Prevalence and characteristics of the Brugada electrocardiogram pattern in patients with arrhythmogenic right ventricular cardiomyopathy

Abstract Background Despite distinct pathophysiology, arrhythmogenic right ventricular cardiomyopathy (ARVC) and Brugada syndrome (BrS) exhibit overlapping phenotypes. We investigated the prevalence and characteristics of the Brugada electrocardiogram (ECG) pattern in ARVC patients. Methods A total of 114 ARVC patients fulfilling the revised Task Force Criteria were enrolled. The Brugada ECG pattern was evaluated according to the consensus report on right precordial leads, and 1141 ECGs (median, 1; interquartile range, 1‐16 ECGs/patient) were analyzed. Results Five patients (4%) showed a Brugada ECG pattern, which disappeared in four patients with ECGs recorded more than 2 years afterward. ARVC patients with the Brugada ECG pattern had a longer PQ interval (220 ± 62 ms vs 180 ± 35 ms, P = .02) and longer QRS duration (138 ± 25 ms vs 102 ± 23 ms, P < .001) than patients without the pattern. During follow‐up (median, 11.4; interquartile range, 5.5‐17.1 years), 19 ARVC patients experienced cardiac death and 29 experienced heart failure (HF) hospitalization. Kaplan‐Meier analysis determined that the Brugada ECG pattern increased the risk of cardiac death and HF hospitalization (log‐rank; P < .001, P < .001 respectively). The mean J‐point and S‐wave amplitudes of the Brugada ECG pattern were 0.29 ± 0.05 mV and 0.34 ± 0.21 mV, respectively, which were significantly lower than those of 26 age‐matched BrS patients with a previous ventricular fibrillation episode (0.66 ± 0.33 mV, P < .001 and 0.67 ± 0.39 mV, P = .02 respectively). Conclusion The Brugada ECG pattern was infrequently encountered, was transient in ARVC patients, and was associated with a longer PQ interval, longer QRS duration, and cardiac events.


| INTRODUC TI ON
and radiofrequency ablation for these potentials can suppress VF occurrence and cause the type 1 Brugada ECG to disappear. 4,5 Several imaging studies have also identified structural abnormalities. 6,7 The ECG diagnosis was established in the 2005 consensus report. 8 Although ARVC and BrS are thought to be different diseases, as validated by the diagnostic criteria of each disease, some reports have suggested that there are overlapping characteristics between the two. [9][10][11][12][13][14] Epicardial abnormality is the primary pathophysiological feature in both ARVC and BrS. Similar features, especially those pertaining to the ECG, can be provoked in some cases. The manifestation of a Brugada phenotype in many ARVC patients with long-term follow-up has not yet been reported. Therefore, the purpose of this study was to investigate the prevalence and clinical significance of the Brugada ECG pattern in patients with ARVC.

| Study group
In this single-center cohort study, we evaluated 114 consecutive ARVC patients who fulfilled the rTFC. In

| Definition of Brugada ECG pattern
A positive Brugada ECG pattern was defined as a type 1 or type 2 ECG with a J-point elevation ≥2 mm in lead V1 to V3, in accordance with previous reports. 15,16 The J-point was defined as the junction between the end of the QRS complex and the beginning of the ST segment determined in lead V5 or V6. A type 1 ECG was defined as a J-point elevation ≥2 mm, followed by a negative T wave. A type 2 ECG was defined as a J-point elevation ≥2 mm, with a gradual ST-segment descent ≥1 mm, followed by a positive or biphasic T wave. A type 2 ECG was also defined as a β angle ≥58° and a duration of the base of the triangle of r' at 5 mm from the high take-off ≥3.5 mm. 17 Analysis was performed in a blinded manner by two independent cardiologists (SN and NU).

| Clinical data
Clinical data were collected from all patients and included their age, gender, echocardiographic data, such as the left ventricular ejection fraction (LVEF), right ventricular ejection fraction (RVEF) measured by magnetic resonance imaging (MRI), morphologies of ECG such as Twave inversion in the right precordial leads and inferior leads, epsilon wave, complete right bundle branch block, J wave, and parameters of an ECG, such as QRS duration and PQ interval. Because a class III antiarrhythmic drug was administered in approximately 40% of patients, QT, corrected QT and Tpeak-Tend intervals were not measured. An epsilon wave was defined as reproducible low-amplitude signals between the ends of the QRS complex and the onset of the T wave in the right precordial leads. 2 Terminal activation duration was measured from the nadir of the S wave to the end of all depolarization deflections. An Conclusion: The Brugada ECG pattern was infrequently encountered, was transient in ARVC patients, and was associated with a longer PQ interval, longer QRS duration, and cardiac events.

K E Y W O R D S
arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome, cardiac death, depolarization abnormality, heart failure inferolateral J wave was defined as a J-point elevation of ≥0.1 mV above the baseline that was either notched (a positive J deflection at the QRScomplex/ST segment transition) or slurred (a smooth transition from QRS to the ST segment) in at least two consecutive leads. 18 Fragmented QRS was defined as deflections at the beginning of the QRS complex, on top of the R wave, or in the nadir of the S wave in at least one lead. 19 The measurement of the ECG parameters was performed at the time of the first ECG recording. Clinical outcomes included the incidence of cardiac death, VAs, and hospitalization because of heart failure (HF).
VA was defined as sustained ventricular tachycardia (VT), VF, or necessary intervention with an implantable cardioverter-defibrillator during follow-up. Hospitalization for HF was defined as the sudden or gradual onset of the signs or symptoms of New York Heart Association class 3 or 4 HF, which required an unplanned hospitalization without subsequent VT/VF episodes. SCD was defined as any natural death that occurred instantaneously or within 1 hour after symptom onset. Cardiac death included SCD, HF-related death, and heart transplantation.

| Follow-up
Patients were followed up in our hospital for a median duration of 11.4 (interquartile range, 5.5-17.1) years. Follow-up information was obtained from an implantable cardioverter-defibrillator and pacemaker follow-up charts, hospital records, and outpatient evaluations.

| Statistical analyses
The results are summarized as the mean ± SD if normally distributed or as the median (interquartile range) if not normally distributed. The categorical data were expressed as counts and percentages. Categorical differences between groups were evaluated using a χ2 test or Fisher's exact test as appropriate. Continuous variables were compared using the Wilcoxon rank-sum test or the Kruskal-Wallis test. A univariate Cox regression analysis was performed to evaluate significant predictors of events. Survival curves were determined by the Kaplan-Meier method and analyzed by the log-rank test. A value of P < .05 was taken as the threshold for statistical significance. All analyses were performed using JMP 12 software (SAS Institute, Cary, NC, USA).

| Clinical characteristics
A Brugada ECG pattern was transiently recorded at least once in 5 of 114 patients (4%). Figures 1-3 and Figures S1-S3 are representative ECGs. Among them, a type 1 ECG was recorded in four patients, and a type 2 ECG was recorded in one patient. After its appearance, the Brugada ECG pattern disappeared in all four patients in whom an ECG was recorded more than 2 years after the initial recording of the pattern. Baseline characteristics among ARVC patients with and without a Brugada ECG pattern are presented in Table 1. The PQ interval (220 ± 62 ms vs 180 ± 35 ms, P = .02) and QRS duration (138 ± 25 ms vs 102 ± 23 ms, P < .001) in patients with a Brugada ECG pattern were significantly longer than in patients without a Brugada ECG pattern. More information about the 5 patients with a Brugada ECG pattern is provided in Documents S2 and S3. A genetic variant associated with ARVC was found in 15 of 18 patients (5 with PKP2 and 10 with DSG2, Table S1); however, genetic analysis was not performed in any of the 5 patients with a Brugada ECG pattern.

| Clinical outcomes
During the follow-up period, 19 patients (5 with  ECG pattern were at a significantly higher risk for cardiac death (logrank, P < .001; Figure 4A) and HF hospitalization (log-rank, P < .001; Figure 4B) than patients without a Brugada ECG pattern. The occurrence of VA was similar between the two groups (log-rank, P = .21; Figure 4C).

| Univariate analysis
As presented in

| Comparison between ARVC and agematched BrS
The comparison between ARVC patients with a Brugada ECG pattern and age-matched BrS patients is presented in Table 3. The amplitudes of the J-point and S wave showing a Brugada ECG pattern were significantly lower in ARVC patients compared to BrS patients (0.29 ± 0.05 mV vs 0.66 ± 0.33 mV, P < .001 and 0.34 ± 0.21 mV vs 0.67 ± 0.39 mV, P = .017 respectively).

| Main findings
To the best of our knowledge, this is the first study to investigate the prevalence and characteristics of the Brugada

| Mechanism of Brugada ECG pattern in ARVC
Two hypotheses for the pathophysiological mechanism of BrS have been reported, the repolarization hypothesis 22 and the depolarization hypothesis. 23,24 The repolarization hypothesis suggests that a functional change causes a subepicardial abbreviation of an action potential and a transmural dispersion of repolarization, which causes an ST-segment elevation. 22 However, the depolarization hypothesis suggests that a structural change in the subepicardium causes conduction abnormalities based on interstitial fibrosis and results in ECG changes 23 that lead to an activation delay or excitation failure by current-to-load mismatch, which underlies BrS. 25

| Relationship between the Brugada ECG pattern and clinical events
This study showed that the Brugada ECG pattern was associated with a longer PQ interval, longer QRS duration, and cardiac events, including cardiac death and HF hospitalization, in ARVC patients. Right ventricular asynergy or aneurysm detected by angiography or MRI was significantly frequent in patients with the Brugada ECG pattern ( Table 1). The RVEF tended to be lower in patients with the Brugada ECG pattern. Severe dysfunction of the

F I G U R E 4
Kaplan-Meier analysis of freedom from cardiac death (A), heart failure (HF) hospitalization (B), and fatal ventricular arrhythmia (VA, C) during the follow-up period in patients with and without a Brugada ECG pattern. Patients with a Brugada pattern ECG (blue line) had a significantly higher risk of cardiac death (log-rank, P < .001) and HF hospitalization (log-rank, P < .001) compared to patients without a Brugada ECG pattern (red line). The occurrence of VA was similar between the two groups (log-rank, P = .21) TA B L E 2 Univariate analyses for prediction of: (A) cardiac death during follow-up and (B) heart failure hospitalization during follow-up   (Table 3). 27 The impact on the changes in autonomic tone or heart rate will be valuable in identifying the differences in ECG characteristics between ARVC and BrS. Further investigation is necessary to understand the mechanism of characteristic J-ST elevation in ARVC and BrS.

| Comparison of ECG between ARVC and BrS patients
The significance of ECG in the diagnosis and risk assessment of ARVC was reported by Neto and Luna. 28 They also mentioned that specific ECG findings in ARVC patients should be carefully evaluated because of high interobserver variability and disagreement between experts. Thus, extreme care should be taken in ECG analysis in patients with ARVC.

| Limitations
This was a single-center, retrospective study. The relatively small number of ARVC patients may therefore limit the interpretation of these results. Moreover, because of the low incidence of a positive

| IRB INFORMATION
This study was approved by the IRB of the National Cerebral and Cardiovascular Center, Suita, Japan (R19114). The IRB approved this study and waived informed consent by disclosing information about the study to the public and ensuring that the patients had the opportunity to refuse to participate.

ACK N OWLED G M ENTS
This study was supported by the intramural research fund (25-4-7, Kengo Kusano) for cardiovascular diseases from the National Cerebral and Cardiovascular Center and JSPS KAKENHI grant number 19K08572, Tokyo, Japan.

DATA AVA I L A B I L I T Y S TAT E M E N T
De-identified participant data will not be shared because the dataset contains sensitive and potentially identifying patient information.