Electrocardiographic characteristics and SCN5A mutations in idiopathic ventricular fibrillation associated with early repolarization.

Abstract

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.

METHODS AND 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.

• Authors: Hiroshi Watanabe, Akihiko Nogami, Kimie Ohkubo, Hiro Kawata, Yuka Hayashi, Taisuke Ishikawa, Takeru Makiyama, Satomi Nagao, Nobue Yagihara, Naofumi Takehara, Yuichiro Kawamura, Akinori Sato, Kazuki Okamura, Yukio Hosaka, Masahito Sato, Satoki Fukae, Masaomi Chinushi, Hirotaka Oda, Masaaki Okabe, Akinori Kimura, Koji Maemura, Ichiro Watanabe, Shiro Kamakura, Minoru Horie, Yoshifusa Aizawa, Wataru Shimizu, Naomasa Makita
• Journal: Circulation. Arrhythmia and electrophysiology (Circ Arrhythm Electrophysiol) Vol. 4 Issue 6 Pg. 874-81 (Dec 2011) ISSN: 1941-3084 [Electronic] United States
• PMID: 22028457 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• NAV1.5 Voltage-Gated Sodium Channel
• SCN5A protein, human
• Sodium Channel Blockers
• Sodium Channels
• Sodium

Topics

• Adult
• Cardiac Pacing, Artificial
• Case-Control Studies
• Cell Line
• Electrocardiography
• Electrophysiologic Techniques, Cardiac
• Female
• Genetic Predisposition to Disease
• Heart Conduction System (metabolism, physiopathology)
• Heart Rate
• Humans
• Immunohistochemistry
• Japan
• Logistic Models
• Male
• Membrane Potentials
• Middle Aged
• Mutation
• NAV1.5 Voltage-Gated Sodium Channel
• Odds Ratio
• Patch-Clamp Techniques
• Phenotype
• Predictive Value of Tests
• Protein Transport
• Sodium (metabolism)
• Sodium Channel Blockers (pharmacology)
• Sodium Channels (drug effects, genetics, metabolism)
• Transfection
• Ventricular Fibrillation (diagnosis, genetics, metabolism, physiopathology)