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Congenital long-QT syndrome is a genetic
disorder encompassing a family of mutations that can lead to
aberrant ventricular electrical activity.
These genetic mutations are called “channelopathies”;
they are the responsible that genes that encode for protein
channels that regulate the flow of sodium, potassium, and
calcium ions in and out of the cardiac myocyte.
The result of these mutations is an increased risk of
ventricular arrhythmia, specifically torsade de pointes, that
can lead to syncope, aborted cardiac arrest, and sudden cardiac
manifests on the patient’s electrocardiogram as a prolongation
of the corrected QT
(QTc) interval and/or abnormal morphology of the
T-wave (Figure 1).
When measuring the degree of QT
interval prolongation, it is necessary to correct for the
patient’s heart rate, termed QTc.
This is done with Bazett’s Formula:
Prior to genetic mapping, LQTS was divided
into two syndromes based on inheritance pattern and associated
The Romano-Ward Syndrome (RWS) has an autosomal dominant
inheritance and no associated genetic defects.
The second and more rare syndrome, Jervell Lange-Nielsen
Syndrome (JLNS), has an autosomal recessive inheritance and the
presence of bilateral sensori-neural deafness.
The hearing loss results from disturbed potassium ion
handling in the inner ear. JLNS represents a more severe form of
cardiac disease with greater risk of fatal arrhythmia.
Currently, LQTS is classified according to10 possible types of
ion channel mutations, LQT1-10,
that encompass the prior classification system with some
8-10 correspond to RWS, while LQT 1 & 5 correspond to JLNS when
associated with deafness.
LQT7, also known as Anderson-Tawil syndrome, is
associated with periodic paralysis, dysmorphic features, and
In the United States,
the incidence of congenital LQTS is estimated to be one in
There is a female preponderance, ranging from 1.6-2.0:1.
Among patients enrolled in The International Long-QT
registry, the average age of presentation is
Presentation most often is with a syncopal episode.
Males often present during pre-adolescence while females
Congenital LQTS is also believed to be one of the causes
of sudden infant death accounting for 5-10% of cases..
Of the ten types of channelopathies, the
first three, LQT1-3, are the most prevalent and most studied.
LQT1 occurs in 30-35%, LQT2 in 25-30%, LQT3 in 5-10%, LQT4 in
1-2%, and LQT5 in 1% of cases.
LQT6-10 are all rare2.
The ventricular myocyte activation cycle,
or action potential, is dependent on ion channels (Figure 2).
During rest (phase 4), molecular pumps in the cell
membrane of the myocyte push sodium and calcium ions out of the
cell and bring potassium ions into the cell.
The cell membrane is impermeable to backflow of the
sodium and calcium. However, via the inward rectifying potassium
channels (IK1 and IKAch), positively charged potassium ions
slowly leak out of the cell and leave the interior negatively
charged at -80mV(also known as the membrane potential).
As the membrane potential becomes less negative, it reaches a
critical threshold value and depolarizes.
The cell membrane voltage-gated sodium channel, NaV1.5
(INa), then opens allowing positively charged sodium to rapidly
flow into the cell.
This is phase 0 or depolarization.
To maintain this depolarization, L and T type calcium
channels (ICaL and ICaT) are activated to allow the influx of
positive calcium ions.
During the next phase, phase 1, two types of delayed
rectifier potassium channels open to allow efflux of potassium
(ITo and IKur) and thereby slightly reducing the cells now
positive internal charge.
During Phase 2, there is equilibrium between influx of
calcium and the efflux of potassium, and the cells internal
During phase 3, efflux of potassium ions predominates with the
activation of the slow and rapid delayed rectifier channels
(IKs, and IKr).
At the terminal portion of Phase 3, the inward rectifying
potassium channels (IK1 and IKach) are activated and further
helps to extrude potassium.
This action results in a return of the membrane potential
to its negative resting potential.
Phases 1-4 are termed repolarization.
In the various sub-types of LQTS, mutations
lead to malfunction of the different ion channels.
In all subtypes, the overall effect is a prolongation of
With the prolonged repolarization, L-type calcium channels can
be promoted to re-open causing a rise in cellular calcium.
This rise then can lead to a premature depolarization of
the myocyte (early after depolarization) resulting in a
premature beat .
Because there is heterogeneity of the repolarization in the
surrounding cells, this early beat can then lead to
depolarization of neighboring myocytes setting off an unstable
ventricular tachycardia or torsade de pointes.
Syncope occurs when torsade de pointes is short lived and
self terminates. However, if the torsade de pointes does not
terminate, it can degenerate to ventricular fibrillation and
ultimately can result in sudden death.
Sub-Types (Table 1):
Broad, late-inset, T wave
low-amplitude, T wave
Prolonged Na+ influx
Biphasic or peaked, late-onset, T wave
Build-up of Na+
within cell and Ca2+ outside of cell
Variable Qt interval prolongation
Modest prolongation of Qt interval
Exaggerated Qt interval prolongation
Prolonged Na+ influx
Extremely rare, found in 1 family
Prolonged Na+ influx
In this subtype, the slowly activating
delayed rectifier potassium channel, IKs, has a loss of function
due to various mutations of the gene KVLQT1 (KCNQ1) at locus
The slow potassium channel is composed of 2 types of proteins:
one alpha sub-unit and one beta subunit.
The alpha subunit forms the ion channel and the beta
subunit works as a modifier of the channels functioning.
The KVLQT1 gene product is responsible for the formation
of the alpha subunit.
Mutations of this gene lead to a prolongation of
repolarization by decreasing potassium efflux.
When a homozygous mutation and sensori-neural deafness
are present, this combination is labeled JLNS 1 as opposed to
electrocardiogram of patients with LQT1 most often has as a
broad-based T-wave or a late-onset normal appearing T-wave7,
Adapted from Moss AJ, Zareba W, Benhorin J, et. al. ECG T wave
patterns in genetically distinct forms of the hereditary long QT
syndrome. Circulation. 1995;92:2929-34.
Mutations in the Human “Ether-a-go-go”
Related Gene (HERG) are responsible for this subtype.
The locus for HERG is 7q35-36 and encodes for the alpha
subunit of the rapidly activating delayed rectifier potassium
channel, IKr. As in LQT1, the channel protein is composed with
an alpha and beta subunit.
Mutations in this gene lead to loss-of-function of this
channel and prolonged repolarization.
The electrocardiogram can display widely split or
low-amplitude T-waves7,3(Figure 2)
Unlike LQT1 and LQT2, the primary mutation
in this subtype leads to continued activation of the
voltage-gated sodium channel.
Mutations in gene SCN5A located on chromosome 3p21-24
lead to a mutation of the alpha subunit resulting in a
gain-of-function of the channel. This mutation prolongs the
influx of sodium, extending repolarization.
The electrocardiogram for these patients will often have
late-onset of the T-wave that can be biphasic or peaked7,3(Figure 2)
The genetic mutation in this subtype
affects sodium, potassium, and calcium ion flow.
Mapped to chromosome 4q25-27, the ANKB gene encodes for
the ankyrin-B adaptor protein.
This protein is responsible in anchoring the Na-K ATPase
and Na/Ca exchanger on the cell membrane.
Loss of function of these proteins leads to a build-up of
sodium within the cell and calcium outside of the cell.
The electrocardiogram in these patients shows variable QT
prolongation and often have a normal QT interval7,3.
Similar to LQT1, the slow delayed rectifier
potassium channel (IKs) in this subtype has a loss of function.
However, LQT5 has mutations of the beta subunit.
The gene that encodes for the beta subunit is the minK
(KCNE1) at locus 21q22.1-2.
As in LQT1, decreased potassium efflux leads to prolonged
Also similar to LQT1, when homozygous mutations and
sensori-neural deafness are present, this combination is called
There is no known pathonemonic finding on
electrocardiogram for LTQ57,3.
Mutations of the MiRP1 gene located on
chromosome 21q22.1 lead to a loss of function of the beta
subunit of the rapid delayed rectifier potassium channel, (IKr).
Similar to LQT2, potassium efflux is decreased and
repolarization is prolonged. Electrocardiogram findings have not
yet been defined for this subtype7,3.
In this subtype, there is a mutation of the
KCNJ2 gene located on chromosome 17q23.
This mutation leads to a loss-of-function of the inward
rectifying channel (IK1), resulting in decreased potassium
The electrocardiogram of these patients has a prominent U wave
and a normal or modestly prolonged QT interval.
Although LQT7 is currently included among
the sub-types of congenital long-QT syndrome, this inclusion is
is now believed that the previous studies that led to the
inclusion of LQT7 inaccurately measured the QT interval by
including the large U wave which is pathonemonic for this
In LQT8, inactivation of the L-type calcium
channel causes prolonged calcium inflow and markedly prolonged
gene responsible for this mutation is CACNA1C which is mapped to
chromosome 12p13.3 and encodes for the alpha subunit of the
L-type calcium channel.
The electrocardiogram of these patients can have an
exaggerated prolongation of their QT interval7,3.
As in LQT3, this subtype has prolonged
activation of the rapid sodium channel.
The gene CAV3 localized to chromosome 3p25 encodes for
the Caveolin-3 protein.
The Caveolin-3 protein forms an invagination in the cell
membrane, and the voltage-gated sodium channel co-localizes
within the “cave” on the cell membrane.
In a mechanism that has not yet been fully defined,
mutations in the CAV3 gene lead to prolonged activation of rapid
sodium channels and a prolonged phase 0 of the action potential2.
Electrocardiographic findings for this subtype have not yet been
The gene SCN4β located on chromosome 11q23
encodes for the beta subunit of the voltage-gated sodium
of this gene lead to a gain-of-function of the sodium channel
akin to the mutations that cause LQT32.
This subtype is very rare, and electrocardiographic findings
have not been defined.
Diagnosis of LQTS is challenging.
Patients can be referred for evaluation for many reasons.
Symptomatic patients are those who have had unexplained
syncope or aborted sudden cardiac death. Asymptomatic patients
have a prolonged QTc on routine electrocardiogram or have a
first-degree relative diagnosed with the disease.
In both the asymptomatic and symptomatic groups, the QTc
interval can be normal on initial presentation.
The asymptomatic patients are also more likely to have a
normal QTc duration then the symptomatic
A scoring system has been created to aid in
the diagnosis of LQTS.
A score of ≥ 4 indicates a high probability of LQTS; 2 or
3 indicates intermediate probability; ≤ 1 indicates a low
≥ 480 ms
450 ms (men)
Torsade de pointes
Notched T-wave in 3 leads
Low heart rate for age (children)
Family member with definite LQTS
Unexplained SCD in immediate family
member younger than 30 years old
³ 4 is diagnostic. However, patients with the
disease who score lower will be missed by this strict criteria.
If a cut-off of 2 is used, greater than 50% of patients
will be diagnosed with only a 10% false positive diagnosis15.
Because use of the electrocardiogram and this scoring system
lead to an under-diagnosis, further testing may be indicated for
patients with a low to intermediate score.
Patients can be followed over time and have repeat
electrocardiograms that may show variability in the QTc interval.
Among patients with LQT1, there is a higher
prevalence of “concealed LQTS” or LQTS with a normal QTc.
Stress testing with either exercise or an epinephrine
infusion can unmask the cases of LQT1 by revealing a
pathonomonic failure of the QTc interval to shorten with
Exercise testing is limited by artifact on the ECG
tracing which results in an inaccurate measurement of the QT
interval. For the
epinephrine QT stress testing, there are currently two protocols
available. The Mayo
Clinic protocol uses a continuous infusion of epinephrine with a
doubling of the dose every 5 minutes.
The diagnosis of LQT1 is supported when there is an
increase in the QT interval of
³ 30ms at a dose of
A positive test is 76% predictive of LQT1.
A negative test can almost virtually rule-out LQT1.
However, a negative test does not rule-out other subtypes of
The second epinephrine protocol, the
Shimuzu protocol, has the added benefit of being able to not
only diagnose LQT1 but also to diagnose some cases of LQT2.
For this protocol, a bolus of epinephrine is given and
then followed by a continuous infusion.
If the QTc is prolonged by greater than 35msec above the
baseline during the infusion portion, this result is 90%
predictive of LQT1.
However, if the QTc does not meet these criteria but is
prolonged by greater than 80msec after the bolus, LTQS2 can be
100% accurately diagnosed.
It is important to note that with any provocative testing
such as exercise or epinephrine infusion, a negative test does
not rule-out LQTS.
Recently, genetic testing has become
commercially available for the diagnosis and sub-typing of LQTS
and is available along with genetic counseling at our Program.
The current recommendations for genetic testing are to
determine the genotype of patients clinically diagnosed with
LQTS and to test first-degree relatives of patients with known
The test can identify 76% of patients with LQT1, LQT2,
LQT3, LQT5, and LQT6.
In those cases with a high suspicion for LQTS but with a
negative test, the false negative result is most likely due to a
mutation that has not yet been identified or a mutation that is
not tested for with the current test.
Treatment of LQTS is guided by the
individual’s risk of sudden cardiac death.
Patients who have already had an aborted sudden cardiac
arrest are considered to have the highest risk of a recurrent
In these patients, medical treatment with beta-blockers and
placement of an implantable cardioverter-defibrillator is
For patients without prior cardiac events,
therapy is initiated with a beta-blocker medication and
lifestyle modifications. This treatment is especially important
for those patients with prolonged QTc intervals, as increasing
QTc interval is directly related to increased risk of sudden
Lifestyle modification includes avoiding
triggers of cardiac events and medications that prolong the QT
Triggers for LQT1 include stress and exercise, especially
swimming. For LQT2,
triggers include auditory stimuli and stress.
For LQT3, the primary triggers are rest and sleep; hence,
here there are no specific triggers to avoid.
For all other subtypes, information on triggers has not
yet been defined.
If patients continue to suffer from syncope
and/or ventricular arrhythmia despite lifestyle modification and
beta-blocker therapy, ICD placement is recommended26.
Another controversial option for these patients is left
cervicothoracic sympathetic ganglionectomy.
This surgical procedure involves removal of nerve plexi
that are believed to modulate sympathetic activity on the heart.
Follow-up of a cohort of patients who
underwent ICD placement found the average number of ICD shocks
to be 1.1
± 2.2 shocks/patient-year, of which 5.3% were
Among the patients with prior aborted sudden cardiac
death, there was a clustering of events with an event rate of
1.3 + 2.5 shocks/patient-year.
For all others, the event rate was lower at 0.2
± 0.3 shocks/year.
With the advent of reliable genetic testing and a better
understanding of the pathophysiology of the various mutations,
genotype-specific pharmacotherapy is also being developed.
For patients with LQT2, researchers have found that by
increasing the extracellular potassium concentration, the QT
interval can be shortened.
In one small trial, eight patients were given potassium
supplementation and spironolactone with a goal potassium of
1.5meq/l above their baseline.
The average potassium level achieved was 1.2meq/l above
the baseline and all but one patient had significant improvement
of their QTc interval.
This study was limited by the requirement for frequent
blood draws and short follow-up.
It is also not known whether this therapy is clinically
significant and leads to a reduction in cardiac events.
For patients with LQT3, use of mexiletine
in conjunction with a beta-blocker or ICD has been suggested.
In a small clinical trial, patients with LQT2 and LQT3
were placed on mexiletine.
Patients in the LQT3 group had a significant reduction in
their QTc interval while LQT2 patients did not.
However, it is not known whether the improvement in the
ECG parameters translates to a reduction in cardiac events.
For both LQT 7 and 8, there are case
reports showing a possible benefit with verapamil.
Use of verapamil was found to reduce the ventricular
tachycardia burden in both sub-types. However, the long-term
safety is unknown.
There are also special considerations for
early ICD implant if the genotype of the patient is known.
Of the three predominant subtypes, LQT3 has the greatest
risk of cardiac events at 0.60%/year, followed by LQT2 at
0.56%/year, and LQT1 at 0.30%/year28.
Current guidelines allow for consideration of ICD placement in
patients with LQT2 and LQT3. However these guidelines are
Priori et. al. recommend using QTc duration and gender to
further risk stratify these three subtypes.
When including QTc duration to determine risk of event,
as the QTc increases, the risk dramatically increases in LQT2
and LQT3 and in males with LQT1. In these patients when the QTc
duration increases to greater than 500 msec the risk of cardiac
events before the age of 40 years old is 50%. .
For females with LQT3, the QTc duration does not affect
their risk of cardiac events and their overall risk is
intermediate (30-49% before the age of 40).
Other genotypes with an intermediate risk include females
with LQT2 and males with LQT3 who have a QTc duration
< 500 msec.
All other variants are low risk and have a risk of causing a
cardiac event before the age of 40 of < 30%28.
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