Electrocardiographic characteristics and SCN5A mutations in idiopathic ventricular fibrillation associated with early repolarization.
BACKGROUND
Recently, we and others reported that early repolarization (J wave) is associated with idiopathic ventricular fibrillation. However, its clinical and genetic characteristics are unclear.


RESULTS
This study included 50 patients (44 men; age, 45 ± 17 years) with idiopathic ventricular fibrillation associated with early repolarization, and 250 age- and sex-matched healthy controls. All of the patients had experienced arrhythmia events, and 8 (16%) had a family history of sudden death. Ventricular fibrillation was inducible by programmed electric stimulation in 15 of 29 patients (52%). The heart rate was slower and the PR interval and QRS duration were longer in patients with idiopathic ventricular fibrillation than in controls. We identified nonsynonymous variants in SCN5A (resulting in A226D, L846R, and R367H) in 3 unrelated patients. These variants occur at residues that are highly conserved across mammals. His-ventricular interval was prolonged in all of the patients carrying an SCN5A mutation. Sodium channel blocker challenge resulted in an augmentation of early repolarization or development of ventricular fibrillation in all of 3 patients, but none was diagnosed with Brugada syndrome. In heterologous expression studies, all of the mutant channels failed to generate any currents. Immunostaining revealed a trafficking defect in A226D channels and normal trafficking in R367H and L846R channels.


CONCLUSIONS
We found reductions in heart rate and cardiac conduction and loss-of-function mutations in SCN5A in patients with idiopathic ventricular fibrillation associated with early repolarization. These findings support the hypothesis that decreased sodium current enhances ventricular fibrillation susceptibility.
Division of Cardiology, Niigata University School of Medicine, Niigata, Japan. hiroshi7@med.niigata-u.ac.jp
Hiroshi
H
Watanabe
Akihiko
A
Nogami
Kimie
K
Ohkubo
Hiro
H
Kawata
Yuka
Y
Hayashi
Taisuke
T
Ishikawa
Takeru
T
Makiyama
Satomi
S
Nagao
Nobue
N
Yagihara
Naofumi
N
Takehara
Yuichiro
Y
Kawamura
Akinori
A
Sato
Kazuki
K
Okamura
Yukio
Y
Hosaka
Masahito
M
Sato
Satoki
S
Fukae
Masaomi
M
Chinushi
Hirotaka
H
Oda
Masaaki
M
Okabe
Akinori
A
Kimura
Koji
K
Maemura
Ichiro
I
Watanabe
Shiro
S
Kamakura
Minoru
M
Horie
Yoshifusa
Y
Aizawa
Wataru
W
Shimizu
Naomasa
N
Makita
D000328:Adult; D002304:Cardiac Pacing, Artificial; D016022:Case-Control Studies; D002460:Cell Line; D004562:Electrocardiography; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D020022:Genetic Predisposition to Disease; D006329:Heart Conduction System / Q000378:metabolism / Q000503:physiopathology; D006339:Heart Rate; D006801:Humans; D007150:Immunohistochemistry; D007564:Japan; D016015:Logistic Models; D008297:Male; D008564:Membrane Potentials; D008875:Middle Aged; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D016017:Odds Ratio; D018408:Patch-Clamp Techniques; D010641:Phenotype; D011237:Predictive Value of Tests; D021381:Protein Transport; D012964:Sodium / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014693:Ventricular Fibrillation / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology
D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D012964:Sodium