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Computational Analyses in Ion Channelopathies

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

¹Cellular and Molecular Engineering Laboratory, Dipartimento di Elettronica, Informatica e Sistemistica, University of Bologna, Cesena; and ²Molecular Cardiology Laboratory, Fondazione Salvatore Maugeri, Istituto di Ricovero e Cura A Carattere Scientifico, Pavia, Italy

Submitted 15 March 2006 ; accepted in final form 12 September 2006

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 (I_Na) 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 (I_TO) and the ratio of slow delayed rectifier potassium (I_Ks) to rapid delayed rectifier current (I_Kr). Administration of flecainide and mexiletine was simulated by appropriately modifying I_Na, calcium current (I_Ca), I_TO, and I_Kr. 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.

computer modeling; genetics; arrhythmias; sodium channel; antiarrhythmic drugs

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