Copyright © 2006, European Society of Cardiology
Low penetrance, subclinical congenital LQTS: Concealed LQTS or silent LQTS?
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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 Top 1. 'Silent long QT... 2. Repolarization reserve3. Congenital long QT...4. Downregulation and...5. ImplicationReferences |
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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 IKs, IKr, INa, IK1
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 IKr, INa and IK1 channels also prolongs ventricular repolarization, resulting in drug-induced LQTs [13]. In contrast, even full pharmacological block of IKs 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 IKs (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 IKs 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 IKs 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 IKr 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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4. Downregulation and pharmacological block of IKs as a possible link to decreased repolarization reserve |
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Top1. 'Silent long QT...2. Repolarization reserve3. Congenital long QT...4. Downregulation and...5. ImplicationReferences |
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IKs 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 IKs 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 IKr channels [18]. In other words, it is possible that there is an
subunit interaction between IKs and IKr, and such changes at the expression level of IKs can secondarily alter IKr. It would be interesting to know how mutated KvLQT1 channels could behave in this setting. |
5. Implication |
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Top1. 'Silent long QT...2. Repolarization reserve3. Congenital long QT...4. Downregulation and...5. ImplicationReferences |
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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 IKs such as that described in the paper by Boulet et al. [1], as with downregulation of IKs 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 IKs mutations may provide an expensive but effective way of avoiding drug-induced sudden cardiac death. Also, it can be assumed that due to silent IKs mutations and possible IKs 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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