Original Article

Follow-Up of 316 Molecularly Defined

Pediatric Long-QT Syndrome Patients
Clinical Course, Treatments, and Side Effects
Mikael Koponen, MD; Annukka Marjamaa, MD, PhD; Anita Hiippala, MD;
Juha-Matti Happonen, MD; Aki S. Havulinna, DSc (tech); Veikko Salomaa, MD, PhD;
Annukka M. Lahtinen, PhD; Taina Hintsa, PhD; Matti Viitasalo, MD, PhD;
Lauri Toivonen, MD, PhD; Kimmo Kontula, MD, PhD; Heikki Swan, MD, PhD

Background—Inherited long-QT syndrome (LQTS) is associated with risk of sudden death. We assessed the clinical course
and the fulfillment of current treatment strategies in molecularly defined pediatric LQTS type 1 and (LQT1) and type 2
(LQT2) patients.
Methods and Results—Follow-up data covering a mean of 12 years were collected for 316 genotyped LQT1 and LQT2
patients aged 0 to 18 years. No arrhythmic deaths occurred during the follow-up. Finnish KCNQ1 and KCNH2 founder
mutations were associated with fewer cardiac events than other KCNQ1 and KCNH2 mutations (hazard ratio [HR], 0.33;
P=0.03 and HR, 0.16; P=0.01, respectively). QTc interval ≥500 ms increased the risk of cardiac events compared with
QTc <470 ms (HR, 3.32; P=0.001). Treatment with β-blocker medication was associated with reduced risk of first cardiac
event (HR, 0.23; P=0.001). Noncompliant LQT2 patients were more often symptomatic than compliant LQT2 patients
(18% and 0%, respectively; P=0.03). Treatment with implantable cardioverter defibrillator was rare (3%) and resulted in
reinterventions in 44% of cases.
Conclusions—Severe cardiac events are uncommon in molecularly defined and appropriately treated pediatric LQTS
mutation carriers. β-Blocker medication reduces the risk of cardiac events and is generally well tolerated in this age group
of LQTS patients.  (Circ Arrhythm Electrophysiol. 2015;8:815-823. DOI: 10.1161/CIRCEP.114.002654.)
Key Words: arrhythmias, cardiac ◼ beta-blockers, adrenergic ◼ defibrillators, implantable
Downloaded from http://ahajournals.org by on January 7, 2020

◼ long QT syndrome ◼ pediatrics

L ong-QT syndrome (LQTS) is an inherited cardiac arrhyth-

mia disorder manifesting with ventricular arrhythmias,
syncopal spells, and sudden cardiac death (SCD). LQT1 and
LQT2, caused by mutations in the KCNQ1 and KCNH2 genes,
respectively, are the most common subtypes of LQTS (40%
to 55% and 35% to 45% of the cases, respectively). Studies
based on international cohorts show that if left untreated the
prognosis of LQTS is poor.1–3 β-blockers are the standard ther-
apy for LQTS and are associated with a significant reduction
in cardiac events.4–9 Preventive measures, such as avoidance of
QT-prolonging drugs, electrolyte disturbances, and adrenergic
stimuli, are essential and apply to all LQTS patients.10
The number of detected asymptomatic mutation carriers
is increasing because of cascade genetic screening of LQTS
family members. Because of incomplete penetrance,11 LQTS
mutation carriers unveiled by cascade screening often show
milder phenotype than clinically diagnosed LQTS patients.
The recent expert consensus statement on the management of
LQTS acknowledges the ambiguity to treat the asymptomatic
mutation carriers with β-blockers.10 At the moment, β-blocker
medication is recommended even in infancy or early child-
hood for primary prevention of cardiac events.
Previous follow-up studies on pediatric LQTS patients
have mainly consisted of ungenotyped patients.7,8 In the pres-
ent follow-up study, we assess the clinical course, efficacy, and
adverse effects of β-blocker and device therapies in molecu-
larly defined pediatric LQT1 and LQT2 patients. The high
prevalence of the 4 founder LQTS mutations in the Finnish
population12,13 provided us with an opportunity to assess their
mutation-specific prognosis.
Methods
Study Population
The study population was drawn from the Finnish Inherited Cardiac
Disorder Research Registry established in 1991 and comprising 4000

Received December 16, 2014; accepted May 26, 2015.

From the Heart and Lung Center, Helsinki University Central Hospital (M.K., A.M., M.V., L.T., H.S.), Children’s Hospital, Helsinki University Central
Hospital (A.H., J.-M.H.), Department of Medicine, Helsinki University Central Hospital (A.M.L., K.K.), and Institute of Behavioural Sciences, Psychology
(T.H.), University of Helsinki, Helsinki, Finland; and Department of Health, National Institute for Health and Welfare, Helsinki, Finland (A.S.H., V.S.).
The Data Supplement is available at http://circep.ahajournals.org/lookup/suppl/doi:10.1161/CIRCEP.114.002654/-/DC1.
Correspondence to Mikael Koponen, MD, Heart and Lung Center, Helsinki University Central Hospital, PO Box 340, FIN-00029 Helsinki, Finland.
E-mail mikael.koponen@helsinki.fi
© 2015 American Heart Association, Inc.
Circ Arrhythm Electrophysiol is available at http://circep.ahajournals.org DOI: 10.1161/CIRCEP.114.002654

815
 816  Circ Arrhythm Electrophysiol  August 2015
WHAT IS KNOWN
• Long-QT syndrome (LQTS) is an inherited
cardiac arrhythmia disorder that is associated
with risk of sudden death.
• The number of detected mutation carriers is in-
creasing because of cascade genetic screening
of LQTS family members.
WHAT THE STUDY ADDS
• Fatal or near-fatal cardiac events are uncom-
mon in molecularly defined and appropriately
treated pediatric LQTS mutation carriers.
• β-Blocker treatment reduces the risk of cardiac
events in genotyped LQTS patients.
• Noncompliance with medication increases risk
of cardiac symptoms.
• The 4 Finnish founder mutations are associ-
ated with a lower risk of cardiac events.
• Implantable cardioverter defibrillator place-
ment in pediatric LQTS patients is associated
with high reintervention rate.
molecularly tested subjects. Baseline characteristics, including per-
sonal and family history of cardiac events, QTc interval using Bazett’s
formula, and treatment history were collected at the study enrollment.
The inclusion criteria for this study were (1) genetically con-
firmed KCNQ1 or KCNH2 mutation, or genetically confirmed non-
Downloaded from http://ahajournals.org by on January 7, 2020
carrier status of the family-specific LQTS mutation and (2) age <16
years on enrollment. In 2011 to 2012, a questionnaire was sent to
the study subjects or to their parents. Collected data included occur-
rence of cardiac events (LQTS-related syncope or aborted cardiac ar-
rest [ACA]), medical therapy, device therapy with a pacemaker or
an implantable cardioverter defibrillator (ICD), and left cardiac sym-
pathetic denervation (LCSD). Data regarding β-blocker medication
included starting date, discontinuation date if appropriate, type of β-
blocker, adverse effects, and compliance defined as forgetting or not
taking medication once a month or more often.
Data of all deaths during the follow-up were obtained from
Statistics Finland. Clinical data were obtained from hospitals for all
patients who had device therapy underwent LCSD, had an ACA, or
died. Collected ICD data included implantation indications, compli-
cations, revisions, and ICD discharges. Autopsy documents of pa-
tients who died during the follow-up were evaluated.
The primary end point of the study was cardiac event compris-
ing LQTS-related syncope, ACA, or SCD which ever occurred first.
LQTS-related syncope was defined as a transient loss of conscious-
ness, abrupt in onset and offset, and triggered by one of the following
factors: swimming, other sports, loud noise, or startle.14,15 Syncope
was considered being vasovagal if it occurred in a setting described
previously by Priori et al.10 Other reasons for syncope included epi-
lepsy, fever, severe pain, and head trauma. A resuscitation that re-
quired external defibrillation or appropriate ICD shock therapy was
defined as ACA. A death was regarded being SCD if it was abrupt in
onset without evident cause if witnessed, or it was not explained by
any other cause if it occurred in an unwitnessed setting, such as sleep.
The follow-up started from birth and ended when subject (1) re-
turned the 2011 to 2012 inquiry, (2) turned 18 years, or (3) deceased.
The closing date for the study was April 12, 2012. An informed consent
was acquired from the study subjects or their parents. The study was
approved by the ethical committee of Helsinki University Hospital.
Direct DNA sequencing and restriction enzyme assays were used
in identification of KCNQ1 and KCNH2 mutations as previously
described.12,16 Mutations were categorized by mutation type as mis-
sense or nonmissense (nonsense, frameshift, splice site, insertion, or
deletion) mutations and by their location as previously described.17,18
Patients carrying >1 LQTS mutation (n=7) were excluded from the
clinical characteristics (Table 1) and the multivariate model (Table 2),
but included in the sections depicting cases of death and device ther-
apy. The specific singular mutations included in the study, by number
of patients, number of families, type, and location, are detailed in
the Table I in the Data Supplement. Data on the 7 patients with >1
mutation in the KCNQ1 or KCNH2 genes are summarized in Table II
in the Data Supplement. Noncarrier family members of the familial
KCNQ1 and KCNH2 mutations served as the comparison group and
are denoted as noncarrier relatives. All study subjects were of Finnish
origin.12,13
Statistical Analysis
Clinical characteristics were compared using χ2 and Fisher’s exact
tests for categorical, and Wilcoxon rank-sum and Kruskal–Wallis
1-way ANOVA tests for continuous variables. Categorical variables
were expressed with number of patients and percentage, and continu-
ous variables were expressed as mean±SD. Kaplan–Meier graphs
were established to depict the cumulative probability (cumulative
rate) of first cardiac event by mutation, QTc, and sex. The signifi-
cance of the differences was tested by the log-rank test. LQT1 Finnish
founder (FF) mutations KCNQ1 G589D and KCNQ1 c.1129-2A>G,
and LQT2 FF mutations KCNH2 R176W and KCNH2 L552S were
combined to form the FF mutation carrier population for LQT1 and
LQT2, respectively.
Multivariate Cox proportional hazards regression model, compris-
ing KCNQ1 and KCNH2 FF mutation, QTc duration categorized as
≥500, 470 to 499, or <470 ms, and time-dependent β-blocker medica-
tion as prespecified covariates, was used to evaluate the independent
contribution of risk factors to first cardiac event in mutation carriers.
The model was stratified by sex and adjusted for family membership
using robust sandwich estimators. No violation of the proportional
hazards assumption was detected as tested by log–log graphs. In an
interaction term analysis, no statistically significant interactions were
discovered, and thus no interaction terms were included in the mul-
tivariate model. A separate QTc missing covariate was used for pa-
tients whose baseline QTc data were not available (n=28).
Efficacy of β-blocker medication in preventing cardiac arrhyth-
mia was also evaluated by assessing incidence rates of cardiac events
per person-years after initiating β-blocker. In this incidence rate
analysis, if a patient already had a cardiac event before beginning of
β-blocker, a secondary end point of first cardiac event after initiation
of β-blocker was taken into consideration. Statistical analyses were
performed using SPSS version 20. A 2-sided P value ≤0.05 was inter-
preted as statistically significant.
Results
A total of 857 subjects fulfilled the inclusion criteria. Three of
them died during the follow-up and 520 (61%) responded to
the inquiry. The final study population (n=523) consisted of
316 LQTS mutation carriers (224 KCNQ1 mutation carriers,
85 KCNH2 mutation carriers, and 7 carriers with >1 KCNQ1
or KCNH2 mutation) and 207 noncarrier relatives. There was
no difference between subjects fulfilling the inclusion crite-
ria (n=857) and subjects of the final study cohort (n=523) in
respect of proportion of sex, LQTS subtypes, FF mutation
carriers, and symptomatic patients at the time of diagnosis,
or QTc intervals. The final study population comprised 130
families. One family had 4, 1 family had 3, and the rest of the
families had 0 to 2 cardiac events during the follow-up. Of the
316 mutation carriers, 40 (13%) were probands. Altogether 28
(9%) were symptomatic at diagnosis. Mean age at enrollment
(=age at diagnosis) was 5.8±5.4 years, prospective follow-up
 Koponen et al   Follow-Up of 316 Pediatric LQTS Patients   817

Table 1.  Characteristics of the FF and Non-FF Mutation Carriers*

KCNQ1 KCNH2
Non-FF† FF Non-FF† FF
G589D, c.1129-2A>G, L552S, R176W,
n=42 (21%) n=164 (72%) n=18 (7%) P Value‡ n=32 (38%) n=23 (27%) n=30 (32%) P Value‡
Females, n (%) 19 (45) 85 (52) 10 (56) 0.71 17 (53) 17 (74) 20 (67) 0.27
Age at follow-up end, y, mean±SD 13.5±4.9 11.6±5.7 10.8±5.8 0.13 13.6±4.8 11.6±5.6 12.9±4.9 0.47
QTc, ms, mean±SD 475±43a‡ 454±35b 465±37a,b 0.01 480±39a 448±32b 436±31b <0.001
QTc ≥470 ms, n (%) 20 (53)a 43 (30)b 9 (56)a 0.006 16 (55)a 5 (22)b 3 (10)b 0.001
β-Blocker, n (%) 36 (86) 138 (84) 18 (100) 0.20 28 (88)a 10 (44)b 14 (47)b 0.001
Age at starting BB, y, mean±SD 4.3±5.1 5.1±5.4 4.5±5.4 0.51 7.2±5.4 7.0±4.7 6.7±5.7 0.98
Side effects, n (%) 9 (25) 29 (21) 5 (28) 0.69 5 (19)a 0a 8 (50)b 0.01
Forgetting ≥ once a month, n (%) 9 (23) 33 (24) 5 (28) 0.93 9 (33) 4 (40) 9 (56) 0.38
Pacemaker, n (%) 1 (2) 2 (1) 0 0.61 0 0 1 (3) 0.62
ICD, n (%) 4 (10)a 1 (1)b 0a,b 0.009 3 (9) 0 0 0.11
LCSD, n (%) 1 (2) 0 0 0.27 0 0 0 1.00
LQTS-related syncope, n (%)§ 9 (21)a 11 (7)b 1 (6)a,b 0.02 9 (29)a 2 (9)a,b 0b 0.001
ACA, n (%)║ 1 (2) 1 (1) 0 0.46 0 0 0 1.00
SCD, n (%)# 0 0 0 1.00 0 0 0 1.00
Age at first cardiac event, mean±SD 6.0±4.1 6.8±4.3 14.6±0 0.34 10.2±4.1 3.3±1.7 ... 0.15
ACA indicates aborted cardiac arrest; BB, β-blocker; FF, Finnish founder; ICD, implantable cardioverter-defibrillator; LCSD, left cardiac sympathetic denervation;
LQTS, long-QT syndrome; and SCD, sudden cardiac death.
*Patients with >1 LQTS-causing mutation (n=7) are excluded.
†There was no statistical difference between KCNQ1 non-FF and KCNH2 non-FF mutation carriers in any of the parameters.
‡Significant P value (≤0.05) indicates that 1 group is different from the other 2 groups, or that all 3 groups differ from each other. Groups with different subscript
letters (a, b, or c) have statistically significant difference.
§Trigger for the syncope was swimming, sport, loud noise, or startle. For 3 people, the data for syncope trigger were not available.
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║A resuscitation that required external defibrillation or appropriate ICD shock.

#Not explained by any other cause and abrupt in onset if witnessed.

time from enrollment was 6.2±3.6 years, and the total follow-
up time including the retrospectively collected data from birth
was 12.0±5.5 years.
Clinical Characteristics
The characteristics of the study population are shown in
Table 1 excluding patients with >1 mutation and noncarrier
relatives. A baseline QTc ≥500 ms was measured in 32 (11%)
individuals. There was no statistically significant difference in
the age at which the first cardiac event occurred between LQT1
and LQT2 patients (6.8±4.4 and 8.9±4.6 years, respectively;
P=0.24). ACA or appropriate ICD shock was experienced by
0.9% of the LQT1 and 1.2% of the LQT2 patients. No SCDs
occurred during the follow-up.
Risk Factors for Cardiac Events
As shown in Figure 1, the cumulative probability of cardiac
events was higher in the carriers of non-FF than FF mutations
by the age of 18 years (in KCNQ1 26% versus 11%, P=0.008;
and in KCNH2 43% versus 4%, P=0.002). Of the non-FF and
FF mutation carriers, 2.7% and 0.4%, respectively (P=0.14),
had ACA or appropriate ICD shock. In KCNQ1 carriers, fam-
ily history of ACA or SCD increased the risk of cardiac events
(cumulative rate, 29% versus 13%; P=0.04).

Table 2.  Time-Dependent Cox Regression Model: Risk Factors for Cardiac Events in
Mutation Carriers*
Hazard Ratio 95% Confidence Interval P Value
KCNQ1 FF vs KCNQ1 non-FF mutation 0.33 0.12–0.91 0.03
KCNH2 FF vs KCNH2 non-FF mutation 0.16 0.04–0.66 0.01
QTc ≥500 vs <470 ms 3.32 1.67–6.62 0.001
QTc ≥500 vs 470–499 ms 2.44 0.99–6.00 0.052
QTc 470–499 vs <470 ms 1.36 0.49–3.76 0.55
β-Blocker vs no β-blocker† 0.23 0.10–0.52 0.001
The model was stratified by sex and adjusted for family membership using robust sandwich estimators.
FF indicates Finnish founder.
*Patients with >1 long-QT syndrome–causing mutation (n=7) are excluded.
†Time-dependent covariate.
 818  Circ Arrhythm Electrophysiol  August 2015
Non-FF LQT2 males had more cardiac events by the age of
10 years compared with non-FF LQT2 females (24% versus 0%,
P=0.05; Figure 2). Thereafter, females had a distinct increase in
events, and by the age of 18 years, the cumulative probabilities
were 24% for men and 48% for women. Such a steep increase in
risk in females was not observed among non-FF LQT1, FF LQT1,
or FF LQT2 patients. Mutation carriers with QTc interval ≥500 ms
had a higher cardiac event rate (46%) than patients with QTc 470
to 499 ms (19%, P=0.03) or <470 ms (10%, P<0.001; Figure 3).
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Vasovagal syncopes were equally common in LQTS
patients and in noncarrier relatives (cumulative rate, 18% and
21%, respectively; P=0.48). Female noncarrier relatives had
a steep increase in syncopal spells triggered by any reason
after the age of 10, and by the age of 18 years, the rate was
41%. However, LQTS patients had significantly more cardiac
events than their noncarrier relatives (male LQTS patients
12% versus noncarrier relatives 2%, P=0.02 and female LQTS
patients 18% versus noncarrier relatives 4%, P=0.007).
Consistent with the findings of the Kaplan–Meier and
log-rank analyses, in the Cox regression model, FF mutation
Figure 1. Kaplan–Meier graph of cumula-
tive probability of cardiac events in carriers of
KCNQ1 and KCNH2 Finnish founder (FF) and
non-FF mutations.
carriers had a lower risk of cardiac events compared with non-
FF mutation carriers (HR, 0.33; P=0.03 in KCNQ1 and HR,
0.16; P=0.01 in KCNH2; Table 2). QTc duration of ≥500 ms
was associated with a 3.3-fold risk of cardiac arrhythmia com-
pared with QTc <470 ms (P=0.001), and a borderline signifi-
cant 2.4-fold risk compared with QTc 470 to 499 ms (P=0.052).
β-Blocker treatment was related to 77% reduction in the risk
of first cardiac event (P=0.001). Cox regression model with
only the firstborn patient from each of the 130 families was not
feasible because of reduction in number of events.
Medical Treatment
All patients received guidance on lifestyle modifications, such
as avoidance of competitive sports, exposure to acoustic stim-
uli (LQT2), and QT-prolonging drugs, as recommended by the
ACC/AHA/ESC guidelines.10 The only antiarrhythmic medi-
cation used was a β-blocker. More LQT1 than LQT2 patients
were treated with β-blockers (86% versus 61%; P<0.001), and
they started taking β-blocker earlier (4.9±5.3 versus 7.0±5.3
years; P=0.02). β-Blocker treatment was more common in
KCNH2 non-FF than FF mutation carriers (P<0.001), but
Figure 2. Kaplan–Meier estimates of cumula-
tive probability of cardiac events in non-Finnish
founder KCNQ1 and KCNH2 mutation carriers
by sex.
 Koponen et al   Follow-Up of 316 Pediatric LQTS Patients   819
equally common in KCNQ1 non-FF and FF patients. All pro-
bands, all but 1 symptomatic patient, and 92% of patients with
family history of ACA or SCD were treated with β-blockers.
The 65 patients whom β-blocker was not prescribed had a
shorter QTc interval (446 versus 461 ms; P=0.003), and they
were less often symptomatic (2% versus 13%; P=0.01) than
patients whom β-blocker was prescribed. There was no differ-
ence in age, female predominance, or family history of ACA
or SCD between these 2 groups. None of the 49 nonproband
mutation carriers with QTc <470 (434±21) ms, who were
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asymptomatic at enrollment and whom β-blocker was not ini-
tiated, had a cardiac event during the follow-up.
Propranolol was the most frequently (43%) prescribed
β-blocker. Atenolol (26%) and bisoprolol (25%) were also used,
whereas metoprolol was prescribed less often (6%). The dosage
(mg/kg per day) was 2.4±0.8, 1.2±0.5, 0.1±0.1, and 1.3±0.4 for
propranolol, atenolol, bisoprolol, and metoprolol, respectively.
Only 15 subjects had a breakthrough cardiac event during
β-blocker treatment. Supporting the findings of the multivariate
Cox regression model, the incidence rate of cardiac events showed
reduction after initiating β-blocker: in non-FF patients, 38.1 and
19.9 cardiac events per 1000 person-years before and after start-
ing β-blocker, respectively. Similar trend was observed among
FF patients (9.9 and 4.3 cardiac events per 1000 person-years).
Side effects were reported with similar frequency (22%–
25%) in LQT1 and LQT2 patients. The most frequent side
effects included nightmares and parasomnias (6%), coldness of
extremities (6%), tiredness (6%), dizziness (4%), and impaired
physical condition (4%). Furthermore, in 6 nondiabetic patients,
β-blocker was suspected to aggravate hypoglycemia. Three of
them were carriers of a single KCNQ1 mutation, 2 were homo-
zygous carriers of the KCNH2 L552S mutation, and 1 was a
double heterozygous carrier of KCNQ1 and KCNH2 mutations.
Side effects did not affect compliance to β-blocker medica-
tion. More LQT2 patients had difficulties in remembering to
take the medicine than LQT1 patients (42% and 24%; P=0.02).
Noncompliance to medication increased the risk of cardiac events
in LQT2 patients; none of the compliant (n=29) but 18% (n=4)
of the noncompliant patients had a cardiac event after initiating
β-blocker medication (P=0.03). Such trend was not observed in
Figure 3. Kaplan–Meier graph of cumulative prob-
ability of cardiac events in KCNQ1 and KCNH2
mutation carriers by QTc duration (ms).
LQT1 patients. A total of 8 LQT1 and 2 LQT2 patients with a
mean QTc duration of 466 ms discontinued taking a β-blocker.
The majority of them (7/10) carried a FF mutation. They were
all asymptomatic at the time of discontinuation and remained
cardiac event-free till the end of the follow-up. Only 1 patient, a
KCNQ1 G589D mutation carrier with QTc duration of 470 ms,
reported a side effect as the reason for discontinuation.
Device Therapy and LCSD
Characteristics of the patients with pacemaker, ICD, or LCSD
are shown in Table 3.
Implantation indications for pacemakers included second-
degree or third-degree atrioventricular block (n=3), neurocar-
diogenic syncope (n=2), and bradycardia (n=1). Implantation
indications for ICDs were ACA or torsades de pointes (n=5),
syncope despite β-blocker medication (n=2), and inadequate
β-blocker compliance (n=2). ICD was implanted more fre-
quently to non-FF than FF mutation carriers (10% and 0.4%;
P<0.001). Two noncompliant patients (22%) under insufficient
β-blocker medication received an appropriate ICD shock during
the follow-up. None of the pacemaker or ICD patients were using
QT-prolonging drugs at the time of cardiac event or ICD shock.
Pacemaker therapy complications (ie, inappropriate sens-
ing and lead damage) were encountered in 2 patients. ICD
therapy complications occurred in 4 (44%) patients: inappro-
priate ICD shocks because of lead damage (n=2), lead tension
(n=1), and perforation of the right ventricle (n=1). All ICD
complications resulted in lead replacement. The incidence rate
of complications in pacemaker and ICD systems was 4.6 and
8.5 per 100 person-years, respectively.
LCSD was performed on 3 (1%) patients because of recur-
rent syncope: a β-blocker medication–compliant compound
heterozygous KCNQ1 mutation carrier, a compliant homo-
zygous KCNQ1 G589D mutation carrier, and a noncompliant
KCNQ1 R366W mutation carrier. Two of them had a LQTS-
related syncope after the procedure.
Causes of Death
A total of 3 patients died, but no SCDs occurred during the
follow-up.
 820  Circ Arrhythm Electrophysiol  August 2015

Table 3.  ICDs, Pacemakers, and LCSDs

Cardiac BB During
Event Prior Cardiac Appropriate Inappropriate Shock BB During
Case Mutation Female QTc ICD* PM* LCSD* Implantation Indication Implantation† Event Shock* Shock* Trigger Shock Complication

1 KCNQ1 G589D No NA No (1.1) No Neurocardiogenic Yes Yes … … … … No

syncope
2 KCNH2 R176W Yes 366 No (0.1) No Congenital tird-degree No … … … … … No
AV block
3 KCNQ1 G589D No 391 No (0.4) No Congenital second- No … … … … … No
degree AV block,
bradycardia
4 KCNQ1 D317N Yes 501 No (1.3) No Neurocardiogenic Yes Yes … … … … Yes
syncope
5‡ KCNH2 L552S Yes 636 No (0.1) No 2:1 second-degree No … … … … … Yes
KCNH2 L552S AV block
6‡§ KCNQ1 G589D No 566 No (9.0) (11.7) Bradycardia, fatigue Yes Yes … … … … No
KCNQ1 Y171Ter
7 KCNQ1 R366W Yes 450 (12.5) No (7.0) Inadequate compliance Yes No NA No … … No
8 KCNH2 No 452 (9.3) No No Inadequate Yes No No No … … No
c.1631_1632delAG compliance, TdP
9 KCNQ1 A341V No 479 (8.7) No No Syncope despite BB Yes Yes No No … … Yes
10 KCNH2 W497Ter Yes 493 (16.0) No No TdP Yes Yes No No … … No
11 KCNQ1 A341V Yes 499 (6.0) No No Syncope despite BB Yes Yes No No … … Yes
12 KCNH2 A561V Yes 517 (13.2) No No Syncope despite BB, Yes Yes║ (14.3) No Startle>>> No No
inadequate compliance TdP
13§ KCNQ1 G589D Yes 459 (8.3) No No ACA, J–L–N? Yes No No No … … No
14‡ KCNH2 L552S Yes 513 (15.7) No No Inadequate Yes Yes║ (16.5) Yes Startle No Yes
KCNH2 L552S compliance, ACA >>>VF,
lead
damage
15 KCNQ1 A341V No 543 (12.4) No No ACA Yes Yes No (15.8) Lead Yes Yes
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damage
16‡§ KCNQ1 G589D No 592 No No (5.8) Syncope despite BB, Yes Yes … … … … No
KCNQ1 G589D J–L–N
ACA indicates aborted cardiac arrest; AV, atrioventricular; BB, β-blocker; FF, Finnish founder; ICD, implantable cardioverter-defibrillator; J–L–N, Jervell–Lange–Nielsen syndrome; LCSD, left
cardiac sympathetic denervation; NA, not available; PM, pacemaker; sdr, syndrome; TdP, torsades de pointes ventricular tachycardia; and VF, ventricular fibrillation.
*The age of ICD or PM implantation, LCSD, or first ICD shock in parenthesis.
†Included long-QT syndrome–related syncope or ACA.
‡Carrier of double mutation.
§Cases 6, 13, and 16: congenital deafness.
║Patient suffered syncope both with and without β-blocker medication.

Case 1 atrioventricular conduction block, R-on-T premature ven-

A 4-year-old nondiabetic boy with a double heterozygous
KCNQ1 G589D and KCNH2 R176W mutation was the pro-
band in the family. He had been examined for small size,
delayed development of speech, and problems in eating. QTc
was prolonged (460 ms) and propranolol was initiated. Six
months later during respiratory infection and fever he lost
consciousness, and severe hypoglycemia of 0.9 mmol/L was
discovered. Intravenous glucose administration resulted in
full recovery of consciousness. However, this was followed
by aspiration of vomitus and a need of mechanical ventila-
tion in the absence of ventricular tachyarrhythmias. Despite
the intensive care, 2 days later, he was declared brain-dead.
Case 2
An 11-year-old symptomatic girl with KCNQ1 G589D muta-
tion and QTc duration of 480 ms died because of an inoper-
able malignant temporal glioma.
Case 3
A nondiabetic girl who was homozygous for KCNH2 L552S
mutation with a QTc time of 680 ms had recurrent 2:1
tricular complexes, and short episodes of ventricular tachy-
cardias since birth, and propranolol was initiated. At the age
of 3 years, she was found unconscious with low (1.1 mmol/L)
blood glucose level that was treated in hospital by rapid intra-
venous glucose administration. She regained consciousness,
but after 15 minutes she vomited, aspirated, and went lifeless.
Monitoring of heart rhythm showed no ventricular tachyar-
rhythmias. She died despite of cardiopulmonary resuscitation.
QTc Duration and Cardiac Events in Finnish
Founder Mutation Carriers
All 4 FF mutations resulted in a significant QT prolongation
compared with noncarrier relatives (451±35 versus 408±23
ms; P<0.001), but the QT-prolonging effect was weaker than
that of non-FF mutations (Table 1). The cumulative probabil-
ity of cardiac events by the age of 18 years was higher in FF
mutation carriers than in noncarrier relatives (9% versus 3%;
P<0.05). However, FF patients with QTc duration <470 ms
had as many cardiac events as noncarrier relatives (6% and
 Koponen et al   Follow-Up of 316 Pediatric LQTS Patients   821
3%, respectively; P=0.18). For comparison, non-FF patients
with an even shorter QTc time (≤450 ms) had an event rate
of 16%.
KCNQ1 G589D FF mutation was associated with a lower
cumulative rate of cardiac events than non-FF KCNQ1 muta-
tions (10% versus 26%; P=0.01), but the event rate in KCNQ1
c.1129-2A>G FF mutation carriers (20%) did not differ from
non-FF KCNQ1 patients (P=0.19). There was no statistical
difference in the cardiac event rate between KCNH2 L552S
FF and non-FF KCNH2 mutation carriers (10% versus 43%,
respectively; P=0.18, crossover at the age of 9 years). Carriers
of KCNH2 R176W FF mutation did not have cardiac events
during the follow-up.
Discussion
The present follow-up study focused on genetically con-
firmed pediatric LQT1 and LQT2 patients of Finnish origin
and showed that, once treated with β-blockers and appropriate
lifestyle modifications,10 the prognosis of the disorder is good.
No SCDs occurred during the follow-up.
Risk Factors for Cardiac Events
In our study, non-FF LQT1 and LQT2 patients had cardiac
events at a cumulative rate of 26% and 43%, respectively,
similarly to the 30% to 45% reported in previous studies.6,19
ACAs, SCDs, and appropriate ICD shocks were less frequent
(2.7% in non-FF patients) than in other studies 5% to 12%.2,6
However, in the previous studies >50% of the patients were
diagnosed based on prolonged QTc time and history of syn-
Downloaded from http://ahajournals.org by on January 7, 2020
cope, whereas our study included only genetically confirmed
LQTS patient irrespective of their QTc interval and syncope
history. Thus, in our study, the mean QTc interval was shorter
(458 versus 491–494 ms) reflecting a more benign phenotype.
In this study, the rate of cardiac events was considerably
lower among patients carrying any of the 4 FF mutations.
This is in accordance with previous observations suggesting
that FF mutations lead to a milder clinical phenotype, even
though all of them prolong the QTc interval, and have been
shown to result in alterations of channel function in vitro.12,20,21
Furthermore, the steep increase in risk in LQT2 females after
the age of 10 years occurred only among non-FF but not in
FF patients.
In our study, a QTc interval of ≥500 ms was associated
with a 3.3-fold risk of cardiac events compared with QTc
<470 ms. This is in line with previous studies, which postulate
that QTc duration is one of the strongest predictors of cardiac
events.1,3 However, non-FF patients had an increased risk even
with a normal QTc time (≤450 ms). Thus, other methods in
the patient risk stratification should be used along with QTc
interval evaluation.22
The number of benign syncopal episodes in noncar-
rier female relatives increased after the age of 10 years, as
described also in another study recently,15 complicating the
differential diagnosis between LQTS-related and benign
syncope. However, 4 noncarrier relatives, with QTc interval
<460 ms, had a syncope triggered by sports, loud noise, or
startle. When assessing an exercise-related syncopal spell, it
is important to know whether the syncope occurred during
or immediately after cessation of physical effort. The latter
is highly suggestive of a syncopal spell because of a sudden
drop in blood pressure.
Medical Treatment
In this study, 79% of the children were on β-blocker medica-
tion in line with the pediatric study by Liu et al6 (72%). In the
study by Etheridge et al7 as much as 98% of pediatric LQTS
patients had β-blocker medication. However, in their study,
the majority of the patients (53%) were diagnosed based on
family history and prolonged QTc (mean 487 ms) suggesting
a more severe phenotype compared with our study population.
In our study, β-blocker medication was associated with a sig-
nificant 77% reduction in cardiac events similarly to the pre-
vious studies.4–9,23 The result was supported by the reduction
in the incidence rate of cardiac events. However, our hazard
ratio estimate for the β-blocker treatment might be optimistic
because we have only considered the first-ever cardiac events
as the end point.
We showed that LQT2 patients had weaker adherence
to β-blocker medication than LQT1 patients. Furthermore,
noncompliant LQT2 patients had more cardiac events than
compliant LQT2 patients. Patient guidance may play a role in
compliance. LQT1 patients may be aware of the high efficacy
of β-blockers in LQT1, and they may be more motivated to
uninterrupted medication. Even though β-blockers may not be
as effective in LQT2,24 they do prevent potentially fatal car-
diac events also in this subtype.18,19,23 Therefore, it is important
to pay attention to patient and parental motivation to ensure
compliance.
Major potential complications of the β-blocker medica-
tion included hypoglycemia. In 2 cases, hypoglycemia was
observed at the beginning of chain of events leading to death.
In addition, 6 (2%) β-blocker users reported hypoglycemia
as an adverse effect of the medication. Especially nonselec-
tive β-blockers are known to predispose young children to
hypoglycemia by reducing glycogenolysis and mobilization
of glucose from the liver.25 β-blockers also attenuate hypo-
glycemic adrenergic symptoms.25,26 Thus, it is possible that
β-blocker was a contributing factor to low blood glucose in
the 2 cases of death in our study. Consequently, it is important
to instruct pediatric LQTS patients and their parents about the
risk of hypoglycemia as a potential side effect of β-blocker
medication. Furthermore, Torekov et al27 reported recently
that a loss-of-function mutation in KCNQ1 itself may cause
hypoglycemia.
Device Therapy
In this study, only 3% of the total study population and 10%
of the carriers of non-FF mutation received an ICD. This
is less than the 15% reported in a previous study of device
therapy on pediatric LQTS patients.7 However, in the previous
study, 10% of the genetically tested subjects were carriers of
an SCN5A mutation and all of them had an ICD implanted.
LQT3 patients are known to respond poorly to the β-blocker
medication and thus are more likely to receive an ICD even
in primary prevention.10 Appropriate ICD shocks, inappropri-
ate ICD discharges, and device reinterventions occurred in
 822  Circ Arrhythm Electrophysiol  August 2015
similar rates as in previous studies.7,8 Although the sample
size of device patients in our study was small, the occurrence
of appropriate ICD shocks in 22% of the ICD patients under-
scores not only the importance of careful medical therapy but
also of device therapy in patients lacking sufficient response
to medication. However, high prevalence of complications and
reinterventions (44%) in the present study does not support a
more active approach to ICD implantation.
Risk Stratification and β-Blocker Treatment
Because of the lack of randomized trials, recommendations for
LQTS management are based on expert opinion. The safety of
β-blockers favors their use in pediatric LQTS patients because
of the risk of arrhythmia later in adolescence. According to
the prevailing treatment strategy among Finnish pediatric car-
diologists, β-blocker should be initiated at the time of diag-
nosis to all patients who are either symptomatic, have QTc
≥470 ms, carry a KCNQ1 mutation, or carry a KCNH2 non-
FF mutation. However, β-blocker may be initiated later but
before the onset of adolescence to asymptomatic LQT2 FF
patients with QTc time <470 ms if there is no family history
of ACA or SCD. However, in the present study patients, to
whom β-blocker medication was not prescribed, had an excel-
lent cardiac event–free survival. This indicates that the current
treatment strategy is adequate.
Conclusions
In the era of genetic screening, the number of detected asymp-
tomatic LQTS mutation carriers is increasing. This study
Downloaded from http://ahajournals.org by on January 7, 2020
shows that life-threatening cardiac events are rare in molecu-
larly defined and appropriately treated pediatric LQT1 and
LQT2 patients. Thus, an active approach to genetic screening,
which enables implementing adequate lifestyle modifications
and β-blocker medication as preventive measures in mutation
carriers, is supported. In line with previous studies, we have
shown that β-blocker medication is associated with reduced
risk of cardiac events and is generally well tolerated. Device
therapy is useful in carefully selected patients, but has a high
reintervention rate.
Acknowledgments
We thank Hanna Ranne, Minna Härkönen, and Ilmari Määttänen, PhD
for their excellent technical assistance.
Sources of Funding
This study has been supported by grants from the Finnish Foundation
for Cardiovascular Research, Helsinki, Finland, the Sigrid Juselius
Foundation, and Finska Läkaresällskapet. Veikko Salomaa was sup-
ported by the Academy of Finland, grant number 139635.
Disclosures
None.
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