Cardiovascular Research 2006 70(3):404-406; doi:10.1016/j.cardiores.2006.04.006
Copyright © 2006, European Society of Cardiology
Low penetrance, subclinical congenital LQTS: Concealed LQTS or silent LQTS?
Andras Varróa,* and
Julius Gy. Pappa,b
aDepartment of Pharmacology and Pharmacotherapy, University of Szeged, H-6720 Szeged, Dóm tér 12, PO Box 427, Hungary
bDivision for Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary
* Corresponding author. Email address: a.varro{at}phcol.szote.u-szeged.hu
Received 20 March 2006; accepted 5 April 2006
See article by Boulet et al. [1] (pages 466–474) in this issue.
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1. ‘Silent long QT syndrome’
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The paper by Boulet et al. in this issue
[1] describes the electrophysiological
basis of an ion channel malfunction reported in ‘a silent
LQTS’ patient. This patient, a 40-year-old woman, had
a documented syncopal event, palpitations, recurrent chest discomfort,
tachycardia, and since diagnosis has been asymptomatic on β-blocker
therapy
[2].
Genetic analysis revealed a loss-of-function mutation in the KCNQ1 gene underlying the 
subunit of the IKs potassium channel. It is important and interesting that this patient had a QTc interval of 430 ms, which is well within the normal range in women. Although there is no strict rule, QT prolongation is generally considered when the QTc interval is longer than 440 ms in men and 460 ms in women [3]. Therefore, the results of Boulet et al. demonstrated and discussed that a loss of function mutation in an important major potassium current (IKs) can result in torsades de pointes arrhythmia and syncope with normal QTc. The authors concluded that this mutation could be considered as a silent LQT1 syndrome, confirming the view regarding the important role of the IKs channel known to contribute to the repolarization reserve. This case and the underlying mechanism resemble well the previously described so-called subclinical congenital LQTS, concealed LQTS, and incomplete or low penetrance [4].
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2. Repolarization reserve
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The concept of repolarization reserve was suggested by Roden
and Yang
[5–7]. According this terminology, normal repolarization
is accomplished by multiple different potassium channels, providing
a strong safety reserve for normal repolarization. Thus, in
an ordinary situation the pharmacological block or impairment
of one single type of potassium channel does not necessarily
lead to QT interval prolongation. However, in the presence of
a subclinical impairment in the repolarization process, an otherwise
mild potassium channel block may precipitate marked QT prolongation,
which can result in torsades de pointes arrhythmia.
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3. Congenital long QT syndromes and IKs
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Congenital LQT syndrome is rather infrequent in the general
population (1/5000) if identified by QT prolongation on the
surface ECG during clinical evaluation of unexplained syncope
[4]. The cause of the syncope that occurs in this disorder is
due to transient rapid polymorphic ventricular tachycardia known
as torsades de pointes linked to delayed repolarization of the
cardiac ventricular muscle. Thus far, seven LQTs (LQT1–7)
caused by several hundred different mutations in the I
Ks, I
Kr,
I
Na, I
K1 and β subunits have been well characterized
[8–11].
"Among the three most common LQTS genotyped (LQT1–3),
LQT1 probably hosts the largest percentage of genotype-positive
individuals displaying a normal/borderline resting QTc" as was
described in a recent review by Ackerman
[12]. Similarly, simple
pharmacological modulation of I
Kr, I
Na and I
K1 channels also
prolongs ventricular repolarization, resulting in drug-induced
LQTs
[13]. In contrast, even full pharmacological block of I
Ks does not lengthen repolarization in the ventricle unless sympathetic
tone is enhanced
[14,15] or repolarization had been delayed
previously by other means
[16]. Based on these observations
it was concluded that the I
Ks (KvLQT1+minK) channel is not a
major contributing factor to "normal" repolarization, but it
is an important source of the repolarization reserve that opposes
excessive lengthening of action potential duration and consequently
protects against torsades de pointes arrhythmia during possible
impairment or change in normal function of other transmembrane
ion channels. The study by Boulet et al.
[1] in this issue may
also indicate that a genetic loss of I
Ks function does not necessarily
prolong repolarization reflecting normal QTc of the patient.
However, under some unfavourable conditions (e.g. hypokalemia,
drug effects, downregulation of potassium channels), the impairment
of the repolarization reserve could not provide the necessary
protection, making this patient more vulnerable toward arrhythmia
than those who lack defective I
Ks channels. In accordance with
this speculation, Kääb et al.
[17] reported that patients
who experienced torsades de pointes arrhythmia with QT-prolonging
drugs developed more QTc lengthening after i.v. sotalol, an
I
Kr blocking drug, than those of the control group consisting
of patients without a history of torsades de pointes. The interesting
observation in this study was that in both groups, the baseline
QTc was normal and did not differ between the groups (see
Fig. 1).
Although genetic testing has not been carried out in these patients,
it can be assumed that the individuals who responded to sotalol
might have had ‘subclinical-concealed-silent’ LQTS.
Based on these results, the authors suggested that the administration
of provocative drug tests under controlled situations might
help in identifying selected patients at risk for developing
torsades de pointes arrhythmia.
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Fig. 1 Individual QTc intervals in control and study groups before and after sotalol. The dotted line indicates a cut-off value of 480 ms that distinguished best between the study population and the control group (from Ref. [17], used with permission).
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4. Downregulation and pharmacological block of IKs as a possible link to decreased repolarization reserve
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I
Ks can be decreased not exclusively by ion channel mutation;
it can be downregulated due to diseases such heart failure,
diabetes, and cardiac hypertrophy. Also, it is not known whether
possible gene polymorphisms or simply the variation of the expression
level of this channel in normal individuals plays a similar
role. This can be an important point, since even large variation
in the I
Ks density cannot be expected to influence normal QTc
duration significantly on the surface ECG, but it may substantially
determine the stability of repolarization. It is of interest
to note in this context, based on a recent study, that the coexpression
of KvLQT1 cDNA with HERG cDNA increased the current-carrying
properties and trafficking of I
Kr channels
[18]. In other words,
it is possible that there is an
subunit interaction between
I
Ks and I
Kr, and such changes at the expression level of I
Ks can secondarily alter I
Kr. It would be interesting to know how
mutated KvLQT1 channels could behave in this setting.
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5. Implication
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The existence of the repolarization reserve has important implications.
Routine clinical diagnoses based on ECG recordings, although
they can be correlated with torsades de pointes, do not reveal
true susceptibility toward this arrhythmia. Silent mutations
of I
Ks such as that described in the paper by Boulet et al.
[1], as with downregulation of I
Ks by disease or cardiac hypertrophy,
may greatly enhance the risk of drug-induced torsades de pointes
arrhythmia by decreasing the strength of the repolarization
reserve. Therefore, genetic screening of possible I
Ks mutations
may provide an expensive but effective way of avoiding drug-induced
sudden cardiac death. Also, it can be assumed that due to silent
I
Ks mutations and possible I
Ks downregulation, the incidence
of repolarization abnormalities is higher than previously thought
and needs more attention in the future.
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Acknowledgements
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Andras Varró and Julius Gy. Papp are supported by grants
from OTKA (T-048698 and NI-61902), KPI (BIO-37), and the Hungarian
Academy of Sciences.
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References
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