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:
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.
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.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
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. |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI's forecasts to outperform average preclinical success rates. Whether you're expanding your R&D pipeline, evaluating a partnership, or simply have a question — we'd love to hear from you.