scholarly journals Functional Characterization of Two Novel Mutations in SCN5A Associated with Brugada Syndrome Identified in Italian Patients

2021 ◽  
Vol 22 (12) ◽  
pp. 6513
Author(s):  
Cristina Balla ◽  
Elena Conte ◽  
Rita Selvatici ◽  
Renè Massimiliano Marsano ◽  
Andrea Gerbino ◽  
...  
Keyword(s):  
Family History ◽  
Sudden Cardiac Death ◽  
Brugada Syndrome ◽  
Cardiac Death ◽  
Sodium Current ◽  
Functional Characterization ◽  
Loss Of Function ◽  
St Segment Elevation ◽  
History Of

Background. Brugada syndrome (BrS) is an autosomal dominantly inherited cardiac disease characterized by “coved type” ST-segment elevation in the right precordial leads, high susceptibility to ventricular arrhythmia and a family history of sudden cardiac death. The SCN5A gene, encoding for the cardiac voltage-gated sodium channel Nav1.5, accounts for ~20–30% of BrS cases and is considered clinically relevant. Methods. Here, we describe the clinical findings of two Italian families affected by BrS and provide the functional characterization of two novel SCN5A mutations, the missense variant Pro1310Leu and the in-frame insertion Gly1687_Ile1688insGlyArg. Results. Despite being clinically different, both patients have a family history of sudden cardiac death and had history of arrhythmic events. The Pro1310Leu mutation significantly reduced peak sodium current density without affecting channel membrane localization. Changes in the gating properties of expressed Pro1310Leu channel likely account for the loss-of-function phenotype. On the other hand, Gly1687_Ile1688insGlyArg channel, identified in a female patient, yielded a nearly undetectable sodium current. Following mexiletine incubation, the Gly1687_Ile1688insGlyArg channel showed detectable, albeit very small, currents and biophysical properties similar to those of the Nav1.5 wild-type channel. Conclusions. Overall, our results suggest that the degree of loss-of-function shown by the two Nav1.5 mutant channels correlates with the aggressive clinical phenotype of the two probands. This genotype-phenotype correlation is fundamental to set out appropriate therapeutical intervention.

scholarly journals Does the Age of Sudden Cardiac Death in Family Members Matter in Brugada Syndrome?

2021 ◽  
Author(s):  
Pattara Rattanawong ◽  
Jakrin Kewcharoen ◽  
Chanavuth Kanitsoraphan ◽  
Timothy Barry ◽  
Anusha Shanbhag ◽  
...  
Keyword(s):  
Family History ◽  
Sudden Cardiac Death ◽  
Brugada Syndrome ◽  
Cardiac Death ◽  
Meta Analysis ◽  
Positive Family History ◽  
Family Members ◽  
Increased Risk ◽  
History Of ◽  
Risk Predictor

Background Brugada syndrome is an inherited cardiac channelopathy associated with major arrhythmic events (MAEs). The presence of a positive family history of sudden cardiac death (SCD) as a risk predictor of MAE remains controversial. We aimed to examine the association between family history of SCD and MAEs stratified by age of SCD with a systematic review and meta‐analysis. Methods and Results We searched the databases of MEDLINE and EMBASE from January 1992 to January 2020. Data from each study were combined using the random‐effects model. Fitted metaregression was performed to evaluate the association between the age of SCD in families and the risk of MAE. Twenty‐two studies from 2004 to 2019 were included in this meta‐analysis involving 3386 patients with Brugada syndrome. The overall family history of SCD was not associated with increased risk of MAE in Brugada syndrome (pooled odds ratio [OR], 1.11; 95% CI, 0.82–1.51; P =0.489, I 2 =45.0%). However, a history of SCD in family members of age younger than 40 years of age did increase the risk of MAE by ≈2‐fold (pooled OR, 2.03; 95% CI, 1.11–3.73; P =0.022, I 2 =0.0%). When stratified by the age of cut point at 50, 45, 40, and 35 years old, a history of SCD in younger family member was significantly associated with a higher risk of MAE (pooled OR, 0.49, 1.30, 1.51, and 2.97, respectively; P =0.046). Conclusions A history of SCD among family members of age younger than 40 years was associated with a higher risk of MAE.

scholarly journals FAMILY HISTORY OF SUDDEN CARDIAC DEATH IN BRUGADA SYNDROME: A SYSTEMIC REVIEW AND META-ANALYSIS

2020 ◽  
Vol 75 (11) ◽  
pp. 459
Author(s):  
Pattara Rattanawong ◽  
Jakrin Kewcharoen ◽  
Chanavuth Kanitsoraphan ◽  
Timothy Barry ◽  
Anusha Shanbhag ◽  
...  
Keyword(s):  
Family History ◽  
Sudden Cardiac Death ◽  
Brugada Syndrome ◽  
Cardiac Death ◽  
Meta Analysis ◽  
Systemic Review ◽  
History Of

scholarly journals Diagnosis of Brugada Syndrome, a Rare Inherited Arrhythmogenic Disorder

2020 ◽  
Vol 3 (2) ◽  
pp. 70-73
Author(s):  
Juwairiya Syed Iqbaluddin ◽  
Fathima Murthuza ◽  
Sumaiya Iqbal
Keyword(s):  
Family History ◽  
Sudden Cardiac Death ◽  
Brugada Syndrome ◽  
Cardiac Death ◽  
Genetic Disorder ◽  
Positive Family History ◽  
Provocation Test ◽  
Increased Risk ◽  
History Of ◽  
Electrocardiogram Ecg

Brugada syndrome (BrS) is a rare, autosomal dominant genetic disorder with mutation in the SCN5A gene. It is associated with an increased risk of arrhythmias and sudden cardiac death. BrS can be diagnosed by characteristic electrocardiogram (ECG) findings and significant events, such as syncope, palpitations, nocturnal respiratory agonia, and family history of sudden cardiac death below the age of 45 years. Special investigations, such as electrophysiology study, ajmaline provocation test, and genetic testing, play an important role in its diagnosis. This case report describes a patient who presented with chest pain and dizziness along with a positive family history of sudden cardiac deaths below the age of 45 years. He was discovered to have type 2 Brugada pattern on ECG, and by ajmaline provocation test, the type 1 pattern was unmasked, which established a definitive diagnosis of BrS. The patient was then advised for an implantable cardioverter-defibrillator. This case highlights the need for physicians to be competent in identifying patients with BrS in order to provide the necessary management and prevent fatal outcomes.

44. Publication history of the Brugada Syndrome: Did labeling stimulate research?

2007 ◽  
Vol 30 (4) ◽  
pp. 50
Author(s):  
M. A. Nault ◽  
A. Baranchuk ◽  
C. S. Simpson ◽  
D. P. Redfearn ◽  
H. Abdollah
Keyword(s):  
Sudden Cardiac Death ◽  
Right Bundle Branch Block ◽  
Brugada Syndrome ◽  
Cardiac Death ◽  
Young Men ◽  
Bundle Branch Block ◽  
St Segment Elevation ◽  
Publication History ◽  
St Segment ◽  
History Of

Sudden cardiac death (SCD) in healthy young men was first recognized in 1917. Combined with an electrocardiographic (ECG) abnormality reported in 1953, the resulting syndrome would by 1996 eventually be recognized worldwide as Brugada Syndrome (BrS). There is evidence that “labeling” (i.e. the process of naming a disease state or ascribing a diagnosis) alters perceptions, awareness and behaviours in medicine. Our objective was to determine whether naming a cluster of signs and symptoms as a specific syndrome raised attention given to a previously recognized though poorly defined condition as evidenced through an increase in publications. We hypothesized that naming BrS resulted in such a “labeling” stimulus. A systematic review of the Pubmed database of indexed journals was performed to identify references to BrS between 1950 and 2006. Search terms were: “Brugada Syndrome”; “Sudden Cardiac Death AND Right Bundle Branch Block”; “Bangungot” (Filipino); “Bangungut” (Filipino); “Pok kuri” (Japanese); “Lai tai” (Thai); “Sudden Unexplained Death Syndrome”; and “SUNDS”. Publications identified after 1996 by search strategies other than “Brugada Syndrome” were omitted to avoid double counting. The search resulted in 1,042 citations. Of these, 208 occurred after 1996 and were omitted, leaving a total of 834 citations to be analyzed. Between 1950 and 1993 a total of 32 publications met the above search criteria. Thereafter, publication rate on this topic increased exponentially from 16 articles in 1994-1995 to 290 in 2005-2006. Though numerous articles recognized either RBBB-like ECG pattern, ST segment elevation or SCD in otherwise healthy young men, it was not until publication of the 1992 Brugada and Brugada paper that the coexistence of these two conditions was recognized as a syndrome. Rising interest, as identified by publication frequency, preceded the naming of this syndrome by 4 years. This finding suggests that factors other than labeling have also contributed to the publication history of BrS. Osher H, Wolff L. Electrocardiographic pattern simulating acute myocardial injury. Am J Med Sci 1953; 226:541-5. Brugada P, Brugada J. Right bundle branch block, persisting ST segment elevation and sudden cardiac death: A distinct clinical and electrocardiographic syndrome. J Am Coll Cardiol 1992; 20:1391-6. Yan G-X, Antzelevitch C. Cellular basis for the electrocardiographic J wave. Circulation 1996; 93:372-9.

scholarly journals Genotype-Phenotype Correlation of SCN5A Genotype in Patients With Brugada Syndrome and Arrhythmic Events: Insights From the SABRUS in 392 Probands

2021 ◽  
Author(s):  
Anat Milman ◽  
Elijah R. Behr ◽  
Belinda Gray ◽  
David C. Johnson ◽  
Antoine Andorin ◽  
...  
Keyword(s):  
Family History ◽  
Sudden Cardiac Death ◽  
Brugada Syndrome ◽  
Odds Ratio ◽  
Cardiac Death ◽  
Variants Of Unknown Significance ◽  
Increased Risk ◽  
Cardiac Sodium Channel ◽  
Arrhythmic Event ◽  
History Of

Background: Brugada syndrome (BrS) is associated with mutations in the cardiac sodium channel gene, SCN5A. However, genetic studies of patients with BrS with arrhythmic events have been limited. We sought to compare various clinical, ECG, and electrophysiological parameters according to SCN5A genotype in a large cohort of BrS probands with first arrhythmic event. Methods: Survey on Arrhythmic Events in Brugada Syndrome is a survey of 10 Western and 4 Asian countries, gathering 678 patients with BrS with first arrhythmic event. Only probands were included, and SCN5A genotype adjudicated. Patients without appropriate genetic data were excluded. Associations of genotype with clinical features were analyzed. Results: The study group comprised 392 probands: 92 (23.5%) SCN5A+ (44 pathogenic/likely pathogenic [P/LP] and 48 variants of unknown significance) and 300 (76.5%) SCN5A−. SCN5A missense variants and the patients hosting them were similar regardless of adjudication. A higher proportion of patients with P/LP were pediatric (<16 years) compared with SCN5A− (11.4% versus 3%, P =0.023). The proportion of females was higher among patients with P/LP compared with SCN5A − (18.2% versus 6.3%, P =0.013). P/LP probands were more likely to have a family history of sudden cardiac death compared with SCN5A − (41.9% versus 16.8%, P <0.001). A higher proportion of patients with P/LP were White compared with SCN5A− (87.5% versus 47%, P <0.001). Ethnicity (odds ratio, 5.41 [2.8–11.19], P <0.001) and family history of sudden cardiac death (odds ratio, 2.73 [1.28–5.82], P =0.009) were independent variables associated with P/LP genotype following logistic regression. Conclusions: The genetic basis of BrS has a complex relationship with gender, ethnicity, and age. Probands hosting a P/LP variant tended to experience their first arrhythmic event at a younger age and to have events triggered by fever compared with patients with SCN5A− . In addition, they were more likely to be White and to have family history of sudden cardiac death. Among females, a P/LP variant suggests an increased risk of being symptomatic. This association should be further studied on an ethnically specific basis in large prospectively collected international cohorts.

scholarly journals Novel SCN5A p.Val1667Asp Missense Variant Segregation and Characterization in a Family with Severe Brugada Syndrome and Multiple Sudden Deaths

2021 ◽  
Vol 22 (9) ◽  
pp. 4700
Author(s):  
Michelle M. Monasky ◽  
Emanuele Micaglio ◽  
Giuseppe Ciconte ◽  
Ilaria Rivolta ◽  
Valeria Borrelli ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Family History ◽  
Risk Stratification ◽  
Brugada Syndrome ◽  
Electrophysiological Study ◽  
Functional Characterization ◽  
The Family ◽  
Novel Variant ◽  
History Of ◽  
Scn5a Gene

Genetic testing in Brugada syndrome (BrS) is still not considered to be useful for clinical management of patients in the majority of cases, due to the current lack of understanding about the effect of specific variants. Additionally, family history of sudden death is generally not considered useful for arrhythmic risk stratification. We sought to demonstrate the usefulness of genetic testing and family history in diagnosis and risk stratification. The family history was collected for a proband who presented with a personal history of aborted cardiac arrest and in whom a novel variant in the SCN5A gene was found. Living family members underwent ajmaline testing, electrophysiological study, and genetic testing to determine genotype-phenotype segregation, if any. Patch-clamp experiments on transfected human embryonic kidney 293 cells enabled the functional characterization of the SCN5A novel variant in vitro. In this study, we provide crucial human data on the novel heterozygous variant NM_198056.2:c.5000T>A (p.Val1667Asp) in the SCN5A gene, and demonstrate its segregation with a severe form of BrS and multiple sudden deaths. Functional data revealed a loss of function of the protein affected by the variant. These results provide the first disease association with this variant and demonstrate the usefulness of genetic testing for diagnosis and risk stratification in certain patients. This study also demonstrates the usefulness of collecting the family history, which can assist in understanding the severity of the disease in certain situations and confirm the importance of the functional studies to distinguish between pathogenic mutations and harmless genetic variants.

Brugada Syndrome: Fatal Consequences of a Must-Not-Miss Diagnosis

2021 ◽  
Vol 41 (5) ◽  
pp. 15-22
Author(s):  
L. Douglas Smith ◽  
Sarah Gast ◽  
Danielle F. Guy
Keyword(s):  
At Risk ◽  
Critical Care ◽  
Sudden Cardiac Death ◽  
Ventricular Arrhythmia ◽  
Brugada Syndrome ◽  
Cardiac Death ◽  
Lifestyle Modification ◽  
Genetic Disorder ◽  
Cardiac Conduction ◽  
St Segment Elevation

Background Brugada syndrome is a genetic disorder of cardiac conduction that predisposes patients to spontaneous ventricular arrhythmia and sudden cardiac death. Although Brugada syndrome is one of the most common causes of sudden cardiac death, patients presenting with the syndrome often go misdiagnosed. This error has potentially fatal consequences for patients, who are at risk for sudden cardiac death without appropriate management. Objective To increase the critical care professional’s knowledge of Brugada syndrome through detailed description of the characteristic electrocardiographic findings, an algorithmic approach to electrocardiogram evaluation, and a case report of a patient with a previously missed diagnosis of Brugada syndrome. The essential concepts of epidemiology, pathophysiology, clinical presentation, risk stratification, and management are reviewed for critical care professionals who may encounter patients with the syndrome. Diagnosis Patients typically present with syncope or cardiac arrest and an abnormal electrocardiographic finding of ST-segment elevation in the precordial leads. The diagnosis of Brugada syndrome centers on identification of its electrocardiographic characteristics by critical care professionals who routinely evaluate electrocardiograms. Critical care professionals, especially nurses and advanced practice nurses, should be proficient in recognizing the electrocardiographic appearance of Brugada syndrome and initiating appropriate management. Interventions Management strategies include prevention of sudden cardiac death through lifestyle modification and placement of an implantable cardioverter-defibrillator. Critical care professionals should be aware of commonly used medications that may exacerbate ventricular arrhythmia and place patients at risk for sudden cardiac death. Conclusion Increased awareness of Brugada syndrome among critical care professionals can decrease patient morbidity and mortality.

Abstract 3667: Comparison of Risk Profiles between Survivors and Victims of Sudden Cardiac Death of an Acute Coronary Event

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Kari S Kaikkonen ◽  
Marja-Leena Kortelainen ◽  
Heikki V Huikuri
Keyword(s):  
Risk Factors ◽  
Family History ◽  
Sudden Cardiac Death ◽  
Cardiac Hypertrophy ◽  
Odds Ratio ◽  
Cardiac Death ◽  
Coronary Event ◽  
Acute Coronary Event ◽  
Risk Profiles ◽  
History Of

Introduction. There is little information on the specific risk factors leading to sudden cardiac death (SCD) during an acute coronary event, because the risk variables may overlap with those of non-fatal coronary event. This study was designed to compare the risk profiles of SCD victims and survivors of an acute coronary event. Methods and Results. A case-control study included consecutive victims of SCD (n=425, mean age 64±11 years) verified to be due to an acute coronary event at medicolegal autopsy and consecutive patients surviving an acute myocardial infarction (AMI, n=644, mean age 62±10 years). Common cardiovascular risk factors, cardiac hypertrophy, and severity of coronary artery disease (CAD) were assessed in both groups. Family history of SCD (odds ratio 1.5, 95% CI 1.0 to 2.2, p=0.03), male gender (odds ratio 1.8, 95% CI 1.3 to 2.4, p<0.001), current smoking (odds ratio 2.0, 95% CI 1.5 to 2.6, p<0.001), cardiac hypertrophy (odds ratio 3.0, 95% CI 2.3 to 3.9, p<0.001) and 3-vessel CAD (odds ratio 5.4, 95% CI 3.6 to 8.2, p<0.001) were more common among the victims of SCD as compared to survivors of AMI. On the contrary, history of hypercholesterolemia (p<0.001) was less common among the SCD victims. There was a cumulative increase of risk of being a SCD victim vs. AMI survivor when more than one risk factor was present, the odds ratio being 44.3 (95% CI 8.0 to 246.7) in a current male smoker with a family history of SCD and cardiac hypertrophy. When 3-vessel CAD was added to the combined risk score, all subjects (7% of the SCD victims) were in the group of SCD giving a 100% sensitivity and specificity, respectively, in differentiating between the SCD victims and AMI survivors. Conclusions. There are specific features that differentiate the victims of SCD from survivors of an acute coronary event. Clustering of several variables, such as family history of SCD, smoking, cardiac hypertrophy, and 3-vessel CAD indicate a very high risk of SCD.

P1000Aetiology and efficacy of atrial fibrillation ablation in young adults

EP Europace ◽  
2020 ◽  
Vol 22 (Supplement_1) ◽  
Author(s):  
R Zhang ◽  
I T Fazmin ◽  
A Porto ◽  
K Divulwewa ◽  
A Reddy ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Young Adults ◽  
Family History ◽  
Sudden Cardiac Death ◽  
Pulmonary Vein ◽  
Cardiac Death ◽  
Univariate Analysis ◽  
Pulmonary Vein Stenosis ◽  
Af Ablation ◽  
History Of

Abstract Introduction Little is known regarding the aetiology or outcome of atrial fibrillation (AF) occurring in young adults. This retrospective analysis was performed to explore the demographics and efficacy of AF ablation in this population. Methods Patients were included who had undergone ≥1 AF ablation under the age of 40 between 2006-2018. Recurrence was defined as return of either documented AF or previous symptoms for &gt;30s following a 3-month blanking period. Initial exploratory co-variates were included in a univariate analysis and those terms with P-value of &lt;0.1 were then used to generate a Cox proportional-hazards multivariate model. Results 124 patients (33.6 ± 4.7 yrs, 77% men), initially presenting with paroxysmal AF (pAF; n = 97) or persistent AF (n = 27), underwent 175 AF ablation procedures. 22.6% (n = 28) also had atrial flutter. Time from symptom onset to first ablation was 50.7 ± 46.2 months. Relevant cardiovascular-related demographics were analysed: hypertension in 8.9% (n = 11); diabetes in 1.6% (n = 2); positive family history of AF in 12.9% (n = 16); and family history of sudden cardiac death in 2.4% (n = 3). Mean CHA2DS2-VASc score was 0.35. Of those patients with documented echocardiogram imaging (n = 91), 26.4% (n = 24) had LA dilatation and 6.6% (n = 6) had LV dysfunction. Patients with LA dilatation underwent more ablations (2.3 ± 0.3) compared to controls (1.5 ± 0.1; p &lt; 0.001). Ablation strategy was pulmonary vein isolation (PVI) only in 67.2% (n = 119), with additional ablation in the remaining: roof line in 18.9% (n = 33); cavotricuspid isthmus line in 13.1% (n = 23); mitral isthmus line in 2.3% (n = 4); superior vena cava isolation in 2.3% (n = 4); complex fractionated atrial electrograms in 14.9% (n = 26). Mean procedure time was 155 ± 41 min, mean ablation time was 1657 ± 991 s and mean fluoroscopy time was 32.6 ± 23.4 min. General anaesthesia was used in 43.4% (n = 76). Complications included femoral haematoma (n = 2), tamponade (n = 1) and pulmonary vein stenosis (n = 2). 90 days of follow-up was available for 137 procedures performed for pAF (n = 105) and persistent AF (n = 32). For pAF, overall recurrence was 61.9% for first ablations and 62.9% overall. Recurrence was 56.3% for persistent AF. Factors significantly associated with increased AF recurrence in univariate analysis were male gender (hazard ratio (HR) 2.3, 95% confidence interval (CI): 1.2-4.4, p = 0.011), hypertension (HR 0.5, CI: 0.2-1.1, p = 0.067), family history of sudden cardiac death (HR 6.8, CI: 1.6-29.0 , p = 0.010) and enlarged LA size (HR 2.2, CI: 1.3-3.6, p = 0.003). In multivariate analysis, the only significant predictor of poor outcome was enlarged LA size (HR 2.0, 95% CI: 1.2-3.5, p = 0.011). Conclusions Young patients with AF may have structurally abnormal hearts, and therefore do not only present with lone AF. LA size may be used as a predictor for success. Surveillance imaging may be useful to detect future structural change, which will be the subject of future prospective studies. Abstract Figure. AF ablation recurrence in young adults

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