Curriculum in Cardiology

Long QT syndrome: Diagnosis and management

Ijaz A. Khan, MD, FACP, FACC Omaha, Neb

Background Long QT syndrome (LQT) is characterized by prolongation of the QT interval, causing torsade de
pointes and sudden cardiac death. The LQT is a disorder of cardiac repolarization caused by alterations in the transmem-
brane potassium and sodium currents. Congenital LQT is a disease of transmembrane ion-channel proteins. Six genetic loci
of the disease have been identified. Sporadic cases of the disease occur as a result of spontaneous mutations. The acquired
causes of LQT include drugs, electrolyte imbalance, marked bradycardia, cocaine, organophosphorus compounds, sub-
arachnoid hemorrhage, myocardial ischemia, protein sparing fasting, autonomic neuropathy, and human immunodeficiency
virus disease.
Methods Data on the diagnosis and management of LQT were thoroughly reviewed.
Results and Conclusions The diagnosis of LQT primarily rests on clinical and electrocardiographic features and
family history. The clinical presentations range from dizziness to syncope and sudden death. Genetic screening is available
primarily as a research tool. Short-term treatment of LQT is aimed at preventing the recurrences of torsades and includes
intravenous magnesium and potassium administration, temporary cardiac pacing, withdrawal of the offending agent, correc-
tion of electrolyte imbalance, and, rarely, intravenous isoproterenol administration. The long-term treatment is aimed at
reducing the QT-interval duration and preventing the torsades and sudden death and includes use of oral β-adrenergic
blockers, implantation of permanent pacemaker/cardioverter-defibrillator, and left thoracic sympathectomy. Sodium channel
blockers are promising agents under investigation. Electrocardiograms are recorded for screening of family members. The
data favor treating asymptomatic patients, if <40 years old at the time of diagnosis, with β-adrenergic blockers. (Am Heart J
2002;143:7-14.)

Long QT syndrome (LQT) is a disorder caused by
lengthening of the repolarization phase of the ventricu-
lar action potential, although the QT interval on the sur-
face electrocardiogram (ECG) represents the total dura-
tion of both the depolarization and the repolarization
phases. Therefore it is the lengthening of the JT interval
that determines the vulnerability for development of
torsade de pointes (torsades), and the lengthening of
QT interval, because of the mere lengthening of the
duration of QRS complex, will not constitute LQT and
will not precipitate torsades. The LQT is caused by con-
genital and acquired factors. Congenital LQT is a herita-
ble ion channel disease caused by a number of muta-
tions in the genes encoding for the transmembrane
sodium or potassium ion channel proteins.1 Six subsets
of congenital LQT (LQT1 to LQT6) have been identified.
Electrophysiologically, these mutations slow the inacti-
vation of inward depolarizing sodium currents or cause
retardation of outward repolarizing potassium currents,
resulting in an increase in after depolarizations and dis-
From the Division of Cardiology, Department of Medicine, Creighton University
School of Medicine, Omaha, Neb.
Submitted April 6, 2001; accepted September 18, 2001.
Reprint requests: Ijaz A. Khan, MD, FACP, FACC, Creighton University Cardiac
Center, 3006 Webster St, Omaha, NE 68131-2044.
E-mail: ikhan@cardiac.creighton.edu
Copyright © 2002 by Mosby, Inc.
0002-8703/2002/$35.00 + 0 4/1/120295
doi:10.1067/mhj.2002.120295
persion of repolarization, both of which contribute to
the final phenotype of the syndrome.2,3 The acquired
factors causing LQT include use of drugs, hypokalemia,
hypomagnesemia, hypocalcemia, marked bradycardia,
cocaine abuse, organophosphorus compound poison-
ing, subarachnoid hemorrhage, stroke, myocardial
ischemia, protein-sparing fasting by using liquid protein
diets, autonomic neuropathy, and human immunodefi-
ciency virus disease.4-10 Multiple risk factors may inter-
play in an individual patient to prolong QT interval and
precipitate torsades.11
Diagnosis of LQT syndrome
The diagnosis of LQT primarily depends on the clini-
cal features, the family history, and the ECG findings of
the patient. Unexplained syncope or sudden cardiac
death in a child or young adult should raise a high suspi-
cion of the possibility of presence of LQT. Electrophysi-
ologic testing is not helpful in making the diagnosis of
LQT. Genetic testing has not become a routine part of
the diagnostic workup in patients with LQT, although it
could be of assistance in the borderline cases or in cases
where a new mutation is suspected. Schwartz12 and
Schwartz et al13 have proposed a set of criteria to assist
in diagnosing the LQT (Table I). These criteria provide a
quantitative approach to the diagnosis of LQT by allocat-
ing numerical points to the clinical features, family his-

8 Khan
Table I. Criteria for diagnosis of LQT syndrome
Characteristics
Clinical history
Syncope
With stress
Without stress
Congenital deafness
Family history*
Family members with definite LQT
Unexplained sudden cardiac death at age
<30 y among immediate family members
Electrocardiographic findings†
QTc
≥480 ms
460-470 ms
450 ms (in males)
Torsade de pointes
T-wave alternans
Notched T wave in 3 leads
Low heart rate for age (<2nd percentile)
Scoring: ≤1 point = low probability, 2-3 points = intermediate probability, ≥4 points
= high probability. Torsade de pointes and syncope are mutually exclusive.
*The sane family member cannot be counted twice.
†In absence of medications or disorders known to affect these electrocardiographic
features.
tory, and ECG findings and divide the possibility of LQT
into low, intermediate, and high probability ranges. In
the borderline cases, exercise testing may be per-
formed to assist in the diagnosis. The QT interval may
lengthen abnormally during the recovery phase of exer-
cise testing in patients with LQT.14,15 In a controlled
study,15 at heart rates of 110 or 100 beats/min during
recovery, 100% of LQT1 patients and 89% of LQT2
patients had QT intervals longer than any of the control
subjects.
Clinical features
The clinical features of LQT are a result of the precip-
itation of torsades, and range from minor symptoms,
such as dizziness, to seizure, syncope, and sudden
death. An individual episode of the torsades is generally
short lived, usually terminates spontaneously, and may
go unrecognized. However, it has a tendency to recur
in rapid succession and therefore may cause syncope
and death. The characteristic electrocardiographic fea-
tures of torsades include a markedly prolonged QT
interval in the last sinus beat preceding the onset of the
arrhythmia, progressive twisting of the QRS complex
polarity around an imaginary baseline, a complete 180-
degree twist of the QRS complexes in 10 to 12 beats,
changing amplitude of the QRS complexes in each
cycle in a sinusoidal fashion, a heart rate between 150
to 300 beats/min, and irregular RR intervals.16,17 The
initiation of torsades is usually dependent on a pause in
the electrical activity created by a longer cycle length,
which may be the result of bradycardia or an extrasys-
American Heart Journal
January 2002
tole. The longer cycle length usually precedes the last
supraventricular beat before initiation of the torsades.
Points
In a typical short-long-short sequence, a sinus beat is
followed by an extrasystole (short cycle), this extrasys-
tole is followed by a sinus beat after a long postex-
2 trasystolic pause (long cycle), and this sinus beat,
1 which has a longer QT interval than the preceding
0.5 sinus beats, is then followed by a ventricular beat,
1 which is the first beat of the torsades. In cases with
0.5 congenital LQT, a sudden intense adrenergic stimula-
tion can precipitate torsades.18 The sudden intense
adrenergic stimulation probably results in an extrasys-
tole, which is followed by a long postextrasystolic
3
2 pause that precipitates arrhythmia in the setting of
1 underlying long QT interval.19
2 The congenital LQT usually manifests before the age of
1 40 years, chiefly in childhood and adolescence. The age
1
0.5
at which disease manifests the first time in an individual
patient depends on the genotype of the family. Accord-
ing to the International Long QT Syndrome Registry data,
the median age at which the first cardiac event occurred
was 9, 12, and 16 years in subjects with LQT1 (n = 112
subjects), LQT2 (n = 72 subjects), and LQT3 (n = 62 sub-
jects), respectively.20 Men are less prone to the develop-
ment of cardiac events because of shorter QT intervals
compared with women, boys, and girls, especially in
LQT1 and LQT2 groups.21-23 The shorter QT interval for
men is most evident for heart rates <60 beats/min. The
risk of torsades and sudden death is highest at the early
waking hours, which correlates with the diurnal peak of
the QT interval at that time.
The prolongation of QT interval is a risk factor for
sudden cardiac death independent of the patient’s age,
history of myocardial infarction, heart rate, and history
of drug use; the patients with a QTc interval of >440
milliseconds are at 2 to 3 times higher risk for sudden
cardiac death than those with a QTc interval of <440
milliseconds.24 The mortality rate in untreated patients
with LQT is in the range of 1% to 2% per year. The inci-
dence of sudden death varies from family to family as a
function of the genotype.20,25 In the data published
from the International Long-QT Syndrome Registry, the
frequency of cardiac events was significantly higher
among subjects with LQT1 (63%) or LQT2 (46%) than
among subjects with LQT3 (18%).20 The cumulative
mortality through the age of 40 years was similar
among subjects of all 3 genotypes, but the likelihood of
dying during a cardiac event was significantly higher
among the subjects with LQT3 (20%) than among those
with LQT1 (4%) or LQT2 (4%). The mean QTc interval
was significantly longer in the LQT3 group (510 ± 48
ms) than that in the LQT1 (490 ± 43 ms) or LQT2 (495
± 43 ms) groups. Sudden cardiac death in patients with
congenital LQT is often precipitated by a triggering
event, such as physical exercise, swimming, sleep
deprivation, auditory stimuli, and sudden intense sym-
American Heart Journal
Volume 143, Number 1
pathetic stimuli including grief, fright, pain, anger, fear,
or startle.26,27 These events tend to cluster in families as
a function of the genotype.26 Physical exercise is more
prone to precipitate cardiac events in patients with
LQT1, auditory stimuli in patients with LQT2, and rest
and sleep in patients with LQT3.26-28 Although the
cause of death during rest and sleep in patients with
LQT3 is not well established, it well reflects brady-
arrhythmia-induced torsades because bradycardia and
pauses have been reported with LQT3. The high-risk
predictors of sudden cardiac death in patients with con-
genital LQT include recurrent episodes of syncope, fail-
ure on conventional medical therapy, survival from car-
diac arrest, congenital deafness, female sex, QTc >600
milliseconds, relative bradycardia, kinship with a symp-
tomatic patient, and sudden cardiac death in a family
member at an early age.29
Family history and genetics
A family history of unexplained syncope or sudden
death, especially in the young family members of a pa-
tient with unexplained syncope or sudden death, should
raise a strong suspicion of congenital LQT. Initially, the 2
well-described forms of the congenital LQT were the
Jervell Lange-Nielsen syndrome and the Romano Ward
syndrome. The Jervell Lange-Nielsen syndrome is a rare
cardioauditory syndrome where the deafness is inherited
in an autosomal recessive pattern, and the marked QTc
prolongation reflects the double-dominant inheritance of
2 mutant alleles.30 The more common Romano Ward syn-
drome, associated with normal hearing, is inherited in an
autosomal dominant pattern.31,32
During last decade, significant advancements have
been made in determining the genetic basis of the con-
genital LQT, and on the basis of ion channel and the
gene involved, 6 subtypes of congenital LQT have been
characterized. Mutations in the KCNQ1 (KVLQT1)
gene, located on chromosome 11, cause LQT1. The
KCNQ1 gene encodes the α-subunit of a cardiac potas-
sium channel IKs—the slowly activating potassium-
delayed rectifier.33 The LQT1 is the principal gene
responsible for both Jervell Lange-Nielsen and Romano
Ward syndromes, and it accounts for approximately
50% of the genotyped LQT families.34 The mutations in
the HERG gene, located on chromosome 7, cause
LQT2. The HERG gene encodes for another cardiac
potassium channel IKr—the rapidly activating potas-
sium-delayed rectifier.35 The LQT2 accounts for
approximately 45% of the genotyped LQT families. The
mutations in the SCN5A gene, located on chromosome
3, cause LQT3. The SCN5A gene encodes a cardiac
sodium channel INa—the cardiac voltage-dependent
sodium channel.36 The LQT3 accounts for approxi-
mately 5% of the genotyped LQT families. Interestingly,
mutations in the same gene but at different loci result
in Brugada syndrome and progressive conduction sys-
Khan 9
tem disease (Lenegre-Lev disease). However, these
mutations are loss of function type mutations contrary
to the gain in function type mutations in LQT3. The
LQT4 locus has been identified at chromosome 4 in
one large French kindred but the responsible gene has
not been identified yet.37 The mutations in the KCNE1
(minK) gene, located on chromosome 21, cause LQT5.
The KCNE1 gene encodes the β-subunit of the cardiac
potassium channel IKs.38 The KCNQ1 (LQT1) and
KCNE1 (LQT5) gene products assemble to form a com-
plete IKs channel protein. The LQT5 accounts for only a
small number of the genotyped LQT families. The muta-
tions in the KCNE2 (MiRP1) gene, located on chromo-
some 21 cause LQT6.39 The KCNE2 (MiRP1) gene
encodes a small membrane protein, which is consid-
ered a part of the IKr channel.39 The HERG (LQT2) and
KCNE2 (LQT6) gene products assemble to form a com-
plete IKr channel protein. Although currently >300
mutations have been discovered in the 5 known LQT
genes, not all the genes responsible for LQT have been
identified. In addition, the sporadic cases of LQT occur
as a result of spontaneous mutations. Therefore a lack
of family history does not entirely preclude the diagno-
sis of congenital LQT.
ECG findings
In the majority of patients with congenital LQT, the
QTc interval is >440 milliseconds, but in 6% to 12% of
patients the QTc interval is within normal limits, and
about one third of the patients have a QTc interval
≤460 milliseconds.20,40 The other ECG features, espe-
cially accompanying T-wave and U-wave abnormalities,
may assist in diagnosis, especially in cases where the
QTc interval is within normal limits or is borderline
high.40 Sinus bradycardia with sinus pauses has been
reported in up to one third of the patients with congen-
ital LQT, especially so in patients with LQT3.41 Another
ECG feature of the LQT is increased QT interval disper-
sion, which is due to labile repolarization in LQT.42
The T wave could be larger, prolonged, and bizarre
looking and may display a notched, bifid, biphasic, or
alternans appearance.40,43 T-wave alternans is a diag-
nostic feature of the LQT and reflects an enhanced elec-
trical instability during repolarization.43 The different
genotypes of LQT may display specific ECG pheno-
types. Zhang et al40 identified 10 ST-T wave repolariza-
tion patterns in LQT (4 in LQT1 genotype, 4 in LQT2
genotype, 2 in LQT3 genotype). The repolarization pat-
terns identified in LQT1 were of infantile ST-T wave,
broad-based T wave, normal-appearing T wave, and
late-onset normal-appearing T wave; those identified in
LQT2 were of obvious bifid T wave, subtle bifid T wave
with second component on top of T wave in limb and
left precordial leads, subtle bifid T wave with second
component on down slope of T wave in inferior and
mid precordial leads, and low-amplitude bifid T wave

10 Khan
with second component merged with U wave; and
those identified with LQT3 were of late-onset peaked/
biphasic T wave and asymmetric peaked T wave. These
repolarization patterns had sensitivity of 61% to 100%,
62% to 100%, and 33% to 100%; and specificity of 71%
to 100%, 87% to 100%, and 98% to 100% for identifying
LQT1, LQT2, and LQT3, respectively. However, overlap
existed among the repolarization patterns of 3 geno-
types, and one third of LQT3 gene carriers had repolar-
ization patterns similar to those of LQT1 gene carriers.
The sensitivities and specificities were higher with fam-
ily-grouped analysis. The U-wave abnormalities re-
ported in LQT include prominent bizarre looking U
waves and U-wave alternans. The T- and U-wave abnor-
malities in LQT have been reported to exaggerate with
excessive sympathetic stimulation.43
Management of LQT syndrome
Short-term treatment
Immediate cardioversion should be done in situations
where torsades does not terminate spontaneously and
results in hemodynamic compromise. The short-term
treatment, which is aimed at prevention of the recur-
rences of torsades, includes withdrawal of the offend-
ing agents, correction of the underlying electrolyte
abnormalities, and administration of magnesium, potas-
sium, temporary transvenous cardiac pacing, and rarely
intravenous isoproterenol. The magnesium, potassium,
and temporary transvenous cardiac pacing are useful
for both congenital and acquired forms of the LQT, but
use of intravenous isoproterenol is limited to acquired
LQT only.
Withdrawal of the offending agent. Withdrawal of
the offending agent is a crucial first step in the preven-
tion of the recurrence of the torsades. Drugs are the
most common offending agents. The important cardiac
drugs that have been reported to prolong the QT inter-
val are bepridil; phenylamine; class IA antiarrhythmic
agents including, quinidine, procainamide, and disopyr-
amide; and class III antiarrhythmic agents including,
sotalol, ibutilide, azimilide, dofetilide, and amiodarone,
although amiodarone is rarely associated with torsades.
Class IC antiarrhythmic drugs have been implicated in
torsades, but such reports are discredited because the
QT-interval prolongation, if any, with the use of class IC
antiarrhythmic drugs will be due to the prolongation of
the QRS-complex duration (depolarization), not the
prolongation of the JT interval (repolarization), and it is
the prolongation of the repolarization that precipitate
torsades, not that of the depolarization. A number of
noncardiac drugs have been reported to prolong QT
interval, including cisapride, probucol, ketanserin,
papaverine, tacrolimus, arsenic trioxide, phenothi-
azines, haloperidol, tricyclic antidepressants, antimicro-
bial agents (erythromycin, grepafloxacin, moxifloxacin,
American Heart Journal
January 2002
pentamidine, amantidine, chloroquine, and trimetho-
prim-sulphamethoxazole), antifungal agents (ketocona-
zole and itraconazole), and antihistamines (terfenadine
and astemizole).44 A full list of cardiac and noncardiac
drugs that have been reported to prolong the QT inter-
val is available at www.qtdrugs.org.
The QT-interval prolongation resulting from the use
of drugs is a patient-specific phenomenon, which indi-
cates that the patients who have a drug-induced long
QT interval may be genetically predisposed because of
the presence of an underlying mild or attenuated form
of congenital LQT.44,45 The principal ion channel
affected by the QT-interval prolonging drugs is IKr
(HERG), which, interestingly, is the same ion channel
that causes congenital LQT2.45 Therefore, a physiologic
relationship may exist between drug-induced LQT and
congenital LQT2, which further strengthens the possi-
bility of a genetic basis for predisposition to the drug-
induced LQT. Hence, drug-induced LQT may raise a
possibility of the presence of an LQT locus in the family
and thus may logically lend an extra caution in using
the QT-prolonging drugs in the other family members,
although this has not been examined prospectively.
Certain acquired factors including left ventricular
hypertrophy, myocardial ischemia, and myocardial
fibrosis have been reported to facilitate the drug-
induced prolongation of the QT interval.44,46 Therefore
the QT prolonging drugs should be used with caution
in patients with these conditions.
Magnesium. Magnesium is very effective for suppres-
sion of the short-term recurrences of torsades and is the
agent of choice for the immediate treatment of the tor-
sades associated with both congenital and acquired
forms of LQT, irrespective of serum magnesium lev-
els.47 A single bolus of 2 g of magnesium sulfate is
administered over a period of 2 to 3 minutes, followed
by an intravenous infusion of magnesium at a rate of 2
to 4 mg/min, and a second bolus of 2 g of magnesium
sulfate may be given if the torsades recurs while the
patient is receiving the intravenous infusion of magne-
sium. The exact mode of action of magnesium in pre-
venting the recurrences of torsades is not clear, but its
effect may be mediated by blockade of sodium cur-
rents.48 Magnesium does not shorten the QTc interval
significantly and has no significant role in the long-term
management of LQT. The treatment with intravenous
magnesium is very safe and can be initiated as soon as
the diagnosis is made. The only side effect reported
with the use of intravenous magnesium therapy is a
flushing sensation during the bolus injection.
Potassium. Administration of potassium is considered
an important adjunct to the intravenous magnesium
therapy for the short-term prevention of the torsades,
especially in the cases where the serum potassium level
is in the lower limits. Data suggest that in patients with
LQT2 high normal (4.5-5 mEq/L) levels of serum potas-
American Heart Journal
Volume 143, Number 1
sium are preferable to low normal (4-4.5 mEq/L) levels.
In a controlled study, Compton et al49 examined the
effect of potassium administration on QT interval in 7
subjects with mutant HERG gene (LQT2). The serum
potassium level was raised by ≥1.5 mEq/L by giving oral
potassium chloride (60 mEq every 2 hours), intra-
venous infusion of potassium chloride (20 mEq/h), and
oral spironolactone (200 mg, followed by 100 mg every
2 hours). The increase in the serum potassium levels
resulted in a significant shortening (24%) in the QTc
interval in subjects with mutant HERG gene (from 617
± 92 ms to 469 ± 23 ms) but not in control subjects. In
addition, by increasing the serum potassium level, the
QTc dispersion decreased significantly in subjects with
mutant HERG gene (133 ± 62 ms to 42 ± 28 ms) but did
not change in control subjects. However, caution
should be used against the development of hyper-
kalemia while intending to maintain the serum potas-
sium level in the high normal range.
Temporary transvenous cardiac pacing. Temporary
transvenous cardiac pacing at rates around 100 beats/
min is another highly effective measure to prevent the
short-term recurrence of the torsades associated with
both acquired and congenital forms of LQT.50 A tempo-
rary transvenous pacemaker should be placed if intra-
venous magnesium therapy fails to prevent the recur-
rence of the torsades. The cardiac pacing prevents
pauses and shortens the QTc interval by enhancing the
repolarizing potassium currents as a result of increased
heart rates.51 Although cardiac pacing is effective in
preventing the recurrence of the torsades irrespective
of the baseline heart rate, it is of particular value in the
patients who display bradycardia or pauses.
Isoproterenol. Isoproterenol used to be the drug of
choice to prevent the short-term recurrence of torsades
before the use of magnesium and cardiac pacing. Iso-
proterenol controls the short-term recurrence of tor-
sades by increasing the heart rate, especially where
recurrence is dependent on the bradycardia or
pauses.52 Isoproterenol may be used when specially
trained medical personnel are not available to insert a
temporary transvenous pacemaker. When used, it is
administered as a continuous intravenous infusion at
doses sufficient to maintain the heart rate at around 100
beats/min. Because of its adrenergic effects, isopro-
terenol should not be used in patients with congenital
LQT. For similar reasons, it should be used cautiously in
patients with structural heart disease. Another limiting
factor in the use of isoproterenol is the scarcity of the
drug. The common side effects reported with the use
of isoproterenol infusion are palpitations and feeling of
flushing sensations.
Long-term treatment
Long-term treatment is generally not required in cases
with acquired prolongation of the QT interval because
Khan 11
the QT interval often becomes normal by treating the
underlying cause. The torsades in these situations, how-
ever, often require acute emergency treatment along
with the withdrawal of the offending agents and cor-
rection of the electrolyte imbalance. The long-term
treatment of acquired LQT is limited to permanent
pacemaker implantation in patients with sick sinus syn-
drome or atrioventricular block in whom a pause or the
bradycardia is a precipitating event for torsades. On the
other hand, long-term treatment of congenital LQT is
mandatory and is aimed to prevent the recurrence of
torsades by shortening the QTc interval. The standard
treatment options available for long-term management
of the patients with congenital LQT are the use of oral
β-adrenergic blockers, permanent pacemaker place-
ment, and implantation of cardioverter-defibrillator.
Therapies targeting the mutated ion channels are under
investigation. Education of the patient is crucial to
avoid risk-associated behaviors.
β-Adrenergic blockers. Long-term treatment with β-
adrenergic blockers has shown to result in a significant
reduction in the incidence of cardiac events in patients
with congenital LQT.52,53 According to a recently pub-
lished report,53 long-term β-adrenergic blocker therapy
has been shown to result in a significant reduction in
the rates of cardiac events in probands (0.97 ± 1.42
events/year before vs 0.31 ± 0.86 events/year after initi-
ation of β-blockers) and in affected family members
(0.26 ± 0.84 events/year before vs 0.15 ± 0.69
events/year after initiation of β-blockers) during a 5-
year matched period. Among β-adrenergic blocking
agents, propranolol has been widely used at a daily
dose of 2 to 3 mg/kg, but all β-blockers should be effec-
tive, as protection against the precipitation of torsades
provided by the use of β-blocker class effect. The dose
of β-adrenergic blocking agent should be maximized,
aiming a maximal heart rate of 130 beats/min or less on
treadmill exercise testing. Therapy with β-adrenergic
blockers should be continued for life and should be
supplemented with implantation of a permanent pace-
maker in cases where bradycardia is a prominent fea-
ture of the syndrome.54 β-Adrenergic blocking agents
are most efficacious in LQT1, where exercise and phys-
ical exertion are the most common triggers for an
arrhythmic event.28
Left thoracic sympathectomy. High left thoracic
sympathectomy has been used, chiefly in Europe, as
second-line therapy in patients who were nonrespon-
ders to β-adrenergic blockers. It is a highly effective
method of surgical antiadrenergic therapy but now has
been largely replaced with permanent pacemaker and
cardioverter-defibrillator implantation.55
Permanent pacemaker and cardioverter-defibrilla-
tor. Implantation of a permanent pacemaker is a stan-
dard adjunct to β-adrenergic blocker therapy in patients
who are symptomatic despite being on the full doses of

12 Khan
β-adrenergic blockers and in cases where bradycardia is
a prominent feature of the syndrome.56,57 β-Adrenergic
blocker therapy should be continued along with im-
plantation of the permanent pacemaker.58 Pacing rates
should be adjusted to normalize QT interval, and the
pacemaker features that allow heart rate slowing be-
yond the lower rate limit or that may trigger pauses
should be turned off because such pauses could be
highly proarrhythmic in this patient population.59 The
patients with LQT3 have been reported to more likely
benefit from permanent cardiac pacing because they
are more prone to have sudden cardiac death at slower
heart rates.54
Implantable cardioverter-defibrillators are used when
the combination of the β-adrenergic blocker therapy
and the pacing fails to prevent presyncopal or syncopal
episodes or when the initial presenting event is a resus-
citated cardiac arrest.60 Because of the availability of
the cardioverter-defibrillator with dual-chamber pacing
capabilities and because of the potential lethality of the
failure of β-blocker therapy, many electrophysiologists
today prefer to use this device as first-line therapy to
prevent sudden cardiac death in all symptomatic
patients with congenital LQT. The implantable car-
dioverter-defibrillator will not prevent the precipitation
of torsades but will prevent sudden cardiac death when
torsades is prolonged or degenerates to ventricular fi-
brillation. Therefore, to prevent the precipitation of tor-
sades, the use of a β-adrenergic blocking agent should
be continued along with the implantation of the car-
dioverter-defibrillator. The unnecessary shocks from
the cardioverter-defibrillator device and the emotional
distress associated with these shocks may cause adren-
ergic stimulation sufficient to result in the precipitation
of torsades, which gives an even stronger position for
continuation of the β-adrenergic blocker therapy after
implantation of a cardioverter-defibrillator.52
Mutation-specific therapies. Knowledge about the
mutations causing congenital LQT has initiated research
on the therapies targeted at the mutant ion channels.61
The sodium channel blockers flecainide and mexiletine
have been reported beneficial in the LQT3, which is
caused by a gain in function-type mutations in SCN5A—
a gene that encodes for a cardiac sodium channel.62-64
Benhorin et al62 tested the effect of flecainide (75 to
150 mg twice daily orally) on QTc interval in 8 asymp-
tomatic carriers of the SCN5A mutation (LQT3). Fle-
cainide therapy significantly shortened the QT interval
(from 523 ± 94 ms to 435 ± 40 ms) and QTc interval
(from 517 ± 45 ms to 468 ± 36 ms). In an animal
model, mexiletine was also reported to markedly
shorten the erythromycin-induced prolongation of the
action potential duration and abolish the erythromycin-
induced early afterdepolarizations.65 Other sodium
channel blockers including lidocaine, phenytoin, and
pentisomide have been reported to be beneficial for
American Heart Journal
January 2002
termination or prevention of short-term recurrences of
the torsades, but the effectiveness of these agents has
not been consistent.66 Similarly, many other experi-
mental agents tested, including potassium channel acti-
vators (nicorandil, pinacidil) and calcium channel
blockers, have shown inconsistent results and await fur-
ther investigation.67,68 Currently, these agents may be
considered only as adjuncts to the standard therapy.
Screening of family members. Each child of a par-
ent affected with Romano Ward syndrome has a 50%
chance of inheriting the LQT gene. The ECGs of all the
family members of a patient with LQT are recorded for
screening. The identification of QTc interval prolonga-
tion and T-wave abnormalities in the family members of
a patients with sudden cardiac death is suggestive of
presence of the LQT gene in the family and will likely
establish LQT as the cause of death in the deceased
family member. The genetic screening is available but
primarily as a research tool. Routine genetic screening
is not feasible currently because only about 60% of fam-
ilies that have been clinically diagnosed with LQT can
be genotyped.69 Furthermore, numerous different
genetic mutations have been discovered involving each
of the known LQT genes, making screening labori-
ous.70,71 Nonetheless, genetic testing is available on a
limited basis for those who want to know whether they
are genetic carriers, but with the caution that negative
results would not entirely rule out the possibility of har-
boring the LQT gene. Family-grouped ECG analysis
improves the accuracy of genotype identification and
can simplify genetic screening by targeting the gene for
initial study.40
Treatment of asymptomatic patients The treatment
option offered for asymptomatic patients with LQT is
the long-term use of a β-adrenergic blocker agent, the
dose of which should be maximized aiming at a maxi-
mal heart rate of ≤130 beats/min on treadmill exercise
testing. It is generally recommended to treat all asymp-
tomatic patients <40 years old at the time of diagnosis
because it is not possible to predict which asympto-
matic patient will become symptomatic and 30% to
40% of sudden deaths occur at the first event.72,73 Fur-
thermore, although most cases of inherited LQT usually
manifest clinically in early childhood, the possibility of
a late manifestation of the disease cannot be ruled out,
which makes the case stronger for treating asympto-
matic patients.74 However, on the other hand, some
investigators have recommended treating asymptomatic
patients only if they have high-risk characteristics,
including the presence of congenital deafness, QTc
interval >600 milliseconds, T-wave alternans, neonates
and infants, or affected siblings of children who have
died suddenly or if the family desires treatment.75
Patient education. Patients with congenital LQT
should be well informed about the risk-associated
behaviors to prevent sudden death, about compliance
American Heart Journal
Volume 143, Number 1
to β-blocker therapy, and about the resources available
to provide information on the progress being made in
the management of LQT. They should be aware of the
drugs and substances with known risk of precipitating
torsades. Educational information for patients is pro-
vided at several Web sites, including www.sads.org and
www.qtsyndrome.ch.
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