Latent genetic backgrounds and molecular pathogenesis in drug-induced long-QT syndrome.
Circ Arrhythm Electrophysiol
; 2(5): 511-23, 2009 Oct.
Article
en En
| MEDLINE
| ID: mdl-19843919
ABSTRACT
BACKGROUND:
Drugs with I(Kr)-blocking action cause secondary long-QT syndrome. Several cases have been associated with mutations of genes coding cardiac ion channels, but their frequency among patients affected by drug-induced long-QT syndrome (dLQTS) and the resultant molecular effects remain unknown. METHODS ANDRESULTS:
Genetic testing was carried out for long-QT syndrome-related genes in 20 subjects with dLQTS and 176 subjects with congenital long-QT syndrome (cLQTS); electrophysiological characteristics of dLQTS-associated mutations were analyzed using a heterologous expression system with Chinese hamster ovary cells together with a computer simulation model. The positive mutation rate in dLQTS was similar to cLQTS (dLQTS versus cLQTS, 8 of 20 [40%] versus 91 of 176 [52%] subjects, P=0.32). The incidence of mutations was higher in patients with torsades de pointes induced by nonantiarrhythmic drugs than by antiarrhythmic drugs (antiarrhythmic versus others, 3 of 14 [21%] versus 5 of 6 [83%] subjects, P<0.05). When reconstituted in Chinese hamster ovary cells, KCNQ1 and KCNH2 mutant channels showed complex gating defects without dominant negative effects or a relatively mild decreased current density. Drug sensitivity for mutant channels was similar to that of the wild-type channel. With the Luo-Rudy simulation model of action potentials, action potential durations of most mutant channels were between those of wild-type and cLQTS.CONCLUSIONS:
dLQTS had a similar positive mutation rate compared with cLQTS, whereas the functional changes of these mutations identified in dLQTS were mild. When I(Kr)-blocking agents produce excessive QT prolongation (dLQTS), the underlying genetic background of the dLQTS subject should also be taken into consideration, as would be the case with cLQTS; dLQTS can be regarded as a latent form of long-QT syndrome.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Síndrome de QT Prolongado
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Análisis Mutacional de ADN
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Canales de Sodio
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Canal de Potasio KCNQ1
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Canales de Potasio Éter-A-Go-Go
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Proteínas Musculares
Tipo de estudio:
Etiology_studies
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Incidence_studies
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Prognostic_studies
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Risk_factors_studies
Límite:
Adult
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Aged
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Animals
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Female
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Humans
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Male
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Middle aged
País/Región como asunto:
Asia
Idioma:
En
Revista:
Circ Arrhythm Electrophysiol
Asunto de la revista:
ANGIOLOGIA
/
CARDIOLOGIA
Año:
2009
Tipo del documento:
Article
País de afiliación:
Japón