Abstract 16997: Reaffirmation of GPD1L-A280V as a Brugada Syndrome Disease-Causing Variant

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Alexander Greiner ◽  
Haider Mehdi ◽  
Chloe Cevan ◽  
Rebecca A Gutmann ◽  
Barry London
Keyword(s):  
Brugada Syndrome ◽  
Snp Array ◽  
Pcr Amplification ◽  
St Segment Elevation ◽  
Linkage Region ◽  
Risk Alleles ◽  
Risk Snps ◽  
Glycerol 3 Phosphate Dehydrogenase ◽  
The Right

Introduction: Brugada Syndrome (BrS) is an inherited arrhythmia syndrome characterized by ST-segment elevation in the right precordial leads (V1-V3) and sudden cardiac death; ~20% of cases are caused by mutations in SCN5A . Over the past two decades, over 20 genes that may cause BrS have been identified. We reported that a Glycerol-3-Phosphate Dehydrogenase 1-Like mutation (GPD1L;p.A280V, chromosome 3p22.3) was linked to BrS in a large, multigenerational family with a LOD score ~4. Recent efforts in the field have called into question the pathogenicity of non- SCN5A genetic variants in BrS. Hypothesis: We sought to confirm the role of GPD1L in this family using a high density SNP array to narrow the linkage region and whole exome sequencing (WES) of the proband to rule out other possible mutations. We also sought to test whether BrS susceptibility SNPs in SCN5A and SCN10A linked to GPD1L may play a role in this family. Methods: SNPs were identified on an Illumina Global Screening Array and used for fine mapping. The exome of the proband was captured with the Agilent V6+UTR kit. SNPs were called using GATK3. BrS susceptibility SNPs were confirmed by PCR amplification and Sanger Sequencing. Results: The linkage region in this family resolved to ~3.07 MB (hg19; 3:29,899,567-32,970,637; Figure). This region contained 14 genes including GPD1L , and lacking SCN5A , SCN10A , or any other BrS-associated gene. WES identified GPD1L;p.A280V as the only coding variant in the linkage region with an allele frequency ≤ 1%. Previously identified BrS risk alleles in SCN5A and SCN10A were linked to the GPD1L;p.A280V allele in most family members (Figure). Conclusions: Our data suggests that GPD1L;p.A280V causes BrS in this family. The pathogenicity of GPD1L;p.A280V may be increased by linkage with SCN5A and SCN10A risk SNPs. The role of GPD1L mutations in the pathogenesis of BrS should be reaffirmed.

scholarly journals Sudden Cause of Cardiac Death—Be Aware of Me: A Case Report and Short Review on Brugada Syndrome

2010 ◽  
Vol 2010 ◽  
pp. 1-3 ◽  
Author(s):  
Jagadeesh K. Kalavakunta ◽  
Vishwaroop Bantu ◽  
Hemasri Tokala ◽  
Mihas Kodenchery
Keyword(s):  
Brugada Syndrome ◽  
Past History ◽  
Short Review ◽  
Case Presentation ◽  
St Segment Elevation ◽  
First Case ◽  
St Segment ◽  
The Right ◽  
Malignant Arrhythmias

Introduction. Brugada syndrome accounts for about 4% of sudden cardiac deaths (SCD). It is characterized by an ST-segment elevation in the right precordial electrocardiogram (EKG) leads.Case Presentation. We describe a 39-year-old healthy Caucasian man who was admitted to the intensive care unit after being cardioverted from ventricular fibrillation (VF) arrest. His past history was significant for an episode of syncope one month prior to this presentation for which he was admitted to an outlying hospital. EKG during that admission showed ST elevations in V1 and V2 leads, a pattern similar to Type 1 Brugada. A diagnosis of Brugada syndrome was missed and the patient had a cardiac arrest a month later. We discuss a short review of Brugada syndrome and emphasize the need to look for it in patients presenting with SCD and malignant arrhythmias.Conclusion. Physicians should always consider Brugada syndrome in the differential diagnosis of ST-segment elevation in anterior precordial leads of EKG and associated VT/VF. Although more than 17 years have passed since the first case was reported, increased awareness of this syndrome is needed to identify patients with EKG changes and treat them accordingly to prevent incidence of (SCD) and its deleterious complications.

scholarly journals Electrocardiographic Effects of Propofol versus Etomidate in Patients with Brugada Syndrome

2020 ◽  
Vol 132 (3) ◽  
pp. 440-451 ◽  
Author(s):  
Panagiotis Flamée ◽  
Varnavas Varnavas ◽  
Wendy Dewals ◽  
Hugo Carvalho ◽  
Wilfried Cools ◽  
...  
Keyword(s):  
Brugada Syndrome ◽  
St Segment Elevation ◽  
St Depression ◽  
St Segment ◽  
Qrs Prolongation ◽  
Significant Difference ◽  
Electrocardiographic Changes ◽  
St Elevation ◽  
The Right ◽  
Double Blinded

Abstract Background Brugada Syndrome is an inherited arrhythmogenic disease, characterized by the typical coved type ST-segment elevation in the right precordial leads from V1 through V3. The BrugadaDrugs.org Advisory Board recommends avoiding administration of propofol in patients with Brugada Syndrome. Since prospective studies are lacking, it was the purpose of this study to assess the electrocardiographic effects of propofol and etomidate on the ST- and QRS-segments. In this trial, it was hypothesized that administration of propofol or etomidate in bolus for induction of anesthesia, in patients with Brugada Syndrome, do not clinically affect the ST- and QRS-segments and do not induce arrhythmias. Methods In this prospective, double-blinded trial, 98 patients with established Brugada syndrome were randomized to receive propofol (2 to 3 mg/kg-1) or etomidate (0.2 to 0.3 mg/kg-1) for induction of anesthesia. The primary endpoints were the changes of the ST- and QRS-segment, and the occurrence of new arrhythmias upon induction of anesthesia. Results The analysis included 80 patients: 43 were administered propofol and 37 etomidate. None of the patients had a ST elevation greater than or equal to 0.2 mV, one in each group had a ST elevation of 0.15 mV. An ST depression up to −0.15mV was observed eleven times with propofol and five with etomidate. A QRS-prolongation of 25% upon induction was seen in one patient with propofol and three with etomidate. This trial failed to establish any evidence to suggest that changes in either group differed, with most percentiles being zero (median [25th, 75th], 0 [0, 0] vs. 0 [0, 0]). Finally, no new arrhythmias occurred perioperatively in both groups. Conclusions In this trial, there does not appear to be a significant difference in electrocardiographic changes in patients with Brugada syndrome when propofol versus etomidate were administered for induction of anesthesia. This study did not investigate electrocardiographic changes related to propofol used as an infusion for maintenance of anesthesia, so future studies would be warranted before conclusions about safety of propofol infusions in patients with Brugada syndrome can be determined. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

scholarly journals Experimental Models of Brugada syndrome

2019 ◽  
Vol 20 (9) ◽  
pp. 2123 ◽  
Author(s):  
Sendfeld ◽  
Selga ◽  
Scornik ◽  
Pérez ◽  
Mills ◽  
...  
Keyword(s):  
Brugada Syndrome ◽  
Experimental Models ◽  
Model Systems ◽  
Patient Specific ◽  
Canine Heart ◽  
Stem Cell Technology ◽  
St Segment Elevation ◽  
St Segment ◽  
Cardiac Sodium Channel ◽  
The Right

Brugada syndrome is an inherited, rare cardiac arrhythmogenic disease, associated with sudden cardiac death. It accounts for up to 20% of sudden deaths in patients without structural cardiac abnormalities. The majority of mutations involve the cardiac sodium channel gene SCN5A and give rise to classical abnormal electrocardiogram with ST segment elevation in the right precordial leads V1 to V3 and a predisposition to ventricular fibrillation. The pathophysiological mechanisms of Brugada syndrome have been investigated using model systems including transgenic mice, canine heart preparations, and expression systems to study different SCN5A mutations. These models have a number of limitations. The recent development of pluripotent stem cell technology creates an opportunity to study cardiomyocytes derived from patients and healthy individuals. To date, only a few studies have been done using Brugada syndrome patient-specific iPS-CM, which have provided novel insights into the mechanisms and pathophysiology of Brugada syndrome. This review provides an evaluation of the strengths and limitations of each of these model systems and summarizes the key mechanisms that have been identified to date.

scholarly journals Pregnancy May Affect the Attenuation of an ST Segment Elevation in the Right Precordial Leads: A Female Patient with Brugada Syndrome

2019 ◽  
Vol 58 (21) ◽  
pp. 3099-3102
Author(s):  
Akihito Ideishi ◽  
Masahiro Ogawa ◽  
Yoshihisa Nagata ◽  
Yoshiaki Idemoto ◽  
Tomo Komaki ◽  
...  
Keyword(s):  
Female Patient ◽  
Brugada Syndrome ◽  
St Segment Elevation ◽  
St Segment ◽  
The Right

scholarly journals Brugada syndrome: Case report

2012 ◽  
Vol 140 (1-2) ◽  
pp. 84-90
Author(s):  
Vesna Bisenic ◽  
Sasa Hinic ◽  
Mirjana Krotin ◽  
Branislav Milovanovic ◽  
Jelena Saric ◽  
...  
Keyword(s):  
Family History ◽  
Sudden Death ◽  
Brugada Syndrome ◽  
Troponin T ◽  
Stable Condition ◽  
St Segment Elevation ◽  
St Segment ◽  
History Of ◽  
The Right

Introduction. Brugada syndrome is an arrhythmogenic disease characterized by coved ST segment elevation and J point elevation of at least 2 mm in at least two of the right precordial ECG leads (V1-3) and ventricular arrhythmias, syncope, and sudden death. Risk stratifications of patients with Brugada electrocardiogram are being strongly debated. Case Outline. A 23-year-old man was admitted to the Coronary Care Unit of the Clinical Centre ?Bezanijska kosa? due to weakness, fatigue and chest discomfort. The patient suffered from fainting and palpitations. There was a family history of paternal sudden death at 36 years. Electrocardiogram showed a coved ST segment elevation of 4 mm in leads V1 and V2, recognised as spontaneous type 1 Brugada pattern. Laboratory investigations revealed normal serum cardiac troponin T and serum potassium, and absence of inflammation signs. Echocardiographic finding was normal, except for a mild enlargement of the right atrium and ventricle. The diagnosis of Brugada syndrome was made by Brugada-type 1 electrocardiogram and the family history of sudden death <45 years. The patient was considered as a high risk, because of pre-syncope and palpitations. He underwent ICD implantation (Medtronic MaximoVR7232Cx) using the standard procedure. After implantation, noninvasive electrophysiology study was done and demonstrated inducible VF that was interrupted with the second 35 J DC shock. The patient was discharged in stable condition with beta-blocker therapy. After a year of pacemaker check-ups, there were no either VT/ VF events or ICD therapy. Conclusion. Clinical presentation is the most important parameter in risk stratification of patients with Brugada electrocardiogram and Brugada syndrome.

Abstract 4413: Accelerated Inactivation of the L-type Calcium due to a Mutation in CACNB2b Underlies the Development of a Brugada ECG Phenotype

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Jonathan M Cordeiro ◽  
Mark Marieb ◽  
Ryan Pfeiffer ◽  
Kirstine Calloe ◽  
Elena Burashnikov ◽  
...  
Keyword(s):  
Action Potential ◽  
Calcium Channel ◽  
Brugada Syndrome ◽  
Vasovagal Syncope ◽  
Total Charge ◽  
Loss Of Function ◽  
St Segment Elevation ◽  
St Segment ◽  
Steady State Inactivation ◽  
The Right

Background: Ion channelopathies are responsible for a number of genetic cardiac arrhythmia syndromes. Recent work demonstrated an association between mutations in CACNA1c and CACNB2b, the genes that encode the α and β subunits of the L-type calcium channel, and the Brugada syndrome (BrS). The mutations previously described all caused a loss of function secondary to a major reduction in peak calcium channel current (I Ca ). In the present study we describe a novel CACNB2b mutation associated with BrS in which loss of function was caused by accelerated inactivation of I Ca . Methods and Results: The proband, a 32 yo male, displayed a saddleback ST segment elevation in the right precordial leads that converted to a coved-type ECG following a procainamide challenge. His EP study was positive with double extrastimuli inducing polymorphic VT/VF. He was also diagnosed with vasovagal syncope. Genomic DNA was isolated from blood lymphocytes. All exons and intron borders of 12 ion channel genes were amplified and sequenced. The only mutation uncovered was a missense mutation (T11I) in CACNB2b. The effect of this mutation was studied by expression of WT or T11I CACNB2b in TSA201 cells co-transfected with WT CANCA1c and CACNA2d. Patch clamp analysis showed no difference in I Ca density between WT and T11I (17.9±1.8 vs 22.5±4.3 pA/pF, respectively at +20mV). Similarly, steady-state inactivation and channel recovery was not different between WT and T11I mutant channels. However, both the fast and slow decay of I Ca produced by T11I mutant were significantly faster compared to WT at potentials between −10 to +30 mV, suggesting a reduction in depolarizing current during the course of an action potential. Application of action potential voltage clamp pulses confirmed that T11I total charge was reduced by 42±2.3% compared to WT (p<0.05). Conclusion: We report the first Brugada syndrome mutation in CaCNB2b resulting in accelerated inactivation of the L-type calcium channel. The T11I mutation caused a faster decay of cardiac L-type calcium current but did not significantly alter the magnitude of the peak current. Our results suggest that a reduced total charge carried by I Ca during the plateau of the action potential predisposes to the Brugada phenotype.

scholarly journals Role of electrocardiogram in diagnosis of inherited arrhythmia syndromes

2020 ◽  
Vol 71 (2) ◽  
pp. 1-7
Author(s):  
Ružica Jurčević ◽  
Lazar Angelkov ◽  
Dejan Vukajlović ◽  
Velibor Ristić ◽  
Dejan Kojić ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Torsades De Pointes ◽  
Pathogenic Mutation ◽  
Polymorphic Ventricular Tachycardia ◽  
Early Repolarization ◽  
St Segment Elevation ◽  
St Segment ◽  
Qt Syndrome ◽  
The Right

The aim of this paper is to define the role of electrocardiogram (ECG) in diagnosis, prognosis and treatment of inherited arrhythmias syndromes. Brugada Syndrome diagnosis is established in presence of coved type ST-segment elevation (type 1) ≥ 2mm in ≥ 1 of the right precordial leads V1 to V2. Long QT Syndrome is diagnosed when one of factors is present: QTc ≥ 480 ms, QTc ≥ 460 ms in patients with unexplained syncope, pathogenic mutation or risk score > 3. Polymorphic ventricular tachycardia (VT) Torsades de Pointes have specific presentation in ECG with characteristic illusion of the QRS complex twisting around the isoelectric baseline. The early repolarization pattern in patients resuscitated from otherwise unexplained ventricular fibrillation (VF)/polymorphic VT or in a sudden cardiac death (SCD) victims makes diagnosis of Early Repolarization Syndrome. Short QT Syndrome is diagnosed in the presence of a QTc ≤ 340 ms or QTc < 360 ms with one or more of the following factors: a pathogenic mutation, survival of a VT/VF episodes, family history of this disease and SCD in family at age ≤ 40. Catecholaminergic Polymorphic Ventricular Tachycardia has ECG appearance of bidirectional VT or polymorphic ventricular premature beats or VT induced by exercise or catecholamine.

scholarly journals Role of Catheter Ablation for Ventricular Arrhythmias in Brugada Syndrome

2021 ◽  
Vol 23 (5) ◽  
Author(s):  
Ronpichai Chokesuwattanaskul ◽  
Koonlawee Nademanee
Keyword(s):  
Catheter Ablation ◽  
Brugada Syndrome ◽  
Ventricular Arrhythmias ◽  
Structural Heart Disease ◽  
Therapeutic Modalities ◽  
Good Target ◽  
Arrhythmogenic Substrate ◽  
Life Threatening ◽  
The Right

Abstract Purpose of Review To discuss the role of catheter ablation in treating life-threatening ventricular arrhythmias associated with Brugada syndrome (BrS), by presenting recent findings of BrS arrhythmogenic substrate, mechanisms underlying ventricular arrhythmias, and how they can be treated with catheter ablation. Recent Findings Almost three decades ago when the clinical entity of Brugada syndrome (BrS) was described in patients who had abnormal coved-type ST elevation in the right precordial EKG leads in patients who had no apparent structural heart disease but died suddenly from ventricular fibrillation. Since its description, the syndrome has galvanized explosive research in this field over the past decades, driving major progress toward better understanding of BrS, gaining knowledge of the genetic pathophysiology and risk stratification of BrS, and creating significant advances in therapeutic modalities. One of such advances is the ability for electrophysiologists to map and identify the arrhythmogenic substrate sites of BrS, which serve as good target sites for catheter ablation. Subsequently, several studies have shown that catheter ablation of these substrates normalizes the Brugada ECG pattern and is very effective in eliminating these substrates and preventing recurrent VF episodes. Summary Catheter ablation has become an important addition for treatment of symptomatic BrS patients with recurrent VT/VF episodes.

scholarly journals Brugada-Like Electrocardiographic Patterns Induced by Hyperkalemia

Medicina ◽  
2013 ◽  
Vol 49 (3) ◽  
pp. 24 ◽  
Author(s):  
Dagmara Reingardienė ◽  
Jolita Vilčinskaitė ◽  
Diana Bilskienė
Keyword(s):  
Brugada Syndrome ◽  
Structural Heart Disease ◽  
Electrolyte Disorders ◽  
St Segment Elevation ◽  
Wave Inversion ◽  
St Segment ◽  
Acute Renal Insufficiency ◽  
Channel Mutation ◽  
The Right ◽  
Ecg Abnormalities

Brugada syndrome was described in 1992 as a new clinical and electrocardiographic syndrome involving susceptibility to ventricular arrhythmias and sudden cardiac death in patients with no obvious structural heart disease. Brugada syndrome is characterized by a hereditary anomaly in the sodium ion channel (mutation of the SCN5A gene) identified by a wide QRS associated with the ST-segment elevation and the T‑wave inversion in the right precordial leads. The Brugada-like electrocardiographic pattern can be caused by sodium channel-blocking drugs and electrolyte disorders. Hyperkalemia may produce multiple ECG abnormalities, including the ST-segment elevation and pseudomyocardial infarction with a resolution of these abnormalities after the correction of hyperkalemia. This article describes 8 cases of pseudoanteroseptal myocardial infarction in acute renal insufficiency with hyperkalemia. The ST-segment elevation related to hyperkalemia is resolved by the reduced serum potassium level. Clinicians should recognize that hyperkalemia is one of the etiologies of the Brugada-like electrocardiographic pattern.

scholarly journals Clinical and Molecular Data Define a Diagnosis of Arrhythmogenic Cardiomyopathy in a Carrier of a Brugada-Syndrome-Associated PKP2 Mutation

Genes ◽  
2020 ◽  
Vol 11 (5) ◽  
pp. 571
Author(s):  
Simone Persampieri ◽  
Chiara Assunta Pilato ◽  
Elena Sommariva ◽  
Angela Serena Maione ◽  
Ilaria Stadiotti ◽  
...  
Keyword(s):  
Brugada Syndrome ◽  
Gene Mutations ◽  
Diagnostic Algorithm ◽  
Ventricular Myocardium ◽  
Molecular Data ◽  
Arrhythmogenic Cardiomyopathy ◽  
Plakophilin 2 ◽  
The Right ◽  
Early Phases

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.

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