Insights into the molecular mechanisms of bradycardia-triggered arrhythmias in long QT-3 syndrome
AUTOR(ES)
Clancy, Colleen E.
FONTE
American Society for Clinical Investigation
RESUMO
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 α 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 (Isus), which can delay repolarization and prolong the QT interval. However, the mechanism of heart-rate dependence of Isus 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 Isus 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 Isus inverse heart-rate dependence.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=151612Documentos Relacionados
- Long QT syndrome: novel insights into the mechanisms of cardiac arrhythmias
- Re-evaluating the efficacy of β-adrenergic agonists and antagonists in long QT-3 syndrome through computational modelling
- Molecular genetic aspects of the Romano-Ward long QT syndrome.
- Is long QT syndrome entering the era of molecular diagnosis?
- Usefulness of Valsalva manoeuvre and cold pressor test for evaluation of arrhythmias in long QT syndrome.