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Short QT syndrome
Short QT syndrome is an inherited cardiac channelopathy characterised by an
abnormally short QT interval and an increased risk of atrial and ventricular
arrhythmias. Diagnosis is based on the evaluation of symptoms (cardiac arrest and
palpitations), patient's family history and 12-lead ECG and can at times be
challenging due to the wide range of QT intervals in healthy subjects. ICD is the first
line therapy in SQTS.
Background
Inherited arrhythmogenic diseases constitute an important cause of sudden death
(SCD). They affect mostly young and otherwise healthy people and have been
considered one of the most common causes of SCD in young athletes (1). These
conditions include long QT syndrome (LQTS), Brugada syndrome, catecholaminergic
polymorphic ventricular tachycardia and, more recently, short QT syndrome (SQTS)
(2).
SQTS is a cardiac channelopathy characterized by an abnormally short QT interval
and an increased risk of atrial and ventricular fibrillation. Although the link between a
short QT interval and sudden cardiac death had been previously suspected (3), the
first clinical cases were reported during the last decade (4,5) and the knowledge about
this syndrome has significantly increased since then.
Mechanism
As in other inherited arrhythmogenic diseases, SQTS has been related to several
mutations affecting the function of ion channels responsible for the currents that
generate the cardiac action potential. Several mutations may cause either
hyperfunction of the delayed rectifier potassium current or hypofunction of the
calcium current (figure 1). These result in a shortening of the repolarization period
and an increase in transmural dispersion of repolarization which explain the main
features of this syndrome: short QT interval, short atrial and ventricular effective
refractory periods and, as a result of them, susceptibility to atrial and ventricular
fibrillation.
Figure 1. Main dysfunction of cardiac ion channels in SQTS.
SQTS is a heterogeneous disease both from genotypic and phenotypic point of view.
Five subtypes of SQTS have been described so far, which correspond to seven
mutations in five different genes encoding different cardiac ion channels (table 1).
Table 1. Classification of SQTS according to genotype.
Most of them are familial cases and the pattern of inheritance seems to be autosomal
dominant. Interestingly, four of these five genes have been implicated in the etiology
of long QT syndrome but with mutations in the opposite sense, that’s to say, loss of
function mutations instead of gain of function mutations of potassium channels.
SQTS 1 was first described in 2004 by Brugada et al (6) and is the variant present in
the majority of patients. They reported gain of function mutations in KCNH2 that
increased IKr current and led to marked shortening of action potential in two families
with short QT interval and high incidence of sudden cardiac death.
SQTS 2 was reported in 2004 by Bellocq et al (7). They presented an alternative
molecular mechanism for a patient with short QT and ventricular fibrillation: a gain of
function mutation in KCNQ1 that enhanced IKs current. However, there are few and
sporadic cases of this variant documented so far.
One year later, Priori et al (8) identified the third variant of this syndrome (SQT3) in
two patients. A genetic defect in the KCNJ2 gene caused a significant increase in the
outward Ik1 current leading to an acceleration of the final phase of the repolarization.
Finally, in 2007, Antzelevitch et al (9) described two new variants with similar
channel dysfunction: loss-of-function mutations in genes encoding the α1- and β2bsubunits of the L-type calcium channel associated with a familial sudden cardiac
death syndrome in which a Brugada syndrome phenotype is combined with QT
intervals shorter than normal. Both mutations have been termed, respectively, SQTS 4
(2 patients) and SQTS 5 (7 patients).
Nevertheless, gene mutations have not been found in all patients with short QT
syndrome and the factors responsible of the malignancy and expression of the known
mutations have not been identified. This heterogeneity, together with the paucity of
cases, makes this a challenging field of research.
Clinical presentation
The clinical presentation of SQTS is also diverse with a high penetrance but a great
variability of expression between different families and even among members of the
same family.
SQTS is characterized by a high lethality. In the largest available case series of SQTS
(10), cardiac arrest was the most frequent symptom (34%) and the most frequent first
clinical presentation (28%). Although it usually occurs in adults (median age 30
years), the age of presentation ranges from a few months to the sixth decade of life.
Unlike LQTS, there were no specific triggers for episodes that took place at rest,
during exercise, or after loud noises. Viskin et al (11) have also reported that men
with idiopathic ventricular fibrillation show a QT shorter and a higher prevalence of
short QT interval than healthy males.
Consequently, this syndrome has to be excluded in patients without structural heart
disease presenting with sudden cardiac death.
Other symptoms often documented are syncope and palpitations. In the series of
Giustetto (10), syncope was the first presenting symptom in 24% of cases and selfterminating ventricular fibrillation (VF) episodes were considered the most likely
mechanism. Up to 31% of patients referred palpitations and atrial fibrillation was
present in more than 80% of them despite his young age (even in adolescents and
children). Atrial fibrillation constitutes one of the main findings of
SQTS and therefore it is recommended to take it into account in the
management of young patients with lone atrial fibrillation.
Diagnosis
SQTS diagnosis is based on the evaluation of symptoms, patient's family history and
12-lead ECG. It is essential to question the patient about the presence of key
symptoms (syncope and palpitations) and family history of syncope, sudden death or
atrial fibrillation at a young age. Secondary causes of short QT must also be excluded
and include hyperthermia, hyperkalemia, hypercalcemia, acidosis and alterations of
the autonomic tone.
When evaluating the ECG (figure 2) in these patients, three main aspects need to be
considered: the duration of the QT interval, the morphology of T wave and the
behaviour of both of them with the heart rate.
Figure 2. ECG taken from a patient diagnosed with SQTS: QTc 320 ms
As in LQTS, there is not a single QTc value to differentiate most cases of SQTS from
healthy individuals. In the first published series (6-8), patients presented QTc with
values shorter than 300-320 ms, while in genotypes more recently described9 (SQTS
4 and 5), they were just shorter than 360 ms. As recently reviewed by Viskin (12),
males with QTc <330 ms and females with QTc <340 ms should be diagnosed
with SQTS even if they are asymptomatic since this values are very rare in
healthy population. In addition, QTc intervals shorter than 360 and 370 ms
(males and females respectively) should only be considered diagnostic of SQTS
when supported by symptoms or family history because they overlap with
healthy population.
It is not only important to assess the value of QT but also its accommodation to heart
rate. Patients with SQTS show constant QT values and a lack of adaptation to heart
rate with failure to prolong adequately at slower heart rates and abnormal shortening
during acceleration (pseudonormalization of the QT interval at rapid rates). Serial
ECGs, Holter monitoring and treadmill testing may be useful for a correct diagnosis
and prevents unrecognition of patients with an elevated heart rate at baseline. In
addition, they can reduce wrong diagnosis in SQT patients with sinus bradycardia
since it is known that Bazett formula overcorrects the QT interval at slow heart rates.
As for the morphology of ST segment, SQTS patients share a short or even absent
ST segment, with the T wave initiating immediately after the S wave. T wave is
usually taller and narrower than in normal subjects. Recently, some features of T
wave have been published to distinguish SQTS from healthy subjects with short QT
interval. Anttonen et al (13) reported that patients with symptomatic SQTS patients
have significantly shorter Jpoint-Tpeak interval and frequently shorter Tpeak-Tend
intervals. Watanabe et al (14)observed that early repolarization was more common in
SQTS patients (65%) and, moreover, that it was associated with the appearance of
arrhythmic events. They also corroborate that duration from T-wave peak to T-wave
end was longer in these patients. T wave features can also guide about the patient’s
genotype. SQTS 16 often have tall, peaked and symmetrical T waves, SQTS 38 show
asymmetrical peaked T wave due to the acceleration of the final phase of the action
potential repolarization, and SQTS 4 and 59 coexist with Brugada type ST elevation
in precordial leads V1 and V2 at baseline or after administration of ajmaline.
Nevertheless, these data should be interpreted carefully given the small number of
patients reported so far, especially in some genotypes.
The role of electrophysiological testing in patients with SQTS remains controversial.
Some studies showed very short atrial and ventricular effective refractory periods,
high rate of inducible atrial and ventricular fibrillation, and a marked vulnerability to
mechanical induction of ventricular fibrillation (figure 3 to 5). However, in the study
of Giustetto et al10, the sensitivity of electrophysiological study for detection of
vulnerability to ventricular fibrillation was 50% (three patients out of six with
documented ventricular fibrillation), some case reports showed that noninducibility
does not exclude future ventricular fibrillation episodes (15) and the clinical
significance of inducible VF in asymptomatic patients is unknown. Therefore, it is
uncertain how useful this test could be in the diagnosis and stratification of these
patients.
Figure 3. Ventricular effective refractory period shorter than 400/140 ms.
Figure 4. Atrial effective refractory period shorter than 400/200 ms.
Figure 5. Induction of ventricular fibrillation during ventricular programmed
stimulation in a patient with SQTS
The contribution of genetic testing is not clearly defined either. To date, seven genetic
mutations have been identified but a correlation between genotype and phenotype
does not yet exist due to the relatively few cases described and genetically confirmed.
Furthermore, not all mutations are known. Isolated reported cases (16) suggest that it
may facilitate appropriate decision-making in symptomatic patients with an abnormal
but nondiagnostic ECG given the prognostic and therapeutic implications. However, a
negative test does not rule out the syndrome, as there are mutations unidentified. It
may also prove useful in family screening not only to diagnose asymptomatic carriers
at an early stage but also to definitively identify non-affected members of a certain
mutation.
Management
SQTS entails a high risk of sudden cardiac death from fatal arrhythmic events and a
high penetrance in affected families. Therefore, ICD is the mainstay therapy for these
patients. While this is obvious in symptomatic patients, doubts may arise when
dealing with asymptomatic patients, especially if they have no family history. So far,
there is not enough evidence for clear risk stratification given the low number of
documented cases and its relatively recent diagnosis. It is generally accepted that
clinical manifestations, family history and a positive electrophysiological study or
genetic test may support the implantation of an ICD. However, a negative result does
not exclude the diagnosis or the possibility of future arrhythmic events.
Even though ICD is the only effective treatment, it also has specific problems in these
patients. On the one hand, some reports showed an increased risk of inappropriate
therapy due to sinus tachycardia, atrial fibrillation and, above all, oversensing of T
wave which are often tall and narrow. In the study published by Schimpf et al (17), 3
of 5 patients received inappropriate shocks due to T wave oversensing shortly after
implantation and despite no evidence of abnormalities at prehospital discharge testing.
The reason was a postoperative reduction of the R wave amplitude and increase of the
T wave signal. Therefore adaptation of standard programming to prevent T wave
oversensing must be considered after implantation and during follow up though
always ensuring an adequate sensing of ventricular arrhythmias. On the other hand,
ICD implantation in children increases technical difficulties and complications and is
not feasible in the youngest.
Although ICD therapy is the fist line therapy, pharmacological therapy can be
indicated in some cases:




As an alternative to ICD implantation in young children
Patients with contraindications or declining ICD implantation
As an adjunctive therapy to prevent appropriate discharges
Prevention of symptomatic episodes of atrial fibrillation
However, drugs must be used with caution since the long-term efficacy of drug
therapy in preventing serious arrhythmic events has been studied only in SQTS 1
patients and is not well established.
Quinidine is considered the most effective pharmacological therapy in these patients.
It blocks several potassium channels (IKr, IKs, Ito, IKATP and IK1) and the inward
sodium and calcium currents. In SQTS 1 quinidine has shown to produce a marked
prolongation of the QT interval and ventricular effective refractory periods,
prolongation of the ST segment and T wave duration, restoration of heart rate
dependence of the QT interval, repolarization dispersion decrease and prevention of
ventricular fibrillation induction (18-20). However, the clinical consequences of these
electrophysiological effects are unknown.
Subsequent studies (21) have revealed that oral disopyramide prolongs QT interval
and ventricular effective refractory periods in patients with SQTS 1 and proposed it as
an alternative to quinidine.
Studies with other antiarrhythmics drugs have failed to show any beneficial effect.
Initially, flecainide seemed to prolong slightly QTc interval and reduce the
inducibility of ventricular fibrillation during electrophysiological study (5) but later
studies have not confirmed this effect (18). Propafenone has shown to be effective in
preventing frequent paroxysms of AF with no recurrence of arrhythmia for more than
two years, and without any effect on QT interval (22). Ibutilide and sotalol, IKr
blockers, have been demonstrated to be ineffective to prolong the QT interval (18).
Wolpert et al (19) proved that this resulted from the mutation in KCNH2 reducing the
affinity reducing the affinity of sotalol for the IKr channel unlike quinidine. It is
possible that the advantage of quinidine over sotalol is also related to its multichannel
effect.