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Arrhythmogenic mechanism of an LQT-3 mutation of the human heart Na(+) channel alpha-subunit: A computational analysis.
Wehrens, X H; Abriel, H; Cabo, C; Benhorin, J; Kass, R S.
Afiliación
  • Wehrens XH; Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
Circulation ; 102(5): 584-90, 2000 Aug 01.
Article en En | MEDLINE | ID: mdl-10920073
BACKGROUND: D1790G, a mutation of SCN5A, the gene that encodes the human Na(+) channel alpha-subunit, is linked to 1 form of the congenital long-QT syndrome (LQT-3). In contrast to other LQT-3-linked SCN5A mutations, D1790G does not promote sustained Na(+) channel activity but instead alters the kinetics and voltage-dependence of the inactivated state. METHODS AND RESULTS: We modeled the cardiac ventricular action potential (AP) using parameters and techniques described by Luo and Rudy as our control. On this background, we modified only the properties of the voltage-gated Na(+) channel according to our patch-clamp analysis of D1790G channels. Our results indicate that D1790G-induced changes in Na(+) channel activity prolong APs in a steeply heart rate-dependent manner not directly due to changes in Na(+) entry through mutant channels but instead to alterations in the balance of net plateau currents by modulation of calcium-sensitive exchange and ion channel currents. CONCLUSIONS: We conclude that the D1790G mutation of the Na(+) channel alpha-subunit can prolong the cardiac ventricular AP despite the absence of mutation-induced sustained Na(+) channel current. This prolongation is calcium-dependent, is enhanced at slow heart rates, and at sufficiently slow heart rate triggers arrhythmogenic early afterdepolarizations.
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Banco de datos: MEDLINE Asunto principal: Síndrome de QT Prolongado / Canales de Sodio / Función Ventricular / Mutación Puntual Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Circulation Año: 2000 Tipo del documento: Article País de afiliación: Estados Unidos
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Banco de datos: MEDLINE Asunto principal: Síndrome de QT Prolongado / Canales de Sodio / Función Ventricular / Mutación Puntual Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Circulation Año: 2000 Tipo del documento: Article País de afiliación: Estados Unidos