不整脈研究グループ
Arrhythmia Research Group研究内容
当研究グループでは医局開設当初より現在に至るまで一環として、基礎と臨床の両研究手法を用いた心室性および心房性不整脈に関する研究を遂行しております。
基礎研究
不整脈発生機序の解明
不整脈発生機序の解明をテーマとし、病的心における光学マッピングを用いた心臓レベル、パッチクランプおよびカルシウムイメージングを用いた心筋細胞レベルでの電気生理現象を解析しています。
肥大心における不整脈機序の検討
肥大心における不整脈発生機序として、Ca2+/カルモジュリン依存性プロテインキナーゼII(CaMKII)とCa2+感受性small-conductance K+チャネル(SKチャネル)に着目してきている。肥大心ではCaMKIIが活性化し、活動電位持続時間の変動をもたらすこと、CaMKIIがSKチャネルを活性化すること、その活性化は心筋虚血や交感神経活性化によって増大し、細胞内Ca動態に影響を及ぼすことを明らかとすることで心室不整脈の発生に関与していることを報告しています。さらに心室筋だけではなく、心房筋におけるSK電流と心房不整脈の関連性についても明らかとしました。
心筋梗塞後不全心における不整脈機序の検討
心筋梗塞後不全心における不整脈発生機序として、カルシウム漏出の結果生じる後脱分極によるトリガードアクティビティの亢進(DADの亢進)に着目し、ミトコンドリアカルシウムユニポーター(MCU)を介したカルシウム取り込みを促進することで不整脈の誘発性が低下することを明らかにしました。さらに現在は、DADの亢進をもたらす機序として自律神経系に着目し、検討を行っております。
#02
糖尿病心における不整脈機序の検討
糖尿病や肥満患者様の数は増加傾向にあり、そのような患者様の不整脈発生リスクを低下させ、再発予防を行う重要性が高まってきています。我々は、糖尿病心における心房筋の伝導および不応期の障害を明らかにし、また、糖尿病治療薬であるナトリウム・ブドウ糖共輸送担体2阻害薬(SGLT2阻害薬)の心疾患への効果が注目されており、SGLT2阻害薬による心室不整脈におけるカルシウム動態や心房細動リモデリングにおけるミトコンドリア機能への影響と不整脈の関係を明らかとしてきました。
光遺伝学を用いた心臓電気生理の解析
光遺伝学は、光刺激によって細胞の電気生理現象を制御する新しい技術です。光刺激によって開口するチャネル(チャネルロドプシン)を発現させるマウスを作成し、短時間の光照射によって心房細動が停止することを確認し、心房細動の停止に必要な電気生理的変化を評価するため、光学マッピングを用いた詳細な解析をおこなっております。
#03
臨床研究
不整脈非薬物療法
植え込み型心臓デバイス治療やカテーテルアブレーションといった不整脈非薬物療法をテーマに日進月歩する本分野を多面的に研究しております。
植え込みデバイス患者における心室性不整脈と心不全との関連性の検討
われわれは、1990年代の治験段階から、植え込み型除細動器(ICD)の植え込みを行ってきました。ICDは心臓突然死の予防治療として有効である一方で、不適切作動やショックによる予後への悪影響の問題が指摘されています。我々は、これまでに不適切作動が起こりやすい患者背景や、累積ショックエネルギーと生命予後との関係性、ICD適切作動前の非持続性心室頻拍の出現増加などを報告してきました。近年、植え込みデバイス患者さんにおける新たな問題として、心房細動やエレクトリカルストームの管理の重要性が指摘されており、エレクトリカルストームが心血管死亡などの臨床転帰に悪影響を与えることを明らかにしました。今後も、臨床に役立つ新たな知見を見出すことを目標に研究を継続していきます。
#04
#05
心房細動の発症、持続に影響する患者背景の検討
心房細動は最も頻度の多い不整脈ですが、発症機序など未だ解明されていない問題がたくさん残されています。我々は、開心術術後の心房細動と心外膜脂肪の関係を明らかとしました。そこでこの心外膜脂肪や自律神経機能に着目し、これらの因子と心房細動の関連性、カテ―テルアブレーション後の再発や心房機能の改善への影響を解明することを目標に研究を行っており、将来の治療に発展させることを目標に取り組んでいます。
動的心電図波形変化による予後予測の検討
心電図は古典的な診断ツールですが、詳細な波形解析を行うことで不整脈の再発や死亡率の予測に役立つことが報告されています。われわれは、当科で施行した心電図や運動負荷心電図、24時間心電図を動的変化に着目して解析し、新たな知見を見出すことを目標にしています。
主な原著論文
2024
Hagiwara, Hikaru; Komoriyama, Hirokazu; Kato, Yoshiya; Anzai, Toshihisa
An adult case of Bland-White-Garland syndrome with Vieussens' arterial ring Journal Article
In: Eur Heart J Case Rep, vol. 8, no. 9, pp. ytae468, 2024, ISSN: 2514-2119.
@article{pmid39286731,
title = {An adult case of Bland-White-Garland syndrome with Vieussens' arterial ring},
author = {Hikaru Hagiwara and Hirokazu Komoriyama and Yoshiya Kato and Toshihisa Anzai},
doi = {10.1093/ehjcr/ytae468},
issn = {2514-2119},
year = {2024},
date = {2024-09-01},
urldate = {2024-09-01},
journal = {Eur Heart J Case Rep},
volume = {8},
number = {9},
pages = {ytae468},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Kadosaka, Takahide; Watanabe, Masaya; Nakao, Motoki; Koya, Taro; Temma, Taro; Anzai, Toshihisa
Normalization of increasing shocking coil impedance with full output synchronized shock Journal Article
In: J Cardiovasc Electrophysiol, 2024, ISSN: 1540-8167.
@article{pmid39169529,
title = {Normalization of increasing shocking coil impedance with full output synchronized shock},
author = {Takahide Kadosaka and Masaya Watanabe and Motoki Nakao and Taro Koya and Taro Temma and Toshihisa Anzai},
doi = {10.1111/jce.16416},
issn = {1540-8167},
year = {2024},
date = {2024-08-01},
urldate = {2024-08-01},
journal = {J Cardiovasc Electrophysiol},
abstract = {INTRODUCTION: Impedance is a crucial parameter in cardiovascular implantable electronic devices (CIEDs). Clinically, most CIEDs measure impedance using low voltage sub-threshold measurement (LVSM). Although the LVSM of shock impedance (LVSM-SI) is generally comparable with high voltage shock impedance (HVSI), LVSM-SI might be inaccurate if peri-lead tissue degeneration occurs.nnMETHODS AND RESULTS: We present a case of elevated LVSM-SI occurring 8 years post-lead implantation, possibly attributed to encapsulation of the right ventricular lead coil. After 0.1 J shock was delivered, a full output synchronized shock was administered to measure HVSI, revealing a normal value. Furthermore, LVSM-SI was normalized and maintained within the normal range during long-term follow-up.nnCONCLUSION: Our findings suggest conducting a full-output synchronized shock test to assess HVSI when abnormal LVSM-SI is detected in the remote phase post-ICD implantation, which may be considered to help normalize LVSM shock impedance.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Natsui, Hiroyuki; Watanabe, Masaya; Yokota, Takashi; Tsuneta, Satonori; Fumoto, Yoshizuki; Handa, Haruka; Shouji, Matsushima; Koya, Jiro; Nishino, Kotaro; Tatsuta, Daishiro; Koizumi, Takuya; Kadosaka, Takahide; Nakao, Motoki; Koya, Taro; Temma, Taro; Ito, Yoichi M; Kanako, Hatanaka C; Hatanaka, Yutaka; Yasushige, Shingu; Wakasa, Satoru; Miura, Shuhei; Masuda, Takahiko; Nishioka, Naritomo; Naraoka, Shuichi; Ochi, Kayoko; Kudo, Tomoko; Ishikawa, Tsugumine; Anzai, Toshihisa
In: Physiol Rep, vol. 12, no. 6, pp. e15957, 2024, ISSN: 2051-817X.
@article{pmid38546216,
title = {Influence of epicardial adipose tissue inflammation and adipocyte size on postoperative atrial fibrillation in patients after cardiovascular surgery},
author = {Hiroyuki Natsui and Masaya Watanabe and Takashi Yokota and Satonori Tsuneta and Yoshizuki Fumoto and Haruka Handa and Matsushima Shouji and Jiro Koya and Kotaro Nishino and Daishiro Tatsuta and Takuya Koizumi and Takahide Kadosaka and Motoki Nakao and Taro Koya and Taro Temma and Yoichi M Ito and Hatanaka C Kanako and Yutaka Hatanaka and Shingu Yasushige and Satoru Wakasa and Shuhei Miura and Takahiko Masuda and Naritomo Nishioka and Shuichi Naraoka and Kayoko Ochi and Tomoko Kudo and Tsugumine Ishikawa and Toshihisa Anzai},
doi = {10.14814/phy2.15957},
issn = {2051-817X},
year = {2024},
date = {2024-03-01},
urldate = {2024-03-01},
journal = {Physiol Rep},
volume = {12},
number = {6},
pages = {e15957},
abstract = {Epicardial adipose tissue (EAT) is an active endocrine organ that is closely associated with occurrence of atrial fibrillation (AF). However, the role of EAT in the development of postoperative AF (POAF) remains unclear. We aimed to investigate the association between EAT profile and POAF occurrence in patients who underwent cardiovascular surgery. We obtained EAT samples from 53 patients to evaluate gene expression, histological changes, mitochondrial oxidative phosphorylation (OXPHOS) capacity in the EAT, and protein secretion in EAT-conditioned medium. EAT volume was measured using computed tomography scan. Eighteen patients (34%) experienced POAF within 7 days after surgery. Although no significant difference was observed in EAT profile between patients with and without POAF, logistic regression analysis identified that the mRNA expression levels of tumor necrosis factor-alpha (TNF-α) were positively correlated and adipocyte size in the EAT was inversely correlated with onset of POAF, respectively. Mitochondrial OXPHOS capacity in the EAT was not associated with POAF occurrence; however, it showed an inverse correlation with adipocyte size and a positive correlation with adiponectin secretion. In conclusion, changes in the secretory profile and adipocyte morphology of the EAT, which represent qualitative aspects of the adipose tissue, were present before the onset of AF.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2023
Hagiwara, Hikaru; Watanabe, Masaya; Kadosaka, Takahide; Koizumi, Takuya; Kobayashi, Yuta; Koya, Taro; Nakao, Motoki; Tsuneta, Satonori; Kato, Yoshiya; Komoriyama, Hirokazu; Kamada, Rui; Nagai, Toshiyuki; Kudo, Kohsuke; Anzai, Toshihisa
Fragmented QRS on 12-lead electrocardiogram predicts long-term prognosis in patients with cardiac sarcoidosis Journal Article
In: Heart Vessels, vol. 38, no. 6, pp. 803–816, 2023, ISSN: 1615-2573.
@article{pmid36635468,
title = {Fragmented QRS on 12-lead electrocardiogram predicts long-term prognosis in patients with cardiac sarcoidosis},
author = {Hikaru Hagiwara and Masaya Watanabe and Takahide Kadosaka and Takuya Koizumi and Yuta Kobayashi and Taro Koya and Motoki Nakao and Satonori Tsuneta and Yoshiya Kato and Hirokazu Komoriyama and Rui Kamada and Toshiyuki Nagai and Kohsuke Kudo and Toshihisa Anzai},
doi = {10.1007/s00380-022-02229-2},
issn = {1615-2573},
year = {2023},
date = {2023-06-01},
urldate = {2023-06-01},
journal = {Heart Vessels},
volume = {38},
number = {6},
pages = {803--816},
abstract = {Fragmented QRS (fQRS) on a 12-lead electrocardiogram is a known marker of fatal arrhythmias or cardiac adverse events in ischemic and non-ischemic cardiomyopathy patients. Nonetheless, the association between fQRS and clinical outcomes in patients with cardiac sarcoidosis (CS) remains unclear. Herein, we investigated whether fQRS is associated with long-term clinical outcomes in CS patients. A total of 78 patients who received immunosuppressive therapy (IST) for clinically diagnosed CS were retrospectively examined. Patients were classified into two groups according to the presence (n = 19) or absence (n = 59) of fQRS on electrocardiogram before IST. The primary outcome was the composite event of all-cause death, ventricular tachyarrhythmias (VTs), and hospitalization for heart failure. Results of late gadolinium enhancement on cardiac magnetic resonance imaging were also analyzed. During a median follow-up period of 3.7 years (interquartile range: 1.6-6.2 years), the primary outcome occurred more frequently in patients with fQRS than in those without (47% vs. 13%, log-rank p = 0.002). Multivariable Cox regression analyses showed that fQRS was an independent determinant of the primary outcome. The incidence of VTs, within 12 months of IST initiation, was comparable between the two groups; however, late-onset VTs, defined as those occurring ≥ 12 months after IST initiation, occurred more frequently in the fQRS group (21% vs. 2%, log-rank p = 0.002). The scar zone and scar border zone were greater in patients with fQRS than in those without it. In conclusion, our analysis suggests that fQRS is an independent predictor of adverse events, particularly late-onset VTs, in patients with CS.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Nakao, Motoki; Watanabe, Masaya; Miquerol, Lucile; Natsui, Hiroyuki; Koizumi, Takuya; Kadosaka, Takahide; Koya, Taro; Hagiwara, Hikaru; Kamada, Rui; Temma, Taro; de Vries, Antoine A F; Anzai, Toshihisa
Optogenetic termination of atrial tachyarrhythmias by brief pulsed light stimulation Journal Article
In: J Mol Cell Cardiol, vol. 178, pp. 9–21, 2023, ISSN: 1095-8584.
@article{pmid36965700,
title = {Optogenetic termination of atrial tachyarrhythmias by brief pulsed light stimulation},
author = {Motoki Nakao and Masaya Watanabe and Lucile Miquerol and Hiroyuki Natsui and Takuya Koizumi and Takahide Kadosaka and Taro Koya and Hikaru Hagiwara and Rui Kamada and Taro Temma and Antoine A F de Vries and Toshihisa Anzai},
doi = {10.1016/j.yjmcc.2023.03.006},
issn = {1095-8584},
year = {2023},
date = {2023-05-01},
urldate = {2023-05-01},
journal = {J Mol Cell Cardiol},
volume = {178},
pages = {9--21},
abstract = {AIMS: The most efficient way to acutely restore sinus rhythm from atrial fibrillation (AF) is electrical cardioversion, which is painful without adequate sedation. Recent studies in various experimental models have indicated that optogenetic termination of AF using light-gated ion channels may provide a myocardium-specific and potentially painless alternative future therapy. However, its underlying mechanism(s) remain(s) incompletely understood. As brief pulsed light stimulation, even without global illumination, can achieve optogenetic AF termination, besides direct conduction block also modulation of action potential (AP) properties may be involved in the termination mechanism. We studied the relationship between optogenetic AP duration (APD) and effective refractory period (ERP) prolongation by brief pulsed light stimulation and termination of atrial tachyarrhythmia (AT).nnMETHODS AND RESULTS: Hearts from transgenic mice expressing the H134R variant of channelrhodopsin-2 in atrial myocytes were explanted and perfused retrogradely. AT induced by electrical stimulation was terminated by brief pulsed blue light stimulation (470 nm, 10 ms, 16 mW/mm) with 68% efficacy. The termination rate was dependent on pulse duration and light intensity. Optogenetically imposed APD and ERP changes were systematically examined and optically monitored. Brief pulsed light stimulation (10 ms, 6 mW/mm) consistently prolonged APD and ERP when light was applied at different phases of the cardiac action potential. Optical tracing showed light-induced APD prolongation during the termination of AT.nnCONCLUSION: Our results directly demonstrate that cationic channelrhodopsin activation by brief pulsed light stimulation prolongs the atrial refractory period suggesting that this is one of the key mechanisms of optogenetic termination of AT.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Kadosaka, Takahide; Watanabe, Masaya; Natsui, Hiroyuki; Koizumi, Takuya; Nakao, Motoki; Koya, Taro; Hagiwara, Hikaru; Kamada, Rui; Temma, Taro; Karube, Fuyuki; Fujiyama, Fumino; Anzai, Toshihisa
Empagliflozin attenuates arrhythmogenesis in diabetic cardiomyopathy by normalizing intracellular Ca handling in ventricular cardiomyocytes Journal Article
In: Am J Physiol Heart Circ Physiol, vol. 324, no. 3, pp. H341–H354, 2023, ISSN: 1522-1539.
@article{pmid36607794,
title = {Empagliflozin attenuates arrhythmogenesis in diabetic cardiomyopathy by normalizing intracellular Ca handling in ventricular cardiomyocytes},
author = {Takahide Kadosaka and Masaya Watanabe and Hiroyuki Natsui and Takuya Koizumi and Motoki Nakao and Taro Koya and Hikaru Hagiwara and Rui Kamada and Taro Temma and Fuyuki Karube and Fumino Fujiyama and Toshihisa Anzai},
doi = {10.1152/ajpheart.00391.2022},
issn = {1522-1539},
year = {2023},
date = {2023-03-01},
urldate = {2023-03-01},
journal = {Am J Physiol Heart Circ Physiol},
volume = {324},
number = {3},
pages = {H341--H354},
abstract = {Diabetic cardiomyopathy has been reported to increase the risk of fatal ventricular arrhythmia. The beneficial effects of the selective sodium-glucose cotransporter-2 inhibitor have not been fully examined in the context of antiarrhythmic therapy, especially its direct cardioprotective effects despite the negligible SGLT2 expression in cardiomyocytes. We aimed to examine the antiarrhythmic effects of empagliflozin (EMPA) treatment on diabetic cardiomyocytes, with a special focus on Ca handling. We conducted echocardiography and hemodynamic studies and studied electrophysiology, Ca handling, and protein expression in C57BLKS/J-lepr mice ( mice) and their nondiabetic lean heterozygous Lepr littermates (/ mice). Preserved systolic function with diastolic dysfunction was observed in 16-wk-old mice. During arrhythmia induction, mice had significantly increased premature ventricular complexes (PVCs) than controls, which was attenuated by EMPA. In protein expression analyses, calmodulin-dependent protein kinase II (CaMKII) Thr287 autophosphorylation and CaMKII-dependent RyR2 phosphorylation (S2814) were significantly increased in diabetic hearts, which were inhibited by EMPA. In addition, global -GlcNAcylation significantly decreased with EMPA treatment. Furthermore, EMPA significantly inhibited ventricular cardiomyocyte glucose uptake. Diabetic cardiomyocytes exhibited increased spontaneous Ca events and decreased sarcoplasmic reticulum (SR) Ca content, along with impaired Ca transient, all of which normalized with EMPA treatment. Notably, most EMPA-induced improvements in Ca handling were abolished by the addition of an -GlcNAcase (OGA) inhibitor. In conclusion, EMPA attenuated ventricular arrhythmia inducibility by normalizing the intracellular Ca handling, and we speculated that this effect was, at least partly, due to the inhibition of -GlcNAcylation via the suppression of glucose uptake into cardiomyocytes. SGLT2is are known to improve cardiovascular outcomes regardless of the presence of diabetes and decrease traditional cardiovascular risk factors. We demonstrated, for the first time, that EMPA inhibited PVCs by normalizing Ca handling in diabetic mice. Our data suggest that the effects of SGLT2is on calcium handling may occur because of suppression of -GlcNAcylation through inhibition of glucose uptake and not because of NHE inhibition, as previously suggested.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Koizumi, Takuya; Watanabe, Masaya; Yokota, Takashi; Tsuda, Masumi; Handa, Haruka; Koya, Jiro; Nishino, Kotaro; Tatsuta, Daishiro; Natsui, Hiroyuki; Kadosaka, Takahide; Koya, Taro; Nakao, Motoki; Hagiwara, Hikaru; Kamada, Rui; Temma, Taro; Tanaka, Shinya; Anzai, Toshihisa
Empagliflozin suppresses mitochondrial reactive oxygen species generation and mitigates the inducibility of atrial fibrillation in diabetic rats Journal Article
In: Front Cardiovasc Med, vol. 10, pp. 1005408, 2023, ISSN: 2297-055X.
@article{pmid36815024,
title = {Empagliflozin suppresses mitochondrial reactive oxygen species generation and mitigates the inducibility of atrial fibrillation in diabetic rats},
author = {Takuya Koizumi and Masaya Watanabe and Takashi Yokota and Masumi Tsuda and Haruka Handa and Jiro Koya and Kotaro Nishino and Daishiro Tatsuta and Hiroyuki Natsui and Takahide Kadosaka and Taro Koya and Motoki Nakao and Hikaru Hagiwara and Rui Kamada and Taro Temma and Shinya Tanaka and Toshihisa Anzai},
doi = {10.3389/fcvm.2023.1005408},
issn = {2297-055X},
year = {2023},
date = {2023-01-01},
urldate = {2023-01-01},
journal = {Front Cardiovasc Med},
volume = {10},
pages = {1005408},
abstract = {INTRODUCTION: Recent studies have demonstrated that sodium-glucose co-transporter-2 inhibitors (SGLT2-i) reduce the risk of atrial fibrillation (AF) in patients with diabetes mellitus (DM), in which oxidative stress due to increased reactive oxygen species (ROS) contributes to the pathogenesis of AF. We aimed to further investigate this, and examine whether the SGLT2-i empagliflozin suppresses mitochondrial-ROS generation and mitigates fibrosis.nnMETHODS: A high-fat diet and low-dose streptozotocin treatment were used to induce type-2 DM (T2DM) in Sprague-Dawley rats. The rats were randomly divided into three groups: control, DM, and DM treated with empagliflozin (30 mg/kg/day) for 8 weeks. The mitochondrial respiratory capacity and ROS generation in the atrial myocardium were measured using a high-resolution respirometer. Oxidative stress markers and protein expression related to mitochondrial biogenesis and dynamics as well as the mitochondrial morphology were examined in the atrial tissue. Additionally, mitochondrial function was examined in H9c2 cardiomyoblasts. Atrial tachyarrhythmia (ATA) inducibility, interatrial conduction time (IACT), and fibrosis were also measured.nnRESULTS: Inducibility of ATA, fibrosis, and IACT were increased in rats with DM when compared to controls, all of which were restored by empagliflozin treatment. In addition, the rats with DM had increased mitochondrial-ROS with an impaired complex I-linked oxidative phosphorylation capacity. Importantly, empagliflozin seemed to ameliorate these impairments in mitochondrial function. Furthermore, empagliflozin reversed the decrease in phosphorylated AMPK expression and altered protein levels related to mitochondrial biogenesis and dynamics, and increased mitochondrial content. Empagliflozin also improved mitochondrial function in H9c2 cells cultured with high glucose medium.nnDISCUSSION: These data suggest that empagliflozin has a cardioprotective effect, at least in part, by reducing mitochondrial ROS generation through AMPK signaling pathways in the atrium of diabetic rats. This suggests that empagliflozin might suppress the development of AF in T2DM.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2022
Koya, Taro; Watanabe, Masaya; Natsui, Hiroyuki; Kadosaka, Takahide; Koizumi, Takuya; Nakao, Motoki; Hagiwara, Hikaru; Kamada, Rui; Temma, Taro; Anzai, Toshihisa
Pharmacological nNOS inhibition modified small-conductance Ca-activated K channel without altering Ca dynamics Journal Article
In: Am J Physiol Heart Circ Physiol, vol. 323, no. 5, pp. H869–H878, 2022, ISSN: 1522-1539.
@article{pmid36149772,
title = {Pharmacological nNOS inhibition modified small-conductance Ca-activated K channel without altering Ca dynamics},
author = {Taro Koya and Masaya Watanabe and Hiroyuki Natsui and Takahide Kadosaka and Takuya Koizumi and Motoki Nakao and Hikaru Hagiwara and Rui Kamada and Taro Temma and Toshihisa Anzai},
doi = {10.1152/ajpheart.00252.2022},
issn = {1522-1539},
year = {2022},
date = {2022-11-01},
urldate = {2022-11-01},
journal = {Am J Physiol Heart Circ Physiol},
volume = {323},
number = {5},
pages = {H869--H878},
abstract = {Atrial fibrillation (AF) is associated with electrical remodeling processes that promote a substrate for the maintenance of AF. Although the small-conductance Ca-activated K (SK) channel is a key factor in atrial electrical remodeling, the mechanism of its activation remains unclear. Regional nitric oxide (NO) production by neuronal nitric oxide synthase (nNOS) is involved in atrial electrical remodeling. In this study, atrial tachyarrhythmia (ATA) induction and optical mapping were performed on perfused rat hearts. nNOS is pharmacologically inhibited by -methylthiocitrulline (SMTC). The influence of the SK channel was examined using a specific channel inhibitor, apamin (APA). Parameters such as action potential duration (APD), conduction velocity, and calcium transient (CaT) were evaluated using voltage and calcium optical mapping. The dominant frequency was examined in the analysis of AF dynamics. SMTC (100 nM) increased the inducibility of ATA and apamin (100 nM) mitigated nNOS inhibition-induced arrhythmogenicity. SMTC caused abbreviations and enhanced the spatial dispersion of APD, which was reversed by apamin. By contrast, conduction velocity and other parameters associated with CaT were not affected by SMTC or apamin administration. Apamin reduced the frequency of SMTC-induced ATA. In summary, nNOS inhibition abbreviates APD by modifying the SK channels. A specific SK channel blocker, apamin, mitigated APD abbreviation without alteration of CaT, implying an underlying mechanism of posttranslational modification of SK channels. We demonstrated that pharmacological nNOS inhibition increased the atrial arrhythmia inducibility and a specific small-conductance Ca-activated K channel blocker, apamin, reversed the enhanced atrial arrhythmia inducibility. Apamin mitigated APD abbreviation without alteration of Ca transient, implying an underlying mechanism of posttranslational modification of SK channels.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Hagiwara, Hikaru; Watanabe, Masaya; Fujioka, Yoichiro; Kadosaka, Takahide; Koizumi, Takuya; Koya, Taro; Nakao, Motoki; Kamada, Rui; Temma, Taro; Okada, Kazufumi; Moreno, Jose Antonio; Kwon, Ohyun; Sabe, Hisakata; Ohba, Yusuke; Anzai, Toshihisa
Stimulation of the mitochondrial calcium uniporter mitigates chronic heart failure-associated ventricular arrhythmia in mice Journal Article
In: Heart Rhythm, vol. 19, no. 10, pp. 1725–1735, 2022, ISSN: 1556-3871.
@article{pmid35660475,
title = {Stimulation of the mitochondrial calcium uniporter mitigates chronic heart failure-associated ventricular arrhythmia in mice},
author = {Hikaru Hagiwara and Masaya Watanabe and Yoichiro Fujioka and Takahide Kadosaka and Takuya Koizumi and Taro Koya and Motoki Nakao and Rui Kamada and Taro Temma and Kazufumi Okada and Jose Antonio Moreno and Ohyun Kwon and Hisakata Sabe and Yusuke Ohba and Toshihisa Anzai},
doi = {10.1016/j.hrthm.2022.05.034},
issn = {1556-3871},
year = {2022},
date = {2022-10-01},
urldate = {2022-10-01},
journal = {Heart Rhythm},
volume = {19},
number = {10},
pages = {1725--1735},
abstract = {BACKGROUND: An aberrant increase in the diastolic calcium concentration ([Ca]) level is a hallmark of heart failure (HF) and the cause of delayed afterdepolarization and ventricular arrhythmia (VA). Although mitochondria play a role in regulating [Ca], whether they can compensate for the [Ca] abnormality in ventricular myocytes is unknown.nnOBJECTIVE: The purpose of this study was to investigate whether enhanced Ca uptake of mitochondria may compensate for an abnormal increase in the [Ca] of ventricular myocytes in HF to effectively mitigate VA.nnMETHODS: We used a HF mouse model in which myocardial infarction was induced by permanent left anterior descending coronary artery ligation. The mitochondrial Ca uniporter was stimulated by kaempferol. Ca dynamics and membrane potential were measured using an epifluorescence microscope, a confocal microscope, and the perforated patch-clamp technique. VA was induced in Langendorff-perfused hearts, and hemodynamic parameters were measured using a microtip transducer catheter.nnRESULTS: Protein expression of the mitochondrial Ca uniporter, as assessed by its subunit expression, did not change between HF and sham mice. Treatment of cardiomyocytes with kaempferol, isolated from HF mice 28 days after coronary ligation, reduced the appearance of aberrant diastolic [Ca] waves and sparks and spontaneous action potentials. Kaempferol effectively reduced VA occurring in Langendorff-perfused hearts. Intravenous administration of kaempferol did not markedly affect left ventricular hemodynamic parameters.nnCONCLUSION: The effects of kaempferol in HF of mice implied that mitochondria may have the potential to compensate for abnormal [Ca]. Mechanisms involved in mitochondrial Ca uptake may provide novel targets for treatment of HF-associated VA.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Koizumi, Takuya; Kamada, Rui; Watanabe, Masaya; Yokoshiki, Hisashi; Temma, Taro; Hagiwara, Hikaru; Koya, Taro; Nakao, Motoki; Kadosaka, Takahide; Natsui, Hiroyuki; Takahashi, Masayuki; Mizukami, Kazuya; Mitsuyama, Hirofumi; Anzai, Toshihisa
Predictors of cardiovascular mortality after an electrical storm in patients with structural heart disease Journal Article
In: J Cardiol, vol. 80, no. 2, pp. 167–171, 2022, ISSN: 1876-4738.
@article{pmid35365376,
title = {Predictors of cardiovascular mortality after an electrical storm in patients with structural heart disease},
author = {Takuya Koizumi and Rui Kamada and Masaya Watanabe and Hisashi Yokoshiki and Taro Temma and Hikaru Hagiwara and Taro Koya and Motoki Nakao and Takahide Kadosaka and Hiroyuki Natsui and Masayuki Takahashi and Kazuya Mizukami and Hirofumi Mitsuyama and Toshihisa Anzai},
doi = {10.1016/j.jjcc.2022.02.016},
issn = {1876-4738},
year = {2022},
date = {2022-08-01},
urldate = {2022-08-01},
journal = {J Cardiol},
volume = {80},
number = {2},
pages = {167--171},
abstract = {BACKGROUND: Electrical storms (ESs) in patients with structural heart disease (SHD) have been reported to be associated with a poor prognosis. However, the detailed cause of death and influence of implantable cardioverter defibrillator (ICD) therapy in ES patients have not been fully investigated. Therefore, we sought to explore the detailed clinical course after an ES and the impact of the ICD therapy in patients with SHDs.nnMETHODS: We retrospectively analyzed 31 consecutive patients with ESs who had undergone an ICD implantation. ESs were defined as three or more ventricular arrhythmias within 24 h.nnRESULTS: During a mean follow up of 4.5 years, 13 patients died. Among them, cardiovascular death (CVD) was observed in 11/13 (85%), and the leading cause of the CVD was end-stage heart failure. A New York Heart Association class ≥III at the time of the ES occurrence (HR 6.51 95% CI 1.94-25.1, p = 0.003) and any shock therapy (HR 5.94 95% CI 1.06-112.2, p = 0.04) were associated with CVD.nnCONCLUSION: In the current single center study, the major cause of death in ES patients with SHDs was end-stage heart failure. Any shock therapy was associated with CVD. Arrhythmia management to avoid ICD shocks might reduce the mortality in ES patients.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2021
Takahashi, Masayuki; Yokoshiki, Hisashi; Mitsuyama, Hirofumi; Watanabe, Masaya; Temma, Taro; Kamada, Rui; Hagiwara, Hikaru; Takahashi, Yumi; Anzai, Toshihisa
SK channel blockade prevents hypoxia-induced ventricular arrhythmias through inhibition of Ca/voltage uncoupling in hypertrophied hearts Journal Article
In: Am J Physiol Heart Circ Physiol, vol. 320, no. 4, pp. H1456–H1469, 2021, ISSN: 1522-1539.
@article{pmid33635168,
title = {SK channel blockade prevents hypoxia-induced ventricular arrhythmias through inhibition of Ca/voltage uncoupling in hypertrophied hearts},
author = {Masayuki Takahashi and Hisashi Yokoshiki and Hirofumi Mitsuyama and Masaya Watanabe and Taro Temma and Rui Kamada and Hikaru Hagiwara and Yumi Takahashi and Toshihisa Anzai},
doi = {10.1152/ajpheart.00777.2020},
issn = {1522-1539},
year = {2021},
date = {2021-04-01},
urldate = {2021-04-01},
journal = {Am J Physiol Heart Circ Physiol},
volume = {320},
number = {4},
pages = {H1456--H1469},
abstract = {Ventricular arrhythmia (VA) is the major cause of death in patients with left ventricular (LV) hypertrophy and/or acute ischemia. We hypothesized that apamin, a blocker of small-conductance Ca-activated K (SK) channels, alters Ca handling and exhibits anti-arrhythmic effects in ventricular myocardium. Spontaneous hypertensive rats were used as a model of LV hypertrophy. A dual optical mapping of membrane potential () and intracellular calcium (Ca) was performed during global hypoxia (GH) on the Langendorff perfusion system. The majority of pacing-induced VAs during GH were initiated by triggered activities. Pretreatment of apamin (100 nmol/L) significantly inhibited the VA inducibility. Compared with SK channel blockers (apamin and NS8593), non-SK channel blockers (glibenclamide and 4-AP) did not exhibit anti-arrhythmic effects. Apamin prevented not only action potential duration (APD) shortening (-18.7 [95% confidence interval, -35.2 to -6.05] ms vs. -2.75 [95% CI, -10.45 to 12.65] ms, = 0.04) but also calcium transient duration (CaTD) prolongation (14.52 [95% CI, 8.8-20.35] ms vs. 3.85 [95% CI, -3.3 to 12.1] ms, < 0.01), thereby reducing CaTD - APD, which denotes "Ca/ uncoupling" (33.22 [95% CI, 22-48.4] ms vs. 6.6 [95% CI, 0-14.85] ms, < 0.01). The reduction of Ca/ uncoupling was attributable to less prolonged Ca decay constant and suppression of diastolic Ca increase by apamin. The inhibition of VA inducibility and changes in APs/CaTs parameters caused by apamin was negated by the addition of ouabain, an inhibitor of Na/K pump. Apamin attenuates APD shortening, Ca handling abnormalities, and Ca/ uncoupling, leading to inhibition of VA occurrence in hypoxic hypertrophied hearts. We demonstrated that hypoxia-induced ventricular arrhythmias were mainly initiated by Ca-loaded triggered activities in hypertrophied hearts. The blockades of small-conductance Ca-activated K channels, especially "apamin," showed anti-arrhythmic effects by alleviation of not only action potential duration shortening but also Ca handling abnormalities, most notably the "Ca/voltage uncoupling."},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2020
Lee, Wei-Chieh; Watanabe, Masaya; Yokoshiki, Hisashi; Temma, Taro; Kamada, Rui; Takahashi, Masayuki; Hagiwara, Hikaru; Takahashi, Yumi; Anzai, Toshihisa
Rapid-rate nonsustained ventricular tachycardias in high-risk dilated cardiomyopathy patients Journal Article
In: Pacing Clin Electrophysiol, vol. 43, no. 10, pp. 1086–1095, 2020, ISSN: 1540-8159.
@article{pmid32735041,
title = {Rapid-rate nonsustained ventricular tachycardias in high-risk dilated cardiomyopathy patients},
author = {Wei-Chieh Lee and Masaya Watanabe and Hisashi Yokoshiki and Taro Temma and Rui Kamada and Masayuki Takahashi and Hikaru Hagiwara and Yumi Takahashi and Toshihisa Anzai},
doi = {10.1111/pace.14027},
issn = {1540-8159},
year = {2020},
date = {2020-10-01},
urldate = {2020-10-01},
journal = {Pacing Clin Electrophysiol},
volume = {43},
number = {10},
pages = {1086--1095},
abstract = {AIMS: Nonsustained ventricular tachycardia (NSVT) occurs frequently in patients with dilated cardiomyopathy (DCM), especially in high-risk patients. The role of rapid-rate NSVT (RR-NSVT) documented by an implantable cardioverter-defibrillator (ICD) in DCM patients has not been fully explored. This study aimed to determine the relationship between RR-NSVT and the occurrence of ventricular tachyarrhythmias (VTAs) in DCM patients with ICD.nnMETHODS: From December 2000 to December 2017, 136 DCM patients received ICD or cardiac resynchronization therapy defibrillator (CRT-D) implantation for primary or secondary prevention of VTAs. Based on the occurrence of documented RR-NSVT, patients were classified into RR-NSVT (-) or RR-NSVT (+) groups.nnRESULT: During the median follow-up of 4.5 years, 50.0% (68/136) patients experienced ≥1 episode, and 25.0% (34/136) patients experienced ≥3 episodes of RR-NSVT. Event-free survival for VTAs was significantly higher in the RR-NSVT (-) group, whereas those for heart failure admission and cardiovascular mortality were comparable between groups. In the multivariate Cox regression analysis, any RR-NSVT showed a positive association with the occurrence of VTAs (hazard ratio: 5.087; 95% confidence interval: 2.374-10.900; P < .001). In RR-NSVT (+) patients, a cluster (≥3 times/6 months) and frequent pattern (≥3 runs/day) of RR-NSVT were observed in 42.6% (29/68) and 30.9% (21/68) patients, respectively, who showed further increased incidence of VTAs.nnCONCLUSION: In DCM patients with ICD/CRT-D, 50.0% patients experienced at least one episode of RR-NSVT. RR-NSVT documentation showed a positive association with subsequent occurrence of VTAs, suggesting the importance of constructive arrhythmia management for patients with RR-NSVT.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2019
Kamada, Rui; Yokoshiki, Hisashi; Mitsuyama, Hirofumi; Watanabe, Masaya; Mizukami, Kazuya; Tenma, Taro; Takahashi, Masayuki; Takada, Shingo; Anzai, Toshihisa
In: Eur J Pharmacol, vol. 844, pp. 110–117, 2019, ISSN: 1879-0712.
@article{pmid30529196,
title = {Arrhythmogenic β-adrenergic signaling in cardiac hypertrophy: The role of small-conductance calcium-activated potassium channels via activation of CaMKII},
author = {Rui Kamada and Hisashi Yokoshiki and Hirofumi Mitsuyama and Masaya Watanabe and Kazuya Mizukami and Taro Tenma and Masayuki Takahashi and Shingo Takada and Toshihisa Anzai},
doi = {10.1016/j.ejphar.2018.12.011},
issn = {1879-0712},
year = {2019},
date = {2019-02-01},
urldate = {2019-02-01},
journal = {Eur J Pharmacol},
volume = {844},
pages = {110--117},
abstract = {Sustained ventricular arrhythmias (SVAs) lead to sudden cardiac death, for which β- adrenoreceptor blockers are effective. We hypothesized that electrophysiological changes and arrhythmias by β- adrenoreceptor stimulation are crucially related to activation of small-conductance calcium-activated potassium (SK) channels via the increase in Ca/calmodulin-dependent protein kinase II (CaMKII) activity. We used normotensive Wistar-Kyoto (WKY) rats and spontaneous hypertensive rats (SHRs). The latter served as a model of left ventricular hypertrophy. We performed dual optical mapping of action potentials and Ca transients, and the effects of isoproterenol and apamin, an SK channel blocker, were evaluated in the Langendorff-perfused hearts. Action potential duration was abbreviated by isoproterenol (100 nM) in both WKY rats and SHRs. In contrast, the CaMKII activity was increased by isoproterenol only in SHRs. In the presence of isoproterenol, apamin prolonged the action potential duration only in SHRs (n = 10, from 116.6 ± 5.05 ms to 125.4 ± 3.80 ms, P = 0.011), which was prevented by KN-93, a CaMKII inhibitor. Increase in Ca transients and shortening of Ca transient duration by isoproterenol were similarly observed in both animals, which was not affected by apamin. Apamin reduced the isoproterenol-induced SVAs and maximal slope of action potential duration restitution curve specifically in SHRs. In conclusion, β- adrenoreceptor stimulation creates arrhythmogenic substrates via the CaMKII-dependent activation of SK channels in cardiac hypertrophy.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2018
Tenma, Taro; Mitsuyama, Hirofumi; Watanabe, Masaya; Kakutani, Naoya; Otsuka, Yutaro; Mizukami, Kazuya; Kamada, Rui; Takahashi, Masayuki; Takada, Shingo; Sabe, Hisataka; Tsutsui, Hiroyuki; Yokoshiki, Hisashi
Small-conductance Ca-activated K channel activation deteriorates hypoxic ventricular arrhythmias via CaMKII in cardiac hypertrophy Journal Article
In: Am J Physiol Heart Circ Physiol, vol. 315, no. 2, pp. H262–H272, 2018, ISSN: 1522-1539.
@article{pmid29631373,
title = {Small-conductance Ca-activated K channel activation deteriorates hypoxic ventricular arrhythmias via CaMKII in cardiac hypertrophy},
author = {Taro Tenma and Hirofumi Mitsuyama and Masaya Watanabe and Naoya Kakutani and Yutaro Otsuka and Kazuya Mizukami and Rui Kamada and Masayuki Takahashi and Shingo Takada and Hisataka Sabe and Hiroyuki Tsutsui and Hisashi Yokoshiki},
doi = {10.1152/ajpheart.00636.2017},
issn = {1522-1539},
year = {2018},
date = {2018-08-01},
urldate = {2018-08-01},
journal = {Am J Physiol Heart Circ Physiol},
volume = {315},
number = {2},
pages = {H262--H272},
abstract = {The molecular and electrophysiological mechanisms of acute ischemic ventricular arrhythmias in hypertrophied hearts are not well known. We hypothesized that small-conductance Ca-activated K (SK) channels are activated during hypoxia via the Ca/calmodulin-dependent protein kinase II (CaMKII)-dependent pathway. We used normotensive Wistar-Kyoto (WKY) rats and spontaneous hypertensive rats (SHRs) as a model of cardiac hypertrophy. The inhibitory effects of SK channels and ATP-sensitive K channels on electrophysiological changes and genesis of arrhythmias during simulated global hypoxia (GH) were evaluated. Hypoxia-induced abbreviation of action potential duration (APD) occurred earlier in ventricles from SHRs versus. WKY rats. Apamin, a SK channel blocker, prevented this abbreviation in SHRs in both the early and delayed phase of GH, whereas in WKY rats only the delayed phase was prevented. In contrast, SHRs were less sensitive to glibenclamide, a ATP-sensitive K channel blocker, which inhibited the APD abbreviation in both phases of GH in WKY rats. SK channel blockers (apamin and UCL-1684) reduced the incidence of hypoxia-induced sustained ventricular arrhythmias in SHRs but not in WKY rats. Among three SK channel isoforms, SK2 channels were directly coimmunoprecipitated with CaMKII phosphorylated at Thr (p-CaMKII). We conclude that activation of SK channels leads to the APD abbreviation and sustained ventricular arrhythmias during simulated hypoxia, especially in hypertrophied hearts. This mechanism may result from p-CaMKII-bound SK2 channels and reveal new molecular targets to prevent lethal ventricular arrhythmias during acute hypoxia in cardiac hypertrophy. NEW & NOTEWORTHY We now show a new pathophysiological role of small-conductance Ca-activated K channels, which shorten the action potential duration and induce ventricular arrhythmias during hypoxia. We also demonstrate that small-conductance Ca-activated K channels interact with phosphorylated Ca/calmodulin-dependent protein kinase II at Thr in hypertrophied hearts.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Tenma, Taro; Yokoshiki, Hisashi; Mitsuyama, Hirofumi; Watanabe, Masaya; Mizukami, Kazuya; Kamada, Rui; Takahashi, Masayuki; Sasaki, Ryo; Maeno, Motoki; Okamoto, Kaori; Chiba, Yuki; Anzai, Toshihisa
Relation between total shock energy and mortality in patients with implantable cardioverter-defibrillator Journal Article
In: Int J Cardiol, vol. 259, pp. 94–99, 2018, ISSN: 1874-1754.
@article{pmid29486995,
title = {Relation between total shock energy and mortality in patients with implantable cardioverter-defibrillator},
author = {Taro Tenma and Hisashi Yokoshiki and Hirofumi Mitsuyama and Masaya Watanabe and Kazuya Mizukami and Rui Kamada and Masayuki Takahashi and Ryo Sasaki and Motoki Maeno and Kaori Okamoto and Yuki Chiba and Toshihisa Anzai},
doi = {10.1016/j.ijcard.2018.02.063},
issn = {1874-1754},
year = {2018},
date = {2018-05-01},
urldate = {2018-05-01},
journal = {Int J Cardiol},
volume = {259},
pages = {94--99},
abstract = {BACKGROUND: Implantable Cardioverter-Defibrillator (ICD) shocks have been associated with mortality. However, no study has examined the relation between total shock energy and mortality. The aim of this study is to assess the association of total shock energy with mortality, and to determine the patients who are at risk of this association.nnMETHODS: Data from 316 consecutive patients who underwent initial ICD implantation in our hospital between 2000 and 2011 were retrospectively studied. We collected shock energy for 3 years from the ICD implantation, and determined the relation of shock energy on mortality after adjusting confounding factors.nnRESULTS: Eighty-seven ICD recipients experienced shock(s) within 3 years from ICD implantation and 43 patients had died during the follow-up. The amount of shock energy was significantly associated with all-cause death [adjusted hazard ratio (HR) 1.26 (per 100 joule increase), p < 0.01] and tended to be associated with cardiac death (adjusted HR 1.30, p = 0.08). The survival rate of patients with high shock energy accumulation (≥182 joule) was lower (p < 0.05), as compared to low shock energy accumulation (<182 joule), likewise to no shock. Besides, the relation between high shock energy accumulation and all-cause death was remarkable in the patients with low left ventricular ejection fraction (LVEF ≤40%) or atrial fibrillation (AF).nnCONCLUSIONS: Increase of shock energy was related to mortality in ICD recipients. This relation was evident in patients with low LVEF or AF.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2015
Mizukami, Kazuya; Yokoshiki, Hisashi; Mitsuyama, Hirofumi; Watanabe, Masaya; Tenma, Taro; Takada, Shingo; Tsutsui, Hiroyuki
In: Am J Physiol Heart Circ Physiol, vol. 309, no. 6, pp. H1066–H1074, 2015, ISSN: 1522-1539.
@article{pmid26297230,
title = {Small-conductance Ca2+-activated K+ current is upregulated via the phosphorylation of CaMKII in cardiac hypertrophy from spontaneously hypertensive rats},
author = {Kazuya Mizukami and Hisashi Yokoshiki and Hirofumi Mitsuyama and Masaya Watanabe and Taro Tenma and Shingo Takada and Hiroyuki Tsutsui},
doi = {10.1152/ajpheart.00825.2014},
issn = {1522-1539},
year = {2015},
date = {2015-09-01},
urldate = {2015-09-01},
journal = {Am J Physiol Heart Circ Physiol},
volume = {309},
number = {6},
pages = {H1066--H1074},
abstract = {Left ventricular hypertrophy is associated with an increased risk of ventricular arrhythmias. However, the underlying molecular basis is poorly understood. It has been reported that small-conductance Ca(2+)-activated K(+) (SK) channels are involved in the pathogenesis of ventricular arrhythmias in heart failure. The present study aimed to test the hypothesis that SK channel activity is increased via the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)-dependent pathway in hypertensive cardiac hypertrophy. Normotensive Wistar-Kyoto (WKY) rats and spontaneous hypertensive rats (SHRs) were used. Whole cell membrane currents were recorded in isolated ventricular myocytes by the patch-clamp method, and apamin-sensitive K(+) current (IKAS), which is inhibited by apamin (100 nM), an SK channel blocker, was evaluated. IKAS at 40 mV was present in SHRs, whereas it was hardly detectable in WKY rats (0.579 ± 0.046 vs. 0.022 ± 0.062 pA/pF, both n = 6, P < 0.05). IKAS was almost completely abolished by 1 μM KN-93, a CaMKII inhibitor, in SHRs. Optical recordings of left ventricular anterior wall action potentials revealed that apamin prolonged the late phase of repolarization only in SHRs. Western blot analysis of SK channel protein isoforms demonstrated that SK2 was significantly increased in SHRs compared with WKY rats (SK2/GAPDH: 0.66 ± 0.07 vs. 0.40 ± 0.02, both n = 6, P < 0.05), whereas SK1 and SK3 did not differ between groups. In addition, autophosphorylated CaMKII was significantly increased in SHRs (phosphorylated CaMKII/GAPDH: 0.80 ± 0.06 vs. 0.58 ± 0.06, both n = 6, P < 0.05) despite a comparable total amount of CaMKII between groups. In conclusion, SK channels are upregulated via the enhanced activation of CaMKII in cardiac hypertrophy in SHRs.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Mizukami, Kazuya; Yokoshiki, Hisashi; Mitsuyama, Hirofumi; Watanabe, Masaya; Tenma, Taro; Matsui, Yoshiro; Tsutsui, Hiroyuki
Predictors of high defibrillation threshold in patients with implantable cardioverter-defibillator using a transvenous dual-coil lead Journal Article
In: Circ J, vol. 79, no. 1, pp. 77–84, 2015, ISSN: 1347-4820.
@article{pmid25391259,
title = {Predictors of high defibrillation threshold in patients with implantable cardioverter-defibillator using a transvenous dual-coil lead},
author = {Kazuya Mizukami and Hisashi Yokoshiki and Hirofumi Mitsuyama and Masaya Watanabe and Taro Tenma and Yoshiro Matsui and Hiroyuki Tsutsui},
doi = {10.1253/circj.CJ-14-0860},
issn = {1347-4820},
year = {2015},
date = {2015-01-01},
urldate = {2015-01-01},
journal = {Circ J},
volume = {79},
number = {1},
pages = {77--84},
abstract = {BACKGROUND: Defibrillation testing (DT) is considered a standard procedure during implantable cardioverter-defibrillator (ICD) implantation. However, little is known about the factors that are significantly related to patients with high defibrillation threshold (DFT) using the present triad system.nnMETHODS AND RESULTS: We examined 286 consecutive patients who underwent ICD implantation with a transvenous dual-coil lead and DT from December 2000 to December 2011. We defined patients who required 25 J or more by the implanted device as the high DFT group, and those who required less than 25 J as the normal DFT group. For each patient, assessment parameters included underlying disease, comorbidities, NYHA functional class, drugs, and echocardiographic measures. The high DFT group consisted of 12 patients (4.2%). Multivariate analysis identified 3 independent predictors for high DFT: atrial fibrillation (odds ratio (OR) 4.85, 95% confidence interval (CI) 1.24-22.33, P=0.023), hypertension (OR 4.01, 95% CI 1.08-15.96, P=0.039), thickness of interventricular septum (IVS) >12 mm (OR 4.82, 95% CI 1.17-20.31, P=0.030).nnCONCLUSIONS: Atrial fibrillation, hypertension and IVS hypertrophy were significantly associated with high DFT. Identification of such patients could help to lower the risk of complications with DT.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Tenma, Taro; Yokoshiki, Hisashi; Mizukami, Kazuya; Mitsuyama, Hirofumi; Watanabe, Masaya; Sasaki, Ryo; Maeno, Motoki; Matsui, Yoshiro; Tsutsui, Hiroyuki
Predictors and Proarrhythmic Consequences of Inappropriate Implantable Cardioverter-Defibrillator Therapy Journal Article
In: Circ J, vol. 79, no. 9, pp. 1920–1927, 2015, ISSN: 1347-4820.
@article{pmid26104029,
title = {Predictors and Proarrhythmic Consequences of Inappropriate Implantable Cardioverter-Defibrillator Therapy},
author = {Taro Tenma and Hisashi Yokoshiki and Kazuya Mizukami and Hirofumi Mitsuyama and Masaya Watanabe and Ryo Sasaki and Motoki Maeno and Yoshiro Matsui and Hiroyuki Tsutsui},
doi = {10.1253/circj.CJ-15-0306},
issn = {1347-4820},
year = {2015},
date = {2015-01-01},
urldate = {2015-01-01},
journal = {Circ J},
volume = {79},
number = {9},
pages = {1920--1927},
abstract = {BACKGROUND: Despite the benefits of implantable cardioverter-defibrillator (ICD) therapy, inappropriate shocks can lead to multiple adverse effects. The aim of this study was to clarify the predictors of inappropriate ICD shocks and their proarrhythmic consequences.nnMETHODS AND RESULTS: We retrospectively studied 316 consecutive patients who underwent ICD implantation from December 2000 to December 2011. Of them, 70 (22%) experienced inappropriate ICD shocks without proarrhythmia requiring some intervention; 2 patients (0.6%) had proarrhythmic inappropriate ICD therapy by antitachycardia pacing (ATP), thereby calculated to be 0.18% of patients per year. However, they did not have syncope from this inappropriate ATP. Multivariate analysis identified younger age (≤56 years: hazard ratio [HR] 1.68, 95% confidence interval [CI] 1.02-2.77, P=0.043), paroxysmal atrial fibrillation (HR 3.00, 95% CI 1.64-5.31, P=0.0002), stroke (HR 2.23, 95% CI 1.11-4.47, P=0.024), and no diuretic use (HR 1.72, 95% CI 1.03-2.93, P=0.039) as independent predictors of the occurrence of inappropriate ICD shocks.nnCONCLUSIONS: Young age, paroxysmal atrial fibrillation, stroke, and no use of diuretics were independently associated with inappropriate ICD shocks. Proarrhythmic inappropriate ICD therapy was observed with an annual incidence of 0.18% by ATP.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2014
Mitsuyama, Hirofumi; Yokoshiki, Hisashi; Watanabe, Masaya; Mizukami, Kazuya; Shimokawa, Junichi; Tsutsui, Hiroyuki
In: Am J Physiol Heart Circ Physiol, vol. 307, no. 2, pp. H199–H206, 2014, ISSN: 1522-1539.
@article{pmid24858851,
title = {Ca2+/calmodulin-dependent protein kinase II increases the susceptibility to the arrhythmogenic action potential alternans in spontaneously hypertensive rats},
author = {Hirofumi Mitsuyama and Hisashi Yokoshiki and Masaya Watanabe and Kazuya Mizukami and Junichi Shimokawa and Hiroyuki Tsutsui},
doi = {10.1152/ajpheart.00387.2012},
issn = {1522-1539},
year = {2014},
date = {2014-07-01},
urldate = {2014-07-01},
journal = {Am J Physiol Heart Circ Physiol},
volume = {307},
number = {2},
pages = {H199--H206},
abstract = {Action potential duration alternans (APD-ALT), defined as long-short-long repetitive pattern of APD, potentially leads to lethal ventricular arrhythmia. However, the mechanisms of APD-ALT in the arrhythmogenesis of cardiac hypertrophy remain undetermined. Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is known to modulate the function of cardiac sarcoplasmic reticulum and play an important role in Ca(2+) cycling. We thus aimed to determine the role of CaMKII in the increased susceptibility to APD-ALT and arrhythmogenesis in the hypertrophied heart. APD was measured by high-resolution optical mapping in left ventricular (LV) anterior wall from normotensive Wistar-Kyoto (WKY; n = 10) and spontaneously hypertensive rats (SHR; n = 10) during rapid ventricular pacing. APD-ALT was evoked at significantly lower pacing rate in SHR compared with WKY (382 ± 43 vs. 465 ± 45 beats/min, P < 0.01). These changes in APD-ALT in SHR were completely reversed by KN-93 (1 μmol/l; n = 5), an inhibitor of CaMKII, but not its inactive analog, KN-92 (1 μmol/l; n = 5). The magnitude of APD-ALT was also significantly greater in SHR than WKY and was completely normalized by KN-93. Ventricular fibrillation (VF) was induced by rapid pacing more frequently in SHR than in WKY (60 vs. 10%; P < 0.05), which was also abolished by KN-93 (0%, P < 0.05). Western blot analyses indicated that the CaMKII autophosphorylation at Thr287 was significantly increased in SHR compared with WKY. The increased susceptibility to APD-ALT and VF during rapid pacing in hypertrophied heart was prevented by KN-93. CaMKII could be an important mechanism of arrhythmogenesis in cardiac hypertrophy.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2012
Watanabe, Masaya; Yokoshiki, Hisashi; Mitsuyama, Hirofumi; Mizukami, Kazuya; Ono, Taisuke; Tsutsui, Hiroyuki
Conduction and refractory disorders in the diabetic atrium Journal Article
In: Am J Physiol Heart Circ Physiol, vol. 303, no. 1, pp. H86–H95, 2012, ISSN: 1522-1539.
@article{pmid22561303,
title = {Conduction and refractory disorders in the diabetic atrium},
author = {Masaya Watanabe and Hisashi Yokoshiki and Hirofumi Mitsuyama and Kazuya Mizukami and Taisuke Ono and Hiroyuki Tsutsui},
doi = {10.1152/ajpheart.00010.2012},
issn = {1522-1539},
year = {2012},
date = {2012-07-01},
urldate = {2012-07-01},
journal = {Am J Physiol Heart Circ Physiol},
volume = {303},
number = {1},
pages = {H86--H95},
abstract = {Diabetes mellitus (DM) is an independent risk of atrial fibrillation. However, its arrhythmogenic substrates remain unclear. This study sought to examine the precise propagation and the spatiotemporal dispersion of the action potential (AP) in the diabetic atrium. DM was induced by streptozotocin (65 mg/kg) in 8-wk-old male Wister rats. Optical mapping and histological analysis were performed in the right atrium (RA) from control (n = 26) and DM (n = 27) rats after 16 wk. Rate-dependent alterations of conduction velocity (CV) and its heterogeneity and the spatial distribution of AP were measured in RA using optical mapping. The duration of atrial tachyarrhythmia (AT) induced by rapid atrial stimulation was longer in DM (2.4 ± 0.6 vs. 0.9 ± 0.3 s, P < 0.05). CV was decreased, and its heterogeneity was greater in DM than control. Average action potential duration of 80% repolarization (APD(80)) at pacing cycle length (PCL) of 200 ms from four areas within the RA was prolonged (53 ± 2 vs. 40 ± 3 ms, P < 0.01), and the coefficient of variation of APD(80) was greater in DM than control (0.20 ± 0.02 vs. 0.15 ± 0.01%, P < 0.05). The ratio of APD(80) at PCL shorter than 200 ms to that at 200 ms was smaller (P < 0.001), and the incidence of APD alternans was higher in DM than control (100 vs. 0%, P < 0.001). Interstitial fibrosis was greater and connexin 40 expression was lower in DM than control. The remodeling of the diabetic atrium was characterized as follows: greater vulnerability to AT, increased conduction slowing and its heterogeneity, the prolongation of APD, the increase in spatial dispersion and frequency-dependent shortening of APD, and increased incidence of APD alternans.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}