Key Words: short
QT interval, congenital short QT syndrome
Congenital short QT syndrome (SQTS) is characterised by
extremely short QT intervals, typically with QTc less than 330
ms and a propensity for life threatening ventricular
arrhythmias and atrial fibrillation [1-3]. The QT interval in
SQTS does not change significantly with heart rate and the T
waves have a narrow base and high voltage, similar to those in
hyperkalemia [4,5].
Before a diagnosis of SQTS can be considered, intake of drugs
like digoxin and hypercalcemia which can shorten the QT
interval have to be excluded. Newly introduced antiepiletptic
drug rufinamide has the potential to shorten QT interval
though clinical adverse effects have not been reported [6].
Shorter QTc intervals have been reported in males with
Klinefelter syndrome, which is further aggravated with the
administration of testosterone [7].
A recent analysis of 6.4 million electrocardiograms (ECG) from
1.7 million persons recorded between 1995 and 2008 gave a
prevalence of short QTc of 0.7 per 100,000 ECGs and 2.7 per
100,000 persons. The cut off for short QTc was 300 ms in this
study [8]. There was a 2.6 fold higher risk of death in those
with short QTc over an 8.3 year follow up period in this large
population based sample.
Analysis of a large hospital based database of 114,334
patients yielded 427 patients with short QT interval [9]. Two
of them developed life threatening events on follow up, of
which one had additional early repolarization pattern.
Prevalence of atrial fibrillation was higher in those with
short QT interval than in general population.
In contrast, a study involving 18,825 low risk individuals
including athletes documented 0.1% prevalence of QT interval
320 ms or less, with no syncope, sinister family history or
mortality [10]. The mean follow up period in this report was
5.3 years.
SQTS was the least common among inherited arrhythmia
syndromes, contributing only 1.97% in a European Heart Rhythm
Association (EHRA) Survey [11].
Genotype and age of onset
Of the six genotypes, SQT1 has later age of onset in SQT1 (35
+/- 19 years) compared to SQT2 (17 +/- 25 years) and SQT3-6
(19+/-15 years) has been reported by Harrell et al
[12]. Villafane J and colleagues [13] identified 4
children in reported series and 2 followed by them with SQTS.
All those children who underwent genetic testing had gain of
function mutation in KCNQ1 gene, corresponding to SQT2. The
authors have documented neonatal atrial fibrillation and
bradycardia with SQTS in a subgroup. This subset of children
may have persistent bradycardia in utero. Righi D et al [14]
has also documented sinus bradycardia with short QT interval
at birth which later progressed to junctional bradycardia in
infancy and atrial fibrillation with slow ventricular rate in
adolescence. This asymptomatic girl had a mutation in KCNQ1
gene and has been followed up for 20 years.
Neurodevelopmental disorders in SQTS
SQTS3 is due to mutations in Kir2.1 channels encoded by the
gene KCNJ2. Neurodevelopmental disorders have been associated
with cardiac rhythm disorders in SQTS3. Ambrosini E et
al [15] noted co-occurrence of short QT interval on ECG and
autism-epilepsy phenotype in monozygotic twins. Their findings
suggested the need for neuropsychiatric evaluation in patients
with SQTS.
Incomplete penetrance
So far it has been thought that SQTS has a high penetrance in
that genotype positive, phenotype negative cases are seldom
seen [16]. But Harrell DT et al [12] noted that the penetrance
was only 82% in their series. Nine of the 51 mutation positive
individuals from 16 SQTS families did not have a short QT, but
had other abnormalities on ECG like atrial fibrillation.
Altered ventricular function in SQTS
Apart from the propensity for arrhythmias, abnormalities of
left ventricular function has also been reported in SQTS. Frea
S and colleagues [17] evaluated left ventricular function and
mechanical dispersion by tissue Doppler and speckle tracking
and tried to correlate with QT interval and genetic mutations.
Of the 15 patients studied, 7 had HERG mutations and 3 had
KCNQ1 mutations. Mechanical dispersion assessed by tissue
Doppler was more in SQTS than in controls and showed an
inverse correlation with QT interval. There was also evidence
of reduced global longitudinal strain and myocardial
performance index.
PQ segment depression in SQTS
The usual causes of PQ segment depression are atrial
infarction and pericarditis. But it has also been suggested as
a marker of SQTS. In one series, 52 of 64 patients with SQTS
(81%) had PQ segment depression [18]. All the nine patients in
this series who presented with atrial tachyarrhythmias had PQ
segment depression. The authors suggested that PQ segment
depression may constitute a novel maker for SQTS.
Role of exercise testing
It is well known that exercise testing has a role in the
evaluation of certain cases of long QT syndrome [19]. The role
of exercise testing in SQTS was evaluated by Giustetto C et al
[Giustetto C 2015]. Twenty one SQTS patients and 20 matched
controls underwent an exercise test. SQTS patients showed a
reduction in the adaptation of QT interval to heart rate,
suggesting that exercise testing could be a useful tool in
diagnosing the disease.
Carnitine deficiency and SQTS
Till recently only mutations in cardiac potassium and calcium
channel genes have been implicated in SQTS. Three patients
with primary systemic carnitine deficiency and SQTS were
reported by Roussel J et al [20]. The presenting symptom in
one of them was ventricular fibrillation during early
adulthood. The authors further created a mouse model of
carnitine deficiency by administration of mildronate and
demostrated shortening of QT interval which correlated
negatively with plasma carnitine concentration. There were
associated ventricular tachyarrhythmias coinciding with QT
interval shortening.
Natural history of SQTS
Cardiac arrest was the most frequent presenting symptom which
occurred in 40% of the probands, with an age range of less
than one month to 41 years [16]. In this large cohort of 73
SQTS patients, cardiac arrest occurred at a rate of 4% in the
first year of life and 1.3% per year in third to fifth
decades. The probability of occurrence of cardiac arrest was
41% within the first four decades of life. Previous history of
cardiac arrest was the only predictor of a recurrence at
follow up, with a p value of less than 0.0000001. The median
follow up was 56 months in 62 patients included in the study.
Risk stratification
After evaluating the data from 61 published cases, Gollob MH
et al proposed diagnostic criteria for SQTS in 2011 [21].
Points were allotted to QT inerval with 1 point if if it was
lesser than 370 ms and 3 points if less than 330 ms, clinical
history of sudden cardiac arrest, documented arrhythmias,
unexplained syncope, family history and genotype. High
probability of SQTS was considered if there were 4 or more
points and low probability if there were only 2 or less number
of points. In this scoring at least one point should be scored
among the electrocardiographic criteria to obtain additional
points from other sections. Points in the clinical history and
family history could be considered only once for the scoring.
A modified Gollob Score was published by Villafane J and
colleagues in 2013 [22]. The modified Gollob Score did not
give points for clinical history and documented arrhythmias
while other criteria were retained. As in the Gollob Score
points for family history could be received only once in the
section.
But in one of the largest single centre natural history study
by Mazzanti et al, [16] 5 of the 8 patients who experienced
cardiac arrest had a low probability modified Gollob score of
3 or less. Hence the authors urged for caution in using the
scoring system for risk stratification.
T wave alternans is considered as a useful risk marker for
arrhythmia. But a study involving 13 patients with SQTS found
that it was negative in 12 of them [23]. Hence measurement of
microvolt T wave alternans using conventional protocol may not
be useful as a risk marker in SQTS.
Pharmacotherapy in SQTS
Hydroquinidine was used for long term prophylaxis in 12 of th
53 patients enrolled in the European Short QT registry. It was
effective in preventing induction of ventricular arrhythmias
as well as prevention of arrhythmic events [24]. It was also
noted that those with HERG (SQT1) mutation who had shorter QTc
at baseline had a greater prolongation of QTc on treatment
with hydoquinidine.
It has been mentioned that combined therapy with potassium
channel blockers and beta blockers are effective in SQTS. But
there could be different effects for betablockers in SQT1 and
SQT2, at least in experimental situations [25]. Nifekalant, an
anti arrhythmic agent being used in Japan produced
prolongation of QT interval after intravenous administration
in patient with SQTS1. But it is not certain whether this will
translate to reduction of the arrhythmic risk in SQTS [26].
Isoprenaline infusion was in successfully managing an
electrical storm in patient with SQTS admitted after an
aborted sudden cardiac death [27]. Recurrent arrhythmias in
SQTS was treated with quinidine in 50%, beta blockers in 19%
and isoprenaline infusion in 8% of cases as per the the recent
EHRA survey report [11] .
Implantable cardioverter defibillator
Implanatable cardioverter defibrillator (ICD) is definitely
indicated in all cases with a history of resuscitated cardiac
arrest. In an EHRA survey, 50% of SQTS patients received an
ICD while 18% received both ICD and drugs [11].
There is a higher incidence of inappropriate shocks in SQTS
because the tall T waves get counted as along with QRS
sometimes, leading to a spurious high heart rate as detected
by the ICD. The most important predictor of appropriate shocks
is a previous history of cardiac arrest.
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