TY - JOUR

T1 - Multifocal atrial and ventricular premature contractions with an increased risk of dilated cardiomyopathy caused by a Nav1.5 gain-of-function mutation (G213D)

AU - Calloe, Kirstine

AU - Broendberg, Anders K

AU - Christensen, Alex H

AU - Pedersen, Lisbeth N

AU - Olesen, Morten S

AU - de Los Angeles Tejada, Maria

AU - Friis, Soren

AU - Thomsen, Morten B

AU - Bundgaard, Henning

AU - Jensen, Henrik K

N1 - Copyright © 2017 Elsevier B.V. All rights reserved.

PY - 2018/4/15

Y1 - 2018/4/15

N2 - BACKGROUND: SCN5A mutations can lead to different cardiac diseases. Recently, SCN5A mutations have been linked to the clinical entity multifocal ectopic Purkinje-related premature contractions (MEPPC) characterized by ventricular ectopy and dilated cardiomyopathy.METHODS & RESULTS: A family with a uniform MEPPC-like phenotype, associated with complex atrial and ventricular arrhythmias and dilated cardiomyopathy caused by a high frequency of ventricular ectopy was clinically assessed. Screening of the SCN5A gene revealed a missense mutation in the linker between segments 3 and 4 in domain 1 of the Nav1.5 protein, resulting in a glycine to aspartate substitution at position 213 (G213D). The phenotype co-segregated with the missense mutation. Electrophysiological studies of wild type (WT) hNav1.5 and hNav1.5_G213D expressed in CHO-K cells showed that the voltage of half-maximal activation (V½) was significantly more negative for hNav1.5_G213D compared to WT (V½=-38.7±0.5mV for WT and V½=-42.4±0.5mV for G213D; P<0.001). This suggests activation of Nav1.5_G231D at more negative potentials. The V½of steady-state inactivation was significantly shifted towards more positive values for Nav1.5_G213D (V½=-86.7±0.2mV for WT and -82.2±0.3mV for G213D; P<0.001), also contributing to a gain-of-function phenotype. Flecainide and amiodarone markedly reduced premature atrial and ventricular contractions in four patients.CONCLUSION: The Nav1.5_G213D mutation is associated with a gain-of-function phenotype, multifocal atrial and ventricular ectopy and dilated cardiomyopathy. Since patients with a MEPPC-like phenotype may specifically benefit from Class-1 antiarrhythmic drugs or amiodarone, clinical identification of this disease entity is important.

AB - BACKGROUND: SCN5A mutations can lead to different cardiac diseases. Recently, SCN5A mutations have been linked to the clinical entity multifocal ectopic Purkinje-related premature contractions (MEPPC) characterized by ventricular ectopy and dilated cardiomyopathy.METHODS & RESULTS: A family with a uniform MEPPC-like phenotype, associated with complex atrial and ventricular arrhythmias and dilated cardiomyopathy caused by a high frequency of ventricular ectopy was clinically assessed. Screening of the SCN5A gene revealed a missense mutation in the linker between segments 3 and 4 in domain 1 of the Nav1.5 protein, resulting in a glycine to aspartate substitution at position 213 (G213D). The phenotype co-segregated with the missense mutation. Electrophysiological studies of wild type (WT) hNav1.5 and hNav1.5_G213D expressed in CHO-K cells showed that the voltage of half-maximal activation (V½) was significantly more negative for hNav1.5_G213D compared to WT (V½=-38.7±0.5mV for WT and V½=-42.4±0.5mV for G213D; P<0.001). This suggests activation of Nav1.5_G231D at more negative potentials. The V½of steady-state inactivation was significantly shifted towards more positive values for Nav1.5_G213D (V½=-86.7±0.2mV for WT and -82.2±0.3mV for G213D; P<0.001), also contributing to a gain-of-function phenotype. Flecainide and amiodarone markedly reduced premature atrial and ventricular contractions in four patients.CONCLUSION: The Nav1.5_G213D mutation is associated with a gain-of-function phenotype, multifocal atrial and ventricular ectopy and dilated cardiomyopathy. Since patients with a MEPPC-like phenotype may specifically benefit from Class-1 antiarrhythmic drugs or amiodarone, clinical identification of this disease entity is important.

U2 - 10.1016/j.ijcard.2017.11.095

DO - 10.1016/j.ijcard.2017.11.095

M3 - Journal article

C2 - 29506689

VL - 257

SP - 160

EP - 167

JO - International Journal of Cardiology

JF - International Journal of Cardiology

SN - 0167-5273

ER -