scholarly journals The Mechanism of Ajmaline and Thus Brugada Syndrome: Not Only the Sodium Channel!

2021 ◽  
Vol 8 ◽  
Author(s):  
Michelle M. Monasky ◽  
Emanuele Micaglio ◽  
Sara D'Imperio ◽  
Carlo Pappone
Keyword(s):  
Sodium Channel ◽  
Brugada Syndrome ◽  
Rare Variants ◽  
Sodium Current ◽  
Gene Mutations ◽  
Calcium Currents ◽  
Sodium Channel Blocker ◽  
Sodium Potassium ◽  
Genetics Research

Ajmaline is an anti-arrhythmic drug that is used to unmask the type-1 Brugada syndrome (BrS) electrocardiogram pattern to diagnose the syndrome. Thus, the disease is defined at its core as a particular response to this or other drugs. Ajmaline is usually described as a sodium-channel blocker, and most research into the mechanism of BrS has centered around this idea that the sodium channel is somehow impaired in BrS, and thus the genetics research has placed much emphasis on sodium channel gene mutations, especially the gene SCN5A, to the point that it has even been suggested that only the SCN5A gene should be screened in BrS patients. However, pathogenic rare variants in SCN5A are identified in only 20–30% of cases, and recent data indicates that SCN5A variants are actually, in many cases, prognostic rather than diagnostic, resulting in a more severe phenotype. Furthermore, the misconception by some that ajmaline only influences the sodium current is flawed, in that ajmaline actually acts additionally on potassium and calcium currents, as well as mitochondria and metabolic pathways. Clinical studies have implicated several candidate genes in BrS, encoding not only for sodium, potassium, and calcium channel proteins, but also for signaling-related, scaffolding-related, sarcomeric, and mitochondrial proteins. Thus, these proteins, as well as any proteins that act upon them, could prove absolutely relevant in the mechanism of BrS.

scholarly journals Left Axis Deviation in Brugada Syndrome: Vectorcardiographic Evaluation during Ajmaline Provocation Testing Reveals Additional Depolarization Abnormalities

2021 ◽  
Vol 22 (2) ◽  
pp. 484
Author(s):  
Martijn H. van der Ree ◽  
Jeroen Vendrik ◽  
Jan A. Kors ◽  
Ahmad S. Amin ◽  
Arthur A. M. Wilde ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Brugada Syndrome ◽  
Right Ventricular Outflow Tract ◽  
Ventricular Outflow Tract ◽  
Conduction Delay ◽  
Channel Blockers ◽  
Axis Deviation ◽  
Provocation Testing ◽  
The Right

Patients with Brugada syndrome (BrS) can show a leftward deviation of the frontal QRS-axis upon provocation with sodium channel blockers. The cause of this axis change is unclear. In this study, we aimed to determine (1) the prevalence of this left axis deviation and (2) to evaluate its cause, using the insights that could be derived from vectorcardiograms. Hence, from a large cohort of patients who underwent ajmaline provocation testing (n = 1430), we selected patients in whom a type-1 BrS-ECG was evoked (n = 345). Depolarization and repolarization parameters were analyzed for reconstructed vectorcardiograms and were compared between patients with and without a >30° leftward axis shift. We found (1) that the prevalence of a left axis deviation during provocation testing was 18% and (2) that this left axis deviation was not explained by terminal conduction slowing in the right ventricular outflow tract (4th QRS-loop quartile: +17 ± 14 ms versus +13 ± 15 ms, nonsignificant) but was associated with a more proximal conduction slowing (1st QRS-loop quartile: +12[8;18] ms versus +8[4;12] ms, p < 0.001 and 3rd QRS-loop quartile: +12 ± 10 ms versus +5 ± 7 ms, p < 0.001). There was no important heterogeneity of the action potential morphology (no difference in the ventricular gradient), but a left axis deviation did result in a discordant repolarization (spatial QRS-T angle: 122[59;147]° versus 44[25;91]°, p < 0.001). Thus, although the development of the type-1 BrS-ECG is characterized by a terminal conduction delay in the right ventricle, BrS-patients with a left axis deviation upon sodium channel blocker provocation have an additional proximal conduction slowing, which is associated with a subsequent discordant repolarization. Whether this has implications for risk stratification is still undetermined.

scholarly journals B-PO04-024 PREDICTION OF A POSITIVE SODIUM CHANNEL BLOCKER PROVOCATION TEST IN PATIENTS SUSPECTED OF BRUGADA SYNDROME

Heart Rhythm ◽  
2021 ◽  
Vol 18 (8) ◽  
pp. S289
Author(s):  
Martijn Hendrik van der Ree ◽  
Jeroen Vendrik ◽  
Tom E. Verstraelen ◽  
Jan A. Kors ◽  
Ahmad S. Amin ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Brugada Syndrome ◽  
Channel Blocker ◽  
Provocation Test ◽  
Sodium Channel Blocker

Sodium channel kinetic changes that produce Brugada syndrome or progressive cardiac conduction system disease

2007 ◽  
Vol 292 (1) ◽  
pp. H399-H407 ◽  
Author(s):  
Zhu-Shan Zhang ◽  
Joseph Tranquillo ◽  
Valentina Neplioueva ◽  
Nenad Bursac ◽  
Augustus O. Grant
Keyword(s):  
Action Potential ◽  
Sodium Channel ◽  
Brugada Syndrome ◽  
Sodium Current ◽  
Conduction System ◽  
Cardiac Conduction ◽  
Cardiac Conduction System ◽  
Wild Type ◽  
System Disease ◽  
Conduction System Disease

Some mutations of the sodium channel gene NaV1.5 are multifunctional, causing combinations of LQTS, Brugada syndrome and progressive cardiac conduction system disease (PCCD). The combination of Brugada syndrome and PCCD is uncommon, although they both result from a reduction in the sodium current. We hypothesize that slow conduction is sufficient to cause S-T segment elevation and undertook a combined experimental and theoretical study to determine whether conduction slowing alone can produce the Brugada phenotype. Deletion of lysine 1479 in one of two positively charged clusters in the III/IV inter-domain linker causes both syndromes. We have examined the functional effects of this mutation using heterologous expression of the wild-type and mutant sodium channel in HEK-293-EBNA cells. We show that ΔK1479 shifts the potential of half-activation, V1/2m, to more positive potentials ( V1/2m = −36.8 ± 0.8 and −24.5 ± 1.3 mV for the wild-type and ΔK1479 mutant respectively, n = 11, 10). The depolarizing shift increases the extent of depolarization required for activation. The potential of half-inactivation, V1/2h, is also shifted to more positive potentials ( V1/2h = −85 ± 1.1 and −79.4 ± 1.2 mV for wild-type and ΔK1479 mutant respectively), increasing the fraction of channels available for activation. These shifts are quantitatively the same as a mutation that produces PCCD only, G514C. We incorporated experimentally derived parameters into a model of the cardiac action potential and its propagation in a one dimensional cable (simulating endo-, mid-myocardial and epicardial regions). The simulations show that action potential and ECG changes consistent with Brugada syndrome may result from conduction slowing alone; marked repolarization heterogeneity is not required. The findings also suggest how Brugada syndrome and PCCD which both result from loss of sodium channel function are sometimes present alone and at other times in combination.

Abstract 5317: Identification and Characterization of a Novel Susceptibility Gene, SCN3B, for Idiopathic Ventricular Fibrillation

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Carmen R Valdivia ◽  
Argelia Mereidos-Domingo ◽  
Thimothy J Algiers ◽  
Michael J Ackerman ◽  
Jonathan C Makielski
Keyword(s):  
Ventricular Fibrillation ◽  
Sodium Channel ◽  
Brugada Syndrome ◽  
Mutational Analysis ◽  
Sodium Current ◽  
Susceptibility Gene ◽  
Site Directed Mutagenesis ◽  
Macromolecular Complex ◽  
Patch Clamp Technique ◽  
Idiopathic Ventricular Fibrillation

Background: Mutations in the Na V 1.5 sodium channel macromolecular complex have been identified in some cases classified as idiopathic ventricular fibrillation (IVF). IVF and Brugada syndrome (BrS) are partially overlapping syndromes. Here, we report a mutation in SCN3B- encoded sodium channel β3 subunit as a novel pathogenic mechanism for IVF. Methods: Comprehensive open reading frame mutational analysis of SCN5A, GPD1L, and the beta subunit genes ( SCN1–4B ) was performed using PCR, DHPLC, and direct DNA sequencing of DNA extracted from a 20-year-old patient diagnosed with IVF. The SCN3B mutation was made by site directed mutagenesis and co-transfected with SCN5A into HEK-293 cells for functional chraracterization using the patch clamp technique. Results: A novel missense mutation, V54G-SCN3B, was identified in a 20-year-old male following collapse and external defibrillation from VF. After recovery, there was no detectable electrocardiographic abnormality. Imaging studies demonstrated a structurally normal heart, and the patient was diagnosed with IVF. The mutation was absent in 800 reference alleles and involved a highly conserved residue in the extracellular domain of the beta 3 subunit. No other mutations were identified in the 5 other genes. HEK cells expressing SCN5A and either WT-, or V54G-SCN3B were studied 24 hours after transfection. Cells expressing V54G-SCN3B showed significant decrease in sodium current density of 60±20 pA/pF compared to 203±35 pA/pF in WT-SCN3B (n=14–19). In addition V54G-SCN3B significantly shifted the activation curve +5 mV without affecting inactivation. Conclusions: This study provides the first molecular and cellular evidence implicating SCN3B in IVF. Given the marked loss-of-function to the sodium channel by V54G-SCN3B and the overlap between IVF and BrS, it will be interesting to determine whether mutations in SCN3B explain some cases of genotype negative Brugada syndrome.

scholarly journals Sodium-channel blocker challenge in the familial screening of Brugada syndrome: Safety and predictors of positivity

Heart Rhythm ◽  
2017 ◽  
Vol 14 (10) ◽  
pp. 1442-1448 ◽  
Author(s):  
Dylan Therasse ◽  
Frederic Sacher ◽  
Bertrand Petit ◽  
Dominique Babuty ◽  
Philippe Mabo ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Brugada Syndrome ◽  
Channel Blocker ◽  
Sodium Channel Blocker ◽  
Familial Screening

scholarly journals Ventricular arrhythmia induced by sodium channel blocker in patients with Brugada syndrome

2003 ◽  
Vol 42 (9) ◽  
pp. 1624-1631 ◽  
Author(s):  
Hiroshi Morita ◽  
Shiho Takenaka Morita ◽  
Satoshi Nagase ◽  
Kimikazu Banba ◽  
Nobuhiro Nishii ◽  
...  
Keyword(s):  
Ventricular Arrhythmia ◽  
Sodium Channel ◽  
Brugada Syndrome ◽  
Channel Blocker ◽  
Sodium Channel Blocker

Value of the sodium-channel blocker challenge in Brugada syndrome

2017 ◽  
Vol 245 ◽  
pp. 178-180 ◽  
Author(s):  
Dylan Therasse ◽  
Frederic Sacher ◽  
Dominique Babuty ◽  
Philippe Mabo ◽  
Jacques Mansourati ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Brugada Syndrome ◽  
Channel Blocker ◽  
Sodium Channel Blocker

scholarly journals Brugada Syndrome was Uncovered with a Sodium Channel Blocker

2014 ◽  
Vol 5 (1) ◽  
pp. 17-20
Author(s):  
Serafettin Demir ◽  
Mucahit Tufenk ◽  
Vedat Davutoglu ◽  
Mehmet Kanadasi ◽  
Zeynep Karakaya
Keyword(s):  
Sodium Channel ◽  
Brugada Syndrome ◽  
Channel Blocker ◽  
Sodium Channel Blocker

Abstract 1832: Location of Making Type 1 Electrocardiogram in Brugada Syndrome: Comparison between Lead Position and Anatomical Location of Right Ventricular Outflow Tract

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Satoshi Nagase ◽  
Shigeki Hiramatsu ◽  
Nobuhiro Nishii ◽  
Masato Murakami ◽  
Takeshi Tada ◽  
...  
Keyword(s):  
Brugada Syndrome ◽  
Channel Blocker ◽  
Right Ventricular Outflow Tract ◽  
Ventricular Outflow Tract ◽  
Anatomical Location ◽  
Sodium Channel Blocker ◽  
Fluoroscopic Image ◽  
Ecg Leads ◽  
The Relationship

Introduction: Recording type 1 ECG in right precordial leads in the presence or absence of a sodium channel blocker is a diagnostic criterion in Brugada syndrome (BrS). It was also suggested that right ventricular outflow tract (RVOT) is the arrhythmogenic substrate in BrS. However, we occasionally observed type 1 ECG only in the third intercostal space (3ics), not standard fourth intercostal space (4ics). Accordingly, we examined the relationship between the position of ECG leads manifesting type 1 and anatomical location of RVOT under fluoroscopic image. Methods: Total 33 BrS patients were examined in this study. All patients had more than one of the following: documented ventricular fibrillation (VF), several episodes of syncope, a family history of sudden death, SCN5A mutation or inducibility of VF by programmed electrical stimulation. Anatomical location of the RVOT was determined under fluoroscopic image with right ventriculography. ECG was also recorded at the 3ics in leads V1 and V2 in addition to the standard V1 and V2 at the 4ics with fluoroscopically visible electrodes. A pure sodium channel blocker, pilsicainide, was administered in all patients without manifesting type 1 ECG under baseline conditions. Relationships between anatomical location and the position of ECG leads manifesting type 1 were examined in all patients. Results: Type 1 ECG was recorded in all patients with pilsicainide administration. The location of RVOT corresponded with lead V1 and V2 at the 4ics in 5 patients and at the 3ics in 28 patients. In 4 out of 5 patients (80.0%) corresponding RVOT with 4ics, type 1 ECG was recorded at the 4ics. However, in 24 out of 28 patients (85.7%) corresponding RVOT with 3ics, type 1 ECG was recorded only at the 3ics. Furthermore, in 7 out of 12 symptomatic patients (58.3%) with documented VF or syncope, type 1 ECG was not recorded at the 4ics, however, could be detected at the 3ics without pilsicainide administration. The location of RVOT was not different between symptomatic and asymptomatic patients. Conclusions: Type 1 ECG is predominantly caused at the RVOT, and the relationship between the position of ECG lead and the RVOT is variable. Recording ECG at the 3ics in addition to the standard 4ics in the right precordial leads is convincing in diagnosis of BrS.

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