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Clinical Characteristics and Long-Term Prognosis of Senior Patients With Brugada Syndrome
JACC: CLINICAL ELECTROPHYSIOLOGY
VOL.
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER
-, NO. -, 2016
ISSN 2405-500X/$36.00 http://dx.doi.org/10.1016/j.jacep.2016.04.004
Clinical Characteristics and Long-Term Prognosis of Senior Patients With Brugada Syndrome Takeshi Kitamura, MD,a Seiji Fukamizu, MD,a Iwanari Kawamura, MD,a Rintaro Hojo, MD,a Yuya Aoyama, MD, PHD,a Mitsuhiro Nishizaki, MD, PHD,b Masayasu Hiraoka, MD, PHD,c Harumizu Sakurada, MD, PHDd
ABSTRACT OBJECTIVES This study investigated clinical characteristics and prognosis of Brugada syndrome (BrS) in patients older than 60 years of age during a long-term follow-up period. BACKGROUND Clinical characteristics and prognosis of senior patients with BrS have not been clearly elucidated. METHODS A total of 181 patients with BrS were divided into 2 groups by age at the time of diagnosis: the younger group was <60 years of age (n ¼ 123), and the senior group was $60 years of age (n ¼ 58). RESULTS Mean ages were 42.7 11 years and 68.6 7.1 years, respectively. Prevalence of spontaneous type 1 electrocardiogram (ECG) was lower in the senior group (22 of 58; 37.9%) than in the younger group (64 of 123; 51.9%) (p ¼ 0.027). Among various ECG parameters, the senior group had a lower incidence of prolonged r-J intervals in V2 $90 ms than the younger group (34 of 58; 58.6% vs. 90 of 123; 73.1%, p ¼ 0.049) and day-to-day variation of Brugada ECG patterns (3 of 58; 5.2% vs. 23 of 123; 18.7%, p ¼ 0.032). During a mean follow-up period of 7.6 5.8 years, no senior patients experienced documented fatal ventricular arrhythmias, but 11 younger patients did. Kaplan-Meier analysis revealed a better prognosis in the senior group than in the younger group (log-rank, p ¼ 0.011). CONCLUSIONS Senior BrS patients, $60 years of age, had a better prognosis than those <60 years of age. Implantable cardioverter-defibrillator insertion for senior patients with BrS needs careful consideration. (J Am Coll Cardiol EP 2016;-:-–-) © 2016 by the American College of Cardiology Foundation.
B
rugada syndrome (BrS) is characterized by
in the elderly population. The mean age of patients
unique electrocardiogram (ECG) patterns on
with BrS has been reported to be in the fourth to fifth
the right precordial leads (V1 to V 3) and
decade (2–4). Brugada type 1 ECGs are observed less
increased risk of sudden cardiac death (SCD) due to
frequently in elderly patients than in the younger
ventricular fibrillation (VF) in the absence of major
patients (4). Recently, 2 studies have indicated a
structural heart disease (1). Although various risk
benign prognosis of elderly BrS patients (5,6). Those
factors for future development of VF have been pro-
studies, however, do not clarify differences in clinical
posed by large numbers of reports, no consensus
and ECG characteristics underlying prognostic factors
has been reached to predict fatal cardiac events, espe-
between the senior and younger patients. Moreover,
cially in BrS patients without a history of documented
the indication for ICDs in senior patients, according
VF or aborted SCD. The only available therapeutic
to the latest consensus statement, has not been
option is insertion of an implantable cardioverter-
verified. Because the United Nations classification
defibrillator (ICD), but the role and indication for
defined people at $60 years of age as senior, we clas-
ICD implantation remain controversial, particularly
sified BrS patients with diagnoses at $60 years of age
From the aDepartment of Cardiology, Tokyo Metropolitan Hiroo Hospital, Tokyo, Japan; bDepartment of Cardiology, Yokohama Minami Kyosai Hospital, Yokohama, Japan; cTokyo Medical and Dental University, Yushima, Tokyo, Japan; and the dTokyo Metropolitan Health and Medical Treatment Corporation, Ohkubo Hospital, Tokyo, Japan. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received January 8, 2016; revised manuscript received March 31, 2016, accepted April 7, 2016.
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Prognosis and Features of Senior Brugada Patients
ABBREVIATIONS
as the senior group and those <60 years of
cardiac magnetic resonance imaging. Acetylcholine
AND ACRONYMS
age as the younger group in our study and
provocation test was performed to exclude vaso-
investigated
spastic angina in 74 patients. ECGs for BrS were
BrS = Brugada syndrome ECG = electrocardiogram ICD = implantable cardioverter-defibrillator
SAECG = signal averaged electrocardiogram
SCD = sudden cardiac death
their
clinical
characteristics
and prognostic variables. In addition, we
classified according to the 2002 and 2005 consensus
reclassified all patients in classes of ICD indi-
reports (7,8), with or without provocation test by
cation according to the latest consensus state-
sodium-channel blockers. Patients with syncope of
ment and then evaluated the distribution and
unknown cause, family history of SCD or atrial
incidence of fatal ventricular arrhythmia dur-
fibrillation (AF; to avoid a possible risk of unexpected
ing a long-term follow-up period.
lethal ventricular arrhythmia to be provoked by sodium channel blockers) were screened by sodium
VF = ventricular fibrillation
METHODS
VT = ventricular tachycardia
channel provocation test if their ECG revealed type 2 or type 3 Brugada ECG. All baseline and drug-induced
STUDY
POPULATION. The
181
12-lead ECG records were obtained at a paper speed of
consecutive patients whose BrS was diagnosed and
25 mm/s and with amplitude of 10 mm/mV with the
followed at the Tokyo Metropolitan Hiroo Hospital
right precordial leads positioned at the 2nd, 3rd, and
from 1992 to 2014. Diagnosis of BrS was defined by the
4th intercostal spaces. All ECGs were analyzed by 3
2 consensus reports in 2002 (7) and 2005 (8). This
independent experienced electrophysiologists. Early
retrospective
was
repolarization pattern was defined in the presence of
approved by the Institutional Review Board of Tokyo
J-point elevation $1 mm in $2 contiguous inferior
Metropolitan Hiroo Hospital, Tokyo, Japan. Patients
and lateral leads of ECG, according to the 2013
were divided into 2 groups according to their age at
consensus statement (9). Fragmented QRS was
the time of diagnosis: the younger group (<60 years
defined in the presence of abnormal fragmentation
of age) and the senior group ($60 years of age).
within the QRS complex as 4 spikes in 1 or 8 spikes in
Clinical histories and 12-lead ECG findings, including
all of leads V 1, V2, and V 3 (10). Day-to-day variation in
those from leads V 1 to V3 placed at the 2nd, 3rd, or 4th
Brugada ECGs was positive if a type 1 Brugada ECG
intercostal space were accessed in all patients.
was present on one day but spontaneously dis-
observational
study
study
included
protocol
Organic heart diseases were excluded by exami-
appeared or changed to type 2 or type 3 ECG on
nations using ultrasound cardiography, coronary
another day during the follow-up period. We acquired
angiography, right and left ventriculography, and
ECGs during the initial follow-up and at each scheduled follow-up, and any unscheduled visits and dur-
F I G U R E 1 Distribution of Patients’ Ages at Diagnosis of BrS
ing any in-hospital stays. The alterations in the ECG were evaluated at rest (commonly 2 h before or after meal) and excluded the ECGs recorded with any stress (during exercise test, drug challenge test, full stomach, and in febrile illness). Significant augmentation of ST-segment elevation during recovery phase in treadmill exercise testing was defined as ST-segment amplitude increase >0.05 mV in at least 1 of leads V1 to V 3 at early recovery (1 to 4 min at recovery) compared with the baseline level (preexercise) (11). The presence of late potentials (LPs) was evaluated with a signal-averaged ECG (noise level: 0.3 V, filtered with a high-pass filter by 40 Hz). Three parameters were assessed using a computer algorithm: the filtered QRS duration (f-QRS); the rootmean-square voltage of the terminal 40 ms in the filtered QRS complex (RMS40); and the duration of low-amplitude signals, 40 mV in the terminal filtered QRS complex (LAS40). LPs were considered positive when 2 of 3 criteria (f-QRS >114 ms; RMS40 <20 mV; and LAS40 >38 ms) were met (12,13). Electrophysio-
Each column is divided by 10 years, and numbers of patients are shown on the top of each column. BrS ¼ Brugada syndrome.
logical study (EPS) findings were evaluated among 115 of 181 patients for diagnosis or risk stratification or both.
Those
patients
underwent
programmed
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Prognosis and Features of Senior Brugada Patients
electrical stimulation to assess ventricular tachycardia (VT) or VF inducibility. Our method for EPS
T A B L E 1 Comparison of Clinical Characteristic and Types of ST Elevation in the Younger
and Senior Groups
and protocol of ventricular stimulation for induction of VT/VF was described previously (14). In short, EPS
Younger Subjects (n ¼ 123)
Senior Subjects (n ¼ 58)
p Value
was performed using 3 multielectrode catheters
Age (yrs)
42.7 11
68.6 7.1
introduced percutaneously through the femoral ves-
Males (%)
113 (91.9%)
56 (96.5%)
sels. Programmed ventricular stimulation was per-
Family history of SCD (%)
26 (21.1%)
15 (25.7%)
0.479
formed with the use of a maximum of 3 ventricular
Family history of type 1 ECG (%)
5 (4.1%)
0 (0%)
0.141
extra-stimuli from the right ventricle apex and
Syncope (%)
28 (22.8%)
14 (24.1%)
0.838
outflow tract. Minimum coupling interval was effec-
SCN5A mutation (%)
2/6
0/4
-
Documented VF (%)
19 (15.4%)
5 (8.6%)
0.206
6/50 (12.0%)
3/21 (14.2%)
0.117
47 (38.2%)
26 (44.8%)
0.397 0.854
tive refractory period during single ventricular extrastimulus, 180 ms during 2 ventricular extra-stimuli,
Vasospastic angina (%) ICD implantation (%)
0.237
200 ms during 3 ventricular extra-stimuli. Patients
Inappropriate therapy (%)
12/47 (25.5%)
6/26 (23.1%)
with VF lasting for more than 30 s or who required
Spontaneous type 1 ECG (%)
64 (51.9%)
22 (37.9%)
0.027
electrical cardioversion were classified as inducible.
Drug-induced type 1 ECG (%)
59 (48.1%)
36 (62.1%)
0.027
Informed consent was obtained from all patients.
Reasons for drug provocation test
Indication for ICD implantation was determined
Documented VF (%)
7/59 (11.9%)
3/36 (8.3%)
0.842
according to the 2002 or 2008 American College
Syncope of unknown cause with type 2 or type 3 ECG (%)
17/59 (28.8%)
9/36 (25.0%)
0.867
Family history of SCD with type 2 or type 3 ECG (%)
18/59 (30.5%)
9/36 (25.0%)
0.732
AF with type 2 or type 3 ECG (%)
of
Cardiology/American
Heart
Association/Heart
Rhythm Society (ACC/AHA/HRS) guideline (15), the Japanese guideline (16), or 2013 HRS/European Heart Rhythm Association/Asia Pacific Heart Rhythm Society (HRS/EHRA/APHRS) consensus statement (9).
17/59 (28.8%)
15/36 (41.7%)
0.198
Newly developed IHD (%)
3 (2.4%)
3 (5.2%)
0.292
Coronary angiography during follow-up (%)
3 (2.4%)
7 (12.1%)
0.013
Because our study period spanned 1992 to 2014 and
Values are mean SD or n (%).
the guidelines for ICD therapy were modified several
AF ¼ atrial fibrillation; ECG ¼ electrocardiogram; ICD ¼ implantable cardioverter-defibrillator; IHD ¼ ischemic heart disease; SCD ¼ sudden cardiac death; VF ¼ ventricular fibrillation.
times during the entire period, we reclassified all patients by the indication for ICD implantation according to the latest consensus statement of the 2013 HRS/EHRA/APHRS (9). Fourteen patients were
RESULTS
registered in the Japan idiopathic ventricular fibrillation study (17). FOLLOW-UP. Patients with ICD implantation under-
went regular follow-up of the device and clinical symptoms, at least, every 3 to 4 months at our outpatient clinic. Patients without ICD implantation were followed every 6 or 12 months with a visit to our outpatient clinic for checking clinical status and examinations of resting ECG and signal averaged ECG (SAECG).
CLINICAL AND ELECTROPHYSIOLOGICAL CHARACTERISTICS OF THE 2 GROUPS. The senior group, $60 years of age,
consisted of 58 cases (32%), and the younger group, <60, was 123 cases (68%). Mean ages were 68.6 7.1 years in the former and 42.7 11 years in the latter group. The age distribution at diagnosis in all patients is shown in Figure 1. The youngest patient was 16 years of age, and the oldest was 91 years of age. In the senior group, there were 35 patients 60 years of age, 19 patients in their 70s, and 4 patients
STATISTICS. Data are mean SD or absolute values
in their 80s. In the younger group, there were
and percentages where appropriate. The chi-square
38 patients in their 50s, 39 patients in their 40s (the
test and Fisher exact test were used to compare cat-
highest number of cases), 29 patients in their 30s, and
egorical variables. Continuous variables between the
17 patients less than 29 years of age.
2 groups were analyzed using the unpaired Student t
Clinical characteristics of the 2 groups are shown in
test or Mann-Whitney U test as appropriate. Survival
Table 1. The proportion of patients with spontaneous
curves were constructed by using the Kaplan-Meier
type 1 ECG was lower, and that of drug-induced type 1
method and compared using the log-rank test. Uni-
was higher in the senior group than in the younger
variate Cox proportional hazards models were used
group. Other clinical parameters, except for their
to assess the effect of each variable on VF during
ages, were not significantly different between the 2
follow-up. A p value <0.05 was considered sta-
groups. Male predominance was similar in the 2
tistically significant. Statistical analyses were con-
groups. Rates of patients with history of syncope,
ducted using SPSS version 19.0 software (SPSS Inc.,
documented VF, and vasospastic angina were not
Chicago, Illinois).
different. There were 5 patients in the younger group
Kitamura et al.
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Prognosis and Features of Senior Brugada Patients
T A B L E 2 Comparison of ECG Findings and Electrophysiological Parameters Between
Younger and Senior Groups
The number of ECGs recorded per patient per year was 4.2 2.8/patient/year. P-wave duration, PQ interval, QRS duration, and QTc intervals were not
Younger Group (n ¼ 123)
Senior Group (n ¼ 58)
p Value
P-wave duration, ms
107.2 16.0
103.1 14.3
0.096
significantly higher ratios in the younger group than
PR interval, ms
171.3 28.7
172.4 24.6
0.794
those in the senior group. However, there were no
QRS duration, ms
113.5 16.2
110.9 17.5
0.317
differences in percentages of patients with frag-
QTc interval, ms
413.3 27.6
416.5 25.7
0.455
mented QRS, inferolateral ER pattern, AF, positive
90 (73.1%)
34 (58.6 %)
0.049
100.0 14.5
96.9 18.1
LP by SAECG, and positive T-wave alternans in the
r-J interval in V2, ms
0.212
Fragmented QRS (%)
19 (15.4%)
6 (10.3%)
0.353
Inferior ERP (%)
14 (11.4%)
11 (19.0%)
0.168
Lateral ERP (%)
9 (7.3%)
3 (5.2%)
0.484
LONG-TERM FOLLOW-UP. After a mean follow-up
Infero-lateral ERP (%)
4 (3.3%)
1 (1.7%)
0.481
period of 7.6 5.8 years (91 69 months), 11 pa-
Day-to-day variation (%)
23 (18.7%)
3 (5.2%)
0.032
tients developed VT/VF episodes (cardiac events),
Documented atrial fibrillation (%)
27 (21.9%)
16 (27.7%)
0.456
and all of the events belonged to the younger group
Positive LP by SAECG (%)
90 (73.1%)
35 (60.3%)
0.082
but none to the senior group. Figure 2 shows age
Augmented ST-segment elevation during recovery after exercise (%)
3/111 (2.7%)
1/52 (1.9%)
0.542
Induced VF (%)
56/74 (75.7%)
35/41 (85.4%)
0.057
recurrences during follow-up period (Figure 2B).
VF induction by single or double extra-stimuli (%)
37/74 (50.0%)
22/41 (53.7%)
0.943
Details of senior patients with VF events at diagnosis
VF induction by triple extra-stimuli (%)
37/74 (50.0%)
19/41 (46.3%)
0.943
r-J interval in V2 $90 ms (%)
different among them. Patients showing r-J interval $90 ms and day-to-day variation of type 1 ECG had
ECG
2 groups.
distributions of VF events at or before the age of diagnosis (VF history) (Figure 2A) and of VT/VF
EPS
are shown in Table 3. The patient’s age at VF history ranged between 19 and 68 years of age, and the range
47.0 10.2
43.9 7.7
0.109
RVA ERP, ms
237.2 20.0
216.0 25.1
0.133
of age at VT/VF recurrences during follow-up period
RVOT ERP, ms
240.0 20.6
245.3 18.7
0.349
was between 19 and 49 years of age. No patients over
HV interval, ms
50 years of age had recurrences, despite history of VF Values are mean SD, n (%), or n/N (%). EPS ¼ electrophysiological studies; ERP ¼ effective refractory period; LP ¼ late potential; RVA ¼ right ventricular apex; RVOT ¼ right ventricular outflow tract; SAECG ¼ signal averaged electrocardiogram; TWA ¼ T-wave alternans.
in 7 patients. Kaplan-Meier analysis revealed a better prognosis for the senior group than the younger group (log-rank p ¼ 0.011) (Figure 3). Univariate Cox regression analysis of each risk factor is shown in
who had a family history of BrS, but all patients in the
Table 4. Patients younger than 60 years of age (p ¼
senior group were probands without family history.
0.042; hazard ratio [HR]: 2.82; 95% confidence inter-
No differences were noted between the 2 groups with
val [CI]: 1.695 to 50.74), documented VF (p < 0.01;
regard to incidence of ICD implantation and inap-
HR: 22.1; 95% CI: 10.22 to 54.33), ER pattern (p < 0.01;
propriate ICD therapy. During follow-up, coronary
HR: 17.43; 95% CI: 4.597 to 66.1), fragmented QRS
angiography was required to identify the cause of
(p < 0.01; HR: 8.574; 95% CI: 2.614 to 28.12), and day-
chest pain in 10 patients. Six patients developed de
to-day variations of type 1 ECG (p < 0.01; HR: 9.617;
novo coronary stenosis, which was treated by percu-
95% CI: 2.43 to 38.06) had a correlation with VF
taneous coronary intervention (mean: 60 11 years of
recurrence. In addition, we also evaluated combina-
age; range: 42 to 74 years). The mean duration from
tions of risk factors for prediction of VF recurrences
diagnosis of BrS to diagnosis of newly developed
(Table 4). Although several risk factors could not
coronary stenosis was 10.5 6.2 years (range: 3.8 to
singly predict VF events, combinations of age <60
16.5 years). Three patients underwent coronary
years and risk factors (syncope, spontaneous type 1
angiography to determine the cause of VF and
ECG, induced VF, VF induction by single or double
appropriate therapy; however, there was no case of
extra-stimuli) might predict a VF event. Five combi-
newly developed coronary stenosis. Other patients
nations with highest HR among all combinations are
with recurrence of VF during follow-up were also
described at the bottom of Table 4. In addition, we
screened for development of ischemic heart disease
evaluated alteration, especially attenuation with age,
by using noninvasive examinations. No positive
in several parameters during follow-up. There were
findings of ischemic events by exercise test or
no changes in r-J interval >90 and fragmented QRS
myocardial perfusion scintigraphy were detected
during follow-up. On the other hand, 2 of 42 patients
among other patients.
had day-to-day variations in ER pattern (ER was not
Parameters of various ECG findings and electro-
documented regularly). Six of 125 patients had a
physiological studies of 2 groups are shown in Table 2.
change from positive to negative LP. According to
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Prognosis and Features of Senior Brugada Patients
F I G U R E 2 VF History and VF Events
(A) Presence and absence of VF history at each age group of diagnosis. (B) VF events during follow-up in each age group. Please note that no VF events occurred at ages older than 50 years. VF ¼ ventricular fibrillation.
the definition of day-to-day variations in type 1
patients in Class 2b. Among senior patients with ICD,
ECG, spontaneous alterations from type 1 to type 2
there were 5 patients in Class 1, 3 patients in Class 2a,
or 3 were observed in 14 of 26 cases. Among the
and 19 patients in Class 2b.
14 patients, 10 (of 26) had their ECGs reidentified
COMPLICATIONS ASSOCIATED WITH THE ICD. Table 5
as spontaneous type 1 ECG. There were only 4 pa-
presents details of complications such as inappro-
tients with type 1 ECG who alternated to persistent
priate shocks and other ICD complications. A total of
type 2 or 3 ECG. The prevalence of attenuating LP
18 patients with ICD implantation had inappropriate
and day-to-day variations was low (LP: 6 of 125
therapy (18 of 73; 24.7%). The cause was AF in 10
[4.8%]; day-to-day variation in type 1 ECG: 4 of
cases, paroxysmal supraventricular tachycardia in 4,
26 [15.3%]).
lead fractures in 2, sinus tachycardia in 1, and T-wave
ICD INDICATION. Figure 4A shows the number of ICD
oversensing in 1. The incidence of inappropriate
indication category modified to the latest guideline
therapy due to AF was not statistically different be-
among all patients and those with implanted ICD.
tween the 2 groups. Other complications (14 events)
There were 24 of 181 cases (13.2%) classified as Class 1;
were found in 14 patients who received ICD (14 of 73;
21 of 181 (11.6%) as Class 2a; 86 of 181 (47.5%) as Class
19.2% [10 lead fractures, 3 ICD infections, and 1 he-
2b; and 5 as Class 3 and 45 as others (e.g., sponta-
matoma at ICD replacement]). Kaplan-Meier analyses
neous type 1 ECG and family history of SCD) in all
of all complications and lead fracture are shown
patients (Figure 4A, left bar). Regarding the numbers
in Figure 5.
of patients who received ICD implantation (Figure 4A, right bar), 23 patients were in Class 1, 6 in Class 2a,
DISCUSSION
and 44 in Class 2b. No patients in Class 3 or other received ICD implantation. Figure 4B compares
CLINICAL CHARACTERISTICS OF SENIOR PATIENTS
patient numbers classified by ICD indication and
WITH BRUGADA SYNDROME IN COMPARISON TO
patients with implanted ICDs between the younger
THOSE IN THE YOUNGER GROUP. BrS is generally
and senior groups. In the senior group, there were
characterized by male predominance with a middle-
5 patients in Class 1, 6 patients in Class 2a, and 32
aged onset of cardiac events or diagnosis at 40 to
5
Kitamura et al.
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AF ¼ atrial fibrillation; ECG ¼ (12-lead) electrocardiogram; ER ¼ early repolarization; ERP ¼ effective refractory period; FH ¼ family history; ICD ¼ implantable cardioverter-defibrillator; IHD ¼ ischemic heart disease; LP ¼ late potential; RVA ¼ right ventricular apex; RVOT ¼ right ventricular out; SAECG ¼ signal-averaged ECG; SCD ¼ sudden cardiac death; VF ¼ ventricular fibrillation.
*Plus/minus (/þ) signs indicate negative or positive in each variable.
0/5 (0%) 0/5 (0%) 1/5 (20%) 1/5 (20%) 236 15 220 8.9 42 7.6 3/5 (60%) 2/5 (40%) 5/5 (100%) 3/5 (60%) 1/5 (20%) 0/5 (0%)
400/240 400/230 42 þ þ þ 5
þ 400/240 400/210 35 þ þ þ 4
400/220 400/210 50 þ þ þ 3
þ
400/220
400/260 400/220
400/230 48
40 þ
þ
þ
þ
þ
2
1
Hematoma at Replacement ICD Infection Lead Fracture Newly Developed IHD RVOT ERP, ms RVA ERP, ms HV Interval, ms VF Induction by Triple VF Induction by Single or Double VF Inducibility Day-to-Day Variations of Brugada ECG
Males
64.8 1.9 5/5 (100%)
63 5
Males 64 4
Males 64 3
Males 65
68 1
2
Males
AF
Positive LP by SAECG
1/5 (20%) 0/5 (0%)
1/5 (20%) 412 9.5
412 100
102 7.4 172 15
189
1/5 (20%) 0/5 (0%)
þ
2/5 (40%) 5/5 (100%)
þ
5/5 (100%) 1/5 (20%)
1/5 (20%)
þ
403 106 155 þ (lead fracture) þ þ þ
407 99 172 þ þ þ
þ 412
428 123
100 162
185
þ
þ þ
þ
þ
þ
QTc r-J Interval in Fragmented Interval, ms V2 >90 ms* QRS* ER Pattern* P-Wave QRS Duration, ms Duration, ms Inappropriate Therapy* Appropriate Therapy* ICD Spontaneous. Type 1 ECG VF Survivor Syncope FH of SCD Sex Age, y Patient #
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Prognosis and Features of Senior Brugada Patients
T A B L E 3 Patient Characteristics of 5 Senior Patients With Brugada Syndrome Who Were Resuscitated From Ventricular Fibrillation at Diagnosis
6
50 years of age, or both. There are, however, certain numbers of patients in whom BrS is diagnosed at $60 years of age in the clinical setting. In the present study, 32% (58 of 181 subjects) of our BrS cohort represented the senior group. Recent reports indicated that the senior BrS patients had benign prognosis compared with the younger age populations in general BrS cohort as well as in high-risk patients (5,6). Our study also confirmed their results with a benign prognosis of the senior group $60 years of age. Furthermore, the results indicated certain clinical characteristics suggestive of better prognostic signs that were not indicated in the previous reports. Many clinical variables have been proposed as risk factors with which to predict cardiac events in patients with BrS. Among these variables, symptomatic patients including a history of VT/VF, syncope of unknown origin, and spontaneous type 1 ECG were assumed to be important predictors (2). Furthermore, whether other symptoms or clinical signs could be applicable to predict cardiac events in senior BrS patients is not known. Conte et al. (5) reported a better prognosis of the senior BrS patients with significantly less frequent prevalence in family history of SCD than in the younger patients. Our study did not show a difference in prevalence of family history of SCD between the senior and younger groups. The discrepant results may be due to differences in the subjects’ backgrounds, as their study population included a relatively high prevalence of family members of BrS (49% in 58 cases), and our cases represented 21.1% to 25.7% of the family history in both groups. The report by Conte et al. (5) also indicated fewer numbers of patients with induced VT/VF during programmed ventricular stimulation in the senior group than the younger group, but we could not observe a difference in the ratio of induced VT/VF between the 2 groups. As to the induced VT/VF by EPS, its positive predictive value for cardiac events has been in intense dispute and a consensus has been reached (2,3,9,18–20). Different outcomes by EPS might be attributed to differences in stimulation protocol, but a prospective study by a fixed stimulation protocol could not demonstrate a predictive value of VT/VF induction for cardiac events (20). In the present study, spontaneous type 1 ECG and day-to-day variations in Brugada ECG patterns were significantly less prevalent in the senior group than in the younger group. Type 1 ECG and day-to day variations of Brugada ECG pattern are thought to be risks factor for fatal ventricular arrhythmia depending on different ethnic groups and population of the study subjects, values, and timing of ECG
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Prognosis and Features of Senior Brugada Patients
F I G U R E 3 Kaplan-Meier Curves of Ventricular Fibrillation in
T A B L E 4 Results of Univariate Cox Regression Analysis of Risk Factors and Combination
the Senior and Younger Groups During Follow-Up Period
of Risk Factors Hazard Ratio
95% Confidence Interval
p Value
Documented VF
Variable
22.1
10.22–54.33
<0.01
Syncope
2.89
Spontaneous type 1 ECG
2.94
0.78–11.01
0.111
Family history of SCD
0.32
0.001–11.18
0.249
Male
22.1
0.022–102.5
0.579
Age <60 yrs
2.82
1.695–50.74
0.042
ER pattern
17.43
4.597–66.1
<0.01
Fragmented QRS
8.574
2.614–28.12
<0.01
0.884–9.5
0.079
<0.01
Day-to-day variation of type 1 ECG
9.617
2.43–38.06
r-J interval $90 ms
4.626
0.592–36.141
0.144
Positive LP by SAECG
0.771
0.226–2.636
0.679
Induced VF during EPS
2.599
0.333–20.31
0.362
VF induction by single or double extra-stimuli
4.235
0.51–35.19
0.181
RVA ERP <200 ms
0.833
0.162–4.295
0.827
RVOT ERP <200 ms
2.837
0.572–14.07
0.202
Combined risk factors
recordings, and selections of ECG lead placements at different intercostal spaces (21–23). Therefore, the lower frequency of those findings might contribute to a better prognosis in the senior group. Among other conditions supposed to predict cardiac events, there were fewer patients with r-J interval >90 ms (17) in the senior group than in the younger group. However, other parameters including positive LP
VF and age <60 yrs
22.18
12.13–82.4
<0.01
Syncope and age <60 yrs
4.918
1.548–15.623
0.007
Spontaneous type 1 ECG and age <60 yrs
4.09
1.229–13.62
0.022
ER pattern and age <60 yrs
20.88
5.602–77.833
<0.01
Fragmented QRS and age <60 yrs
10.74
3.457–33.37
<0.01
Day-to-day variation of type 1 ECG and age <60 yrs
9.347
2.614–33.42
<0.01
Positive LP and age <60 yrs
1.511
0.479–4.762
0.481
Induced VF and age <60 yrs
10.7
1.364–83.32
0.024
VF induction by single or double extra-stimuli and age <60 yrs
11.64
RVOT ERP <200 ms and age <60 yrs
0.955
1.4–96.8 0.193–4.733
0.023 0.955
Five combined risk factors with the highest hazard ratios VF and fragmented QRS
55.2
16.25–98.2
<0.01
VF and day-to-day variation of type 1 ECG
26.5
7.954–88.34
<0.01
by SAECG (12,24), fragmented QRS (10), history of
VF and ER pattern
25.0
7.556–82.7
<0.01
AF (17,25,26), ER patterns (22,27,28), augmented ST
VF and age <60 yrs
22.18
12.13–82.4
<0.01
elevation during recovery phase after exercise (11),
ER pattern and age <60 yrs
20.88
5.602–77.833
<0.01
and ventricular effective refractory period <200 ms (20) were not different between the 2 groups.
Abbreviations as in Tables 1 and 2.
POSSIBLE REASONS FOR BETTER PROGNOSIS IN SENIOR PATIENTS
spontaneous
WITH BRUGADA SYNDROME
observed in the senior group with better prognosis
type
1
ECG
were
less
frequently
might be explained by decreased hormonal influence Our results indicated that BrS patients $60 years of
of testosterone with age (31,32). In addition, a pro-
age had a better prognosis than those <60 years of
longed r-J interval of $90 ms, which might indicate
age over 7-year follow-up, confirming the results
conduction abnormality and day-to-day variations of
of previous reports (5,6). Five patients with a history
Brugada ECG patterns, which might indicate auto-
of VF at the age of diagnosis older than 60 years of age
nomic tone disorder as markers of the proposed risk
did not experience any recurrence of VF events dur-
(13,29), were less frequent in the senior group.
ing the follow-up (11.7 3.2 years). Furthermore,
Moreover, attenuation or disappearance of several
patients including the younger group older than 50
risk factors with age during follow-up were observed
years of age had no recurrences of VF. As to the
in a small number of patients. Therefore, the true
mechanism of ST-segment elevation and develop-
reason why the senior patients showed a better
ment of VT, repolarization theory (29) and depolari-
prognosis than the younger group <60 years of age
zation theory (30) have been proposed without
was not clarified by the present study, and further
reaching
a
firm
consensus.
The
results
that
exploration should be continued. In addition, in our
8
Kitamura et al.
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Prognosis and Features of Senior Brugada Patients
F I G U R E 4 Number of Patients in Each Class of ICD Indication and Actual Numbers of Patients With ICD
(A) Graphs show numbers of each class of ICD indication in all cases (left) and numbers of patients with ICD (ICDþ) (right). (B) Graphs present numbers of each class of ICD indication in all cases and numbers of ICD(þ) in the younger group (left) and those in the senior group (right). ICD ¼ implantable cardioverter-defibrillator.
case series, there were no VF events after 5-year
AGE AS A PROGNOSTIC FACTOR. A number of clin-
follow-up, contrary to our expectations. We antici-
ical prognostic factors have been shown to predict VF
pated that there would be events in the late period of
in patients with BrS, as mentioned above. In our case
follow-up, as reported in other studies (18,20).
series, younger patients, <60 years of age, had worse
Therefore, we also expected that there would be pa-
prognosis than senior patients based on the log-rank
tients with VF events during later follow-up period
test and univariate Cox regression analysis. In the
in future. One possible reason could be that the
Cox regression model, documented VF, fragmented
patients had more time to receive education at
QRS, ER pattern, and day-to-day variation in type 1
outpatient clinics to avoid being exposed to circum-
ECG could also predict VF events. Moreover, although
stances such as high-grade fever, taking medication
several risk factors (syncope, spontaneous type 1
worsening BrS ECG (Na channel blockers, calcium
ECG, induced VF, VF induction mode single or dou-
channel blockers, and so forth) (33,34), or hyper-
ble) do not alone statistically predict VF events,
activated parasympathetic tone as the follow-up
combinations of age <60 years and those factors
duration became longer. However, we do not have
(syncope, spontaneous type 1 ECG, induced VF, VF
evidence or data in support of this.
induction mode single or double) may predict VF
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events. Recently, a combination of risk factors has been proposed to predict VF in patients with BrS
T A B L E 5 Inappropriate Therapy and Complication During Follow-Up
in 2 Groups
(35,36). Age <60 years might be helpful not only as a simple prognostic factor but also as one of the reasonable risk factors in combination with other risk
Inappropriate therapy (%)
Younger Group (n ¼ 47)
Senior Group (n ¼ 26)
12/47 (25.5%)
6/26 (23.1%)
6/12 (50.0%)
4/6 (66.7%)
0.86 0.536
p Value
0.854
factors to stratify VF recurrence risk. However, we
AF (%)
could not conduct a multivariate analysis because of
Other SVTs (%)
3/12 (25.0%)
1/6 (3.9%)
an insufficient number of VF events. Therefore, a
Lead fracture (as cause of inappropriate therapy) (%)
2/12 (4.3%)
0/6 (0%)
-
0/6 (0%)
-
study with a larger sample size with enough VF events to conduct multivariate analysis is warranted to confirm the results.
Sinus tachycardia (%) T-wave oversensing (%) Other complications (%)
ICD INDICATION FOR THE SENIOR PATIENTS WITH BRUGADA SYNDROME. In the present study, all
patients were reclassified by ICD indication according to the latest consensus statement (9). Figure 4 shows the distribution of reclassified patients. Pa-
1/12 (2.1%) 0/47 (0%) 10/47 (21.3%)
1/26 (3.9%)
-
4/26 (15.4%)
0.224
Lead fracture (%)
7/10 (70.0%)
3/4 (75.0%)
0.64
ICD infection (%)
2/10 (20.0%)
1/4 (25.0%)
0.595
Hematoma at implantation or replacement of ICD (%)
1/10 (10.0%)
0/6 (0%)
Values are n/N (%). SVT ¼ supraventricular tachycardia; other abbreviations as in Tables 1 and 2.
tients with ICD insertion were reclassified into class 1, 2a, or 2b, but none in class 3 or other. There were 5 patients reclassified into class 1, and 6 patients
the implantation (6). Therefore, the risk stratifica-
into class 2a in senior group. There was no VT/VF in
tion of cardiac events and a better prognosis of the
those
follow-up
senior patients must be carefully considered for the
period. The indication for ICD implantation has
selection of ICD implantation. However, it should
not been clarified in senior BrS patients. In the
be emphasized that 5 senior patients in their 60s
consensus statements for BrS (9), a specific con-
already had VF episodes at the time of diagnosis in
sideration of ICD implantation for senior BrS pa-
the present study. Results further indicate that pa-
tients was not described. Although ICD implantation
tients with BrS over 60 years of age have the po-
is supposed to be the only therapeutic means to
tential to develop VF and that ICD indication should
protect against SCD at the present time, there are
not be avoided simply because of advanced age at
factors associated with device complications after
the time of diagnosis; the decision should be made
patients
during
the
long-term
F I G U R E 5 ICD Complications
Kaplan-Meier curves of all ICD complications (A) and lead fractures (B) during follow-up (8.2 6.8 years). The incidence of ICD complication and lead fracture per 73 cases increased over time. Abbreviations as in Figure 4.
-
9
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Prognosis and Features of Senior Brugada Patients
by weighing the risks and benefits of implantation in each individual.
might have overestimated the impact of those risk factors, and the results in Table 4 should be inter-
COMPLICATIONS ASSOCIATED WITH THE ICD. In
the present study, there were no statistical differences between the 2 groups in the prevalence of total number of inappropriate therapies or inappropriate therapy due to AF and other supraventricular tachycardias (SVT). However, during the follow-up period, complications or lead fracture incidence gradually increased, which is a finding in line with that of a previous study (6). Kamakura et al. (6) reported that numbers of SVT and inappropriate shocks increased with age. In our study, this did not achieve statistical significance; however, the prevalence of inappropriate therapy due to AF was slightly higher in the senior group than in the younger group. Therefore, considering the increasing accumulation of complications and inappropriate therapy due to SVT including AF in senior patients, careful decision making for ICD implantation may be necessary in
preted carefully. Moreover, because a multivariate analysis needs at least 10 events per risk factor, we could not conduct a multivariate Cox regression analysis to confirm the independence of each risk factor. A large-scale prospective study is needed to confirm these results and to clarify the mechanism.
CONCLUSIONS Senior BrS patients $60 years of age at diagnosis seem to have a better prognosis than younger patients. ICD implantations for BrS patients $60 years of age should be carefully evaluated. REPRINT REQUESTS AND CORRESPONDENCE: Dr.
Takeshi Kitamura, Department of Cardiology, Tokyo Metropolitan Hiroo Hospital, 2-34-10 Ebisu, Shibuyaku, Tokyo, Japan. E-mail: [email protected].
senior patients with BrS, particularly in patients with PERSPECTIVES
Class 2b indication. STUDY LIMITATIONS. Our study has several limita-
tions: it is a single-center study with retrospective analysis with heterogeneous clinical characteristics. The numbers of the study subjects were rather small. In addition, a direct correlation between cardiac events during follow-up and the positive findings (i.e., type 1 ECG, day-to-day variation, or prolonged R-J interval) was not confirmed. Furthermore, there were only 11 events during the follow-up period in the present study, which contributed to several risk factors with large hazard ratios and large confidence
COMPETENCY IN MEDICAL KNOWLEDGE: Senior BrS patients $60 years of age at diagnosis have a better prognosis than the younger age group. ICD implantations for BrS patients $60 years of age should be carefully evaluated. TRANSLATIONAL OUTLOOK: A study with a larger population and a longer follow-up period, specifically a span lasting until the end of life in senior patients, is needed.
intervals in Cox regression analysis. Therefore, we
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7. Wilde AA, Antzelevitch C, Borggrefe M, et al. Proposed diagnostic criteria for the Brugada syndrome: consensus report. Eur Heart J 2002;23:
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KEY WORDS Brugada syndrome, implantable cardioverter-defibrillator, ventricular fibrillation
11
VOL.
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER
-, NO. -, 2016
ISSN 2405-500X/$36.00 http://dx.doi.org/10.1016/j.jacep.2016.04.004
Clinical Characteristics and Long-Term Prognosis of Senior Patients With Brugada Syndrome Takeshi Kitamura, MD,a Seiji Fukamizu, MD,a Iwanari Kawamura, MD,a Rintaro Hojo, MD,a Yuya Aoyama, MD, PHD,a Mitsuhiro Nishizaki, MD, PHD,b Masayasu Hiraoka, MD, PHD,c Harumizu Sakurada, MD, PHDd
ABSTRACT OBJECTIVES This study investigated clinical characteristics and prognosis of Brugada syndrome (BrS) in patients older than 60 years of age during a long-term follow-up period. BACKGROUND Clinical characteristics and prognosis of senior patients with BrS have not been clearly elucidated. METHODS A total of 181 patients with BrS were divided into 2 groups by age at the time of diagnosis: the younger group was <60 years of age (n ¼ 123), and the senior group was $60 years of age (n ¼ 58). RESULTS Mean ages were 42.7 11 years and 68.6 7.1 years, respectively. Prevalence of spontaneous type 1 electrocardiogram (ECG) was lower in the senior group (22 of 58; 37.9%) than in the younger group (64 of 123; 51.9%) (p ¼ 0.027). Among various ECG parameters, the senior group had a lower incidence of prolonged r-J intervals in V2 $90 ms than the younger group (34 of 58; 58.6% vs. 90 of 123; 73.1%, p ¼ 0.049) and day-to-day variation of Brugada ECG patterns (3 of 58; 5.2% vs. 23 of 123; 18.7%, p ¼ 0.032). During a mean follow-up period of 7.6 5.8 years, no senior patients experienced documented fatal ventricular arrhythmias, but 11 younger patients did. Kaplan-Meier analysis revealed a better prognosis in the senior group than in the younger group (log-rank, p ¼ 0.011). CONCLUSIONS Senior BrS patients, $60 years of age, had a better prognosis than those <60 years of age. Implantable cardioverter-defibrillator insertion for senior patients with BrS needs careful consideration. (J Am Coll Cardiol EP 2016;-:-–-) © 2016 by the American College of Cardiology Foundation.
B
rugada syndrome (BrS) is characterized by
in the elderly population. The mean age of patients
unique electrocardiogram (ECG) patterns on
with BrS has been reported to be in the fourth to fifth
the right precordial leads (V1 to V 3) and
decade (2–4). Brugada type 1 ECGs are observed less
increased risk of sudden cardiac death (SCD) due to
frequently in elderly patients than in the younger
ventricular fibrillation (VF) in the absence of major
patients (4). Recently, 2 studies have indicated a
structural heart disease (1). Although various risk
benign prognosis of elderly BrS patients (5,6). Those
factors for future development of VF have been pro-
studies, however, do not clarify differences in clinical
posed by large numbers of reports, no consensus
and ECG characteristics underlying prognostic factors
has been reached to predict fatal cardiac events, espe-
between the senior and younger patients. Moreover,
cially in BrS patients without a history of documented
the indication for ICDs in senior patients, according
VF or aborted SCD. The only available therapeutic
to the latest consensus statement, has not been
option is insertion of an implantable cardioverter-
verified. Because the United Nations classification
defibrillator (ICD), but the role and indication for
defined people at $60 years of age as senior, we clas-
ICD implantation remain controversial, particularly
sified BrS patients with diagnoses at $60 years of age
From the aDepartment of Cardiology, Tokyo Metropolitan Hiroo Hospital, Tokyo, Japan; bDepartment of Cardiology, Yokohama Minami Kyosai Hospital, Yokohama, Japan; cTokyo Medical and Dental University, Yushima, Tokyo, Japan; and the dTokyo Metropolitan Health and Medical Treatment Corporation, Ohkubo Hospital, Tokyo, Japan. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received January 8, 2016; revised manuscript received March 31, 2016, accepted April 7, 2016.
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ABBREVIATIONS
as the senior group and those <60 years of
cardiac magnetic resonance imaging. Acetylcholine
AND ACRONYMS
age as the younger group in our study and
provocation test was performed to exclude vaso-
investigated
spastic angina in 74 patients. ECGs for BrS were
BrS = Brugada syndrome ECG = electrocardiogram ICD = implantable cardioverter-defibrillator
SAECG = signal averaged electrocardiogram
SCD = sudden cardiac death
their
clinical
characteristics
and prognostic variables. In addition, we
classified according to the 2002 and 2005 consensus
reclassified all patients in classes of ICD indi-
reports (7,8), with or without provocation test by
cation according to the latest consensus state-
sodium-channel blockers. Patients with syncope of
ment and then evaluated the distribution and
unknown cause, family history of SCD or atrial
incidence of fatal ventricular arrhythmia dur-
fibrillation (AF; to avoid a possible risk of unexpected
ing a long-term follow-up period.
lethal ventricular arrhythmia to be provoked by sodium channel blockers) were screened by sodium
VF = ventricular fibrillation
METHODS
VT = ventricular tachycardia
channel provocation test if their ECG revealed type 2 or type 3 Brugada ECG. All baseline and drug-induced
STUDY
POPULATION. The
181
12-lead ECG records were obtained at a paper speed of
consecutive patients whose BrS was diagnosed and
25 mm/s and with amplitude of 10 mm/mV with the
followed at the Tokyo Metropolitan Hiroo Hospital
right precordial leads positioned at the 2nd, 3rd, and
from 1992 to 2014. Diagnosis of BrS was defined by the
4th intercostal spaces. All ECGs were analyzed by 3
2 consensus reports in 2002 (7) and 2005 (8). This
independent experienced electrophysiologists. Early
retrospective
was
repolarization pattern was defined in the presence of
approved by the Institutional Review Board of Tokyo
J-point elevation $1 mm in $2 contiguous inferior
Metropolitan Hiroo Hospital, Tokyo, Japan. Patients
and lateral leads of ECG, according to the 2013
were divided into 2 groups according to their age at
consensus statement (9). Fragmented QRS was
the time of diagnosis: the younger group (<60 years
defined in the presence of abnormal fragmentation
of age) and the senior group ($60 years of age).
within the QRS complex as 4 spikes in 1 or 8 spikes in
Clinical histories and 12-lead ECG findings, including
all of leads V 1, V2, and V 3 (10). Day-to-day variation in
those from leads V 1 to V3 placed at the 2nd, 3rd, or 4th
Brugada ECGs was positive if a type 1 Brugada ECG
intercostal space were accessed in all patients.
was present on one day but spontaneously dis-
observational
study
study
included
protocol
Organic heart diseases were excluded by exami-
appeared or changed to type 2 or type 3 ECG on
nations using ultrasound cardiography, coronary
another day during the follow-up period. We acquired
angiography, right and left ventriculography, and
ECGs during the initial follow-up and at each scheduled follow-up, and any unscheduled visits and dur-
F I G U R E 1 Distribution of Patients’ Ages at Diagnosis of BrS
ing any in-hospital stays. The alterations in the ECG were evaluated at rest (commonly 2 h before or after meal) and excluded the ECGs recorded with any stress (during exercise test, drug challenge test, full stomach, and in febrile illness). Significant augmentation of ST-segment elevation during recovery phase in treadmill exercise testing was defined as ST-segment amplitude increase >0.05 mV in at least 1 of leads V1 to V 3 at early recovery (1 to 4 min at recovery) compared with the baseline level (preexercise) (11). The presence of late potentials (LPs) was evaluated with a signal-averaged ECG (noise level: 0.3 V, filtered with a high-pass filter by 40 Hz). Three parameters were assessed using a computer algorithm: the filtered QRS duration (f-QRS); the rootmean-square voltage of the terminal 40 ms in the filtered QRS complex (RMS40); and the duration of low-amplitude signals, 40 mV in the terminal filtered QRS complex (LAS40). LPs were considered positive when 2 of 3 criteria (f-QRS >114 ms; RMS40 <20 mV; and LAS40 >38 ms) were met (12,13). Electrophysio-
Each column is divided by 10 years, and numbers of patients are shown on the top of each column. BrS ¼ Brugada syndrome.
logical study (EPS) findings were evaluated among 115 of 181 patients for diagnosis or risk stratification or both.
Those
patients
underwent
programmed
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Prognosis and Features of Senior Brugada Patients
electrical stimulation to assess ventricular tachycardia (VT) or VF inducibility. Our method for EPS
T A B L E 1 Comparison of Clinical Characteristic and Types of ST Elevation in the Younger
and Senior Groups
and protocol of ventricular stimulation for induction of VT/VF was described previously (14). In short, EPS
Younger Subjects (n ¼ 123)
Senior Subjects (n ¼ 58)
p Value
was performed using 3 multielectrode catheters
Age (yrs)
42.7 11
68.6 7.1
introduced percutaneously through the femoral ves-
Males (%)
113 (91.9%)
56 (96.5%)
sels. Programmed ventricular stimulation was per-
Family history of SCD (%)
26 (21.1%)
15 (25.7%)
0.479
formed with the use of a maximum of 3 ventricular
Family history of type 1 ECG (%)
5 (4.1%)
0 (0%)
0.141
extra-stimuli from the right ventricle apex and
Syncope (%)
28 (22.8%)
14 (24.1%)
0.838
outflow tract. Minimum coupling interval was effec-
SCN5A mutation (%)
2/6
0/4
-
Documented VF (%)
19 (15.4%)
5 (8.6%)
0.206
6/50 (12.0%)
3/21 (14.2%)
0.117
47 (38.2%)
26 (44.8%)
0.397 0.854
tive refractory period during single ventricular extrastimulus, 180 ms during 2 ventricular extra-stimuli,
Vasospastic angina (%) ICD implantation (%)
0.237
200 ms during 3 ventricular extra-stimuli. Patients
Inappropriate therapy (%)
12/47 (25.5%)
6/26 (23.1%)
with VF lasting for more than 30 s or who required
Spontaneous type 1 ECG (%)
64 (51.9%)
22 (37.9%)
0.027
electrical cardioversion were classified as inducible.
Drug-induced type 1 ECG (%)
59 (48.1%)
36 (62.1%)
0.027
Informed consent was obtained from all patients.
Reasons for drug provocation test
Indication for ICD implantation was determined
Documented VF (%)
7/59 (11.9%)
3/36 (8.3%)
0.842
according to the 2002 or 2008 American College
Syncope of unknown cause with type 2 or type 3 ECG (%)
17/59 (28.8%)
9/36 (25.0%)
0.867
Family history of SCD with type 2 or type 3 ECG (%)
18/59 (30.5%)
9/36 (25.0%)
0.732
AF with type 2 or type 3 ECG (%)
of
Cardiology/American
Heart
Association/Heart
Rhythm Society (ACC/AHA/HRS) guideline (15), the Japanese guideline (16), or 2013 HRS/European Heart Rhythm Association/Asia Pacific Heart Rhythm Society (HRS/EHRA/APHRS) consensus statement (9).
17/59 (28.8%)
15/36 (41.7%)
0.198
Newly developed IHD (%)
3 (2.4%)
3 (5.2%)
0.292
Coronary angiography during follow-up (%)
3 (2.4%)
7 (12.1%)
0.013
Because our study period spanned 1992 to 2014 and
Values are mean SD or n (%).
the guidelines for ICD therapy were modified several
AF ¼ atrial fibrillation; ECG ¼ electrocardiogram; ICD ¼ implantable cardioverter-defibrillator; IHD ¼ ischemic heart disease; SCD ¼ sudden cardiac death; VF ¼ ventricular fibrillation.
times during the entire period, we reclassified all patients by the indication for ICD implantation according to the latest consensus statement of the 2013 HRS/EHRA/APHRS (9). Fourteen patients were
RESULTS
registered in the Japan idiopathic ventricular fibrillation study (17). FOLLOW-UP. Patients with ICD implantation under-
went regular follow-up of the device and clinical symptoms, at least, every 3 to 4 months at our outpatient clinic. Patients without ICD implantation were followed every 6 or 12 months with a visit to our outpatient clinic for checking clinical status and examinations of resting ECG and signal averaged ECG (SAECG).
CLINICAL AND ELECTROPHYSIOLOGICAL CHARACTERISTICS OF THE 2 GROUPS. The senior group, $60 years of age,
consisted of 58 cases (32%), and the younger group, <60, was 123 cases (68%). Mean ages were 68.6 7.1 years in the former and 42.7 11 years in the latter group. The age distribution at diagnosis in all patients is shown in Figure 1. The youngest patient was 16 years of age, and the oldest was 91 years of age. In the senior group, there were 35 patients 60 years of age, 19 patients in their 70s, and 4 patients
STATISTICS. Data are mean SD or absolute values
in their 80s. In the younger group, there were
and percentages where appropriate. The chi-square
38 patients in their 50s, 39 patients in their 40s (the
test and Fisher exact test were used to compare cat-
highest number of cases), 29 patients in their 30s, and
egorical variables. Continuous variables between the
17 patients less than 29 years of age.
2 groups were analyzed using the unpaired Student t
Clinical characteristics of the 2 groups are shown in
test or Mann-Whitney U test as appropriate. Survival
Table 1. The proportion of patients with spontaneous
curves were constructed by using the Kaplan-Meier
type 1 ECG was lower, and that of drug-induced type 1
method and compared using the log-rank test. Uni-
was higher in the senior group than in the younger
variate Cox proportional hazards models were used
group. Other clinical parameters, except for their
to assess the effect of each variable on VF during
ages, were not significantly different between the 2
follow-up. A p value <0.05 was considered sta-
groups. Male predominance was similar in the 2
tistically significant. Statistical analyses were con-
groups. Rates of patients with history of syncope,
ducted using SPSS version 19.0 software (SPSS Inc.,
documented VF, and vasospastic angina were not
Chicago, Illinois).
different. There were 5 patients in the younger group
Kitamura et al.
4
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Prognosis and Features of Senior Brugada Patients
T A B L E 2 Comparison of ECG Findings and Electrophysiological Parameters Between
Younger and Senior Groups
The number of ECGs recorded per patient per year was 4.2 2.8/patient/year. P-wave duration, PQ interval, QRS duration, and QTc intervals were not
Younger Group (n ¼ 123)
Senior Group (n ¼ 58)
p Value
P-wave duration, ms
107.2 16.0
103.1 14.3
0.096
significantly higher ratios in the younger group than
PR interval, ms
171.3 28.7
172.4 24.6
0.794
those in the senior group. However, there were no
QRS duration, ms
113.5 16.2
110.9 17.5
0.317
differences in percentages of patients with frag-
QTc interval, ms
413.3 27.6
416.5 25.7
0.455
mented QRS, inferolateral ER pattern, AF, positive
90 (73.1%)
34 (58.6 %)
0.049
100.0 14.5
96.9 18.1
LP by SAECG, and positive T-wave alternans in the
r-J interval in V2, ms
0.212
Fragmented QRS (%)
19 (15.4%)
6 (10.3%)
0.353
Inferior ERP (%)
14 (11.4%)
11 (19.0%)
0.168
Lateral ERP (%)
9 (7.3%)
3 (5.2%)
0.484
LONG-TERM FOLLOW-UP. After a mean follow-up
Infero-lateral ERP (%)
4 (3.3%)
1 (1.7%)
0.481
period of 7.6 5.8 years (91 69 months), 11 pa-
Day-to-day variation (%)
23 (18.7%)
3 (5.2%)
0.032
tients developed VT/VF episodes (cardiac events),
Documented atrial fibrillation (%)
27 (21.9%)
16 (27.7%)
0.456
and all of the events belonged to the younger group
Positive LP by SAECG (%)
90 (73.1%)
35 (60.3%)
0.082
but none to the senior group. Figure 2 shows age
Augmented ST-segment elevation during recovery after exercise (%)
3/111 (2.7%)
1/52 (1.9%)
0.542
Induced VF (%)
56/74 (75.7%)
35/41 (85.4%)
0.057
recurrences during follow-up period (Figure 2B).
VF induction by single or double extra-stimuli (%)
37/74 (50.0%)
22/41 (53.7%)
0.943
Details of senior patients with VF events at diagnosis
VF induction by triple extra-stimuli (%)
37/74 (50.0%)
19/41 (46.3%)
0.943
r-J interval in V2 $90 ms (%)
different among them. Patients showing r-J interval $90 ms and day-to-day variation of type 1 ECG had
ECG
2 groups.
distributions of VF events at or before the age of diagnosis (VF history) (Figure 2A) and of VT/VF
EPS
are shown in Table 3. The patient’s age at VF history ranged between 19 and 68 years of age, and the range
47.0 10.2
43.9 7.7
0.109
RVA ERP, ms
237.2 20.0
216.0 25.1
0.133
of age at VT/VF recurrences during follow-up period
RVOT ERP, ms
240.0 20.6
245.3 18.7
0.349
was between 19 and 49 years of age. No patients over
HV interval, ms
50 years of age had recurrences, despite history of VF Values are mean SD, n (%), or n/N (%). EPS ¼ electrophysiological studies; ERP ¼ effective refractory period; LP ¼ late potential; RVA ¼ right ventricular apex; RVOT ¼ right ventricular outflow tract; SAECG ¼ signal averaged electrocardiogram; TWA ¼ T-wave alternans.
in 7 patients. Kaplan-Meier analysis revealed a better prognosis for the senior group than the younger group (log-rank p ¼ 0.011) (Figure 3). Univariate Cox regression analysis of each risk factor is shown in
who had a family history of BrS, but all patients in the
Table 4. Patients younger than 60 years of age (p ¼
senior group were probands without family history.
0.042; hazard ratio [HR]: 2.82; 95% confidence inter-
No differences were noted between the 2 groups with
val [CI]: 1.695 to 50.74), documented VF (p < 0.01;
regard to incidence of ICD implantation and inap-
HR: 22.1; 95% CI: 10.22 to 54.33), ER pattern (p < 0.01;
propriate ICD therapy. During follow-up, coronary
HR: 17.43; 95% CI: 4.597 to 66.1), fragmented QRS
angiography was required to identify the cause of
(p < 0.01; HR: 8.574; 95% CI: 2.614 to 28.12), and day-
chest pain in 10 patients. Six patients developed de
to-day variations of type 1 ECG (p < 0.01; HR: 9.617;
novo coronary stenosis, which was treated by percu-
95% CI: 2.43 to 38.06) had a correlation with VF
taneous coronary intervention (mean: 60 11 years of
recurrence. In addition, we also evaluated combina-
age; range: 42 to 74 years). The mean duration from
tions of risk factors for prediction of VF recurrences
diagnosis of BrS to diagnosis of newly developed
(Table 4). Although several risk factors could not
coronary stenosis was 10.5 6.2 years (range: 3.8 to
singly predict VF events, combinations of age <60
16.5 years). Three patients underwent coronary
years and risk factors (syncope, spontaneous type 1
angiography to determine the cause of VF and
ECG, induced VF, VF induction by single or double
appropriate therapy; however, there was no case of
extra-stimuli) might predict a VF event. Five combi-
newly developed coronary stenosis. Other patients
nations with highest HR among all combinations are
with recurrence of VF during follow-up were also
described at the bottom of Table 4. In addition, we
screened for development of ischemic heart disease
evaluated alteration, especially attenuation with age,
by using noninvasive examinations. No positive
in several parameters during follow-up. There were
findings of ischemic events by exercise test or
no changes in r-J interval >90 and fragmented QRS
myocardial perfusion scintigraphy were detected
during follow-up. On the other hand, 2 of 42 patients
among other patients.
had day-to-day variations in ER pattern (ER was not
Parameters of various ECG findings and electro-
documented regularly). Six of 125 patients had a
physiological studies of 2 groups are shown in Table 2.
change from positive to negative LP. According to
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Kitamura et al.
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Prognosis and Features of Senior Brugada Patients
F I G U R E 2 VF History and VF Events
(A) Presence and absence of VF history at each age group of diagnosis. (B) VF events during follow-up in each age group. Please note that no VF events occurred at ages older than 50 years. VF ¼ ventricular fibrillation.
the definition of day-to-day variations in type 1
patients in Class 2b. Among senior patients with ICD,
ECG, spontaneous alterations from type 1 to type 2
there were 5 patients in Class 1, 3 patients in Class 2a,
or 3 were observed in 14 of 26 cases. Among the
and 19 patients in Class 2b.
14 patients, 10 (of 26) had their ECGs reidentified
COMPLICATIONS ASSOCIATED WITH THE ICD. Table 5
as spontaneous type 1 ECG. There were only 4 pa-
presents details of complications such as inappro-
tients with type 1 ECG who alternated to persistent
priate shocks and other ICD complications. A total of
type 2 or 3 ECG. The prevalence of attenuating LP
18 patients with ICD implantation had inappropriate
and day-to-day variations was low (LP: 6 of 125
therapy (18 of 73; 24.7%). The cause was AF in 10
[4.8%]; day-to-day variation in type 1 ECG: 4 of
cases, paroxysmal supraventricular tachycardia in 4,
26 [15.3%]).
lead fractures in 2, sinus tachycardia in 1, and T-wave
ICD INDICATION. Figure 4A shows the number of ICD
oversensing in 1. The incidence of inappropriate
indication category modified to the latest guideline
therapy due to AF was not statistically different be-
among all patients and those with implanted ICD.
tween the 2 groups. Other complications (14 events)
There were 24 of 181 cases (13.2%) classified as Class 1;
were found in 14 patients who received ICD (14 of 73;
21 of 181 (11.6%) as Class 2a; 86 of 181 (47.5%) as Class
19.2% [10 lead fractures, 3 ICD infections, and 1 he-
2b; and 5 as Class 3 and 45 as others (e.g., sponta-
matoma at ICD replacement]). Kaplan-Meier analyses
neous type 1 ECG and family history of SCD) in all
of all complications and lead fracture are shown
patients (Figure 4A, left bar). Regarding the numbers
in Figure 5.
of patients who received ICD implantation (Figure 4A, right bar), 23 patients were in Class 1, 6 in Class 2a,
DISCUSSION
and 44 in Class 2b. No patients in Class 3 or other received ICD implantation. Figure 4B compares
CLINICAL CHARACTERISTICS OF SENIOR PATIENTS
patient numbers classified by ICD indication and
WITH BRUGADA SYNDROME IN COMPARISON TO
patients with implanted ICDs between the younger
THOSE IN THE YOUNGER GROUP. BrS is generally
and senior groups. In the senior group, there were
characterized by male predominance with a middle-
5 patients in Class 1, 6 patients in Class 2a, and 32
aged onset of cardiac events or diagnosis at 40 to
5
Kitamura et al.
JACC: CLINICAL ELECTROPHYSIOLOGY VOL.
AF ¼ atrial fibrillation; ECG ¼ (12-lead) electrocardiogram; ER ¼ early repolarization; ERP ¼ effective refractory period; FH ¼ family history; ICD ¼ implantable cardioverter-defibrillator; IHD ¼ ischemic heart disease; LP ¼ late potential; RVA ¼ right ventricular apex; RVOT ¼ right ventricular out; SAECG ¼ signal-averaged ECG; SCD ¼ sudden cardiac death; VF ¼ ventricular fibrillation.
*Plus/minus (/þ) signs indicate negative or positive in each variable.
0/5 (0%) 0/5 (0%) 1/5 (20%) 1/5 (20%) 236 15 220 8.9 42 7.6 3/5 (60%) 2/5 (40%) 5/5 (100%) 3/5 (60%) 1/5 (20%) 0/5 (0%)
400/240 400/230 42 þ þ þ 5
þ 400/240 400/210 35 þ þ þ 4
400/220 400/210 50 þ þ þ 3
þ
400/220
400/260 400/220
400/230 48
40 þ
þ
þ
þ
þ
2
1
Hematoma at Replacement ICD Infection Lead Fracture Newly Developed IHD RVOT ERP, ms RVA ERP, ms HV Interval, ms VF Induction by Triple VF Induction by Single or Double VF Inducibility Day-to-Day Variations of Brugada ECG
Males
64.8 1.9 5/5 (100%)
63 5
Males 64 4
Males 64 3
Males 65
68 1
2
Males
AF
Positive LP by SAECG
1/5 (20%) 0/5 (0%)
1/5 (20%) 412 9.5
412 100
102 7.4 172 15
189
1/5 (20%) 0/5 (0%)
þ
2/5 (40%) 5/5 (100%)
þ
5/5 (100%) 1/5 (20%)
1/5 (20%)
þ
403 106 155 þ (lead fracture) þ þ þ
407 99 172 þ þ þ
þ 412
428 123
100 162
185
þ
þ þ
þ
þ
þ
QTc r-J Interval in Fragmented Interval, ms V2 >90 ms* QRS* ER Pattern* P-Wave QRS Duration, ms Duration, ms Inappropriate Therapy* Appropriate Therapy* ICD Spontaneous. Type 1 ECG VF Survivor Syncope FH of SCD Sex Age, y Patient #
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Prognosis and Features of Senior Brugada Patients
T A B L E 3 Patient Characteristics of 5 Senior Patients With Brugada Syndrome Who Were Resuscitated From Ventricular Fibrillation at Diagnosis
6
50 years of age, or both. There are, however, certain numbers of patients in whom BrS is diagnosed at $60 years of age in the clinical setting. In the present study, 32% (58 of 181 subjects) of our BrS cohort represented the senior group. Recent reports indicated that the senior BrS patients had benign prognosis compared with the younger age populations in general BrS cohort as well as in high-risk patients (5,6). Our study also confirmed their results with a benign prognosis of the senior group $60 years of age. Furthermore, the results indicated certain clinical characteristics suggestive of better prognostic signs that were not indicated in the previous reports. Many clinical variables have been proposed as risk factors with which to predict cardiac events in patients with BrS. Among these variables, symptomatic patients including a history of VT/VF, syncope of unknown origin, and spontaneous type 1 ECG were assumed to be important predictors (2). Furthermore, whether other symptoms or clinical signs could be applicable to predict cardiac events in senior BrS patients is not known. Conte et al. (5) reported a better prognosis of the senior BrS patients with significantly less frequent prevalence in family history of SCD than in the younger patients. Our study did not show a difference in prevalence of family history of SCD between the senior and younger groups. The discrepant results may be due to differences in the subjects’ backgrounds, as their study population included a relatively high prevalence of family members of BrS (49% in 58 cases), and our cases represented 21.1% to 25.7% of the family history in both groups. The report by Conte et al. (5) also indicated fewer numbers of patients with induced VT/VF during programmed ventricular stimulation in the senior group than the younger group, but we could not observe a difference in the ratio of induced VT/VF between the 2 groups. As to the induced VT/VF by EPS, its positive predictive value for cardiac events has been in intense dispute and a consensus has been reached (2,3,9,18–20). Different outcomes by EPS might be attributed to differences in stimulation protocol, but a prospective study by a fixed stimulation protocol could not demonstrate a predictive value of VT/VF induction for cardiac events (20). In the present study, spontaneous type 1 ECG and day-to-day variations in Brugada ECG patterns were significantly less prevalent in the senior group than in the younger group. Type 1 ECG and day-to day variations of Brugada ECG pattern are thought to be risks factor for fatal ventricular arrhythmia depending on different ethnic groups and population of the study subjects, values, and timing of ECG
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7
Prognosis and Features of Senior Brugada Patients
F I G U R E 3 Kaplan-Meier Curves of Ventricular Fibrillation in
T A B L E 4 Results of Univariate Cox Regression Analysis of Risk Factors and Combination
the Senior and Younger Groups During Follow-Up Period
of Risk Factors Hazard Ratio
95% Confidence Interval
p Value
Documented VF
Variable
22.1
10.22–54.33
<0.01
Syncope
2.89
Spontaneous type 1 ECG
2.94
0.78–11.01
0.111
Family history of SCD
0.32
0.001–11.18
0.249
Male
22.1
0.022–102.5
0.579
Age <60 yrs
2.82
1.695–50.74
0.042
ER pattern
17.43
4.597–66.1
<0.01
Fragmented QRS
8.574
2.614–28.12
<0.01
0.884–9.5
0.079
<0.01
Day-to-day variation of type 1 ECG
9.617
2.43–38.06
r-J interval $90 ms
4.626
0.592–36.141
0.144
Positive LP by SAECG
0.771
0.226–2.636
0.679
Induced VF during EPS
2.599
0.333–20.31
0.362
VF induction by single or double extra-stimuli
4.235
0.51–35.19
0.181
RVA ERP <200 ms
0.833
0.162–4.295
0.827
RVOT ERP <200 ms
2.837
0.572–14.07
0.202
Combined risk factors
recordings, and selections of ECG lead placements at different intercostal spaces (21–23). Therefore, the lower frequency of those findings might contribute to a better prognosis in the senior group. Among other conditions supposed to predict cardiac events, there were fewer patients with r-J interval >90 ms (17) in the senior group than in the younger group. However, other parameters including positive LP
VF and age <60 yrs
22.18
12.13–82.4
<0.01
Syncope and age <60 yrs
4.918
1.548–15.623
0.007
Spontaneous type 1 ECG and age <60 yrs
4.09
1.229–13.62
0.022
ER pattern and age <60 yrs
20.88
5.602–77.833
<0.01
Fragmented QRS and age <60 yrs
10.74
3.457–33.37
<0.01
Day-to-day variation of type 1 ECG and age <60 yrs
9.347
2.614–33.42
<0.01
Positive LP and age <60 yrs
1.511
0.479–4.762
0.481
Induced VF and age <60 yrs
10.7
1.364–83.32
0.024
VF induction by single or double extra-stimuli and age <60 yrs
11.64
RVOT ERP <200 ms and age <60 yrs
0.955
1.4–96.8 0.193–4.733
0.023 0.955
Five combined risk factors with the highest hazard ratios VF and fragmented QRS
55.2
16.25–98.2
<0.01
VF and day-to-day variation of type 1 ECG
26.5
7.954–88.34
<0.01
by SAECG (12,24), fragmented QRS (10), history of
VF and ER pattern
25.0
7.556–82.7
<0.01
AF (17,25,26), ER patterns (22,27,28), augmented ST
VF and age <60 yrs
22.18
12.13–82.4
<0.01
elevation during recovery phase after exercise (11),
ER pattern and age <60 yrs
20.88
5.602–77.833
<0.01
and ventricular effective refractory period <200 ms (20) were not different between the 2 groups.
Abbreviations as in Tables 1 and 2.
POSSIBLE REASONS FOR BETTER PROGNOSIS IN SENIOR PATIENTS
spontaneous
WITH BRUGADA SYNDROME
observed in the senior group with better prognosis
type
1
ECG
were
less
frequently
might be explained by decreased hormonal influence Our results indicated that BrS patients $60 years of
of testosterone with age (31,32). In addition, a pro-
age had a better prognosis than those <60 years of
longed r-J interval of $90 ms, which might indicate
age over 7-year follow-up, confirming the results
conduction abnormality and day-to-day variations of
of previous reports (5,6). Five patients with a history
Brugada ECG patterns, which might indicate auto-
of VF at the age of diagnosis older than 60 years of age
nomic tone disorder as markers of the proposed risk
did not experience any recurrence of VF events dur-
(13,29), were less frequent in the senior group.
ing the follow-up (11.7 3.2 years). Furthermore,
Moreover, attenuation or disappearance of several
patients including the younger group older than 50
risk factors with age during follow-up were observed
years of age had no recurrences of VF. As to the
in a small number of patients. Therefore, the true
mechanism of ST-segment elevation and develop-
reason why the senior patients showed a better
ment of VT, repolarization theory (29) and depolari-
prognosis than the younger group <60 years of age
zation theory (30) have been proposed without
was not clarified by the present study, and further
reaching
a
firm
consensus.
The
results
that
exploration should be continued. In addition, in our
8
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Prognosis and Features of Senior Brugada Patients
F I G U R E 4 Number of Patients in Each Class of ICD Indication and Actual Numbers of Patients With ICD
(A) Graphs show numbers of each class of ICD indication in all cases (left) and numbers of patients with ICD (ICDþ) (right). (B) Graphs present numbers of each class of ICD indication in all cases and numbers of ICD(þ) in the younger group (left) and those in the senior group (right). ICD ¼ implantable cardioverter-defibrillator.
case series, there were no VF events after 5-year
AGE AS A PROGNOSTIC FACTOR. A number of clin-
follow-up, contrary to our expectations. We antici-
ical prognostic factors have been shown to predict VF
pated that there would be events in the late period of
in patients with BrS, as mentioned above. In our case
follow-up, as reported in other studies (18,20).
series, younger patients, <60 years of age, had worse
Therefore, we also expected that there would be pa-
prognosis than senior patients based on the log-rank
tients with VF events during later follow-up period
test and univariate Cox regression analysis. In the
in future. One possible reason could be that the
Cox regression model, documented VF, fragmented
patients had more time to receive education at
QRS, ER pattern, and day-to-day variation in type 1
outpatient clinics to avoid being exposed to circum-
ECG could also predict VF events. Moreover, although
stances such as high-grade fever, taking medication
several risk factors (syncope, spontaneous type 1
worsening BrS ECG (Na channel blockers, calcium
ECG, induced VF, VF induction mode single or dou-
channel blockers, and so forth) (33,34), or hyper-
ble) do not alone statistically predict VF events,
activated parasympathetic tone as the follow-up
combinations of age <60 years and those factors
duration became longer. However, we do not have
(syncope, spontaneous type 1 ECG, induced VF, VF
evidence or data in support of this.
induction mode single or double) may predict VF
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Prognosis and Features of Senior Brugada Patients
events. Recently, a combination of risk factors has been proposed to predict VF in patients with BrS
T A B L E 5 Inappropriate Therapy and Complication During Follow-Up
in 2 Groups
(35,36). Age <60 years might be helpful not only as a simple prognostic factor but also as one of the reasonable risk factors in combination with other risk
Inappropriate therapy (%)
Younger Group (n ¼ 47)
Senior Group (n ¼ 26)
12/47 (25.5%)
6/26 (23.1%)
6/12 (50.0%)
4/6 (66.7%)
0.86 0.536
p Value
0.854
factors to stratify VF recurrence risk. However, we
AF (%)
could not conduct a multivariate analysis because of
Other SVTs (%)
3/12 (25.0%)
1/6 (3.9%)
an insufficient number of VF events. Therefore, a
Lead fracture (as cause of inappropriate therapy) (%)
2/12 (4.3%)
0/6 (0%)
-
0/6 (0%)
-
study with a larger sample size with enough VF events to conduct multivariate analysis is warranted to confirm the results.
Sinus tachycardia (%) T-wave oversensing (%) Other complications (%)
ICD INDICATION FOR THE SENIOR PATIENTS WITH BRUGADA SYNDROME. In the present study, all
patients were reclassified by ICD indication according to the latest consensus statement (9). Figure 4 shows the distribution of reclassified patients. Pa-
1/12 (2.1%) 0/47 (0%) 10/47 (21.3%)
1/26 (3.9%)
-
4/26 (15.4%)
0.224
Lead fracture (%)
7/10 (70.0%)
3/4 (75.0%)
0.64
ICD infection (%)
2/10 (20.0%)
1/4 (25.0%)
0.595
Hematoma at implantation or replacement of ICD (%)
1/10 (10.0%)
0/6 (0%)
Values are n/N (%). SVT ¼ supraventricular tachycardia; other abbreviations as in Tables 1 and 2.
tients with ICD insertion were reclassified into class 1, 2a, or 2b, but none in class 3 or other. There were 5 patients reclassified into class 1, and 6 patients
the implantation (6). Therefore, the risk stratifica-
into class 2a in senior group. There was no VT/VF in
tion of cardiac events and a better prognosis of the
those
follow-up
senior patients must be carefully considered for the
period. The indication for ICD implantation has
selection of ICD implantation. However, it should
not been clarified in senior BrS patients. In the
be emphasized that 5 senior patients in their 60s
consensus statements for BrS (9), a specific con-
already had VF episodes at the time of diagnosis in
sideration of ICD implantation for senior BrS pa-
the present study. Results further indicate that pa-
tients was not described. Although ICD implantation
tients with BrS over 60 years of age have the po-
is supposed to be the only therapeutic means to
tential to develop VF and that ICD indication should
protect against SCD at the present time, there are
not be avoided simply because of advanced age at
factors associated with device complications after
the time of diagnosis; the decision should be made
patients
during
the
long-term
F I G U R E 5 ICD Complications
Kaplan-Meier curves of all ICD complications (A) and lead fractures (B) during follow-up (8.2 6.8 years). The incidence of ICD complication and lead fracture per 73 cases increased over time. Abbreviations as in Figure 4.
-
9
10
Kitamura et al.
JACC: CLINICAL ELECTROPHYSIOLOGY VOL.
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Prognosis and Features of Senior Brugada Patients
by weighing the risks and benefits of implantation in each individual.
might have overestimated the impact of those risk factors, and the results in Table 4 should be inter-
COMPLICATIONS ASSOCIATED WITH THE ICD. In
the present study, there were no statistical differences between the 2 groups in the prevalence of total number of inappropriate therapies or inappropriate therapy due to AF and other supraventricular tachycardias (SVT). However, during the follow-up period, complications or lead fracture incidence gradually increased, which is a finding in line with that of a previous study (6). Kamakura et al. (6) reported that numbers of SVT and inappropriate shocks increased with age. In our study, this did not achieve statistical significance; however, the prevalence of inappropriate therapy due to AF was slightly higher in the senior group than in the younger group. Therefore, considering the increasing accumulation of complications and inappropriate therapy due to SVT including AF in senior patients, careful decision making for ICD implantation may be necessary in
preted carefully. Moreover, because a multivariate analysis needs at least 10 events per risk factor, we could not conduct a multivariate Cox regression analysis to confirm the independence of each risk factor. A large-scale prospective study is needed to confirm these results and to clarify the mechanism.
CONCLUSIONS Senior BrS patients $60 years of age at diagnosis seem to have a better prognosis than younger patients. ICD implantations for BrS patients $60 years of age should be carefully evaluated. REPRINT REQUESTS AND CORRESPONDENCE: Dr.
Takeshi Kitamura, Department of Cardiology, Tokyo Metropolitan Hiroo Hospital, 2-34-10 Ebisu, Shibuyaku, Tokyo, Japan. E-mail: [email protected].
senior patients with BrS, particularly in patients with PERSPECTIVES
Class 2b indication. STUDY LIMITATIONS. Our study has several limita-
tions: it is a single-center study with retrospective analysis with heterogeneous clinical characteristics. The numbers of the study subjects were rather small. In addition, a direct correlation between cardiac events during follow-up and the positive findings (i.e., type 1 ECG, day-to-day variation, or prolonged R-J interval) was not confirmed. Furthermore, there were only 11 events during the follow-up period in the present study, which contributed to several risk factors with large hazard ratios and large confidence
COMPETENCY IN MEDICAL KNOWLEDGE: Senior BrS patients $60 years of age at diagnosis have a better prognosis than the younger age group. ICD implantations for BrS patients $60 years of age should be carefully evaluated. TRANSLATIONAL OUTLOOK: A study with a larger population and a longer follow-up period, specifically a span lasting until the end of life in senior patients, is needed.
intervals in Cox regression analysis. Therefore, we
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KEY WORDS Brugada syndrome, implantable cardioverter-defibrillator, ventricular fibrillation
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