decreased peak INa may cause a variety of arrhythmogenic syndromes such as Brugada syndrome [characterized by the elevation of the ST segment in the right precordial leads of the ECG (BrS)], progressive cardiac conduction disease, sick sinus syndrome, atrial fibrillation (AF) [4], and sudden infant death syndrome [2-4]. Furthermore, loss-of-function Nav1.5 mutations have been described in patients with idiopathic ventricular fibrillation (IVF), an uncommon and lethal condition which presents itself as syncope or sudden cardiac death in young people with normal hearts and without electrophysiological manifestations of inherited arrhythmogenic syndromes [5-7]. Therefore, Nav1.5 mutations can render a broad spectrum of inherited cardiac arrhythmias. "
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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.
    Full-text · Article · Nov 2013 · PLoS ONE
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    • "In blacks (that are so rarely affected by the syndrome), SCN5A variation are common [183], and can be related to PR prolongation [184]. Mutations of SCN5A genes have been found in patients with Long and short QT Syndromes [185] [186], Early Repolarization Syndrome, Lev-Lenegre Disease, Idiopathic Ventricular Fibrillation, in dilated cardiomyopathy, in sinus node dysfunction and in atrial fibrillation [187] [188] [189]. Van Hoorn [153] reported that mutations were associated with increased cardiac dimensions and reduced contractility. "
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    ABSTRACT: The true history of the "so called" Brugada Syndrome
    Full-text · Chapter · Jan 2013
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