Journal of the American College of Cardiology
© 2010 by the American College of Cardiology Foundation
Published by Elsevier Inc.
Vol. 55, No. 8, 2010
ISSN 0735-1097/10/$36.00
doi:10.1016/j.jacc.2009.11.042
QUARTERLY FOCUS ISSUE: HEART RHYTHM DISORDERS
Long QT Syndrome
Risk of Fatal Arrhythmic Events in
Long QT Syndrome Patients After Syncope
Christian Jons, MD,* Arthur J. Moss, MD,* Ilan Goldenberg, MD,* Judy Liu, MS,* Scott McNitt, MS,*
Wojciech Zareba, MD, PHD,* Ming Qi, MD,† Jennifer L. Robinson, MS*
Rochester, New York
Objectives
The aim of this study was to identify risk factors for fatal arrhythmias in long QT syndrome (LQTS) patients presenting with syncope.
Background
Syncope is highly predictive for future fatal arrhythmias in the LQTS. However, there are no data regarding risk
stratification and management strategies in the high-risk subset of LQTS patients presenting with syncope.
Methods
A total of 1,059 LQTS patients with a corrected QT interval ⱖ450 ms presenting with syncope as a first symptom were drawn from the International LQTS Registry. Cox proportional hazards regression was used to identify
risk factors for a severe arrhythmic events comprising aborted cardiac arrest, appropriate implantable
cardioverter-defibrillator therapy, and sudden cardiac death.
Results
The lowest risk was found in patients with only 1 syncopal episode occurring before the start of beta-blocker
therapy. In contrast, patients experiencing syncope after starting beta-blocker therapy had a 3.6-fold increase in
the risk of severe arrhythmic events (p ⬍ 0.001) relative to this low-risk group and displayed a risk of severe
arrhythmic events similar to that of patients not treated with beta-blockers. Multiple syncopal episodes occurring
before initiation of beta-blocker therapy were associated with an intermediate risk (hazard ratio: 1.8,
p ⬍ 0.001). The risk of syncope during beta-blocker therapy is high during childhood in both sexes but is
higher in women than in men (hazard ratio: 2.3, p ⬍ 0.001).
Conclusions
Patients with syncope during beta-blocker therapy are at high risk of life-threatening events, and implantable
cardioverter-defibrillator therapy should be considered in these patients. The risk of beta-blocker failure is highest in young children and in women. (J Am Coll Cardiol 2010;55:783–8) © 2010 by the American College of
Cardiology Foundation
Long QT syndrome (LQTS) is caused by mutations in genes
encoding cardiac potassium and sodium ion channel subunits
or cellular structural proteins. Patients often present with
symptoms at a young age and are at high risk of nonfatal
(syncope) and fatal (sudden cardiac death [SCD]) cardiac
events (1). The incidence of syncope in LQTS patients is
approximately 5% per year (1), depending on the mutation
causing the syndrome (2,3), whereas the incidence of SCD is
much lower, approximately 1.9% per year (1). However,
nonfatal events remain the strongest predictor of fatal events in
LQTS patients (1,4), and the overall risk of subsequent SCD
in an LQTS patient who has experienced a previous episode of
syncope is approximately 5% per year (1). Thus, an LQTS
patient who presents for clinical assessment after a nonfatal
From the Cardiology Division of the Departments of *Medicine, and †Pathology,
University of Rochester Medical Center, Rochester, New York. Dr. Moss has received
a research grant from Bioreference Labs. Dr. Liu has received a fellowship funded by
the Clinical and Translational Science Institute, and a grant from the NIH.
Manuscript received August 13, 2009, revised manuscript received November 23,
2009, accepted November 30, 2009.
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syncopal episode is already at high risk of a subsequent
LQTS-related fatal event. Recent studies from the International LQTS Registry identified risk factors for cardiac events
in LQTS patients (1,3,5–9). However, there are no data
regarding specific risk factors for SCD within the high-risk
subgroup of symptomatic LQTS patients who have experienced a previous syncopal episode. Thus, the subsequent
treatment of these patients depends largely on the clinical
judgment of the physician based on risk assessment. Specifically, a paucity of data exists regarding the management of
LQTS patients who experience syncope while on beta-blocker
therapy. The aim of this study was to determine clinical
predictors of subsequent SCD in LQTS patients presenting to
the clinician with first syncopal episode and to evaluate the
efficacy of beta-blocker therapy for the prevention of sudden
death in this high-risk population.
Methods
Study population. The study population was drawn from
the International LQTS Registry (10) and included affected or
784
Jons et al.
Risk Stratification After the First Syncope Event in LQTS
genotype-positive individuals born
after 1959 to maximize the number of patients who were treated
HR ⴝ hazard ratio
with beta-blockers. Patients were
ICD ⴝ implantable
followed through age 41 years. Afcardioverter-defibrillator
fected individuals were defined as
LCTS ⴝ left cervicothoracic
any subject with a corrected QT
sympathectomy
(QTc) interval of ⱖ450 ms, as
LQTS ⴝ long QT syndrome
corrected by Bazett’s formula (11),
QTc ⴝ corrected QT
who experienced a syncopal epiSAE ⴝ severe arrhythmic
sode. The final study group comevent
prised 1,059 LQTS subjects from
SCD ⴝ sudden cardiac
764 families. The LQTS genotype
death
was determined with standard
mutational analytic techniques involving 5 established genetic laboratories associated with the
International LQTS Registry. Genotype data were available
for 445 patients (LQT1 ⫽ 212, LQT2 ⫽ 163, LQT3 ⫽ 35,
LQT5 ⫽ 4, LQT6 ⫽ 3, LQT7 ⫽ 2, LQT8 ⫽ 1; genotypenegative affected ⫽ 36). Symptomatic genotype-negative subjects according to the above criteria were included if incomplete
genetic studies had been performed.
Beta-blocker therapy. Beta-blocker therapy was initiated at
the discretion of each patient’s attending physician. During the
initial patient contact, information was collected on whether
beta-blocker treatment had been started, the specific betablocker initiated, the date started, the prescribed dose, and the
patient’s weight. At subsequent yearly contacts, information
was recorded on whether the patient continued taking betablockers and, if so, the daily dose; if patients discontinued
therapy, the date that the medication was stopped was recorded. Among patients who died, we retrospectively determined whether the patient had been taking a prescribed
beta-blocker before and on the day of death.
Syncopal events. Episodes of loss of consciousness were
categorized as syncope if the episode was abrupt in onset and
offset. Patients were classified into 3 prespecified categories
based on the clinical nature of the syncopal events: 1) a first
syncopal event in patients not receiving beta-blocker therapy;
2) repeated syncopal events in patients not receiving betablocker therapy; and 3) any syncopal event occurring in
patients receiving beta-blocker therapy. Patients in the last
category could have had any number of syncopal episodes while
off beta-blocker therapy before the final episode while on
beta-blocker therapy. Once a patient experienced a syncopal
event while receiving beta-blocker therapy, the patient remained in this group independently of future syncopal events
and treatment.
End points. The primary end point was a life-threatening
cardiac event. Twenty percent (n ⫽ 212) of the study population had an implantable cardioverter-defibrillator (ICD) implanted. We therefore used the end point of severe arrhythmic
events (SAEs) defined as LQTS-related SCD, aborted cardiac
arrest, or appropriate ICD therapy for an LQTS-related
ventricular tachyarrhythmia, whichever occurred first. Adjudication of the ICD treatment as appropriate or inappropriate
Abbreviations
and Acronyms
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JACC Vol. 55, No. 8, 2010
February 23, 2010:783–8
was performed by the treating electrophysiologist at the time of
ICD interrogation.
Statistical analysis. Variables were tested for normality using
visual inspection. Student t test and Pearson’s chi-square test
were used in the univariate comparison analyses where appropriate. The cumulative probability of a first cardiac event was
assessed by the Kaplan-Meier method with significance testing
by the log-rank statistic. The Cox proportional hazards survivorship model was used to evaluate the independent contribution of clinical and genetic factors to the first occurrence of
time-dependent cardiac events from birth through age 40
years. Pre-specified covariates included in the multivariate
model were QTc duration, sex, history of syncope, and
time-dependent beta-blocker therapy. Beta-blocker treatment,
syncope, and the interaction between recurrent syncope and
beta-blocker therapy were treated as time-dependent covariates
in a Cox model, and all reported hazard ratios (HRs) and p
values stem from these models.
To illustrate the risk associated with syncopal events occurring while on and off beta-blocker therapy, Kaplan-Meier
survival curves for patients, all experiencing 1 syncopal event
while off beta-blocker therapy, were created for the following
treatment and syncopal groups: 1) patients not starting betablocker treatment after first syncope; 2) patients starting
beta-blocker treatment after the first syncopal event and
experiencing no subsequent syncope during beta-blocker treatment; and 3) patients starting beta-blocker treatment after
the first episode of syncope and experiencing subsequent
syncope episodes during beta-blocker treatment. All patients
were initially in group 1, and the time of the syncope occurring
while off beta-blocker therapy was used as time origin. If
patients started beta-blocker therapy, they moved into group 2,
now using time of initiation of beta-blocker treatment as the
time origin for outcome. If patients in group 2 experienced
syncope during beta-blocker treatment, they moved into group
3, now with the time of the syncope occurring while receiving
beta-blocker treatment as the time origin.
Similarly, the figure showing the risk of syncope occurring during beta-blocker treatment was constructed with
patients in the corresponding age and sex groups at the time
of beta-blocker treatment initiation. If the patients started
beta-blocker treatment before age 14 years and were followed past age 14 years, the patient was censored at age 14
years and restarted at time 0 in the appropriate sex group
with the 14th birthday as the origin of the curve. The
methodology shown in Figures 1 and 2 was used for
illustrative purposes only, and no hypothesis testing was
done using this approach.
All statistical analyses were performed using SAS version
9.1.3 (SAS Institute, Cary, North Carolina).
Results
Study population. Baseline characteristics of the study
population by the occurrence of SAEs during follow-up are
shown in Table 1. The group with SAEs had a lower
JACC Vol. 55, No. 8, 2010
February 23, 2010:783–8
Figure 1
Jons et al.
Risk Stratification After the First Syncope Event in LQTS
785
The Cumulative Risk of Severe Arrhythmic Events and Beta-Blocker Therapy
The solid black line represents all patients after the first syncopal event until start of beta-blocker (BB) therapy. After the start of beta-blocker therapy, patients are represented by the red dashed line. Patients with a syncopal event occurring while off beta-blocker therapy are represented by the purple dashed line. See the Methods
section for how this graph was constructed.
frequency of beta-blocker use, but initiated beta-blocker
therapy at a younger age than those without SAEs. A larger
proportion of patients with SAEs was treated with device
therapy or surgery, indicating the severe clinical presentation of the syndrome in this group. The type and dose of
beta-blocker treatment were balanced in the 2 groups.
Figure 2
Risk factor for SAEs. A total of 210 SAEs occurred, of
which 82 (39%) occurred during beta-blocker treatment.
There were no differences in the proportion of the SAEs
that occurred during beta-blocker treatment among patients
with LQT1 (45%), LQT2 (33%), and LQT3 (40%) (p ⫽
0.48).
Risk of the First Syncope Event on Beta-Blocker Treatment
From the Start of Beta-Blocker Treatment or From the 14th Birthday
Patients were followed from the time that beta-blocker therapy was started in the respective sex groups. See the Methods section for how this graph was constructed.
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Jons et al.
Risk Stratification After the First Syncope Event in LQTS
786
Treatment
Clinical
Characteristics
inClinical
the Study
Population
and
Characteristics
and
Table 1
Treatment in the Study Population
No Severe
Arrhythmic
Events
Severe
Arrhythmic
Events
Clinical variables
n
Male
849
210
536 (63)
143 (68)
Deafness
28 (3)
17 (8)*
Proband
440 (61)
217 (66)
12.3 ⫾ 7.8
11.4 ⫾ 7.8
Age at first syncope, yrs
Genotyped subjects (n ⫽ 409)
LQT1
181 (21)
31 (15)
LQT2
127 (15)
36 (17)
LQT3
30 (4)
5 (2)
Other genotype
8 (1)
2 (1)
11 (3)
5 (7)
QTc interval at baseline (ms)
502 ⫾ 5
510 ⫾ 6
Number of subjects with QTc interval ⬎500 ms
290 (34)
107 (51)*
Multiple mutations†
Electrocardiogram
Treatment during the study
Beta-blocker therapy started (n ⫽ 830)
Age at initiation of beta-blocker therapy, yrs
Propranolol (n ⫽ 433)
722 (85)
108 (51)*
15.5 ⫾ 9.3
12.9 ⫾ 8.4*
372 (52)
64 (59)
Nadolol (n ⫽ 89)
87 (12)
7 (7)
Metoprolol (n ⫽ 92)
82 (11)
10 (9)
Atenolol (n ⫽ 179)
166 (23)
22 (20)
Other beta-blocker (n ⫽ 20)
15 (2)
5 (5)
—
82 (39)
Pacemaker implanted
106 (13)
20 (16)
ICD implanted
177 (21)
35 (17)
LCTS surgery
41 (5)
11 (5)
Received beta-blocker therapy during SAE
Values are n (%) or mean ⫾ SD. *Significant differences between the 2 groups with p ⬍ 0.05. †Of
16 patients with compound mutations, 4 patients had mutations in the same gene, whereas 12
patients had mutations in multiple genes (LQT1 ⫹ LQT2 ⫽ 4, LQT1 ⫹ LQT2 ⫽ 4, LQT1 ⫹ LQT5 ⫽ 1,
LQT2 ⫹ LQT3 ⫽ 2, LQT1 ⫹ SNTA1 ⫽ 1).
ICD ⫽ implantable cardioverter-defibrillator; LCTS ⫽ left cervicothoracic sympathectomy; QTc ⫽
corrected QT; SAE ⫽ severe arrhythmic event.
The most important risk factor for SAEs was whether a
syncopal episode occurred during beta-blocker treatment.
This is illustrated in Figure 1. Patients who began betablocker therapy after their first and only syncopal episode
and did not experience further episodes were at low risk of
SAEs. However, patients experiencing syncopal episodes
during beta-blocker therapy were at the same high risk of
SAEs as patients who never started beta-blocker therapy.
Accordingly, in a multivariate analysis (Table 2), syncope
occurring during beta-blocker treatment was the most
powerful predictor of subsequent SAEs (HR: 3.6, p ⬍
0.001). Patients who experienced multiple versus single
syncopal episodes while off beta-blocker treatment had
twice the risk of an SAE. Beta-blockers were generally
protective against SAEs, and there were no significant sex or
age group interactions. The risk of SAEs after a syncopal
event was also significantly increased among patients with
severe QTc interval prolongation (QTc interval ⬎500 ms)
and female patients in the 14 to 40 years age group. Females
and males have a similar risk of SAEs after the first syncopal
episode during the preteen years, but after age 14 years,
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February 23, 2010:783–8
female patients had almost twice the risk of SAEs compared
with male patients in the same age group (HR: 1.86, p ⬍
0.001).
Fifty-two patients were treated with left cervicothoracic
sympathectomy (LCTS) during the course of the study. All
patients started beta-blocker therapy before LCTS, and
most patients (43 [83%]) remained on beta-blocker therapy
throughout the study. Six SAEs occurred in this group
despite concomitant treatment with beta-blockers. The
patients receiving LCTS had longer QTc intervals, both
among subjects with SAEs (QTc interval ⫽ 519 ⫾ 5 ms)
and without SAEs (QTc interval ⫽ 520 ⫾ 5 ms), but were
in other aspects similar to the study population. The few
individuals with sympathectomy did not allow evaluation of
this treatment in the Cox models.
Risk factors for recurrent syncope during treatment with
beta-blockers. To determine the risk for recurrent syncope
while receiving beta-blocker therapy, 746 patients in whom
beta-blocker therapy was initiated after experiencing syncope were included in a subset analysis. In this analysis,
follow-up time was assessed from the date beta-blocker
therapy was initiated.
As illustrated in Figure 2, the risk of syncope during
beta-blocker treatment did not show any association with
the QTc interval, but the risk was markedly influenced by
the age and sex of the patients. Figure 2 shows a high but
similar risk of syncope during beta-blocker treatment before
puberty in both sexes. However, after puberty, female
patients remain at high risk, whereas the risk in male
patients decreases markedly. Table 3 shows the results from
the multivariate analysis. There were no significant differences between male and female patients ages 0 to 13 years
(HR: 1.04, p ⫽ 0.85) as well as between female patients ages
0 to 13 years and female patients ages 14 to 40 years (HR:
1.39, p ⫽ 0.10).
Discussion
This study highlights the association of syncopal episodes
with the subsequent risk of potentially fatal arrhythmic
Cox Off
Cardiac
Syncope
and
Model
Beta-Blocker
Events
Event
for
Risk
and
inModel
Patients
Repeated
Factors
Therapy
Presenting
Related
Syncope
to With
Events
Severe
theOn
First
Cox
for Risk
Factors
Related
to Severe
Cardiac Events in Patients Presenting With the
Table 2
First Syncope Event and Repeated Syncope Events
On and Off Beta-Blocker Therapy
Parameter
HR
95% Cl
p Value
ⱖ1 syncopal events on beta-blocker
therapy*
3.59
2.25–5.74
⬍0.001
⬎1 syncopal event off beta-blocker
therapy*
1.96
1.37–2.82
⬍0.001
QTc interval ⬎500 ms
1.76
1.32–2.27
⬍0.001
Female subjects age 14 to 40 yrs†
1.86
1.40–2.49
⬍0.001
Time-dependent beta-blocker therapy
0.46
0.32–0.65
⬍0.001
Syncopal episodes and beta-blocker therapy
*Relative to subjects with only 1 syncopal episode occurring while off beta-blocker therapy.
†Relative to male subjects age 14 to 40 years.
CI ⫽ confidence interval; HR ⫽ hazard ratio; QTc ⫽ corrected QT.
Jons et al.
Risk Stratification After the First Syncope Event in LQTS
JACC Vol. 55, No. 8, 2010
February 23, 2010:783–8
Risk Factors
After
Long
Episodes
QT
theSyndrome
of
Start
Syncope
forofthe
Beta-Blocker
Patients
First for
Syncope
With
Previous
Event
in Event
Risk
Factors
theTreatment
First
Syncope
After the Start of Beta-Blocker Treatment in
Table 3
Long QT Syndrome Patients With Previous
Episodes of Syncope
HR
95% Cl
p Value
Male subjects age 0 to 13 yrs vs.
male subjects age 14 to 40 yrs
Parameter
3.16
1.92–5.78
⬍0.001
Female subjects age 0 to 13 yrs vs.
male subjects age 14 to 40 yrs
3.04
1.82–5.08
⬍0.001
Female subjects age 14 to 40 yrs vs.
male subjects age 14 to 40 yrs
2.27
1.45–3.58
⬍0.001
QTc interval ⬎500 ms
1.10
0.86–1.42
0.46
Abbreviations as in Table 2.
events in LQTS patients. New important findings in this
study are as follows: 1) in LQTS patients presenting with
the first syncopal episode, fatal arrhythmic events are effectively prevented with beta-blocker treatment in those without recurrent syncope; 2) patients experiencing syncope
while receiving beta-blocker therapy are at high risk of
subsequent SAEs, a risk similar to that observed in patients
who are not treated with beta-blockers; and 3) there is an
important sex difference in the risk of experiencing syncope
while being treated with beta-blockers. Before puberty, the
efficacy of beta-blockers in preventing subsequent syncopal
episodes seems to be equal in both sexes, whereas after age
14 years, this risk is drastically lowered in male patients, but
not among female patients. The risk of syncope while being
treated with beta-blockers among patients with previous
syncopal events does not seem to be related to the QTc
interval.
Syncope, beta-blocker treatment, and prevention of cardiac
death in LQTS patients. Why some patients keep having
symptoms despite treatment with beta-blockers is unknown.
A possible explanation may be the known patient variability
in beta-blocker efficacy in blocking sympathetic activation
(12,13) that may have genetic underpinnings. In a previous
study, failure of beta-blocker therapy was related to the
genotype, because LQT1 genotype-positive subjects
showed the highest proportion of beta-blocker therapy
failures, and to the type of beta-blocker used (14). This
finding contrasts with our study in which the type of
beta-blocker did not significantly influence the results,
and beta-blocker effects were consistent across genotypes.
Instead we found that sex and age had an influence on the
risk of syncope while receiving beta-blocker treatment.
Those experiencing syncope on beta-blocker therapy
were at high risk of SAEs.
A recent study evaluated occurrences of aborted cardiac
arrest/SCD in LQTS subjects receiving beta-blocker therapy and found that a significant number of these events were
due to noncompliance or concomitant treatment with QTprolonging drugs (15). We were not able to investigate this,
but noncompliance is an important confounder in this
population consisting of mainly young individuals prone to
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787
side effects. However, we cannot explain why noncompliance should be much higher in female patients older than 14
years than in male patients older than 14 years, and we
believe that other factors such as sex hormones are likely to
play a role in this difference.
ICD treatment in LQTS patients presenting with a
syncope. When to treat a symptomatic LQTS patient with
an ICD is an important clinical question, and the benefits
and risk of ICD therapy in high-risk LQTS patients have
yet to be defined. The risk of SAEs in LQTS patients
presenting with syncope is low if treated with beta-blockers.
However, experiencing syncope while being treated with
beta-blocking agents is a high-risk situation, and this study
shows that the risk of fatal arrhythmias in such patients can
be considered equal to the risk in patients not treated with
beta-blockers. Even though some of the syncope episodes in
this study could have occurred because of noncompliance or
undertreatment, it is unlikely that these nontherapy factors
explain our findings. ICD therapy is very effective in
preventing SCD in LQTS patients (16 –18), and ICD
therapy should be considered in patients experiencing syncope during beta-blocker treatment.
Study limitations. Beta-blocker treatment was not allocated at random, and unmeasured factors could have influenced the effects of therapy. Also, the efficacy of betablockers has been linked to the genotype of the patients.
Only a subset of the study subjects in this study was
genotyped, and the small number of end points in these
patients did not allow us to address differences between the
different genotypes. We did separate models for LQT1 and
LQT2 patients and found identical patterns for the betablocker treatment. We believe that the bias caused by
unknown phenotype is small and that the reported results
are applicable to most genotypes. Family membership of the
study subjects is likely to be influenced by other genotypic
traits in the family. In this study, only a few study subjects
were related, and we did not find any difference in the
results when using the covariance estimator sandwich (19)
to adjust for family membership. The impact of LCTS
surgery on the study results could not be fully evaluated due
to limited power in the Cox analysis.
Conclusions
In general, LQTS patients presenting with syncope are
effectively treated with beta-blockers. However, patients
experiencing ⱖ1 syncopal events during beta-blocker therapy are at the same risk of fatal events as patients who were
not treated with beta-blockers. Thus, ICD treatment should
be considered in these high-risk patients. The risk of
syncopal events during beta-blocker treatment is highest
before puberty. After puberty, the risk remains high in
female patients.
788
Jons et al.
Risk Stratification After the First Syncope Event in LQTS
Reprint requests and correspondence: Dr. Christian Jons, The
Heart Research Follow-up Program, University of Rochester
Medical Center, Box 653, Elmwood Avenue, Rochester, New
York 14642. E-mail: Christian.jons@heart.rochester.edu.
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Key Words: beta-blockers y long QT syndrome y syncope y sudden
cardiac death.
APPENDIX
For a list of the investigators from the International Long QT Syndrome
Registry who contributed patients to the study, please see the online
version of this article.