Predicting and Recognizing Drug-Induced Type I Brugada Pattern Using ECG-Based Deep Learning.

BACKGROUND: Brugada syndrome (BrS) has been associated with sudden cardiac death in otherwise healthy subjects, and drug-induced BrS accounts for 55% to 70% of all patients with BrS. This study aims to develop a deep convolutional neural network and evaluate its performance in recognizing and predicting BrS diagnosis. METHODS AND RESULTS: Consecutive patients who underwent ajmaline testing for BrS following a standardized protocol were included. ECG tracings from baseline and during ajmaline were transformed using wavelet analysis and a deep convolutional neural network was separately trained to (1) recognize and (2) predict BrS type I pattern. The resultant networks are referred to as BrS-Net. A total of 1188 patients were included, of which 361 (30.3%) patients developed BrS type I pattern during ajmaline infusion. When trained and evaluated on ECG tracings during ajmaline, BrS-Net recognized a BrS type I pattern with an AUC-ROC of 0.945 (0.921-0.969) and an AUC-PR of 0.892 (0.815-0.939). When trained and evaluated on ECG tracings at baseline, BrS-Net predicted a BrS type I pattern during ajmaline with an AUC-ROC of 0.805 (0.845-0.736) and an AUC-PR of 0.605 (0.460-0.664). CONCLUSIONS: BrS-Net, a deep convolutional neural network, can identify BrS type I pattern with high performance. BrS-Net can predict from baseline ECG the development of a BrS type I pattern after ajmaline with good performance in an unselected population.

Identification of Brugada syndrome based on P-wave features: an artificial intelligence-based approach.

AIMS: Brugada syndrome (BrS) is an inherited disease associated with an increased risk of ventricular arrhythmias. Recent studies have reported the presence of an altered atrial phenotype characterized by abnormal P-wave parameters. The aim of this study was to identify BrS based exclusively on P-wave features through an artificial intelligence (AI)-based model. METHODS AND RESULTS: Continuous 5 min 12-lead ECG recordings were obtained in sinus rhythm from (i) patients with spontaneous or ajmaline-induced BrS and no history of AF and (ii) subjects with suspected BrS and negative ajmaline challenge. The recorded ECG signals were processed and divided into epochs of 15 s each. Within these epochs, P-waves were first identified and then averaged. From the averaged P-waves, a total of 67 different features considered relevant to the classification task were extracted. These features were then used to train nine different AI-based supervised classifiers. A total of 2228 averaged P-wave observations, resulting from the analysis of 33 420 P-waves, were obtained from 123 patients (79 BrS+ and 44 BrS-). Averaged P-waves were divided using a patient-wise split, allocating 80% for training and 20% for testing, ensuring data integrity and reducing biases in AI-based model training. The BrS+ patients presented with longer P-wave duration (136 ms vs. 124 ms, P < 0.001) and higher terminal force in lead V1 (2.5 au vs. 1.7 au, P < 0.01) compared with BrS- subjects. Among classifiers, AdaBoost model had the highest values of performance for all the considered metrics, reaching an accuracy of over 81% (sensitivity 86%, specificity 73%). CONCLUSION: An AI machine-learning model is able to identify patients with BrS based only on P-wave characteristics. These findings confirm the presence of an atrial hallmark and open new horizons for AI-guided BrS diagnosis.

Can specific ECG markers identify a pharmacologically induced type 1 Brugada pattern? Insights from a large, single-center cohort.

BACKGROUND: In patients with a type 2 or 3 Brugada pattern, the pharmacological (IC drugs) induction of a type 1 pattern confirms the diagnosis of Brugada syndrome. OBJECTIVE: To evaluate the value of various ECG markers in predicting IC drug test results. METHODS: We retrospectively analysed 443 consecutive patients referred to our Center (from January 2010 to December 2019) to undergo Ajmaline/Flecainide testing; all had a type 2 or 3 Brugada pattern or were relatives with Brugada syndrome. Clinical parameters and ECG markers (r1V1 and SV6 duration and amplitude, QRSV1/QRSV6 duration, V1 and V2 ST amplitude) were independently evaluated for their association to pharmacological test positivity, and a logistic regression model was applied. RESULTS: The drug test was positive in 151 (34%) patients. On multivariate logistic regression analysis, age > 45 years, female gender, HR >60 bpm, QRSV1/QRSV6 duration >1 and non-isoelectric pattern in V2 were associated with a positive test. The percentage of patients who tested positive increased according to the presence of the above ECG markers (from 11.3% in the absence to 57.6% in the presence of both factors). During long-term follow-up, the clinical event rate was higher in patients with predictive ECG markers and very low in those without. CONCLUSIONS: In our population we confirmed the ability of QRSV1/QRSV6 duration >1 and of a non-isoelectric pattern in V2 to predict a pharmacologically induced type 1 Brugada pattern. Patients with neither of these ECG markers had a rather low event rate during follow-up.

T-Peak to T-End Interval for Prediction of Positive Response to Ajmaline Challenge Test in Suspected Brugada Syndrome Patients.

BACKGROUND: Brugada syndrome (BrS) is diagnosed in patients with ST-segment elevation with coved-type morphology in the right precordial leads, occurring spontaneously or after provocative drugs. Due to electrocardiographic (ECG) inconsistency, provocative drugs, such as sodium-channel blockers, are useful for unmasking BrS. Ajmaline is superior to flecainide and procainamide to provoke BrS. Prolonged T-peak to T-end (TpTe) is associated with an increased risk of ventricular arrhythmia and sudden cardiac death in Brugada syndrome patients. OBJECTIVE: This study aimed to investigate the predictive value of T-peak to T-end interval and corrected T-peak to T-end interval for predicting the positive response of the ajmaline challenge test in suspected Brugada syndrome patients. METHODS: Patients who underwent the ajmaline test in our center were enrolled. Clinical characteristics and electrocardiographic parameters were analyzed, including TpTe, corrected TpTe, QT, corrected QT(QTc) interval, and S-wave duration, compared with the result of the ajmaline challenge test. RESULTS: The study found that TpTe and corrected TpTe interval in suspected BrS patients were not significantly associated with a positive response to the ajmaline challenge test. CONCLUSIONS: The T-peak to T-end interval and corrected T-peak to T-end interval could not predict the positive response of the ajmaline challenge test in suspected Brugada syndrome patients.

Impact of SMART Pass filter in patients with ajmaline-induced Brugada syndrome and subcutaneous implantable cardioverter-defibrillator eligibility failure: results from a prospective multicentre study.

AIMS: Ajmaline challenge can unmask subcutaneous implantable cardioverter-defibrillator (S-ICD) screening failure in patients with Brugada syndrome (BrS) and non-diagnostic baseline electrocardiogram (ECG). The efficacy of the SMART Pass (SP) filter, a high-pass filter designed to reduce cardiac oversensing (while maintaining an appropriate sensing margin), has not yet been assessed in patients with BrS. The aim of this prospective multicentre study was to investigate the effect of the SP filter on dynamic Brugada ECG changes evoked by ajmaline and to assess its value in reducing S-ICD screening failure in patients with drug-induced Brugada ECGs. METHODS AND RESULTS: The S-ICD screening with conventional automated screening tool (AST) was performed during ajmaline challenge in subjects with suspected BrS. The S-ICD recordings were obtained before, during and after ajmaline administration and evaluated by the means of a simulation model that emulates the AST behaviour with and without SP filter. A patient was considered suitable for S-ICD if at least one sensing vector was acceptable in all tested postures. A sensing vector was considered acceptable in the presence of QRS amplitude >0.5 mV, QRS/T-wave ratio >3.5, and sense vector score >100. Of the 126 subjects (mean age: 42 ± 14 years, males: 61%, sensing vectors: 6786), 46 (36%) presented with an ajmaline-induced Brugada type 1 ECG. Up to 30% of subjects and 40% of vectors failed the screening during the appearance of Brugada type 1 ECG evoked by ajmaline. The S-ICD screening failure rate was not significantly reduced in patients with Brugada ECGs when SP filter was enabled (30% vs. 24%). Similarly, there was only a trend in reduction of vector-failure rate attributable to the SP filter (from 40% to 36%). The most frequent reason for screening failure was low QRS amplitude or low QRS/T-wave ratio. None of these patients was implanted with an S-ICD. CONCLUSION: Patients who pass the sensing screening during ajmaline can be considered good candidates for S-ICD implantation, while those who fail might be susceptible to sensing issues. Although there was a trend towards reduction of vector sensing failure rate when SP filter was enabled, the reduction in S-ICD screening failure in patients with Brugada ECGs did not reach statistical significance. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov Unique Identifier NCT04504591.

Predicting cardiac electrical response to sodium-channel blockade and Brugada syndrome using polygenic risk scores.

AIMS: Sodium-channel blockers (SCBs) are associated with arrhythmia, but variability of cardiac electrical response remains unexplained. We sought to identify predictors of ajmaline-induced PR and QRS changes and Type I Brugada syndrome (BrS) electrocardiogram (ECG). METHODS AND RESULTS: In 1368 patients that underwent ajmaline infusion for suspected BrS, we performed measurements of 26 721 ECGs, dose-response mixed modelling and genotyping. We calculated polygenic risk scores (PRS) for PR interval (PRSPR), QRS duration (PRSQRS), and Brugada syndrome (PRSBrS) derived from published genome-wide association studies and used regression analysis to identify predictors of ajmaline dose related PR change (slope) and QRS slope. We derived and validated using bootstrapping a predictive model for ajmaline-induced Type I BrS ECG. Higher PRSPR, baseline PR, and female sex are associated with more pronounced PR slope, while PRSQRS and age are positively associated with QRS slope (P < 0.01 for all). PRSBrS, baseline QRS duration, presence of Type II or III BrS ECG at baseline, and family history of BrS are independently associated with the occurrence of a Type I BrS ECG, with good predictive accuracy (optimism-corrected C-statistic 0.74). CONCLUSION: We show for the first time that genetic factors underlie the variability of cardiac electrical response to SCB. PRSBrS, family history, and a baseline ECG can predict the development of a diagnostic drug-induced Type I BrS ECG with clinically relevant accuracy. These findings could lead to the use of PRS in the diagnosis of BrS and, if confirmed in population studies, to identify patients at risk for toxicity when given SCB.

Management of untreatable ventricular arrhythmias during pharmacologic challenges with sodium channel blockers for suspected Brugada syndrome.

Pharmacologic challenge with sodium channel blockers is part of the diagnostic workout in patients with suspected Brugada syndrome. The test is overall considered safe but both ajmaline and flecainide detain well known pro-arrhythmic properties. Moreover, the treatment of patients with life-threatening arrhythmias during these diagnostic procedures is not well defined. Current consensus guidelines suggest to adopt cautious protocols interrupting the sodium channel blockers as soon as any ECG alteration appears. Nevertheless, the risk of life-threatening arrhythmias persists, even adopting a safe and cautious protocol and in absence of major arrhythmic risk factors. The authors revise the main published case studies of sodium channel blockers challenge in adults and in children, and summarize three cases of untreatable ventricular arrhythmias discussing their management. In particular, the role of advanced cardiopulmonary resuscitation with extra-corporeal membrane oxygenation is stressed as it can reveal to be the only reliable lifesaving facility in prolonged cardiac arrest.

Mechanisms Underlying Epicardial Radiofrequency Ablation to Suppress Arrhythmogenesis in Experimental Models of Brugada Syndrome.

OBJECTIVES: This study sought to test the hypothesis that elimination of sites of abnormal repolarization, via epicardial RFA, suppresses the electrocardiographic and arrhythmic manifestations of BrS. BACKGROUND: Brugada syndrome (BrS) is associated with ventricular tachycardia and ventricular fibrillation leading to sudden cardiac death. Nademanee et al. reported that radiofrequency ablation (RFA) of right ventricular outflow tract epicardium significantly reduced the electrocardiogram and arrhythmic manifestations of BrS. These authors concluded that low-voltage fractionated electrogram activity and late potentials are caused by conduction delay within the right ventricular outflow tract and that the ameliorative effect of RFA is caused by elimination of this substrate. Szel et al. recently demonstrated that the abnormal electrogram activity is associated with repolarization defects rather than depolarization or conduction defects. METHODS: Action potentials (AP), electrograms, and pseudoelectrocardiogram were simultaneously recorded from coronary-perfused canine right ventricular wedge preparations. Two pharmacological models were used to mimic BrS genotype: combination of INa blocker ajmaline (1 to 10 µM) and IK-ATP agonist pinacidil (1 to 5 µM); or combination of Ito agonist NS5806 (4 to 10 µM) and ICa blocker verapamil (0.5 to 2 µM). After stable induction of abnormal electrograms and arrhythmic activity, the preparation was mapped and epicardial RFA was applied. RESULTS: Fractionated low-voltage electrical activity was observed in right ventricular epicardium but not endocardium as a consequence of heterogeneities in the appearance of the second upstroke of the epicardial AP. Discrete late potentials developed as a result of delay of the second upstroke of the AP and of concealed phase 2 re-entry. Epicardial RFA of these abnormalities normalized Brugada pattern and abolished arrhythmic activity, regardless of the pharmacological model used. CONCLUSIONS: Our results suggest that epicardial RFA exerts its ameliorative effect in the setting of BrS by destroying the cells with the most prominent AP notch, thus eliminating sites of abnormal repolarization and the substrate for ventricular tachycardia ventricular fibrillation.

Long-term prognosis of drug-induced Brugada syndrome.

BACKGROUND: Patients with drug-induced Brugada syndrome (BS) are considered at a lower risk than those with a spontaneous type I pattern. Nevertheless, they can present arrhythmic events. OBJECTIVE: The purpose of this study was to investigate their clinical characteristics, long-term prognosis and risk factors. METHODS: A consecutive cohort of 343 patients with drug-induced BS was included and compared with 78 patients with a spontaneous type I pattern. RESULTS: The mean age was 40.7 ± 18.3 years. Sudden cardiac death (SCD) was the clinical presentation in 13 (3.8%) and syncope in 86 (25.1%); 244 (71.1%) were asymptomatic. Patients with drug-induced BS were less frequently men (180 (52.5%) vs 63 (80.8%); P < .01), were more frequently asymptomatic (244 (71.1%) vs 44 (56.4%); P < .01), and had less ventricular arrhythmias (VAs) induced during electrophysiology study (41 (13.2%) vs 31 (42.4%); P < .01). An implantable cardioverter-defibrillator was implanted in 128 patients (37.3%). During a median follow-up of 62.5 months (interquartile range 28.9-115.6 months), 34 patients presented arrhythmic events. The event rate was 1.1% person-year (vs 2.3% person-year in patients with a spontaneous type I pattern; P < .01). Presentation as SCD and inducible VAs were independent risk factors significantly associated with arrhythmic events (adjusted hazard ratio 22.0 and 3.5). Drug-induced BS was related to a better prognosis only in asymptomatic individuals. CONCLUSION: Drug-induced BS has a good prognosis if asymptomatic; however, SCD is possible. Clinical presentation as SCD and inducible VAs during electrophysiology study are independent risk factors for arrhythmic events. In asymptomatic patients, proband status and inducible VAs can help to identify patients at higher risk, but further evidence is needed.

Cholestatic hepatitis after diagnostic ajmaline challenge.

We report a cholestatic hepatitis in an elderly woman after ajmaline challenge during electrophysiological testing for Brugada syndrome. No other medication was reported in the previous 6 months of the onset of jaundice. Liver biopsy showed a cholestatic hepatitis with mild biliary damage. Liver enzymes normalized within 2 weeks as well as jaundice. To the best of our knowledge this is the second case of histologically proved cholestatic hepatitis induced by intravenous ajmaline testing.

Pharmacological Provocation of Outflow-Tract Tachycardia in a Patient With Brugada Syndrome.

We present a case of a symptomatic patient with Brugada syndrome, who had sustained right ventricular outflow tract tachycardia after pronounced exercise-induced ST segment elevation in V1 and V2. In electrophysiological study he developed right ventricular outflow tract tachycardia provoked by combined infusion of ajmaline and orciprenaline. After ablation no further arrhythmia was provoked by pharmacological stimulation.

Prevalence of type 1 Brugada ECG pattern after administration of Class 1C drugs in patients with type 1 myotonic dystrophy: Myotonic dystrophy as a part of the Brugada syndrome.

BACKGROUND: Both type 1 myotonic dystrophy (MD1) and Brugada syndrome (BrS) may be complicated by conduction disturbances and sudden death. Spontaneous BrS has been observed in MD1 patients, but the prevalence of drug-induced BrS in MD1 is unknown. OBJECTIVE: The purpose of this study was to prospectively assess the prevalence of type 1 ST elevation as elicited during pharmacologic challenge with Class 1C drugs in a subgroup of MD1 patients and to further establish correlations with ECG and electrophysiologic variables and prognosis. METHODS: From a group of unselected 270 MD1 patients, ajmaline or flecainide drug challenge was performed in a subgroup of 44 patients (27 men, median age 43 years) with minor depolarization/repolarization abnormalities suggestive of possible BrS. The presence of type 1 ST elevation after drug challenge was correlated to clinical, ECG, and electrophysiologic variables. RESULTS: Eight of 44 patients (18%) presented with BrS after drug challenge. BrS was seen more often in men (26% vs 6%, P = .09) and was related to younger age (35 vs 48 years, P = .07). BrS was not correlated to symptoms, baseline ECG, HV interval, results of signal-averaged ECG, or abnormalities on ambulatory recordings. MD1 patients with BrS had longer corrected QT intervals, greater increase in PR interval after drug challenge, and higher rate of inducible ventricular arrhythmias (62% vs 21%, P = .03). Twelve patients were implanted with a pacemaker and 5 with an implantable cardioverter-defibrillator. Significant bradycardia did not occur in any patients, and malignant ventricular arrhythmia never occurred during median 7-year follow-up (except 1 hypokalemia-related ventricular fibrillation). CONCLUSION: BrS is elicited by a Class 1 drug in 18% of MD1 patients presenting with minor depolarization/repolarization abnormalities at baseline, but the finding seems to be devoid of a prognostic role.

Drug-induced brugada syndrome in children: clinical features, device-based management, and long-term follow-up.

OBJECTIVES: The goal of this study was to investigate the clinical features, management, and long-term follow-up of children with drug-induced Brugada syndrome (BS). BACKGROUND: Patients with BS <12 years of age with a spontaneous type I electrocardiogram have a higher risk of arrhythmic events. Data on drug-induced BS in patients <12 years of age are lacking. METHODS: Among 505 patients with ajmaline-induced BS, subjects ≤12 years of age at the time of diagnosis were considered as children and eligible for this study. RESULTS: Forty children (60% male; age 8 ± 2.8 years) were included. Twenty-four children (60%) had a family history of sudden death. Two (5%) had a previous episode of aborted sudden death, and 8 (20%) had syncope. Children experienced more frequent episodes of sinus node dysfunction (SND) compared with older subjects (7.5% vs. 1.5%; p = 0.04) and had a comparable incidence of atrial tachyarrhythmias. Children more frequently experienced episodes of ajmaline-induced sustained ventricular arrhythmias (VAs) compared with older patients (10.0% vs. 1.3%; p = 0.005). Twelve children (30%) received an implantable cardioverter-defibrillator (ICD). After a mean follow-up time of 83 ± 51 months, none of the children died suddenly. Spontaneous sustained VAs were documented in 1 child (2%). Among children with ICD, 1 (8%) experienced an appropriate shock, 4 (33%) had inappropriate ICD shocks, and 4 (33%) experienced device-related complications. CONCLUSIONS: Drug-induced BS is associated with atrial arrhythmias and SND. Children are at higher risk of ajmaline-induced VAs. The rate of device-related complications, leading to lead replacement or inappropriate shocks, is considerable and even higher than with appropriate interventions. Based on these findings, the optimal management of BS in childhood should remain individualized, taking into consideration the patient's clinical history and family's wishes.

Severe cholestatic jaundice after a single administration of ajmaline; a case report and review of the literature.

BACKGROUND: Ajmaline is a pharmaceutical agent now administered globally for a variety of indications, particularly investigation of suspected Brugada syndrome. There have been previous reports suggesting that repetitive use of this agent may cause severe liver injury, but little evidence exists demonstrating the same effect after only a single administration. CASE PRESENTATION: A 33-year-old man of Libyan origin with no significant past medical history underwent an ajmaline provocation test for investigation of suspected Brugada syndrome. Three weeks later, he presented with painless cholestatic jaundice which peaked in severity at eleven weeks after the test. Blood tests confirmed no evidence of autoimmune or viral liver disease, whilst imaging confirmed the absence of biliary tract obstruction. A liver biopsy demonstrated centrilobular cholestasis and focal rosetting of hepatocytes, consistent with a cholestatic drug reaction. Over the course of the next few months, he began to improve clinically and biochemically, with complete resolution by one year post-exposure. CONCLUSION: Whilst ajmaline-related hepatotoxicity was well-recognised in the era in which the drug was administered as a regular medication, clinicians should be aware that ajmaline may induce severe cholestatic jaundice even after a single dose administration.

Life-threatening ventricular arrhythmias during ajmaline challenge in patients with Brugada syndrome: incidence, clinical features, and prognosis.

BACKGROUND: Sustained ventricular arrhythmias (sVAs), such as polymorphic ventricular tachycardia or ventricular fibrillation, can complicate ajmaline challenge in patients with Brugada syndrome (BS). OBJECTIVE: To assess the incidence of life-threatening sVAs during ajmaline administration in a large series of patients with BS. In addition, clinical characteristics as well as prognosis of these patients were evaluated. METHODS: All consecutive patients with ajmaline-induced diagnosis of BS were eligible for this study. RESULTS: A total of 503 patients were included. Nine (1.8%) patients (44% men; mean age 26 ± 18 years) developed a life-threatening sVA during ajmaline challenge. Three patients (33%)were children, and 2 (22%) patients experienced sVAs refractory to the first external defibrillation. One patient underwent venoarterial extracorporeal membrane oxygenation to restore sinus rhythm. Age at the time of ajmaline challenge was significantly lower in patients with sVAs compared with patients without sVAs (26 ± 18 years vs 41 ± 18 years; P = .01). Moreover, patients with sVAs presented more frequently with sinus node dysfunction compared with patients with normal response to ajmaline (22.2% vs 1.4%; P = .01). After a mean follow-up time of 29 ± 8 months, none of the patients who had developed a sVA during ajmaline challenge died suddenly or developed further life-threatening ventricular arrhythmias. CONCLUSIONS: sVA during ajmaline challenge is not a rare event in BS occurring in 9 (1.8%) patients. Despite its challenging acute treatment, the occurrence of ajmaline-induced sVAs in patients with BS might not identify a category at higher risk for further arrhythmic events.