Incessant atrial and ventricular tachycardias associated with an SCN5A mutation.
Ontology highlight
ABSTRACT:
SUBMITTER: Papagiannis J
PROVIDER: S-EPMC8695285 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Objective: Voltage-gated sodium channel Nav1.5 encoded by the SCN5A gene plays crucial roles in cardiac electrophysiology. Previous genetic studies have shown that mutations in SCN5A are associated with multiple inherited cardiac arrhythmias. Here, we investigated the molecular defect in a Chinese boy with clinical manifestations of arrhythmias. Methods: Gene variations were screened using whole-exome sequencing and validated by direct Sanger sequencing. A minigene assay and reverse transcription PCR (RT-PCR) were performed to confirm the effects of splice variants in vitro. Western blot analysis was carried out to determine whether the c.2262+3A>T variant produced a truncated protein. Results: By genetic analysis, we identified a novel splice variant c.2262+3A>T in SCN5A gene in a Chinese boy with incessant ventricular tachycardias (VT). This variant was predicted to activate a new cryptic splice donor site and was identified by in silico analysis. The variant retained 79 bp at the 5' end of intron 14 in the mature mRNA. Furthermore, the mutant transcript that created a premature stop codon at 818 amino acids [p.(R818*)] could be produced as a truncated protein. Conclusion: We verified the pathogenic effect of splicing variant c.2262+3A>T, which disturbed the normal mRNA splicing and caused a truncated protein, suggesting that splice variants play an important role in the molecular basis of early onset incessant ventricular tachycardias, and careful molecular profiling of these patients will be essential for future effective personalized treatment options.
| S-EPMC8371685 | biostudies-literature
Project description:Mutations in SCN5A, which encodes the cardiac sodium channel NaV1.5, typically cause ventricular arrhythmia or conduction slowing. Recently, SCN5A mutations have been associated with heart failure combined with variable atrial and ventricular arrhythmia.The purpose of this study was to determine the clinical, genetic, and functional features of an amiodarone-responsive multifocal ventricular ectopy-related cardiomyopathy associated with a novel mutation in a NaV1.5 voltage sensor domain.A novel, de novo SCN5A mutation (NaV1.5-R225P) was identified in a boy with prenatal arrhythmia and impaired cardiac contractility followed by postnatal multifocal ventricular ectopy suppressible by amiodarone. We investigated the functional consequences of NaV1.5-R225P expressed heterologously in tsA201 cells.Mutant channels exhibited significant abnormalities in both activation and inactivation leading to large, hyperpolarized window and ramp currents that predict aberrant sodium influx at potentials near the cardiomyocyte resting membrane potential. Mutant channels also exhibited significantly increased persistent (late) sodium current. This profile of channel dysfunction shares features with other SCN5A voltage sensor mutations associated with cardiomyopathy and overlapped that of congenital long QT syndrome. Amiodarone stabilized fast inactivation, suppressed persistent sodium current, and caused frequency-dependent inhibition of channel availability.We determined the functional consequences and pharmacologic responses of a novel SCN5A mutation associated with an arrhythmia-associated cardiomyopathy. Comparisons with other cardiomyopathy-associated NaV1.5 voltage sensor mutations revealed a pattern of abnormal voltage dependence of activation as a shared biophysical mechanism of the syndrome.
| S-EPMC4108519 | biostudies-literature
Project description:INTRODUCTION:Atrial fibrillation (AF) ablation patients often manifest atrial tachycardias (AT) with atypical ECG morphologies that preclude accurate localization and mechanism. Diagnostic maneuvers used to define ATs during electrophysiology studies can be limited by tachycardia termination or transformation. Additional methods of characterizing post-AF ablation ATs are required. METHODS AND RESULTS:We evaluated the utility of noninvasive ECG signal analytics in postablation AF patients for the following features: (1) Localization of ATs (i.e., right vs. left atrium), and (2) Identification of common left AT mechanisms (i.e., focal vs. macroreentrant). Atrial waveforms from the surface ECG were used to analyze (1) spectral organization, including dominant amplitude (DA) and mean spectral profile (MP), and (2) temporospatial variability, using temporospatial correlation coefficients. We studied 94 ATs in 71 patients who had undergone prior pulmonary vein isolation for AF and returned for a second ablation: (1) right atrial cavotricuspid-isthmus dependent (CTI) ATs (n = 21); (2) left atrial macroreentrant ATs (n = 41) and focal ATs (n = 32). Right CTI ATs manifested higher DAs and lower MPs than left ATs, indicative of greater stability and less complexity in the frequency spectrum. Left macroreentrant ATs possessed higher temporospatial organization than left focal ATs. CONCLUSIONS:Noninvasively recorded atrial waveform signal analyses show that right ATs possess more stable activation properties than left ATs, and left macroreentrant ATs manifest higher temporospatial organization than left focal ATs. Further prospective analyses evaluating the role these novel ECG-derived tools can play to help localize and identify mechanisms of common ATs in AF ablation patients are warranted.
| S-EPMC4733590 | biostudies-literature
Project description:Sudden cardiac death is hypothesized to be one of the leading causes of mortality in peripartum cardiomyopathy. This case illustrates a patient who presented with cardiac arrest, and it discusses the importance of considering multiple causes of fulminant ventricular arrhythmias in the setting of decreased left ventricular function during the peripartum period. (Level of Difficulty: Advanced.).
| S-EPMC9270586 | biostudies-literature
Project description:Transgenic expression of SCN5A mutation N1325S creates a mouse model for type-3 long QT syndrome (LQT3), TG-NS/LQT3. Optical mapping is a high temporal and spatial resolution fluorescence mapping system that records 256 action potentials simultaneously in a Langendorff-perfused heart. Here for the first-time, we provide a spatial view of VT in a genetic LQT3 model using optical mapping. Spontaneous VT was detected in TG-NS/LQT3 hearts, but not in littermate control hearts. VT was initiated primarily by activation of a new firing focus as well as functional conduction block of new activation waves. New firing was initiated at many different Loci in the heart, suggesting that "increased automaticity" is a key mechanism for initiation of VT. The sustained VT was maintained by a reentry mechanism. Nifedipine, an L-type calcium channel blocker, decreased the frequency of VT, indicating the involvement of abnormalities of the calcium homeostasis in the genesis of VT in TG-NS/LQT3 mice.
| S-EPMC2699586 | biostudies-literature
Project description:BACKGROUND:Inherited autosomal dominant mutations in cardiac sodium channels (NaV1.5) cause various arrhythmias, such as long QT syndrome and Brugada syndrome. Although dozens of mutations throughout the protein have been reported, there are few reported mutations within a voltage sensor S4 transmembrane segment and few that are homozygous. Here we report analysis of a novel lidocaine-sensitive recessive mutation, p.R1309H, in the NaV1.5 DIII/S4 voltage sensor in a patient with a complex arrhythmia syndrome. METHODS AND RESULTS:We expressed the wild type or mutant NaV1.5 heterologously for analysis with the patch-clamp and voltage clamp fluorometry (VCF) techniques. p.R1309H depolarized the voltage-dependence of activation, hyperpolarized the voltage-dependence of inactivation, and slowed recovery from inactivation, thereby reducing the channel availability at physiologic membrane potentials. Additionally, p.R1309H increased the "late" Na(+) current. The location of the mutation in DIIIS4 prompted testing for a gating pore current. We observed an inward current at hyperpolarizing voltages that likely exacerbates the loss-of-function defects at resting membrane potentials. Lidocaine reduced the gating pore current. CONCLUSIONS:The p.R1309H homozygous NaV1.5 mutation conferred both gain-of-function and loss-of-function effects on NaV1.5 channel activity. Reduction of a mutation-induced gating pore current by lidocaine suggested a therapeutic mechanism.
| S-EPMC4789166 | biostudies-literature
Project description:BackgroundVentricular arrhythmia in left ventricular assist device (LVAD) recipients represents a challenging clinical scenario and the optimal treatment strategy in this unique patient population still needs to be defined.Case summaryWe report on a 61-year-old LVAD patient with incessant ventricular fibrillation (VF) despite multiple unsuccessful attempts to restore normal rhythm with external defibrillation and antiarrhythmic medication. He remained initially stable as an outpatient and subsequently developed secondary organ failure.DiscussionThis case demonstrates that under LVAD support long-term haemodynamic stability is possible even in case of VF, a situation that resembles Fontan circulation. However, ventricular arrhythmias are associated with a high risk of secondary organ damage due to right heart failure if left untreated. In case of refractory ventricular tachycardia or electrical storm listing for heart transplantation with high priority status should be pursued when possible. Alternatively, catheter ablation may be considered in selected cases and be performed in experienced centres in close collaboration with all involved specialists.
| S-EPMC8453423 | biostudies-literature
Project description:The N(1325)S mutation in the cardiac sodium channel gene SCN5A causes the type-3 long-QT syndrome but the arrhythmogenic trigger associated with N(1325)S has not been characterized. In this study, we investigated the triggers for cardiac events in the expanded N(1325)S family. Among 11 symptomatic patients with document triggers, six died suddenly during sleep or while sitting (bradycardia-induced trigger), three died suddenly, and two developed syncope due to stress and excitement (non-bradycardia-induced). Patch-clamping studies revealed that the late sodium current (I(Na,L)) generated by mutation N(1325)S in ventricular myocytes from TG-NS/LQT3 mice was reduced with increased pacing, which explains bradycardia-induced mortalities in the family. The non-bradycardic triggers are related to the finding that APD became prolonged and unstable at increasing rates, often with alternating repolarization phases which was corrected with verapamil. This implies that Ca2+ influx and intracellular Ca2+ ([Ca2+]i) ions are involved and that [Ca2+]i inhomogeneity may be the underlying mechanisms behind non-bradycardia LQT3 arrhythmogenesis associated with mutation N(1325)S.
| S-EPMC1773013 | biostudies-literature
Project description:Ryanodine receptor (RyR2) is the major Ca(2+) channel of the cardiac sarcoplasmic reticulum (SR) and plays a crucial role in the generation of myocardial force. Changes in RyR2 gating properties and resulting increases in its open probability (Po) are associated with Ca(2+) leakage from the SR and arrhythmias; however, the effects of RyR2 dysfunction on myocardial contractility are unknown. Here, we investigated the possibility that a RyR2 mutation associated with catecholaminergic polymorphic ventricular tachycardia, R4496C, affects the contractile function of atrial and ventricular myocardium. We measured isometric twitch tension in left ventricular and atrial trabeculae from wild-type mice and heterozygous transgenic mice carrying the R4496C RyR2 mutation and found that twitch force was comparable under baseline conditions (30°C, 2 mM [Ca(2+)]o, 1 Hz). However, the positive inotropic responses to high stimulation frequency, 0.1 µM isoproterenol, and 5 mM [Ca(2+)]o were decreased in R4496C trabeculae, as was post-rest potentiation. We investigated the mechanisms underlying inotropic insufficiency in R4496C muscles in single ventricular myocytes. Under baseline conditions, the amplitude of the Ca(2+) transient was normal, despite the reduced SR Ca(2+) content. Under inotropic challenge, however, R4496C myocytes were unable to boost the amplitude of Ca(2+) transients because they are incapable of properly increasing the amount of Ca(2+) stored in the SR because of a larger SR Ca(2+) leakage. Recovery of force in response to premature stimuli was faster in R4496C myocardium, despite the unchanged rates of recovery of L-type Ca(2+) channel current (ICa-L) and SR Ca(2+) content in single myocytes. A faster recovery from inactivation of the mutant R4496C channels could explain this behavior. In conclusion, changes in RyR2 channel gating associated with the R4496C mutation could be directly responsible for the alterations in both ventricular and atrial contractility. The increased RyR2 Po and fractional Ca(2+) release from the SR induced by the R4496C mutation preserves baseline contractility despite a slight decrease in SR Ca(2+) content, but cannot compensate for the inability to increase SR Ca(2+) content during inotropic challenge.
| S-EPMC4692489 | biostudies-literature
Project description:BackgroundAutomaticity is the dominant mechanism in maternal focal atrial tachycardia (FAT) during pregnancy and if incessant, can cause tachycardia-induced cardiomyopathy. Medication failure for FATs is common, however, for the subgroup due to increased automaticity ivabradine sensitivity has been described and may represent a valuable treatment option. Little data are available regarding the safety profile of ivabradine during pregnancy.Case summaryWe report the case of a 38-year-old woman with background of peripartum cardiomyopathy and incessant atrial tachycardia with deteriorating ventricular function during her second pregnancy unresponsive to betablockade and demonstrating the immediate successful rate-controlling effect of ivabradine.DiscussionEarly recognition of persistent maternal FAT is essential due to its frequent association with tachycardia-mediated cardiomyopathy. Our case report highlights the challenges of providing an equally safe and effective treatment of these notoriously difficult to treat arrhythmias during pregnancy. Ivabradine in combination with a betablocker can be effective for abnormal automaticity but its safety profile during pregnancy remains uncertain.
| S-EPMC8497877 | biostudies-literature