Coved-type ST-segment Elevation Research Articles

Brugada syndrome, early repolarization syndrome/j-wave syndromes, and a subtype of idiopathic ventricular fibrillation: microstructural cardiomyopathies

Brugada Syndrome is an inherited cardiac channelopathy with a high incidence of ventricular fibrillation and sudden cardiac death in patients with structurally normal hearts. Diagnosis is based on a characteristic electrocardiographic pattern (coved type ST-segment elevation ≥2 mm followed by a negative T-wave in ≥1 in the right precordial leads V1-V2) combined with an absence of gross structural abnormalities and several other criteria. The cornerstone of BrS diagnosis and definition, is its characteristic ECG pattern that can be present spontaneously or unmasked by drugs. This entity was described by the Brugada brothers in 1992 and belongs to a group of diseases known as inherited primary arrhythmia syndromes. The prevalence varies among regions and ethnicities, affecting mostly males. Despite several genes identified, SCN5A seems to be the most affected gene related BrS (≈ 30% of patients). The current main therapy is an implantable cardioverter-defibrillator, but radiofrequency catheter ablation has been recently reported as an effective new treatment.

Brugada Syndrome: Focus for the General Pediatrician.

Brugada Syndrome is an "inherited" channelopathy characterized by a predisposition to syncope and sudden death. It typically presents in young adults but is also known to affect the pediatric population, even if the prevalence is low compared to the adult population. The diagnostic ECG pattern shows coved-type ST-segment elevation in the right precordial leads, occurring spontaneously or after provocative drug tests with IV administration of Class I antiarrhythmic drugs. However, the electrocardiographic findings may vary, and transient or concealed forms of the syndrome further complicate diagnosis, necessitating thorough evaluation and close clinical follow-up. The clinical presentation of Brugada Syndrome may range from asymptomatic individuals to patients who have experienced syncope or sudden cardiac arrest. The syndrome remains underdiagnosed due to its elusive symptoms and the absence of abnormal findings between episodes. Additionally, specific triggers such as fever, certain medications and alcohol consumption may unmask the electrocardiographic changes and provoke arrhythmias in susceptible individuals. Given its elusive nature, early diagnosis and risk stratification are crucial in identifying individuals who may benefit from an implantable cardioverter defibrillator, the mainstay of treatment for high-risk patients, or pharmacological interventions.

Population-specific and cross-ancestry genome-wide association study identifies shared genetic architecture and 6 new risk loci including CAMK2D associated for Brugada syndrome

Abstract Introduction The Brugada syndrome (BrS) is an inherited arrhythmia characterized by coved-type ST-segment elevation in the right precordial leads and an increased risk for sudden cardiac death. Genome-wide association studies (GWAS) of BrS, mainly performed in European ancestry, have illustrated its complex genetic architecture as an polygenic disease besides a monogenic trait due to mutations in the major responsible cardiac sodium channel gene SCN5A. Clinical manifestations of BrS including the disease prevalence and the incidence of sudden death are known to be variable between Asian and European populations, however, its underlying mechanisms are largely unknown. Objectives We aimed to identify novel BrS-associated loci and to assess ancestry-dependent genetic heterogeneity that may underlie the variable clinical manifestations of BrS patients across different populations. Methods We performed a genome-wide meta-analysis of BrS in the Japanese ancestry (940 cases and 1,634 controls), followed by a cross-ancestry meta-analysis of Japanese and European GWAS (total of 3,760 cases and 11,635 controls) to identify novel risk loci and compared the allelic effects between two ancestries. We characterized the novel loci based on fine-mapping of potential causal variants, and expression and splicing quantitative trait associations using the Genotype-Tissue Expression (GTEx) database. Results The Japanese-specific genome-wide meta-analysis identified a novel association signal near the ZSCAN20 (lead variant, rs2336244; P=1.0E-08) besides previously reported 4 association signals at the SCN5A-SCN10A and HEY2 loci. Cross-ancestry genome-wide meta-analysis identified 17 association signals including 6 novel loci. The effect directions were consistent for 94.1% of the variants (16 of 17; P for sign test = 0.00027) and their allelic effects were highly correlated across ancestries (Pearson’s R=0.91 [P=2.9E-07]). The genetic risk score (GRS) derived from European-ancestry GWAS of BrS was significantly associated with the risk of BrS in the Japanese populations (odds ratio, 2.12 [95% confidence interval, 1.94–2.31]; P=1.2E-61), suggesting the shared genetic architecture across ancestries. The functional characterization of the 6 novel loci showed that one lead SNP on CAMK2D promotes an alternative splicing resulting in an isoform switch of calmodulin kinase II that favors up-regulation of the pro-inflammatory isoform δ9 and down-regulation of the pro-survival isoform δ3. Conclusions Our results identified 6 novel susceptible loci associated with BrS and revealed shared genetic architecture across ancestries.GWAS Manhattan plotShared genetic architecture

Brugada Syndrome

Brugada syndrome (BrS) is an inherited ion channel channelopathy predisposing to ventricular arrhythmias and sudden cardiac death. Originally believed to be predominantly associated with mutations in SCN5A encoding for the cardiac sodium channel, mutations of 18 genes other than SCN5A have been implicated in the pathogenesis of BrS to date. Diagnosis is based on the presence of a spontaneous or drug-induced coved-type ST segment elevation. If untreated, the irregular heartbeats even can sudden death.

Warning about use of pesticides containing inpyrfluxam for suicide.

Warning about use of pesticides containing inpyrfluxam for suicide.

820 VARIABLE EXPRESSIVITY OF SCN5A MUTATION IN A FAMILY WITH CARDIAC DYSFUNCTION AND SUSPECTED BRUGADA SYNDROME

Abstract Background Inherited arrhythmogenic diseases (IADs) represent a group of life-threatening genetic cardiomyopathies that predispose young individuals to sudden cardiac death (SCD), often in the absence of structural cardiac alterations. Some IADs share mutations in genes encoding for surface membrane ion channels, and the gene for the alpha subunit of the voltage-dependent channel Nav1.5 (SCN5A) is among the ones mostly involved. Brugada syndrome represents one of the possible spectrum deriving from SCN5A gene mutations, and it is characterized by “loss-of-function” genetic alterations. Interestingly, both loss-of and gain-of-function mutations have been associated with familial dilated cardiomyopathy (DCM). Materials and Methods In the context of an Italian Ministry of Health-funded research project devoted to identify genetic isolates of IADs in the Calabria region, we found a family affected by different cardiovascular manifestations including cardiac dysfunction, ventricular tachyarrhythmias, atrioventricular block and suspected Brugada syndrome pattern in first-degree relatives in association with a newly identified SCN5A mutation. Results The proband came to our attention with a diagnosis of DCM, echocardiographic assessment of reduced left ventricular ejection fraction (EF) to 38%, high occurrence of premature ventricular complexes (PVCs) and first-degree atrioventricular block (PR = 240ms) at electrocardiogram. In spite of negative electrophysiologic study, he underwent implantable cardioverter defibrillator implantation (ICD), hypothesizing lamin A/C mutation; genetic analysis turned out negative for lamin A/C and CACNA1C, while a SCN5A gene mutation (c.4554 G<T p.Gln1518His) was detected. Proband's sons and his brother underwent clinical evaluations as well as genetic testing: the second son's ECG showed first-degree AV block (PR = 220ms), QTc interval 426ms, and coved type ST-segment elevation of 1.5mm, in the context of normal cardiac function; the remaining male (see Figure 1) was asymptomatic, while the daughter had a hypokinetic non-dilated cardiomyopathy. The proband's brother had first-degree AV block and very frequent monomorphic ventricular couplets. Conclusions These phenotypic differences in first degree-relatives, can be explained by the concept of variable expressivity of genes, according to which individuals carrying the same mutation can have different clinical features. Therefore, the search for genetic mutations assumes a preponderant role for stratifying the risk of SCN5A-related diseases and to adopt appropriate diagnostic and therapeutic strategies.

P377 CHALLENGING RISK STRATIFICATION IN BRUGADA SYNDROME: A CASE OF VENTRICULAR TACHYCARDIA IN A LOW–RISK PATIENT

Abstract A 22–year–old healthy athlete was referred to our hospital for electrocardiographic findings consistent with intermittent type–1 Brugada pattern. A routine electrocardiogram (ECG) performed during a check–up showed sinus rhythm, normal PR interval and QRS duration, rSR’ with a coved type ST–segment elevation in V2 lead (Figure 1).The patients denied history of syncope or palpitations and his family history did not show sudden cardiac death or Brugada syndrome (BrS). Transthoracic echocardiography was normal and a 12–lead Holter monitoring revealed the intermittence of the type–1 Brugada pattern. The patient was hospitalized for further investigation. On admission, ECG showed a type–2 Brugada pattern; therefore, Ajmaline challenge test (1 mg/kg injection in 10 minutes) was performed and resulted positive. Subsequently, the patient underwent an electrophysiological study (EPS) which was negative for induction of sustained arrhythmias. The protocol adopted consisted of double extrastimuli programmed electrical stimulation until refractoriness (drive 600/220 ms and 400/210 ms), at double sites (right ventricle apex and right ventricular outflow tract). Furthermore a genetic test was performed using next–generation sequencing, showing a heterozygous mutation in the SCN5A gene, encoding for sodium channel alpha subunit (variant c.5363delA), not previously described in the literature. Since the low arrhythmic risk, the patient was implanted with a loop recorder (ILR, Medtronic Reveal LINQ), entering a program of home monitoring. After a 15–months follow–up, an episode of ventricular polymorphic tachycardia lasting 2 minutes and 11 seconds, associated with lightheadedness and palpitations, was detected by the remote monitoring (Figure 2). The patient was therefore hospitalized. During the in–hospital stay a cardiac magnetic resonance was performed to exclude other underlying diseases, identifying an enlarged right ventricle (EDVi 114 ml/m2) and abnormal free wall motion (Figure 3), thus reaching one major criteria of arrhythmogenic cardiomyopathy (however not sufficient for the diagnosis). The patient was then implanted with a subcutaneous implantable cardiac defibrillator (Boston Scientific EMBLEM MRI S–ICD). We presented a case of complex arrhythmic risk stratification in a possible overlap of an arrhythmogenic cardiomyopathy and a Brugada Syndrome in a young athlete who experienced a sustained ventricular tachycardia during loop–recorder monitoring.

Radiofrequency ablation in Brugada syndrome.

Radiofrequency ablation in Brugada syndrome.

Mutations in MYBPC3 and MYH7 in Association with Brugada Type 1 ECG Pattern: Overlap between Brugada Syndrome and Hypertrophic Cardiomyopathy?

Brugada syndrome (BrS) is an inherited disorder with high allelic and genetic heterogeneity clinically characterized by typical coved-type ST segment elevation at the electrocardiogram (ECG), which may occur either spontaneously or after provocative drug testing. BrS is classically described as an arrhythmic condition occurring in a structurally normal heart and is associated with the risk of ventricular fibrillation and sudden cardiac death (SCD). We studied five patients with spontaneous or drug-induced type 1 ECG pattern, variably associated with symptoms and a positive family history through a Next Generation Sequencing panels approach, which includes genes of both channelopathies and cardiomyopathies. We identified variants in MYBPC3 and in MYH7, hypertrophic cardiomyopathy (HCM) genes (MYBPC3: p.Lys1065Glnfs*12 and c.1458-1G > A, MYH7: p.Arg783His, p.Val1213Met, p.Lys744Thr). Our data propose that Brugada type 1 ECG may be an early electrocardiographic marker of a concealed structural heart disease, possibly enlarging the genotypic overlap between Brugada syndrome and cardiomyopathies.

Relationship Between Brugada Syndrome and Poisoning

Brugada syndrome is an inherited arrhythmogenic disease, characterised by a coved-type ST segment elevation in right precordial leads and an increased risk of sudden cardiac death due to ventricular arrhythmia. Electrocardiographic patterns of the disease is divided into three as: a) type I, characterized by a coved-type ST-segment elevation ≥ 2 mm in more than one right precordial lead (V1-V3), followed by negative T wave; b) type II, characterized by ST-segment elevation ≥ 2 mm in right precordial leads followed by positive or biphasic T waves, resulting in a saddleback configuration; and c) type III, defined as any of the 2 previous types if ST-segment elevation is ≤ 1 mm. Although genetic basis of the disease is described (mutations in SCN5A, a cardiac sodium channel gene, transmitted in an autosomal dominant pattern), there is a lack of information about its relationship with triggering factors, particularly toxins. Even though the literature knowledge mainly depends on case reports, in this review, our aim was to investigate the relationship between BrS and toxins, and create awareness on clinicians about this fatal entity.

Epicardial Ablation in Brugada Syndrome.

Brugada syndrome is an inherited cardiac condition characterized by a typical electrocardiogram signature of coved-type ST-segment elevation in the right precordial leads and ventricular arrhythmias leading to sudden cardiac death, in the absence of unequivocal structural heart disease. Brugada syndrome specifically affects the right ventricle, which predisposes to cardiac arrest. Besides medical management with quinidine, emerging data indicate that catheter ablation can help reduce the ventricular arrhythmia burden in these patients. This review explores the mechanisms of ventricular arrhythmia, current approaches and evidence for ablating the epicardial arrhythmogenic substrate in this condition.

Brugada Syndrome: Oligogenic or Mendelian Disease?

Brugada syndrome (BrS) is diagnosed by a coved-type ST-segment elevation in the right precordial leads on the electrocardiogram (ECG), and it is associated with an increased risk of sudden cardiac death (SCD) compared to the general population. Although BrS is considered a genetic disease, its molecular mechanism remains elusive in about 70–85% of clinically-confirmed cases. Variants occurring in at least 26 different genes have been previously considered causative, although the causative effect of all but the SCN5A gene has been recently challenged, due to the lack of systematic, evidence-based evaluations, such as a variant’s frequency among the general population, family segregation analyses, and functional studies. Also, variants within a particular gene can be associated with an array of different phenotypes, even within the same family, preventing a clear genotype–phenotype correlation. Moreover, an emerging concept is that a single mutation may not be enough to cause the BrS phenotype, due to the increasing number of common variants now thought to be clinically relevant. Thus, not only the complete list of genes causative of the BrS phenotype remains to be determined, but also the interplay between rare and common multiple variants. This is particularly true for some common polymorphisms whose roles have been recently re-evaluated by outstanding works, including considering for the first time ever a polygenic risk score derived from the heterozygous state for both common and rare variants. The more common a certain variant is, the less impact this variant might have on heart function. We are aware that further studies are warranted to validate a polygenic risk score, because there is no mutated gene that connects all, or even a majority, of BrS cases. For the same reason, it is currently impossible to create animal and cell line genetic models that represent all BrS cases, which would enable the expansion of studies of this syndrome. Thus, the best model at this point is the human patient population. Further studies should first aim to uncover genetic variants within individuals, as well as to collect family segregation data to identify potential genetic causes of BrS.

Brugada Syndrome – Report of Familial Occurrence Diagnosed in the Emergency Department

Abstract Introduction: Brugada syndrome represents the clinical manifestation of a rare disease with genetic etiology. The syndrome is characterized by ventricular dysrhythmias associated with syncope or sudden cardiac death in the lack of any structural cardiac disease. The diagnosis of Brugada syndrome is established if a type 1 electrocardiographic (ECG) pattern of ST-segment and QRS morphology is present, in association with certain clinical manifestations and/or familial history. Case presentation: A 31-year-old male patient, without any medical history, presented in the emergency department (ED) of a clinical center. His only complaints consisted in palpitations, chest discomfort, and emotional stress related to the recent death of his wife. Earlier on the same day, his wife, a 25-year-old female was brought via emergency medical services (EMS) to the ED after presenting ventricular fibrillation. The female patient presented a long term history of chest pain and one year prior to this episode she presented idiopathic ventricular fibrillation, for which she had undergone implantation of an automated cardioverter defibrillator. As the couple were cousins, the EMS specialist suspected the presence of a familial cardiac disorder. The electrocardiogram of the male patient revealed a coved-type ST-segment elevation of 4 mm in leads V1–V3 compatible with type 1 Brugada syndrome. Conclusion: In case of Brugada syndrome, a genetic disorder associated with increased risk of SCD, the patient's first-degree relatives should be investigated as well, in order to identify the presence of the syndrome and to prevent SCD. As the sole established effective therapeutic measure for patients diagnosed with Brugada syndrome, ICD implantation should be considered in order to decrease the risk of syncope and SCD. This case is particular because a rare disease with familial etiology was identified in both husband and wife, who were cousins.

Uloga elektrokardiograma u dijagnozi naslednih aritmijskih sindroma

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.

Clinical approach to the patient with Brugada Syndrome: risk stratification and optimal management.

The Brugada Syndrome (BrS) is an inherited cardiac ion channel disorder associated with increased risk of ventricular arrhythmias and mortality. Diagnosis is based on a characteristic electrocardiographic (ECG) pattern of coved type ST-segment elevation >2 mm followed by a negative T-wave in ≥1 of the right precordial leads V1 to V3. Since the first description of BrS, the definition of disease and underlying pathophysiological mechanisms have been significantly improved in recent years. Also, significant progress has been made in the field of genetic testing in these patients. Still, there are several open questions regarding the management and outcome of these patients. There is more information about patients who would need an implantable cardiac defibrillator for the primary prevention of sudden cardiac death (that is, those with spontaneous Type I Brugada ECG pattern and arrhythmia-related syncope), but currently published data concerning asymptomatic patients with Brugada ECG pattern and other less-well defined presentations are conflicting. Whereas the role of cardiac defibrillator in patients with Brugada Syndrome is clear, optimal use of catheter ablation and antiarrhythmic drug therapy needs to be further investigated. In this review, we summarize current evidence and contemporary management of patients with BrS.

Role of SCN5A coding and non-coding sequences in Brugada syndrome onset: What's behind the scenes?

BackgroundBrugada syndrome (BrS) is a rare inherited cardiac arrhythmia associated with a high risk of sudden cardiac death (SCD) due to ventricular fibrillation (VF). BrS is characterized by coved-type ST-segment elevation in the right precordial leads (V1-V3). Mutations in SCN5A gene coding for the α-subunit of the NaV1.5 cardiac sodium channel are identified in 15–30% of BrS cases. Genetic testing of BrS patients generally involves sequencing of the protein-coding portions and flanking intronic regions of SCN5A. This excludes the 5′UTR and 3′UTR from the routine genetic testing. MethodsWe here screened the coding sequence, the flanking intronic regions as well as the 5′ and 3′UTR regions of SCN5A gene and further five candidate genes (GPD1L, SCN1B, KCNE3, SCN4B, and MOG1) in a Tunisian family diagnosed with BrS. ResultsA new SCN5A-Q1000K mutation was identified along with two common polymorphisms (H558R and D1819). Multiple genetic variants were identified on the SCN5A 3′UTR, one of which is predicted to create additional microRNA binding site for miR-1270. Additionally, we identified the hsa-miR-219a-rs107822. No relevant coding sequence variant was identified in the remaining studied candidate genes. ConclusionsThe absence of genotype-phenotype concordance within all the identified genetic variants in this family gives extra evidences about the complexity of the disease and suggests that the occurrence and prognosis of BrS is most likely controlled by a combination of multiple genetic factors, rather than a single variant. Most SCN5A variants were localized in non-coding regions hypothesizing an impact on the miRNA-target complementarities.

Sudden Cardiac Death in Brugada Syndrome.

The Brugada syndrome is an inherited channelopathy that alters the main transmembrane ion currents that constitute the cardiac action potential. These changes not only modify the resting electrocardiogram but also predispose patients to develop malignant ventricular tachyarrhythmias that can lead to syncope, cardiac arrest, and sudden cardiac death. This syndrome is responsible for nearly 20% of all sudden cardiac deaths in patients with structurally normal hearts and up to 12% of all sudden cardiac deaths. Brugada syndrome is diagnosed by its characteristic electrocardiogram consisting of a coved-type ST-segment elevation of at least 2 mm followed by a negative T wave in either one of the right precordial leads. These changes can be observed spontaneously or after administration of a sodium channel blocker. While our understanding of this disease has increased tremendously since its first description in 1992, the primary therapeutic option remains implantation of an implantable cardioverter-defibrillator to avoid sudden cardiac death. Therefore, tremendous effort is being made to effectively risk stratify patients to determine who would benefit from implantable cardioverter-defibrillator implantation.

Risk management in early stage arrhythmogenic cardiomyopathy associated with Provocable Brugada ECG

Risk factors of malignant tachyarrythmias should be assessed in cases with early stage arrhythmogenic cardiomyopathy and provocable Brugada ECG. Spontaneous right precordial coved-type ST segment elevation, tall R wave in lead aVR, QRS fragmentation, 1° AV block, inducibility during electrophysiological examination, low amplitude coved-type ST elevation and localised right precordial QRS prolongation should be tested in 20 out of 128 patients. Only QRS fragmentation and localised right precordial QRS prolongation were positive in these patients. QRS fragmentation was positive in two patients, one with aborted sudden cardiac and one patient without any further arrhythmic events. Localised right precordial QRS prolongation was positive in five patients with serious arrhythmic events – four cases with previous ventricular fibrillation and one case with subsequent slow ventricular tachycardia. All other risk factors could be ruled out. In summary, localised right precordial QRS prolongation seems to be the strongest risk marker in cases of developing arrhythmogenic cardiomyopathy and provocable Brugada ECG.

Signal-averaged Electrocardiograph Can Evaluate Citrate Response and Vasovagal Reflex During Apheresis Donation

We herein describe a case of an acute pericarditis, in which type 1 Brugada phenocopy (BrP) was documented. The patient was referred to our hospital due to severe chest pain. The twelve-lead electrocardiogram (ECG) on admission showed type 1 Brugada ECG pattern (coved-type) in the precordial leads. Echocardiography only showed mild pericardial effusion. However, his ST segment elevation returned to normal and chest discomfort disappeared 3 weeks later. Our report addresses the possibility that the coved-type ST-segment elevation cannot be a sensitive finding for Brugada syndrome (BrS). Detailed tests are anyway needed to make appropriate diagnostic and therapeutic decisions.

Evaluation of the mortality in patients with atrial fibrillation in a large electronic cohort: Clinical Outcomes in Digital Electrocardiography (CODE) study

We herein describe a case of an acute pericarditis, in which type 1 Brugada phenocopy (BrP) was documented. The patient was referred to our hospital due to severe chest pain. The twelve-lead electrocardiogram (ECG) on admission showed type 1 Brugada ECG pattern (coved-type) in the precordial leads. Echocardiography only showed mild pericardial effusion. However, his ST segment elevation returned to normal and chest discomfort disappeared 3 weeks later. Our report addresses the possibility that the coved-type ST-segment elevation cannot be a sensitive finding for Brugada syndrome (BrS). Detailed tests are anyway needed to make appropriate diagnostic and therapeutic decisions.