Research Article| Volume 257, P160-167, April 15, 2018

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


      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 ± 0.5 mV for WT and V½ = −42.4 ± 0.5 mV for G213D; P < 0.001). This suggests activation of Nav1.5_G231D at more negative potentials. The V½ of steady-state inactivation was significantly shifted towards more positive values for Nav1.5_G213D (V½ = −86.7 ± 0.2 mV for WT and −82.2 ± 0.3 mV 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.


      AF (atrial fibrillation), DCM (dilated cardiomyopathy), ECG (electrocardiogram), EPS (electrophysiological study), LA (left atrium), LV (left ventricle), LVEF (left ventricular ejection fraction), MEPPC (multifocal ectopic Purkinje-related premature contractions), CMR (cardiac magnetic resonance imaging), MAT (multifocal atrial tachycardia), PAC (premature atrial contractions), PVC (premature ventricular contractions), (the half-maximal activation or inactivation voltage)


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