TY - JOUR
T1 - In silico assessment of Y1795C and Y1795H SCN5A mutations
T2 - Implication for inherited arrhythmogenic syndromes
AU - Vecchietti, Stefania
AU - Grandi, Eleonora
AU - Severi, Stefano
AU - Rivolta, Ilaria
AU - Napolitano, Carlo
AU - Priori, Silvia G.
AU - Cavalcanti, Silvio
PY - 2007/1
Y1 - 2007/1
N2 - 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.
AB - 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.
KW - Antiarrhythmic drugs
KW - Arrhythmias
KW - Computer modeling
KW - Genetics
KW - Sodium channel
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U2 - 10.1152/ajpheart.00270.2006
DO - 10.1152/ajpheart.00270.2006
M3 - Article
C2 - 16980337
AN - SCOPUS:33846231066
VL - 292
JO - American Journal of Physiology
JF - American Journal of Physiology
SN - 0363-6119
IS - 1
ER -