European Heart Journal (2004) 25, 1405–1411
Clinical research
Low incidence of cardiac events with
b-blocking therapy in children with long QT syndrome
a
Cardiologie Pédiatrique, Hôpital Necker-Enfants-Malades, 149 Rue de Sevres, 75015 Paris Cedex, Paris, France
Cardiologie, Hôpital Lariboisière, Paris, France
c
INSERM U582, Institut de Myologie, Hôpital Pitié-Salpêtrière, Paris, France
d
Cardiologie Pédiatrique, Hôpital Robert Debré, Paris, France
e
Biochimie, Hôpital Pitié-Salpêtrière Paris
f
Cardiologie Pédiatrique, Château des Côtes, Les Loges en Josas, France
b
Received 4 November 2003; revised 19 May 2004; accepted 10 June 2004
KEYWORDS
Aims To evaluate the effect of beta-blockers in children with long QT syndrome
(LQTS) we reviewed the outcome of 122 patients (pts).
Methods LQTS was diagnosed in 24 neonates and in 98 pts aged 0.5–15 years. Diagnosis was made because of syncope in 51 pts, bradycardia in 10 neonates and family
history in 61 pts. The longest QTc ranged from 400 to 700 ms. Thirteen pts had 2:1
atrioventricular block and/or ventricular arrhythmias. Screening for mutations was
performed in 118 pts. All children were treated with beta-blockers, annually checked
by exercise testing and/or 24 h ECG monitoring.
Results Four pts died. Survivors were followed-up for 1–18 years (7.5 ± 5.3 years).
Five neonates and 3 older pts received a prophylactic pacemaker (1 death) so that only
111/122 pts survived and were followed-up with beta-blockers alone. None of them
died and five experienced a non-fatal cardiac event. There was no cardiac event
among pts who were diagnosed because of familial history and among symptomatic
KCNQ1 pts who were effectively treated with beta-blockers.
Conclusion The outcome of children with LQTS under effective beta-blockers is
favourable. Persisting arrhythmia or symptoms despite beta-blockers should aim at
identifying other genotypes than KCNQ1.
c 2004 The European Society of Cardiology. Published by Elsevier Ltd. All rights
reserved.
Long QT syndrome;
Sudden death;
Beta-blockers;
Paediatric arrhythmia
Introduction
The long QT syndrome (LQTS) is a familial disease characterised by prolonged and abnormal repolarisation, associated with a high risk of ventricular arrhythmias, syncope
* Corresponding author. Tel.: +33-142-73-84-86.
E-mail address: [email protected] (E. Villain).
and sudden death. Recent molecular genetic studies have
shown that LQTS is due to mutations in genes encoding
cardiac ion channels.1 As cardiac events are most often
triggered by stress, emotion and acute arousal, betablockers are considered the treatment of choice in LQTS
patients.2 Although beta-blockers have been shown to significantly reduce cardiac events, various studies have
raised controversies on the adequate therapeutic
strategies to be applied to patients with LQTS to prevent
0195-668X/$ - see front matter c 2004 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.ehj.2004.06.016
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E. Villaina,*, I. Denjoyb,c,d, J.M. Lupoglazoffc,d, P. Guicheneyc, B. Hainquee
V. Lucetf, D. Bonneta
1406
E. Villain et al.
potentially fatal cardiac events.3–5 However, data from
the International Long QT Registry may be inaccurate,
due to information gathered and transmitted from many
centres in which management of patients is in essence heterogeneous.4 In this study, we sought to determine if betablockers are sufficient for secondary, as well as primary,
prevention of cardiac events in children with LQTS. We
therefore retrospectively evaluated our experience of
LQTS in a series of 122 children treated with beta-blockers
with a standardised follow-up.
Methods
Patients
Table 1 Clinical data of LQTS patients
Group 1: symptomatic
Group 2: familial screening
N
Sex
61
35 M, 26 F
61
25 M, 36 F
Symptoms
44 syncope, 7 cardiac arrest
4 AVB, 6 sinus bradycardia
0
Age
18 neonates
43 pts: 0.5–15 years
m: 7.2 ± 3.8, M: 7 years
8 neonates
43 pts: 0.3–14 years
m: 6 ± 3.7, M: 5 years
QTc
420–700 ms
m: 510 ± 62, M: 500 ms
4 pts
27 pts
400–574 ms
m: 469 ± 31, M: 470 ms
11 pts
8 pts
30
13
1
4 homozygous: JLN, HERG + KCNQ1, KCNQ1 · 2, SCN5A · 2
31
23
1
1 homozygous: JLN
Risk
Low
Intermediate
High
18
2
35
39
10
8
b-Alone
Cardiac events
51/61
5
60/61
0
<450 ms
>500 ms
Gene
KCNQ1
HERG
SCN5A
AVB: atrioventricular block, b-: beta-blockers, F: female, JLN: Jevell Lange Nielsen, M: male, pts: patients.
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The study population included 122 children, who were diagnosed
with LQTS between 1984 and 2002. Diagnosis was made in the
first month of life in 26 patients and episodes of bradycardia
had been documented during routine in utero screening in seven
of them. In the other children, age at diagnosis ranged from 5
months to 15 years, mean (SD) 6.4 (3.7) years, median: 6 years.
Sixty-one patients including 35 males and 26 females were
symptomatic (Table 1, group 1): 51 had experienced non-fatal
cardiac events, syncope in 44 cases and cardiac arrest requiring
resuscitation in seven cases; the other 10 had been referred for
neonatal slow heart rate due to sinus bradycardia in six cases
and 2:1 atrioventricular (AV) block in four cases. Age at diagnosis was less than one month in 18/61 and ranged from 0.5 to 15
years, mean (SD) 7.2 (3.8) years, median: 7 years (n = 43) in the
rest of this group. Another group of 61 patients, including 25
males and 36 females, had no symptoms and were diagnosed after systematic familial screening (Table 1, group 2). Eight were
neonates and age at diagnosis ranged from 0.3 to 14 years, mean
(SD) 6 (3.7) years, median 5 years for the others.
The QT interval was measured prior to therapy in lead II (lead
I or III if it could not be measured in lead II) from the 12-lead
ECG during stable sinus rhythm and corrected by using Bazett’s
formula. At the time of diagnosis, the longest corrected QT
(QTc) interval ranged from 400 to 700 ms, mean (SD) 495 (59)
ms, median: 480 ms. QTc was longer in symptomatic compared
to asymptomatic patients (510 (62) ms versus 469 (31) ms, respectively; p = 0.009). Fifteen children had a QTc < 450 ms6 of
which four were symptomatic and 11 asymptomatic. Diagnosis
of LQTS was confirmed by molecular biology in all 15 cases.
Thirteen symptomatic patients had documented ventricular
arrhythmias at the time of diagnosis. Nine neonates had episodes of partial AV-block, mostly 2:1, and intermittent bundle
branch block, with torsades de pointes and/or ventricular tachycardia in 5 (Fig. 1) and with premature ventricular beats in one.
Two older children had 2:1 AV-block on the ECG recorded after
an initial syncope. Finally, two patients had episodes of torsades
de pointes during permanent ECG-monitoring while they were in
hospital for non-cardiological reasons (orthopaedic operation
and ventilatory support in a premature baby).
Screening for mutations in KCNQ1, HERG and SCN5A was performed in 118/122 children.
Children were characterised as high risk, intermediate and
low, taking in account QTc value, sex, and genotype when available, according to the stratification proposed in the reference.7
Low incidence of cardiac events with b-blocking therapy
1407
Beta-blocking treatment
All children were treated with beta-blockers, with standardised doses and follow-up. The choice of the drug was made
according to age, weight and body surface area and treatment was started during hospitalisation with continuous
monitoring in all neonates and in the symptomatic group.
Nadolol (50 mg/m2 body surface area/day, in two doses)
was given to 74 patients, propranolol to 30 (3–5 mg/kg/
day in three to four doses), acebutolol to 10 (10 mg/kg/
day in three doses). In patients diagnosed because of family
history, atenolol was given in three cases (50 mg/day) and
bisoprolol in five others (10 mg/day). Temporary pacing was
performed in 6/9 neonates who had partial AV-block with a
ventricular rate of 120 beats per minute (bpm) combined
with beta-blocking treatment, because of poor clinical tolerance at admission. Patients were only discharged when
they had a stable cardiac rhythm, with no arrhythmia,
and a limited maximum heart rate indicating effective beta-blockade. Beta-blocker treatment was considered effective if the maximum heart rate did not exceed 150 bpm
in patients less than 2 years and 130 bpm in children and
teenagers.
Close follow-up was performed every 6–12 months in three
institutions in Paris: Necker Enfants-Malades, Robert Debré
and Lariboisière. Controls relied on clinical events and 12-lead
ECG. Twenty-four hour ECG monitoring and/or exercise testing were performed at least once a year. Exercise testing
was performed by treadmill or by bicycle; when sufficient
activity for age was not obtained, due to poor compliance
or insufficient graded test, effective beta-blockade was assessed on 24-h Holter monitoring, showing a flattened heart
rate curve with limited maximal heart rate. When the maximum heart rate was found to be higher than the maximum accepted value for age, patients were hospitalised; the
treatment was given under medical control, 24-h Holter monitoring was checked again and beta-blocker dosage was increased if necessary.
Statistics
All statistical analyses were done using StatView SE software.
Data were expressed as means ± SD or medians (ranges). Univariate comparison of parameters between groups was performed
by ANOVA for quantitative parameters with an unpaired t test
and by the v2 test for qualitative parameters. The cumulative
probability of a first cardiac event during follow-up were determined in the population of patients receiving beta-blockers only
and in each genetic subgroup by means of the life-table method
of Kaplan–Meier, and results were compared with the use of the
log-rank test. Values of p < 005 were considered statistically
significant.
Results
Genotype
A heterozygous mutation was identified in KCNQ1 in 61
(51.2%) patients, in HERG in 36 (30.5%) patients and in
SCN5A in two (1.7%). Interestingly, five (4.2%) patients
had two mutations, each one being inherited from one
parent (Table 1). No mutation was identified in the 14 remaining patients so far. Mutations were found in 48/61
symptomatic patients and in 56/61 asymptomatic
patients diagnosed because of family history, without
any difference of distribution of mutations in KCNQ1
(Table 1).
Risk stratification
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Fig. 1 ECG tracings of a neonate with HERG mutation (DI): (A) second degree atrioventricular block with intermittent bundle branch block; (B) 2:1 AV
block with narrow QRS; (C) ventricular arrhythmia.
Death
Death
Death
Death
10
1.5
10
9
4,5
8
3
7
12
9
9.5
11
KCNQ1 + HERG
HERG
SCN5A
KCNQ1 · 2
SCN5A · 2
HERG
KCNQ1 · 2
HERG
HERG
HERG
N
N
P,
P,
P,
P,
P,
P
N
N
N
N
N
N
P
P,
pacing
pacing
pacing
pacing
pacing
pacing
Sudden death
Car accident
2:1 AVB
2:1 AVB
2:1 AVB
2:1 AVB
2:1 AVB
2:1 AVB
T-alternans (holter)
AV-dissociation (holter)
2:1 AVB (holter)
Syncope
Syncope AV-dissociation (holter)
Syncope (TDP)
Syncope (TDP)
Syncope (TDP)
Stopped treatment
N
Died 9 days
PM (3 days) P
PM (11 days) N
PM (3 days) P
PM (3 days) N
PM (9 days) N
PM (3 yrs) N
PM (7 yrs) N
PM (6 yrs) N
PM (14 yrs) N
PM (7 yrs) N
S (8 yrs) N
PM (8 yrs) ICD (9 yrs) N
PM (7 yrs) S (9 yrs) N
Gene
1st treat.
Event
Two neonates died before hospital discharge. One patient died at 9 days of sudden AV-block, three days after
the femoral pacing lead had been removed because of
apparent recovery of a stable 1:1 sinus rhythm under propranonol (pt 3). Another one (pt 4) died of infection after
implantation of a permanent pacemaker (PM). One fatal
cardiac event occurred after hospital discharge in a patient in whom the family had stopped the beta-blocking
treatment (pt 1). Finally, one death was unrelated to
LQTS (car accident). Survivors (n = 118) were followedup for 1–18 years, mean (SD) 7.5 (5.3) years, median:
7.5 years (see Table 2).
KCNQ1
KCNQ1
HERG
Overall deaths (Table 2)
2:1 AVB TDP
2:1 AVB
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
F
M
M
M
F
F
M
M
M
M
M
F
M
M
F
M
9 yrs
12 yrs
1 day
1 day
1 day
1 day
4 days
1 day
1.5 yrs
1 day
5 yrs
13.5
1 day
6 yrs
6 months
1 day
Syncope
Syncope
Cardiac arrest
Syncope
Bradycardia
Cardiac arrest
Bradycardia
Bradycardia
Cardiac arrest
Family
Syncope
Syncope
Bradycardia
Syncope
Syncope
Cardiac arrest
2:1 AVB
2:1 AVB
2:1 AVB
2:1 AVB
2:1 AVB
2:1 AVB
TDP
TDP
VT
TDP
PVCs
420
415
560
620
480
650
640
680
500
500
520
560
640
524
650
700
QTc
1st ECG
Diagnosis
Age
S
Before being discharged from the hospital, five neonates
(pts 4–8) required implantation of a single chamber ventricular PM because they had episodes of 2:1 AV-block
despite a slower sinus rate with beta-blocking therapy
(1/5 death).
Although they had remained asymptomatic with betablockers, three patients received a prophylactic PM during follow-up, because they had abnormal 24-h ECG monitoring (pts 9–11). One patient had T-wave alternans at
night. Another one had dissociation between a slow sinus
rhythm and a faster junctional escape rhythm, as his older brother (pt 13) prior to syncope. The third patient had
paroxysmal 2:1 AV-block, with block below the His.8
These three patients belonged to the high risk group.
Table 2 Patients with additional therapy and cardiac events
Additional therapy (Table 2)
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In three cases, the maximum heart rate reached by the
patient was higher than the authorized threshold and this
ineffective beta-blockade was due to non-compliance.
There were 6 side effects of the therapy: two patients
had asthma that disappeared when nadolol was changed
for bisoprolol and celiprolol, two patients had postural
hypotension, one patient had transient hypoglycaemia,
and the last had Raynaud phenomenon that disappeared
with bisoprolol.
During follow-up, acebutolol and propranolol were
systematically changed to nadolol in 10 patients, for drug
administration convenience. A total of 86 patients were
on nadolol at the end of the follow-up.
Fu
Control of beta-blocker treatment
Final treatment
Risk
Risk stratification could be performed in 112/122 children (Table 1). In the symptomatic group, 35 children
were classified as high risk patients and 18 as low risk
patients. In the pre-symptomatic group, 39 children were
classified as low risk and eight at high risk.
AVB: atrioventricular, F: female, ICD: intracardiac cardioverter defibrillator, M: male, N: nadolol, pacing: temporary pacing, P: propranolol, PM: pacemaker, fu: follow-up, S: sex, S-: sympathectomy, TDP:
torsade de pointes, treat.: treatment, yrs: years, 1st treat.: initial treatment.
E. Villain et al.
Low
Low
High
High
Intermediate
High
High
High
High
High
High
High
High
High
High
High
1408
Low incidence of cardiac events with b-blocking therapy
1409
Fig. 2 Distribution of patients. b-: beta-blocking treatment, CE: cardiac
event, PM: pacemaker, SD: sudden death.
Thus, among the whole population, 111/122 patients
survived and had a complete follow-up with betablockers alone (Fig. 2). None of these patients died,
but 5/111 experienced non-fatal cardiac events during
follow-up, with documented ventricular arrhythmias in
three of them. Three patients are doing well since PM
implantation (pt 12–13) or sympathectomy (pt 14).
Two other patients had recurrent syncope and event
counters of the PM memory displayed ventricular arrhythmia contempory to syncope: patient 15 received
an implantable cardioverter defibrillator (ICD) and patient 16’s parents have always refused ICD implantation. These five patients all belonged to the high risk
group.
The other 106 patients, including 46/51 symptomatic
cases and 60/61 diagnosed after familial screening (Table 1) remained free of symptoms with beta-blockers
alone over a maximal follow-up of 18 years. Exercise
testing and 24-h ECG monitoring showed 1:1 properly beta-blocked sinus rhythm without significant bradycardia
or ventricular arrhythmia, including ventricular premature beats.
Genetic screening and correlation
genotype-cardiac event
Among the 111 survivors who were treated with betablockers alone, 0/59 KCNQ1, 2/32 HERG and 2/5 patients
with two mutations had a non-fatal cardiac event. All together, 4/5 patients with two mutations required additional therapy.
Kaplan–Meier analysis showed that the cumulative
rate of survival without cardiac event in the 111 patients receiving beta-blockers was 94.4 ± 0.025%. The
cumulative rate of survival without cardiac events or
death at 12 years after diagnosis differed among the
subgroups according to the genotype (p < 0.001 by the
log-rank test). It is of note that we did not exclude
from this analysis the two patients with KCNQ1 mutations who died during follow-up. If these two patients
Fig. 3 Kaplan Maier estimates of survival free of cardiac events among
104 genotyped children with LQT syndrome.
were excluded, no cardiac event was observed in the
subgroup of patients with KCNQ1 mutation. Specifically, the cumulative survival rate without cardiac
event or need for additional treatment on top of
beta-blockers was lower among patients with a mutation in KCNH2 or SCN5A or with two mutations than
among those with a single mutation in KCNQ1
(Fig. 3). The same pattern was observed when the
analysis was performed with a risk stratification analysis according to the risks groups defined by QTc length,
sex and genotype7 (p = 0.001 by the log-rank test).
Discussion
There was no sudden death in our group of children with
LQTS under beta-blocking therapy, provided the choice
and dosage of beta-blocker was appropriate and the
compliance carefully checked. None of the LQT1 patients
and pre-symptomatic children treated with beta-blockers alone had syncope, cardiac arrest or sudden death
during follow-up.
The use of beta-blockers is now widespread in patients with LQTS and with such treatment, reports based
on large populations showed a radical improvement in
outcome with a 15 year-mortality below 10%.2 However,
recent studies have suggested that beta-blockers are not
fully effective in preventing cardiac events and sudden
death. Moss et al.4 have reported their analysis of
beta-blocking therapy in LQTS patients, including adults
and children. Therapy significantly reduced the rate of
cardiac events but 32% of symptomatic patients experienced recurrent symptoms or death within 5 years while
on beta-blockers. The risk of cardiac event was higher in
patients with beta-blocking therapy initiated before ten
years of age and in those who had a history of aborted
cardiac death. In Garson’s series about 287 LQTS patients
less than 21 years, 5% of patients who were thought to be
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Outcome of patients treated with betablockers alone (Table 2)
1410
a high risk of sudden death.10–12 In our population, five neonates required PM implantation (one death) and another
died early in the series, shortly after temporary pacing
was stopped. Beyond neonatal period, cardiac pacing
may effectively prevent recurrence of torsade de pointes, and PM implantation is indicated when pause or
bradycardia-dependent ventricular arrhythmias are
documented.13–15 In our population, three patients had
a prophylactic PM implantation after the neonatal period,
on the basis of 24-h ECG monitoring.
Despite adequate beta-blocking therapy, five patients
had unexpected non-fatal events during follow-up. Four
patients received a PM because of recurrent syncope,
with two successes and two failures. As long-term studies
suggest that sympathectomy can reduce arrhythmias
when beta-blockers fail16 two patients had left cardiac
sympathetic denervation performed by the same surgeon, with one success and one failure. Finally, ICDs
are increasingly being used to prevent sudden death in
patients with LQTS.17,18 Due to a higher rate of complications in young children, it is not our policy to implant ICD
in children as a first line therapy, even in patients who
experienced aborted sudden death. We have recommended ICD implantation in two patients who had syncope with documented ventricular arrhythmias despite
additional therapy with permanent pacing in one case,
permanent pacing and sympathectomy in the other.
Cardiac events occur under specific circumstances,
which vary in a gene-specific manner.3,7 In Schwartz’s recent series 81% of LQT1 patients remained free from recurrence, with a total mortality rate of 4%.3 In our group of
patients, all heterozygous KCNQ1 patients are doing well
with beta-blockers alone. Neonatal conduction disorders
are especially frequent in HERG mutations, which were
found in all six genotyped neonates who presented with
2:1 AV-block.19 Beyond the neonatal period, 2/32 HERG
patients treated with beta-blockers alone experienced a
non-fatal cardiac event. Patients with SCN5A mutations
mainly have cardiac event and sudden death at rest, so
that prophylactic pacing will have more indications in
those patients. Additional treatment with a Na+ channel
blocker could be discussed. Although QT shortening under
mexiletine has been documented, no prospective study
has established a beneficial effect on cardiac events and
mortality. Finally, 4/5 patients of our series with two mutations required additional therapy, prophylactically or
after a cardiac event. Thus, in the future, identification
of mutation(s) may help in adjusting the therapy.
Limitations of the study
The high potential of the long QT syndrome to cause
lethal events is demonstrated by the incidence of cardiac
arrest/sudden death among untreated patients.
Beta-blocking treatment has become the standard prophylactic therapy of LQTS, and it appears now ethically
unjustifiable to perform double blind placebo controlled
trials to evaluate its efficacy. We lack any effective
marker of drug efficacy other than continued absence
of syncope or sudden death in the group of children that
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‘‘effectively’’ treated had sudden death; however, the
authors noticed that, among the children who died suddenly, fewer patients had had 24-h ECG monitoring and
treadmill tests performed than those who did not die,
which raises the question about the control of betablocking therapy.5 They also found that age at presentation was related to sudden death, as 16% of those who
presented at less than 1 month of age died, compared
with 7% of those presenting at older age. Our population
is similar to those described in the literature regarding
age at diagnosis and severity of prognosis in neonates,
as 9/26 patients who were diagnosed at birth required
additional treatment during follow-up or died before being discharged from the hospital.
The main limitation of these studies is that the authors
did not know how compliant the patients were in taking the
prescribed therapy. Assessment of the response to betablockers is difficult, due to the difficulties in standardising
therapeutic protocols, obtaining regular and updated information about the patients and collecting the data. This
is the reason why we selected an homogeneous group of
children, who received uniform dosages of beta-blockers,
had a standardised follow-up including yearly exercise
tests and 24 h ECG monitoring, and were checked by only
three physicians. Among beta-blockers, we recommend
nadolol as first choice because of its long half-life, demonstrated powerful beta-blocking effect9 and low brain penetration, improving the efficacy/tolerance ratio. It is
noticeable that 86 of our patients were treated with this
drug, at a dose of 50 mg/m2 body surface area/day, in
two doses. Beta-blockers had very few side effects in the
group of children we have treated.
In our population, there was no death among the 111
children who survived the neonatal period, received
beta-blockers alone and were compliant to treatment.
Furthermore, 106/111 (95.5%) had no cardiac event during
the follow-up. All LQT1 patients belong to this uneventful
group, including those who were diagnosed because of syncope or aborted cardiac arrest and who were considered to
have the highest risk of cardiac event, according to Priori’s
risk stratification.7 The incidence of cardiac event was also very rare in the group of 61 pre-symptomatic patients,
including 18 intermediate or high risk patients, who received beta-blockers alone; only one of these patients, a
Jervell and Lange-Nielsen syndrome, received a prophylactic PM. We believe that all the LQTS children should
be treated and carefully checked. In the whole population,
the only patient who died had a mutation in KCNQ1 with a
normal QTc interval and an estimated low risk of cardiac
event; the family had stopped treatment because the child
was doing well. This confirms that a normal phenotype in
the presence of an abnormal genotype may be associated
with a risk of syncope or death.
Additional treatments, other than beta-blockers, may
be necessary in some patients with LQTS particularly with
other genotypes. Incomplete AV-block mainly occurs in
neonates, because they have faster atrial rates and the
P-waves occur before the end of a prolonged ventricular
repolarisation, leading to functional AV-block. Implantation of a PM, in combination with beta-blocking therapy,
is mandatory in neonates who have AV-block, as they have
E. Villain et al.
Low incidence of cardiac events with b-blocking therapy
References
1. Splawski I, Shen J, Timothy K et al. Spectrum of mutations in long QT
syndrome genes KLQT1, HERG, KCNE1, and KCNE2. Circulation
2000;102:1178–85.
2. Schwartz P, Locati E. The idiopathic long QT syndrome. Pathogenetic
mechanisms and therapy. Eur Heart J(Suppl. D):103–14.
3. Schwartz PJ, Priori S, Spazzolini C et al. Genotype-phenotype
correlation in the long QT syndrome: gene specific triggers for lifethreatening arrhythmias. Circulation 2001;103:89–95.
4. Moss AJ, Zareba W, Hall WJ et al. Effectiveness and limitations of bblocker therapy in congenital long-QT syndrome. Circulation
2000;101:616–23.
5. Garson A, Dick M, Fournier A et al. The long QT syndrome in children:
an international study of 287 patients. Circulation 1993;87:1866–72.
6. Rijnbeek PR, Witsenburg M, Schrama E et al. New normal limits for
the pediatric electrocardiogram. Eur Heart J 2001;22:702–11.
7. Priori SG, Schwartz PJ, Napolitano C et al. Risk stratification in the
long QT syndrome. N Engl J Med 2003;348:1866–74.
8. Lupoglazoff JM, Cheav T, Baroudi G et al. Homozygous SCN5A
mutation in long QT syndrome with functional two-to-one atrioventricular block. Circ Res 2001;89:e16–21.
9. Coumel P, Escoubet B, Attuel P. Betablocking therapy in atrial and
ventricular tachyarrhythmias: experience with nadolol. Am Heart J
1984;108:1098–108.
10. Trippel DL, Parsons MK, Gillette PC. Infants with long QT
syndrome and 2/1 atrio-ventricular block. Am Heart J 1995;130:
1130–4.
11. Gorgels A, Fadley A, Zaman L et al. The long QT syndrome with
impaired atrio-ventricular conduction: a malignant variant in infants.
J Cardiovasc Electrophysiol 1998;9:1225–32.
12. Van Hare GF, Franz MR, Roge C, Scheinman MM. Persistent functional
atrio-ventricular block in two patients with prolonged QT interval:
elucidation of the mechanism of block. Pacing Clin Electrophysiol
1990;13:608–18.
13. Eldar M, Griffin JC, Van Hare GF et al. Combined used of betaadrenergic blocking agents and long term cardiac pacing for
patients with the long QT syndrome. J Am Coll Cardiol 1992;20:
830–7.
14. Viskin S. Cardiac pacing in the long QT syndrome: review of available
data and practical recommendations. J Cardiovasc Electrophysiol
2000;11:593–600.
15. Viskin S, Fish R, Zeltser D et al. Arrhythmias in the congenital long QT
syndrome. How often is torsade de pointe pause dependent?. Heart
2000;83:661–6.
16. Schwartz PJ, Locati E, Moss A et al. Left cardiac sympathic
denervation in the therapy of congenital long QT syndrome. Circulation 1991;84:503–11.
17. Silka MJ, Kron J, Dunnigan A et al. Sudden cardiac death and the use
Downloaded from http://eurheartj.oxfordjournals.org/ at Pennsylvania State University on March 5, 2014
we have studied, and patients can only serve as their own
control. So far, risk stratification has not allowed identifying patients who have absolutely no risk of sudden
death, even in pre-symptomatic patients and it is noticeable that in our series, the only patient who died despite
an estimated low risk7 was not taking his beta-blocking
treatment.
In conclusion, the outcome of children with LQTS who
were effectively treated with beta-blockers was satisfactory: there was no death among children taking their
medications and 95.5% of them had no symptoms. No
cardiac events were reported in patients with KCNQ1
mutations and in patients diagnosed because of family
history. Among patients who experienced an unexpected
clinical cardiac event, despite adequate beta-blocking
treatment, none have died nor have sequelae. Additional
therapy such as PM and ICD implantation may be indicated in certain forms of LQTS such as LQT2 neonates
with conduction disorders, in LQT3 patients or when molecular biology reveals two mutations in the same
patient.
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