In silico assessment of Y1795C and Y1795H SCN5A mutations: implication for inherited arrhythmogenic syndromes.
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.
Vecchietti
Stefania
S
DEIS, Viale Risorgimento, 2, I-40136, Bologna, Italy.
Grandi
Eleonora
E
Severi
Stefano
S
Rivolta
Ilaria
I
Napolitano
Carlo
C
Priori
Silvia G
SG
Cavalcanti
Silvio
S
D000200:Action Potentials / Q000502:physiology; D000293:Adolescent; D000328:Adult; D001145:Arrhythmias, Cardiac / Q000151:congenital* / Q000503:physiopathology*; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D005260:Female; D006329:Heart Conduction System / Q000502:physiology*; D006339:Heart Rate / Q000502:physiology; D006352:Heart Ventricles / Q000166:cytology; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D008955:Models, Cardiovascular; D009124:Muscle Proteins / Q000502:physiology*; D009154:Mutation; D032383:Myocytes, Cardiac / Q000502:physiology*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015222:Sodium Channels / Q000502:physiology*; D013329:Structure-Activity Relationship; D013577:Syndrome; D016276:Ventricular Function
D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels