RARE DISEASE
Brugada syndrome
Brugada syndrome
Brugada syndrome
Synonyms: Idiopathic ventricular fibrillation, Brugada type
Synonyms: Idiopathic ventricular fibrillation, Brugada type
Synonyms: Idiopathic ventricular fibrillation, Brugada type
Drug discovery
2
drugs
With orphan designations
Overview
Brugada syndrome is an inherited cardiac ion channelopathy characterized by coved ST-segment elevation in right precordial leads (V1–V3) on ECG, predisposing to ventricular fibrillation and sudden cardiac death, particularly during rest or sleep. Diagnosis requires exclusion of structural heart disease and may involve sodium channel blocker challenge [1][6][9][18].
Burden
Mortality: Accounts for 4–12% of sudden cardiac deaths worldwide; 12–16% of diagnosed patients experience ventricular tachyarrhythmias [4][5][9].
Regional impact: Represents ~20% of sudden deaths in structurally normal hearts in Asia [4][17].
Economic: ICD-related complications (e.g., inappropriate shocks) occur in 20–30% of patients over 5 years [5][12][16].
Therapies
First-line: Implantable cardioverter-defibrillator (ICD) for high-risk patients (cardiac arrest survivors, syncope with spontaneous type 1 ECG) [3][5][9].
Adjunctive: Quinidine (class 1A antiarrhythmic) or isoproterenol for arrhythmia storm/episodes; catheter ablation of right ventricular outflow tract substrate in refractory cases [8][16][20].
Preventive: Fever control, avoidance of sodium channel blockers/other proarrhythmic drugs [6][14][18].
Categories: rare cardiac diseases, rare genetic diseases
Research Papers
886 drug discovery papers about Brugada syndrome, with 1 first-in-class and 18 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
886 drug discovery papers about Brugada syndrome, with 1 first-in-class and 18 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-13 | Expression Defects of SCN5A Common Polymorphisms S524Y and H558R in the Q1077 Splice Variant Can Be Rescued by Mexiletine.
The cardiac sodium channel NaV1.5, encoded by SCN5A, generates the inward sodium current required for myocardial excitability and impulse conduction. Loss-of-function mutations of NaV1.5 have been implicated in inherited arrhythmia syndromes, including Brugada syndrome, progressive cardiac conduction disease, and congenital sick sinus syndrome. The common SCN5A polymorphism H558R has reported minor allele frequencies ranging from 9.2% to 29% across ethnic groups, whereas S524Y has been described in individuals of African ancestry with a minor allele frequency of approximately 3.3%. Two splice variants of human SCN5A, one lacking a glutamine at position 1077 (Q1077del) and one containing Q1077, exist in every human in a 2:1 mRNA transcript ratio. We engineered these two polymorphisms in both backgrounds and reported that when S524Y and H558R were expressed in the Q1077del variant, current densities were normal. In the Q1077 variant, however, the current densities showed a dramatic reduction compared to those in the Q1077del variant or WT-Q1077. We previously reported that incubation with the antiarrhythmic drug mexiletine "rescued" expression deficiencies in the Brugada syndrome. Cells expressing S524Y/Q1077 and H558R/Q1077 were incubated for 48 h with or without mexiletine (500 μM), followed by drug washout before electrophysiological assessment. Mexiletine significantly increased current density for both S524Y/Q1077 and H558R/Q1077 compared with untreated cells, restoring current density to levels comparable to WT-Q1077. Flow cytometry using a FLAG-tagged channel demonstrated that mexiletine-mediated rescue was associated with increased cell-surface expression. The magnitude of the expression defects caused by H558R and S524Y in the Q1077 splice background is similar to that observed with arrhythmia-associated SCN5A mutations, and we show for the first time that the defects for both polymorphisms can be rescued with mexiletine. Although it is unknown whether they result in heightened arrhythmia susceptibility in patients homozygous for the minor allele, our result may have implications for therapy for mutations with loss-of-function phenotypes modified by these common polymorphisms.
2026-08-04 | Islands of Fractionation for Automated Fractionation Mapping in Epicardial Brugada Syndrome Substrate Ablation.
Brugada syndrome epicardial RVOT ablation reduces VF, but procedural endpoints remain debated. Automated fractionation maps are often interpreted as scattered points, which may reflect artifacts. We propose Islands of Fractionation (IOF), a framework comparing EnSite X fractionation count settings against voltage-defined lesion-effect reference region. This case series included six Brugada syndrome patients undergoing epicardial substrate ablation. Mapping was performed in sinus rhythm using EnSite X with an Advisor HD Grid catheter. Automated fractionation maps were generated with the EnSite X CFE-count algorithm using refractory settings of 14 and 20 ms. Abnormal points were defined as fractionation count ≥3; lesion-effect reference region was defined by voltage change (pre >0.5 mV, post <0.3 mV). Island overlap was quantified using DBSCAN clustering and mesh-based area estimation. IOF revealed a consistent coverage-parsimony trade-off between refractory settings. The 14-ms setting produced broader islands with higher reference-region coverage (median overlap 84.6% [IQR 80.8-93.7]) but larger extraneous mapped area (up to 72.9 cm2). The 20-ms setting produced more compact islands with markedly reduced extraneous area (0.0-34.8 cm2) but lower coverage (59.9% [IQR 37.2-74.7]). In parallel, fractionation burden within the ablated region decreased substantially after ablation in both settings (median total burden reduction 86% vs 93%), supporting lesion-effect concordance of automated fractionation metrics. IOF provides an island-based framework for interpreting automated fractionation mapping and describing its spatial concordance with lesion-effect regions. In this retrospective series, 14 ms favored broader coverage, whereas 20 ms favored greater parsimony.
2026-07-17 | Late INa as a Therapeutic Target: New Strategies, Computational Modelling, Drug Development, and Clinical Translation.
The Nav1.5 channel, a major isoform of voltage-gated sodium ion channel, is mainly found in ventricular cardiomyocytes, playing a key role in generating essential cardiac action potentials for normal heart rhythms. Mutations in Nav1.5 have been associated with severe heart conditions such as long QT syndrome, Brugada syndrome, cardiac conduction disorders, atrial fibrillation, and dilated cardiomyopathy. Recent research has linked Nav1.5 to cardiac fibrosis and proposed its role in non-cardiac illnesses, including specific neurological disorders and cancers, subjects that will be reviewed in this paper. On the other hand, sodium-glucose cotransporter 2 inhibitors (SGLT2i), initially designed to manage diabetes by facilitating glucose excretion through urine, have demonstrated unexpected and encouraging cardioprotective benefits in clinical trials. This review compares the important SGLT2 inhibitors empagliflozin, dapagliflozin, and canagliflozin in terms of their interactions with Nav1.5 and their therapeutic effects on the heart. We also investigate new medications and compounds being developed to regulate Nav1.5 function, providing a preview of potential future treatments. Past attempts to develop late INa inhibitors and difficulties in transitioning from the research phase to clinical trials have raised doubts about the optimal design of such trials. In addition, we cover the applications of molecular dynamics simulations in understanding the mechanism of action of these drugs within the Nav1.5 channel computationally. We hope that this review identifies new opportunities to generate more effective inhibitors using novel methods and advanced multiscale molecular modelling techniques.
2026-07-16 | Case Report: Lurasidone-Induced Type 2 Brugada Pattern in a Pediatric Patient.
Brugada syndrome, a cardiac channelopathy, manifests with ventricular arrhythmia. Diagnosis relies on a type 1 Brugada electrocardiogram (ECG) pattern, while type 2 and type 3 patterns may necessitate electrophysiologic testing to uncover an underlying type 1 Brugada pattern. Differentiation between these patterns is important, as type 1 patterns pose a significantly greater risk of arrhythmia relative to types 2 and 3 counterparts. A 14-year-old male with autism presented after a syncopal episode following a lurasidone dosage increase. His ECG revealed a type 2 Brugada pattern. He was monitored overnight in the pediatric intensive care unit, where he remained asymptomatic. After being discharged with a Holter monitor, a quaternary hospital's procainamide challenge test weeks later contradicted an official diagnosis of Brugada syndrome, as dictated by elucidation of a type 1 Brugada pattern. After reverting to the initial lurasidone dose, a follow-up ECG after two months showed no Brugada pattern. In syncope cases, an ECG is crucial for identifying arrhythmogenic causes, including Brugada syndrome. This case highlights an ECG suggestive of Brugada syndrome with negative pharmacological tests and resolution post-discontinuation of the offending agent. Emergency physicians should be vigilant for Brugada and long QT syndromes in patients on antipsychotic medications.
2026-06-12 | Dynamic Expression of the Type 1 Brugada ECG Pattern During Tilt Table Testing Using Continuous High Precordial Lead Positioning.
Background/Objectives: The Type 1 Brugada ECG pattern (BrP1) fluctuates according to autonomic influences. Tilt table testing induces changes in both sympathetic and parasympathetic activity. It may provide insights into the dynamic behavior of BrP1 when combined with high-precordial lead placement. However, the clinical significance of BrP1 variability during tilt table testing remains poorly defined. Methods: This cross-sectional study evaluated patients with confirmed Brugada syndrome who underwent tilt table testing with continuous ECG monitoring using high-precordial leads. BrP1 behavior was assessed during predefined phases: baseline supine position, orthostatic tilt, nitrate administration, recovery, and syncope when present. Subsequently, clinical characteristics and test results were analyzed for associations with dynamic BrP1 expression. Results: Forty-four patients (mean age 49 years; 72.7% men) were included. Thirty-five patients (79.5%) had a spontaneous type 1 Brugada ECG pattern, and nine (20.5%) had a drug-induced pattern. BrP1 expression varied dynamically/heterogeneously during tilt table testing. No patient without BrP1 at admission developed the pattern during tilt phases. Thirty patients (68.1%) remained negative throughout testing, while five lost the pattern during the test (11.3%), and nine (20.4%) showed persistent BrP1 in all phases. Persistent BrP1 was associated with more frequent presumed arrhythmic syncope and implantable cardioverter defibrillator implantation (p < 0.05). No atrial or ventricular arrhythmias or device-related complications occurred. Conclusions: Tilt table testing with high precordial leads does not unmask BrP1 and should not be used as a diagnostic provocation tool. However, it allows for the characterization of autonomic modulation and phenotypic stability in Brugada syndrome. Any potential prognostic relevance of dynamic BrP1 behavior remains speculative and requires evaluation in adequately powered prospective studies.
gene therapies
2026-03-09 | Characterization of the R893C NaV1.5 mutation in Brugada syndrome.
Brugada syndrome (BrS) is a genetically determined cardiac arrhythmogenic syndrome with increased risk of sudden cardiac death. BrS is mostly caused by mutations in SCN5A gene encoding the primary ɑ-subunit of the cardiac sodium channel NaV1.5. We aimed at characterizing the functional alterations caused by the R893C mutation, identified in a proband diagnosed with BrS, and establishing whether the mutation is associated with BrS. Although several mutations have been reported in the close vicinity of R893, the functional role of this region remains unknown and, in addition, exploring SCN5A mutations in patients with inherited arrhythmogenic syndromes is critical for understanding the pathogenesis of arrhythmias. The mutations were introduced by site-directed mutagenesis. The variants were transiently expressed in CHO cells and potassium currents were measured using the whole-cell patch clamp technique. Patch clamp recordings have demonstrated that R893C almost completely abolished the sodium current, INa, though the mutation did not exert dominant-negative effect on wild-type NaV1.5 channels. We also observed significant decrease in channel activation and a depolarized shift of steady-state inactivation curve, however, the kinetics of inactivation and recovery from fast inactivation were not changed by the mutation. Moreover, the reducing agent Dithiotreitol partially restored the normal function of NaV1.5 in the R893C mutant highlighting a likely mechanism for loss of conduction via formation of disulphide bridges. We showed that R893H channels also failed to produce any detectable INa that confirms the importance of the highly conserved R893 in gating. Our study reveals R893C is a loss-of-function mutation with altered electrophysiological characteristics of NaV1.5. Thus, R893C may contribute to the BrS phenotype of the proband. Our findings may facilitate the understanding of the mechanisms of arrhythmogenesis in BrS, as it helps to identify mutational hotspots in BrS. Moreover, our work may improve novel gene therapy and new therapeutic drug design targeting NaV1.5 channelopathies.
2026-01-23 | Brugada Syndrome: New Implications for Heterozygous Carriers of the Pathogenic SCN5A c.689T>C(p.Ile230Thr) Variant.
Pathogenic variants in the SCN5A gene and its subunits have been identified in individuals with Brugada Syndrome. One such SCN5A variant, c.689T>C(p.Ile230Thr), was previously reported as disease-causing only in homozygous individuals, with heterozygous carriers being unaffected. Presently, we discuss the case of an adolescent patient who presented for further evaluation of pre-syncopal episodes with ECG findings consistent with Brugada pattern who on further genetic evaluation was found to be a heterozygous carrier of the pathogenic SCN5A c.689T>C(p.Ile230Thr) variant. This unique case allows us to think differently about heterozygous carriers for this specific mutation, and while the risk for developing a life-threatening arrhythmia may be low, heterozygous carriers may benefit from clinical monitoring to reduce the potential for adverse cardiac outcomes. A 17-year-old male presented after a pre-syncopal episode whose ECG demonstrated sinus bradycardia and type 1 Brugada pattern. Genetic testing revealed this patient to be a heterozygous carrier of a pathogenic SCN5A variant (c.689T>C(p.Ile230Thr)) which was also found in his father and brother, neither of whom had symptoms but did have ECG changes. He was diagnosed with Brugada Syndrome and advised to avoid known triggers. This case highlights the potential risk of severe cardiac arrhythmias in heterozygous carriers of the SCN5A c.689T>C (p.Ile230Thr) variant, previously thought to be benign. The 17-year-old patient, along with his asymptomatic father and brother who also carried the variant, exhibited ECG changes consistent with Brugada pattern. This finding suggests that heterozygous carriers may require closer monitoring and early intervention to prevent future life-threatening cardiac events.
2025-10-30 | Gene Therapy for Inherited Cardiac Arrhythmias.
Inherited cardiac arrhythmias are genetic disorders that impact the heart's electrical circuitry. These disorders are caused by inherited mutations and markedly increase the mortality risk of affected individuals. Conventional treatments, such as pharmacological agents for rate and rhythm control or surgical interventions, are often not efficacious and cause long-term complications. Gene therapy has recently emerged as a feasible and potentially curative approach for treating inherited cardiac arrhythmia syndromes. Advancements in elucidating the molecular mechanisms, pinpointing essential candidate genes, and improving gene delivery have rendered gene therapy as a feasible treatment alternative. This review examines recent studies on gene therapy applications in Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, long QT syndrome, familial atrial fibrillation, and arrhythmogenic cardiomyopathy. Additionally, we analyze current advancements in viral and non-viral gene delivery methods, highlighting their therapeutic potential and related challenges.
2025-10-22 | CRISPR/Cas9-Based Gene Editing for Correcting Inherited Channelopathies.
Inherited cardiac channelopathies, including long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia, are major causes of arrhythmic morbidity and sudden cardiac death in young individuals. Current therapies, such as pharmacologic agents, implantable cardioverter-defibrillators, and lifestyle modifications, reduce risk but fail to correct the underlying genetic substrate, creating an urgent need for curative strategies. CRISPR/Cas9 genome editing has emerged as a transformative platform with the potential to directly repair pathogenic variants. Recent advances in base and prime editing, together with novel viral and nonviral delivery platforms, have enabled precise correction of disease-causing mutations in preclinical models. Proof-of-concept studies using animal models and patient-derived iPSC-cardiomyocytes demonstrate restoration of electrophysiologic stability, suppression of arrhythmias, and durable functional benefit. Nevertheless, translational challenges remain, including off-target effects, delivery barriers, immune responses, scalability, and ethical considerations. Ongoing innovations-such as engineered nucleases, improved delivery vectors, immunogenicity mitigation strategies, and integration of artificial intelligence for personalized guide design-are expected to accelerate clinical translation. This review synthesizes current knowledge on CRISPR-based strategies for inherited channelopathies, highlighting both the promise and limitations of gene editing as a path toward durable, disease-modifying therapies capable of preventing sudden cardiac death.
2025-08-26 | Gene Therapy for Cardiac Arrhythmias: Mechanisms, Modalities and Therapeutic Applications.
Cardiac arrhythmias remain a major source of morbidity and mortality, often stemming from molecular and structural abnormalities that are insufficiently addressed by current pharmacologic and interventional therapies. Gene therapy has emerged as a transformative approach, offering precise and durable interventions that directly target the arrhythmogenic substrate. Across the spectrum of inherited and acquired arrhythmias-including long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, atrial fibrillation, and post-infarction ventricular tachycardia-gene-based strategies such as allele-specific silencing, gene replacement, CRISPR-mediated editing, and suppression-and-replacement constructs are showing growing translational potential. Advances in delivery platforms, including cardiotropic viral vectors, lipid nanoparticle-encapsulated mRNA, and non-viral reprogramming tools, have further enhanced the specificity and safety of these approaches. Additionally, innovative applications such as biological pacemaker development and mutation-agnostic therapies underscore the versatility of genetic modulation. Nonetheless, significant challenges remain, including vector tropism, immune responses, payload limitations, and the translational gap between preclinical models and human electrophysiology. Integration of patient-derived cardiomyocytes, computational simulations, and large-animal studies is expected to accelerate clinical translation. This review provides a comprehensive synthesis of the mechanistic rationale, therapeutic strategies, delivery platforms, and translational frontiers of gene therapy for cardiac arrhythmias.
oligonucleotides
2025-10-20 | Characterization of a Splice-Altering Variant in SCN5A Associated With Brugada Syndrome - Insights Into Splice Error Correction.
Brugada syndrome (BrS) is an arrhythmic disease associated with SCN5A loss-of-function variants. We identified a novel single nucleotide substitution, SCN5A c.1338G>A, in the last codon of exon10 in a patient with drug-induced BrS. The aim of this study was to investigate the impact of this splice-altering variant and examine whether antisense oligonucleotides (ASOs) could correct the splice alteration. Genomic DNA was extracted from the patient's blood lymphocytes. Coding exons of inherited arrhythmia genes were screened and SCN5A c.1338G>A was identified. SpliceAI predicted its prominent potential to alter splicing among 168 single nucleotide variants in the SCN5A region including 10 variants with allele frequency (AF) <0.01, and the usage of a cryptic splice donor site 4 bp downstream from the authentic splice donor site. Minigene splicing reporter assays were performed using HEK-293 cells and induced pluripotent stem cells-cardiomyocytes, and successfully demonstrated a dominant selection of the predicted splice site. Three different ASOs were tested in the same platform. Although the ASOs reduced the production of splice error products, they did not succeed in increasing authentically spliced products. We confirmed a splice site alteration by SCN5A c.1338G>A and propose extended use of SpliceAI for screening a target genomic region. The attempts to correct mis-splicing near the canonical splice site were not entirely successful, so further development of technology is awaited.
2024-01-11 | The Role of MAPRE2 and Microtubules in Maintaining Normal Ventricular Conduction.
Brugada syndrome is associated with loss-of-function SCN5A variants, yet these account for only ≈20% of cases. A recent genome-wide association study identified a novel locus within MAPRE2, which encodes EB2 (microtubule end-binding protein 2), implicating microtubule involvement in Brugada syndrome. A mapre2 knockout zebrafish model was generated using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated protein 9) and validated by Western blot. Larval hearts at 5 days post-fertilization were isolated for voltage mapping and immunocytochemistry. Adult fish hearts were used for ECG, patch clamping, and immunocytochemistry. Morpholinos were injected into embryos at 1-cell stage for knockdown experiments. A transgenic zebrafish line with cdh2 tandem fluorescent timer was used to study adherens junctions. Microtubule plus-end tracking and patch clamping were performed in human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) with MAPRE2 knockdown and knockout, respectively. Voltage mapping of mapre2 knockout hearts showed a decrease in ventricular maximum upstroke velocity of the action potential and conduction velocity, suggesting loss of cardiac voltage-gated sodium channel function. ECG showed QRS prolongation in adult knockout fish, and patch clamping showed decreased sodium current density in knockout ventricular myocytes and arrhythmias in knockout iPSC-CMs. Confocal imaging showed disorganized adherens junctions and mislocalization of mature Ncad (N-cadherin) with mapre2 loss of function, associated with a decrease of detyrosinated tubulin. MAPRE2 knockdown in iPSC-CMs led to an increase in microtubule growth velocity and distance, indicating changes in microtubule dynamics. Finally, knockdown of ttl encoding tubulin tyrosine ligase in mapre2 knockout larvae rescued tubulin detyrosination and ventricular maximum upstroke velocity of the action potential. Genetic ablation of mapre2 led to a decrease in voltage-gated sodium channel function, a hallmark of Brugada syndrome, associated with disruption of adherens junctions, decrease of detyrosinated tubulin as a marker of microtubule stability, and changes in microtubule dynamics. Restoration of the detyrosinated tubulin fraction with ttl knockdown led to rescue of voltage-gated sodium channel-related functional parameters in mapre2 knockout hearts. Taken together, our study implicates microtubule dynamics in the modulation of ventricular conduction.
2023-11-01 | The role of MAPRE2 and microtubules in Brugada syndrome pathogenesis
Abstract Background Brugada syndrome (BrS) is associated with loss-of-function variants in SCN5A (encoding NaV1.5), which are found in only ∼20% of patients. Recent genome-wide association studies identified a novel locus within an intron of MAPRE2 (encoding microtubule end-binding protein 2, EB2), implicating microtubule (MT) involvement in BrS. Purpose To understand the role of MAPRE2 and MT in BrS pathogenesis. Methods A mapre2 knock-out (KO) zebrafish model was generated using CRISPR/Cas9 and validated by western blot. Larval hearts at 5 day-post-fertilization (dpf) were isolated for voltage mapping and immunohistochemistry with confocal imaging. Morpholino targeting mapre2 or ttl (encoding tubulin tyrosine ligase) were injected into zebrafish embryos at the one-cell stage. A transgenic zebrafish line with cdh2 (encoding N-cadherin) tandem fluorescent timer (tFT) was used to study adherens junction. MT plus-end tracking experiments were performed in iPSC-derived cardiomyocytes (CM) with MAPRE2 knockdown (KD) using siRNA. ECG was recorded in adult fish. Results Voltage mapping of larval hearts (14 WTs vs. 19 KOs) showed a significant decrease in ventricular conduction velocity (17.4±1.5 vs. 13.4±0.8 mm/s; p<0.05) and action potential upstroke velocity (Vmax; 86.1±3.6 vs. 73.9±3.2 1/s; p<0.05), suggesting loss of cardiac NaV function. Correspondingly, ECG of adult fish (11 WTs vs. 10 KOs) showed a significant increase in QRS duration (27.8±0.5 vs. 32.3±0.7 ms; p<0.0001). Confocal imaging of KO hearts showed disorganized adherens junction based on N-cadherin staining. Similarly, morpholino KD of mapre2 in the cdh2 tFT line showed ∼40% mislocalization of mature N-cadherin relative to ZO-1 staining in larval ventricles (8 KDs vs 9 control hearts; p<0.05), suggesting disruption of adherens junction. In terms of MT, immunohistochemistry showed a 23% decrease of detyrosinated tubulin relative to total alpha tubulin in KO hearts (16 vs. 8 WT hearts; p<0.01). MAPRE2 KD in iPSC-CM (337 control vs. 285 KD MT in 4 sets of cells) showed an increase in MT velocity (7.9±0.2 vs. 8.8±0.2 µm/min; p<0.001), distance (5.8±0.2 vs. 7.1±0.2 µm; p<0.0001), and duration (46.2±1.4 vs. 52.2±1.6 s; p<0.001), suggesting changes to MT dynamics. Finally, morpholino KD of ttl in mapre2 KO embryos restored the fraction of detyrosinated tubulin (46% increase; 16 controls vs. 16 KDs; p<0.01) as well as Vmax (74.3±3.0 vs. 88.3±2.1 1/s; 13 controls vs. 9 KDs; p<0.01) to WT levels. Conclusion Genetic ablation of mapre2 led to a decrease in cardiac NaV function, a hallmark of BrS. This is associated with disruption of adherens junction, a decrease of detyrosinated tubulin as a marker of MT stability, and changes in MT dynamics. Restoration of detyrosinated tubulin fraction with ttl KD led to a rescue of NaV function in zebrafish larval hearts. Taken together, MAPRE2 loss-of-function may contribute to BrS pathogenesis by disruption of adherens junction via changes in MT dynamics.
2016-09-28 | Embryonic type Na+ channel β-subunit, SCN3B masks the disease phenotype of Brugada syndrome
SCN5A is abundant in heart and has a major role in INa. Loss-of-function mutation in SCN5A results in Brugada syndrome (BrS), which causes sudden death in adults. It remains unclear why disease phenotype does not manifest in the young even though mutated SCN5A is expressed in the young. The aim of the present study is to elucidate the timing of the disease manifestation in BrS. A gain-of-function mutation in SCN5A also results in Long QT syndrome type 3 (LQTS3), leading to sudden death in the young. Induced pluripotent stem cells (iPSCs) were generated from a patient with a mixed phenotype of LQTS3 and BrS with the E1784K SCN5A mutation. Here we show that electrophysiological analysis revealed that LQTS3/BrS iPSC-derived cardiomyocytes recapitulate the phenotype of LQTS3 but not BrS. Each β-subunit of the sodium channel is differentially expressed in embryonic and adult hearts. SCN3B is highly expressed in embryonic hearts and iPSC-derived cardiomyocytes. A heterologous expression system revealed that INa of mutated SCN5A is decreased and SCN3B augmented INa of mutated SCN5A. Knockdown of SCN3B in LQTS3/BrS iPSC-derived cardiomyocytes successfully unmasked the phenotype of BrS. Isogenic control of LQTS3/BrS (corrected-LQTS3/BrS) iPSC-derived cardiomyocytes gained the normal electrophysiological properties.
2015-10-01 | Genetic defects in a His-Purkinje system transcription factor, IRX3, cause lethal cardiac arrhythmias.
Ventricular fibrillation (VF), the main cause of sudden cardiac death (SCD), occurs most frequently in the acute phase of myocardial infarction: a certain fraction of VF, however, develops in an apparently healthy heart, referred as idiopathic VF. The contribution of perturbation in the fast conduction system in the ventricle, the His-Purkinje system, for idiopathic VF has been implicated, but the underlying mechanism remains unknown. Irx3/IRX3 encodes a transcription factor specifically expressed in the His-Purkinje system in the heart. Genetic deletion of Irx3 provides a mouse model of ventricular fast conduction disturbance without anatomical or contraction abnormalities. The aim of this study was to examine the link between perturbed His-Purkinje system and idiopathic VF in Irx3-null mice, and to search for IRX3 genetic defects in idiopathic VF patients in human. Telemetry electrocardiogram recording showed that Irx3-deleted mice developed frequent ventricular tachyarrhythmias mostly at night. Ventricular tachyarrhythmias were enhanced by exercise and sympathetic nerve activation. In human, the sequence analysis of IRX3 exons in 130 probands of idiopathic VF without SCN5A mutations revealed two novel IRX3 mutations, 1262G>C (R421P) and 1453C>A (P485T). Ventricular fibrillation associated with physical activities in both probands with IRX3 mutations. In HL-1 cells and neonatal mouse ventricular myocytes, IRX3 transfection up-regulated SCN5A and connexin-40 mRNA, which was attenuated by IRX3 mutations. IRX3 genetic defects and resultant functional perturbation in the His-Purkinje system are novel genetic risk factors of idiopathic VF, and would improve risk stratification and preventive therapy for SCD in otherwise healthy hearts.
cell therapies
2026-02-13 | [Cardiac arrhythmias-Cellular mechanisms, consequences and challenges in the diagnostics using human models].
Cardiac arrhythmias significantly contribute to morbidity and mortality in cardiovascular diseases. Hereditary ion channel disorders, including Brugada syndrome, long/short QT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT), represent critical entities with elevated risk of malignant ventricular arrhythmias. Although beta-blockers, ion channel modulators and implantable cardioverter defibrillators (ICD) are available and the indications for them are increasingly based on genetic analyses, variants of uncertain significance (VUS) substantially impair the risk stratification. Atrial tachyarrhythmias, particular atrial fibrillation, can cause an often-reversible arrhythmia-induced cardiomyopathy (AIC). Pathophysiologically, the Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays an important role in atrial and ventricular arrhythmias. It can be activated by various pathological triggers, such as high heart rate, neuroendocrine activation and oxidative stress, the latter often resulting from mechano-energetic uncoupling. The development of effective treatment options for arrhythmia-associated cardiovascular diseases requires the use of human model systems in addition to animal experimental approaches, due to the genetic heterogeneity and systemic comorbidities. Patient-specific cardiac stem cell-models enable the classification of VUS and personalised drug testing. The integration of new methodological approaches into existing animal experimental approaches thus paves the way for functionally validated precision medicine and could fundamentally transform the treatment of both disease patterns.
2024-11-27 | The Role of Human-Induced Pluripotent Stem Cells in Studying Cardiac Channelopathies.
Cardiac channelopathies are inherited diseases that increase the risk of sudden cardiac death. While different genes have been associated with inherited channelopathies, there are still subtypes, e.g., catecholaminergic polymorphic ventricular tachycardia and Brugada syndrome, where the genetic cause remains unknown. Various models, including animal models, heterologous expression systems, and the human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSCs-CMs) model, have been used to study the pathophysiological mechanisms of channelopathies. Recently, researchers have focused on using hiPSCs-CMs to understand the genotype-phenotype correlation and screen drugs. By combining innovative techniques such as Clustered Regularly Interspaced Short Palindromic Repeats/Clustered Regularly Interspaced Short Palindromic Repeats associated protein 9 (CRISPR/Cas9)-mediated genome editing, and three-dimensional (3D) engineered heart tissues, we can gain new insights into the pathophysiological mechanisms of channelopathies. This approach holds promise for improving personalized drug treatment. This review highlights the role of hiPSCs-CMs in understanding the pathomechanism of Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia and how these models can be utilized for drug screening.
2021-11-15 | Modeling genetic cardiac channelopathies using induced pluripotent stem cells - Status quo from an electrophysiological perspective.
Long QT syndrome (LQTS), Brugada syndrome (BrS), and catecholaminergic polymorphic ventricular tachycardia (CPVT) are genetic diseases of the heart caused by mutations in specific cardiac ion channels and are characterized by paroxysmal arrhythmias, which can deteriorate into ventricular fibrillation. In LQTS3 and BrS different mutations in the SCN5A gene lead to a gain-or a loss-of-function of the voltage-gated sodium channel Nav1.5, respectively. Although sharing the same gene mutation, these syndromes are characterized by different clinical manifestations and functional perturbations and in some cases even present an overlapping clinical phenotype. Several studies have shown that Na+ current abnormalities in LQTS3 and BrS can also cause Ca2+-signaling aberrancies in cardiomyocytes (CMs). Abnormal Ca2+ homeostasis is also the main feature of CPVT which is mostly caused by heterozygous mutations in the RyR2 gene. Large numbers of disease-causing mutations were identified in RyR2 and SCN5A but it is not clear how different variants in the SCN5A gene produce different clinical syndromes and if in CPVT Ca2+ abnormalities and drug sensitivities vary depending on the mutation site in the RyR2. These questions can now be addressed by using patient-specific in vitro models of these diseases based on induced pluripotent stem cells (iPSCs). In this review, we summarize different insights gained from these models with a focus on electrophysiological perturbations caused by different ion channel mutations and discuss how will this knowledge help develop better stratification and more efficient personalized therapies for these patients.
2017-08-18 | Induced pluripotent stem cell technology and inherited arrhythmia syndromes
Inherited arrhythmia syndromes, including familial long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and Brugada syndrome, can cause life-threatening arrhythmias and are responsible for a significant proportion of sudden deaths in the young. Identification of genetic mutations and pathophysiological changes that underlie disease development can inform clinical practice and guide novel drug development. However, disease mechanisms in a large number of patients remain elusive and pharmacologic treatment is suboptimal, so many patients rely on implantable cardioverter–defibrillator therapy. Induced pluripotent stem cell models of disease facilitate analysis of disease mechanisms in patient-specific cardiomyocytes, overcoming limitations of animal models and human tissue restrictions. This review outlines how studies using induced pluripotent stem cell–derived cardiomyocytes are contributing to our understanding of the mechanisms that underpin disease pathogenesis and their potential to facilitate new pharmacologic therapies and personalized medicine. Inherited arrhythmia syndromes, including familial long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and Brugada syndrome, can cause life-threatening arrhythmias and are responsible for a significant proportion of sudden deaths in the young. Identification of genetic mutations and pathophysiological changes that underlie disease development can inform clinical practice and guide novel drug development. However, disease mechanisms in a large number of patients remain elusive and pharmacologic treatment is suboptimal, so many patients rely on implantable cardioverter–defibrillator therapy. Induced pluripotent stem cell models of disease facilitate analysis of disease mechanisms in patient-specific cardiomyocytes, overcoming limitations of animal models and human tissue restrictions. This review outlines how studies using induced pluripotent stem cell–derived cardiomyocytes are contributing to our understanding of the mechanisms that underpin disease pathogenesis and their potential to facilitate new pharmacologic therapies and personalized medicine.
2016-11-18 | Will cardiac optogenetics find the way through the obscure angles of heart physiology?
Optogenetics is a technique exploded in the last 10 years, which revolutionized several areas of biological research. The brightest side of this technology is the use of light to modulate non-invasively, with high spatial resolution and millisecond time scale, excitable cells genetically modified to express light-sensitive microbial ion channels (opsins). Neuroscience has first benefited from such fascinating strategy, in intact organisms. By shining light to specific neuronal subpopulations, optogenetics allowed unearth the mechanisms involved in cell-to-cell communication within the context of intact organs, such as the brain, formed by complex neuronal circuits. More recently, scientists looked at optogenetics as a tool to answer some of the questions, remained in the dark, of cardiovascular physiology. In this review, we focus on the application of optogenetics in the study of the heart, a complex multicellular organ, homing different populations of excitable cells, spatially and functionally interconnected. Moving from the first proof-of-principle works, published in 2010, to the present time, we discuss the in vitro and in vivo applications of optogenetics for the study of electrophysiology of the different cardiac cell types, and for the dissection of cellular mechanisms underlying arrhythmias. We also present how molecular biology and technology foster the evolution of cardiac optogenetics, with the aim to further our understanding of fundamental questions in cardiac physiology and pathology. Finally, we confer about the therapeutic potential of such biotechnological strategy for the treatment of heart rhythm disturbances (e.g. cardiac pacing, cardioversion).
other
2026-04-22 | Brugada phenocopy induced by Russell's viper envenomation: resolution following anti-snake venom therapy.
Russell's viper envenomation is known to cause complications such as coagulopathy, acute kidney injury and haemolysis. Cardiac involvement, though rare, has been reported in the form of arrhythmias, myocardial infarction and ECG changes such as ST-segment elevation or T-wave inversions. We report a case of a middle-aged farmer who presented to our centre with Russell's viper envenomation, characterised by local envenomation, coagulopathy, haemolysis and ocular manifestations. His ECG showed a Brugada pattern, with no evidence of any structural cardiac abnormalities or elevated cardiac enzymes. A repeat ECG performed 72 hours after anti-snake venom therapy showed resolution of the ECG findings. A diagnosis of Brugada phenocopy secondary to Russell's viper envenomation was made. The most likely mechanism causing a Brugada phenocopy in Russell's viper envenomation may be due to phospholipase A2 present in the venom, causing alteration in the cardiac voltage-gated sodium channels.
2025-01-01 | Phenotypes in Brugada syndrome with different genotypes triggered by fever or inflammation using gene-edited iPSCs
Abstract Background Fever or inflammation state may enhance the Brugada syndrome (BrS) phenotype in some but not all patients. However, the underlying mechanism in human cardiomyocytes has not yet been clarified. Methods Human induced pluripotent stem cell (hiPSC) lines generated from fibroblasts of three BrS patients harboring variants in SCN10A (abbreviated as BrS1) and CACNB2 (abbreviated as BrS2), SCN5A (abbreviated as BrS3) and one healthy donor (abbreviated as WT) and a site-corrected (using CRISPR/Cas9) hiPSC line of each BrS patient (abbreviated as isogenic1, isogenic2 and isogenic3) were used for differentiation into cardiomyocytes (hiPSC-CMs). Western blot, patch clamp and calcium transient analyses were carried out. Results All 3 BrS cell lines showed a significantly reduced peak sodium current (INa) compared with isogenic or WT cells at baseline. Hyperthermia challenge (40 °C) significantly decreased INa and enhanced arrhythmogeneity in BrS1 and BrS3 but not in BrS2 cells. The hyperthermia effects involved PKA reduction. The lipopolysaccharide (LPS) challenge exacerbated the phenotype in electrophysiological characteristics in all 3 BrS cell lines. ROS-Blocker abolished the LPS effects in all BrS hiPSC-CMs, while an interleukin-6 receptor blocker abolished the proarrhythmic effect of LPS in BrS1 and BrS3 hiPSC-CMs but not in hiPSC-CMs of BrS2. Conclusions Hyperthermia exacerbated the BrS phenotype in hiPSC-CMs carrying SCN10A and SCN5A variants, whereas LPS aggravated the phenotype in all three BrS variants through distinct mechanisms; Hyperthermia and LPS effects on BrS phenotype may be genotype-dependent. Graphical abstract
2022-06-30 | Trafficking and Gating Cooperation Between Deficient Nav1.5-mutant Channels to Rescue INa
Pathogenic variants in SCN5A, the gene encoding the cardiac Na+ channel α-subunit Nav1.5, result in life-threatening arrhythmias, e.g., Brugada syndrome, cardiac conduction defects and long QT syndrome. This variety of phenotypes is underlied by the fact that each Nav1.5 mutation has unique consequences on the channel trafficking and gating capabilities. Recently, we established that sodium channel α-subunits Nav1.5, Nav1.1 and Nav1.2 could dimerize, thus, explaining the potency of some Nav1.5 pathogenic variants to exert dominant-negative effect on WT channels, either by trafficking deficiency or coupled gating.The present study sought to examine whether Nav1.5 channels can cooperate, or transcomplement each other, to rescue the Na+ current (INa). Such a mechanism could contribute to explain the genotype-phenotype discordance often observed in family members carrying Na+-channel pathogenic variants.Patch-clamp and immunocytochemistry analysis were used to investigate biophysical properties and cellular localization in HEK293 cells and rat neonatal cardiomyocytes transfected respectively with WT and 3 mutant channels chosen for their particular trafficking and/or gating properties.As previously reported, the mutant channels G1743R and R878C expressed alone in HEK293 cells both abolished INa, G1743R through a trafficking deficiency and R878C through a gating deficiency. Here, we showed that coexpression of both G1743R and R878C nonfunctioning channels resulted in a partial rescue of INa, demonstrating a cooperative trafficking of Nav1.5 α-subunits. Surprisingly, we also showed a cooperation mechanism whereby the R878C gating-deficient channel was able to rescue the slowed inactivation kinetics of the C-terminal truncated R1860X (ΔCter) variant, suggesting coupled gating.Altogether, our results add to the evidence that Nav channels are able to interact and regulate each other's trafficking and gating, a feature that likely contributes to explain the genotype-phenotype discordance often observed between members of a kindred carrying a Na+-channel pathogenic variant.
2022-03-24 | Transmembrane protein 168 mutation reduces cardiomyocyte cell surface expression of Nav1.5 through αB-crystallin intracellular dynamics.
Transmembrane protein 168 (TMEM168) was found to be localized on the nuclear membrane. A heterozygous mutation (c.1616G>A, p. R539Q) in TMEM168 was identified in patients with Brugada syndrome. This mutation reduced expression of cardiomyocyte sodium channel Nav1.5 via Nedd4-2 E3 ubiquitin ligase-induced ubiquitination and degradation. However, the detailed molecular mechanism provoked by the TMEM168 mutant remains unclear. Here, we demonstrated that small heat shock protein αB-crystallin, which can bind to Nav1.5 and Nedd4-2 and interfere with the association of both proteins, was strongly recruited from the cell surface to the perinuclear region because of the much higher affinity of αB-crystallin with the TMEM168 mutant than with wild-type TMEM168. Following knockdown of αB-crystallin in HL-1 cardiomyocytes, the interaction of Nav1.5 with Nedd4-2 was increased, despite the reduced expression of Nav1.5. Moreover, reduction of Nav1.5 expression by αB-crystallin knockdown was rescued in the presence of a proteasome inhibitor MG-132, suggesting the importance of the αB-crystallin-modulated ubiquitin-proteasome system for the stability of Nav1.5 expression. Collectively, the balance of molecular interactions among Nav1.5, Nedd4-2 and αB-crystallin plays a role in the regulation of cardiomyocyte cell surface expression of Nav1.5, and the TMEM168 mutant disturbs this balance, resulting in a decrease in Nav1.5 expression.
2018-11-26 | Electroanatomic and Pathologic Right Ventricular Outflow Tract Abnormalities in Patients With Brugada Syndrome
The prevalence and significance of structural abnormalities in Brugada syndrome (BrS) are still largely debated. The authors investigated the relationship between genetic background, electroanatomic abnormalities, and pathologic substrate in BrS. 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. 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). 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.
small molecules
2026-08-13 | Expression Defects of SCN5A Common Polymorphisms S524Y and H558R in the Q1077 Splice Variant Can Be Rescued by Mexiletine.
The cardiac sodium channel NaV1.5, encoded by SCN5A, generates the inward sodium current required for myocardial excitability and impulse conduction. Loss-of-function mutations of NaV1.5 have been implicated in inherited arrhythmia syndromes, including Brugada syndrome, progressive cardiac conduction disease, and congenital sick sinus syndrome. The common SCN5A polymorphism H558R has reported minor allele frequencies ranging from 9.2% to 29% across ethnic groups, whereas S524Y has been described in individuals of African ancestry with a minor allele frequency of approximately 3.3%. Two splice variants of human SCN5A, one lacking a glutamine at position 1077 (Q1077del) and one containing Q1077, exist in every human in a 2:1 mRNA transcript ratio. We engineered these two polymorphisms in both backgrounds and reported that when S524Y and H558R were expressed in the Q1077del variant, current densities were normal. In the Q1077 variant, however, the current densities showed a dramatic reduction compared to those in the Q1077del variant or WT-Q1077. We previously reported that incubation with the antiarrhythmic drug mexiletine "rescued" expression deficiencies in the Brugada syndrome. Cells expressing S524Y/Q1077 and H558R/Q1077 were incubated for 48 h with or without mexiletine (500 μM), followed by drug washout before electrophysiological assessment. Mexiletine significantly increased current density for both S524Y/Q1077 and H558R/Q1077 compared with untreated cells, restoring current density to levels comparable to WT-Q1077. Flow cytometry using a FLAG-tagged channel demonstrated that mexiletine-mediated rescue was associated with increased cell-surface expression. The magnitude of the expression defects caused by H558R and S524Y in the Q1077 splice background is similar to that observed with arrhythmia-associated SCN5A mutations, and we show for the first time that the defects for both polymorphisms can be rescued with mexiletine. Although it is unknown whether they result in heightened arrhythmia susceptibility in patients homozygous for the minor allele, our result may have implications for therapy for mutations with loss-of-function phenotypes modified by these common polymorphisms.
2026-08-04 | Islands of Fractionation for Automated Fractionation Mapping in Epicardial Brugada Syndrome Substrate Ablation.
Brugada syndrome epicardial RVOT ablation reduces VF, but procedural endpoints remain debated. Automated fractionation maps are often interpreted as scattered points, which may reflect artifacts. We propose Islands of Fractionation (IOF), a framework comparing EnSite X fractionation count settings against voltage-defined lesion-effect reference region. This case series included six Brugada syndrome patients undergoing epicardial substrate ablation. Mapping was performed in sinus rhythm using EnSite X with an Advisor HD Grid catheter. Automated fractionation maps were generated with the EnSite X CFE-count algorithm using refractory settings of 14 and 20 ms. Abnormal points were defined as fractionation count ≥3; lesion-effect reference region was defined by voltage change (pre >0.5 mV, post <0.3 mV). Island overlap was quantified using DBSCAN clustering and mesh-based area estimation. IOF revealed a consistent coverage-parsimony trade-off between refractory settings. The 14-ms setting produced broader islands with higher reference-region coverage (median overlap 84.6% [IQR 80.8-93.7]) but larger extraneous mapped area (up to 72.9 cm2). The 20-ms setting produced more compact islands with markedly reduced extraneous area (0.0-34.8 cm2) but lower coverage (59.9% [IQR 37.2-74.7]). In parallel, fractionation burden within the ablated region decreased substantially after ablation in both settings (median total burden reduction 86% vs 93%), supporting lesion-effect concordance of automated fractionation metrics. IOF provides an island-based framework for interpreting automated fractionation mapping and describing its spatial concordance with lesion-effect regions. In this retrospective series, 14 ms favored broader coverage, whereas 20 ms favored greater parsimony.
2026-07-17 | Late INa as a Therapeutic Target: New Strategies, Computational Modelling, Drug Development, and Clinical Translation.
The Nav1.5 channel, a major isoform of voltage-gated sodium ion channel, is mainly found in ventricular cardiomyocytes, playing a key role in generating essential cardiac action potentials for normal heart rhythms. Mutations in Nav1.5 have been associated with severe heart conditions such as long QT syndrome, Brugada syndrome, cardiac conduction disorders, atrial fibrillation, and dilated cardiomyopathy. Recent research has linked Nav1.5 to cardiac fibrosis and proposed its role in non-cardiac illnesses, including specific neurological disorders and cancers, subjects that will be reviewed in this paper. On the other hand, sodium-glucose cotransporter 2 inhibitors (SGLT2i), initially designed to manage diabetes by facilitating glucose excretion through urine, have demonstrated unexpected and encouraging cardioprotective benefits in clinical trials. This review compares the important SGLT2 inhibitors empagliflozin, dapagliflozin, and canagliflozin in terms of their interactions with Nav1.5 and their therapeutic effects on the heart. We also investigate new medications and compounds being developed to regulate Nav1.5 function, providing a preview of potential future treatments. Past attempts to develop late INa inhibitors and difficulties in transitioning from the research phase to clinical trials have raised doubts about the optimal design of such trials. In addition, we cover the applications of molecular dynamics simulations in understanding the mechanism of action of these drugs within the Nav1.5 channel computationally. We hope that this review identifies new opportunities to generate more effective inhibitors using novel methods and advanced multiscale molecular modelling techniques.
2026-07-16 | Case Report: Lurasidone-Induced Type 2 Brugada Pattern in a Pediatric Patient.
Brugada syndrome, a cardiac channelopathy, manifests with ventricular arrhythmia. Diagnosis relies on a type 1 Brugada electrocardiogram (ECG) pattern, while type 2 and type 3 patterns may necessitate electrophysiologic testing to uncover an underlying type 1 Brugada pattern. Differentiation between these patterns is important, as type 1 patterns pose a significantly greater risk of arrhythmia relative to types 2 and 3 counterparts. A 14-year-old male with autism presented after a syncopal episode following a lurasidone dosage increase. His ECG revealed a type 2 Brugada pattern. He was monitored overnight in the pediatric intensive care unit, where he remained asymptomatic. After being discharged with a Holter monitor, a quaternary hospital's procainamide challenge test weeks later contradicted an official diagnosis of Brugada syndrome, as dictated by elucidation of a type 1 Brugada pattern. After reverting to the initial lurasidone dose, a follow-up ECG after two months showed no Brugada pattern. In syncope cases, an ECG is crucial for identifying arrhythmogenic causes, including Brugada syndrome. This case highlights an ECG suggestive of Brugada syndrome with negative pharmacological tests and resolution post-discontinuation of the offending agent. Emergency physicians should be vigilant for Brugada and long QT syndromes in patients on antipsychotic medications.
2026-06-12 | Dynamic Expression of the Type 1 Brugada ECG Pattern During Tilt Table Testing Using Continuous High Precordial Lead Positioning.
Background/Objectives: The Type 1 Brugada ECG pattern (BrP1) fluctuates according to autonomic influences. Tilt table testing induces changes in both sympathetic and parasympathetic activity. It may provide insights into the dynamic behavior of BrP1 when combined with high-precordial lead placement. However, the clinical significance of BrP1 variability during tilt table testing remains poorly defined. Methods: This cross-sectional study evaluated patients with confirmed Brugada syndrome who underwent tilt table testing with continuous ECG monitoring using high-precordial leads. BrP1 behavior was assessed during predefined phases: baseline supine position, orthostatic tilt, nitrate administration, recovery, and syncope when present. Subsequently, clinical characteristics and test results were analyzed for associations with dynamic BrP1 expression. Results: Forty-four patients (mean age 49 years; 72.7% men) were included. Thirty-five patients (79.5%) had a spontaneous type 1 Brugada ECG pattern, and nine (20.5%) had a drug-induced pattern. BrP1 expression varied dynamically/heterogeneously during tilt table testing. No patient without BrP1 at admission developed the pattern during tilt phases. Thirty patients (68.1%) remained negative throughout testing, while five lost the pattern during the test (11.3%), and nine (20.4%) showed persistent BrP1 in all phases. Persistent BrP1 was associated with more frequent presumed arrhythmic syncope and implantable cardioverter defibrillator implantation (p < 0.05). No atrial or ventricular arrhythmias or device-related complications occurred. Conclusions: Tilt table testing with high precordial leads does not unmask BrP1 and should not be used as a diagnostic provocation tool. However, it allows for the characterization of autonomic modulation and phenotypic stability in Brugada syndrome. Any potential prognostic relevance of dynamic BrP1 behavior remains speculative and requires evaluation in adequately powered prospective studies.
gene therapies
2026-03-09 | Characterization of the R893C NaV1.5 mutation in Brugada syndrome.
Brugada syndrome (BrS) is a genetically determined cardiac arrhythmogenic syndrome with increased risk of sudden cardiac death. BrS is mostly caused by mutations in SCN5A gene encoding the primary ɑ-subunit of the cardiac sodium channel NaV1.5. We aimed at characterizing the functional alterations caused by the R893C mutation, identified in a proband diagnosed with BrS, and establishing whether the mutation is associated with BrS. Although several mutations have been reported in the close vicinity of R893, the functional role of this region remains unknown and, in addition, exploring SCN5A mutations in patients with inherited arrhythmogenic syndromes is critical for understanding the pathogenesis of arrhythmias. The mutations were introduced by site-directed mutagenesis. The variants were transiently expressed in CHO cells and potassium currents were measured using the whole-cell patch clamp technique. Patch clamp recordings have demonstrated that R893C almost completely abolished the sodium current, INa, though the mutation did not exert dominant-negative effect on wild-type NaV1.5 channels. We also observed significant decrease in channel activation and a depolarized shift of steady-state inactivation curve, however, the kinetics of inactivation and recovery from fast inactivation were not changed by the mutation. Moreover, the reducing agent Dithiotreitol partially restored the normal function of NaV1.5 in the R893C mutant highlighting a likely mechanism for loss of conduction via formation of disulphide bridges. We showed that R893H channels also failed to produce any detectable INa that confirms the importance of the highly conserved R893 in gating. Our study reveals R893C is a loss-of-function mutation with altered electrophysiological characteristics of NaV1.5. Thus, R893C may contribute to the BrS phenotype of the proband. Our findings may facilitate the understanding of the mechanisms of arrhythmogenesis in BrS, as it helps to identify mutational hotspots in BrS. Moreover, our work may improve novel gene therapy and new therapeutic drug design targeting NaV1.5 channelopathies.
2026-01-23 | Brugada Syndrome: New Implications for Heterozygous Carriers of the Pathogenic SCN5A c.689T>C(p.Ile230Thr) Variant.
Pathogenic variants in the SCN5A gene and its subunits have been identified in individuals with Brugada Syndrome. One such SCN5A variant, c.689T>C(p.Ile230Thr), was previously reported as disease-causing only in homozygous individuals, with heterozygous carriers being unaffected. Presently, we discuss the case of an adolescent patient who presented for further evaluation of pre-syncopal episodes with ECG findings consistent with Brugada pattern who on further genetic evaluation was found to be a heterozygous carrier of the pathogenic SCN5A c.689T>C(p.Ile230Thr) variant. This unique case allows us to think differently about heterozygous carriers for this specific mutation, and while the risk for developing a life-threatening arrhythmia may be low, heterozygous carriers may benefit from clinical monitoring to reduce the potential for adverse cardiac outcomes. A 17-year-old male presented after a pre-syncopal episode whose ECG demonstrated sinus bradycardia and type 1 Brugada pattern. Genetic testing revealed this patient to be a heterozygous carrier of a pathogenic SCN5A variant (c.689T>C(p.Ile230Thr)) which was also found in his father and brother, neither of whom had symptoms but did have ECG changes. He was diagnosed with Brugada Syndrome and advised to avoid known triggers. This case highlights the potential risk of severe cardiac arrhythmias in heterozygous carriers of the SCN5A c.689T>C (p.Ile230Thr) variant, previously thought to be benign. The 17-year-old patient, along with his asymptomatic father and brother who also carried the variant, exhibited ECG changes consistent with Brugada pattern. This finding suggests that heterozygous carriers may require closer monitoring and early intervention to prevent future life-threatening cardiac events.
2025-10-30 | Gene Therapy for Inherited Cardiac Arrhythmias.
Inherited cardiac arrhythmias are genetic disorders that impact the heart's electrical circuitry. These disorders are caused by inherited mutations and markedly increase the mortality risk of affected individuals. Conventional treatments, such as pharmacological agents for rate and rhythm control or surgical interventions, are often not efficacious and cause long-term complications. Gene therapy has recently emerged as a feasible and potentially curative approach for treating inherited cardiac arrhythmia syndromes. Advancements in elucidating the molecular mechanisms, pinpointing essential candidate genes, and improving gene delivery have rendered gene therapy as a feasible treatment alternative. This review examines recent studies on gene therapy applications in Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, long QT syndrome, familial atrial fibrillation, and arrhythmogenic cardiomyopathy. Additionally, we analyze current advancements in viral and non-viral gene delivery methods, highlighting their therapeutic potential and related challenges.
2025-10-22 | CRISPR/Cas9-Based Gene Editing for Correcting Inherited Channelopathies.
Inherited cardiac channelopathies, including long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia, are major causes of arrhythmic morbidity and sudden cardiac death in young individuals. Current therapies, such as pharmacologic agents, implantable cardioverter-defibrillators, and lifestyle modifications, reduce risk but fail to correct the underlying genetic substrate, creating an urgent need for curative strategies. CRISPR/Cas9 genome editing has emerged as a transformative platform with the potential to directly repair pathogenic variants. Recent advances in base and prime editing, together with novel viral and nonviral delivery platforms, have enabled precise correction of disease-causing mutations in preclinical models. Proof-of-concept studies using animal models and patient-derived iPSC-cardiomyocytes demonstrate restoration of electrophysiologic stability, suppression of arrhythmias, and durable functional benefit. Nevertheless, translational challenges remain, including off-target effects, delivery barriers, immune responses, scalability, and ethical considerations. Ongoing innovations-such as engineered nucleases, improved delivery vectors, immunogenicity mitigation strategies, and integration of artificial intelligence for personalized guide design-are expected to accelerate clinical translation. This review synthesizes current knowledge on CRISPR-based strategies for inherited channelopathies, highlighting both the promise and limitations of gene editing as a path toward durable, disease-modifying therapies capable of preventing sudden cardiac death.
2025-08-26 | Gene Therapy for Cardiac Arrhythmias: Mechanisms, Modalities and Therapeutic Applications.
Cardiac arrhythmias remain a major source of morbidity and mortality, often stemming from molecular and structural abnormalities that are insufficiently addressed by current pharmacologic and interventional therapies. Gene therapy has emerged as a transformative approach, offering precise and durable interventions that directly target the arrhythmogenic substrate. Across the spectrum of inherited and acquired arrhythmias-including long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, atrial fibrillation, and post-infarction ventricular tachycardia-gene-based strategies such as allele-specific silencing, gene replacement, CRISPR-mediated editing, and suppression-and-replacement constructs are showing growing translational potential. Advances in delivery platforms, including cardiotropic viral vectors, lipid nanoparticle-encapsulated mRNA, and non-viral reprogramming tools, have further enhanced the specificity and safety of these approaches. Additionally, innovative applications such as biological pacemaker development and mutation-agnostic therapies underscore the versatility of genetic modulation. Nonetheless, significant challenges remain, including vector tropism, immune responses, payload limitations, and the translational gap between preclinical models and human electrophysiology. Integration of patient-derived cardiomyocytes, computational simulations, and large-animal studies is expected to accelerate clinical translation. This review provides a comprehensive synthesis of the mechanistic rationale, therapeutic strategies, delivery platforms, and translational frontiers of gene therapy for cardiac arrhythmias.
oligonucleotides
2025-10-20 | Characterization of a Splice-Altering Variant in SCN5A Associated With Brugada Syndrome - Insights Into Splice Error Correction.
Brugada syndrome (BrS) is an arrhythmic disease associated with SCN5A loss-of-function variants. We identified a novel single nucleotide substitution, SCN5A c.1338G>A, in the last codon of exon10 in a patient with drug-induced BrS. The aim of this study was to investigate the impact of this splice-altering variant and examine whether antisense oligonucleotides (ASOs) could correct the splice alteration. Genomic DNA was extracted from the patient's blood lymphocytes. Coding exons of inherited arrhythmia genes were screened and SCN5A c.1338G>A was identified. SpliceAI predicted its prominent potential to alter splicing among 168 single nucleotide variants in the SCN5A region including 10 variants with allele frequency (AF) <0.01, and the usage of a cryptic splice donor site 4 bp downstream from the authentic splice donor site. Minigene splicing reporter assays were performed using HEK-293 cells and induced pluripotent stem cells-cardiomyocytes, and successfully demonstrated a dominant selection of the predicted splice site. Three different ASOs were tested in the same platform. Although the ASOs reduced the production of splice error products, they did not succeed in increasing authentically spliced products. We confirmed a splice site alteration by SCN5A c.1338G>A and propose extended use of SpliceAI for screening a target genomic region. The attempts to correct mis-splicing near the canonical splice site were not entirely successful, so further development of technology is awaited.
2024-01-11 | The Role of MAPRE2 and Microtubules in Maintaining Normal Ventricular Conduction.
Brugada syndrome is associated with loss-of-function SCN5A variants, yet these account for only ≈20% of cases. A recent genome-wide association study identified a novel locus within MAPRE2, which encodes EB2 (microtubule end-binding protein 2), implicating microtubule involvement in Brugada syndrome. A mapre2 knockout zebrafish model was generated using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated protein 9) and validated by Western blot. Larval hearts at 5 days post-fertilization were isolated for voltage mapping and immunocytochemistry. Adult fish hearts were used for ECG, patch clamping, and immunocytochemistry. Morpholinos were injected into embryos at 1-cell stage for knockdown experiments. A transgenic zebrafish line with cdh2 tandem fluorescent timer was used to study adherens junctions. Microtubule plus-end tracking and patch clamping were performed in human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) with MAPRE2 knockdown and knockout, respectively. Voltage mapping of mapre2 knockout hearts showed a decrease in ventricular maximum upstroke velocity of the action potential and conduction velocity, suggesting loss of cardiac voltage-gated sodium channel function. ECG showed QRS prolongation in adult knockout fish, and patch clamping showed decreased sodium current density in knockout ventricular myocytes and arrhythmias in knockout iPSC-CMs. Confocal imaging showed disorganized adherens junctions and mislocalization of mature Ncad (N-cadherin) with mapre2 loss of function, associated with a decrease of detyrosinated tubulin. MAPRE2 knockdown in iPSC-CMs led to an increase in microtubule growth velocity and distance, indicating changes in microtubule dynamics. Finally, knockdown of ttl encoding tubulin tyrosine ligase in mapre2 knockout larvae rescued tubulin detyrosination and ventricular maximum upstroke velocity of the action potential. Genetic ablation of mapre2 led to a decrease in voltage-gated sodium channel function, a hallmark of Brugada syndrome, associated with disruption of adherens junctions, decrease of detyrosinated tubulin as a marker of microtubule stability, and changes in microtubule dynamics. Restoration of the detyrosinated tubulin fraction with ttl knockdown led to rescue of voltage-gated sodium channel-related functional parameters in mapre2 knockout hearts. Taken together, our study implicates microtubule dynamics in the modulation of ventricular conduction.
2023-11-01 | The role of MAPRE2 and microtubules in Brugada syndrome pathogenesis
Abstract Background Brugada syndrome (BrS) is associated with loss-of-function variants in SCN5A (encoding NaV1.5), which are found in only ∼20% of patients. Recent genome-wide association studies identified a novel locus within an intron of MAPRE2 (encoding microtubule end-binding protein 2, EB2), implicating microtubule (MT) involvement in BrS. Purpose To understand the role of MAPRE2 and MT in BrS pathogenesis. Methods A mapre2 knock-out (KO) zebrafish model was generated using CRISPR/Cas9 and validated by western blot. Larval hearts at 5 day-post-fertilization (dpf) were isolated for voltage mapping and immunohistochemistry with confocal imaging. Morpholino targeting mapre2 or ttl (encoding tubulin tyrosine ligase) were injected into zebrafish embryos at the one-cell stage. A transgenic zebrafish line with cdh2 (encoding N-cadherin) tandem fluorescent timer (tFT) was used to study adherens junction. MT plus-end tracking experiments were performed in iPSC-derived cardiomyocytes (CM) with MAPRE2 knockdown (KD) using siRNA. ECG was recorded in adult fish. Results Voltage mapping of larval hearts (14 WTs vs. 19 KOs) showed a significant decrease in ventricular conduction velocity (17.4±1.5 vs. 13.4±0.8 mm/s; p<0.05) and action potential upstroke velocity (Vmax; 86.1±3.6 vs. 73.9±3.2 1/s; p<0.05), suggesting loss of cardiac NaV function. Correspondingly, ECG of adult fish (11 WTs vs. 10 KOs) showed a significant increase in QRS duration (27.8±0.5 vs. 32.3±0.7 ms; p<0.0001). Confocal imaging of KO hearts showed disorganized adherens junction based on N-cadherin staining. Similarly, morpholino KD of mapre2 in the cdh2 tFT line showed ∼40% mislocalization of mature N-cadherin relative to ZO-1 staining in larval ventricles (8 KDs vs 9 control hearts; p<0.05), suggesting disruption of adherens junction. In terms of MT, immunohistochemistry showed a 23% decrease of detyrosinated tubulin relative to total alpha tubulin in KO hearts (16 vs. 8 WT hearts; p<0.01). MAPRE2 KD in iPSC-CM (337 control vs. 285 KD MT in 4 sets of cells) showed an increase in MT velocity (7.9±0.2 vs. 8.8±0.2 µm/min; p<0.001), distance (5.8±0.2 vs. 7.1±0.2 µm; p<0.0001), and duration (46.2±1.4 vs. 52.2±1.6 s; p<0.001), suggesting changes to MT dynamics. Finally, morpholino KD of ttl in mapre2 KO embryos restored the fraction of detyrosinated tubulin (46% increase; 16 controls vs. 16 KDs; p<0.01) as well as Vmax (74.3±3.0 vs. 88.3±2.1 1/s; 13 controls vs. 9 KDs; p<0.01) to WT levels. Conclusion Genetic ablation of mapre2 led to a decrease in cardiac NaV function, a hallmark of BrS. This is associated with disruption of adherens junction, a decrease of detyrosinated tubulin as a marker of MT stability, and changes in MT dynamics. Restoration of detyrosinated tubulin fraction with ttl KD led to a rescue of NaV function in zebrafish larval hearts. Taken together, MAPRE2 loss-of-function may contribute to BrS pathogenesis by disruption of adherens junction via changes in MT dynamics.
2016-09-28 | Embryonic type Na+ channel β-subunit, SCN3B masks the disease phenotype of Brugada syndrome
SCN5A is abundant in heart and has a major role in INa. Loss-of-function mutation in SCN5A results in Brugada syndrome (BrS), which causes sudden death in adults. It remains unclear why disease phenotype does not manifest in the young even though mutated SCN5A is expressed in the young. The aim of the present study is to elucidate the timing of the disease manifestation in BrS. A gain-of-function mutation in SCN5A also results in Long QT syndrome type 3 (LQTS3), leading to sudden death in the young. Induced pluripotent stem cells (iPSCs) were generated from a patient with a mixed phenotype of LQTS3 and BrS with the E1784K SCN5A mutation. Here we show that electrophysiological analysis revealed that LQTS3/BrS iPSC-derived cardiomyocytes recapitulate the phenotype of LQTS3 but not BrS. Each β-subunit of the sodium channel is differentially expressed in embryonic and adult hearts. SCN3B is highly expressed in embryonic hearts and iPSC-derived cardiomyocytes. A heterologous expression system revealed that INa of mutated SCN5A is decreased and SCN3B augmented INa of mutated SCN5A. Knockdown of SCN3B in LQTS3/BrS iPSC-derived cardiomyocytes successfully unmasked the phenotype of BrS. Isogenic control of LQTS3/BrS (corrected-LQTS3/BrS) iPSC-derived cardiomyocytes gained the normal electrophysiological properties.
2015-10-01 | Genetic defects in a His-Purkinje system transcription factor, IRX3, cause lethal cardiac arrhythmias.
Ventricular fibrillation (VF), the main cause of sudden cardiac death (SCD), occurs most frequently in the acute phase of myocardial infarction: a certain fraction of VF, however, develops in an apparently healthy heart, referred as idiopathic VF. The contribution of perturbation in the fast conduction system in the ventricle, the His-Purkinje system, for idiopathic VF has been implicated, but the underlying mechanism remains unknown. Irx3/IRX3 encodes a transcription factor specifically expressed in the His-Purkinje system in the heart. Genetic deletion of Irx3 provides a mouse model of ventricular fast conduction disturbance without anatomical or contraction abnormalities. The aim of this study was to examine the link between perturbed His-Purkinje system and idiopathic VF in Irx3-null mice, and to search for IRX3 genetic defects in idiopathic VF patients in human. Telemetry electrocardiogram recording showed that Irx3-deleted mice developed frequent ventricular tachyarrhythmias mostly at night. Ventricular tachyarrhythmias were enhanced by exercise and sympathetic nerve activation. In human, the sequence analysis of IRX3 exons in 130 probands of idiopathic VF without SCN5A mutations revealed two novel IRX3 mutations, 1262G>C (R421P) and 1453C>A (P485T). Ventricular fibrillation associated with physical activities in both probands with IRX3 mutations. In HL-1 cells and neonatal mouse ventricular myocytes, IRX3 transfection up-regulated SCN5A and connexin-40 mRNA, which was attenuated by IRX3 mutations. IRX3 genetic defects and resultant functional perturbation in the His-Purkinje system are novel genetic risk factors of idiopathic VF, and would improve risk stratification and preventive therapy for SCD in otherwise healthy hearts.
cell therapies
2026-02-13 | [Cardiac arrhythmias-Cellular mechanisms, consequences and challenges in the diagnostics using human models].
Cardiac arrhythmias significantly contribute to morbidity and mortality in cardiovascular diseases. Hereditary ion channel disorders, including Brugada syndrome, long/short QT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT), represent critical entities with elevated risk of malignant ventricular arrhythmias. Although beta-blockers, ion channel modulators and implantable cardioverter defibrillators (ICD) are available and the indications for them are increasingly based on genetic analyses, variants of uncertain significance (VUS) substantially impair the risk stratification. Atrial tachyarrhythmias, particular atrial fibrillation, can cause an often-reversible arrhythmia-induced cardiomyopathy (AIC). Pathophysiologically, the Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays an important role in atrial and ventricular arrhythmias. It can be activated by various pathological triggers, such as high heart rate, neuroendocrine activation and oxidative stress, the latter often resulting from mechano-energetic uncoupling. The development of effective treatment options for arrhythmia-associated cardiovascular diseases requires the use of human model systems in addition to animal experimental approaches, due to the genetic heterogeneity and systemic comorbidities. Patient-specific cardiac stem cell-models enable the classification of VUS and personalised drug testing. The integration of new methodological approaches into existing animal experimental approaches thus paves the way for functionally validated precision medicine and could fundamentally transform the treatment of both disease patterns.
2024-11-27 | The Role of Human-Induced Pluripotent Stem Cells in Studying Cardiac Channelopathies.
Cardiac channelopathies are inherited diseases that increase the risk of sudden cardiac death. While different genes have been associated with inherited channelopathies, there are still subtypes, e.g., catecholaminergic polymorphic ventricular tachycardia and Brugada syndrome, where the genetic cause remains unknown. Various models, including animal models, heterologous expression systems, and the human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSCs-CMs) model, have been used to study the pathophysiological mechanisms of channelopathies. Recently, researchers have focused on using hiPSCs-CMs to understand the genotype-phenotype correlation and screen drugs. By combining innovative techniques such as Clustered Regularly Interspaced Short Palindromic Repeats/Clustered Regularly Interspaced Short Palindromic Repeats associated protein 9 (CRISPR/Cas9)-mediated genome editing, and three-dimensional (3D) engineered heart tissues, we can gain new insights into the pathophysiological mechanisms of channelopathies. This approach holds promise for improving personalized drug treatment. This review highlights the role of hiPSCs-CMs in understanding the pathomechanism of Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia and how these models can be utilized for drug screening.
2021-11-15 | Modeling genetic cardiac channelopathies using induced pluripotent stem cells - Status quo from an electrophysiological perspective.
Long QT syndrome (LQTS), Brugada syndrome (BrS), and catecholaminergic polymorphic ventricular tachycardia (CPVT) are genetic diseases of the heart caused by mutations in specific cardiac ion channels and are characterized by paroxysmal arrhythmias, which can deteriorate into ventricular fibrillation. In LQTS3 and BrS different mutations in the SCN5A gene lead to a gain-or a loss-of-function of the voltage-gated sodium channel Nav1.5, respectively. Although sharing the same gene mutation, these syndromes are characterized by different clinical manifestations and functional perturbations and in some cases even present an overlapping clinical phenotype. Several studies have shown that Na+ current abnormalities in LQTS3 and BrS can also cause Ca2+-signaling aberrancies in cardiomyocytes (CMs). Abnormal Ca2+ homeostasis is also the main feature of CPVT which is mostly caused by heterozygous mutations in the RyR2 gene. Large numbers of disease-causing mutations were identified in RyR2 and SCN5A but it is not clear how different variants in the SCN5A gene produce different clinical syndromes and if in CPVT Ca2+ abnormalities and drug sensitivities vary depending on the mutation site in the RyR2. These questions can now be addressed by using patient-specific in vitro models of these diseases based on induced pluripotent stem cells (iPSCs). In this review, we summarize different insights gained from these models with a focus on electrophysiological perturbations caused by different ion channel mutations and discuss how will this knowledge help develop better stratification and more efficient personalized therapies for these patients.
2017-08-18 | Induced pluripotent stem cell technology and inherited arrhythmia syndromes
Inherited arrhythmia syndromes, including familial long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and Brugada syndrome, can cause life-threatening arrhythmias and are responsible for a significant proportion of sudden deaths in the young. Identification of genetic mutations and pathophysiological changes that underlie disease development can inform clinical practice and guide novel drug development. However, disease mechanisms in a large number of patients remain elusive and pharmacologic treatment is suboptimal, so many patients rely on implantable cardioverter–defibrillator therapy. Induced pluripotent stem cell models of disease facilitate analysis of disease mechanisms in patient-specific cardiomyocytes, overcoming limitations of animal models and human tissue restrictions. This review outlines how studies using induced pluripotent stem cell–derived cardiomyocytes are contributing to our understanding of the mechanisms that underpin disease pathogenesis and their potential to facilitate new pharmacologic therapies and personalized medicine. Inherited arrhythmia syndromes, including familial long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and Brugada syndrome, can cause life-threatening arrhythmias and are responsible for a significant proportion of sudden deaths in the young. Identification of genetic mutations and pathophysiological changes that underlie disease development can inform clinical practice and guide novel drug development. However, disease mechanisms in a large number of patients remain elusive and pharmacologic treatment is suboptimal, so many patients rely on implantable cardioverter–defibrillator therapy. Induced pluripotent stem cell models of disease facilitate analysis of disease mechanisms in patient-specific cardiomyocytes, overcoming limitations of animal models and human tissue restrictions. This review outlines how studies using induced pluripotent stem cell–derived cardiomyocytes are contributing to our understanding of the mechanisms that underpin disease pathogenesis and their potential to facilitate new pharmacologic therapies and personalized medicine.
2016-11-18 | Will cardiac optogenetics find the way through the obscure angles of heart physiology?
Optogenetics is a technique exploded in the last 10 years, which revolutionized several areas of biological research. The brightest side of this technology is the use of light to modulate non-invasively, with high spatial resolution and millisecond time scale, excitable cells genetically modified to express light-sensitive microbial ion channels (opsins). Neuroscience has first benefited from such fascinating strategy, in intact organisms. By shining light to specific neuronal subpopulations, optogenetics allowed unearth the mechanisms involved in cell-to-cell communication within the context of intact organs, such as the brain, formed by complex neuronal circuits. More recently, scientists looked at optogenetics as a tool to answer some of the questions, remained in the dark, of cardiovascular physiology. In this review, we focus on the application of optogenetics in the study of the heart, a complex multicellular organ, homing different populations of excitable cells, spatially and functionally interconnected. Moving from the first proof-of-principle works, published in 2010, to the present time, we discuss the in vitro and in vivo applications of optogenetics for the study of electrophysiology of the different cardiac cell types, and for the dissection of cellular mechanisms underlying arrhythmias. We also present how molecular biology and technology foster the evolution of cardiac optogenetics, with the aim to further our understanding of fundamental questions in cardiac physiology and pathology. Finally, we confer about the therapeutic potential of such biotechnological strategy for the treatment of heart rhythm disturbances (e.g. cardiac pacing, cardioversion).
other
2026-04-22 | Brugada phenocopy induced by Russell's viper envenomation: resolution following anti-snake venom therapy.
Russell's viper envenomation is known to cause complications such as coagulopathy, acute kidney injury and haemolysis. Cardiac involvement, though rare, has been reported in the form of arrhythmias, myocardial infarction and ECG changes such as ST-segment elevation or T-wave inversions. We report a case of a middle-aged farmer who presented to our centre with Russell's viper envenomation, characterised by local envenomation, coagulopathy, haemolysis and ocular manifestations. His ECG showed a Brugada pattern, with no evidence of any structural cardiac abnormalities or elevated cardiac enzymes. A repeat ECG performed 72 hours after anti-snake venom therapy showed resolution of the ECG findings. A diagnosis of Brugada phenocopy secondary to Russell's viper envenomation was made. The most likely mechanism causing a Brugada phenocopy in Russell's viper envenomation may be due to phospholipase A2 present in the venom, causing alteration in the cardiac voltage-gated sodium channels.
2025-01-01 | Phenotypes in Brugada syndrome with different genotypes triggered by fever or inflammation using gene-edited iPSCs
Abstract Background Fever or inflammation state may enhance the Brugada syndrome (BrS) phenotype in some but not all patients. However, the underlying mechanism in human cardiomyocytes has not yet been clarified. Methods Human induced pluripotent stem cell (hiPSC) lines generated from fibroblasts of three BrS patients harboring variants in SCN10A (abbreviated as BrS1) and CACNB2 (abbreviated as BrS2), SCN5A (abbreviated as BrS3) and one healthy donor (abbreviated as WT) and a site-corrected (using CRISPR/Cas9) hiPSC line of each BrS patient (abbreviated as isogenic1, isogenic2 and isogenic3) were used for differentiation into cardiomyocytes (hiPSC-CMs). Western blot, patch clamp and calcium transient analyses were carried out. Results All 3 BrS cell lines showed a significantly reduced peak sodium current (INa) compared with isogenic or WT cells at baseline. Hyperthermia challenge (40 °C) significantly decreased INa and enhanced arrhythmogeneity in BrS1 and BrS3 but not in BrS2 cells. The hyperthermia effects involved PKA reduction. The lipopolysaccharide (LPS) challenge exacerbated the phenotype in electrophysiological characteristics in all 3 BrS cell lines. ROS-Blocker abolished the LPS effects in all BrS hiPSC-CMs, while an interleukin-6 receptor blocker abolished the proarrhythmic effect of LPS in BrS1 and BrS3 hiPSC-CMs but not in hiPSC-CMs of BrS2. Conclusions Hyperthermia exacerbated the BrS phenotype in hiPSC-CMs carrying SCN10A and SCN5A variants, whereas LPS aggravated the phenotype in all three BrS variants through distinct mechanisms; Hyperthermia and LPS effects on BrS phenotype may be genotype-dependent. Graphical abstract
2022-06-30 | Trafficking and Gating Cooperation Between Deficient Nav1.5-mutant Channels to Rescue INa
Pathogenic variants in SCN5A, the gene encoding the cardiac Na+ channel α-subunit Nav1.5, result in life-threatening arrhythmias, e.g., Brugada syndrome, cardiac conduction defects and long QT syndrome. This variety of phenotypes is underlied by the fact that each Nav1.5 mutation has unique consequences on the channel trafficking and gating capabilities. Recently, we established that sodium channel α-subunits Nav1.5, Nav1.1 and Nav1.2 could dimerize, thus, explaining the potency of some Nav1.5 pathogenic variants to exert dominant-negative effect on WT channels, either by trafficking deficiency or coupled gating.The present study sought to examine whether Nav1.5 channels can cooperate, or transcomplement each other, to rescue the Na+ current (INa). Such a mechanism could contribute to explain the genotype-phenotype discordance often observed in family members carrying Na+-channel pathogenic variants.Patch-clamp and immunocytochemistry analysis were used to investigate biophysical properties and cellular localization in HEK293 cells and rat neonatal cardiomyocytes transfected respectively with WT and 3 mutant channels chosen for their particular trafficking and/or gating properties.As previously reported, the mutant channels G1743R and R878C expressed alone in HEK293 cells both abolished INa, G1743R through a trafficking deficiency and R878C through a gating deficiency. Here, we showed that coexpression of both G1743R and R878C nonfunctioning channels resulted in a partial rescue of INa, demonstrating a cooperative trafficking of Nav1.5 α-subunits. Surprisingly, we also showed a cooperation mechanism whereby the R878C gating-deficient channel was able to rescue the slowed inactivation kinetics of the C-terminal truncated R1860X (ΔCter) variant, suggesting coupled gating.Altogether, our results add to the evidence that Nav channels are able to interact and regulate each other's trafficking and gating, a feature that likely contributes to explain the genotype-phenotype discordance often observed between members of a kindred carrying a Na+-channel pathogenic variant.
2022-03-24 | Transmembrane protein 168 mutation reduces cardiomyocyte cell surface expression of Nav1.5 through αB-crystallin intracellular dynamics.
Transmembrane protein 168 (TMEM168) was found to be localized on the nuclear membrane. A heterozygous mutation (c.1616G>A, p. R539Q) in TMEM168 was identified in patients with Brugada syndrome. This mutation reduced expression of cardiomyocyte sodium channel Nav1.5 via Nedd4-2 E3 ubiquitin ligase-induced ubiquitination and degradation. However, the detailed molecular mechanism provoked by the TMEM168 mutant remains unclear. Here, we demonstrated that small heat shock protein αB-crystallin, which can bind to Nav1.5 and Nedd4-2 and interfere with the association of both proteins, was strongly recruited from the cell surface to the perinuclear region because of the much higher affinity of αB-crystallin with the TMEM168 mutant than with wild-type TMEM168. Following knockdown of αB-crystallin in HL-1 cardiomyocytes, the interaction of Nav1.5 with Nedd4-2 was increased, despite the reduced expression of Nav1.5. Moreover, reduction of Nav1.5 expression by αB-crystallin knockdown was rescued in the presence of a proteasome inhibitor MG-132, suggesting the importance of the αB-crystallin-modulated ubiquitin-proteasome system for the stability of Nav1.5 expression. Collectively, the balance of molecular interactions among Nav1.5, Nedd4-2 and αB-crystallin plays a role in the regulation of cardiomyocyte cell surface expression of Nav1.5, and the TMEM168 mutant disturbs this balance, resulting in a decrease in Nav1.5 expression.
2018-11-26 | Electroanatomic and Pathologic Right Ventricular Outflow Tract Abnormalities in Patients With Brugada Syndrome
The prevalence and significance of structural abnormalities in Brugada syndrome (BrS) are still largely debated. The authors investigated the relationship between genetic background, electroanatomic abnormalities, and pathologic substrate in BrS. 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. 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). 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.
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Drug Discovery Landscape
2 orphan drug designations for Brugada syndrome.
2 orphan drug designations for Brugada syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Hydroquinidine hydrochloride | small molecules | EMA | 2022-07-18 | — | Teofarma S.r.l. |
Bethanidine sulfate | small molecules | FDA | 1989-11-24 | — | Medco Research, Inc. |
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