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Brugada syndrome is a rare cardiac condition characterized by distinctive electrocardiogram patterns, predisposing individuals to fatal arrhythmias. While primarily linked to a loss-of-function mutation in the SCN5A gene, acquired forms of the syndrome have been associated with various factors, including drug use. We present a case of a 31-year-old female who presented to the emergency department unresponsive following cocaine use and developed type 1 Brugada ECG patterns alongside an incomplete right bundle branch block in V1-V3, ST elevations with biphasic waves, and diffuse repolarization abnormalities with J point deviations while in the intensive care unit. This study aimed to discuss the complexity of managing drug-induced Brugada-like findings and highlights the need for further research into the mechanisms underlying cocaine-induced cardiac effects. We aimed to discuss potential mechanisms for the impact of cocaine as its role as a sodium channel blocker and its potential effects on connexin 43 in the context of Brugada syndrome. This study also reinforced the importance of differentiating between true Brugada syndrome and other similar ECG changes for appropriate care management.
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Background: Brugada syndrome (BrS) is a rare genetic disorder with specific electrocardiographic (ECG) patterns carrying an increased risk of sudden cardiac death. Case presentation: The authors present a 36-year-old gentleman who had a travel history to the Central African Republic and came to the hospital with a fever and chest pain. The lab investigation revealed Falciparum Malaria infection and the ECG pattern revealed the type 1 Brugada pattern, which was normalized with anti-malarial medication and symptomatic treatment of fever. Discussion: BrS is a disorder with high prevalence in males and people of the Asian continent. Patients can present with symptoms like syncope, seizure, and nocturnal agonal respiration or may be asymptomatic. The ECG pattern of BrS could be seen in the febrile phase and normalized when non-febrile, like in our patient. Prompt treatment of fever and follow-up with cardiologists would be an effective treatment of asymptomatic patients, whereas ICD is a management of choice for symptomatic patients. Conclusion: For a patient with chest pain, fever, and an ECG pattern of ST elevation, a clinician should think BrS one of the differential diagnoses.
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Background: Diagnosis of Brugada syndrome (BrS) may be established by exposing a Type 1 Brugada pattern using a sodium channel blocker. Data on the outcomes of different patient populations with drug-induced Type 1 Brugada pattern are limited. The present study reports on the characteristics and outcome of subjects with ajmaline induced Type 1 Brugada pattern. Methods: A multicenter retrospective study including all consecutive cases of ajmaline-induced Type 1 Brugada pattern from seven centers. Results: A total of 260 patients (69.9% males, mean age 43.4 ± 13.5) were included. Additional characteristics included history of syncope (n = 56, 21.5%), family history of BrS (n = 58, 22.3%) or sudden cardiac death (n = 47, 18.1%) and ventricular fibrillation (n = 3, 1.2%). Patients were divided into those meeting current diagnostic criteria for drug-induced BrS (DIBrS) and compared to the drug-induced Brugada pattern (DIBrECG). Females were significantly overrepresented in the DIBrS group (n = 50, 40% vs. n = 29, 21.5%, p = .001). A significantly higher prevalence of type 2/3 Brugada ECG at baseline was found in the DIBrECG group (n = 108, 80.8% vs. n = 75, 60% in the DIBrS, p = .026). During a median follow up of three (IQR 1.50-5.32) years, a single event of significant arrhythmia occurred in the DIBrS group. Conclusion: Less than half of subjects with ajmaline-induced Brugada pattern met current criteria for BrS. These individuals had very low rate of adverse outcomes during a follow up of 3 years, irrespective of the indication for the test or eligibility for the BrS diagnosis.
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Brugada syndrome (BrS) is a rare autosomal dominant inherited channel disorder characterized by a specific electrocardiographic pattern of right precordial ST-segment elevation. Clinically, patients may experience polymorphic ventricular tachycardia and ventricular fibrillation, leading to recurrent syncope and sudden cardiac death (SCD) in the absence of structural cardiomyopathy. The A-kinase anchor protein 9 (AKAP9) gene, located on chromosome 7, encodes the AKAP9 protein, which plays a crucial role in regulating the phosphorylation of slowly activating delayed rectifier potassium channels (IKs). Here, we present a rare case of BrS associated with an insertion mutation in AKAP9, resulting in a frameshift mutation.
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Genetic arrhythmia disorders are rare diseases; however, they are a common cause of sudden cardiac death in children, adolescents, and young adults. In principle, a distinction can be made between channelopathies and cardiomyopathies in the context of genetic diseases. This paper focuses on the channelopathies long and short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia (CPVT). Early diagnosis of these diseases is essential, as drug therapy, behavioral measures, and if necessary, implantation of a cardioverter defibrillator can significantly improve the prognosis and quality of life of patients. This paper highlights the pathophysiological and genetic basis of these channelopathies, describes their clinical manifestations, and comments on the principles of diagnosis, risk stratification and therapy.
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Arritmias Cardíacas , Síndrome de Brugada , Canalopatias , Humanos , Arritmias Cardíacas/genética , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/terapia , Arritmias Cardíacas/fisiopatologia , Canalopatias/genética , Canalopatias/diagnóstico , Canalopatias/terapia , Síndrome de Brugada/genética , Síndrome de Brugada/diagnóstico , Síndrome de Brugada/fisiopatologia , Síndrome de Brugada/terapia , Taquicardia Ventricular/genética , Taquicardia Ventricular/terapia , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/fisiopatologia , Adolescente , Criança , Síndrome do QT Longo/genética , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/terapia , Síndrome do QT Longo/fisiopatologia , Morte Súbita Cardíaca/prevenção & controle , Morte Súbita Cardíaca/etiologia , Adulto , Desfibriladores Implantáveis , EletrocardiografiaRESUMO
Brugada Syndrome (BrS) is a primary electrical epicardial disease characterized by ST-segment elevation followed by a negative T-wave in the right precordial leads on the surface electrocardiogram (ECG), also known as the 'type 1' ECG pattern. The risk stratification of asymptomatic individuals with spontaneous type 1 ECG pattern remains challenging. Clinical and electrocardiographic prognostic markers are known. As none of these predictors alone is highly reliable in terms of arrhythmic prognosis, several multi-factor risk scores have been proposed for this purpose. This article presents a new workflow for processing endocardial signals acquired with high-density RV electro-anatomical mapping (HDEAM) from BrS patients. The workflow, which relies solely on Matlab software, calculates various electrical parameters and creates multi-parametric maps of the right ventricle. The workflow, but it has already been employed in several research studies involving patients carried out by our group, showing its potential positive impact in clinical studies. Here, we will provide a technical description of its functionalities, along with the results obtained on a BrS patient who underwent an endocardial HDEAM.
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Síndrome de Brugada , Eletrocardiografia , Fluxo de Trabalho , Humanos , Síndrome de Brugada/fisiopatologia , Eletrocardiografia/métodos , Software , Ventrículos do Coração/fisiopatologia , Ventrículos do Coração/diagnóstico por imagem , Processamento de Sinais Assistido por ComputadorRESUMO
Hypothyroidism can have a significant impact on cardiac contractility, vascular resistance, blood pressure, and cardiac rhythm. Ventricular arrhythmias induced by hypothyroidism are infrequently reported, especially in pediatric cases. A 15-year-old girl with autoimmune hypothyroidism experienced pulseless ventricular arrhythmias on 2 separate occasions because of nonadherence to levothyroxine medication. Subsequent investigations revealed an SCN5A mutation associated with Brugada syndrome. A loop recorder captured polymorphic ventricular tachycardia (PMVT), specifically Torsades de Pointes during her second event. Both arrhythmias were addressed only after stabilizing her thyroid hormone levels with replacement therapy. Although rare, patients with uncontrolled hypothyroidism may present with ventricular arrhythmias, particularly PMVT. The cornerstone of treatment for hypothyroidism-induced ventricular arrhythmia is thyroid replacement therapy. The identification of an SCN5A mutation unmasked by overt hypothyroidism emphasizes the need for a comprehensive cardiac evaluation in patients with hypothyroidism being assessed for PMVT.
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BACKGROUND: Brugada syndrome is an inheritable arrhythmia condition that is associated with rare, loss-of-function variants in SCN5A. Interpreting the pathogenicity of SCN5A missense variants is challenging, and ≈79% of SCN5A missense variants in ClinVar are currently classified as variants of uncertain significance. Automated patch clamp technology enables high-throughput functional studies of ion channel variants and can provide evidence for variant reclassification. METHODS: An in vitro SCN5A-Brugada syndrome automated patch clamp assay was generated and independently studied at Vanderbilt University Medical Center and Victor Chang Cardiac Research Institute. The assay was calibrated according to ClinGen Sequence Variant Interpretation recommendations using high-confidence variant controls (n=49). Normal and abnormal ranges of function were established based on the distribution of benign variant assay results. Odds of pathogenicity values were derived from the experimental results according to ClinGen Sequence Variant Interpretation recommendations. The calibrated assay was then used to study SCN5A variants of uncertain significance observed in 4 families with Brugada syndrome and other arrhythmia phenotypes associated with SCN5A loss-of-function. RESULTS: Variant channel parameters generated independently at the 2 research sites showed strong correlations, including peak INa density (R2=0.86). The assay accurately distinguished benign controls (24/25 concordant variants) from pathogenic controls (23/24 concordant variants). Odds of pathogenicity values yielded 0.042 for normal function and 24.0 for abnormal function, corresponding to strong evidence for both American College of Medical Genetics and Genomics/Association for Molecular Pathology benign and pathogenic functional criteria (BS3 and PS3, respectively). Application of the assay to 4 clinical SCN5A variants of uncertain significance revealed loss-of-function for 3/4 variants, enabling reclassification to likely pathogenic. CONCLUSIONS: This validated high-throughput assay provides clinical-grade functional evidence to aid the classification of current and future SCN5A-Brugada syndrome variants of uncertain significance.
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Brugada syndrome (BrS) is an inherited arrhythmogenic disorder marked by distinctive ST-segment elevations on electrocardiograms (ECG) and an increased risk of sudden cardiac death. Characterized by mutations primarily in the SCN5A gene, BrS disrupts cardiac ion channel function, leading to abnormal electrical activity and arrhythmias. Although BrS primarily affects young, healthy males, it poses significant diagnostic challenges due to its often concealed or intermittent ECG manifestations and clinical presentation that can mimic other cardiac disorders. Current management strategies focus on symptom control and prevention of sudden death, with implantable cardioverter-defibrillators (ICD) serving as the primary intervention for high-risk patients. However, the complications associated with ICDs and the lack of effective pharmacological options necessitate a cautious and personalized approach. Recent advancements in catheter ablation have shown promise, particularly for managing ventricular fibrillation (VF) storms and reducing ICD shocks. Additionally, pharmacological treatments such as quinidine have been effective in specific cases, though their use is limited by availability and side effects. This review highlights significant gaps in the BrS literature, particularly in terms of long-term management and novel therapeutic approaches. The importance of genetic screening and tailored treatment strategies to better identify and manage at-risk individuals is emphasized. The review aims to enhance the understanding of BrS and improve patient outcomes, advocating for a multidisciplinary approach to this complex syndrome.
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Brugada syndrome (BrS) is characterized by ST segment elevations in the right precordial leads, V1 - V3, with additional findings of ventricular arrhythmias and family history (FH) of sudden cardiac death (SCD) at a young age. Here, we describe a case of hyperthermia, unveiling the Brugada electrocardiography (EKG) pattern and the resolution of EKG findings with appropriate hyperthermia management. It is important to distinguish the Brugada EKG pattern from other causes of ST elevations and treat appropriately to prevent patients from developing ventricular fibrillation and SCD. It is key to identify environmental triggers in patients presenting with Brugada EKG pattern and closely monitor for ventricular fibrillation. Educating patients on prompt fever treatment with antipyretics and avoiding medications like sodium channel blockers during the febrile event is paramount to counter patients going into ventricular fibrillation. It is also crucial for close follow-up of these patients, offering them genetic testing for BrS and screening families of patients with BrS.
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BACKGROUND AND AIMS: Patients suffering from Brugada syndrome (BrS) are predisposed to life-threatening cardiac arrhythmias. Diagnosis is challenging due to the elusive electrocardiographic (ECG) signature that often requires unconventional ECG lead placement and drug challenges to be detected. Although NaV1.5 sodium channel dysfunction is a recognized pathophysiological mechanism in BrS, only 25% of patients have detectable SCN5A variants. Given the emerging role of autoimmunity in cardiac ion channel function, this study explores the presence and potential impact of anti-NaV1.5 autoantibodies in BrS patients. METHODS: Using engineered HEK293A cells expressing recombinant NaV1.5 protein, plasma from 50 BrS patients and 50 controls was screened for anti-NaV1.5 autoantibodies via western blot, with specificity confirmed by immunoprecipitation and immunofluorescence. The impact of these autoantibodies on sodium current density and their pathophysiological effects were assessed in cellular models and through plasma injection in wild-type mice. RESULTS: Anti-NaV1.5 autoantibodies were detected in 90% of BrS patients vs. 6% of controls, yielding a diagnostic area under the curve of .92, with 94% specificity and 90% sensitivity. These findings were consistent across varying patient demographics and independent of SCN5A mutation status. Electrophysiological studies demonstrated a significant reduction specifically in sodium current density. Notably, mice injected with BrS plasma showed Brugada-like ECG abnormalities, supporting the pathogenic role of these autoantibodies. CONCLUSIONS: The study demonstrates the presence of anti-NaV1.5 autoantibodies in the majority of BrS patients, suggesting an immunopathogenic component of the syndrome beyond genetic predispositions. These autoantibodies, which could serve as additional diagnostic markers, also prompt reconsideration of the underlying mechanisms of BrS, as evidenced by their role in inducing the ECG signature of the syndrome in wild-type mice. These findings encourage a more comprehensive diagnostic approach and point to new avenues for therapeutic research.
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BACKGROUND: Brugada syndrome (BrS) is an inherited primary channelopathy syndrome associated with the risk of ventricular fibrillation (VF) and sudden cardiac death in a structurally normal heart. AIM OF THE STUDY: The aim of this study was to clinically and genetically evaluate a large family with severe autosomal dominant Brugada syndrome. METHODS: Clinical and genetic studies were performed. Genetic analysis was conducted with NGS technologies (WES) using the Illumina instrument. According to the standard procedure, variants found by WES were confirmed in all available families by Sanger sequencing. The effect of the variants was studied by using in silico prediction of pathogenicity. RESULTS: The proband was a 52-year-old man who was admitted to the emergency department for syncope at rest. WES of the index case identified a heterozygous VUS CASQ2, c.532T>C, p.(Tyr178His). We studied the segregation of the variation in all pedigree members. All the patients were heterozygous for the variation CASQ2 p.(Tyr178His), whereas the remaining healthy individuals in the family were homozygous for the normal allele. Structural analysis of CASQ2 p.(Tyr178His) was performed and revealed an important effect of the missense variation on monomer stability. The CASQ2 Tyr180 residue is located inside the sarcoplasmic reticulum (SR) junctional face membrane interaction domain and is predicted to disrupt filamentation. CONCLUSIONS: Our data suggest that the p.Tyr178His substitution is associated with BrS in the family investigated, affecting the stability of the protein, disrupting filamentation at the interdimer interface, and affecting the subsequent formation of tetramers and polymers that contain calcium-binding sites.
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Síndrome de Brugada , Calsequestrina , Mutação de Sentido Incorreto , Linhagem , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome de Brugada/genética , Síndrome de Brugada/patologia , Calsequestrina/genética , Feminino , AdultoRESUMO
We describe the case of a 28-year-old man with Brugada syndrome who received single-shot adductor canal and sciatic nerve blocks for the management of post-operative pain related to extensive orthopedic injuries. Low-dose ropivacaine with glucocorticoid additives was administered without any EKG changes, arrhythmias, or syncopal sensations. The patient experienced pain relief for over 24 h and was monitored on telemetry with defibrillator pads as a cardiac precaution. This case adds a valuable data point in the limited canon of information on the safety and efficacy of regional anesthesia in Brugada syndrome for the perioperative physician.
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INTRODUCTION: Patients with Brugada syndrome (BrS) face an increased risk of ventricular arrhythmias and sudden cardiac death. Implantable cardiac monitors (ICMs) have emerged as effective tools for detecting arrhythmias in BrS. Technological advancements, including temperature sensors and improved subcutaneous electrocardiogram (subECG) signal quality, hold promise for further enhancing their utility in this population. METHODS AND RESULTS: We present a case of a 40-year-old man exhibiting a BrS type 2 pattern on 12-lead ECG, who underwent ICM insertion (BIOMONITOR IIIm, BIOTRONIK) due to drug-induced BrS type 1 pattern and a history of syncope, with a negative response to programmed ventricular stimulation. The device contains an integrated temperature sensor and can transmit daily vital data, such as mean heart rate and physical activity. Several months later, remote alerts indicated a temperature increase, along with transmitted subECGs suggesting a fever-induced BrS type 1 pattern. The patient was promptly advised to commence antipyretic therapy. Over the following days, remotely monitored parameters showed decreases in mean temperature, physical activity, and mean heart rate, without further recurrence of abnormal subECGs. CONCLUSION: ICMs offer valuable insights beyond arrhythmia detection in BrS. Early detection of fever using embedded temperature sensors may improve patient management, while continuous subECG morphological analysis has the potential to enhance risk stratification in BrS patients.
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Síndrome de Brugada , Humanos , Síndrome de Brugada/fisiopatologia , Masculino , Adulto , Eletrocardiografia Ambulatorial/instrumentação , Temperatura Corporal , Tecnologia de Sensoriamento Remoto/instrumentação , Eletrocardiografia , Desenho de EquipamentoRESUMO
Background: Chronic diseases have a negative impact on quality of life (QOL) and psychological health. There are limited related data regarding this topic in Brugada syndrome (BrS). We evaluated the effects of the diagnosis of BrS on health-related QOL and psychological status among patients and their relatives. Methods: Patients with BrS and their relatives underwent psychological evaluation at diagnosis (T0), 1 and 2 years after diagnosis (T1 and T2) using questionnaires on mental QOL, anxiety, depression, stress, post-traumatic stress, and resilience resources. Results: Sixty-one patients and 39 relatives were enrolled. Compared with controls, patients showed increased physical QOL (54.1 ± 6.5 vs. 50.1 ± 8.0, p = 0.014), reduced mental QOL (43.2 ± 11.8 vs. 49.6 ± 9.1, p = 0.018) and increased anxiety (9.9 ± 6.6 vs. 6.9 ± 7.7, p = 0.024) at T0; reduced resilience scores (3.69 ± 0.40 vs. 3.96 ± 0.55, p = 0.008) at T1; and reduced resilience (3.69 ± 0.35 vs. 3.96 ± 0.55, p = 0.019) and increased anxiety scores (16.4 ± 12.8 vs. 6.9 ± 7.7, p = 0.006) at T2. Relatives presented higher stress (17.63 ± 3.77 vs. 12.90 ± 6.0, p = 0.02) at T0 and higher anxiety scores at T0 (13.5 ± 7.6 vs. 6.9 ± 7.7, p < 0.001), T1 (12.0 ± 8.7 vs. 6.9 ± 7.7, p = 0.005), and T2 (16.4 ± 12.8 vs. 6.9 ± 7.7, p = 0.006) than controls. Female sex was significantly independently associated with worse mental QOL scores in patients at T0 (odds ratio = 0.10; 95% confidence interval = 0.05-0.94; p = 0.04). Conclusions: The diagnosis of BrS impairs the QOL and psychological status of patients and their relatives. Female sex is independently associated with worse mental QOL in patients at diagnosis.
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BACKGROUND: Epicardial unipolar mapping has not been thoroughly investigated in Brugada syndrome (BrS). OBJECTIVES: This study aims to examine the characteristics of epicardial unipolar potentials in BrS and investigate the differences from overt cardiomyopathy. METHODS: Epicardial mapping was performed in 8 patients with BrS and 6 patients with cardiomyopathy. We investigated the J-wave amplitudes using unipolar recordings at delayed potential (DP) sites via bipolar recordings. The repolarization time (RT) at and around the DP recording sites was measured, and maximum dispersion of the RT divided by the distance was defined as the RT dispersion index. RESULTS: Epicardial mapping at baseline revealed significantly higher J-wave amplitude with bipolar DP in patients with BrS than in patients with cardiomyopathy. J-wave amplitude ≥0.42 mV had 99.1% sensitivity and 100% specificity for diagnosing BrS. The RT dispersion index was significantly higher in patients with BrS than in patients with cardiomyopathy at baseline. In all patients with BrS, coved-type unipolar electrograms without negative T waves (short RT) appeared close to coved-type electrograms with negative T waves (long RT) at the DP recording sites after pilsicainide administration. Thus, a steep RT dispersion was observed in this region, and ventricular arrhythmias emerged from this shorter RT area in all 3 patients with BrS in whom ventricular arrhythmias were induced. CONCLUSIONS: Bipolar DP-related prominent unipolar J waves and steep repolarization gradients may be more specific for characterizing BrS than for overt cardiomyopathy. Ventricular arrhythmias in BrS are associated with a steep repolarization gradient, indicating phase 2 re-entry as a possible cause.
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Síndrome de Brugada , Eletrocardiografia , Mapeamento Epicárdico , Humanos , Síndrome de Brugada/fisiopatologia , Masculino , Pessoa de Meia-Idade , Feminino , Adulto , Técnicas Eletrofisiológicas Cardíacas/métodos , Idoso , Cardiomiopatias/fisiopatologiaRESUMO
Voltage-gated sodium channels (VGSCs) are transmembrane protein complexes that are vital to the generation and propagation of action potentials in nerve and muscle fibers. The canonical VGSC is generally conceived as a heterotrimeric complex formed by 2 classes of membrane-spanning subunit: an α-subunit (pore forming) and 2 ß-subunits (non-pore forming). NaV1.5 is the main sodium channel α-subunit of mammalian ventricle, with lower amounts of other α-subunits, including NaV1.6, being present. There are 4 ß-subunits (ß1-ß4) encoded by 4 genes (SCN1B-SCN4B), each of which is expressed in cardiac tissues. Recent studies suggest that in addition to assignments in channel gating and trafficking, products of Scn1b may have novel roles in conduction of action potential in the heart and intracellular signaling. This includes evidence that the ß-subunit extracellular amino-terminal domain facilitates adhesive interactions in intercalated discs and that its carboxyl-terminal region is a substrate for a regulated intramembrane proteolysis (RIP) signaling pathway, with a carboxyl-terminal peptide generated by ß1 RIP trafficked to the nucleus and altering transcription of various genes, including NaV1.5. In addition to ß1, the Scn1b gene encodes for an alternative splice variant, ß1B, which contains an identical extracellular adhesion domain to ß1 but has a unique carboxyl-terminus. Although ß1B is generally understood to be a secreted variant, evidence indicates that when co-expressed with NaV1.5, it is maintained at the cell membrane, suggesting potential unique roles for this understudied protein. In this review, we focus on what is known of the 2 ß-subunit variants encoded by Scn1b in heart, with particular focus on recent findings and the questions raised by this new information. We also explore data that indicate ß1 and ß1B may be attractive targets for novel antiarrhythmic therapeutics.