著者
Mamoru Hayano Takeru Makiyama Tsukasa Kamakura Hiroshi Watanabe Kenichi Sasaki Shunsuke Funakoshi Yimin Wuriyanghai Suguru Nishiuchi Takeshi Harita Yuta Yamamoto Hirohiko Kohjitani Sayako Hirose Fumika Yokoi Jiarong Chen Osamu Baba Takahiro Horie Kazuhisa Chonabayashi Seiko Ohno Futoshi Toyoda Yoshinori Yoshida Koh Ono Minoru Horie Takeshi Kimura
出版者
日本循環器学会
雑誌
Circulation Journal (ISSN:13469843)
巻号頁・発行日
pp.CJ-17-0064, (Released:2017-06-20)
参考文献数
38
被引用文献数
10

Background:TheSCN5Agene encodes the α subunit of the cardiac voltage-gated sodium channel, NaV1.5. The missense mutation, D1275N, has been associated with a range of unusual phenotypes associated with reduced NaV1.5 function, including cardiac conduction disease and dilated cardiomyopathy. Curiously, the reported biophysical properties ofSCN5A-D1275N channels vary with experimental system.Methods and Results:First, using a human embryonic kidney (HEK) 293 cell-based heterologous expression system, theSCN5A-D1275N channels showed similar maximum sodium conductance but a significantly depolarizing shift of activation gate (+10 mV) compared to wild type. Second, we generated human-induced pluripotent stem cells (hiPSCs) from a 24-year-old female who carried heterozygousSCN5A-D1275N and analyzed the differentiated cardiomyocytes (CMs). AlthoughSCN5Atranscript levels were equivalent between D1275N and control hiPSC-CMs, both the total amount of NaV1.5 and the membrane fractions were reduced approximately half in the D1275N cells, which were rescued by the proteasome inhibitor MG132 treatment. Electrophysiological assays revealed that maximum sodium conductance was reduced to approximately half of that in control hiPSC-CMs in the D1275N cells, and maximum upstroke velocity of action potential was lower in D1275N, which was consistent with the reduced protein level of NaV1.5.Conclusions:This study successfully demonstrated diminished sodium currents resulting from lower NaV1.5 protein levels, which is dependent on proteasomal degradation, using a hiPSC-based model forSCN5A-D1275N-related sodium channelopathy.
著者
Kenichi Kaseno Shigeto Naito Kohki Nakamura Tamotsu Sakamoto Takehito Sasaki Naofumi Tsukada Mamoru Hayano Suguru Nishiuchi Etsuko Fuke Yuko Miki Keijiro Nakamura Eiji Yamashita Koji Kumagai Shigeru Oshima Hiroshi Tada
出版者
日本循環器学会
雑誌
Circulation Journal (ISSN:13469843)
巻号頁・発行日
vol.76, no.10, pp.2337-2342, 2012 (Released:2012-09-25)
参考文献数
26
被引用文献数
53 67

Background: Periprocedural anticoagulation using uninterrupted warfarin could reduce the risk of thromboembolic complications of atrial fibrillation (AF) ablation. Few studies, however, have evaluated the efficacy and safety of periprocedural dabigatran in AF ablation. Methods and Results: A total of 211 consecutive patients who underwent AF ablation, including 110 patients who received 110mg dabigatran twice daily (group D) and 101 patients who received dose-adjusted warfarin (international normalized ratio, 2.0–3.0; group W), were evaluated. Dabigatran was discontinued on the morning of the procedure, and resumed on the next morning. Warfarin was continued throughout the procedure. During the procedure, heparin infusion was maintained to achieve an activated clotting time of >300s. Postprocedural cerebral magnetic resonance imaging (MRI) was performed in 60 patients (group D, n=31; group W, n=29). No periprocedural deaths or symptomatic thromboembolic complications were observed in either group. MRI indicated a silent cerebral infarction in 1 patient in each group. Five patients in group D and 11 in group W had minor bleeding (P=0.12). Cardiac tamponade occurred in 2 patients in group W, but in none in group D. Total bleeding complications occurred less frequently in group D (4.5%) than in group W (12.9%; P<0.05). Conclusions: Dabigatran at a dose of 110mg twice daily was safe for AF ablation in patients with a relatively low risk of thromboemboli, suggesting that it may become an alternative to warfarin in those patients.  (Circ J 2012; 76: 2337–2342)