Atrial Abnormalities in Brugada Syndrome: Evaluation With ECG Imaging.

BACKGROUND: Patients with Brugada syndrome (BrS) have an increased risk of arrhythmias, including atrial tachyarrhythmias (ATas). OBJECTIVES: The purpose of this study was to assess underlying atrial cardiomyopathy in BrS and the effect of ajmaline (AJM) test on the atrium of BrS patients using electrocardiogram imaging (ECGI). METHODS: All consecutive patients diagnosed with BrS in a monocentric registry were screened and included if they met the following criteria: 1) BrS diagnosed following current recommendations; and 2) ECGI map performed before and after AJM with a standard protocol. Consecutive patients with no structural heart disease or BrS who had undergone ECGI were included as a control group. Genetic analysis for SCN5A was performed in all BrS patients. Total atrial conduction time (TACT) and local atrial conduction time (LACT) were calculated from atrial ECGI. The primary endpoint was ATas during follow-up. RESULTS: Forty-three consecutive BrS patients and 40 control patients were included. Both TACT and LACT were significantly prolonged in BrS patients compared with control patients. Furthermore, TACT and LACT were significantly higher after AJM administration and in BrS patients who were carriers of a pathogenic/likely pathogenic SCN5A variant. After a mean follow-up of 40.9 months, 6 patients experienced a first ATa occurrence (all in the BrS group, 13.9%). TACT was the only independent predictor of ATas with a cutoff of >138.5 ms (sensitivity 0.92 [95% CI: 0.83-0.98], specificity 0.70 [95% CI: 0.59-0.81]). CONCLUSIONS: ECGI-calculated TACT and LACT are significantly prolonged in BrS patients compared with control patients, and in BrS patients after AJM. This may be consistent with a concealed atrial cardiomyopathy in BrS.

Risk stratification of patients with Brugada syndrome: the impact of myocardial strain analysis using cardiac magnetic resonance feature tracking.

OBJECTIVE: This study evaluated the prognostic significance of cardiac magnetic resonance myocardial feature tracking (CMR-FT) in patients with Brugada syndrome (BrS) to detect subclinical alterations and predict major adverse events (MAE). METHODS: CMR was performed in 106 patients with BrS and 25 healthy controls. Biventricular global strain analysis was assessed using CMR-FT. Patients were followed over a median of 11.6 [8.8 ± 13.8] years. RESULTS: The study cohort was subdivided according to the presence of a spontaneous type 1 ECG (sECG) into sBrS (BrS with sECG, n = 34 (32.1%)) and diBrS (BrS with drug-induced type 1 ECG, n = 72 (67.9%)). CMR-FT revealed morphological differences between sBrS and diBrS patients with regard to right ventricular (RV) strain (circumferential (%) (sBrS -7.9 ± 2.9 vs diBrS - 9.5 ± 3.1, p = 0.02) and radial (%) (sBrS 12.0 ± 4.3 vs diBrS 15.4 ± 5.4, p = 0.004)). During follow-up, MAE occurred in 11 patients (10.4%). Multivariable analysis was performed to identify independent predictors for the occurrence of events during follow-up. The strongest predictive value was found for RV circumferential strain (OR 3.2 (95% CI 1.4 - 6.9), p = 0.02) and RVOT/BSA (OR 3.1 (95% CI 1.0 - 7.0), p = 0.03). CONCLUSIONS: Myocardial strain analysis detected early subclinical alterations, prior to apparent changes in myocardial function, in patients with BrS. While usual functional parameters were within the normal range, CMR-FT revealed pathological results in patients with an sECG. Moreover, RV circumferential strain and RVOT size provided additional prognostic information on the occurrence of MAE during follow-up, which reflects electrical vulnerability.

Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes.

Most causal genes for inherited arrhythmia syndromes (IASs) encode cardiac ion channel-related proteins. Genotype-phenotype studies and functional analyses of mutant genes, using heterologous expression systems and animal models, have revealed the pathophysiology of IASs and enabled, in part, the establishment of causal gene-specific precision medicine. Additionally, the utilization of induced pluripotent stem cell (iPSC) technology have provided further insights into the pathophysiology of IASs and novel promising therapeutic strategies, especially in long QT syndrome. It is now known that there are atypical clinical phenotypes of IASs associated with specific mutations that have unique electrophysiological properties, which raises a possibility of mutation-specific precision medicine. In particular, patients with Brugada syndrome harboring an SCN5A R1632C mutation exhibit exercise-induced cardiac events, which may be caused by a marked activity-dependent loss of R1632C-Nav1.5 availability due to a marked delay of recovery from inactivation. This suggests that the use of isoproterenol should be avoided. Conversely, the efficacy of ß-blocker needs to be examined. Patients harboring a KCND3 V392I mutation exhibit both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral (epilepsy) phenotypes, which may be associated with a unique mixed electrophysiological property of V392I-Kv4.3. Since the epileptic phenotype appears to manifest prior to cardiac events in this mutation carrier, identifying KCND3 mutations in patients with epilepsy and providing optimal therapy will help prevent sudden unexpected death in epilepsy. Further studies using the iPSC technology may provide novel insights into the pathophysiology of atypical clinical phenotypes of IASs and the development of mutation-specific precision medicine.

Right ventricular function and dyssynchrony in Brugada syndrome: Highlighting the importance of the mechanical substrate in the right ventricular outflow tract.

BACKGROUND: Current evidence suggests that Brugada syndrome (BrS), far from being a purely electrical condition, is associated with subtle mechanical abnormalities primarily affecting the right ventricle (RV). We aimed to characterize RV function in BrS and investigate the echocardiographic profile of patients with arrhythmic events, with a special focus on parameters of RV dyssynchrony using speckle-tracking echocardiography (STE). METHODS: An echocardiogram was performed in 71 BrS patients and 25 healthy controls. STE was performed to assess regional and global RV mechanics, including RV outflow tract shortening (RVOTS). RVOT contraction time was considered to calculate the modified RV mechanical dispersion (RVMDm). Arrhythmic events were prospectively evaluated in the BrS cohort. RESULTS: Compared to controls, BrS patients showed subtle contractile abnormalities, including impaired RV longitudinal strain, higher RV index of myocardial performance (RIMP) and lower RVOTS. BrS patients also exhibited a greater contraction delay between the lateral and the septal aspect of the RV. After a median follow-up of 7.3 year (IQR 5.2-10.8), 6 patients presented malignant arrhythmic events. RIMP >0.50, RVOTS <16.2% and RVMDm > 42 ms showed high sensitivity for the identification of BrS patients with arrhythmic events during follow-up. CONCLUSIONS: Subtle RV mechanical abnormalities were present in BrS patients. RIMP and RVOTS, a novel STE-derived parameter, were found to be sensitive markers of arrhythmic events. Adding the RVOT contraction time to the analysis of RVMD may help identify patients at higher risk, reflecting the importance of the RVOT mechanical substrate in the assessment of the arrhythmic risk in BrS.

Electrocardiographic imaging of the arrhythmogenic substrate of Brugada syndrome: Current evidence and future perspectives.

Brugada syndrome is responsible for about 20% of sudden cardiac deaths in patients with apparently normal hearts. Basic and clinical research has elucidated some of the mechanisms that are responsible for life-threatening ventricular arrhythmias in this syndrome. Delays in activation and repolarization over the right ventricular outflow tract are the most likely cause of the ECG typical pattern and arrhythmogenesis. Invasive epicardial and endocardial mapping has identified the epicardium as the principal region of interest for these anomalies, and areas of fragmented potentials at invasive mapping are a target for epicardial ablation. Noninvasive mapping systems have been developed to study the epicardial depolarization and repolarization and may be particularly useful in assessing the epicardial arrhythmogenic substrate of Brugada syndrome for both clinical and research purpose. This review focuses on recent advances in this field.

Relationship between sodium channel function and clinical phenotype in SCN5A variants associated with Brugada syndrome.

The identification of a pathogenic SCN5A variant confers an increased risk of conduction defects and ventricular arrhythmias (VA) in Brugada syndrome (BrS). However, specific aspects of sodium channel function that influence clinical phenotype have not been defined. A systematic literature search identified SCN5A variants associated with BrS. Sodium current (INa ) functional parameters (peak current, decay, steady-state activation and inactivation, and recovery from inactivation) and clinical features (conduction abnormalities [CA], spontaneous VA or family history of sudden cardiac death [SCD], and spontaneous BrS electrocardiogram [ECG]) were extracted. A total of 561 SCN5A variants associated with BrS were identified, for which data on channel function and clinical phenotype were available in 142. In the primary analysis, no relationship was found between any aspect of channel function and CA, VA/SCD, or spontaneous BrS ECG pattern. Sensitivity analyses including only variants graded pathogenic or likely pathogenic suggested that reduction in peak current and positive shift in steady-state activation were weakly associated with CA and VA/SCD, although sensitivity and specificity remained low. The relationship between in vitro assessment of channel function and BrS clinical phenotype is weak. The assessment of channel function does not enhance risk stratification. Caution is needed when extrapolating functional testing to the likelihood of variant pathogenicity.

Electromechanical delay by speckle-tracking echocardiography: A novel tool to distinguish between Brugada syndrome and isolated right bundle branch block.

BACKGROUND: The electrocardiographic (ECG) definition of Brugada syndrome (BS) can be challenging because benign ECG abnormalities, such as right bundle branch block (RBBB), may mimic pathological ECG characteristics of BrS. However, although myocardial delay and deformation can be quantified by advanced imaging, it has not yet been used to differentiate between BrS and RBBB. The aim of this study was to characterize the electro-mechanical behavior of the heart of patients with type-1 BrS and isolated complete RBBB in order to differentiate these conditions. METHODS: In this two-center study, 66 subjects were analyzed by standard and speckle-tracking echocardiography (STE): 22 type-1 BrS, 24 isolated complete RBBB, and 20 healthy subjects. The participants were not treated by any drug potentially influencing myocardial conduction. RESULTS: Standard echocardiographic parameters did not differ among the groups. The greatest right ventricular (RV) mechanical dispersion was found in RBBB. Mean absolute deviations (MADs) of time-to-peak longitudinal strain calculated for each left ventricular (LV) region were greater in patients with RBBB as compared to BrS (p < .01). No differences were found between BrS and controls (p = .36). MADs in the basal segments in RBBB group were greater than MADs found in BrS group and controls (37.3 ms vs. 26.7 ms and 29.0 ms, respectively, p < .05). The greatest differences were found in the antero-septal, anterior, lateral, and infero-septal basal segments. CONCLUSIONS: Advanced echocardiographic techniques may help to differentiate between BrS and RBBB. Indeed, STE allows to identify an electro-mechanical conduction delay in RBBB patients that is not found in patients affected by type-1 BrS.

Double Anomalies: Brugada Syndrome Presenting with a Persistent Left Superior Vena Cava.

BACKGROUND The presentation of Brugada syndrome (BrS) with a persistent left superior vena cava (PLSVC) is expected to be a rare entity. It is unknown if this venous anomaly is linked to the arrhythmogenesis seen in BrS, or it is coincidental. This case describes a clinical presentation of the 2, in tandem, and displays the anomaly in association with BrS. CASE REPORT A 54-year-old female presented to the Emergency Department with non-prodromal syncope. This was on a background of a number of similar episodes in the past, and a current suspected viral illness comprising fever and diarrhea. Her resting electrocardiogram was suggestive of BrS. The later was confirmed with an ajmaline provocation test after ECG normalization in the subsequent 24 hours post admission. Pre-intracardiac defibrillator (ICD) procedure imaging displayed the PLSVC. An ICD was implanted, and the advancement of the guidewires displayed the venous anomaly. Post-procedure echocardiography confirmed appropriate positioning of the leads. The patient recovered well and is currently symptom free. CONCLUSIONS PLSVC presenting with BrS is a rare occurrence. It is unknown whether or not the PLSVC and BrS are linked in their presentation, or merely a coincidence.

Genotype-Phenotype Correlation in a Family with Brugada Syndrome Harboring the Novel p.Gln371* Nonsense Variant in the SCN5A Gene.

Brugada syndrome (BrS) is marked by coved ST-segment elevation and increased risk of sudden cardiac death. The genetics of this syndrome are elusive in over half of the cases. Variants in the SCN5A gene are the single most common known genetic unifier, accounting for about a third of cases. Research models, such as animal models and cell lines, are limited. In the present study, we report the novel NM_198056.2:c.1111C>T (p.Gln371*) heterozygous variant in the SCN5A gene, as well as its segregation with BrS in a large family. The results herein suggest a pathogenic effect of this variant. Functional studies are certainly warranted to characterize the molecular effects of this variant.

The Spectrum of Idiopathic Ventricular Fibrillation and J-Wave Syndromes: Novel Mapping Insights.

Idiopathic ventricular fibrillation and J-wave syndromes are causes of sudden cardiac death (SCD) without any identified structural cardiac disease after extensive investigations. Recent data show that high-density electrophysiological mapping may ultimately offer diagnoses of subclinical diseases in most patients including those termed "unexplained" SCD. Three major conditions can underlie the occurrence of SCD: (1) localized depolarization abnormalities (due to microstructural myocardial alteration), (2) Purkinje abnormalities manifesting as triggering ectopy and inducible reentry; or (3) repolarization heterogeneities. Each condition may result from a spectrum of pathophysiologic processes with implications for individual therapy.

Ethnic differences in patients with Brugada syndrome and arrhythmic events: New insights from Survey on Arrhythmic Events in Brugada Syndrome.

BACKGROUND: There is limited information on ethnic differences between patients with Brugada syndrome (BrS) and arrhythmic events (AEs). OBJECTIVE: The purpose of this study was to compare clinical, electrocardiographic (ECG), electrophysiological, and genetic characteristics between white and Asian patients with BrS and AEs. METHODS: The Survey on Arrhythmic Events in Brugada Syndrome is a multicenter survey from Western and Asian countries, gathering 678 patients with BrS and first documented AE. After excluding patients with other (n = 14 [2.1%]) or unknown (n = 30 [4.4%]) ethnicity, 364 (53.7%) whites and 270 (39.8%) Asians comprised the study group. RESULTS: There was no difference in AE age onset (41.3 ± 16.1 years in whites vs 43.3 ± 12.3 years in Asians; P = .285). Higher proportions of whites were observed in pediatric and elderly populations. Asians were predominantly men (98.1% vs 85.7% in whites; P < .001) and frequently presented with aborted cardiac arrest (71.1% vs 56%; P < .001). Asians tended to display more spontaneous type 1 BrS-ECG pattern (71.5% vs 64.3%; P = .068). A family history of sudden cardiac death was noted more in whites (29.1% vs 11.5%; P < .001), with a higher rate of SCN5A mutation carriers (40.1% vs 13.2% in Asians; P < .001), as well as more fever-related AEs (8.5% vs 2.9%; P = .011). No difference was observed between the 2 groups regarding history of syncope and ventricular arrhythmia inducibility. CONCLUSION: There are important differences between Asian and white patients with BrS. Asian patients present almost exclusively as male adults, more often with aborted cardiac arrest and spontaneous type 1 BrS-ECG. However, they have less family history of sudden cardiac death and markedly lower SCN5A mutation rates. The striking difference in SCN5A mutation rates should be tested in future studies.

Ventricular conduction stability test: a method to identify and quantify changes in whole heart activation patterns during physiological stress.

AIMS: Abnormal rate adaptation of the action potential is proarrhythmic but is difficult to measure with current electro-anatomical mapping techniques. We developed a method to rapidly quantify spatial discordance in whole heart activation in response to rate cycle length changes. We test the hypothesis that patients with underlying channelopathies or history of aborted sudden cardiac death (SCD) have a reduced capacity to maintain uniform activation following exercise. METHODS AND RESULTS: Electrocardiographical imaging (ECGI) reconstructs >1200 electrograms (EGMs) over the ventricles from a single beat, providing epicardial whole heart activation maps. Thirty-one individuals [11 SCD survivors; 10 Brugada syndrome (BrS) without SCD; and 10 controls] with structurally normal hearts underwent ECGI vest recordings following exercise treadmill. For each patient, we calculated the relative change in EGM local activation times (LATs) between a baseline and post-exertion phase using custom written software. A ventricular conduction stability (V-CoS) score calculated to indicate the percentage of ventricle that showed no significant change in relative LAT (<10 ms). A lower score reflected greater conduction heterogeneity. Mean variability (standard deviation) of V-CoS score over 10 consecutive beats was small (0.9 ± 0.5%), with good inter-operator reproducibility of V-CoS scores. Sudden cardiac death survivors, compared to BrS and controls, had the lowest V-CoS scores post-exertion (P = 0.011) but were no different at baseline (P = 0.50). CONCLUSION: We present a method to rapidly quantify changes in global activation which provides a measure of conduction heterogeneity and proof of concept by demonstrating SCD survivors have a reduced capacity to maintain uniform activation following exercise.

Epinephrine Administered for Anaphylaxis Unmasking a Type 1 Brugada Pattern on Electrocardiogram.

BACKGROUND: Brugada pattern on electrocardiography (ECG) can manifest as type 1 (coved pattern) and type 2 (saddleback pattern). Brugada syndrome represents an ECG with Brugada pattern in a patient with symptoms or clinical factors, including syncope, cardiac arrest, ventricular dysrhythmias, and family history. Brugada syndrome is caused by a genetic channelopathy, but the Brugada pattern may be drug-induced. Epinephrine-induced Brugada pattern has not been reported previously. CASE REPORT: A 63-year-old man developed anaphylaxis secondary to a bee sting, had a transient loss of consciousness, and self-administered intramuscular epinephrine. He subsequently presented to the emergency department and was found to have a type 1 Brugada pattern on ECG that resolved during observation. A historic ECG was reviewed that demonstrated a baseline type 2 Brugada pattern. His anaphylaxis was managed with steroids and antihistamines. He was observed without subsequent dysrhythmic events on telemetry or any further symptoms. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The differential diagnosis for syncope includes dysrhythmia, such as Brugada syndrome. Among other possible drugs, epinephrine may induce a type 1 Brugada pattern. Patients with Brugada pattern on ECG should be referred immediately to electrophysiology for consideration of implantation of a cardioverter-defibrillator device, given the association of Brugada pattern with sudden cardiac arrest and ventricular dysrhythmias.

Electroanatomic and Pathologic Right Ventricular Outflow Tract Abnormalities in Patients With Brugada Syndrome.

BACKGROUND: The prevalence and significance of structural abnormalities in Brugada syndrome (BrS) are still largely debated. OBJECTIVES: The authors investigated the relationship between genetic background, electroanatomic abnormalities, and pathologic substrate in BrS. METHODS: They performed 3-dimensional electroanatomic unipolar and bipolar mapping in 30 patients with BrS. Twenty patients underwent 3-dimensional electroanatomic unipolar and bipolar mapping-guided right ventricular outflow tract (RVOT) endomyocardial biopsy. Programmed ventricular stimulation and genetic analysis were performed in all patients. RESULTS: Low-voltage areas (LVAs) were observed at unipolar map in 93% of patients and at bipolar map in 50% of cases. Unipolar LVAs were always larger than bipolar LVAs, were always colocalized, and in all cases included RVOT. Disease-causing mutations were detected in 10 (33%) patients. Programmed ventricular stimulation was positive in 16 cases (53%). In 75% of patients, RVOT histology showed pathologic findings with myocardial inflammation in 80% of them. Among patients with abnormal bipolar map submitted to endomyocardial biopsy, 9 (81%) showed evidence of myocardial inflammation. Conversely, bipolar map was abnormal in 83% of patients with myocardial inflammation. Myocardial inflammation was also more prevalent among inducible patients (83% vs. 25% in noninducible; p = 0.032). CONCLUSIONS: BrS is characterized by electroanatomical and structural abnormalities localized to RVOT with a gradient of the pathologic substrate from epicardium to endocardium possibly driven by myocardial inflammation. These findings reclassify BrS as a combination of structural and electrical defects opening the way to new risk stratification and therapeutic strategies.

Type 1 Brugada phenocopy in a patient with acute pericarditis.

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.

Brugada Syndrome Manifesting Only During Fever in Patient with Septic Shock Secondary to Post-Obstructive Pneumonia.

BACKGROUND Brugada syndrome is a cardiac disorder associated with sudden death due to sodium channelopathy, most commonly the SCN5a mutation. There are 3 different patterns of electrocardiogram (ECG) changes characterized as type I, II, and III. ECG patterns consist of variations of incomplete RBBB and ST elevation in anterior precordial leads only. Treatment, if warranted, consists of implantable cardioverter-defibrillator. CASE REPORT A 63-year-old male presented with abdominal pain for 4 days that was persistent, and after further imaging, he was found to have hepatic metastases from a stage IV small cell carcinoma of the lung. The patient was started on chemotherapy with carboplatin and VP-16. The patient decompensated, developed septic shock secondary to post-obstructive pneumonia, and eventually required intubation. He became tachycardic, and an ECG was ordered to evaluate the heart rhythm. It was determined that the patient had Brugada wave/syndrome. The patient's condition deteriorated with worsening septic shock, suspected type II NSTEMI, and multiorgan failure. The patient was designated DNR ("do not resuscitate") and passed away. CONCLUSIONS This case represents how channelopathies can be provoked with fever. It is believed that this occurs due to denaturing of the ion channel leading to abnormal ST segment changes typically seen on ECG and an increased risk of developing lethal arrhythmias. Spontaneous presentation of nondrug-induced Brugada syndrome carries an increased risk of deadly arrhythmia, for which this patient would have required electrophysiological studies. Unfortunately, this patient was unable to undergo genetic testing or electrophysiological studies, as he passed away.