Shanghai Score System for Diagnosis of Brugada Syndrome: Validation of the Score System and System and Reclassification of the Patients.

OBJECTIVES: The principal objective was to perform an initial test of the Shanghai Brugada Scoring System. Diagnosis of probable and/or definite Brugada syndrome (BrS), possible BrS, and nondiagnostic outcomes were assigned scores of ≥3.5, 2 to 3, and <2 points, respectively. The proposed score system was based on the available published reports and on weighted coefficients derived from limited datasets, with the understanding that these recommendations would need to undergo continuing validation. BACKGROUND: The 2016 HRS/EHRA/APHRS/SOLAECE J-Wave Syndrome Consensus Report proposed a scoring system for diagnosis of BrS that takes into account electrocardiographic recordings, genetic results, clinical characteristics, and family history. METHODS: The patient population consisted of 393 patients evaluated at our hospital for BrS (271 asymptomatic, 99 with syncope, and 23 with ventricular fibrillation [VF]) between 1996 and 2016. Subjects were classified into 4 groups: group A with a score of ≤3.0 points (n = 45); group B with a score of 3.5 points (n = 186); group C with a score of 4.0 to 5.0 points (n = 81); and group D with a score of ≥5.5 points (n = 81). RESULTS: A total of 348 (88%) patients had probable and/or definite BrS, and 81 (20%) had a score ≥5.5. During a follow-up of 97.3 months (range: 39.7 to 142.1 months), 43 patients experienced VF. Significant differences were seen among the 4 groups (p = 0.01). A malignant arrhythmic event did not occur in any patient with possible or nondiagnostic BrS. CONCLUSIONS: This study provided validation for the use of the Shanghai Score System for the diagnosis and risk stratification of patients with BrS.

Multivariate classification of Brugada syndrome patients based on autonomic response to exercise testing.

Ventricular arrhythmias in Brugada syndrome (BS) typically occur at rest and especially during sleep, suggesting that changes in the autonomic modulation may play an important role in arrhythmogenesis. The autonomic response to exercise and subsequent recovery was evaluated on 105 patients diagnosed with BS (twenty-four were symptomatic), by means of a time-frequency heart rate variability (HRV) analysis, so as to propose a novel predictive model capable of distinguishing symptomatic and asymptomatic BS populations. During incremental exercise, symptomatic patients showed higher HFnu values, probably related to an increased parasympathetic modulation, with respect to asymptomatic subjects. In addition, those extracted HRV features best distinguishing between populations were selected using a two-step feature selection approach, so as to build a linear discriminant analysis (LDA) classifier. The final features subset included one third of the total amount of extracted autonomic markers, mostly acquired during incremental exercise and active recovery, thus evidencing the relevance of these test segments in BS patients classification. The derived predictive model showed an improved performance with respect to previous works in the field (AUC = 0.92 ± 0.01; Se = 0.91 ± 0.06; Sp = 0.90 ± 0.05). Therefore, based on these findings, some of the analyzed HRV markers and the proposed model could be useful for risk stratification in Brugada syndrome.

Variants of Brugada Syndrome and Early Repolarization Syndrome: An Expanded Concept of J-Wave Syndrome.

BACKGROUND: The role of J-waves in the pathogenesis of ventricular fibrillation (VF) occurring in structurally normal hearts is important. METHODS: We evaluated 127 patients who received an implantable cardioverter-defibrillator (ICD) for Brugada syndrome (BS, n = 53), early repolarization syndrome (ERS, n = 24), and patients with unknown or deferred diagnosis (n = 50). Electrocardiography (ECG), clinical characteristics, and ICD data were analyzed. RESULTS: J-waves were found in 27/50 patients with VF of unknown/deferred diagnosis. The J-waves were reminiscent of those seen in BS or ERS, and this subgroup of patients was termed variants of ERS and BS (VEB). In 12 VEB patients, the J/ST/T-wave morphology was coved, although amplitudes were <0.2 mV. In 15 patients, noncoved-type J/ST/T-waves were present in the right precordial leads. In the remaining 23 patients, no J-waves were identified. VEB patients exhibited clinical characteristics similar to those of BS and ERS patients. Phenotypic transition and overlap were observed among patients with BS, ERS, and VEB. Twelve patients with BS had background inferolateral ER, while five ERS patients showed prominent right precordial J-waves. Patients with this transient phenotype overlap showed a significantly lower shock-free survival than the rest of the study patients. CONCLUSIONS: VEB patients demonstrate ECG phenotype similar to but distinct from those of BS and ERS. The spectral nature of J-wave morphology/distribution and phenotypic transition/overlap suggest a common pathophysiologic background in patients with VEB, BS, and ERS. Prognostic implication of these ECG variations requires further investigation.

New methodologies for measuring Brugada ECG patterns cannot differentiate the ECG pattern of Brugada syndrome from Brugada phenocopy.

BACKGROUND: Brugada phenocopies (BrP) are clinical entities characterized by ECG patterns that are identical to true Brugada syndrome (BrS), but are elicited by various clinical circumstances. A recent study demonstrated that the patterns of BrP and BrS are indistinguishable under the naked eye, thereby validating the concept that the patterns are identical. OBJECTIVE: The aim of our study was to determine whether recently developed ECG criteria would allow for discrimination between type-2 BrS ECG pattern and type-2 BrP ECG pattern. METHODS: Ten ECGs from confirmed BrS (aborted sudden death, transformation into type 1 upon sodium channel blocking test and/or ventricular arrhythmias, positive genetics) cases and 9 ECGs from confirmed BrP were included in the study. Surface 12-lead ECGs were scanned, saved in JPEG format for blind measurement of two values: (i) ß-angle; and (ii) the base of the triangle. Cut-off values of ≥58° for the ß-angle and ≥4mm for the base of the triangle were used to determine the BrS ECG pattern. RESULTS: Mean values for the ß-angle in leads V1 and V2 were 66.7±25.5 and 55.4±28.1 for BrS and 54.1±26.5 and 43.1±16.1 for BrP respectively (p=NS). Mean values for the base of the triangle in V1 and V2 were 7.5±3.9 and 5.7±3.9 for BrS and 5.6±3.2 and 4.7±2.7 for BrP respectively (p=NS). The ß-angle had a sensitivity of 60%, specificity of 78% (LR+ 2.7, LR- 0.5). The base of the triangle had a sensitivity of 80%, specificity of 40% (LR+ 1.4, LR- 0.5). CONCLUSIONS: New ECG criteria presented relatively low sensitivity and specificity, positive and negative predictive values to discriminate between BrS and BrP ECG patterns, providing further evidence that the two patterns are identical.

Characterization of repolarization in Brugada syndrome patients during exercise testing: Dynamic angle evaluation.

BACKGROUND: A new ECG criterion has been studied in Brugada syndrome (BrS) at rest to differentiate type 2 and incomplete right bundle branch block (IRBBB). METHODS: We assessed this criterion during exercise comparing BrS (46 patients) and IRBBB (17 patients). A beta angle was measured from lead V1 between the upslope of S-wave and the downslope of the r'-wave. RESULTS: Beta angle was significantly larger in BrS at rest (58±24° vs 25±15°, p<0.001), exercise (47±26° vs 15±11°, p<0.001), and recovery (46±24° vs 21±12°, p<0.001) with a reduction in angle at exercise compared to rest. There was a significant rebound in angle at recovery in the control group to (p<0.001); no such rebound was observed in the BrS group (p=NS). CONCLUSION: Beta angle study at rest and its evolution at exercise could help discriminate BrS patients from healthy subjects.

Ischemia-induced Brugada phenocopy.

A 65-year-old man with history of schizoaffective disorder was admitted with a suspicion for syncope. ECG changes consistent with type-1 Brugada pattern were noted on admission. A personal history of angina was reported but a family history of sudden cardiac death or ICD implantation was denied. A fixed perfusion defect and hypokinesis of the distal infero-lateral wall were reported on a pharmacological stress test prompting a coronary angiography. A stent was deployed across a 95% stenosis of the dominant mid right coronary artery with satisfactory results. Resolution of the Brugada type pattern was noted on ECGs repeated after the stenting.

Enhanced Classification of Brugada Syndrome-Associated and Long-QT Syndrome-Associated Genetic Variants in the SCN5A-Encoded Na(v)1.5 Cardiac Sodium Channel.

BACKGROUND: A 2% to 5% background rate of rare SCN5A nonsynonymous single nucleotide variants (nsSNVs) among healthy individuals confounds clinical genetic testing. Therefore, the purpose of this study was to enhance interpretation of SCN5A nsSNVs for clinical genetic testing using estimated predictive values derived from protein-topology and 7 in silico tools. METHODS AND RESULTS: Seven in silico tools were used to assign pathogenic/benign status to nsSNVs from 2888 long-QT syndrome cases, 2111 Brugada syndrome cases, and 8975 controls. Estimated predictive values were determined for each tool across the entire SCN5A-encoded Na(v)1.5 channel as well as for specific topographical regions. In addition, the in silico tools were assessed for their ability to correlate with cellular electrophysiology studies. In long-QT syndrome, transmembrane segments S3-S5+S6 and the DIII/DIV linker region were associated with high probability of pathogenicity. For Brugada syndrome, only the transmembrane spanning domains had a high probability of pathogenicity. Although individual tools distinguished case- and control-derived SCN5A nsSNVs, the composite use of multiple tools resulted in the greatest enhancement of interpretation. The use of the composite score allowed for enhanced interpretation for nsSNVs outside of the topological regions that intrinsically had a high probability of pathogenicity, as well as within the transmembrane spanning domains for Brugada syndrome nsSNVs. CONCLUSIONS: We have used a large case/control study to identify regions of Na(v)1.5 associated with a high probability of pathogenicity. Although topology alone would leave the variants outside these identified regions in genetic purgatory, the synergistic use of multiple in silico tools may help promote or demote a variant's pathogenic status.

[Possible prognostic value of atrial fibrillation and atrial flutter in Brugada syndrome]. / Posible valor pronóstico de la fibrilación y el flutter auricular en el síndrome de Brugada.

OBJECTIVE: To analyze the specific risk for the variables: type 1 spontaneous pattern, type 1 induced pattern, type 1 pattern with spontaneous variability, syncope, family history of sudden death, atrial fibrillation and atrial flutter with the subsequent development of malignant arrhythmic events. METHODS: Forty-three Brugada patients (90% males; mean age 40.4 years), with a type 1 spontaneous pattern (74.4%) or induced by ajmaline (25.6%) were retrospectively analyzed. Of these, 58.1% presented spontaneous variability, 18.6% had family history of sudden death, 39.5% were symptomatic, and 18.6% presented atrial fibrillation or atrial flutter. The antecedents of resuscitated cardiac arrest, sudden death or appropriate shock from implantable automatic defibrillator were considered malignant arrhythmic events. During a mean follow up of 51 months, no deaths were recorded, 6.9% of the patients presented a malignant arrhythmic event, and all of them were appropriate shocks. The annual rate of events in patients with syncope was 1.7%, with a spontaneous type 1 pattern was 2.79%, and spontaneous variability was 2.87%. No malignant arrhythmic event was observed in asymptomatic patients or in those with a persistent pattern or induced type 1 pattern. The annual rate of events with positive or negative history of family sudden death was 2.94 and 1.7%, respectively. In the presence of atrial fibrillation, atrial flutter and atrial fibrillation/atrial flutter were 7.3, 15.69 and 10%, respectively. In the absence of atrial fibrillation/atrial flutter no malignant arrhythmic events were observed. CONCLUSION: Of the variables analyzed, the one that was most related to a malignant arrhythmic event was the presence of atrial fibrillation (P=.046) and atrial flutter (P=.03).

Posible valor pronóstico de la fibrilación y el flutter auricular en el síndrome de Brugada / Possible prognostic value of atrial fibrillation and atrial flutter in Brugada syndrome

Objetivo: Analizar el riesgo específico para las variables: patrón tipo 1 espontáneo, patrón tipo 1 inducido, patrón tipo 1 con variabilidad espontánea, síncope, antecedente de muerte súbita familiar, fibrilación auricular y flutter auricular, con el desarrollo subsecuente de eventos arrítmicos malignos. Métodos: Se analizaron retrospectivamente 43 pacientes con síndrome de Brugada (90% hombres; edad media 40.4 años), con patrón tipo 1 espontáneo (74.4%) o inducido por ajmalina (25.6%). El 58.1% presentó variabilidad espontánea. El 18.6% tenía antecedente de muerte súbita familiar. El 39.5% era sintomático. El 18.6% presentó fibrilación auricular o flutter auricular. El antecedente de un paro cardiaco resucitado, muerte súbita o choque apropiado del desfibrilador automático implantable se consideró evento arrítmico maligno. Durante un seguimiento promedio de 51 meses no se registraron muertes, el 6.9% de los pacientes presentó un evento arrítmico maligno, y en su totalidad fueron choques apropiados. La tasa anual de eventos arrítmicos malignos en los pacientes con síncope fue del 1.7%, con un patrón tipo 1 espontáneo, del 2.79%, y con variabilidad espontánea, del 2.87%. No se observaron eventos arrítmicos malignos en los asintomáticos y en aquellos con un patrón persistente o tipo 1 inducido. La tasa anual de eventos con antecedente positivo o negativo de muerte súbita familiar fue del 2.94 y 1.7%, respectivamente. En presencia de fibrilación auricular, flutter auricular y fibrilación auricular/flutter auricular fue del 7.3, 15.69 y 10%, respectivamente. En ausencia de fibrilación/flutter no se observaron eventos arrítmicos malignos. Conclusión: De las variables analizadas, las que tuvieron mayor relación con la presencia de un evento arrítmico maligno fueron la presencia de fibrilación auricular (p = 0,046) y de flutter auricular (p = 0,03).

Objective: To analyze the specific risk for the variables: type 1 spontaneous pattern, type 1 induced pattern, type 1 pattern with spontaneous variability, syncope, family history of sudden death, atrial fibrillation and atrial flutter with the subsequent development of malignant arrhythmic events. Methods: Forty-three Brugada patients (90% males; mean age 40.4 years), with a type 1 spontaneous pattern (74.4%) or induced by ajmaline (25.6%) were retrospectively analyzed. Of these, 58.1% presented spontaneous variability, 18.6% had family history of sudden death, 39.5% were symptomatic, and 18.6% presented atrial fibrillation or atrial flutter. The antecedents of resuscitated cardiac arrest, sudden death or appropriate shock from implantable automatic defibrillator were considered malignant arrhythmic events. During a mean follow up of 51 months, no deaths were recorded, 6.9% of the patients presented a malignant arrhythmic event, and all of them were appropriate shocks. The annual rate of events in patients with syncope was 1.7%, with a spontaneous type 1 pattern was 2.79%, and spontaneous variability was 2.87%. No malignant arrhythmic event was observed in asymptomatic patients or in those with a persistent pattern or induced type 1 pattern. The annual rate of events with positive or negative history of family sudden death was 2.94 and 1.7%, respectively. In the presence of atrial fibrillation, atrial flutter and atrial fibrillation/atrial flutter were 7.3, 15.69 and 10%, respectively. In the absence of atrial fibrillation/atrial flutter no malignant arrhythmic events were observed. Conclusion: Of the variables analyzed, the one that was most related to a malignant arrhythmic event was the presence of atrial fibrillation (P= .046) and atrial flutter (P= .03).

Brugada phenocopy: new terminology and proposed classification.

Brugada syndrome is a channelopathy characterized on ECG by coved ST-segment elevation (≥2 mm) in the right precordial leads and is associated with an increased risk of malignant ventricular arrhythmias. The term Brugada phenocopy is proposed to describe conditions that induce Brugada-like ECG manifestations in patients without true Brugada syndrome. An extensive review of the literature identified case reports that were classified according to their suspected etiological mechanism. Future directions to learn more about these intriguing cases is discussed.

New electrocardiographic criteria for discriminating between Brugada types 2 and 3 patterns and incomplete right bundle branch block.

OBJECTIVES: The aim of this study was to evaluate new electrocardiographic (ECG) criteria for discriminating between incomplete right bundle branch block (RBBB) and the Brugada types 2 and 3 ECG patterns. BACKGROUND: Brugada syndrome can manifest as either type 2 or type 3 pattern. The latter should be distinguished from incomplete RBBB, present in 3% of the population. METHODS: Thirty-eight patients with either type 2 or type 3 Brugada pattern that were referred for an antiarrhythmic drug challenge (AAD) were included. Before AAD, 2 angles were measured from ECG leads V(1) and/or V(2) showing incomplete RBBB: 1) α, the angle between a vertical line and the downslope of the r'-wave, and 2) ß, the angle between the upslope of the S-wave and the downslope of the r'-wave. Baseline angle values, alone or combined with QRS duration, were compared between patients with negative and positive results on AAD. Receiver-operating characteristic curves were constructed to identify optimal discriminative cutoff values. RESULTS: The mean ß angle was significantly smaller in the 14 patients with negative results on AAD compared to the 24 patients with positive results on AAD (36 ± 20° vs. 62 ± 20°, p < 0.01). Its optimal cutoff value was 58°, which yielded a positive predictive value of 73% and a negative predictive value of 87% for conversion to type 1 pattern on AAD; α was slightly less sensitive and specific compared with ß. When the angles were combined with QRS duration, it tended to improve discrimination. CONCLUSIONS: In patients with suspected Brugada syndrome, simple ECG criteria can enable discrimination between incomplete RBBB and types 2 and 3 Brugada patterns.

Classification and assessment of computerized diagnostic criteria for Brugada-type electrocardiograms.

BACKGROUND: Although a Brugada-type electrocardiogram (ECG) is occasionally detected in mass health screening examinations in apparently healthy individuals, the automatic computerized diagnostic criteria for Brugada-type ECGs have not been established. OBJECTIVE: This study was performed to establish the criteria for the computerized diagnosis of Brugada-type ECGs and to evaluate their diagnostic accuracy. METHODS: We examined the ECG parameters in leads V1 to V3 in patients with Brugada syndrome and cases with right bundle branch block. Based on the above parameters, we classified the ECGs into 3 types of Brugada-type ECGs, and the conditions for defining each type were explored as the diagnostic criteria. The diagnostic effectiveness of the proposed criteria was assessed using 548 ECGs from 49 cases with Brugada-type ECGs and the recordings from 192,673 cases (36,674 adults and 155,999 school children) obtained from their annual health examinations. RESULTS: The Brugada-type ST-segment elevation in V1 to V3 was classified into 3 types, types 1, 2/3, and a suggestive Brugada ECG (type S). The automatic diagnostic criteria for each type were established by the J-point amplitude, ST-segment elevation with its amplitude and configuration, as well as the T-wave morphology in leads V1 to V3. CONCLUSION: The proposed criteria demonstrated a reasonable accuracy (type 1: 91.9%, type 2/3: 86.2%, type S: 76.2%) for diagnosing Brugada-type ECG in comparison to the macroscopic diagnosis by experienced observers. Moreover, the automatic criteria had a comparable detection rate (0.6% in adults, 0.16% in children) of Brugada-type ECGs to the macroscopic inspection in the health screening examinations.