BACKGROUND: Although the hallmark of long-QT syndrome (LQTS) is abnormal cardiac repolarization, there are varying degrees of phenotypic expression and arrhythmic risk. Our aim was to evaluate the performance of a morphological T-wave analysis program in defining breakthrough LQTS arrhythmic risk beyond the QTc value. METHODS AND RESULTS: We analyzed 407 genetically confirmed patients with LQT1 (n=246; 43% men) and LQT2 (n=161; 41% men) over the mean follow-up period of 6.4±3.9 years. ECG analysis was conducted using a novel, proprietary T-wave analysis program. Time to a LQTS-associated cardiac event was analyzed using Cox proportional hazards regression methods. Twenty-three patients experienced ≥1 defined breakthrough cardiac arrhythmic events with 5- and 10-year event rates of 4% and 7%. Two independent predictors of future LQTS-associated cardiac events from the surface ECG were identified: left slope of T wave in lead V6 (hazard ratio=0.40 [0.24-0.69]; P<0.001) and T-wave center of gravity x axis (last 25% of wave) in lead I (hazard ratio=1.90 [1.21-2.99]; P=0.005), C statistic of 0.77 (0.65-0.89). When added to the QTc (C statistic 0.68 for QTc alone), discrimination improved to 0.78. Genotype analysis showed weaker association between these T-wave variables and LQT1-triggered events while these features were stronger in patients with LQT2 and significantly outperformed the QTc (C statistic, 0.82 [0.71-0.93]). CONCLUSION: Detailed morphological analysis of the T wave provides novel insights into risk of breakthrough arrhythmic events in LQTS, particularly LQT2. This observation has the potential to guide clinical decision making and further refine risk stratification.
- MeSH
- akční potenciály MeSH
- antiarytmika terapeutické užití MeSH
- časové faktory MeSH
- dítě MeSH
- dospělí MeSH
- elektrokardiografie * MeSH
- fenotyp MeSH
- genetická predispozice k nemoci MeSH
- hodnocení rizik MeSH
- Kaplanův-Meierův odhad MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- prediktivní hodnota testů MeSH
- převodní systém srdeční účinky léků patofyziologie MeSH
- proporcionální rizikové modely MeSH
- rizikové faktory MeSH
- Romanův-Wardův syndrom diagnóza farmakoterapie genetika patofyziologie MeSH
- rozdělení chí kvadrát MeSH
- srdeční frekvence účinky léků MeSH
- syndrom dlouhého QT diagnóza farmakoterapie genetika patofyziologie MeSH
- výsledek terapie MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
AIMS: Mutations in KCNQ1, encoding for Kv7.1, the α-subunit of the IKs channel, cause long-QT syndrome type 1, potentially predisposing patients to ventricular tachyarrhythmias and sudden cardiac death, in particular, during elevated sympathetic tone. Here, we aim at characterizing the p.Lys557Glu (K557E) Kv7.1 mutation, identified in a Dutch kindred, at baseline and during (mimicked) increased adrenergic tone. METHODS AND RESULTS: K557E carriers had moderate QTc prolongation that augmented significantly during exercise. IKs characteristics were determined after co-expressing Kv7.1-wild-type (WT) and/or K557E with minK and Yotiao in Chinese hamster ovary cells. K557E caused IKs loss of function with slowing of the activation kinetics, acceleration of deactivation kinetics, and a rightward shift of voltage-dependent activation. Together, these contributed to a dominant-negative reduction in IKs density. Confocal microscopy and western blot indicated that trafficking of K557E channels was not impaired. Stimulation of WT IKs by 3'-5'-cyclic adenosine monophosphate (cAMP) generated strong current up-regulation that was preserved for K557E in both hetero- and homozygosis. Accumulation of IKs at fast rates occurred both in WT and in K557E, but was blunted in the latter. In a computational model, K557E showed a loss of action potential shortening during β-adrenergic stimulation, in accordance with the lack of QT shortening during exercise in patients. CONCLUSION: K557E causes IKs loss of function with reduced fast rate-dependent current accumulation. cAMP-dependent stimulation of mutant IKs is preserved, but incapable of fully compensating for the baseline current reduction, explaining the long QT intervals at baseline and the abnormal QT accommodation during exercise in affected patients.
- MeSH
- agonisté adrenergních beta-receptorů farmakologie MeSH
- akční potenciály MeSH
- AMP cyklický metabolismus MeSH
- CHO buňky MeSH
- Cricetulus MeSH
- cytoskeletální proteiny genetika metabolismus MeSH
- dědičnost MeSH
- dospělí MeSH
- draslíkové kanály řízené napětím genetika metabolismus MeSH
- draslíkový kanál KCNQ1 účinky léků genetika metabolismus MeSH
- elektrokardiografie MeSH
- fenotyp MeSH
- gating iontového kanálu * účinky léků MeSH
- genetická predispozice k nemoci MeSH
- kinetika MeSH
- kotevní proteiny kinázy A genetika metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- modely kardiovaskulární MeSH
- mutace * MeSH
- mutageneze cílená MeSH
- počítačová simulace MeSH
- psi MeSH
- Romanův-Wardův syndrom diagnóza genetika metabolismus patofyziologie MeSH
- studie případů a kontrol MeSH
- systémy druhého messengeru MeSH
- transfekce MeSH
- upregulace MeSH
- zvířata MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- psi MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
In a 7-year-old boy with normal hearing suffering from repeated syncope an extremely prolonged QTc interval (up to 700 ms) was found. The mother was completely asymptomatic and the father had an intermittently borderline QTc interval (maximum 470 ms) but no symptoms. In the proband a mutation analysis of KCNQ1 gene revealed a homozygous 1893insC mutation. The parents were heterozygous for this mutation. There was no consanguineous marriage in the family. The clinical relevance of these findings is that apparently normal individuals may have a latent reduction of repolarizing currents, a "reduced repolarization reserve," because they are carriers of latent ion channel genes mutations.
- MeSH
- dítě MeSH
- draslíkový kanál KCNQ1 * genetika MeSH
- elektrokardiografie metody MeSH
- genetická predispozice k nemoci genetika MeSH
- geny recesivní * genetika MeSH
- heterozygot MeSH
- jednonukleotidový polymorfismus genetika MeSH
- lidé MeSH
- molekulární sekvence - údaje MeSH
- mutace MeSH
- Romanův-Wardův syndrom * diagnóza genetika MeSH
- sekvence nukleotidů MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- práce podpořená grantem MeSH