In silico assessment of Y1795C and Y1795H SCN5A mutations: Implication for inherited arrhythmogenic syndromes

Stefania Vecchietti, Eleonora Grandi, Stefano Severi, Ilaria Rivolta, Carlo Napolitano, Silvia G. Priori, Silvio Cavalcanti

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

The effects of two SCN5A mutations (Y1795C, Y1795H), previously identified in one Long QT syndrome type 3 (LQT3) and one Brugada syndrome (BrS) families, were investigated by means of numerical modeling of ventricular action potential (AP). A Markov model capable of reproducing a wild-type as well as a mutant sodium current (INa) was identified and was included into the Luo-Rudy ventricular cell model for action potential (AP) simulation. The characteristics of endocardial, midmyocardial, and epicardial cells were reproduced by differentiating the transient outward current (ITO) and the ratio of slow delayed rectifier potassium (IKs) to rapid delayed rectifier current (IKr). Administration of flecainide and mexiletine was simulated by appropriately modifying INa, calcium current (ICa), ITO, and IKr. Y1795C prolonged AP in a rate-dependent manner, and early afterdepolarizations (EADs) appeared during bradycardia in epicardial and midmyocardial cells; flecainide and mexiletine shortened AP and abolished EADs. Y1795H resulted in minimal changes in the APs; flecainide but not mexiletine induced APs heterogeneity across the ventricular wall that accounts for the ST segment elevation induced by flecainide in Y1795H carriers. The AP abnormalities induced by Y1795H and Y1795C can explain the clinically observed surface ECG phenotype. For the first time by modeling the effects of flecainide and mexiletine, we are able to gather mechanistic insights on the response to drugs administration observed in affected patients.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume292
Issue number1
DOIs
StatePublished - Jan 1 2007
Externally publishedYes

Keywords

  • Antiarrhythmic drugs
  • Arrhythmias
  • Computer modeling
  • Genetics
  • Sodium channel

ASJC Scopus subject areas

  • Physiology

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