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Copyright © 2009 American Heart Association. All rights reserved. Print ISSN: 1941-3149. Online ISSN:
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Circulation: Arrhythmia and Electrophysiology is published by the American Heart Association. 7272
DOI: 10.1161/CIRCEP.108.816892
Circ Arrhythm Electrophysiol 2009;2;495-503; originally published online August 2, 2009;
Hideo Okamura and Hitonobu Tomoike
Wataru Shimizu, Takashi Kurita, Kazuhiro Suyama, Takashi Noda, Kazuhiro Satomi,
Naomasa Makita, Nobuhisa Hagiwara, Hiroshi Inoue, Hirotsugu Atarashi, Naohiko Aihara,
Minoru Horie, Satoshi Ogawa, Ken Okumura, Kazufumi Tsuchihashi, Kaoru Sugi,
Shiro Kamakura, Tohru Ohe, Kiyoshi Nakazawa, Yoshifusa Aizawa, Akihiko Shimizu,
V3CLINICAL PERSPECTIVE
Long-Term Prognosis of Probands With Brugada-Pattern ST-Elevation in Leads V1-
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Long-Term Prognosis of Probands With Brugada-Pattern
ST-Elevation in Leads V1–V3
Shiro Kamakura, MD, PhD; Tohru Ohe, MD, PhD; Kiyoshi Nakazawa, MD, PhD;
Yoshifusa Aizawa, MD, PhD; Akihiko Shimizu, MD, PhD; Minoru Horie, MD, PhD;
Satoshi Ogawa, MD, PhD; Ken Okumura, MD, PhD; Kazufumi Tsuchihashi, MD, PhD;
Kaoru Sugi, MD, PhD; Naomasa Makita, MD, PhD; Nobuhisa Hagiwara, MD, PhD;
Hiroshi Inoue, MD, PhD; Hirotsugu Atarashi, MD, PhD; Naohiko Aihara, MD;
Wataru Shimizu, MD, PhD; Takashi Kurita, MD, PhD; Kazuhiro Suyama, MD, PhD;
Takashi Noda, MD, PhD; Kazuhiro Satomi, MD, PhD; Hideo Okamura, MD;
Hitonobu Tomoike, MD, PhD; for the Brugada Syndrome Investigators in Japan
Background—The prognosis of patients with saddleback or noncoved type (non–type 1) ST-elevation in Brugada
syndrome is unknown. The purpose of this study was to clarify the long-term prognosis of probands with non–type 1
ECG and those with coved (type 1) Brugada-pattern ECG.
Methods and Results—A total of 330 (123 symptomatic, 207 asymptomatic) probands with a coved or saddleback
ST-elevation 1 mm in leads V1–V3 were divided into 2 ECG groups—type 1 (245 probands) and non–type 1 (85
probands)—and were prospectively followed for 48.715.0 months. The absence of type 1 ECG was confirmed by drug
provocation test and multiple recordings. The ratio of individuals with a family history of sudden cardiac death (14%)
was lower than previous studies. Clinical profiles and outcomes were not notably different between the 2 groups (annual
arrhythmic event rate of probands with ventricular fibrillation; type 1: 10.2%, non–type 1: 10.6%, probands with
syncope; type 1: 0.6%, non–type 1: 1.2%, and asymptomatic probands; type 1: 0.5%, non–type 1: 0%). Family history
of sudden cardiac death at age45 years and coexistence of inferolateral early repolarization with Brugada-pattern ECG were
independent predictors of fatal arrhythmic events (hazard ratio, 3.28; 95% confidence interval, 1.42 to 7.60; P0.005; hazard
ratio, 2.66; 95% confidence interval, 1.06 to 6.71; P0.03, respectively, by multivariate analysis), although spontaneous type
1 ECG and ventricular fibrillation inducibility by electrophysiological study were not reliable parameters.
Conclusions—The long-term prognosis of probands in non–type 1 group was similar to that of type 1 group. Family history
of sudden cardiac death and the presence of early repolarization were predictors of poor outcome in this study, which
included only probands with Brugada-pattern ST-elevation. (Circ Arrhythmia Electrophysiol. 2009;2:495-503.)
Key Words: death, sudden prognosis follow-up studies electrocardiography Brugada syndrome
Brugada syndrome is a hereditary arrhythmogenic disease
characterized by ST-elevation in the right precordial lead
of standard ECGs and an increased risk of sudden cardiac
death (SCD).1 The prognosis for this condition and the
management approaches have been reported in several multicenter
studies of patients with the coved type 1 ECG.
However, no prospective data have been reported in patients
with saddleback type or noncoved Brugada-pattern STelevation
before, because they were excluded from previous
Clinical Perspective on p 503
studies as atypical Brugada patients showing a benign clinical
course. Besides, the data from previous studies are all
conflicting with regard to the prognosis of the typical Bru-
Received August 22, 2008; accepted July 14, 2009.
From the Division of Cardiology (S.K., N.A., W.S., T.K., K.S., T.N., K.S., H.O., H.T.), National Cardiovascular Center, Suita, Japan; the Department
of Cardiovascular Medicine (T.O.), Okayama University Graduate School of Medicine, Okayama, Japan; the Department of Cardiology (K.N.), St
Marianna University, Kawasaki, Japan; the Division of Cardiology (Y.A.), Niigata University Graduate School of Medical and Dental Sciences, Niigata,
Japan; the Division of Cardiology (A.S.), Yamaguchi University Graduate School of Medicine, Ube, Japan; the Department of Cardiovascular Medicine
(M.H.), Shiga University of Medical Science, Otsu, Japan; the Department of Cardiopulmonary Medicine (S.O.), Keio University, Tokyo, Japan; the
Second Department of Internal Medicine (K.O.), Hirosaki University School of Medicine, Hirosaki, Japan; the Second Department of Internal Medicine
(K.T.), Sapporo Medical University School of Medicine, Sapporo, Japan; the Division of Cardiovascular Medicine (K.S.), Toho University Medical
Center Ohashi Hospital, Tokyo, Japan; the Department of Cardiovascular Medicine (N.M.), Hokkaido University Graduate School of Medicine, Sapporo,
Japan; the Department of Cardiology (N.H.), Tokyo Women’s Medical University; the Second Department of Internal Medicine (H.I.), Toyama
University, Toyama, Japan; and the Department of Internal Medicine, Nippon Medical School, Tama-Nagayama Hospital, Tokyo, Japan.
Correspondence to Shiro Kamakura, MD, PhD, Division of Cardiology, Department of Internal Medicine, National Cardiovascular Center, 5-7-1
Fujishiro-dai, Suita, Osaka, 565-8565, Japan. E-mail
[email protected]
© 2009 American Heart Association, Inc.
Circ Arrhythmia Electrophysiol is available at http://circep.ahajournals.org DOI: 10.1161/CIRCEP.108.816892
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gada syndrome.2–5 This may be caused by cohort studies
that included a significant number of family members
other than probands, in which the prognosis of pedigree
members can be affected by the disease severity of
probands. Furthermore, a selection bias can be present if
the data are analyzed retrospectively. Therefore, we aimed
to investigate the long-term prognosis of probands with
noncoved type ST-elevation in leads V1–V3, prospectively,
and compared it with that of probands with the type 1
ST-elevation.
Methods
Patient Population
A total of 330 individuals with spontaneous ST-elevation were
registered consecutively in this study, namely, “a multicenter study
for risk stratification and management in patients with Brugada
syndrome.” The study was conducted at 26 institutions across Japan
beginning in July 2001. These individuals were prospectively followed
up for more than 12 months to the end of March 2007.
Subjects were enrolled in this study if they met the following
inclusion criteria: (1) proband, (2) J-point (QRS-ST junction) amplitude
of 0.1 mV (1 mm) with either coved or saddle back type
ST-segment elevation in at least 2 of the 3 precordial leads (V1–V3)
on resting standard 12-lead ECG, (3) normal findings on physical
examination, and (4) no abnormality in either right or left ventricular
morphology and/or function demonstrated by chest radiography and
echocardiography. Patients with vasospastic angina and those with
vasovagal syncope were excluded from this study. Patients were not
administered antiarrhythmic drugs and did not have electrolyte
abnormalities at the time of baseline ECG recording and other
examinations.
Classification of Groups
We divided the 330 patients with Brugada-pattern ECG into 3 groups
according to their symptoms: The ventricular fibrillation (VF) group
consisted of 56 probands with aborted sudden death and/or documented
VF, the syncope group consisted of 67 probands with
syncope without documented arrhythmias that was not typical for
vasovagal syncope, and the asymptomatic group consisted of 207
asymptomatic individuals whose ECGs were mainly detected by
individual annual medical checkup or health screening in their place
of employment.
We also divided these patients into 2 groups according to ECG
morphology: The type 1 group consisted of 245 probands with a
spontaneous type 1 ECG or those who developed type 1 ECG with
a drug provocation test. The non–type 1 group consisted of the
remaining 85 probands who never showed type 1 ST-elevation even
with the drug provocation test (Figure 1) and during the follow-up on
standard 12-lead ECGs.
Clinical Data, ECG, and
Electrophysiological Testing
Clinical data including age at the enrollment, sex, family history of
SCD, and the presence of atrial fibrillation were collected for all
patients. The standard ECGs were recorded more than 5 times during
the follow-up period in all patients. ECG recording on higher
intercostals spaces (third and/or second) in leads V1–V3
6 was
encouraged in patients who had cardiac events during the follow-up
period.
A type 1 ECG was defined as a prominent coved ST-segment
elevation displaying J-point wave amplitude or ST-segment elevation
2 mm or 0.2 mV.7,8 ECG patterns with a prominent coved
ST-elevation 2 mm followed by a positive or flat T wave were also
included in type 1 group (Figure 2A through C). A non–type 1 ECG
was defined as one of the following: type 2 ECG,7 type 3 ECG,7 and
ECG displaying coved or saddleback ST-elevation with J-wave
amplitude 1 mm and 2 mm (Figures 1 and 2D through 2G).
The presence of early repolarization in the inferolateral leads9 was
evaluated by baseline 12-lead ECGs at the time of enrollment to
elucidate ECG findings associated with Brugada syndrome. Early
repolarization was defined as an elevation of the J point in at least 2
leads. The amplitude of the J wave or J-point elevation had to be at
least 1 mm above the baseline level, either as QRS slurring or
notching in the inferior lead (II, III, and aVF), lateral (I, aVL, and
V4–V6) lead, or both.9
ECGs were evaluated by 3 independent investigators (S.K., N.A.,
and W.S.) who were unaware of the patients’ other clinical information.
The ECG type or morphology was established by the
evaluation in which at least 2 of the 3 observers were in agreement.
Sodium channel blocker pilsicainide (1 mg/kg body weight at a
rate of 5 to 10 mg/min), disopyramide (1.5 mg/kg, 10 mg/min),
flecainide (2 mg/kg, 10 mg/min), or procainamide (10 mg/kg, 100
mg/min) was administered intravenously in 270 (82%) patients (233,
15, 14, and 8, respectively) to test the conversion to typical coved
ST-elevation.8,10,11
Baseline electrophysiological studies (EPS) were performed in
232 (70%) patients. A maximum of 3 ventricular extrastimuli were
delivered from 2 right ventricular (RV) sites (RV apex and RV
outflow tract) unless VF or polymorphic ventricular tachycardia
(VT) (lasting 10 beats) that terminated spontaneously within 30
seconds, causing syncope, or requiring intervention to be terminated
was elicited at a previous step. Premature beats were started in late
diastole; coupling intervals were then reduced in 10-ms decrements
until refractoriness was reached. Stimulation was performed at twice
the diastolic threshold. Patients with inducible ventricular arrhythmias
lasting less than 10 beats were classified as noninducible. The
indices including age, sex distribution, a family history of SCD at
Figure 1. Presentation of 12-lead ECGs of a
patient with non–type 1 ST-elevation. A, Baseline
12-lead ECG; B, 12-lead ECG after provocation
by intravenous administration of 50 mg
pilsicainide in the same patient. Saddlebacktype
ST-elevation in leads V1 and V2 was
enhanced after pilsicainide but was not
changed to type 1 ST-elevation. This 46-yearold
male patient with a history of syncope but
with no family history of SCD had inducible VF
by electrophysiological study. He had spontaneous
VF 11 months after enrollment.
496 Circ Arrhythmia Electrophysiol October 2009
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less than 45 years of age, and VF/polymorphic VT inducibility were
compared with those reported in previously published studies2,3,5
(Table 1). In addition to these parameters, the presence of atrial
fibrillation, cardiac events at night, and inferolateral early repolarization
were compared between type 1 and non–type 1 groups.
Patient treatment was based on clinical judgment of the participating
hospital. Twenty-eight (8%) probands received antiarrhythmic
drugs (quinidine sulfate 400 mg, bepridil 200 mg, disopyramide
300 mg, aprindine 30 mg, and amiodarone 200 mg/d)
for prevention of atrial fibrillation or VF. Calcium antagonists were
administered in 18 (5%) probands for hypertension. Quinidine and
bepridil were administered only after a documentation of VF during
follow-up. Among the 330 patients, 125 (38%) received an implantable
cardioverter-defibrillator (ICD). During follow-up, patients
were considered to have an arrhythmic event if sudden death
occurred or VF was documented.
Statistical Analysis
Data are presented as meanstandard deviation. The Fisher exact
test or the 2 test was used for categorical variables. One-way
ANOVA was used for comparisons of continuous variables among
the different groups. Survival curves were plotted by the Kaplan-
Meier method and analyzed by the log-rank test. Cox proportional
hazards models were used to analyze factors associated with the time
to the first arrhythmic event during follow-up in all probands as well
as in type 1, non–type 1, VF, and non-VF (syncope and asymptomatic)
groups. Variables were included in the multivariate analysis
with the use of a forward stepwise procedure with a criteria of
P0.05 for inclusion and P0.15 for removal from the model. A
probability value of P0.05 was considered statistically significant.
This study was performed under the ethical code approved by the
Health, Labor, and Welfare Ministry of Japan. Written informed
consent was obtained from all individuals.
Results
Clinical Profiles of All Probands
The mean age of the 330 probands was 51.414.8 years
(median, 53 years; range, 4 to 86 years). The majority (315;
95%) of probands were male. A low percentage (14%) of
patients had a family history of SCD occurring before the age
of 45 years. The induction rate of VF/polymorphic VT by
EPS was higher (77/109: 72%, P0.005) in symptomatic
than asymptomatic probands (61/123: 50%) (Table 1).
Comparison of Clinical Characteristics Between
Type 1 and Non–Type 1 Groups
Type 1 ECG was found in 245 probands (VF group: 45,
18%; syncope group: 46, 19%; and asymptomatic group:
154, 63%). Of these 245 probands, 173 (71%) showed type
1 ECG spontaneously and the remaining 72 (29%) showed
characteristic type 1 morphology after class Ic or Ia
antiarrhythmic drug administration. In 85 probands of the
non–type 1 group (VF group: 11, 13%; syncope group: 21,
25%; and asymptomatic group: 53, 62%), non–type 1 ECG
remained during the drug provocation test (type 2: 61,
Figure 2. Presentation of type 1 and non–type
1 ECG. Coved-type ST-elevation with a J-wave
amplitude 2 mm followed by a negative T
wave (A) or a positive/flat T wave (B), and a
coved ST-elevation followed by a smaller J
wave than T wave (C) were defined as type 1
ECG. Coved (D) or saddleback-type
ST-elevation (E) with a J-wave amplitude
2 mm, a saddleback ST-elevation with a
J-wave amplitude 2 mm (F), and a saddleback
ST-elevation displaying bigger J wave
than T wave (G) were defined as non–type 1
ECG.
Table 1. Comparison of Patient Characteristics Among 3 Large Registries
Brugada et al2 Eckardt et al5 Kamakura et al
Sympt Asympt Sympt Asympt Sympt (VF, S) Asympt
No. 144 190 89 123 123 (56, 67) 207
Age, y 4116* 4016 4614 4414 50.416.6 51.913.6
Men, % 83 71 76 68 96 95
FH of SCD, % 34 72 21 33 19 (25, 13) 11
VF/VT inducibility, % 73 33 63 39 71 (65, 75) 50
Values in parentheses are for the patients with aborted sudden death and an episode of syncope. Sympt indicates symptomatic; Asympt,
asymptomatic; S, syncope; FH of SCD, prevalence of patients with a family history of sudden cardiac death at 45 years old; and VF/VT
inducibility, induction rate of VF or polymorphic ventricular tachycardia by EPS.
*Age of patients with VF.
Kamakura et al Prognosis of Probands With Brugada ECG 497
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72%; coved with J-point amplitude 2 mm: 24, 28%) and
the follow-up period. Most of the clinical parameters
except for VF/VT inducibility, namely, age, sex distribution,
the prevalence of atrial fibrillation, the presence of a
family history of SCD, cardiac events at night (8 PM to 8
AM), and early repolarization, were of similar occurrence
between type 1 and non–type 1 groups (Table 2). Only 8%
(7/85) of probands in the non–type 1 group and 11%
(26/245) of those in the type 1 group were associated with
early repolarization in the inferolateral leads.
Follow-Up and Predictors of Outcome
The mean follow-up period for the entire study population
was 48.714.9 months. Follow-up time was similar among
VF (51.915.0 months), syncope (48.514.0 months),
and asymptomatic (47.715.0 months) groups and between
type 1 (48.615.2 months) and non–type 1
(48.914.2 months) groups. Twenty-four patients had
fatal arrhythmic events during follow-up. The frequency of
events in the type 1 group—15 of 45 (33%) in patients with
VF, 1 of 46 (2%) in syncope patients, and 3 of 154 (2%) in
asymptomatic patients— was similar to that in the non–
type 1 group (4/11: 36%, 1/21: 5%, and 0/53: 0%,
respectively, P0.22; Figure 3). In 5 patients who had
events in the non–type 1 group, 2 had shown a type 1
ST-elevation only in the higher (second or third) intercostal
spaces—1 in a follow-up ECG and 1 after drug
provocation test. The observed frequency of arrhythmic
events was significantly highly in patients with early
repolarization in the inferolateral leads (7/33; 21% versus
17/297; 6%, P0.005), although there was no difference in
risk between the 2 groups (type 1: 6/26; 23%, non–type 1:
1/7; 14%, P0.67). One asymptomatic patient with type 1
ECG died suddenly 3 months after enrollment. Six patients
died of nonarrhythmic causes; 3 died of cancer, 1 because
of rupture of abdominal aortic aneurysm, 1 because of
pneumonia, and cause of death for 1 patient was unknown.
Seven percent of all patients who entered the study
dropped out, the most frequent reason for drop-out was
inability of follow-up due to patient’s change of address.
Figure 4 shows the Kaplan–Meier analysis of arrhythmic
events in probands with type 1 and non–type 1 ECG.
Probands in the VF group had significantly worse prognosis
than those in the syncope and asymptomatic groups. The
Table 2. Comparison of Clinical Profiles Between Probands With Type 1 ECG and Those With Non–Type 1 ECG
Type 1 (n245) Non-Type 1 (n85)
VF Syncope Asympt VF Syncope Asympt P Value
No. 45 46 154 11 21 53 0.33
Age, y 48.217.8 52.515.6 52.313.1 48.018.1 51.915.8 50.715.2 0.99
Men, n (%) 44 (98) 44 (96) 146 (95) 11 (100) 19 (90) 51 (96) 0.90
FH of SCD, n (%) 11 (24) 8 (17) 17 (11) 3 (27) 1 (5) 5 (9) 0.06
Event at night, n (%) 37/45 (82) 15/45 (33) 5/9 (56) 7/18 (39) 0.06
Inferolateral ER, n (%) 8 (18) 3 (7) 15 (10) 2 (18) 1 (5) 4 (8) 0.85
Prevalence of AF, n (%) 19 (42) 7 (15) 21 (14) 4 (36) 3 (14) 8 (15) 0.87
VF/VT inducibility, n (%) 27/41 (66) 31/40 (78) 52/91 (57) 7/11 (64) 12/17 (71) 9/32 (28) 0.04
n (%) indicates the number and the ratio of patients with each parameter; event at night, event developed at night (8 PM to 8 AM); inferolateral ER, inferolateral
early repolarization; AF, atrial fibrillation; VF/VT inducibility, induction rate of VF or polymorphic ventricular tachycardia by EPS.
Figure 3. Flow chart of proband groups categorized according to symptom, ECG morphology, and VF/VT inducibility by electrophysiological
study. Sp. Type 1 indicates spontaneous type 1 group; Dr. Type 1, drug-induced type 1 group; VF, a group with inducible
VF/VT; Non, a group with noninducible VF/VT; EP, a group in which electrophysiological study was not performed; AE, fatal arrhythmic
event during follow-up. The number indicates the number of probands in each category.
498 Circ Arrhythmia Electrophysiol October 2009
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annual rate of arrhythmic events in probands with type 1 ECG
was 10.2% in the VF group, 0.6% in the syncope group, and
0.5% in the asymptomatic group (Figure 4A). The cumulative
rate of arrhythmic events in probands with non–type 1 ECG was
similar to those with type 1 ECG. The annual arrhythmic event
rate was 10.6%, 1.2%, and 0%, respectively (Figure 4B).
By univariate analysis, a family history of SCD was a
predictor for arrhythmic events in the type 1 group (hazard
ratio [HR], 5.1; 95% CI, 2.0 to 12.8; P0.0004) and the
non–type 1 group (HR, 12.3; 95% CI, 2.0 to 74.8;
P0.006). Coexistence of posterolateral early repolarization
with precordial Brugada-pattern ECG was another
predictor in the type 1 group (HR, 4.2; 95% CI, 1.6 to 11.2;
P0.003); however, other parameters were not reliable.
Figure 5 shows the Kaplan–Meier curves of arrhythmic
events in the type 1 group during follow-up, depending on
the presence of a family history of SCD (Figure 5A),
inferolateral early repolarization (Figure 5B), a spontaneous
type 1 ST-elevation (Figure 5C), and inducibility of
ventricular arrhythmias by EPS (Figure 5D). Multivariate
analysis in all probands identified that the former 2
parameters were independent risk factors for arrhythmic
events (a family history of SCD: HR, 3.28; 95% CI, 1.42
to 7.60; P0.005; early repolarization: HR, 2.66; 95% CI,
1.06 to 6.71; P0.03, Table 3) as well as a family history
of SCD in analysis of probands without VF (syncope and
asymptomatic groups) (HR, 12.5; 95% CI, 2.0 to 75.0;
P0.005).
Discussion
Main Findings
We present one of the largest series of consecutive patients
with Brugada-pattern ECG. Importantly, in the present study
only probands were included. Also, this study has the longest
follow-up ever reported. The main finding is that probands
who have a non–type 1 ECG, even after challenged with a
sodium channel blocker, do not necessarily have a better
prognosis than patients with spontaneous or drug-induced
type 1 ECG. Patients presenting with aborted cardiac arrest
had a grim prognosis and those presenting with syncope or no
symptoms had an excellent prognosis irrespective of their
ECG pattern (that is, type 1 versus non–type 1). Also, a
family history of sudden death at age 45 years and
coexistence of early repolarization in the inferolateral leads
were predictors of poor outcome. In contrast, VF/VT inducibility
during EPS was not a predictor of outcome.
Comparison With Previous Studies
In this study, the follow-up time was uniform among the 3
groups. The mean follow-up time for the asymptomatic
individuals was the longest (47.715.0 months) compared
with the studies by Brugada et al2 (2729 months), Priori
et al3 (3444 months), and Eckardt et al5 (33.752.2
months). The percentage of female patients (5%) and
patients with a family history of SCD (14%) was significantly
smaller than 2 of these previous reports (5% versus
24% to 28%2,3,5; P0.001, and 14% versus 28% to
54%2,3,5; P0.001), although the percentage (14%) of a
family history of SCD was similar to that of probands
(20%) that Priori et al3 had reported. The values observed
in the present study may reflect the true profile of the
probands of Brugada syndrome in contrast to previous
studies in which a significant number of family members
were also enrolled.
Prognosis of Probands Presenting With Syncope
and Without Symptoms
The prognosis of probands in the syncope and asymptomatic
groups was very good, and the annual rate of arrhythmic
events was 1.2%. In the syncope group, this rate is
far less than reported in previous studies,2–5 although the
0
. 2
. 4
. 6
. 8
1
Free of SCD or VF
0 10 20 30 40 50 60 70
Months
0
. 2
. 4
. 6
. 8
1
Free of SCD or VF
0 10 20 30 40 50 60 70
Months
A Asymptomatic group B
Syncope group
VF group
Asymptomatic group
Syncope group
VF group
Type 1 group Non-Type 1 group
Asymptomatic 154 152 142 123 113 90 48
Syncope 46 45 42 35 33 26 10
VF 45 40 31 27 25 23 13
N. of patients
Asymptomatic 53 53 52 43 40 29 16
Syncope 21 21 20 19 16 13 7
VF 11 11 11 7 6 3 2
N. of patients
P<0.0001 P=0.009
Figure 4. Kaplan–Meier analysis of arrhythmic events (SCD or documented VF) during follow-up depending on the clinical presentation
(VF/aborted sudden death, syncope, or asymptomatic) in probands with type 1 ECG (A) and those with non–type 1 ECG (B). P0.0001
represents overall comparison, and P0.009 is for comparison between the VF group and the syncope group. There was no statistically
significant difference (P0.95) in the events-free survival of VF probands comparing type 1 and non–type 1 groups.
Kamakura et al Prognosis of Probands With Brugada ECG 499
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rate in the asymptomatic group is similar to that in the
Eckardt registry5 and the rate of around 10% for the VF
group is comparable to the rate reported in the Brugada
registries.2,8 The reason that the patients in the syncope
group showed excellent prognosis is not entirely clear but
may be related to the method of registry. Poor prognosis in
prior studies is possibly related to the retrospective design
of the studies consisting of probands and family members,
2,3,5 in which only severe syncope directly linked to
VF tends to be categorized later as a syncope, despite
difficulty to determine the cause of syncope at the onset.
Even so, we cannot exclude the possibility that some
patients with vasovagal syncope were inevitably included
in the syncope group because not a few patients have
undefined syncope and 30% of Brugada patients are
reported to have both vasovagal syncope and the syncope
due to ventricular arrhythmia.12 Another reason for the
good prognosis is the difference of genetic background.
Brugada syndrome is known to be common in Asian
people, which possibly relates to the higher prevalence of
polymorphism of haplotype B, associated with the cardiac
sodium channel.13,14 The average prognosis of Asian patients
with Brugada syndrome may be better than that of
the white population, because individuals without a critical
genetic defect are easily detected as a Brugada patient in a
routine medical checkup. Further genetic studies are required
to clarify the racial difference of outcome. Nevertheless,
the patients in this study with an aborted sudden
death showed worse prognosis than European people in the
study by Eckardt et al5 and had a similar outcome to those
who underwent ICD implantation.15
Prognosis of Probands With Non–Type 1 ECG
The outcome of probands with non–type 1 ECG was
similar to those with type 1 ECG and the rate of arrhythmic
events in the VF group was considerably higher. Some of
these patients had shown a coved (type 1) ST-elevation
only in the higher (second or third) intercostal spaces
during the drug provocation test or follow-up. Miyamoto et
al16 reported that men with a spontaneous type 1 ECG
A
FH of SCD - 209 207 191 167 154 124 63
FH of SCD + 36 30 24 18 18 15 9
N. of pts. with FH
FH of SCD -
FH of SCD +
p < 0.0001
0
. 2
. 4
. 6
. 8
1
Free of SCD or VF
0 10 20 30 40 50 60 70
Months
0
. 2
. 4
. 6
. 8
1
Free of SCD or VF
0 10 20 30 40 50 60 70
Months
Early Rep - 219 214 197 166 155 127 63
Early Rep + 26 23 19 19 17 12 9
N. of pts. with early repolarization
P=0.0013
Early Repolarization -
Early Repolarization +
B
0
. 2
. 4
. 6
. 8
1
Free of SCD or VF
0 10 20 30 40 50 60 70
Months
0
. 2
. 4
. 6
. 8
1
Free of SCD or VF
0 10 20 30 40 50 60 70
Months
Drug induced 72 71 65 57 54 46 22
Spontaneous 173 165 149 128 118 93 49
N. of pts. with Type 1 ECG
Noninducible 62 60 54 47 46 38 25
Inducible 110 105 97 85 77 63 26
N. of pts. with EPS
P=0.16
Drug induced Type 1
Spontaneous Type 1
P=0.54
Noninducible VF
Inducible VF
C D
Figure 5. Kaplan–Meier analysis of fatal arrhythmic events during follow-up depending on a family history (FH) of SCD (FH of SCD
versus FH of SCD ) (A), inferolateral early repolarization (early repolarization versus early repolarization) (B), a spontaneous type 1
ST-elevation (drug-induced type 1 versus spontaneous type 1) (C), and inducibility of ventricular arrhythmias by EPS (noninducible VF
versus inducible VF) (D).
500 Circ Arrhythmia Electrophysiol October 2009
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recorded only at the higher leads V1 and V2 showed a
prognosis similar to that of men with a type 1 ECG when
using standard leads. In the past, patients with non–type 1
ST-elevation in standard ECG had been excluded from
studies as a benign entity of Brugada syndrome. However,
if patients had a history of aborted sudden death or
agonizing nocturnal dyspnea, non–type 1 Brugada-pattern
ECG should not be disregarded. Careful follow-up including
ECG recording at the higher intercostals spaces and the
implantation of ICD is probably required in such a patient
to prevent SCD.
Clinical Features of Probands With Non–Type
1 ECG
The clinical profiles of probands were very similar between
the non–type 1 group and the type 1 group (Table 2).
Inferolateral early repolarization occurred equally in small
percentage of patients in both groups (8% and 11%, respectively),
which is comparable to the prevalence (12%) of early
repolarization that Letsas et al17 reported in patients with
Brugada syndrome. This means that the patient characteristics
of the non–type 1 group are much closer to Brugada syndrome
than early repolarization syndrome reported by Haı¨ssaguerre
et al,9 in which the VF occurrence rate during
sleeping was low (19%) and VF inducibility by EPS was only
34%. Moreover, they reported that several aspects including
the relapsing VF and the efficacy of isoproterenol and
quinidine,9,18 which were observed in some patients with
early repolarization, were exactly like those of typical Brugada
syndrome. Haı¨ssaguerre et al9 excluded patients with
Brugada syndrome, defined as right bundle-branch block and
ST-segment elevation 0.2mV in leads V1–V3, at the enrollment.
However, considering that they possibly included
patients with non–type 1 ECG as non-Brugada pattern in
their study, some patients with prior VF and early repolarization
might have represented non–type 1 Brugada
patients of high risk.
Predictors of Outcome
It was reported that male sex, a previous episode of
syncope, a spontaneous type 1 ECG, and inducibility of
ventricular arrhythmias by EPS are predictors for poor
outcome.2– 4 Brugada et al demonstrated that inducibility of
ventricular arrhythmias was a reliable marker in patients
with and without VF/SCD,2,4 although Priori et al3 did not
find any significant difference in the analysis of all
patients. A spontaneous type 1 ECG was also indicated as
a reliable marker of poor prognosis by Brugada et al4 in the
analysis of patients without VF/SCD and by Eckardt et al5
in all patients.5 However, we could not find any reliability
in these markers (Figures 3 and 5). Inducibility of ventricular
arrhythmias was not a significant predictor even if it
was evaluated by programmed pacing only from the RV
apex (type 1 group: HR, 1.9 [95% CI, 0.7 to 5.2], P0.18;
all probands: HR, 1.5 [95% CI, 0.6 to 4.1], P0.34, by
univariate analysis).
In contrast, a family history of SCD occurring at age of
45 years is an independent risk factor of a poor prognosis in
probands of any groups irrespective of their ECG type (type
1 or non–type 1) or symptoms (with VF or without VF). This
was probably caused by a smaller proportion of probands
with a family history of SCD as compared with previous
studies2–5 A family history was not found to be a marker in
studies that enrolled many patients with SCD or a family
history of Brugada syndrome. These results indicate that we
should evaluate risks for arrhythmic events cautiously in
studies with a significant number of family members.
Early repolarization pattern in the inferolateral leads was
another indicator of poor prognosis, although Letsas et al17
did not find any association with arrhythmic events in the
data collected from 3 European centers, which also included
30% of patients with a family history of SCD. The reason
for the poor outcome in probands with early repolarization in
this study is not clear. However, it is conceivable that the
combination of precordial Brugada-pattern ST-elevation with
inferolateral early repolarization may represent electric heterogeneity
in extensive regions of ventricles, which can result
in lethal ventricular arrhythmias.
Study Limitations
In this study, premature ventricular electric stimulation
was given until refractoriness was reached. The minimal
Table 3. Probability of Sudden Death or VF During Follow-Up Depending on Clinical and
Electrophysiological Variables in All Probands (Type 1 and Non–Type 1 Groups)
Univariate Analysis Multivariate Analysis
HR 95% CI P Value HR 95% CI P Value
Prior VF 21.46 8.00 –57.53 0.0001 17.48 6.22– 49.11 0.0001
FH of SCD 6.35 2.84–14.19 0.0001 3.28 1.42–7.60 0.005
Inferolateral ER 4.14 1.71–10.00 0.001 2.66 1.06–6.71 0.03
AF 2.15 0.92–5.03 0.07 0.87 0.36–2.09 0.75
Syncope 0.35 0.08–1.09 0.15
Sp. type1 2.31 0.67–7.94 0.18
VF induc. (apex/OT) 1.81 0.72–4.70 0.20
VF induc. (apex) 1.58 0.60–4.11 0.34
Male NA
FH indicates family history; inferolateral ER, inferolateral early repolarization; AF, atrial fibrillation; Sp. type 1, spontaneous type 1
ST-elevation on 12-lead ECG at baseline; VF induc. (apex/OT), VF induction by programmed pacing at the RV apex or RV outflow tract;
and VF induc. (apex), VF induction by programmed pacing at the RV apex.
Kamakura et al Prognosis of Probands With Brugada ECG 501
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coupling interval of extrastimuli was not constant between
participating hospitals and was sometimes shortened to
200 ms to induce ventricular arrhythmias.
We did not show the results of genetic analysis in this
report, although more than half of the patients underwent
genetic screening. Detailed results will be presented in a
future report. So far, no positive relationship between genetic
findings and patient outcomes has been found.3,19
We did not record ECGs at the higher intercostals spaces
systematically except for probands with cardiac events, because
the importance of “high-recording” became apparent in
the course of this study.6 Therefore, some patients of the
non–type 1 group may have shown type 1 ST-elevation at the
higher precordial positions.
Conclusions
This study described the long-term prognosis of probands
with noncoved (non–type 1) Brugada-pattern ECG compared
with type 1 ECG. The annual incidence of fatal arrhythmic
events was similar between the 2 groups, which reached
10.6% in probands with non–type 1 ECG and a prior episode
of VF. A family history of SCD occurring at age of 45 years
and the presence of early repolarization were indicators of
poor outcome although VF inducibility and a spontaneous
type 1 ST-elevation were not reliable indicators in this
prospective study including only probands.
Appendix
The following investigators and institutions participated in
this study: A. Hukui, Yamagata University, Yamagata; M.
Hiraoka, Tokyo Dental and Medical University, Tokyo; S.
Takata, Kanazawa University, Kanazawa; H. Sakurada, Hiroo
Metropolitan Hospital, Tokyo; Y. Eki, Ibaragi-higashi
National Hospital, Tokai; Y. Sasaki, Nagano National Hospital,
Ueda; Y. Tomita, Nagoya Medical Center, Nagoya; U.
Shintani, Mie-chuo Medical Center, Tsu; T. Hashizume,
Minami-Wakayama Medical Center, Tanabe; Y. Fujimoto,
Okayama Medical Center, Okayama; W. Matsuura, Higashihiroshima
Medical Center, Higashihiroshima; K. Sakabe,
Zentuuji National Hospital, Zentuuji; and I. Matsuoka, Kagoshima
Medical Center, Kagoshima, Japan.
Sources of Funding
This work was supported by a research grant for cardiovascular
diseases (13A-1, 16C-3) from the Ministry of Health, Labor, and
Welfare of Japan.
Disclosures
None.
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CLINICAL PERSPECTIVE
The prognosis of patients with saddleback or noncoved type (non–type 1) ST-elevation in Brugada syndrome is unknown.
We compared the long-term prognosis of 85 probands with non–type 1 ECG with 245 probands with coved (type 1)
Brugada-pattern ECG prospectively. The absence of type 1 ECG was confirmed by drug provocation test and multiple
recordings. Clinical profiles and outcomes did not differ between the non–type 1 and type 1 groups. The annual rate of fatal
arrhythmic events was very low in asymptomatic probands and those with syncope but was higher in probands with
ventricular fibrillation. A family history of sudden cardiac death at age 45 years and the presence of inferolateral early
repolarization were indicators of poor prognosis, although ventricular fibrillation inducibility and a spontaneous type 1
ST-elevation were not reliable parameters in this prospective study including only probands.
Kamakura et al Prognosis of Probands With Brugada ECG 503
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最終更新：2013年06月12日 07:39
