Abstract
Background:
Catheter ablation (CA) is effective for recurrent episodes of ventricular fibrillation (VF) in Brugada syndrome (BrS). VF development in BrS is associated with several electrocardiogram (ECG) abnormalities. This study investigated changes in ECG parameters in high-risk BrS patients who underwent epicardial CA.
Methods and Results:
In all, 27 BrS patients were implanted with an implantable cardioverter-defibrillator (ICD). Patients were divided into 2 groups: (1) an ablation group (n=11) that underwent epicardial CA because of VF recurrence; and (2) a primary prevention (PP) group (n=16) with ICD implantation only. ECG parameters were evaluated before and 12 months after CA and compared with ECG parameters in the PP group. The T wave peak-to-end interval was significantly longer and the number of abnormal spikes in leads V1–V3 at the second, third, and fourth intercostal spaces was greater in the ablation than PP group. After ablation, ST levels and the sum of abnormal spikes in leads V1–V3 were significantly decreased. The mean (±SD) number of ICD shocks decreased markedly during a mean follow-up period of 42.0 months (from 3.8±3.7 to 0.2±0.4/year). Four patients had an ICD shock following the ablation procedure. Greater reductions in ST-segment elevation and abnormal spikes were observed in the group without than with VF recurrence.
Conclusions:
Improvements in surface ECG parameters appear to be associated with successful ablation in high-risk BrS patients.
Brugada syndrome (BrS) is an arrhythmic disease with a high risk of sudden cardiac death due to ventricular fibrillation (VF).1
BrS is characterized by the presence of coved-type ST-segment elevation followed by T wave inversion in the right precordial leads on electrocardiography (ECG). Implantable cardioverter-defibrillators (ICD) are effective in preventing sudden cardiac death in high-risk patients with BrS.2
However, some patients with malignant BrS have recurrent VF episodes causing frequent ICD discharges or VF storms. There are several factors that are typically associated with the development of ventricular arrhythmia, including a history of syncope, spontaneous type I ECG, family history, a genetic background of sodium voltage-gated channel α subunit 5 (SCN5A) mutations, and inducibility of ventricular arrhythmia on electrophysiological studies. In addition, some specific ECG findings associated with VF development in BrS include QRS duration, T wave amplitude in lead V1, longer QTc, fragmented QRS complex (fQRS), peak-to-end of the T wave (Tpe), inferolateral early repolarization, aVR sign, and a large S wave.3–8
Based on previous reports, an arrhythmic substrate is associated with progressive deterioration in BrS; therefore, a similar tendency can be expected for the abovementioned abnormal ECG markers.2,9–11
Editorial p 1294
Catheter ablation is a recently developed approach for the treatment of recurrent episodes of VF in BrS.12–15
Elimination of the abnormal substrate, as demonstrated by delayed and fragmented potentials at the epicardial site of the right ventricular outflow tract (RVOT), resulted in decreased ICD shock therapy and ST-segment resolution on ECG. However, changes in ECG parameters after successful epicardial catheter ablation have not yet been fully assessed. It is unknown whether elimination of abnormal substrate can affect altered ECG parameters in high-risk patients with BrS.
Thus, the purpose of the present study was to investigate changes in ECG parameters after epicardial substrate ablation in high-risk patients with BrS and to evaluate the extent of recovery of the ECG parameters compared with patients without any symptoms who underwent ICD implantation for primary prevention.
Methods
Study Population
Data from a catheter ablation database at Nagoya University Hospital, Japan, were analyzed retrospectively.
Eleven patients (mean [±SD] age 45.1±15.1 years) with BrS who underwent epicardial catheter ablation between June 2010 and November 2019 at Nagoya University Hospital were included in the analysis (ablation group). All patients diagnosed with BrS had a typical BrS ECG pattern with an episode of aborted sudden cardiac arrest, syncope, family history, or VF occurrence on an electrophysiological study and were implanted with an ICD based on the guidelines.16,17
All patients underwent catheter ablation for recurrent VF episodes and increased shock therapy after ICD implantation, except for 1 high-risk patient with BrS who had increased VF inducibility on the electrophysiological study.
In addition, a further 16 patients with BrS who underwent ICD implantation only for primary prevention at Nagoya University Hospital between 2010 and 2019 were included in the study. The clinical characteristics of patients and ECG parameters were compared between the ablation and primary prevention groups.
Antiarrhythmic drugs, including quinidine, cilostazol, and bepridil, were discontinued before ablation. Information regarding examination data and baseline characteristics were collected from patient medical records.
This study was performed in compliance with the principles of the Declaration of Helsinki and was approved by the Institutional Review Board of Nagoya University Graduate School of Medicine (Approval no. 2015-0192). Prior to the ablation procedure and ICD implantation, informed consent was obtained from all patients.
Electroanatomical Mapping and Radiofrequency Ablation
The ablation procedures were performed in patients under moderate conscious sedation. After insertion of the sheaths, electrode catheters were positioned in the right ventricle (RV) and bundle of His region. Epicardial access was obtained by the percutaneous subxiphoid approach or the intercostal space approach through a Tuohy needle under echocardiography and fluoroscopy guidance.18
First, an endocardial electroanatomical map of the RV was obtained during sinus rhythm. Subsequently, a detailed epicardial electroanatomical map of the RV was obtained using multipolar electrode mapping catheters (PentaRay®
and DECANAV®; Biosense-Webster, Diamond Bar, CA, USA) during sinus rhythm. All mapping procedures were navigated with a 3-dimentional mapping system (CARTOTM; Biosense Webster). Abnormal potentials included the following: local bipolar potentials with low voltage (≤1.0 mV); continuous and fractionated potentials with at least 2 distinct peaks; and long duration (≥150 ms) or distinct delayed potentials extending beyond the peak of the QRS complex on the surface ECG. A potential duration map was manually created based on the delayed epicardial electrograms recorded in all patients (Supplementary File). After mapping the epicardial side of the RV at baseline, pilsicainide (50 mg) was infused intravenously, and mapping was repeated in a similar manner to evaluate abnormal potentials for the epicardial site. A target ablation site consisted of an area involving all the abnormal potentials that were detected at baseline and after pilsicainide infusion.
Epicardial radiofrequency energy was delivered to eliminate all the abnormal potentials using an irrigated 3.5-mm tip ablation catheter (NaviStar ThermoCool; Biosense-Webster) with a power setting of 30 W. A point-by-point strategy for radiofrequency ablation was used that consisted of observation of changes in electrograms at the target site in order to completely eliminate all the abnormal fractionated, long duration, and delayed potentials. After ablation, pilsicainide was infused again to check whether all local abnormal potentials had been successfully eliminated from the target ablation area. When residual abnormal potentials provoked by pilsicainide infusion were detected, additional ablations were applied. The endpoint of the ablation procedure was complete elimination of the abnormal potentials on the epicardial side after the final pilsicainide infusion. The elimination of abnormal potentials was confirmed by at least 2 investigators related to the procedure. Simultaneously, programed stimulation from the RV electrode catheter was used to evaluate VF inducibility. The pacing coupling interval was decreased to 180 ms with up to double extra stimuli from the RV apex and RVOT, respectively. VF inducibility was diagnosed based on sustained VF with an unstable hemodynamic condition resulting in loss of consciousness and requiring defibrillator cardioversion.
ECG Analysis
The ECG was recorded with a standard digital recorder as 12 simultaneous leads at a paper speed of 25 mm/s, 10 mm/mV, and a bandpass filter of 0.05–150 Hz (Cardio Star, FCP-7541; Fukuda Denshi, Tokyo, Japan). The ECG was recorded with patients in the supine position during a 3-min resting. All intervals and parameters of the 12-lead ECG were measured using a digital caliper in high amplification (≥20 mm/mV, 50 mm/s). We measured the PR interval in lead II, QRS duration in lead V2, S wave width in lead V1, QT interval, ST-segment level at the J point in leads V1–V3, the number of positive spikes within the QRS complex, and Tpe interval. We also evaluated spontaneous type 1 ECG in the right precordial leads, inferolateral early repolarization, aVR sign, and large S wave on the ECG. The ST-segment level and number of abnormal positive spikes within the QRS complex were also assessed in the second and third intercostal spaces in leads V1–V3, respectively. All ECG parameters were evaluated in the ablation group before ablation and 12 months after the procedure. In the primary prevention group, ECG parameters were evaluated before ICD implantation.
Spontaneous type 1 ECG was defined as the appearance of ST-segment elevation ≥0.2 mV at the J point in the right precordial lead (V1–V3).16
The presence of fQRS was defined as an abnormal fragmentation within the QRS complex as ≥4 spikes in 1 of the leads V1–V3, ≥8 positive spikes in all leads V1–V3, or >2 positive spikes within the QRS complex in 2 contiguous inferior leads.19
Inferolateral early repolarization was defined as J point elevation with slurring or notched J wave (≥0.1 mV) in at least 2 contiguous leads of the inferior leads (II, III, and aVF), lateral leads (I, aVL, and V4–V6), or both.16
The aVR sign was defined as an R wave amplitude ≥0.3 mV or an R/q ratio ≥0.75 in lead aVR.6
A large S wave in lead I was defined as an S wave amplitude ≥0.1 mV and/or duration ≥40 ms.5
In particular, the number of spikes and fQRS were evaluated by ECGs magnified to a maximum size of 400%. The ECG patterns were reviewed by 2 investigators (A.F., S.Y.) who were blinded to the outcomes and baseline characteristics of the study population.
Follow-up
Patients were followed by continuous ECG monitoring for 5 days after ablation. After discharge, patients in both groups (ablation and primary prevention groups) were followed up at 1, 3, 6, and 12 months and every 6 months thereafter in an outpatient clinic of the Nagoya University Graduate School of Medicine. Device programming was set at the discretion of the attending electrophysiologist and clinical engineer. VF was treated initially with high-voltage shocks. The general therapy zones began at 200 beats/min for VF (number of intervals to detect: 18/24). ICD device interrogation was performed every 6 months after discharge. When any symptom related to BrS occurred during the follow-up period, patients were asked to come to the hospital, where their condition was assessed and device interrogation was performed.
Statistical Analysis
Continuous variables are expressed as the mean±SD or median with interquartile range (IQR). The significance of differences in baseline characteristics was analyzed using Student’s t-test or the Mann-Whitney U-test for continuous variables and the Chi-squared test or Fisher’s exact test for categorical variables. The significance of differences in outcome parameters between baseline and follow-up was assessed using paired t-tests. Interobserver variability for evaluating the number of notches on the ECG was quantified by calculating intraclass correlation coefficients (ICCs). Two-sided P<0.05 was considered significant.
Results
Baseline Characteristics
Table 1
shows the baseline characteristics of the study population. In the ablation group, all patients were male. Eight patients (72%) were survivors of VF occurrence, and the remaining 3 patients had syncope and VF inducibility on an electrophysiological study at the time of ICD implantation. Ten patients experienced at least 1 ICD shock before ablation, and the median number of ICD shocks was 3.0 (IQR 1.0–5.0) for the 1 year before ablation. VF storm occurred in 4 patients (38%). The median duration from the time of ICD implantation to the ablation was 4.0 years (IQR 1.1–8.8 years). In contrast, in the primary prevention group, 2 patients had syncope and 7 patients had a family history of sudden death before ICD therapy. There was no
SCN5A
mutation in the 8 patients examined in the primary prevention group.
Table 1.
Baseline Characteristics in the Ablation and Primary Prevention Groups
| |
Ablation group
(n=11) |
Primary prevention
group (n=16) |
P value |
| Age (years) |
45.2±15.1 |
44.9±14.2 |
0.958 |
| Male sex |
11 (100) |
16 (100) |
0.999 |
| Body mass index (kg/m2) |
24.2±3.7 |
21.4±2.2 |
0.023 |
| SCN5A mutation |
1/3 (33) |
0/8 (0) |
0.273 |
| Spontaneous type I ECG |
10 (91) |
12 (75) |
0.296 |
| Syncope before ICD implantation |
4 (36) |
2 (13) |
0.187 |
| VF episode before ICD implantation |
8 (72) |
– |
N/A |
| VF inducibility at EPS before ICD implantation |
3/3 (100) |
15 (94) |
0.999 |
| VF/ICD shock episode after ICD implantation |
10 (91) |
– |
N/A |
| No. ICD shocks during 1 year before ablation |
3.0 [1.0–5.0] |
– |
N/A |
| VF storm |
4 (36) |
– |
N/A |
| Family history of sudden death |
1 (9) |
7 (44) |
0.090 |
| Medications |
| Quinidine |
0 (0) |
0 (0) |
0.999 |
| Bepridil |
4 (36) |
0 (0) |
0.019 |
| Cilostazol |
3 (27) |
0 (0) |
0.056 |
| Comorbidities |
| Hypertension |
4 (36) |
1 (6) |
0.125 |
| Diabetes |
1 (9) |
1 (6) |
0.999 |
| LVEF (%) |
64.3±4.4 |
64.9±4.4 |
0.743 |
| BNP (pg/dL) |
10.7±6.7 |
8.0±3.0 |
0.173 |
| Duration after ICD implantation (years) |
4.0 [1.1–8.8] |
– |
|
Unless indicated otherwise, data are given as the mean±SD, median [interquartile range], or as n (%). BNP, B-type natriuretic peptide; ECG, electrocardiogram; EPS, electrophysiological study; ICD, implantable cardioverter-defibrillator; LVEF, left ventricular ejection fraction; SCN5A, sodium voltage-gated channel alpha subunit 5; VF, ventricular fibrillation.
Comparisons of ECG parameters between the ablation and primary prevention groups at baseline are given in
Table 2. Prior to the ablation procedure, spontaneous type I ECG at any intercostal space was observed in 10 (91%) and 12 (75%) patients in the ablation and primary prevention groups, respectively (P=0.296). No significant difference in QT intervals was seen; however, the Tpe interval in leads V1 (104±20 vs. 87±14 ms; P=0.016), V3 (110±11 vs. 98±9 ms; P=0.004), and V5 (103±14 vs. 89±11 ms; P=0.010) was significantly longer in the ablation than primary prevention group. With regard to spikes within the QRS complex, there was significantly greater number of abnormal spikes in leads V1–V3 at the fourth (4.4±2.6 vs. 2.0±1.4; P=0.005), third (4.6±2.0 vs. 2.8±1.6; P=0.014), and second (5.3±1.4 vs. 1.9±1.1; P<0.001) intercostal spaces in the ablation than primary prevention group. The total number of the spikes in leads V1–V3 at all intercostal spaces was significantly greater in the ablation than primary prevention group (14.3±4.9 vs. 6.5±3.7; P=0.001). Abnormal fragmentation within the QRS complex was detected in 5 (46%) and 2 (13%) patients in the ablation and primary prevention groups (P=0.084), respectively. No significant differences were observed between the 2 groups in the aVR sign, large S wave in lead I, and the presence of inferolateral early repolarization. The interobserver agreement for number of the spikes on the ECG (ICC) was 0.911 (95% confidence interval 0.870–0.939).
Table 2.
Electrocardiogram Parameters in the Ablation and Primary Prevention Groups
| |
Ablation group
(n=11) |
Primary prevention
group (n=16) |
P value |
| Spontaneous type I ECG at the fourth ICS |
5 (45) |
8 (50) |
0.124 |
| Spontaneous type I ECG at any ICS |
10 (91) |
12 (75) |
0.296 |
| PR interval in lead II (ms) |
183±41 |
179±30 |
0.788 |
| QRS interval in lead V2 (ms) |
123±47 |
125±13 |
0.878 |
| ST level in lead V1 (mV) |
0.13±0.10 |
0.14±0.11 |
0.853 |
| ST level in lead V2 (mV) |
0.27±0.20 |
0.37±0.15 |
0.158 |
| ST level in lead V3 (mV) |
0.17±0.12 |
0.21±0.04 |
0.276 |
| ST level in lead V1 at the third ICS (mV) |
0.17±0.12 |
0.18±0.14 |
0.818 |
| ST level in lead V2 at the third ICS (mV) |
0.35±0.23 |
0.51±0.21 |
0.080 |
| ST level in lead V3 at the third ICS (mV) |
0.19±0.12 |
0.12±0.09 |
0.046 |
| ST level in lead V1 at the second ICS (mV) |
0.20±0.15 |
0.16±0.13 |
0.468 |
| ST level in lead V2 at the second ICS (mV) |
0.33±0.23 |
0.53±0.28 |
0.110 |
| ST level in lead V3 at the second ICS (mV) |
0.23±0.16 |
0.29±0.17 |
0.386 |
| QT interval in lead V1 (ms) |
400±45 |
380±31 |
0.174 |
| QT interval in lead V2 (ms) |
412±42 |
410±29 |
0.989 |
| QT interval in lead V3 (ms) |
410±32 |
407±18 |
0.756 |
| Tpe interval in lead V1 (ms) |
104±20 |
87±14 |
0.016 |
| Tpe interval in lead V2 (ms) |
107±18 |
95±12 |
0.061 |
| Tpe interval in lead V3 (ms) |
110±11 |
98±9 |
0.004 |
| Tpe interval in lead V5 (ms) |
103±14 |
89±11 |
0.010 |
| Sum of the spike in leads V1–3 at the fourth ICS |
4.4±2.6 |
2.0±1.4 |
0.005 |
| Sum of the spike in leads V1–3 at the third ICS |
4.6±2.0 |
2.8±1.6 |
0.014 |
| Sum of the spike in leads V1–3 at the second ICS |
5.3±1.4 |
1.9±1.1 |
<0.001 |
| Sum of the spike in leads V1–3 at all ICSs |
14.3±4.9 |
6.5±3.7 |
0.001 |
| Abnormal fragmentation within QRS complex in the right precordial lead at any ICS |
3 (27) |
0 (0) |
0.056 |
| Abnormal fragmentation within QRS complex in the inferior lead |
4 (36) |
2 (13) |
0.187 |
| aVR sign |
3 (27) |
0 (0) |
0.056 |
| Large S wave in lead I |
8 (73) |
7 (44) |
0.239 |
| Inferolateral early repolarization |
2 (18) |
0 (0) |
0.157 |
Unless indicated otherwise, data are given as the mean±SD or as n (%). ECG, electrocardiogram; ICD, implantable cardioverter-defibrillator; ICS, intercostal space; Tpe, T wave peak-to-end interval; VF, ventricular fibrillation.
The ablation procedure was successfully performed in all patients without any complications. There was no abnormal delayed potential or low voltage area at the endocardial site of the RV; however, at the epicardial site of the RVOT, abnormal potentials, including continuous, delayed, and fractionated potentials, were detected in all patients. The mean abnormal potential area after pilsicainide infusion was 19.7±9.4 cm2. In 5 patients, the abnormal potential area was extended to the lateral epicardial site of the RV. Patients with abnormal substrate area on the lateral side experienced a higher number of the spikes in the inferior leads on the ECG than those without abnormal substrate in that area (4.6±1.9 vs. 1.8±1.5). The mean total ablation energy applied to the area and ablation time were 80,705±16,006 J and 40.4±10.3 min, respectively (Table 3). The abnormal potential area was completely eliminated after repeated pilsicainide infusion in all except 2 patients (Cases 2 and 10). These incomplete cases had extended abnormal potentials in the lateral epicardial side of the RV and left ventricular side beyond the septum. However, a branch of the coronary artery passed through these abnormal areas and, consequently, to prevent a coronary flow injury, ablation could not be applied to the area. At the end of the session, VF was induced by programed ventricular stimulation in 3 patients.
Table 3.
Characteristics of Patients in the Ablation Group
Patient
no. |
Age
(years) |
Sex |
Epi or
endo
ablation |
Abnormal
delayed potential
area (cm2) |
Abnormal delayed
potential area after
pilsicainide (cm2) |
Delayed potential
in lateral RV side of
the epicardium |
Total ablation
energy applied
(J) |
Total ablation
time (min) |
VF inducibility
at end of
session |
No. ICD shocks
in the 1 year
prior to ablation |
ICD shock after ablation |
Follow-up
duration after
ablation (months) |
Medications
after ablation |
| <1 year |
>1 year |
| 1 |
20 |
M |
Epi |
18.5 |
17.4 |
− |
82,700 |
37.3 |
− |
12 |
0 |
1 |
76.8 |
– |
| 2 |
36 |
M |
Epi |
N/A |
13.2 |
+ |
89,790 |
52.0 |
+ |
9 |
0 |
1 |
67.4 |
– |
| 3 |
44 |
M |
Epi |
N/A |
23.8 |
− |
67,830 |
37.7 |
− |
4 |
0 |
0 |
54.7 |
– |
| 4 |
63 |
M |
Epi |
N/A |
13.3 |
− |
58,800 |
28.5 |
− |
0 |
0 |
0 |
53.4 |
– |
| 5 |
67 |
M |
Epi |
N/A |
16.5 |
− |
70,350 |
32.8 |
− |
1 |
0 |
0 |
54.6 |
– |
| 6 |
51 |
M |
Epi |
21.6 |
16.5 |
+ |
92,620 |
47.0 |
− |
1 |
0 |
0 |
31.3 |
– |
| 7 |
43 |
M |
Epi |
45.0 |
46.2 |
+ |
97,890 |
53.0 |
− |
5 |
2 |
0 |
30.0 |
Quinidine |
| 8 |
45 |
M |
Epi |
5.5 |
15.4 |
+ |
86,256 |
54.8 |
− |
2 |
1 |
2 |
30.6 |
Bepridil |
| 9 |
64 |
M |
Epi |
14.8 |
17.0 |
− |
55,830 |
30.0 |
+ |
3 |
0 |
0 |
27.2 |
Cilostazol |
| 10 |
36 |
M |
Epi |
30.2 |
21.8 |
+ |
79,790 |
44.5 |
− |
4 |
0 |
0 |
17.6 |
– |
| 11 |
28 |
M |
Epi |
5.8 |
15.4 |
− |
105,901 |
26.8 |
+ |
1 |
0 |
0 |
17.9 |
– |
Endo, endocardial; Epi, epicardial; ICD, implantable cardioverter-defibrillator; M, male; RV, right ventricle; VF, ventricular fibrillation.
After ablation, ST levels in the precordial leads were significantly reduced at all intercostal spaces (Table 4). In contrast, no significant changes in QT intervals and Tpe intervals were observed at the 12-month follow-up after ablation. Compared with baseline, at the 12-month follow-up after ablation the number of spikes in leads V1–V3 decreased significantly at the fourth (4.4±2.6 to 2.6±2.0; P=0.039), third (4.6±2.0 to 2.5±1.5; P=0.003), and second (5.3±1.4 to 3.2±1.3; P=0.001) intercostal spaces (Table 4). In addition, the sum of the spikes in leads V1–V3 at all intercostal spaces decreased significantly 12 months after ablation compared with baseline (from 14.3±4.9 to 8.3±4.0; P=0.002). Abnormal fragmentation within the QRS complex in the right precordial lead was not observed after ablation (P=0.041).
Table 4.
Changes in Electrocardiogram Parameters Before and After Ablation in the Ablation Group
| Parameters |
Before |
After 12 months |
P value |
| Spontaneous type I ECG at the fourth ICS |
5 (45) |
2 (18) |
0.083 |
| Spontaneous type I ECG at any ICS |
10 (91) |
2 (18) |
0.005 |
| PR interval in lead II (ms) |
183±41 |
185±44 |
0.509 |
| QRS interval in lead V2 (ms) |
123±47 |
123±40 |
0.999 |
| ST level in lead V1 (mV) |
0.13±0.10 |
0.06±0.07 |
0.011 |
| ST level in lead V2 (mV) |
0.27±0.20 |
0.13±0.14 |
0.032 |
| ST level in lead V3 (mV) |
0.17±0.12 |
0.08±0.06 |
0.068 |
| ST level in lead V1 at the third ICS (mV) |
0.17±0.12 |
0.06±0.08 |
0.010 |
| ST level in lead V2 at the third ICS (mV) |
0.35±0.23 |
0.13±0.16 |
0.008 |
| ST level in lead V3 at the third ICS (mV) |
0.19±0.12 |
0.10±0.05 |
0.015 |
| ST level in lead V1 at the second ICS (mV) |
0.20±0.15 |
0.05±0.06 |
0.011 |
| ST level in lead V2 at the second ICS (mV) |
0.33±0.23 |
0.11±0.14 |
0.011 |
| ST level in lead V3 at the second ICS (mV) |
0.23±0.16 |
0.09±0.08 |
0.029 |
| QT interval in lead V1 (ms) |
400±45 |
398±45 |
0.893 |
| QT interval in lead V2 (ms) |
412±42 |
410±40 |
0.799 |
| QT interval in lead V3 (ms) |
410±32 |
406±27 |
0.679 |
| Tpe interval in lead V1 (ms) |
104±20 |
101±12 |
0.712 |
| Tpe interval in lead V2 (ms) |
107±19 |
111±13 |
0.332 |
| Tpe interval in lead V3 (ms) |
110±11 |
107±14 |
0.391 |
| Tpe interval in lead V5 (ms) |
103±14 |
103±16 |
0.886 |
| Sum of the spike in leads V1–3 at the fourth ICS |
4.4±2.6 |
2.6±2.0 |
0.039 |
| Sum of the spike in leads V1–3 at the third ICS |
4.6±2.0 |
2.5±1.5 |
0.003 |
| Sum of the spike in leads V1–3 at the second ICS |
5.3±1.4 |
3.2±1.3 |
0.001 |
| Sum of the spike in leads V1–3 at all ICSs |
14.3±4.9 |
8.3±4.0 |
0.002 |
| Abnormal fragmentation within QRS complex in the right precordial lead at any ICS |
3 (27) |
0 (0) |
0.250 |
| Abnormal fragmentation within QRS complex in the inferior lead |
4 (36) |
4 (36) |
0.999 |
| aVR sign |
3 (27) |
3 (27) |
0.999 |
| Deep S wave in lead I |
8 (73) |
9 (82) |
0.999 |
| Inferolateral early repolarization |
2 (18) |
1 (9) |
0.999 |
Unless indicated otherwise, data are given as the mean±SD or as n (%). Abbreviations as in Table 2.
Figure 1
shows a representative case of VF with successful epicardial ablation for ICD shock (Case 6 in
Table 3). During epicardial mapping of the RV, an abnormal potential area was found in the outflow tract and lateral side. Before the procedure, the magnified ECG in lead V1 showed several abnormal spikes in the QRS complex (Figure 1C). At 12 months after ablation, these spikes disappeared, with significant improvement in the ST elevation. This patient had no ICD shock or VF after ablation over a follow-up period of 31.3 months.
Follow-up and Prognosis After Ablation
The mean number of ICD shocks decreased significantly at the 1-year follow-up after ablation compared with 1 year before ablation (from 3.8±3.7 to 0.3±0.6/year) and at 42 months after ablation (0.2±0.4/year). Four patients experienced ICD shock following the procedure, and 2 patients (Cases 7 and 8) had ICD shock within 1 year after ablation, having received quinidine and bepridil after the shock. Another 2 patients (Cases 1 and 2) had ICD shocks more than 1 year after the procedure. The ablation group was divided into 2 groups based on VF primary, with 7 patients in the non-recurrence group and 4 in the recurrence group. Changes in ECG parameters were compared between these 2 groups. Although both groups demonstrated decreases ST-segment levels and the number of spikes in the precordial leads after ablation, a greater reduction was observed in the non-recurrence than recurrence group (Figures 2,3). Notably, differences in the number of spikes were more marked in leads at the second and third intercostal spaces compared with the fourth intercostal space. For the 2 patients (Cases 7 and 8) with recurrence within 1 year after the procedure, the total number of spikes in all precordial leads remained relatively high even after 1 year (Case 7, from 19 to 14; Case 8, from 20 to 14). Specifically, after pilsicainide infusion in Case 7, a huge abnormal potential area (46.2 cm2) extended to the lateral side as well as the ROVT at the epicardial site (Figure 4). In this case, the greatest sum of spikes was also detected in the inferior leads on the ECG (Figure 4E). Among the 2 patients with insufficient ablation for complete elimination of abnormal potentials (Cases 2 and 10), the total number of spikes in all precordial leads remained relatively high even after 1 year (Case 2, from 17 to 8; Case 10, from 16 to 12). In contrast, the ST-segment levels were significantly decreased in Case 10, but not in Case 2 (Supplementary Table).
After ablation, the mean number of ICD shocks decreased in both the non-recurrence (from 2.0±1.6 to 0.0±0.0/year) and recurrence (from 7.0±4.4 to 0.6±0.5/year) groups. The type I Brugada ECG pattern remained in 2 patients (Cases 2 and 7). These patients did not have a significant improvement in ST elevation on the ECG after the procedure (Supplementary Table).
In addition, changes in ST-segment elevation and the number of abnormal spikes on the ECG before, the day after, and 1, 6, and 12 months after the ablation in the recurrence and non-recurrence groups are shown in the
Supplementary Figure. Both ECG parameters gradually improved after the procedure in the non-recurrence group. Moreover, differences in ECG parameters between the 2 groups became apparent 1 month after ablation.
Discussion
In the present study we investigated changes in ECG parameters after epicardial catheter ablation in high-risk patients with BrS. ST-segment elevation and the number of abnormal spikes on the ECG, as well as the number of ICD shocks, were significantly decreased after ablation. Moreover, these improvements in ECG parameters were more significant in the non-recurrence than recurrence group.
BrS is recognized as a distinct clinical entity characterized by a right bundle branch block pattern and ST-segment elevation in the right chest leads on ECG.1
Several additional features on the ECG may be associated with high risk for VF in BrS. Indeed, prolonged PQ intervals and QRS width, as markers of depolarization, and increased Tpe and QT intervals, as makers of repolarization, have been demonstrated in BrS, and these findings on the ECG reflect abnormalities of both depolarization and repolarization in BrS.3,4,8,9
Recently, Morita et al reported that a high prevalence of fQRS, which reflects a depolarization abnormality, was associated with VF occurrence in patients with BrS.7
The abovementioned ECG abnormalities may be related to electrical arrhythmogenic substrate present in the RVOT. Specifically, a low-voltage area and continuous and delayed distinct potentials on the epicardial site of the RV may be associated with surface ECG abnormalities. In addition, the BrS substrate may be associated with progressive deterioration over time. This hypothesis may be supported by the results of a previous study showing prolonged PQ interval and QRS duration during a follow-up period of 10 years in patients with BrS with an
SCN5A
mutation.9
Changes in QRS interval, QT interval, Tpe, and fQRS are also observed up to several years before VF occurrence.10
In the present study, the ablation group, with patients who had recently experienced a VF episode, had significantly longer Tpe intervals and a higher number of spikes in the right precordial leads than the primary prevention group, which is consistent with previous studies. Notably, 3 patients in the ablation group with a primary indication for ICD implantation without prior VF episodes developed a malignant type of BrS, with the occurrence of several repetitive ICD shocks over time after ICD implantation. In these patients, the number of spikes within the QRS complex increased after ICD implantation (data not shown).
Regarding the therapeutic approach, recent studies reported that catheter ablation targeting epicardial abnormal substrate was effective in suppressing VF occurrence in BrS.12–15
After complete elimination of the electrical substrate with robust ablation, ST elevation on the ECG improved and returned to normal, indicating that ablation therapy may have an effect on abnormal ECG parameters, and that some ECG parameters may be altered after ablation.12,14,15
However, to date, no reports have discussed the outcomes in BrS after ablation in terms of changes in specific electrical abnormalities on the surface ECG. The present study found a dominant improvement in ST-segment elevation, the number of spikes in the QRS, and fQRS 1 year after ablation. In contrast, no significant difference in PR and QRS intervals, or QT and Tpe intervals were observed following ablation. Although the exact reason for this is unknown, the different changes in ECG parameters following epicardial ablation may contribute to an increased understanding of the underlying mechanism and detailed nature of the abnormal substrate in BrS. The decrease in the number of spikes in the QRS and fQRS may be associated with elimination of epicardial abnormal substrate. These improvements observed in ECG parameters are related to an improvement of depolarization abnormalities, suggesting that these abnormalities may be a possible cause of BrS and a changeable characteristic after ablation in high-risk patients with BrS. However, this hypothesis requires further investigation. Indeed, there is only 1 representative case in a previous study showing improved fQRS after epicardial ablation.19
In addition to the previous case, the present study is the first to systematically assess a significant number of decreased abnormal spikes and fQRS after BrS ablation.
Notably, in this study, the degree of the decrease in the number of spikes in the QRS complex and ST-segment resolution was greater after ablation in the non-recurrence than recurrence group. Indeed, 1 patient in the recurrence group (Case 2) had a clear limitation for application of ablation on the whole substrate, because part of the substrate was proximal to the branch of the coronary artery. Other patients in the recurrence group (Cases 1 and 7) may have received adequate ablation to eliminate the abnormal potentials at the time of the procedure. However, in Case 7, the substantial size of the abnormal substrate area that included the RV at the epicardial site may have not been completely eliminated despite robust ablation. The large number of spikes in the inferior leads on the ECG also suggests extensive damage to the epicardial substrate at the lateral side. Thus, a longer duration and greater energy were required for ablation to eliminate the entire portion related to the abnormal potential. Moreover, the ablation energy may not have been sufficient to achieve necrosis of the myocardium. A portion of adipose tissue covering the myocardium could prevent sufficient ablation from reaching the myocardium. Although we checked all abnormal potentials that were eliminated by ablation using the mapping catheter, some residual potentials masked by thick adipose tissue that had been initially diminished may not have been eliminated, which may have resulted in a continued risk of VF occurrence. In another patient (Case 1), the abnormal potentials were successfully eliminated using a careful mapping approach, and the ST-segment in the precordial leads returned to normal levels after ablation. However, in this patient, ICD shock occurred more than 6 years after ablation. It is possible that some progressive abnormalities of the BrS substrate may develop after the procedure. In contrast, although we are unable to explain the favorable outcome after ablation in Case 10, in which complete elimination of the abnormal potential was not achieved, the significant reduction in ST-segment elevation in this patient could also support the favorable clinical outcome of an absence of recurrent shock after the procedure.
Between the recurrence and non-recurrence groups, differences in ST-segment elevation and decreases in abnormal spikes were observed not just following ablation, but also at >1 month after ablation. An inflammatory response to ablation may be an explanation for the remaining ST-segment elevation, masking the changes in the abnormal spikes, and it seems difficult to assess successful ablation on the EGG recording just after the ablation procedure. However, we observed that even in the recurrence group the number of ICD shocks decreased significantly after epicardial ablation. Although the extent to which decreased abnormal spikes and improved ST-segment elevation can predict favorable outcomes after ablation is unclear, changes in specific ECG parameters following the acute phase of the procedure may help with risk stratification and validation of the effect of ablation in high-risk patients with BrS, who are often young and middle-aged populations requiring long-term follow-up.
Study Limitations
First, this was a retrospective study with a limited sample size that was performed at a single center. Second, several patients received arrhythmic drugs for recurrence after ablation, which may have influenced the ECG parameters during follow-up. Third, patients with BrS show circadian changes in ECG characteristics.20
Although we recorded all ECGs in the supine position during a 3-min resting, the effect of circadian changes and patients’ conditions on ECG changes, especially on the ST-segment, could not be excluded in the present analysis. Furthermore, the ECG examinations at baseline and follow-up should have been recorded after pilsicainide infusion, which could allow for an accurate interpretation of ECG changes under the same conditions and clear up the residual ECG elements in excluding the effect of circadian variation and condition. Fourth, the potential duration map at the epicardium was created manually, and careful attention was required to distinguish whether local electrograms were abnormal or just a noise and artifact with waviness of the isoelectric line. In this regard, we put considerable effort into creating a potential duration map, collecting a large number of annotation points (as much as possible) and checking the consistency with the surrounding potentials simultaneously. Nonetheless, determining the area with abnormal potentials and confirming the complete elimination of the abnormal potential after ablation may be subjective to some extent, which may have affected the outcomes and following strategy. Finally, although each ECG parameter was manually evaluated by multiple investigators and the ECGs were recorded by expert electrocardiography technicians, there may have been some bias in the evaluation of the abnormal spikes and the quality of the ECG, including noise and record timing. There is a need for a mechanical method and an objective approach to systematically evaluate abnormal spikes and changes in fQRS on ECG recordings. Improvements in ST-segment elevation were clinically significant in the non-recurrence compared with recurrence group, although the differences were not statistically significant. This may be due to the limited sample size of the study. Further large-scale multicenter studies are needed with adequate samples to evaluate the association between epicardial substrate ablation and changes in ECG parameters in BrS.
Conclusions
The normalization of the spontaneous type 1 ECG pattern and a decrease in abnormal spikes in the precordial leads on the ECG was remarkable following catheter ablation in high-risk patients with BrS. Catheter ablation for epicardial arrhythmogenic substrate in BrS effectively reduced the number of ICD shocks, with possible related changes in ECG parameters.
Acknowledgment
The authors thank Hiroshi Ichiyanagi (Clinical Engineering, Nagoya University Hospital) for his excellent assistance and support with the mapping procedure.
Sources of Funding
This study did not receive any specific funding.
Disclosures
S.Y. and R.S. are affiliated with a department sponsored by Medtronic Japan. T.M. is a member of the
Circulation Journal’s Editorial Team. The remaining authors have no conflicts of interest to declare.
IRB Information
This study was approved by the Institutional Review Board of Nagoya University Graduate School of Medicine (Approval no. 2015-0192).
Data Availability
The deidentified participant data will not be shared.
Supplementary Files
Please find supplementary file(s);
http://dx.doi.org/10.1253/circj.CJ-20-1060
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