Insights into the molecular mechanisms of bradycardia-triggered arrhythmias in long QT-3 syndrome.
J Clin Invest
; 110(9): 1251-62, 2002 Nov.
Article
em En
| MEDLINE
| ID: mdl-12417563
ABSTRACT
Congenital long QT syndrome is a rare disease in which the electrocardiogram QT interval is prolonged due to dysfunctional ventricular repolarization. Variant 3 (LQT-3) is associated with mutations in SCN5A, the gene coding for the heart Na(+) channel alpha subunit. Arrhythmias in LQT-3 mutation carriers are more likely to occur at rest, when heart rate is slow. Several LQT-3 Na(+) channel mutations exert their deleterious effects by promoting a mode of Na(+) channel gating wherein a fraction of channels fails to inactivate. This gating mode, termed "bursting, " results in sustained macroscopic inward Na(+) channel current (I(sus)), which can delay repolarization and prolong the QT interval. However, the mechanism of heart-rate dependence of I(sus) has been unresolved at the single-channel level. We investigate an LQT-3 mutant (Y1795C) using experimental and theoretical frameworks to elucidate the molecular mechanism of I(sus) rate dependence. Our results indicate that mutation-induced changes in the length of time mutant channels spend bursting, rather than how readily they burst, determines I(sus) inverse heart-rate dependence. Our results indicate that mutation-induced changes in the length of time mutant channels spend bursting, rather than how readily they burst, determines I(sus) inverse heart-rate dependence. These results link mutation-induced changes in Na+ channel gating mode transitions to heart rate-dependent changes in cellular electrical activity underlying a key LQT-3 clinical phenotype.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Arritmias Cardíacas
/
Bradicardia
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Síndrome do QT Longo
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Canais de Sódio
Limite:
Humans
Idioma:
En
Ano de publicação:
2002
Tipo de documento:
Article