Risk stratification in individuals with Brugada electrocardiographic pattern (BrECG) remains challenging. The dST-Tiso ECG criterion, defined as an interval between the onset of coved ST-segment elevation and its return to the isoelectric line >300 ms, has been validated as a predictor of ventricular arrhythmia (VA) inducibility during programmed ventricular stimulation. We aimed to assess the association between this criterion and the arrhythmic risk during follow-up. Consecutive patients with BrECG were prospectively enrolled. The dST-Tiso interval was measured during a manifest type 1 BrECG (spontaneous or drug-induced). The primary endpoint was a composite of sudden cardiac death or documented VA, either symptomatic or treated with appropriate implantable cardioverter-defibrillator therapy. The cohort included 281 patients (median age 42 years; 64% male; 10% spontaneous type 1; 23% VA-inducible). Among them, 197 (70%) had a negative and 84 (30%) a positive dST-Tiso criterion. Over a median follow-up of 3.2 years, 11 patients (3.9%) reached the primary endpoint: 1 sudden cardiac death, 5 implantable cardioverter-defibrillator-treated VA, and 5 self-terminating VA episodes. All events occurred in patients with positive dST-Tiso (log-rank p <0.001). Within this group, 5 patients had spontaneous and 6 drug-induced type 1 BrECG; 7 had inducible and 4 noninducible VA. As a continuous variable, the dST-Tiso was also associated with events (hazard ratio per ms: 1.02; 95% confidence interval [95% CI] 1.01 to 1.03; p <0.001). In conclusion, individuals with BrECG and a negative dST-Tiso criterion had a very low risk of arrhythmic events. This ECG marker may enhance multiparametric risk stratification.
Brugada syndrome is an inherited cardiac channelopathy affecting sodium channel function, and a leading cause of sudden cardiac death (SCD) in young adults without structural heart disease. It is characterized by a type 1 electrocardiographic pattern (BrECG), coved ST-segment elevation ≥2 mm followed by a negative T wave in right precordial leads (V1 to V2), which may appear spontaneously or after drug challenge. Although estimates of its prevalence range from 1 to 30 per 10,000 individuals depending on ethnic background. , The true burden of disease is likely underestimated due to diagnostic challenges and transient ECG expression.
Risk stratification remains a major clinical challenge, especially in asymptomatic individuals, who account for approximately two-thirds of cases. , Longitudinal studies have shown that up to 10% of these patients may experience life-threatening ventricular arrhythmias (VAs) or SCD over follow-up periods extending up to a decade. , Many studies have focused on identifying diagnostic ECG features associated with increased SCD risk. , Recently, we proposed a novel ECG-based marker, the dST-Tiso interval. A positive dST-Tiso criterion, defined as the interval between the onset of coved ST-segment elevation and its return to the isoelectric line >300 ms, has shown a strong association with VA inducibility during programmed ventricular stimulation (PVS) in patients with drug-induced type 1 BrECG. , However, its long-term prognostic value remains unexplored.
This study aimed to evaluate whether the dST-Tiso criterion is associated with major arrhythmic events in a real-world cohort of individuals with BrECG.
Methods
Study population
This prospective, observational, single-center registry included all patients with BrECG referred to our institution between December 2018 and February 2024, with follow-up extending through May 2025. The study was approved by the local ethics committee, and all participants provided written informed consent for research purposes.
Prior to enrollment, structural cardiac abnormalities and cardiomyopathies were excluded using transthoracic echocardiography and exercise stress testing. Demographic data, including symptoms, history of syncope, and family history of Brugada syndrome or SCD were collected before any study procedures. A type 1 BrECG was documented (coved type), either spontaneously or following a provocative test involving intravenous ajmaline administration at a dose of 1 mg/kg over 5 minutes. BrECG was evaluated according to the original Consensus Conference criteria and subsequent updates. , A diagnostic pattern was defined as a coved-type ST-segment elevation ≥2 mm followed by a negative T wave in one or more right precordial leads (V1 and V2).
All diagnosed patients subsequently underwent PVS during a manifest BrECG. The PVS protocol included 2 basic drive cycles (600 and 400 ms, S1-S1) and up to 3 extrastimuli (S2 to S4). The coupling interval of the extrastimuli was reduced in 10 ms increments to a minimum of 200 ms, or higher if right ventricular refractoriness was observed. If the VA was not inducible at the right ventricular apex, stimulation was performed from the right ventricular outflow tract. VA inducibility was considered positive if PVS resulted in sustained or hemodynamically significant polymorphic ventricular tachycardia or ventricular fibrillation requiring direct current cardioversion. A genetic test, searching for mutations in SCN5A (sodium voltage-gated channel alpha subunit 5) and other Brugada susceptibility genes, was proposed to patients with type 1 pattern.
Recommendations for implantable cardioverter-defibrillator (ICD) implantation were based on current guidelines. In asymptomatic patients, decisions were made on a case-by-case basis, weighing the potential risk of future arrhythmic events against procedural risks, the likelihood of inappropriate shocks, and overall impact on quality of life.
dST-Tiso criterion
As previously described, the dST-Tiso interval is an ECG marker defined as the duration from the point where the terminal portion of the QRS complex intersects the isoelectric baseline (marking the onset of the coved-type ST-segment elevation) to the return of the T wave to the isoelectric line (only the positive deflection that intersects the isoelectric baseline). A positive dST-Tiso criterion (interval >300 ms) was initially identified in a cohort of 76 patients with an ajmaline-induced type 1 pattern, in whom demonstrated significant predictive value for VA inducibility. The criterion was subsequently validated in an independent cohort of 128 patients.
For the present study, the dST-Tiso interval was measured in leads V1 and V2 at the second, third, or fourth intercostal space. Measurements were performed on consecutive beats corresponding to the peak time of the pharmacological effect of ajmaline on sodium channel blockade, representing the point of maximal unmasking of the ECG pattern. Only the longest interval among these was considered for analysis. Measurements were performed on 12-lead ECG tracings acquired at a paper speed of 25 mm/s and a standard gain of 0.1 mV/mm at 1-minute intervals. ECG recording continued for another 10 minutes after the last administration or attenuation of the pattern. The isoelectric baseline was obtained by connecting the TP segment (segment between T wave and P wave) of the complex in which the dST-Tiso interval was measured with the TP segment of the preceding complex. The onset of the interval was identified at the intersection between the terminal portion of the QRS complex and the isoelectric line. The terminal T-wave morphology and its positive component were delineated until its final crossing of the isoelectric line. In cases where the T wave exhibited low-amplitude morphology (flat or isoelectric), the point of return to the isoelectric baseline was determined using both visual inspection and the tangent method, referencing corresponding complexes in the same lead group to improve accuracy and ensure reproducibility. Examples of dST-Tiso interval measurements are provided in the supplementary Figure S1 and S2 .
All ECGs were independently reviewed by 3 experienced electrophysiologists. The final dST-Tiso value for each patient was calculated as the average of the 3 measurements.
Primary endpoint definition and follow-up
The aim of this study was to evaluate the association between the dST-Tiso criterion and the risk of major arrhythmic events during follow-up in patients with BrECG.
The primary endpoint was a composite of SCD or documented VA that was either symptomatic or treated with appropriate ICD therapy. SCD was defined as death with documented VA at the time of the event or in the absence of an identifiable alternative cause. Appropriate ICD therapy was defined as the delivery of shocks or antitachycardia pacing (ATP) for sustained VAs, including monomorphic ventricular tachycardia, polymorphic ventricular tachycardia, or ventricular fibrillation (VF), with a cycle length falling within the programmed therapy zone of the device. ICDs were programmed with a long detection time and a single VF zone set at ≥210 beats per minute, with ATP delivered during or prior to capacitor charging.
All patients underwent regular outpatient follow-up at our institution, with evaluations conducted at least annually with assessment of potential arrhythmia-related symptoms, 12-lead ECG, and 24-hour Holter monitoring. Patients with ICDs were also monitored remotely. ICD-related complications were recorded throughout the follow-up period.
Statistical analysis
Descriptive statistics were reported as medians and interquartile ranges (IQRs) for continuous variables, and as percentages for categorical variables. Group comparisons were performed using the Mann–Whitney U test for continuous variables and the chi-squared test or Fisher’s exact test for categorical variables, as appropriate.
Event-free survival for the primary endpoint was estimated using the Kaplan–Meier (product-limit) method and reported with 95% confidence intervals (CIs) for the overall population and for each dST-Tiso group. Kaplan–Meier survival curves were compared using the log-rank test. As a sensitivity analysis, a nonparametric bootstrap procedure with 1,000 replications was applied to the log-rank test to assess the robustness of the difference in the primary endpoint survival between the study groups.
Univariate Cox proportional hazards models were used to assess the association between the primary endpoint and the following variables: dST-Tiso interval, history of syncope, family history of SCD, spontaneous type 1 BrECG, and VA inducibility at PVS. Results were expressed as hazard ratios (HRs) with corresponding 95% CIs.
A 2-sided p value <0.05 was considered statistically significant. All analyses were performed using Stata software, version 19.0 (StataCorp, College Station, TX, USA).
Results
Baseline characteristics
A total of 281 consecutive patients with spontaneous or drug-induced type 1 BrECG were prospectively included in this analysis. The median age was 42 years (IQR 33 to 52), and the majority were male (63.7%). The study cohort primarily consisted of asymptomatic individuals, with only 16.7% reporting a history of syncope and 1.8% having documented VAs.
A negative dST-Tiso criterion was observed in 197 patients (70.1%), whereas 84 patients (29.9%) had a positive dST-Tiso. As expected, several significant differences in ECG characteristics were observed between the 2 groups, as detailed in Table 1 . Notably, the prevalence of a spontaneous type 1 BrECG was significantly higher in the positive dST-Tiso group (22.6% vs 4.6%, p <0.001). As known, a dST-Tiso interval >300 ms was also strongly associated with VA inducibility during PVS (65.5% vs 5.1%, p <0.001).
Table 1
Patients’ characteristics in the overall study population and by dST-Tiso interval
| Overall (n = 281) | Negative dST-Tiso (n = 197) | Positive dST-Tiso (n = 84) | p Value | |
|---|---|---|---|---|
| Age (years) | 42 (33 to 52) | 41 (32 to 51) | 48 (38 to 54) | 0.002 |
| Men | 179 (63.7%) | 112 (56.9%) | 67 (79.8%) | <0.001 |
| Probands | 209 (74.4%) | 142 (72.1%) | 69 (79.8%) | 0.177 |
| History of syncope | 47 (16.7%) | 28 (14.2%) | 19 (22.6%) | 0.084 |
| Cardiac arrest survivors | 1 (0.4%) | 0 (0%) | 1 (1.2%) | 0.125 |
| Family history of sudden death | 62 (22.1%) | 37 (18.8%) | 25 (29.8%) | 0.042 |
| Documented VA | 5 (1.8%) | 3 (1.5%) | 2 (2.4%) | 0.618 |
| History of AF | 13 (4.6%) | 8 (4.1%) | 5 (6.0%) | 0.490 |
| Baseline ECG | ||||
| Spontaneous type 1 | 28 (10.0%) | 9 (4.6%) | 19 (22.6%) | <0.001 |
| QRS duration (ms) | 100 (90 to 110) | 100 (90 to 108) | 100 (96 to 110) | 0.008 |
| PQ interval (ms) | 160 (144 to 180) | 154 (140 to 170) | 172 (158 to 188) | <0.001 |
| QT interval (ms) | 420 (400 to 435) | 420 (400 to 440) | 404 (385 to 430) | <0.001 |
| Early repolarization | 4 (1.4%) | 2 (1.0%) | 2 (2.4%) | 0.372 |
| PVCs | 11 (3.9%) | 6 (3.0%) | 5 (6.0%) | 0.250 |
| Drug provocative test | ||||
| QRS duration (ms) | 120 (110 to 130) | 120 (110 to 130) | 126 (110 to 130) | 0.005 |
| PQ interval (ms) | 210 (200 to 240) | 206 (190 to 226) | 210 (200 to 240) | <0.001 |
| QT interval (ms) | 467 (446 to 488) | 468 (447 to 490) | 467 (443 to 486) | 0.819 |
| Presence of PVCs | 45 (16.0%) | 22 (11.2%) | 23 (27.4%) | <0.001 |
| J peak (mV) | 0.4 (0.3 to 0.6) | 0.4 (0.3 to 0.5) | 0.6 (0.5 to 0.7) | <0.001 |
| PVS | ||||
| VA inducibility | 65 (23.1%) | 10 (5.1%) | 55 (65.5%) | <0.001 |
| Inducibility site | <0.001 | |||
| RV Apex | 41 (14.6%) | 7 (3.6%) | 34 (40.5%) | – |
| RVOT | 22 (7.8%) | 3 (1.5%) | 19 (22.6%) | – |
| Spontaneous | 2 (0.7%) | 0 (0%) | 2 (2.4%) | – |
| Induced with | <0.001 | |||
| S1 | 3 (1.1%) | 0 (0%) | 3 (3.6%) | – |
| S2 | 10 (3.6%) | 0 (0%) | 10 (11.9%) | – |
| S3 | 29 (10.3%) | 8 (4.1%) | 21 (25.0%) | – |
| S4 | 21 (7.5%) | 2 (1.0%) | 19 (22.6%) | – |
| CIED implanted | <0.001 | |||
| None | 198 (70.5%) | 180 (91.4%) | 18 (21.4%) | – |
| Transvenous ICD | 68 (24.2%) | 11 (5.6%) | 57 (67.9%) | – |
| sICD | 9 (3.2%) | 1 (0.5%) | 8 (9.5%) | – |
| ICM | 6 (2.1%) | 5 (2.5%) | 1 (1.2%) | – |
Data are reported as median (interquartile range) or as number (percentage).
Abbreviations: AF = atrial fibrillation; ECG = electrocardiogram; ICD = implantable cardioverter-defibrillator; PVCs = pre-ventricular contractions; BrS = Brugada syndrome; PVS = programmed ventricular stimulation; sICD = subcutaneous implantable cardioverter-defibrillator; VA = ventricular arrhythmia; VT = ventricular tachycardia; VF = ventricular fibrillation; RV = right ventricle; RVOT = right ventricle outflow track.
An ICD, either transvenous or subcutaneous, was implanted in 77 patients (27.4%), the majority of whom (n = 65) were in the positive dST-Tiso group. Additionally, 6 patients (2.1%) received an implantable cardiac monitor.
Primary point events
During a median follow-up of 3.2 years (IQR 2.2 to 4.5), 11 patients (3.9%) experienced the primary endpoint. Specifically, 1 patient without an ICD died suddenly during sleep, and 10 patients had VA episodes. Five patients received ICD therapy (3 shock, 2 ATP only), and 5 patients had symptomatic self-extinguishing VA episodes. Baseline clinical characteristics of these patients are summarized in Table 2 .
Table 2
Clinical characteristics of patients with primary endpoint
| Patient no. | Sex | Age | dST-Tiso | Type 1 BrECG pattern | History of syncope | History of VA/aSD | Family history of SD | PVS | Genetic | CIED | Event | Follow-up (mo) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 52 | Male | 57 | Positive | Induced | 0 | 0 | 0 | Positive | Negative | ICD | ATP on VA | 14 |
| 85 | Male | 34 | Positive | Induced | 0 | 0 | 0 | Positive | Negative | sICD | VA | 25 |
| 101 | Male | 59 | Positive | Induced | 0 | 0 | 1 | Positive | Negative | ICD | ATP on VA | 3 |
| 111 | Male | 34 | Positive | Induced | 0 | 0 | 0 | Negative | Negative | None | SD | 31 |
| 116 | Female | 36 | Positive | Induced | 0 | 0 | 0 | Positive | Negative | ICD | VA | 1 |
| 124 | Male | 54 | Positive | Induced | 1 | 0 | 1 | Positive | Negative | ICD | VA | 4 |
| 151 | Female | 63 | Positive | Spontaneous | 1 | 1 | 0 | Negative | Negative | ICD | VA | 6 |
| 173 | Female | 70 | Positive | Spontaneous | 1 | 0 | 0 | Negative | Negative | ICD | Shock on VA | 22 |
| 183 | Male | 49 | Positive | Spontaneous | 0 | 0 | 0 | Positive | Positive | ICD | Shock on VA | 13 |
| 190 | Male | 58 | Positive | Spontaneous | 0 | 0 | 1 | Negative | Negative | ICD | Shock in VA | 16 |
| 251 | Female | 64 | Positive | Spontaneous | 0 | 0 | 0 | Positive | Negative | ICD | VA | 18 |
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