A consistent arrhythmogenic trait in Brugada syndrome cellular phenotype.
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ABSTRACT:
SUBMITTER: Al Sayed ZR
PROVIDER: S-EPMC8181201 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundBrugada Syndrome (BrS) is a cardiogenetic disease known for its association with sudden cardiac death (SCD) in individuals with structurally normal hearts. The prevalence of BrS is higher in males, who also face a greater risk of SCD. Its higher prevalence and worse outcome in male subjects may be due to testosterone effects on ion channels expression and function. The influence of testosterone on cardiac action potentials, both genomically and non-genomically, underscores its potential role in unmasking the syndrome and triggering life-threatening arrhythmias. Notably, testosterone replacement therapy (TRT), used for hypogonadism and gender reassignment, has been linked to BrS unmasking. The role of epicardial ablation in symptomatic BrS patients where hormonal therapy cannot be discontinued is unknown.Methods and resultsIn this study we describe the first two cases of substrate mapping and ablation in BrS patients experiencing arrhythmic events while on TRT. In both cases, high-density epicardial mapping revealed abnormal areas of prolonged and fragmented electrograms in the right ventricular (RV) outflow tract and anterior wall. These abnormalities were completely abolished by radiofrequency ablation (RFA). After ablation, both patients showed a persistent normalization of the ECG and were free from ventricular arrhythmias at follow-up, despite ongoing TRT.ConclusionRFA can be considered as a therapeutic option in symptomatic BrS patients with a high-risk profile who cannot discontinue TRT, being essential for restoring their normal physiology or preserving their sexual identity. As testosterone use is increasing, further studies are warranted to define a standardized diagnostic and therapeutic strategy in this specific subset of BrS patients.
| S-EPMC10472325 | biostudies-literature
Project description:AimsBrugada syndrome (BrS) is associated with an increased risk of sudden cardiac death due to ventricular tachycardia/fibrillation (VT/VF) in young, otherwise healthy individuals. Despite SCN5A being the most commonly known mutated gene to date, the genotype-phenotype relationship is poorly understood and remains uncertain. This study aimed to elucidate the genotype-phenotype correlation in BrS.Methods and resultsBrugada syndrome probands deemed at high risk of future arrhythmic events underwent genetic testing and phenotype characterization by the means of epicardial arrhythmogenic substrate (AS) mapping, and were divided into two groups according to the presence or absence of SCN5A mutation. Two-hundred probands (160 males, 80%; mean age 42.6 ± 12.2 years) were included in this study. Patients harbouring SCN5A mutations exhibited a spontaneous type 1 pattern and experienced aborted cardiac arrest or spontaneous VT/VF more frequently than the other subjects. SCN5A-positive patients exhibited a larger epicardial AS area, more prolonged electrograms and more frequently observed non-invasive late potentials. The presence of an SCN5A mutation explained >26% of the variation in the epicardial AS area and was the strongest predictor of a large epicardial area.ConclusionIn BrS, the genetic background is the main determinant for the extent of the electrophysiological abnormalities. SCN5A mutation carriers exhibit more pronounced epicardial electrical abnormalities and a more aggressive clinical presentation. These results contribute to the understanding of the genetic determinants of the BrS phenotypic expression and provide possible explanations for the varying degrees of disease expression.
| S-EPMC7955973 | biostudies-literature
Project description:Brugada syndrome (BrS) is an inherited cardiac arrhythmia syndrome first described as a new clinical entity in 1992. Electrocardiographically characterized by distinct coved type ST segment elevation in the right-precordial leads, the syndrome is associated with a high risk for sudden cardiac death in young adults, and less frequently in infants and children. The electrocardiographic manifestations of BrS are often concealed and may be unmasked or aggravated by sodium channel blockers, a febrile state, vagotonic agents, as well as by tricyclic and tetracyclic antidepressants. An implantable cardioverter defibrillator is the most widely accepted approach to therapy. Pharmacologic therapy is designed to produce an inward shift in the balance of currents active during the early phases of the right ventricular action potential (AP) and can be used to abort electrical storms or as an adjunct or alternative to device therapy when use of an implantable cardioverter defibrillator is not possible. Isoproterenol, cilostazol, and milrinone boost calcium channel current and drugs like quinidine, bepridil, and the Chinese herb extract Wenxin Keli inhibit the transient outward current, acting to diminish the AP notch and thus to suppress the substrate and trigger for ventricular tachycardia or fibrillation. Radiofrequency ablation of the right ventricular outflow tract epicardium of patients with BrS has recently been shown to reduce arrhythmia vulnerability and the electrocardiographic manifestation of the disease, presumably by destroying the cells with more prominent AP notch. This review provides an overview of the clinical, genetic, molecular, and cellular aspects of BrS as well as the approach to therapy.
| S-EPMC4737702 | biostudies-literature
Project description:Ventricular fibrillation (VF) has been proposed to be maintained by localized high-frequency sources. We tested whether spectral-phase analysis of the precordial ECG enabled identification of periodic activation patterns generated by such sources.Precordial ECGs were recorded from 15 ischemic cardiomyopathy and 15 Brugada syndrome (type 1 ECG) patients during induced VF and analyzed in the frequency-phase domain. Despite temporal variability, induced VF episodes lasting 19.6±7.9 s displayed distinctly high power at a common frequency (shared frequency, 5.7±1.1 Hz) in all leads about half of the time. In patients with Brugada syndrome, phase analysis of shared frequency showed a V1-V6 sequence as would be expected from patients displaying a type 1 ECG pattern (P<0.001). Hilbert-based phases confirmed that the most stable sequence over the whole VF duration was V1-V6. Analysis of shared frequency in ischemic cardiomyopathy patients with anteroseptal (n=4), apical (n=3), and inferolateral (n=4) myocardial infarction displayed a sequence starting at V1-V2, V3-V4, and V5-V6, respectively, consistent with an activation origin at the scar location (P=0.005). Sequences correlated with the Hilbert-based phase analysis (P<0.001). Posterior infarction (n=4) displayed no specific sequence. On paired comparison, phase sequences during monomorphic ventricular tachycardia correlated moderately with VF (P<0.001). Moreover, there was a dominant frequency gradient from precordial leads facing the scar region to the contralateral leads (5.8±0.8 versus 5.4±1.1 Hz; P=0.004).Noninvasive analysis of ventricular tachycardia and early VF in patients with Brugada syndrome and ischemic cardiomyopathy shows a predictable sequence in the frequency-phase domain, consistent with anatomic location of the arrhythmogenic substrate.
| S-EPMC4608487 | biostudies-literature
Project description:Brugada syndrome (BrS) is an arrhythmogenic disorder that has been linked to mutations in SCN5A, the gene encoding for the pore-forming ?-subunit of the cardiac sodium channel. Typically, BrS mutations in SCN5A result in a reduction of sodium current with some mutations even exhibiting a dominant-negative effect on wild-type (WT) channels, thus leading to an even more prominent decrease in current amplitudes. However, there is also a category of apparently benign (atypical) BrS SCN5A mutations that in vitro demonstrates only minor biophysical defects. It is therefore not clear how these mutations produce a BrS phenotype. We hypothesized that similar to dominant-negative mutations, atypical mutations could lead to a reduction in sodium currents when coexpressed with WT to mimic the heterozygous patient genotype.WT and atypical BrS mutations were coexpressed in Human Embryonic Kidney-293 cells, showing a reduction in sodium current densities similar to typical BrS mutations. Importantly, this reduction in sodium current was also seen when the atypical mutations were expressed in rat or human cardiomyocytes. This decrease in current density was the result of reduced surface expression of both mutant and WT channels.Taken together, we have shown how apparently benign SCN5A BrS mutations can lead to the ECG abnormalities seen in patients with BrS through an induced defect that is only present when the mutations are coexpressed with WT channels. Our work has implications for risk management and stratification for some SCN5A-implicated BrS patients.
| S-EPMC3989843 | biostudies-literature
Project description:A novel clinical entity characterized by ST segment elevation in right precordial leads (V1 to V3), incomplete or complete right bundle branch block, and susceptibility to ventricular tachyarrhythmia and sudden cardiac death has been described by Brugada et al. in 1992. This disease is now frequently called "Brugada syndrome" (BrS). The prevalence of BrS in the general population is unknown. The suggested prevalence ranges from 5/1,000 (Caucasians) to 14/1,000 (Japanese). Syncope, typically occurring at rest or during sleep (in individuals in their third or fourth decades of life) is a common presentation of BrS. In some cases, tachycardia does not terminate spontaneously and it may degenerate into ventricular fibrillation and lead to sudden death. Both sporadic and familial cases have been reported and pedigree analysis suggests an autosomal dominant pattern of inheritance. In approximately 20% of the cases BrS is caused by mutations in the SCN5A gene on chromosome 3p21-23, encoding the cardiac sodium channel, a protein involved in the control of myocardial excitability. Since the use of the implantable cardioverter defibrillator (ICD) is the only therapeutic option of proven efficacy for primary and secondary prophylaxis of cardiac arrest, the identification of high-risk subjects is one of the major goals in the clinical decision-making process. Quinidine may be regarded as an adjunctive therapy for patients at higher risk and may reduce the number of cases of ICD shock in patients with multiple recurrences.
| S-EPMC1592481 | biostudies-literature
Project description:BackgroundThe use of next-generation sequencing enables a rapid analysis of many genes associated with sudden cardiac death in diseases like Brugada Syndrome. Genetic variation is identified and associated with 30-35% of cases of Brugada Syndrome, with nearly 20-25% attributable to variants in SCN5A, meaning many cases remain undiagnosed genetically. To evaluate the role of genetic variants in arrhythmogenic diseases and the utility of next-generation sequencing, we applied this technology to resequence 28 main genes associated with arrhythmogenic disorders.Materials and methodsA cohort of 45 clinically diagnosed Brugada Syndrome patients classified as SCN5A-negative was analyzed using next generation sequencing. Twenty-eight genes were resequenced: AKAP9, ANK2, CACNA1C, CACNB2, CASQ2, CAV3, DSC2, DSG2, DSP, GPD1L, HCN4, JUP, KCNE1, KCNE2, KCNE3, KCNH2, KCNJ2, KCNJ5, KCNQ1, NOS1AP, PKP2, RYR2, SCN1B, SCN3B, SCN4B, SCN5A, SNTA1, and TMEM43. A total of 85 clinically evaluated relatives were also genetically analyzed to ascertain familial segregation.Results and discussionTwenty-two patients carried 30 rare genetic variants in 12 genes, only 4 of which were previously associated with Brugada Syndrome. Neither insertion/deletion nor copy number variation were detected. We identified genetic variants in novel candidate genes potentially associated to Brugada Syndrome. These include: 4 genetic variations in AKAP9 including a de novo genetic variation in 3 positive cases; 5 genetic variations in ANK2 detected in 4 cases; variations in KCNJ2 together with CASQ2 in 1 case; genetic variations in RYR2, including a de novo genetic variation and desmosomal proteins encoding genes including DSG2, DSP and JUP, detected in 3 of the cases. Larger gene panels or whole exome sequencing should be considered to identify novel genes associated to Brugada Syndrome. However, application of approaches such as whole exome sequencing would difficult the interpretation for clinical purposes due to the large amount of data generated. The identification of these genetic variants opens new perspectives on the implications of genetic background in the arrhythmogenic substrate for research purposes.ConclusionsAs a paradigm for other arrhythmogenic diseases and for unexplained sudden death, our data show that clinical genetic diagnosis is justified in a family perspective for confirmation of genetic causality. In the era of personalized medicine using high-throughput tools, clinical decision-making is increasingly complex.
| S-EPMC4521779 | biostudies-literature
Project description:Plakophilin-2 (PKP2) is the most frequently mutated desmosomal gene in arrhythmogenic cardiomyopathy (ACM), a disease characterized by structural and electrical alterations predominantly affecting the right ventricular myocardium. Notably, ACM cases without overt structural alterations are frequently reported, mainly in the early phases of the disease. Recently, the PKP2 p.S183N mutation was found in a patient affected by Brugada syndrome (BS), an inherited arrhythmic channelopathy most commonly caused by sodium channel gene mutations. We here describe a case of a patient carrier of the same BS-related PKP2 p.S183N mutation but with a clear diagnosis of ACM. Specifically, we report how clinical and molecular investigations can be integrated for diagnostic purposes, distinguishing between ACM and BS, which are increasingly recognized as syndromes with clinical and genetic overlaps. This observation is fundamentally relevant in redefining the role of genetics in the approach to the arrhythmic patient, progressing beyond the concept of "one mutation, one disease", and raising concerns about the most appropriate approach to patients affected by structural/electrical cardiomyopathy. The merging of genetics, electroanatomical mapping, and tissue and cell characterization summarized in our patient seems to be the most complete diagnostic algorithm, favoring a reliable diagnosis.
| S-EPMC7288341 | biostudies-literature
Project description: Not available
| S-EPMC7454489 | biostudies-literature
Project description:BACKGROUND:Brugada syndrome (BrS) is a highly arrhythmogenic cardiac disorder, associated with an increased incidence of sudden death. Its arrhythmogenic substrate in the intact human heart remains ill-defined. METHODS AND RESULTS:Using noninvasive ECG imaging, we studied 25 BrS patients to characterize the electrophysiological substrate and 6 patients with right bundle-branch block for comparison. Seven healthy subjects provided control data. Abnormal substrate was observed exclusively in the right ventricular outflow tract with the following properties (in comparison with healthy controls; P<0.005): (1) ST-segment elevation and inverted T wave of unipolar electrograms (2.21±0.67 versus 0 mV); (2) delayed right ventricular outflow tract activation (82±18 versus 37±11 ms); (3) low-amplitude (0.47±0.16 versus 3.74±1.60 mV) and fractionated electrograms, suggesting slow discontinuous conduction; (4) prolonged recovery time (381±30 versus 311±34 ms) and activation-recovery intervals (318±32 versus 241±27 ms), indicating delayed repolarization; (5) steep repolarization gradients (?recovery time/?x=96±28 versus 7±6 ms/cm, ?activation-recovery interval/?x=105±24 versus 7±5 ms/cm) at right ventricular outflow tract borders. With increased heart rate in 6 BrS patients, reduced ST-segment elevation and increased fractionation were observed. Unlike BrS, right bundle-branch block had delayed activation in the entire right ventricle, without ST-segment elevation, fractionation, or repolarization abnormalities on electrograms. CONCLUSIONS:The results indicate that both slow discontinuous conduction and steep dispersion of repolarization are present in the right ventricular outflow tract of BrS patients. ECG imaging could differentiate between BrS and right bundle-branch block.
| S-EPMC4452400 | biostudies-literature