研究等業績 - 原著論文 - 渡邊　博之

Prognostic value of coronary calcification detected via non-electrocardiogram-gated computed tomography in patients with cardiovascular disease: A retrospective cohort study

Wakaki T.

IJC Heart and Vasculature ( IJC Heart and Vasculature )  56   2025年02月  [査読有り]

研究論文（学術雑誌）  

DOI

Cubital vein access provides a practical alternative to internal jugular vein access for coronary sinus catheter placement

Tashiro H.

Journal of Arrhythmia ( Journal of Arrhythmia )  40 ( 4 ) 991 - 997   2024年08月  [査読有り]

研究論文（学術雑誌）  

DOI

Efficacy and Safety of High-Power Short-Duration Ablation for Cavo-Tricuspid Isthmus With a Flexible-Tip Temperature-Controlled Power Regulation Catheter Performed by Electrophysiology Trainees

Iwakawa H.

Journal of Cardiovascular Electrophysiology ( Journal of Cardiovascular Electrophysiology )    2024年  [査読有り]

研究論文（学術雑誌）  

DOI

Coconut Atrium Causing Restrictive Physiology in the Right Ventricle

Wakaki Tomitaka, Sato Wakana, Suzuki Mayu, Watanabe Hiroyuki

Internal Medicine ( 一般社団法人 日本内科学会 )  advpub ( 0 )   2023年12月  [査読有り]

研究論文（学術雑誌）   国内共著

<p>We herein report a 61-year-old woman with a history of mitral valve replacement for rheumatic fever who presented with crural edema and ascites. Computed tomography showed massive left atrial (LA) calcification involving the interatrial septum, termed "coconut atrium." Catheterization revealed not only pulmonary artery hypertension but also a large V-wave in the pulmonary artery wedge pressure waveform and a dip-and-plateau pattern of right ventricular pressure. Three-dimensional transthoracic echocardiography confirmed the early attainment of peak LA volume and a decreased LA expansion index. Stiff LA syndrome due to coconut LA results in the development of restrictive right ventricular physiology. </p>

DOI PubMed CiNii Research

Pathological Analysis of Medial and Intimal Calcification in Lower Extremity Artery Disease: Impact of Hemodialysis

Tsukasa Kato, Sho Torii, Norihito Nakamura, Kazuki Aihara, Yuta Terabe, Osamu Iida, Takahiro Tokuda, Tatsuya Nakama, Yo Kawahara, Junichi Miyamoto, Takafumi Saito, Norihiko Kamioka, Tsutomu Murakami, Takeshi Ijichi, Makoto Natsumeda, Shigemitsu Tanaka, Yohei Ohno, Gaku Nakazawa, Hiroyuki Watanabe, and Yuji Ikari

JACC: Advances ( JACC: Advances )  2 ( 9 )   2023年11月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Superiority of the Combination of Input and Output Parameters to the Single Parameter for Lesion Size Estimation

Hidehiro Iwakawa, Masateru Takigawa, Junji Yamaguchi, Claire A Martin, Masahiko Goya, Tasuku Yamamoto, Miki Amemiya, Takashi Ikenouchi, Miho Negishi, Iwanari Kawamura, Kentaro Goto, Takatoshi Shigeta, Takuro Nishimura, Tomomasa Takamiya, Susumu Tao, Shinsuke Miyazaki , Hiroyuki Watanabe, Tetsuo Sasano

Circulation Journal ( Circulation Journal )  87 ( 12 ) 1757 - 1764   2023年10月  [査読有り]

研究論文（学術雑誌）   国内共著

<b><i>Background:</i></b> For lesion size prediction, each input parameter, including ablation energy (AE), and output parameter, such as impedance, is individually used. We hypothesize that using both parameters simultaneously may be more optimal.

<b><i>Methods and Results:</i></b> Radiofrequency applications at a range of power (30–50 W), contact force (10 g and 20 g), duration (10–60 s), and catheter orientation with normal saline (NS)- or half-normal saline (HNS)-irrigation were performed in excised porcine hearts. The correlations, with lesion size of AE, absolute impedance drop (∆Imp-drop), relative impedance drop (%Imp-drop), and AE*%Imp-drop were examined. Lesion size was analyzed in 283 of 288 lesions (NS-irrigation, n=142; HNS-irrigation, n=141) without steam pops. AE*%Imp-drop consistently showed the strongest correlations with lesion maximum depth (NS-irrigation, ρ=0.91; HNS-irrigation, ρ=0.94), surface area (NS-irrigation, ρ=0.87; HNS-irrigation, ρ=0.86), and volume (NS-irrigation, ρ=0.94; HNS-irrigation, ρ=0.94) compared with the other parameters. Moreover, compared with AE alone, AE*%Imp-drop significantly improved the strength of correlation with lesion maximum depth (AE vs. AE*%Imp-drop, ρ=0.83 vs. 0.91, P<0.01), surface area (ρ=0.73 vs. 0.87, P<0.01), and volume (ρ=0.84 vs. 0.94, P<0.01) with NS-irrigation. This tendency was also observed with HNS-irrigation. Parallel catheter orientation showed a better correlation with lesion depth and volume using ∆Imp-drop, %Imp-drop, and AE*%Imp-drop than perpendicular orientation.

<b><i>Conclusions:</i></b> The combination of input and output parameters is more optimal than each single parameter for lesion prediction.

DOI リポジトリ PubMed CiNii Research

Successful treatment of lead-related superior vena cava syndrome in combination with transvenous lead extraction and venous stenting

Hidehiro Iwakawa, Tomohito Suzuki, Ken Terata, Hiroyuki Watanabe

Journal of Arrhythmia ( Journal of Arrhythmia )  39 ( 5 ) 813 - 815   2023年09月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Asymmetric remodeling between the left and right atria in patients with advanced interatrial block and atrial fibrillation

Ryota Kaimori, Hidehiro Iwakawa, Nobuhiro Suzuki, Mako Aokawa, Haruwo Tashiro, Ken Terata, Hiroyuki Watanabe

Journal of Electrocardiology ( Journal of Electrocardiology )  80   63 - 68   2023年05月  [査読有り]

研究論文（学術雑誌）   国内共著

BACKGROUND: Advanced interatrial block (A-IAB) on electrocardiography (ECG) represents the conduction delay between the left and right atria. We investigated the association of A-IAB with left and right atrial (LA/RA) remodeling in patients with atrial fibrillation (AF). METHODS: We enrolled 74 patients who underwent ECG, cardiac computed tomography (CCT), and echocardiography during sinus rhythm before catheter ablation of AF. A-IAB was defined as P-wave duration ≥120 ms with a biphasic morphology in leads III and aVF or notched morphology in lead II. We compared the maximum and minimum LA/RA volume indices (max and min LAV/RAVI), LA/RA expansion index (LAEI/RAEI), and total, passive, and active LA/RA emptying fraction (LAEF/RAEF) between patients with and without A-IAB. RESULTS: Of the 74 patients (mean age, 64.3 ± 9.6 years), 35 (47%) showed A-IAB. Patients with A-IAB had a significantly higher likelihood of hypertension and left ventricular diastolic dysfunction than those without. Patients with A-IAB had significantly larger max (69.2 [60.7-79.7]mL/m2 vs. 60.9 [50.4-68.3]mL/m2, P < 0.01) and min (44.0 [37.2-52.1]mL/m2 vs. 34.1 [29.2-43.5]mL/m2, P < 0.01) LAVI than those without. The max and min RAVI were not significantly different between groups. LAEI (55.1 [48.2-78.5]% vs. 72.1 [57.8-84.8]%, P < 0.05), total LAEF (35.5 [32.5-44.0]% vs. 41.9 [36.6-45.9]%, P < 0.05), and passive LAEF (12.2 [10.0-14.4]% vs. 15.5 [11.2-19.6]%, P < 0.05) were significantly lower in patients with A-IAB than without. CONCLUSIONS: A-IAB was associated with LA, but not RA enlargement, in patients with AF. A-IAB may indicate LA functional remodeling in the reservoir and conduit phases.

DOI PubMed

Status of adult outpatients with congenital heart disease in Japan: The Japanese Network of Cardiovascular Departments for Adult Congenital Heart Disease Registry

Yao A.

Journal of Cardiology ( Journal of Cardiology )  80 ( 6 ) 525 - 531   2022年12月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI リポジトリ

Utility of P-wave abnormalities for distinguishing embolic stroke from non-embolic stroke

Iwakawa H.

International Journal of Cardiology ( International Journal of Cardiology )  368   72 - 77   2022年12月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Comparison of Radiofrequency and Cryoballoon Pulmonary Vein Ablation for the Early and Late Recurrence of Atrial Fibrillation

Terata K.

Internal Medicine ( Internal Medicine )  61 ( 22 ) 3315 - 3322   2022年11月  [査読有り]

研究論文（学術雑誌）   国内共著

<p><b>Objective </b>Early recurrence (ER) after pulmonary vein isolation (PVI) for atrial fibrillation (AF) is expected to resolve within the recommended 3-month blanking period, irrespective of the ablation device used. To compare the occurrence and relationship of AF within the blanking period and subsequent late recurrence (LR) with radiofrequency (RF) and cryoballoon (CB) ablation. </p><p><b>Methods </b>A retrospective analysis of 294 patients (mean age=62±9, 70.0% male) undergoing PVI for drug-refractory paroxysmal AF was done. After categorizing the patients into the RF group (n=152) and the CB group (n=142), a group-wise comparison was done to investigate the impact of ER on LR throughout a 2-year follow-up. </p><p><b>Results </b>The groups were similar regarding the occurrence of ER (RF=22.4%, CB=24.6%, p=0.62), while LR was significantly higher in the RF group (p=0.003). ER was associated with LR in the RF group (p<0.01) but not in the CB group (p=0.08), while a significant independent association with an increased LR risk was observed [hazard ratio (HR) 6.12; 95% confidence interval (CI) 3.56-10.51, p<0.01]. RF ablation also significantly increased the risk of LR (HR=2.93; 95% CI=1.64-5.23, p<0.01). </p><p><b>Conclusion </b>A recurrence of atrial arrhythmia is more frequent with RF-PVI than with CB-PVI for patients with paroxysmal AF. ER and RF-ablation are strong predictors for LR after the 3-month blanking period. </p>

DOI PubMed CiNii Research

Utility of Superb Microvascular Imaging in the Assessment of Foot Perfusion in Patients with Critical Limb Ischemia

Suto Y.

Diagnostics ( Diagnostics )  12 ( 11 )   2022年11月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI リポジトリ

Narrow QRS complex tachycardia with and without ventriculoatrial block: What is the mechanism?

Iwakawa H.

Heart Rhythm ( Heart Rhythm )  19 ( 11 ) 1907 - 1909   2022年11月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Female Reproductive Events and Subclinical Atherosclerosis of the Brain and Carotid Arteriopathy: the Ohasama Study

Sato Wakana, Nomura Kyoko, Satoh Michihiro, Hara Azusa, Tsubota-Utsugi Megumi, Murakami Takahisa, Asayama Kei, Tatsumi Yukako, Kobayashi Yuki, Hirose Takuo, Inoue Ryusuke, Totsune Tomoko, Kikuya Masahiro, Hozawa Atsushi, Metoki Hirohito, Imai Yutaka, Watanabe Hiroyuki, Ohkubo Takayoshi

Ｊｏｕｒｎａｌ　ｏｆ　Ａｔｈｅｒｏｓｃｌｅｒｏｓｉｓ　ａｎｄ　Ｔｈｒｏｍｂｏｓｉｓ ( 一般社団法人 日本動脈硬化学会 )  advpub ( 0 )   2022年10月  [査読有り]

研究論文（学術雑誌）   国内共著

<p><b>Aims: </b>Few studies have investigated the subclinical atherosclerotic changes in the brain and carotid artery, and in East Asian populations. We sought to investigate whether gravidity, delivery, the age at menarche and menopause and estrogen exposure period are associated with subclinical atherosclerosis of the brain and carotid arteriopathy.<b> </b></p><p><b>Methods: </b>This cross-sectional study formed part of a cohort study of Ohasama residents initiated in 1986. Brain atherosclerosis and carotid arteriopathy were diagnosed as white matter hyperintensity (WMH) and lacunae evident on brain magnetic resonance imaging (MRI) and carotid intimal media thickness (IMT) or plaque revealed by ultrasound, respectively. The effect of the reproductive events on brain atherosclerosis and carotid arteriopathy was investigated using logistic regression and general linear regression models after adjusting for covariates.<b> </b></p><p><b>Results: </b>Among 966 women aged ≥ 55 years in 1998, we identified 622 and 711 women (mean age: 69.2 and 69.7 years, respectively) who underwent either MRI or carotid ultrasound between 1992–2008 or 1993–2018, respectively. The highest quartile of gravidity (≥ 5 vs. 3) and delivery (≥ 4 vs. 2), and the highest and second highest (3 vs. 2) quartiles of delivery were associated with an increased risk of WMH and carotid artery plaque, respectively. Neither of age at menarche, menopause, and estrogen exposure period estimated by subtracting age at menarche from age at menopause was associated with atherosclerotic changes of brain and carotid arteries.<b> </b></p><p><b>Conclusions: </b>Higher gravidity and delivery are associated with subclinical atherosclerosis of the brain and carotid plaque.</p>

DOI リポジトリ CiNii Research

Carotid Artery Revascularization Improves Cardiac Sympathetic Nerve Activity in Patients With Carotid Artery Stenosis

Kato T.

Cardiology Research ( Cardiology Research )  13 ( 5 ) 289 - 296   2022年10月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI リポジトリ

Asymptomatic Coarctation of the Aorta in Adults with Preserved Exercise Capacity: A Case Report

Tashiro Haruwo, Sato Wakana, Seki Katsuhito, Ono Yuto, Kato Tsukasa, Sato Teruki, Watanabe Hiroyuki

Internal Medicine ( 一般社団法人 日本内科学会 )  advpub ( 0 )   2022年09月  [査読有り]

研究論文（学術雑誌）   国内共著

<p>We herein report a case of coarctation of the aorta (CoA) in an asymptomatic adult who had a preserved exercise capacity. A 56-year-old man with mild hypertension exhibited left ventricular hypertrophy on an electrocardiogram during an annual medical checkup. Echocardiography showed a bicuspid aortic valve and cor triatriatum sinister, and subsequent computed tomography revealed CoA with developed collaterals. Cardiopulmonary exercise testing showed a good exercise capacity. He refused surgical repair and has been asymptomatic for five years. This case is of special interest, as CoA is usually rarely noticed during adulthood if there are no severe congenital anomalies, and in addition, this patient had good exercise capacity. </p>

DOI CiNii Research

Wide QRS complex tachycardia and alternating bundle branch block aberration: What is the mechanism?

Iwakawa H.

Journal of Arrhythmia ( Journal of Arrhythmia )  38 ( 3 ) 478 - 481   2022年06月  [査読有り]

研究論文（学術雑誌）  

DOI リポジトリ

Bilateral deep vein thrombosis in pregnancy as first manifestation of an anomalous inferior vena cava

Kato T.

Journal of Echocardiography ( Journal of Echocardiography )    2022年03月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

皆が納得する拡張の機能評価法：循環器　初級

飯野 貴子, 渡邊 博之

超音波医学 ( 公益社団法人 日本超音波医学会 )  49 ( 2 ) 97 - 104   2022年03月  [査読有り]  [招待有り]

研究論文（学術雑誌）   国内共著

<p>左室拡張機能は，様々な心疾患において予後に影響する重要な因子の一つである．心臓超音波検査によって，非侵襲的に左室弛緩能，左室充満圧上昇の有無について評価することができる．心臓超音波検査による左室拡張機能評価は，循環器疾患の診断，予後予測に有用なだけでなく，特に心不全症例においては治療方針をも左右する．そのため，個々の病態に適した複数の指標を用いて，左室拡張機能を的確に判定することが求められる．左室拡張機能は様々な指標を用いて評価される．代表的指標の一つである左室流入血流速波形は，左室弛緩能，左室充満圧だけでなく，その他様々な要素の影響を受け，変化する．それぞれの指標の特徴と限界を理解したうえで，適切に用い，解釈することが必要である．本稿では，2016年米国心エコー図学会（ASE）/欧州心血管画像協会（EACVI）より提唱されたガイドラインを用いた左室拡張機能評価と代表的な拡張機能指標の特徴と限界について概説する．</p>

DOI CiNii Research

Sudden and severe cardiotoxicity induced with pembrolizumab, its clinical course, therapeutic intervention, and outcome

Matsumoto.T

International Cancer Conference Journal   11 ( 1 ) 81 - 86   2022年01月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Lead dislodgement after a very long-term period of cardiac implantable electronic device implantation

Hidehiro Iwakawa,Ken Terata,Takayuki Yamanaka,Haruwo Tashiro,Hiroyuki Watanabe

Journal of arrhythmia   37 ( 6 ) 1570 - 1571   2021年12月  [査読有り]

研究論文（学術雑誌）  

A 74-year-old man was admitted for a second replacement of a transvenous implantable cardioverter-defibrillator (ICD) generator at 15 years after implantation. Postoperatively, electrocardiographic monitoring showed atrial lead malfunction. Chest X-ray revealed that the tip of the active fixation atrial lead was dislocated. We present a case of atrial lead dislodgement after a very long-term period of an ICD implantation.

DOI

Clinical implications of antegrade diastolic pulmonary artery flow in adults

Umeta Y.

Journal of Cardiology ( Journal of Cardiology )  78 ( 6 ) 542 - 549   2021年12月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Large non-coronary sinus of Valsalva aneurysm: A case report of an unusual cause of angina pectoris

Iwakawa H.

European Heart Journal - Case Reports ( European Heart Journal - Case Reports )  4 ( 5 ) 1 - 6   2021年09月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

An advanced ultrasound application used to assess peripheral vascular diseases: superb microvascular imaging

Sato W.

Journal of Echocardiography ( Journal of Echocardiography )  19 ( 3 ) 150 - 157   2021年09月  [査読有り]  [招待有り]

研究論文（学術雑誌）   国内共著

DOI

Thrombosed sinus of Valsalva aneurysm masquer ading as a cardiac tumour: A case report

Sato W.

European Heart Journal - Case Reports ( European Heart Journal - Case Reports )  5 ( 8 )   2021年08月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI リポジトリ

Clinical implications of local impedance measurement using the IntellaNav MiFi OI ablation catheter: an ex vivo study

Hidehiro Iwakawa,Masateru Takigawa,Masahiko Goya,Toyoto Iwata,Claire A Martin,Tatsuhiko Anzai,Kunihiko Takahashi,Miki Amemiya,Tasuku Yamamoto,Masahiro Sekigawa,Yasuhiro Shirai,Susumu Tao,Tatsuya Hayashi,Yoshihide Takahashi,Hiroyuki Watanabe,Tetsuo Sasano

Journal of Interventional Cardiac Electrophysiology ( Journal of Interventional Cardiac Electrophysiology )  63 ( 1 ) 185 - 195   2021年01月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

B38-CAP is a bacteria-derived ACE2-like enzyme that suppresses hypertension and cardiac dysfunction

Minato T.

Nature Communications ( Nature Communications )  11 ( 1 )   2020年12月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

医療過疎地域における植込み型心臓電気デバイス装着遺体の火葬時の取扱い

佐藤 誠, 藤原 優人, 加澤 隆康, 北嶋 久寛, 珍田 優奈, 渡部 健一, 藤田 美幸, 渡邊 博之

心臓 ( 公益財団法人 日本心臓財団 )  52 ( 12 ) 1368 - 1372   2020年12月  [査読有り]

研究論文（学術雑誌）   国内共著

<p>　ペースメーカなどの植込み型心臓電気デバイス装着遺体の火葬に関する対応は統一されていない．そこで我々は2018年9月より病院死亡，在宅・介護施設死亡にかかわらず，死亡確認後に医師はデバイス摘出は行わずに「デバイス証明」を遺族に渡すこと，行政窓口では埋火葬許可証内に追加したペースメーカ装着の有無欄をチェックするという方法で統一した．運用開始後1年間で14例すべてのデバイス植込み症例の情報が火葬場職員に確実に伝達され，トラブルなく火葬がなされた．</p>

DOI CiNii Research

Cardiac emerinopathy: A nonsyndromic nuclear envelopathy with increased risk of thromboembolic stroke due to progressive atrial standstill and left ventricular noncompaction

Taisuke Ishikawa, Hiroyuki Mishima,Julien Barc,Masanori P. Takahashi,Keiichi Hirono,Shigenori Terada,Shinya Kowase,Teruki Sato,Yasushi Mukai,Yoshiaki Yui,Kimie Ohkubo,Hiroki Kimoto,Hiroyuki Watanabe, Yukiko Hata,Takeshi Aiba,Seiko Ohno,Akiko Chishaki, Wataru Shimizu,Minoru Horie,Fukiko Ichida,Akihiko Nogami,Koh Ichiro Yoshiura,Jean Jacques Schott,Naomasa Makita

Circulation: Arrhythmia and Electrophysiology ( Circulation: Arrhythmia and Electrophysiology )  13 ( 10 ) 1165 - 1174   2020年10月  [査読有り]

研究論文（学術雑誌）  

DOI

m⁶A demethylase ALKBH5 promotes proliferation of esophageal squamous cell carcinoma associated with poor prognosis

Nagaki Y.

Genes to Cells ( Genes to Cells )  25 ( 8 ) 547 - 561   2020年08月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Association of Obesity with Prevalence of White-coat and Sustained Hypertension in Young Adults

Kobayashi Masao,Sato Wakana,Tashiro Haruwo,Namura Ikuro,Fushimi Masahito,Watanabe Hiroyuki

秋田医学 ( 秋田医学会 )  47 ( 1 ) 31 - 38   2020年06月  [査読有り]

研究論文（学術雑誌）  

Purpose : This study was performed to determine whether obesity is associated with white-coat hypertension (WHT) and sustained hypertension (SHT) in young adults.
Methods : Blood pressure (BP) was measured at home by university students (n=95) who exhibited BP readings ≥ 140/90 mmHg during their annual health exam and post-exam measurements between 2005 and 2014. Subject characteristics and BP readings from the WHT and SHT groups were compared to those of normotensive (NT) subjects.
Results : The mean body-mass index (BMI) was higher in both the WHT (p<0.05) and SHT groups (p<0.01) compared to the NT group, and the mean BMI in the SHT group was higher (p<0.01) than the WHT group. The ratio of WHT to NT subjects in the obese group (BMI ≥ 30) was higher than in the normal weight group (18.5 ≤ BMI < 25) (p<0.05). The ratio of SHT to NT subjects in the obese group was higher than in the normal weight and overweight groups (25 ≤ BMI < 30) (each, p<0.01).
Conclusion : Obesity is associated with both WHT and SHT in university students, which suggests that maintaining a healthy weight is important for the management of WHT and SHT in young adults.

DOI リポジトリ

Renal blood circulation as a manifestation of systemic atherosclerosis

Takako Iino,Hiroyuki Watanabe

Internal Medicine ( Internal Medicine )  59 ( 7 ) 885 - 886   2020年04月  [査読有り]

研究論文（学術雑誌）  

DOI

Manifestation of coronary subclavian steal phenomenon using reactive hyperemia in the ipsilateral forearm

Iino T.

Echocardiography ( Echocardiography )  36 ( 10 ) 1956 - 1958   2019年10月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

秋田大学医学部附属病院

飯野 健二, 渡邊 博之

循環器専門医 ( 一般社団法人 日本循環器学会 )  28 ( 0 ) 136 - 139   2019年08月

研究論文（学術雑誌）   国内共著

DOI

Visualization of arterial wall vascularization using superb microvascular imaging in active-stage Takayasu arteritis

Sato W.

European Heart Journal Cardiovascular Imaging ( European Heart Journal Cardiovascular Imaging )  20 ( 6 )   2019年06月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Urinary D-serine level as a predictive biomarker for deterioration of renal function in patients with atherosclerotic risk factors

Iwakawa H.

Biomarkers ( Biomarkers )  24 ( 2 ) 159 - 165   2019年02月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Loss of apelin augments angiotensin ii-induced cardiac dysfunction and pathological remodeling

Sato T.

International Journal of Molecular Sciences ( International Journal of Molecular Sciences )  20 ( 2 )   2019年01月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Validity of ultrasound lungcomets for assessment of the severity of interstitial pneumonia

Asano M.

Journal of Ultrasound in Medicine ( Journal of Ultrasound in Medicine )  37 ( 6 ) 1523 - 1531   2018年06月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Morphological determinants of obstructive hypertrophic cardiomyopathy obtained using echocardiography

Nara I.

International Heart Journal ( International Heart Journal )  59 ( 2 ) 339 - 346   2018年03月  [査読有り]

研究論文（学術雑誌）   国内共著

<p>The morphological determinants of left ventricular outflow tract (LVOT) obstruction in hypertrophic cardiomyopathy (HCM) are not completely understood. We aimed to identify the anatomical risks of the obstruction using echocardiography.</p><p>Fifty patients with untreated HCM were classified into two groups: those with LVOT pressure gradient (LVOTPG) ≥ 30 mmHg (obstructive HCM [HOCM] group) and those with LVOTPG < 30 mmHg (HNCM group). The echocardiographic morphological variables were analyzed to determine whether they were predictive of LVOT obstruction. Systolic anterior motions of the mitral valve were observed in 100% of patients in the HOCM group but only in 58% in the HNCM group. There were no significant differences in wall thickness, end-systolic LV dimension (LVDs), or LVOT diameter between the two groups. However, HOCM subjects had a shorter distance from papillary muscles to the inter-ventricular septum (5.97 ± 2.3 versus 9.20 ± 1.9 mm, respectively, <i>P</i> < 0.0001) and a longer anterior mitral leaflet (AML) length (24.7 ± 5.8 versus 20.1 ± 5.4 mm, respectively, <i>P</i> < 0.01) compared to the HNCM group. The AML length/LVDs ratio was significantly higher in the HOCM group compared to the HNCM group (1.02 ± 0.34 versus 0.78 ± 0.26, <i>P</i> < 0.01), and an LVOT obstruction was predicted with an area under the curve of 0.71 (<i>P</i> < 0.05). Multiple linear regression revealed that only the AML length/LVDs ratio was independently associated with LVOTPG (<i>P</i> < 0.01).</p><p>The AML length/LVDs ratio has a significant predictive value for LVOT obstruction and a strong relationship with LVOTPGs. The AML length/LVDs ratio determines the anatomical risk of LVOT obstruction in HCM.</p>

DOI

The CCR4-NOT deadenylase complex controls atg7-dependent cell death and heart function

Yamaguchi T.

Science Signaling ( Science Signaling )  11 ( 516 )   2018年02月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Simultaneous appearance of intracardiac masses following chemotherapy in a patient with lung cancer

Shimbo M.

European Heart Journal Cardiovascular Imaging ( European Heart Journal Cardiovascular Imaging )  19 ( 1 )   2018年01月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

A cardiac calcified amorphous tumor associated with end-stage renal disease: An emerging disease concept

Watanabe H.

Internal Medicine ( Internal Medicine )  56 ( 22 ) 2967 - 2968   2017年11月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Inflammatory aneurysm of ileocolic artery discovered on fluorine 18-fluorodeoxyglucose-positron emission tomography/computed tomography

Sato W.

Journal of Vascular Surgery ( Journal of Vascular Surgery )  66 ( 5 ) 1574 - 1575   2017年11月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Stromal interaction molecule 1 haploinsufficiency causes maladaptive response to pressure overload

Ohba T.

PLoS ONE ( PLoS ONE )  12 ( 11 )   2017年11月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Association between endothelial progenitor cells and treatment response in non-squamous non-small cell lung cancer treated with bevacizumab

Sudo K.

Anticancer Research ( Anticancer Research )  37 ( 10 ) 5565 - 5571   2017年10月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Acute aortic regurgitation in a bicuspid aortic valve due to the rupture of an anomalous cord

Watanabe H.

Anatolian Journal of Cardiology ( Anatolian Journal of Cardiology )  17 ( 6 )   2017年06月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

ELABELA-APJ axis protects from pressure overload heart failure and angiotensin II-induced cardiac damage

Sato T.

Cardiovascular Research ( Cardiovascular Research )  113 ( 7 ) 760 - 769   2017年06月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Low plasma concentration of gefitinib in patients with EGFR exon 21 L858R point mutations shortens progression-free survival

Okuda Y.

Cancer Chemotherapy and Pharmacology ( Cancer Chemotherapy and Pharmacology )  79 ( 5 ) 1013 - 1020   2017年05月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Rapidly growing intraventricular mass in a patient with hereditary haemorrhagic telangiectasia

Shimbo M.

European Heart Journal Cardiovascular Imaging ( European Heart Journal Cardiovascular Imaging )  18 ( 4 )   2017年04月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

In vivo visualization of the blood separation in the left ventricular chamber: a case of fulminant myocarditis requiring venoarterial extracorporeal membrane oxygenation

Iwakawa H.

Intensive Care Medicine ( Intensive Care Medicine )  43 ( 1 ) 135 - 136   2017年01月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Vps34 regulates myofibril proteostasis to prevent hypertrophic cardiomyopathy

Kimura H.

JCI Insight ( JCI Insight )  2 ( 1 )   2017年01月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Blunt traumatic rupture of the right ventricle: visualization of spurting blood using transthoracic echocardiography.

Mai Shimbo, Hiroyuki Watanabe, Kumiko Watanabe, Genbu Yamaura, Hiroshi Ito

European heart journal. Cardiovascular Imaging   17 ( 11 ) 1258 - 1258   2016年11月  [査読有り]

研究論文（学術雑誌）  

PubMed

An unusual cause of superior vena cava syndrome after pacemaker implantation.

Hiroyuki Watanabe, Takako Iino, Hiroshi Ito

Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology   18 ( 5 ) 657 - 657   2016年05月  [査読有り]

研究論文（学術雑誌）  

DOI PubMed

The association of circulating inflammatory and oxidative stress biomarker levels with diagonal earlobe crease in patients with atherosclerotic diseases.

Takashi Koyama, Hiroyuki Watanabe, Hiroshi Ito

Journal of cardiology   67 ( 4 ) 347 - 51   2016年04月  [査読有り]

研究論文（学術雑誌）  

BACKGROUND: Earlobe creases (ELC) are frequently observed in patients with atherosclerosis. Atherosclerosis is considered to be a systemic vascular inflammatory disease, and oxidative stress is known to be a contributor to vascular inflammation. It is well known that inflammatory biomarkers [high-sensitivity C-reactive protein (hs-CRP), pentraxin3 (PTX3)] and oxidative stress markers [malondialdehyde low-density lipoprotein (MDA-LDL)] are associated with atherosclerotic changes. This study was designed to test the hypothesis that biomarkers of inflammation and oxidative stress are increased in patients with ELC. METHODS: A total of 223 consecutive patients with atherosclerotic risk factors were enrolled and divided into two groups. One group consisted of patients with ELC (ELC group, n=134) and the other was without ELC (non-ELC group, n=89). Medical information and biomarker levels related to atherosclerosis were acquired from these patients. RESULTS: The male ratio, prevalence of hypertension, diabetes mellitus, and MDA-LDL, hs-CRP, and PTX3 levels were found to be higher in the ELC group, compared with the non-ELC group. A multiple logistic regression analysis showed that PTX3 levels, rather than hs-CRP, constituted the strongest predictive factor for the appearance of ELC. CONCLUSIONS: Vascular inflammation and oxidative stress are associated with the presence of ELC.

DOI PubMed

Tricuspid valve chordae tendineae as protective filter to prevent massive pulmonary embolism.

Hiroyuki Watanabe, Mai Shimbo, Mai Terada, Hironori Kiso, Seiya Shimizu, Yasunori Oguma, Kenji Iino, Hiroshi Ito

Journal of thoracic disease   8 ( 3 ) E225-8   2016年03月  [査読有り]  [招待有り]

研究論文（学術雑誌）  

DOI PubMed

Respiratory Intervention in Patients With Chronic Heart Failure.

Takashi Koyama, Hiroyuki Watanabe, Hiroshi Ito

Circulation journal : official journal of the Japanese Circulation Society   80 ( 1 ) 60 - 1   2016年01月  [査読有り]

研究論文（学術雑誌）  

DOI PubMed

Isolated Atrial Septal Defect Complicated by Tricuspid Valve Infective Endocarditis.

Mai Shimbo, Hiroyuki Watanabe, Tatsumi Abe, Teruki Sato, Takashi Koyama, Hiroshi Yamamoto, Hiroshi Ito

Internal medicine (Tokyo, Japan)   54 ( 19 ) 2463 - 5   2015年10月  [査読有り]

研究論文（学術雑誌）  

Infective endocarditis (IE) associated with atrial septal defect (ASD) is extremely rare. However, tricuspid regurgitation (TR) secondary to right ventricular overload is a potential cause of IE, and once it occurs, the development of a paradoxical embolism may lead to fatal complications. We herein report the case of a 50-year-old woman who was admitted due to a persistent fever resistant to antibiotics. Echocardiography showed secundum ASD, moderate TR and a mobile vegetation measuring 15×10 mm attached to the tricuspid valve. Given the risk of developing a paradoxical embolism, urgent surgery was successfully performed.

DOI PubMed

Steroid-induced metamorphosis of the heart: a case of cardiac sarcoidosis.

Takako Iino, Hiroyuki Watanabe, Kenji Iino, Hiroshi Ito

European heart journal. Cardiovascular Imaging   16 ( 6 ) 694 - 694   2015年06月  [査読有り]

研究論文（学術雑誌）  

DOI PubMed

Quality of life and heart rate variability following acute myocardial infarction

SHIMBO Mai,KOSAKA Toshimitsu,FUSHIMI Etsuko,KOYAMA Takashi,IINO Kenji,WATANABE Hiroyuki,ITO Hiroshi

秋田医学   42 ( 1 ) 29 - 36   2015年06月  [査読有り]

研究論文（学術雑誌）  

Objective : The aim of this study was to investigate whether cardiac autonomic function measured
by heart rate variability (HRV) indices are related to quality of life (QOL) improvements in
patients with acute myocardial infarction (AMI) treated by percutaneous coronary intervention.
Methods : We enrolled 20 consecutive patients with AMI. Measures of HRV, obtained from
both frequency and time domain analyses using 24-h Holter monitoring before discharge, were as
follows : low and high frequency (HF) domain measures, the square root of the mean squared differences
of successive R-R intervals (rMSSD), and the percentage of differences between adjacent
normal R-R intervals >50 ms for the whole analysis (pNN50). QOL was determined by
physical and mental component summary (PCS and MCS, respectively) scores derived from the
Japanese Medical Outcomes Study 36-item Short Form Health Survey before and 6 months after
discharge.
Results : The subjects showed significant improvement in the MCS, but not the PCS score.　
There were also positive correlations between the parasympathetic parameters of HF, rMSSD,
and pNN50 and the change in MCS score. In a multivariate analysis, rMSSD was found to be
independently associated with the change in MCS score.
Conclusions : Parasympathetic tone, as measured by HRV, is independently associated with
QOL, which emphasizes the role of cardiac autonomic function on QOL in patients with AMI.

Involvement of the orexin system in sympathetic nerve regulation.

Manabu Murakami, Takayoshi Ohba, Testuya Kushikata, Hidetoshi Niwa, Akira Kurose, Tadaatsu Imaizumi, Hiroyuki Watanabe, Teruyuki Yanagisawa, Shigeyuki Nakaji, Kyoichi Ono, Kazuyoshi Hirota

Biochemical and biophysical research communications   460 ( 4 ) 1076 - 81   2015年05月  [査読有り]

研究論文（学術雑誌）  

Orexin, also known as hypocretin, is a secreted neuropeptide implicated in the regulation of sleep and food intake. In the present study, we examined the importance of orexin in regulation of the sympathetic nervous system using an orexin/ataxin-3 transgenic (OXTg) rat, which has a minimal number of orexin neurons. RT-PCR analysis identified expression of prepro-orexin and orexin receptor-1 (OX1R) in the superior cervical ganglion (SCG), and expression of another receptor (OX2R) was marginal in the wild-type rat. The orexin/ataxin-3 transgenic rat showed increased expression of OX1R and OX2R, whereas expression of prepro-orexin was undetectable, suggesting a compensatory increase in both receptors. In the ECG recording (R-R interval), orexin/ataxin-3 transgenic rats showed decreased responsiveness to the β-adrenergic blocker propranolol. Furthermore, OXTg rats had deteriorated R-R interval regulation, indicating involvement of the orexin system in sympathetic nerve regulation. This was accompanied by decreased baroreflex and responsiveness to β-adrenergic blocker in blood pressure recording, also suggesting involvement of the orexin system in sympathetic nerve regulation. Histological examination revealed hypotrophic changes in the transgenic heart, suggesting involvement of the orexin system in cardiac development. Taken together, our present results indicate involvement of the orexin system in sympathetic nerve control.

DOI PubMed

Modified autonomic regulation in mice mutated in the β4 subunit of the lh/lh calcium channel.

Manabu Murakami, Takashi Suzuki, Tsai-Wen Wu, Kenji Kuwasako, Eiki Takahashi, Hiroyuki Watanabe, Agnieszka M Murakami, Ichiro Miyoshi, Teruyuki Yanagisawa, Hironobu Sasano, Kyoichi Ono, Takayoshi Ohba

Biochemical and biophysical research communications   461 ( 2 ) 200 - 5   2015年05月  [査読有り]

研究論文（学術雑誌）  

Genetic analyses have revealed an important association between P/Q-type calcium channel activities and hereditary neurological disorders. The P/Q-type channels are composed principally of heterologous multimeric subunits including CaV2.1 and CaVβ4. Of these, the β4 subunit is thought to play a significant role in channel physiology, because a mouse line mutant in that subunit (the lethargic mouse: lh) exhibits a severe ataxic phenotype. The aim of the present study was to elucidate the physiological importance of the β4 subunit. ECG analysis showed that the T wave was high in 8-week-old lh mutants; this may be associated with hyperkalemia. Upon pharmacological ECG analysis, 2-3-week-old lh mutants exhibited reduced responses to a β-blocker and a muscarinic receptor antagonist. Analysis of heart rate variability revealed that the R-R interval was unstable in lh mutants and that both the low- and high-frequency components had increased in extent, indicating that the tonus of both the sympathetic and parasympathetic nervous systems was modified. Thus, our present study revealed that the β4 subunit played a significant role in regulation of sympathetic and parasympathetic nerve activities.

DOI PubMed

Serial Changes in Hamman's Sign Secondary to the Evolution of a Shallow Left-Sided Spontaneous Pneumothorax.

Katsuhito Seki, Hiroyuki Watanabe, Ryo Morita, Kazuhiro Sato, Mariko Asano, Takako Iino, Kenji Iino, Hiroshi Ito

Respiratory care   60 ( 5 ) e110-2   2015年05月  [査読有り]

研究論文（学術雑誌）  

DOI PubMed

Beneficial effects of adaptive servo-ventilation therapy on albuminuria in patients with heart failure.

Yoshikazu Tamura, Takashi Koyama, Hiroyuki Watanabe, Tomoki Hosoya, Hiroshi Ito

Journal of cardiology   65 ( 5 ) 412 - 7   2015年05月  [査読有り]

研究論文（学術雑誌）  

BACKGROUND: Short-duration adaptive servo-ventilation (ASV) therapy can be effective for heart failure (HF) patients. Albuminuria is recognized as a prognostic marker for HF. We investigated whether short-duration and short-term ASV therapy reduced albuminuria in HF patients. METHODS AND RESULTS: Twenty-one consecutive HF patients were divided into two groups: those who tolerated ASV therapy (ASV group, n=14) and those who did not (non-ASV group, n=7). ASV therapy was administered to enrolled patients for 1 week for 2h per day (1h in the morning and 1h in the afternoon). The urinary albumin to creatinine ratio (UACR), urinary 24h norepinephrine (NE) excretion, high-sensitivity C-reactive protein (hs-CRP), and plasma brain natriuretic peptide (BNP) levels were measured before and 1 week after ASV therapy. In the ASV group, but not the non-ASV group, the UACR significantly decreased, together with a decrease in urinary NE and hs-CRP levels. There were significant correlations between the changes in UACR and hs-CRP and between the changes in urinary NE and hs-CRP. Multiple linear regression analyses indicated that ASV use was the strongest predictor of decreased UACR. CONCLUSION: Albuminuria, urinary NE, and hs-CRP levels reduced in HF patients who could receive short-duration and short-term ASV therapy. Anti-inflammatory effects of ASV therapy may partly mediate the reduction of albuminuria.

DOI PubMed

Nocturnal effects of diurnal adaptive servo-ventilation therapy in patients with heart failure.

Takashi Koyama, Hiroyuki Watanabe, Hiroshi Ito

International journal of cardiology   182   216 - 8   2015年03月  [査読有り]

研究論文（学術雑誌）  

DOI PubMed

Obstructed bi-leaflet prosthetic mitral valve imaging with real-time three-dimensional transesophageal echocardiography.

Mai Shimbo, Hiroyuki Watanabe, Shunsuke Kimura, Mai Terada, Takako Iino, Kenji Iino, Hiroshi Ito

Journal of clinical ultrasound : JCU   43 ( 1 ) 64 - 7   2015年01月  [査読有り]

研究論文（学術雑誌）  

Real-time three-dimensional transesophageal echocardiography (RT3D-TEE) can provide unique visualization and better understanding of the relationship among cardiac structures. Here, we report the case of an 85-year-old woman with an obstructed mitral prosthetic valve diagnosed promptly by RT3D-TEE, which clearly showed a leaflet stuck in the closed position. The opening and closing angles of the valve leaflets measured by RT3D-TEE were compatible with those measured by fluoroscopy. Moreover, RT3D-TEE revealed, in the ring of the prosthetic valve, thrombi that were not visible on fluoroscopy. RT3D-TEE might be a valuable diagnostic technique for prosthetic mitral valve thrombosis.

DOI PubMed

Apnea during Cheyne-Stokes-like breathing detected by a piezoelectric sensor for screening of sleep disordered breathing

Takashi Koyama, Shinichi Sato, Takashi Kanbayashi, Hideaki Kondo, Hiroyuki Watanabe, Seiji Nishino, Tetsuo Shimizu, Hiroshi Ito, Kyoichi Ono

SLEEP AND BIOLOGICAL RHYTHMS   13 ( 1 ) 57 - 67   2015年01月  [査読有り]

研究論文（学術雑誌）  

A simplified diagnostic/monitoring instrument for use in primary screening for sleep-disordered breathing (SDB) has been desired. This study was designed to assess the validity of a newly developed piezoelectric sensor as a simple and noninvasive tool for primary screening for sleep-disordered breathing. Forty-three consecutive patients suspected of having sleep-disordered breathing and 10 healthy volunteers were enrolled. Breathing movement was detected with the piezoelectric sensor (180 × 30 × 1 mm), which was placed under a bed sheet under patients, and simultaneous polysomnographic recordings were obtained. We counted the number of apneas of >10 s, irrespective of central or obstructive, that appeared during Cheyne-Stokes-like breathing with a waxing and waning pattern with an amplitude ratio of >10 in the piezoelectric sensor signal. The correlation coefficient between the number of apneas and apnea–hypopnea index (AHI) was 0.74 (P < 0.0001). The sensitivity/specificity of the number of apneas for distinguishing non-SDB patients from mild SDB patients (AHI ≥ 5) were 92.1/60.0% and those for separating moderate to severe (AHI ≥ 15) and severe (AHI ≥ 30) SDB patients from the other patients were 96.9/100% and 93.8/86.5%, respectively. There were no complaints from patients about the use of the piezoelectric sensor. The results indicate that the number of apneas detected by this piezoelectric sensor during Cheyne-Stokes-like breathing is a potential new index for primary screening for SDB at least for cardiac patients. Thus, the piezoelectric-sensor system might be useful for simple, noninvasive and comfortable SDB screening at home, hospitals and health care facilities.

DOI

Blood balloon induced by an atrial myxoma in the heart.

Hiroyuki Watanabe, Ikumi Nara, Genbu Yamaura, Kenji Iino, Takako Iino, Mai Shimbo, Katsuhito Seki, Hiroshi Ito

Circulation   130 ( 25 ) 2351 - 3   2014年12月  [査読有り]

研究論文（学術雑誌）  

DOI PubMed

Subclinical microalbuminuria as a predictor of heart failure prognosis.

Hiroyuki Watanabe, Kenji Iino, Hiroshi Ito

Circulation journal : official journal of the Japanese Circulation Society   78 ( 12 ) 2838 - 9   2014年12月  [査読有り]

研究論文（学術雑誌）  

PubMed

Morning pentraxin3 levels reflect obstructive sleep apnea-related acute inflammation.

Yusuke Kobukai, Takashi Koyama, Hiroyuki Watanabe, Hiroshi Ito

Journal of applied physiology (Bethesda, Md. : 1985)   117 ( 10 ) 1141 - 8   2014年11月  [査読有り]

研究論文（学術雑誌）  

This study investigated morning levels of pentraxin3 (PTX3) as a sensitive biomarker for acute inflammation in patients with obstructive sleep apnea (OSA). A total of 61 consecutive patients with OSA were divided into two groups: non-to-mild (n = 20) and moderate-to-severe (n = 41) OSA based on their apnea-hypopnea index (AHI) score. Those patients with moderate-to-severe OSA were further divided into continuous positive airway pressure (CPAP) treated (n = 21) and non-CPAP-treated (n = 20) groups. Morning and evening serum PTX3 and high-sensitivity (hs) C-reactive protein (CRP) levels were measured before and after 3 mo of CPAP therapy. The baseline hs-CRP and PTX3 levels were higher in patients with moderate-to-severe OSA than in those with non-to-mild OSA. Moreover, the serum PTX3 levels, but not the hs-CRP levels, were significantly higher after than before sleep in the moderate-to-severe OSA group (morning PTX3, 1.96 ± 0.52; evening PTX3, 1.71 ± 0.44 ng/ml). OSA severity as judged using the AHI was significantly correlated with serum PTX3 levels but not hs-CRP levels. The highest level of correlation was found between the AHI and morning PTX3 levels (r = 0.563, P < 0.001). CPAP therapy reduced evening and morning serum hs-CRP and PTX3 levels in patients with moderate-to-severe OSA; however, the reduction in PTX3 levels in the morning was greater than that in the evening (morning -29.8 ± 16.7% vs. evening -12.6 ± 26.8%, P = 0.029). Improvement in the AHI score following CPAP therapy was strongly correlated with reduced morning PTX3 levels(r = 0.727, P < 0.001). Based on these results, morning PTX3 levels reflect OSA-related acute inflammation and are a useful marker for improvement in OSA following CPAP therapy.

DOI PubMed

Successful treatment of a patient with purulent pericarditis by daily intrapericardial washouts.

Mai Terada, Hiroyuki Watanabe, Yusuke Kobukai, Takashi Koyama, Mamika Motokawa, Fumio Yamamoto, Hiroshi Ito

The Annals of thoracic surgery   98 ( 4 ) 1451 - 4   2014年10月  [査読有り]

研究論文（学術雑誌）  

Purulent pericarditis in adults is rare, but once it develops, it carries a high mortality rate. Adequate pericardial drainage and proper antibiotic treatment are essential in the successful management of purulent effusions, for which percutaneous catheter drainage is the most commonly performed technique. We herein report the case of a 75-year-old woman with purulent pericarditis attributable to methicillin-resistant Staphylococcus aureus. Although percutaneous pericardial drainage by catheter was used, the drainage was insufficient because of hyperviscous effusion. We performed surgical subxiphoid pericardial drainage, and a piece of a purulent stone was found in the pericardial cavity with purulent effusion. Additionally, daily intrapericardial washouts with physiologic saline alone were used as adjunct therapy. Five weeks later, the patient had a decreasing inflammatory reaction and symptom relief. She was discharged with no complications such as constrictive pericarditis.

DOI PubMed

Contralateral pulmonary embolism caused by pulmonary artery stump thrombosis after pneumonectomy.

Wakana Sato, Hiroyuki Watanabe, Teruki Sato, Kenji Iino, Kazuhiro Sato, Hiroshi Ito

The Annals of thoracic surgery   97 ( 5 ) 1797 - 8   2014年05月  [査読有り]

研究論文（学術雑誌）  

A 73-year-old man with atrial fibrillation and previous left pneumonectomy was admitted with pleural effusion. Anticoagulant therapy was discontinued because of chest tube drainage. Six days later, the patient experienced chest discomfort. Echocardiography showed a pedunculated thrombus with swaying motion in the left pulmonary artery (PA) stump. Contrast-enhanced computed tomography of the chest revealed filling defects in not only the left PA stump but also the right PA, implying contralateral pulmonary embolism. Anticoagulants were resumed, and thrombolysis was successful 3 days later. Patients undergoing pneumonectomy in whom anticoagulant therapy is discontinued should be recognized as being at high risk for PA stump thrombosis and subsequent contralateral pulmonary embolism.

DOI PubMed

Inhalation anesthesia is preferable for recording rat cardiac function using an electrocardiogram.

Manabu Murakami, Hidetoshi Niwa, Tetsuya Kushikata, Hiroyuki Watanabe, Kazuyoshi Hirota, Kyoichi Ono, Takayoshi Ohba

Biological & pharmaceutical bulletin   37 ( 5 ) 834 - 9   2014年05月  [査読有り]

研究論文（学術雑誌）  

The effects of inhalation anesthesia (2% isoflurane, sevoflurane, or enflurane) and intraperitoneal anesthesia with pentobarbital (65 mg/kg) were compared in rats using an electrocardiogram (ECG) and determination of blood oxygen saturation (SPO2) levels. Following inhalation anesthesia, heart rate (HR) and SPO2 were acceptable while pentobarbital anesthesia decreased HR and SPO2 significantly. This indicates that inhalation anesthesia is more preferable than pentobarbital anesthesia when evaluating cardiovascular factors. Additionally, pentobarbital significantly increased HR variability (HRV), suggesting a regulatory effect of pentobarbital on the autonomic nervous system, and resulted in a decreased response of the baro-reflex system. Propranolol or atropine had limited effects on ECG recording following pentobarbital anesthesia. Taken together, these data suggest that inhalation anesthesia is suitable for conducting hemodynamic analyses in the rat.

PubMed

Immunochemical fecal occult blood tests predict dual antiplatelet therapy discontinuation after coronary stenting.

Ken Ikeda, Takashi Koyama, Masaru Ishida, Megumi Okawa, Yasunori Oguma, Yutaka Terata, Kenji Iino, Toshimitsu Kosaka, Hiroyuki Watanabe, Hiroshi Ito

Internal medicine (Tokyo, Japan)   53 ( 5 ) 375 - 81   2014年03月  [査読有り]

研究論文（学術雑誌）  

OBJECTIVE: The discontinuation of dual antiplatelet therapy (DAPT) increases the risk of stent thrombosis after coronary stenting. Some patients must discontinue DAPT due to gastrointestinal (GI) tract disease; however, the type of examination that is most useful for detecting GI tract diseases has not been fully evaluated. The purpose of this study was to clarify whether the immunochemical fecal occult blood test (iFOBT) can be used to predict GI tract disease-related DAPT discontinuation following stent implantation in patients with coronary artery disease. METHODS: A total of 181 consecutive DAPT-naïve patients who underwent coronary stenting were divided into two groups according to the results of iFOBTs: a positive iFOBT group (n=32) and a negative iFOBT group (n=149). During the 12-month follow-up period, the DAPT discontinuation rate was lower in the negative iFOBT group than in the positive iFOBT group (3.4 vs. 18.8%, p=0.005). Kaplan-Meier event-free curves showed that the DAPT discontinuation rate in the negative iFOBT group was lower than that observed in the positive iFOBT group (log-rank test: p=0.001). Logistic and Cox regression analyses showed that a positive iFOBT result was the strongest predictor of the risk of DAPT discontinuation after coronary stenting. CONCLUSION: A positive iFOBT result is associated with DAPT discontinuation following coronary stenting.

PubMed

Apelin is a positive regulator of ACE2 in failing hearts.

Teruki Sato, Takashi Suzuki, Hiroyuki Watanabe, Ayumi Kadowaki, Akiyoshi Fukamizu, Peter P Liu, Akinori Kimura, Hiroshi Ito, Josef M Penninger, Yumiko Imai, Keiji Kuba

The Journal of clinical investigation   123 ( 12 ) 5203 - 11   2013年12月  [査読有り]

研究論文（学術雑誌）  

Angiotensin converting enzyme 2 (ACE2) is a negative regulator of the renin-angiotensin system (RAS), catalyzing the conversion of Angiotensin II to Angiotensin 1-7. Apelin is a second catalytic substrate for ACE2 and functions as an inotropic and cardioprotective peptide. While an antagonistic relationship between the RAS and apelin has been proposed, such functional interplay remains elusive. Here we found that ACE2 was downregulated in apelin-deficient mice. Pharmacological or genetic inhibition of angiotensin II type 1 receptor (AT1R) rescued the impaired contractility and hypertrophy of apelin mutant mice, which was accompanied by restored ACE2 levels. Importantly, treatment with angiotensin 1-7 rescued hypertrophy and heart dysfunctions of apelin-knockout mice. Moreover, apelin, via activation of its receptor, APJ, increased ACE2 promoter activity in vitro and upregulated ACE2 expression in failing hearts in vivo. Apelin treatment also increased cardiac contractility and ACE2 levels in AT1R-deficient mice. These data demonstrate that ACE2 couples the RAS to the apelin system, adding a conceptual framework for the apelin-ACE2-angiotensin 1-7 axis as a therapeutic target for cardiovascular diseases.

DOI PubMed

Remote ischemic pre-conditioning alleviates contrast-induced acute kidney injury in patients with moderate chronic kidney disease.

Gen Igarashi, Kenji Iino, Hiroyuki Watanabe, Hiroshi Ito

Circulation journal : official journal of the Japanese Circulation Society   77 ( 12 ) 3037 - 44   2013年12月  [査読有り]

研究論文（学術雑誌）  

BACKGROUND: Although remote ischemic preconditioning (RIPC) is shown to preserve kidney function in patients at high risk of contrast-induced acute kidney injury (CI-AKI), the effect in patients at low-moderate risk remains unknown. The preventive effects of RIPC in patients not at high risk of CI-AKI were examined, and biomarkers with anticipated roles in renal protection via RIPC investigated. METHODS AND RESULTS: Sixty patients who had moderate chronic kidney disease and who underwent angiography were randomly assigned to the control (n=30) or RIPC (intermittent arm ischemia, n=30) group. The baseline characteristics in the 2 groups did not differ significantly. CI-AKI was evaluated by measuring urinary liver-type fatty acid-binding protein (L-FABP). Biomarkers were measured before and 24 and 48 h after angiography. Twenty-four hours after angiography, the percent change in urinary L-FABP level in the RIPC group was significantly smaller than in the control group (41.3±15.6 vs. 159±34.1%, P=0.003). L-FABP-based CI-AKI developed in 8 control patients (26.9%) vs. only 2 patients in the RIPC group (7.7%), suggesting that RIPC prevents CI-AKI. Factors contributing to CI-AKI were analyzed. Neither high-sensitivity C-reactive protein nor pentraxine-3 level differed significantly between the 2 groups, while the percent change in asymmetrical dimethy larginine (ADMA) level and blood derivatives of reactive oxidative metabolite levels were significantly smaller in the RIPC group. CONCLUSIONS: RIPC alleviates CI-AKI in patients at low-moderate risk. This effect might be mediated partly by decreasing oxidative stress and plasma ADMA level.

PubMed

Impaired renal function is a major determinant of left ventricular diastolic dysfunction: assessment by stress myocardial perfusion imaging.

Wakana Sato, Toshimitsu Kosaka, Takashi Koyama, Masaru Ishida, Kenji Iino, Hiroyuki Watanabe, Hiroshi Ito

Annals of nuclear medicine   27 ( 8 ) 729 - 36   2013年10月  [査読有り]

研究論文（学術雑誌）  

OBJECTIVE: Relationships between myocardial scintigraphic parameters and renal function have not been fully determined. We investigated correlations between estimated glomerular filtration rate (eGFR) and left ventricular (LV) diastolic function using stress electrocardiographic (ECG)-gated myocardial single photon emission computed tomography (SPECT). METHODS: We enrolled 136 consecutive patients with suspected coronary artery disease (CAD) who were assessed using technetium-99m stress ECG-gated myocardial SPECT. We evaluated SPECT images using 17-segment defect scores graded on a 5-point scale, summed stress score, summed rest score and summed difference score (SDS). The parameters for assessing LV diastolic function were peak filling rate (PFR), 1/3 mean filling rate and time to peak filling. The CAD was defined as SDS ≥2. Chronic kidney disease (CKD) was defined as eGFR <60 mL/min/1.73 m(2). Patients were assigned to the following four groups (no CAD/no CKD: control group, n = 68; CAD/no CKD: CAD group, n = 24; no CAD/CKD: CKD group, n = 34; CAD/CKD: CAD + CKD group, n = 10). RESULTS: The PFR was significantly impaired after stress in the CKD and CAD + CKD groups compared with controls (p < 0.001 for both). Furthermore, PFR at rest positively correlated with eGFR (r = 0.29, p < 0.001) and inversely correlated with SDS (r = -0.18, p < 0.05). Multivariate stepwise regression analysis independently associated eGFR with PFR (β coefficient = 0.260, p = 0.002). CONCLUSIONS: Our data suggest that impaired renal function is a significant determinant of LV diastolic dysfunction in patients with suspected CAD.

DOI PubMed

Rho-kinase in leukocytes. An emerging biomarker for heart failure.

Hiroyuki Watanabe, Kenji Iino, Hiroshi Ito

Circulation journal : official journal of the Japanese Circulation Society   77 ( 10 ) 2471 - 2   2013年10月  [査読有り]

研究論文（学術雑誌）  

PubMed

Increased circulating CD3+/CD31+ T cells in patients with acute coronary syndrome.

Manabu Kakizaki, Kiyoshi Nobori, Hiroyuki Watanabe, Kenji Iino, Masaru Ishida, Hiroshi Ito

Heart and vessels   28 ( 5 ) 566 - 9   2013年09月  [査読有り]

研究論文（学術雑誌）  

The number of circulating endothelial progenitor cells (EPCs) is considered to be a surrogate marker for coronary artery disease (CAD). Recent studies have identified a novel T-cell subset labeled with CD3(+)/CD31(+), which is necessary for EPC colony formation and constitutes the central cluster. However, the clinical relevance of the CD3(+)/CD31(+) T cells in CAD remains unclear. We sought to clarify whether circulating CD3(+)/CD31(+) T cells are increased in patients with acute coronary syndrome (ACS). Circulating CD3(+)/CD31(+) T cells were determined in 16 ACS patients undergoing emergency percutaneous coronary intervention (PCI) and in 16 control subjects with angiographically normal coronary arteries. Although no differences between the groups were found in baseline patient characteristics, the ratio of circulating CD3(+)/CD31(+) T cells before PCI was higher in ACS patients as compared with that in control subjects (51.8 % ± 7.8 % vs 31.8 % ± 9.6 %, respectively; P < 0.001). The increased ratio of CD3(+)/CD31(+) T cells in ACS patients was not altered 24 h after PCI, but became comparable with that in control subjects within 6 months after PCI. These results suggest that mobilization of CD3(+)/CD31(+) T cells occurs in ACS, but is no longer detectable at 6 months after PCI.

DOI PubMed

Adaptive servo-ventilation therapy improves cardiac sympathetic nerve activity in patients with heart failure.

Takashi Koyama, Hiroyuki Watanabe, Yoshikazu Tamura, Yasunori Oguma, Toshimitsu Kosaka, Hiroshi Ito

European journal of heart failure   15 ( 8 ) 902 - 9   2013年08月  [査読有り]

研究論文（学術雑誌）  

AIMS: This study investigated whether abnormal cardiac sympathetic nerve activity (SNA) is associated with the severity of central sleep apnoea (CSA) and whether adaptive servo-ventilation (ASV) therapy can improve cardiac SNA in heart failure (HF) patients with predominant CSA. METHODS AND RESULTS: Overnight polysomnography was conducted to diagnose CSA. Cardiac SNA was analysed by [123I]metaiodobenzylguanidine scintigraphy in 26 consecutive HF patients with predominant CSA. Of the 26 patients, 10 agreed to ASV therapy. Cardiac SNA was analysed 6 months after initiating ASV based on a non-randomized protocol. The apnoea-hypopnoea index and central apnoea index were significantly correlated with the washout rate (WR) and a delayed heart to mediastinal (H/M) ratio, suggesting that SNA is associated with abnormal breathing patterns. The WR, H/M ratio, plasma BNP level, and LVEF were significantly improved (WR, 40.0 ± 11.6% vs. 34.6 ± 11.4%, P = 0.046; H/M ratio, 1.5 ± 0.1 vs.1.8 ± 0.3, P = 0.013; ln BNP, 5.4 ± 1.0 vs. 4.6 ± 1.2, P = 0.007; and LVEF, 43.8 ± 10.4% vs. 47.0 ± 10.6%, P < 0.001) in the ASV group patients, but not in the non-ASV group patients. Multiple linear regression analyses showed that a decreased WR was strongly associated with an increased LVEF (coefficient = -0.454, P = 0.013). CONCLUSIONS: Abnormal cardiac SNA could be significantly correlated with the severity of CSA in HF patients. ASV therapy might improve cardiac function in these patients by partially mediating cardiac SNA regulation.

DOI PubMed

Sildenafil prevents the up-regulation of transient receptor potential canonical channels in the development of cardiomyocyte hypertrophy.

Hironori Kiso, Takayoshi Ohba, Kenji Iino, Kazuhiro Sato, Yutaka Terata, Manabu Murakami, Kyoichi Ono, Hiroyuki Watanabe, Hiroshi Ito

Biochemical and biophysical research communications   436 ( 3 ) 514 - 8   2013年07月  [査読有り]

研究論文（学術雑誌）  

BACKGROUND: Transient receptor potential canonical (TRPCs) channels are up-regulated in the development of cardiac hypertrophy. Sildenafil inhibits TRPC6 activation and expression, leading to the prevention of cardiac hypertrophy. However, the effects of sildenafil on the expression of other TRPCs remain unknown. We hypothesized that in addition to its effects of TRPC6, sildenafil blocks the up-regulation of other TRPC channels to suppress cardiomyocyte hypertrophy. METHODS AND RESULTS: In cultured neonatal rat cardiomyocytes, a 48 h treatment with 10nM endothelin (ET)-1 induced hypertrophic responses characterized by nuclear factor of activated T cells activation and enhancement of brain natriuretic peptide expression and cell surface area. Co-treatment with sildenafil (1 μM, 48 h) inhibited these ET-1-induced hypertrophic responses. Although ET-1 enhanced the gene expression of TRPCs, sildenafil inhibited the enhanced gene expression of TRPC1, C3 and C6. Moreover, co-treatment with sildenafil abolished the augmentation of SOCE in the hypertrophied cardiomyocytes. CONCLUSIONS: These results suggest that sildenafil inhibits cardiomyocyte hypertrophy by suppressing the up-regulation of TRPC expression.

DOI PubMed

Involvement of the orexin system in adrenal sympathetic regulation.

Takayuki Nemoto, Fumiyo Toyoshima-Aoyama, Yuto Ueda, Takayoshi Ohba, Toshihiko Yanagita, Hiroyuki Watanabe, Tetsuro Shirasaka, Isao Tsuneyoshi, Yasushi Ishida, Kazuyoshi Hirota, Akira Sawaguchi, Manabu Murakami

Pharmacology   91 ( 5-6 ) 250 - 8   2013年04月  [査読有り]

研究論文（学術雑誌）  

Orexin (hypocretin) is a neuropeptide secreted from hypothalamic neurons that is known to be activated during motivated behaviors and active waking. Presently, our knowledge of orexin is mainly limited to the central nervous system, and the involvement of the orexin system in peripheral tissues has received little attention. In the present study, we analyzed the existence of the orexin system in the adrenal medulla, which is part of the sympathetic nervous system. Orexin and its receptors are expressed in the bovine adrenal medulla. Orexins stimulated intracellular calcium changes and epinephrine release from cultured bovine adrenal medullary cells. Applied orexin decreased expression of prepro-orexin, orexin receptor-1 and orexin receptor-2, suggesting negative feedback regulation in the adrenal gland. Our results indicate involvement of the orexin system in the sympathetic regulation of the adrenal medulla.

DOI PubMed

Possible involvement of TRP channels in cardiac hypertrophy and arrhythmia.

Hiroyuki Watanabe, Kenji Iino, Takayoshi Ohba, Hiroshi Ito

Current topics in medicinal chemistry   13 ( 3 ) 283 - 94   2013年03月  [査読有り]

研究論文（学術雑誌）  

Over the past 20 years, studies of transient receptor potential (TRP) channels have significantly extended our knowledge regarding the molecular basis of Ca2+ signals in cardiac myocytes. The functional significance of cardiac TRP channels is likely connected to the alteration of membrane potential or Ca2+ entry into a noncontractile compartment, where gene expression responsible for various cardiac diseases is induced. This review highlights some aspects of TRP channels with anticipated roles in cardiac disease. Evidence suggests that (a) increased activities of TRPC1, TRPC3, or TRPC6 are involved in the development of cardiac hypertrophy, where these TRPC channels act as unique sensors for a wide range of hypertrophic stimuli, and (b) mutations in TRPM4 are now recognized as causes of human cardiac conduction disorders. Ultimately, TRP channels may become novel pharmacological targets in the treatment of human cardiac disease.

PubMed

Questionnaire survey on the continuity of home oxygen therapy after a disaster with power outages.

Kazuhiro Sato, Ryo Morita, Kazuhito Tsukamoto, Narumi Sato, Yumiko Sasaki, Mariko Asano, Yuji Okuda, Hajime Miura, Masaaki Sano, Toshimitsu Kosaka, Hiroyuki Watanabe, Takanobu Shioya, Hiroshi Ito

Respiratory investigation   51 ( 1 ) 9 - 16   2013年03月  [査読有り]

研究論文（学術雑誌）  

BACKGROUND: After the Great East Japan Earthquake, oxygen-dependent patients in areas experiencing power outages could not continue home oxygen therapy (HOT) without oxygen cylinders. The purpose of this study was to examine use of oxygen cylinders in areas experiencing power outages and the effects of HOT interruption on patients' health. METHODS: Questionnaires were mailed to 1106 oxygen-dependent patients and HOT-prescribing physicians in Akita, near the disaster-stricken area. We investigated patients' actions when unable to use an oxygen concentrator and classified the patients based on oxygen cylinder use. Patients who experienced an interruption of or reduction in oxygen flow rate by their own judgment were assigned to the "interruption" and "reduction" groups, respectively; those who maintained their usual flow rate were assigned to the "continuation" group. Differences were tested using analysis of variance and the χ2 tests. RESULTS: In total, 599 patients responded to the questionnaire. Oxygen cylinders were supplied to 574 patients (95.8%) before their oxygen cylinders were depleted. Comparison of the continuation (n=356), reduction (n=64), and interruption (n=154) groups showed significant differences in family structure (p=0.004), underlying disease (p=0.014), oxygen flow rate (p<0.001), situation regarding use (p<0.001), knowledge of HOT (p<0.001), and anxiety about oxygen supply (p<0.001). There were no differences in changes in physical condition. CONCLUSIONS: Most patients could receive oxygen cylinders after the disaster. Some patients discontinued their usual oxygen therapy, but their overall health status was not affected.

DOI PubMed

Comparison of anti-inflammatory effects and high-density lipoprotein cholesterol levels between therapy with quadruple-dose rosuvastatin and rosuvastatin combined with ezetimibe.

Daisuke Yamazaki, Masaru Ishida, Hiroyuki Watanabe, Kiyoshi Nobori, Yasunori Oguma, Yutaka Terata, Takashi Koyama, Kenji Iino, Toshimitsu Kosaka, Hiroshi Ito

Lipids in health and disease   12   9 - 9   2013年02月  [査読有り]

研究論文（学術雑誌）  

BACKGROUND: Statins are frequently administered to reduce low-density lipoprotein cholesterol (LDL-C) and vascular inflammation, because LDL-C and high sensitive C-reactive protein (hs-CRP) are associated with high risk for cardiovascular events. When statins do not reduce LDL-C to desired levels in high-risk patients with coronary artery disease (CAD), ezetimibe can be added or the statin dose can be increased. However, which strategy is more effective for treating patients with CAD has not been established. The present study compares anti-inflammatory effects and lipid profiles in patients with CAD and similar LDL-C levels who were treated by increasing the statin dose or by adding ezetimibe to the original rosuvastatin dose to determine the optimal treatment for such patients. METHODS: 46 patients with high-risk CAD and LDL-C and hs-CRP levels of >70 mg/dL and >1.0 mg/L, respectively, that were not improved by 4 weeks of rosuvastatin (2.5 mg/day) were randomly assigned to receive 10 mg (R10, n = 24) of rosuvastatin or 2.5 mg/day of rosuvastatin combined with 10 mg/day of ezetimibe (R2.5/E10, n = 22) for 12 weeks. The primary endpoint was a change in hs-CRP. RESULTS: Baseline characteristics did not significantly differ between the groups. At 12 weeks, LDL-C and inflammatory markers (hs-CRP, interleukin-6, tumour necrosis factor-alpha and pentraxin 3) also did not significantly differ between the two groups (LDL-C: R10 vs. R2.5/E10: -19.4 ± 14.2 vs. -22.4 ± 14.3 mg/dL). However, high-density lipoprotein cholesterol (HDL-C) was significantly improved in the R10, compared with R2.5/E10 group (4.6 ± 5.9 vs. 0.0 ± 6.7 mg/dL; p < 0.05). CONCLUSION: Both enhanced therapies exerted similar anti-inflammatory effects under an equal LDL-C reduction in patients with high-risk CAD despite 2.5 mg/day of rosuvastatin. However, R10 elevated HDL-C more effectively than R2.5/E10. TRIAL REGISTRATION: UMIN000003746.

DOI PubMed

Effect of short-duration adaptive servo-ventilation therapy on cardiac function in patients with heart failure.

Takashi Koyama, Hiroyuki Watanabe, Gen Igarashi, Yoshikazu Tamura, Ken Ikeda, Shigenori Terada, Hiroshi Ito

Circulation journal : official journal of the Japanese Circulation Society   76 ( 11 ) 2606 - 13   2012年11月  [査読有り]

研究論文（学術雑誌）  

BACKGROUND: The aim of this study was to investigate whether short-duration adaptive servo-ventilation (ASV) therapy improves cardiac function in heart failure (HF) patients. METHODS AND RESULTS: Consecutive HF patients (n=86) were divided into 3 groups: group A, ASV for a mean of ≥4 h; group B, ASV for ≥1 to <4 h per day; and group C, no ASV or ASV <1 h. The frequency of ASV use did not significantly differ between groups A (79.3±19.2%) and B (70.9±17.4%). After 6 months, a significant increase in left ventricular ejection fraction (LVEF), significant decrease in plasma brain natriuretic peptide (BNP) and decrease in LV end-diastolic volume (LVEDV) were observed in groups A (LVEF, 5.0±8.1%; BNP, -24.9±33.7%; LVEDV, -6.2±10.1%) and B (LVEF, 3.5±5.5%; BNP, -16.5±24.6%; LVEDV, -5.1±8.2%) as compared with group C (LVEF, -1.5±6.0%, P=0.004, P=0.017; BNP, 2.8±10.2%, P=0.002, P=0.017; LVEDV, 0.8±9.1%, P=0.031, P=0.043). Significant correlation was seen between the total ASV time and changes of LVEF (r=0.369, P=0.002), BNP (r=-0.445, P<0.001), and LVEDV (r=-0.374, P=0.001). Admission rate was lower in groups A (4.1%) and B (7.1%) than in group C (25%, log-rank test; P=0.042, P=0.045). Multivariate analysis showed that the frequency of ASV use was a strong parameter for the improvement of LVEF (coefficient=0.284, standard error=0.035, P=0.019). CONCLUSIONS: Even a short-duration of ASV therapy may improve cardiac function in HF patients.

PubMed

Caput medusae in the mediastinum.

Kazuhiro Sato, Hiroyuki Watanabe, Masaaki Sano, Takanobu Shioya, Hiroshi Ito

American journal of respiratory and critical care medicine   186 ( 8 ) 803 - 803   2012年10月  [査読有り]

研究論文（学術雑誌）  

DOI PubMed

Right atrial giant myxoma occupying the right ventricular cavity.

Teruki Sato, Hiroyuki Watanabe, Megumi Okawa, Takako Iino, Kenji Iino, Kazuyuki Ishibashi, Hiroshi Yamamoto, Fumio Yamamoto, Hiroshi Ito

The Annals of thoracic surgery   94 ( 2 ) 643 - 6   2012年08月  [査読有り]

研究論文（学術雑誌）  

We report a case of a giant right atrial myxoma mimicking the right ventricular tumor. The 75-year-old patient underwent cardiac surgery, and the tumor was excised along with the stalk. Tricuspid valve annuloplasty was performed before closure of the right atriotomy. The tumor may have caused intraventricular stenosis, hepatic dysfunction, and progressive fatigue as a result of low cardiac output. This case is of special interest because the myxoma was very large compared with those ever reported, and a right atrial myxoma occupying the right ventricular cavity is rare.

DOI PubMed

A free-floating left atrial thrombus develops intermittent entrapment in the mid-ventricle during diastole.

Mikiko Fujiwara, Hiroyuki Watanabe, Yasunori Oguma, Genbu Yamaura, Kazuyuki Ishibashi, Hiroshi Yamamoto, Kiyoshi Nobori, Kenji Iino, Fumio Yamamoto, Hiroshi Ito

Heart and vessels   27 ( 4 ) 428 - 31   2012年07月  [査読有り]

研究論文（学術雑誌）  

Free-floating left atrial thrombi are rare. Here we report a case of a 75-year-old woman with atrial fibrillation who was admitted for treatment of acute myocardial infarction. A free-floating left atrial thrombus was found incidentally on echocardiography. Ten days after percutaneous coronary intervention, the patient had mild faintness with transient hypotension, and it was found that the left atrial thrombus had developed intermittent entrapment in the mid-ventricle during diastole, with abrupt rebound back to the left atrial cavity during systole. Urgent removal of the thrombus was performed successfully. Although the free-floating thrombus had appeared to be spherical, like a ball thrombus, on echocardiography, the excised thrombus was pedunculated. A cut section revealed a laminated thrombus with an onion-skin-like appearance.

DOI PubMed

Candesartan improves impaired endothelial function in the human coronary artery.

Kenji Iino, Hiroyuki Watanabe, Takako Iino, Mitsuaki Katsuta, Takashi Koyama, Toshimitsu Kosaka, Gen Terui, Hiroshi Ito

Coronary artery disease   23 ( 4 ) 278 - 83   2012年06月  [査読有り]

研究論文（学術雑誌）  

BACKGROUND: Endothelial dysfunction is closely related to cardiovascular events. Several studies have documented that angiotensin II type 1 receptor blockers (ARB) improve peripheral endothelial dysfunction. However, the effect of ARB on coronary endothelial function remains elusive. The purpose of this study was to ascertain the beneficial effects of ARB on human coronary artery endothelial function. METHODS AND RESULTS: Twenty-seven patients were randomly assigned to either the candesartan group (n=14) or the control group (n=13) and followed for 12 months. Coronary blood flow velocity was measured in the left anterior descending artery without stenosis using an intracoronary Doppler-tipped guide-wire. We evaluated coronary endothelial function as the coronary blood flow velocity reserve (CFR), which was defined as the percent change in the coronary blood flow velocity after an intracoronary acetylcholine infusion. At baseline, the CFR in both groups was below 300%, implying that these patients had endothelial dysfunction. After treatment with candesartan for 6 months, the CFR increased significantly from 199 ± 20 to 337 ± 27% (P<0.001), whereas the CFR did not change in the control group (194 ± 32 vs. 185 ± 41%, P=0.52). During 12 months of observation, the cardiovascular event-free survival rate of the patients with an increased CFR was significantly greater than the rate in patients with a decreased CFR (P=0.02). Moreover, the cardiovascular event-free survival rate was greater in the candesartan group than in the control group (P=0.04). CONCLUSION: Our results suggest that candesartan improves coronary endothelial dysfunction of human coronary arteries and may prevent cardiac events.

DOI PubMed

Impact of obesity on plasma B-type natriuretic peptide levels in Japanese community-based subjects.

Megumi Koizumi, Hiroyuki Watanabe, Yoshihiro Kaneko, Kenji Iino, Masaru Ishida, Toshimitsu Kosaka, Yutaka Motohashi, Hiroshi Ito

Heart and vessels   27 ( 3 ) 287 - 94   2012年05月  [査読有り]

研究論文（学術雑誌）  

The plasma B-type natriuretic peptide (BNP) concentration was recently shown to be inversely correlated with body mass index (BMI). However, very few attempts have been made to associate abdominal obesity and BNP in the Japanese general population. Here, we conducted a cross-sectional study, and examined 339 male and 429 female residents without heart disease in a rural Japanese community who received an annual health checkup in 2006. BNP was inversely associated with both BMI and abdominal circumference (AC) in the age-adjusted regression analysis (p < 0.05). Following adjustment for traditional risk factors, multiple regression analysis revealed that BNP was negatively correlated with AC (p < 0.05), but not BMI. Although metabolic syndrome was not associated with BNP levels, AC had an influence on low BNP levels in the multiple regression analysis using both AC and BMI concurrently (p < 0.05 for AC and p > 0.60 for BMI). These effects were more prominent in men than in women. Collectively, plasma BNP levels are inversely related with obesity, as measured by AC, in Japanese community-based subjects.

DOI PubMed

An unusual interventricular communication after acute myocardial infarction.

Takako Iino, Hiroyuki Watanabe, Makoto Yoshida, Hiroshi Ito

European heart journal   33 ( 8 ) 937 - 937   2012年04月  [査読有り]

研究論文（学術雑誌）  

DOI PubMed

Adequate pulmonary stenosis allowed long-term survival in a patient with unoperated single ventricle.

Mai Terada, Hiroyuki Watanabe, Kenji Iino, Manabu Kakizaki, Masato Takahashi, Hiroshi Ito

Journal of the American College of Cardiology   59 ( 13 ) e25   2012年03月  [査読有り]

研究論文（学術雑誌）  

DOI PubMed

Two cases of calcified amorphous tumor mimicking mitral valve vegetation.

Mikiko Fujiwara, Hiroyuki Watanabe, Takako Iino, Yusuke Kobukai, Kazuyuki Ishibashi, Hiroshi Yamamoto, Kenji Iino, Fumio Yamamoto, Hiroshi Ito

Circulation   125 ( 10 ) e432-4   2012年03月  [査読有り]

研究論文（学術雑誌）  

DOI PubMed

Adaptive servo-ventilation improves renal function in patients with heart failure.

Takashi Koyama, Hiroyuki Watanabe, Shigenori Terada, Shin Makabe, Gen Igarashi, Kiyoshi Nobori, Hiroshi Ito

Respiratory medicine   105 ( 12 ) 1946 - 53   2011年12月  [査読有り]

研究論文（学術雑誌）  

BACKGROUND: Impaired cardiac function and sleep-disordered breathing (SDB) are associated with progression of chronic kidney disease (CKD) in heart failure (HF) patients. Adaptive servo-ventilation (ASV) therapy improves cardiac function in HF patients regardless of the SDB severity through hemodynamic support and prevention of repetitive hypoxic stress. This study was designed to test the hypothesis that ASV therapy improves renal function in HF patients with SDB. METHODS AND RESULTS: Of 59 consecutively enrolled HF patients, 43 with moderate-to-severe SDB underwent ASV therapy. HF patients were divided into the ASV-treated group (n = 27) and the non-ASV-treated group (n = 16). Estimated glomerular filtration rate (eGFR), echocardiographic parameters, and inflammatory biomarkers were measured before and 12 months after ASV initiation. Improvement in the eGFR was found in the ASV-treated group, but not in the non-ASV-treated group. There was a positive correlation between the increases in eGFR and left ventricular ejection fraction (r = 0.488, p = 0.001). The changes in high-sensitivity C-reactive protein were negatively correlated with change in the eGFR (r = -0.416, p = 0.006). CONCLUSIONS: ASV therapy could improve renal dysfunction in HF patients through hemodynamic support. Additionally, prevention of SDB with the use of ASV therapy could exert anti-inflammatory effects, which could contribute to the improvement of renal function in HF patients.

DOI PubMed

Endothelial progenitor cells are associated with response to chemotherapy in human non-small-cell lung cancer.

Ryo Morita, Kazuhiro Sato, Mariko Nakano, Hajime Miura, Hidesato Odaka, Kiyoshi Nobori, Toshimitsu Kosaka, Masaaki Sano, Hiroyuki Watanabe, Takanobu Shioya, Hiroshi Ito

Journal of cancer research and clinical oncology   137 ( 12 ) 1849 - 57   2011年12月  [査読有り]

研究論文（学術雑誌）  

PURPOSE: Bone marrow-derived endothelial progenitor cells (EPCs) play an important role in angiogenesis and tumor growth. However, the clinical relevance of EPCs in non-small-cell lung cancer (NSCLC) remains unclear. Recently, some reports suggested that EPCs correlate with clinical behavior of cancer patients. We assessed the hypothesis that EPCs correlate with efficient of therapy, prognosis, and clinicopathological factors, and EPCs may offer a possible biomarker for treatment outcome in NSCLC. METHODS: EPCs labeled with CD34, CD133, and vascular endothelial growth factor receptor-2 (VEGFR-2) antibodies were counted by flow cytometry in the peripheral blood of 31 NSCLC patients. We categorized two groups of NSCLC patients according to circulating EPC numbers. We examined age, pathological stage, histological type, Fluoro-D: -glucose Positron emission tomography (FDG-PET), response to therapy, progression-free survival, and tumor size of NSCLC patients and investigated whether these factors correlate with EPC counts. RESULTS: Circulating EPC numbers before antitumor therapy were increased in NSCLC patients compared with healthy controls (P < 0.05). In NSCLC patients, therapy was significantly effective in low circulating EPC group compared with that of high (P < 0.05). Furthermore, the low EPC group showed significantly longer progression-free survival times than that of high (P < 0.05). However, no significant associations with age, gender, histological type, pathological stage, or FDG-PET were detected. CONCLUSION: Peripheral blood levels of bone marrow-derived EPCs are significantly increased in patients with NSCLC and correlate with response to chemotherapy. EPCs may offer a possible biomarker for efficient of treatment and prognosis.

DOI PubMed

Low mean corpuscular hemoglobin level is a predictor of discontinuation of antiplatelet therapy in patients with acute coronary syndrome.

Masaru Ishida, Hiroyuki Watanabe, Kenji Iino, Megumi Okawa, Toshimitsu Kosaka, Hiroshi Ito

Internal medicine (Tokyo, Japan)   50 ( 24 ) 2933 - 9   2011年12月  [査読有り]

研究論文（学術雑誌）  

OBJECTIVE: Premature discontinuation of antiplatelet therapy (APT) increases the risk of thrombosis in patients who have undergone placement of a drug-eluting stent for acute coronary syndrome (ACS). The goal of the present study was to identify predictors of patients who would prematurely discontinue APT following stent implantation. METHODS: One-hundred and sixty-one ACS patients who underwent percutaneous coronary intervention in our institution between November 2004 and September 2008 were enrolled in this study. RESULTS: Over the 12-month follow-up period, 18 patients (11.2%) discontinued APT. Among baseline demographic and laboratory variables, multivariate analysis revealed that mean corpuscular hemoglobin (MCH) level was an independent risk factor for APT discontinuation (OR: 0.738, p=0.017). Kaplan-Meier survival analysis showed that the incidence of APT discontinuation was significantly higher in patients with low MCH (<30.0 pg) than in patients with high MCH (≥30.0 pg) (p=0.0006). CONCLUSION: Low baseline MCH level was a predictor of APT discontinuation in ACS patients. Thus, careful consideration should be made before employing a drug-eluting stent in patients with low MCH levels.

PubMed

Expression of the transient receptor potential channel c3 correlates with a favorable prognosis in patients with adenocarcinoma of the lung.

Hajime Saito, Yoshihiro Minamiya, Hiroyuki Watanabe, Naoko Takahashi, Manabu Ito, Hiroshi Toda, Hayato Konno, Masafumi Mitsui, Satoru Motoyama, Jun-ichi Ogawa

Annals of surgical oncology   18 ( 12 ) 3377 - 83   2011年11月  [査読有り]

研究論文（学術雑誌）  

BACKGROUND: The cation channels of the transient receptor potential (TRP) superfamily are implicated in cancer formation; in particular, TRPC3 has been shown to contribute to the progression of human ovarian cancer. However, the relationship between TRP expression and the clinicopathological characteristics of lung cancer and patient prognosis is not well understood. Therefore, we investigated the relationship between TRP expression and the prognosis of patients with adenocarcinoma of the lung. METHODS: We used semiquantitative real-time reverse transcription polymerase chain reaction to assess the expression of TRP mRNA in tumor samples from 95 patients with adenocarcinoma of the lung. We then correlated the TRP mRNA levels with clinicopathological factors. We also used immunohistochemical staining to determine the localization of expressed TRP. RESULTS: The 5-year overall and disease-free survival rates among patients expressing higher levels of TRPC3 mRNA were significantly better than the corresponding rates among patients expressing lower levels (P=0.004, P=0.002, respectively, by log-rank test). Multivariate Cox proportional hazard analyses revealed that tumor size (hazard ratio, 2.46; 95% confidence interval [CI], 1.06 to 5.79; P=0.036), n2 (hazard ratio, 3.81; 95% CI, 1.29 to 11.77; P=0.015) and TRPC3 (hazard ratio, 2.71; 95% CI, 1.33 to 5.59; P=0.006) were independent factors affecting the 5-year overall survival rate. Immunohistochemistry showed that the cytoplasm of tumor cells were stained positively for TRPC3. CONCLUSIONS: Higher levels of TRPC3 expression in tumor cells are an independent predictor of a better prognosis in patients with adenocarcinoma of the lung.

DOI PubMed

Position-dependent right-to-left shunt causing a brain abscess.

Teruki Sato, Hiroyuki Watanabe, Kenji Iino, Takako Iino, Takashi Koyama, Masaru Ishida, Toshimitsu Kosaka, Fumio Yamamoto, Hiroshi Ito

Circulation   124 ( 15 ) e387-9   2011年10月  [査読有り]

研究論文（学術雑誌）  

DOI PubMed

The prevalence of apical wall motion abnormalities in patients with long-term right ventricular apical pacing.

Takako Sato-Iino, Hiroyuki Watanabe, Takashi Koyama, Kenji Iino, Toshimitsu Kosaka, Hiroshi Ito

Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography   24 ( 5 ) 556 - 564   2011年05月  [査読有り]

研究論文（学術雑誌）  

BACKGROUND: Long-term right ventricular apical pacing (RVAP) can lead to adverse clinical outcomes. Although left ventricular (LV) dyssynchrony is the major causative factor, other potential mechanisms are not fully understood. We sought to clarify whether RVAP elicits apical wall motion abnormalities that contribute to LV contractile dysfunction. METHODS: We studied annual echocardiographic data over a 5-year period after pacemaker implantation (PMI) for 74 patients who underwent RVAP. The patients were divided into two groups according to the percentage of ventricular pacing: right ventricular (RV) pacing < 50% and RV pacing ≥ 50%. We assessed LV ejection fraction, LV end-diastolic volume, and left atrial dimension. To assess regional wall motion abnormalities, the wall motion score index was calculated. RESULTS: LV wall motion abnormality was observed in 64% of the subjects and was more pronounced in apical segments than in other segments. At 2 years after PMI, brain natriuretic peptide levels were significantly higher in the group with RV pacing ≥ 50% than in the group with RV pacing < 50%. The subjects with RV pacing ≥ 50% had higher LV end-diastolic dimension and lower ejection fraction at 3 years after PMI. CONCLUSION: Long-term RVAP elicits apical wall motion abnormalities that could in part contribute to LV contractile dysfunction.

DOI PubMed

Short-term prognosis of adaptive servo-ventilation therapy in patients with heart failure.

Takashi Koyama, Hiroyuki Watanabe, Gen Igarashi, Shigenori Terada, Shin Makabe, Hiroshi Ito

Circulation journal : official journal of the Japanese Circulation Society   75 ( 3 ) 710 - 2   2011年03月  [査読有り]

研究論文（学術雑誌）  

BACKGROUND: This study tested the hypothesis that adaptive servo-ventilation (ASV) therapy improves the prognosis of heart failure (HF) patients, regardless of the severity of sleep-disordered breathing (SDB). METHODS AND RESULTS: 88 consecutive patients were divided into 4 groups based on ASV therapy and SDB severity. The incidence of HF, brain natriuretic peptide (BNP) levels, and left ventricular ejection fraction (LVEF) were followed for 12 months. Fewer HF events, together with an increase in LVEF and a decrease in BNP, occurred in ASV-treated patients with both non-to-mild and moderate-to-severe SDB. CONCLUSIONS: ASV therapy improves the short-term prognosis in HF-patients, regardless SDB severity.

PubMed

Abnormal coagulation and platelet profile in patients with obstructive sleep apnea syndrome.

Shigenori Terada, Takashi Koyama, Hiroyuki Watanabe, Shin Makabe, Gen Igarashi, Katsuhito Seki, Hiroshi Ito

International journal of cardiology   146 ( 3 ) 423 - 5   2011年02月  [査読有り]

研究論文（学術雑誌）  

DOI PubMed

TRPV1 and TRPA1 in pulmonary vagal afferents and their relations to airway sensitivity

Hiroyuki Watanabe, Takayoshi Ohba, Kazuhiro Satoh, Masaaki Sano, Takanobu Shioya and Hiroshi Ito

Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry   10 ( 1 ) 18 - 30   2011年02月  [査読有り]

研究論文（学術雑誌）  

In the last 15 years, studies of transient receptor potential (TRP) channels have significantly extended our knowledge about the molecular basis of sensory function in pulmonary vagal afferents. In particular, TRPV1 and TRPA1 channels are unique cellular sensors for a wide range of inflammatory mediators and noxious irritants. These channels act as the molecular integrator of multiple nociceptive stimuli and are involved in multiple cellular functions, ranging from transduction of sensory signals to the release of neuropeptides in pulmonary vagal afferents. Increased activity of TRPV1 channels is now recognized as a cause of airway hypersensitivity in inflammatory airway diseases. In this review, we summarize current knowledge about the activation mechanisms of TRPV1 and TRPA1, and discuss the possible functional implications of TRPV1 and TRPA1 in human physiology and pathophysiology, such as the cough reflex and hypersensitivity.

DOI

Cardiac Diagnosing by a Piezoelectric-transducer-based Heart Sound Monitor System

Shinichi Sato, Takashi Koyama, Kyoichi Ono, Gen Igarashi, Hiroyuki Watanabe, Hiroshi Ito, Mikio Muraoka

BIODEVICES     280 - 283   2011年01月  [査読有り]

研究論文（学術雑誌）  

Fluvastatin protects vascular smooth muscle cells against oxidative stress through the Nrf2-dependent antioxidant pathway.

Shin Makabe, Yoichiro Takahashi, Hiroyuki Watanabe, Manabu Murakami, Takayoshi Ohba, Hiroshi Ito

Atherosclerosis   213 ( 2 ) 377 - 84   2010年12月  [査読有り]

研究論文（学術雑誌）  

OBJECTIVE: HMG-CoA reductase inhibitors (statins) have pleiotropic actions, including the ability to reduce vascular oxidative stress. Transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) is an important regulator of cellular oxidative stress. This study examined the role of Nrf2 in statin-mediated antioxidant effects in vascular smooth muscle cells. METHODS AND RESULTS: In cultured human coronary artery smooth muscle cells (hCASMCs), fluvastatin activated the nuclear translocation of Nrf2, as evaluated by Western blotting and immunocytochemical analyses. Nrf2-antioxidant response element (ARE) activity was measured with a luciferase assay after transfection of reporter plasmids containing AREs. Fluvastatin significantly increased the transcriptional activity of the ARE. Electromobility shift assays using an ARE probe detected a complex that was significantly increased in intensity by fluvastatin. Western blotting and luciferase assay revealed fluvastatin activated Nrf2 via the PI3K/Akt pathway. Statins upregulated the Nrf2-related antioxidant genes heme oxygenase-1, NAD(P)H quinone oxidoreductase-1, and glutamate-cysteine ligase modifier subunits. Inhibition of Nrf2 by siRNA reduced statin-induced upregulation of these antioxidant genes. Moreover, Nrf2 siRNA markedly reduced the cytoprotective effects of fluvastatin against H(2)O(2) administration in hCASMCs. CONCLUSIONS: Fluvastatin exerts cytoprotective effects against oxidative stress, inducing antioxidant genes through Nrf2/ARE in hCASMCs. These results suggest that the Nrf2/ARE pathway plays an important role in the regulation of statin-mediated antioxidant effects in vascular smooth muscle cells.

DOI PubMed

Beneficial effects of adaptive servo ventilation in patients with chronic heart failure.

Takashi Koyama, Hiroyuki Watanabe, Yusuke Kobukai, Shin Makabe, Yoshiko Munehisa, Kenji Iino, Toshimitsu Kosaka, Hiroshi Ito

Circulation journal : official journal of the Japanese Circulation Society   74 ( 10 ) 2118 - 24   2010年10月  [査読有り]

研究論文（学術雑誌）  

BACKGROUND: Sleep-disordered breathing (SDB) is thought to be a state of inflammation caused by hypoxic stress. Whether adaptive servo ventilation (ASV) attenuates the inflammatory response and improves the cardiac function of patients with congestive heart failure (CHF) accompanied by SDB was not been investigated. METHODS AND RESULTS: Seventeen inpatients with New York Heart Association (NYHA) II or III underwent polysomnography. There was a positive correlation between the apnea hypopnea index and high-sensitivity C-reactive protein (hs-CRP) level (r=0.753, P=0.016). The patients were divided into ASV (n=10) and non-ASV groups (n=7), and CHF-parameters were measured before and after ASV treatment. Improvement was noted for the NYHA class in the ASV group but not in the non-ASV group. In contrast to the non-ASV group, the level of brain natriuretic peptide (BNP), ejection fraction, and hs-CRP levels in the ASV group significantly improved (BNP, 212.1 ± 181.2 to 77.3 ± 54.0 pg/ml [P<0.05]; ejection fraction, 43.5 ± 6.4 to 53.3 ± 6.1% [P=0.002]; hs-CRP, 0.85 ± 0.58 to 0.21 ± 0.19 mg/dl, [P=0.008]). The increase in ejection fraction was correlated with a decrease in the hs-CRP level (r=-0.753, P=0.001). CONCLUSIONS: Anti-inflammatory effects of ASV are important contributors for improving cardiac function in patients with CHF accompanied by SDB.

PubMed

Decreased calcium channel currents and facilitated epinephrine release in the Ca2+ channel beta3 subunit-null mice.

Toshio Ohta, Takayoshi Ohba, Takashi Suzuki, Hiroyuki Watanabe, Hironobu Sasano, Manabu Murakami

Biochemical and biophysical research communications   394 ( 3 ) 464 - 9   2010年04月  [査読有り]

研究論文（学術雑誌）  

The beta subunits of voltage-dependent calcium channels are known to modify calcium channel currents through pore-forming alpha1 subunits. The beta3 subunit is expressed in the adrenal gland and participates in forming various calcium channel types. We performed a series of experiments in beta3-null mice to determine the role of the beta3 subunit in catecholamine release from the adrenal chromaffin system. Protein levels of N-type channel forming CaV2.2 and L-type forming CaV1.2 decreased. The beta3-null mice showed a decreased baroreflex, suggesting decreased sympathetic tonus, whereas plasma catecholamine levels did not change. Pulse-voltage stimulation revealed significantly increased amperometrical currents in beta3-null mice, while patch-clamp recordings showed a significant reduction in Ca(2+)-currents due to reduced L- and N-type currents, indicating facilitated exocytosis. A biochemical analysis revealed increased InsP3 production. In conclusion, our results indicate the importance of the beta3 subunit in determining calcium channel characteristics and catecholamine release in adrenal chromaffin cells.

DOI PubMed

Double transgenic mice crossed GFP-LC3 transgenic mice with alphaMyHC-mCherry-LC3 transgenic mice are a new and useful tool to examine the role of autophagy in the heart.

Mai Terada, Kiyoshi Nobori, Yoshiko Munehisa, Manabu Kakizaki, Takayoshi Ohba, Yoichiro Takahashi, Takashi Koyama, Yutaka Terata, Masaru Ishida, Kenji Iino, Toshimitsu Kosaka, Hiroyuki Watanabe, Hitoshi Hasegawa, Hiroshi Ito

Circulation journal : official journal of the Japanese Circulation Society   74 ( 1 ) 203 - 6   2010年01月  [査読有り]

研究論文（学術雑誌）  

BACKGROUND: The involvement of autophagy in heart disease has been reported. Transgenic mice expressing GFP-LC3 have been a useful tool in detecting autophagosomes systemically. It is difficult to differentiate increased formation of autophagosomes from decreased clearance of autophagosomes in the heart using GFP-LC3 mice. METHODS AND RESULTS: We generated transgenic mice expressing mCherry-LC3 under alphaMyHC promoter and crossed the mice with transgenic mice expressing GFP-LC3. The deference of resistance to acidic conditions between GFP and mCherry overcame the limitation. CONCLUSIONS: This method is an innovative approach to examine the role of autophagy and to analyze autophagosome maturation in cardiomyocytes. (Circ J 2010; 74: 203 - 206).

PubMed

Essential role of STIM1 in the development of cardiomyocyte hypertrophy.

Takayoshi Ohba, Hiroyuki Watanabe, Manabu Murakami, Takako Sato, Kyoichi Ono, Hiroshi Ito

Biochemical and biophysical research communications   389 ( 1 ) 172 - 6   2009年11月  [査読有り]

研究論文（学術雑誌）  

Store-operated Ca(2+) entry (SOCE) through transient receptor potential (TRP) channels is important in the development of cardiac hypertrophy. Recently, stromal interaction molecule 1 (STIM1) was identified as a key regulator of SOCE. In this study, we examined whether STIM1 is involved in the development of cardiomyocyte hypertrophy. RT-PCR showed that cultured rat cardiomyocytes constitutively expressed STIM1. Endothelin-1 (ET-1) treatment for 48h enhanced TRPC1 expression, SOCE, and nuclear factor of activated T cells activation without upregulating STIM1. However, the knockdown of STIM1 suppressed these effects, thereby preventing a hypertrophic response. These results suggest that STIM1 plays an essential role in the development of cardiomyocyte hypertrophy.

DOI PubMed

Direct effect of percutaneous transluminal angioplasty on the heart in patient with peripheral artery disease

Oguma Yasunori,Iino Kenji,Watanabe Hiroyuki,Kosaka Toshimitsu,Hasegawa Hitoshi,Ito Hiroshi

秋田医学   36 ( 2 ) 107 - 113   2009年11月  [査読有り]

研究論文（学術雑誌）  

Background and Purpose : The patient with peripheral artery disease (PAD) is known to have a poor prognosis for life. Recently, it has been reported that percutaneous transluminal angioplasty (PTA) for PAD improves the prognosis. However, the detailed mechanisms remain unclear.
Augmentation index (AIx) or central aortic pressure (CAP) is shown to increase myocardial mechanical stress and facilitate myocardial hypertrophy. The aim of this study is to clarify the direct cardioprotective effects of PTA mediated by decreasing CAP and AIx.
Methods : 28 patients with PAD were enrolled. They were divided into two groups ; control group (n=12) and PTA group (n=16). Both radial AIx and CAP were measured by using pulse waveform analysis of arterial waveform recorded non-invasively by applanation tonometry in radial artery. We used a plasma B-type natriuretic peptide (BNP) level as a marker of myocardial mechanical stress. Plasma BNP levels, radial AIx and CAP which were measured after PTA or angiography, were compared with the data on admission.
Result : Although plasma BNP levels in the control group were not changed, those in the PTA group were significantly decreased from 68.44 to 42.08 pg/ml (p<0.05). Pulse waveform analysis demonstrated that radial AIx and CAP in the control group remain unchanged. On the other hand, radial AIx and CAP were significantly reduced in the PTA group. The reduction rates of radial AIx, CAP and plasma BNP levels were −11.3%, −8.9% and −34% respectively.
Conclusion : These results suggest that PTA can decrease myocardial mechanical stress in patients with PAD. The mechanisms may be mediated in part by reduction of radial AIx and CAP.

Cardioprotective effect of an L/N-type calcium channel blocker in patients with hypertensive heart disease.

Toshimitsu Kosaka, Masayasu Nakagawa, Masaru Ishida, Kenji Iino, Hiroyuki Watanabe, Hitoshi Hasegawa, Hiroshi Ito

Journal of cardiology   54 ( 2 ) 262 - 72   2009年10月  [査読有り]

研究論文（学術雑誌）  

BACKGROUND: Left ventricular (LV) diastolic dysfunction is related to increased cardiac sympathetic activity. We investigated the effect of cilnidipine, an L/N-type calcium channel blocker, on LV diastolic function and cardiac sympathetic activity in patients with hypertensive heart disease (HHD) using radionuclide myocardial imaging. METHODS AND RESULTS: Thirty-two frame electrocardiography (ECG) -gated (99m)Tc-sestamibi (MIBI) myocardial single photon emission computed tomography (SPECT), and (123)I-metaiodobenzylguanidine (MIBG) imaging were performed before and 6 months after drug administration in 32 outpatients with HHD. Sixteen of the patients were treated with cilnidipine and the other 16 were treated with nifedipine retard. The parameters for assessing LV diastolic function evaluated using ECG-gated (99m)Tc-MIBI SPECT were peak filling rate (PFR), first-third filling rate (1/3FR), and time to peak filling (TPF). Cardiac sympathetic activity was assessed as early and delayed heart to mediastinum (H/M) ratios and a washout rate (WR), using (123)I-MIBG imaging. The PFR and 1/3FR significantly increased after 6 months of treatment with cilnidipine (p<0.05 for both), but did not with nifedipine retard. The H/M ratios significantly increased (p<0.05 for both) in conjunction with a decreased WR (p<0.05) in the cilnidipine group. Moreover, a significant positive correlation was seen between the rate of change in PFR and the rate of change in early and delayed H/M ratios in the cilnidipine group (p<0.05 for both). The same results were obtained for the relationship between the rate of change in 1/3FR and the rate of change in H/M ratios (p<0.05 for both). However, no such relationship was seen in the nifedipine group. CONCLUSION: These data indicate that cilnidipine seems to suppress cardiac sympathetic overactivity via blockade of N-type calcium channels and improves LV diastolic function in patients with HHD.

DOI PubMed

[Pathological role of TRP channels in cardiovascular and respiratory diseases].

Hiroyuki Watanabe

Nihon yakurigaku zasshi. Folia pharmacologica Japonica   134 ( 3 ) 127 - 30   2009年09月  [査読有り]

研究論文（学術雑誌）  

DOI PubMed

Association between perceived stress and plasma B-type natriuretic peptide concentrations.

Megumi Koizumi, Yoshihiro Kaneko, Shinya Tosa, Hiroyuki Watanabe, Toshimitsu Kosaka, Hitoshi Hasegawa, Yutaka Motohashi, Hiroshi Ito

Circulation journal : official journal of the Japanese Circulation Society   73 ( 6 ) 1055 - 61   2009年06月  [査読有り]

研究論文（学術雑誌）  

BACKGROUND: Many patients with heart disease continue to have cardiac events despite receiving optimal treatments for traditional risk factors. Consequently, non-traditional risk factors for heart disease, such as perceived stress, have attracted attention. Associations between perceived stress and plasma B-type natriuretic peptide (BNP) were explored, while controlling for traditional heart disease risk factors. METHODS AND RESULTS: This cross-sectional study examined 360 male and 446 female (age, >40 years) residents of a rural Japanese community who received annual health checkups in 2006. A lifestyle questionnaire was used to obtain information regarding perceived stress and medical history, and routine anthropometric and blood pressure measurements and a laboratory assessment of cardiovascular risk factors, including plasma BNP concentrations and an electrocardiogram, were done. After adjusting for traditional heart disease risk factors, multiple regression analysis showed that perceived stress was associated with BNP concentrations, particularly in women (F=6.12, P=0.026). In addition, multiple tests using Bonferroni's procedure showed that BNP concentrations decreased with perceived stress level in men and women. Similar trends were observed in the sub-analyses of subjects with and without known heart disease. CONCLUSIONS: Perceived stress in our study was negatively associated with plasma BNP concentrations, independently of traditional heart disease risk factors.

PubMed

Renal transplantation improves cardiac function

MUNEHISA Yoshiko,WATANABE Hiroyuki,TERATA Shigenori,KOSAKA Toshimitsu,HASEGAWA Hitoshi,SATOH Shigeru,HABUCHI Tomonori,ITO Hiroshi

秋田医学   36 ( 1 ) 59 - 66   2009年06月  [査読有り]

研究論文（学術雑誌）  

There is mounting evidence that chronic kidney disease is a major contributor to severe cardiac damage. Although renal transplantation (RT) is an effective strategy in patients with end-stage renal disease (ESRD), the effects on cardiac function remain unclear. This study determined the effects of RT on left ventricular (LV) morphology and function in a retrospective longitudinal analysis of echocardiographic data collected in RT (n=17) and maintenance hemodialysis (HD ; n=19) groups from 2003 to 2008.
Echocardiographic data obtained within 6 months and at over 3 years were compared with the data before transplantation. Improved blood pressure and anemia were observed with RT, but not HD. In contrast to the HD group, the left ventricular mass index (LVMI) in the RT group was decreased from 195.2 ± 52.1 to 162.5 ± 30.8 g/m2 ( p<0.05). In addition, the LV ejection fraction was improved in the RT group from 63.0 ± 17.1% to 79.5 ± 3.3% ( p<0.01), but not in the HD group. The rate of reduction of LVMI in the RT group was greater in patients with good control of hemoglobin.
In conclusion, RT has beneficial effects on LV hypertrophy and function, as well as on ESRD.

The pathological role of transient receptor potential channels in heart disease.

Hiroyuki Watanabe, Manabu Murakami, Takayoshi Ohba, Kyoichi Ono, Hiroshi Ito

Circulation journal : official journal of the Japanese Circulation Society   73 ( 3 ) 419 - 27   2009年03月  [査読有り]

研究論文（学術雑誌）  

Transient receptor potential (TRP) channels are expressed in almost every human tissue, including the heart and vasculature. Most are permeable to Ca(2+) and play unique roles as multifunctional cellular sensors. Their involvement in many fundamental cell functions (eg, contraction, proliferation, and cell death) has made investigating their roles in human disease an urgent priority for medical science. This review presents an overview of current knowledge about the pathological role of TRP channels in heart disease and highlights some TRP channels with anticipated roles in disease. Evidence suggests that (a) upregulation of TRPC channels is involved in the development of cardiac hypertrophy and heart failure; (b) TRPC1, TRPC6, and TRPV2 play a role in the pathogenesis of cardiomyopathy associated with muscular dystrophy; (c) TRPC6 or TRPM4 is involved in the delayed after-depolarization; (d) TRPP2 is involved in the normal development of the interventricular and interatrial septa; and (e) neuronal TRPV1 acts as a detector of pain-producing stimuli. Ultimately, TRP channels might become novel pharmacological targets in the treatment of human heart disease.

PubMed

Usefulness of plasma BNP levels as a marker of left ventricular wall stress in obese individuals.

Shinya Tosa, Hiroyuki Watanabe, Kenji Iino, Gen Terui, Toshimitsu Kosaka, Hitoshi Hasegawa, Hiroshi Ito

International heart journal   50 ( 2 ) 173 - 82   2009年03月  [査読有り]

研究論文（学術雑誌）  

Plasma brain natriuretic peptide (BNP) level is known to reflect left ventricular wall stress (LVWS). Recent studies have shown that obese individuals have lower BNP levels. However, the usefulness of BNP level as a marker of LVWS in obese individuals remains unclear. This study examined whether BNP reflects LVWS even in obese individuals.This study enrolled 136 hospital inpatients who had suffered chronic heart failure (NYHA class I or II), or who had undergone a thorough examination for angina pectoris. On the basis of body mass index (BMI), we divided the inpatients into nonobese (< 25) and obese (> or = 25) groups. All BNP measurements, cardiac catheterizations, and echocardiographic examinations were carried out within 24 hours. Although no significant differences were found between the two groups in the hemodynamic parameters examined, including end-diastolic LVWS (LV-EDWS) and end-systolic LVWS (LV-ESWS), BNP levels were significantly lower in the obese group compared to the nonobese group. In the nonobese group, a definite correlation between LV-EDWS or LV-ESWS and BNP (r = 0.43, r = 0.46, respectively) was observed, whereas no correlation was found between LV-EDWS or LV-ESWS and BNP in the obese group (r = -0.09, r = 0.06, respectively). To explore the mechanism for suppressed BNP levels in obese individuals, the correlation of BNP with biochemical markers was analyzed. Statistical significance was found only between adiponectin and BNP (r = 0.44), implying that BNP or adiponectin might influence the plasma levels of the other.In conclusion, BNP levels cannot be used as a marker of LVWS in obese individuals.

PubMed

Molecular and electrical remodeling of L- and T-type Ca(2+) channels in rat right atrium with monocrotaline-induced pulmonary hypertension.

Takashi Koyama, Kyoichi Ono, Hiroyuki Watanabe, Takayoshi Ohba, Manabu Murakami, Kenji Iino, Hiroshi Ito

Circulation journal : official journal of the Japanese Circulation Society   73 ( 2 ) 256 - 63   2009年02月  [査読有り]

研究論文（学術雑誌）  

BACKGROUND: Atrial arrhythmia is often encountered in chronic pulmonary disease with pulmonary hypertension (PH), but few studies have investigated the electrical remodeling of atrial Ca(2+) channels under PH. METHODS AND RESULTS: Wistar rats were injected with monocrotaline (MCT), resulting in PH with right atrial and ventricular hypertrophy. The L-type Ca(2+) channel current density was significantly decreased in right atrial cells of MCT-treated rats, accompanied by a significant reduction in mRNA expression of the CaV1.2 (alpha(1C)) subunit and accessory beta(2) subunit. Conversely, the low voltage-activated Ca(2+) current was more marked in the right atrial cells of MCT-treated rats than in those of control rats. The current-voltage relationship and the time course of inactivation closely resembled those of T-type Ca(2+) channels, although the current was only slightly inhibited by 10-100 micromol/L Ni(2+). No significant differences were observed in the mRNA expression levels of CaV3.1 (alpha(1G)) and CaV3.2 (alpha(1H)) or the protein level of the CaV3.1 subunit. In left atrial cells, the electrophysiological molecular properties of Ca(2+) channels were unaffected by MCT treatment. CONCLUSIONS: PH causes right atrial hypertrophy, associated with alteration of the electrophysiological molecular properties of Ca(2+) channels.

PubMed

Modified sympathetic nerve system activity with overexpression of the voltage-dependent calcium channel beta3 subunit.

Manabu Murakami, Takayoshi Ohba, Feng Xu, Eisaku Satoh, Ichiro Miyoshi, Takashi Suzuki, Yoichirou Takahashi, Eiki Takahashi, Hiroyuki Watanabe, Kyoichi Ono, Hironobu Sasano, Noriyuki Kasai, Hiroshi Ito, Toshihiko Iijima

The Journal of biological chemistry   283 ( 36 ) 24554 - 60   2008年09月  [査読有り]

研究論文（学術雑誌）  

N-type voltage-dependent calcium channels (VDCCs) play determining roles in calcium entry at sympathetic nerve terminals and trigger the release of the neurotransmitter norepinephrine. The accessory beta3 subunit of these channels preferentially forms N-type channels with a pore-forming CaV2.2 subunit. To examine its role in sympathetic nerve regulation, we established a beta3-overexpressing transgenic (beta3-Tg) mouse line. In these mice, we analyzed cardiovascular functions such as electrocardiography, blood pressure, echocardiography, and isovolumic contraction of the left ventricle with a Langendorff apparatus. Furthermore, we compared the cardiac function with that of beta3-null and CaV2.2 (alpha1B)-null mice. The beta3-Tg mice showed increased expression of the beta3 subunit, resulting in increased amounts of CaV2.2 in supracervical ganglion (SCG) neurons. The beta3-Tg mice had increased heart rate and enhanced sensitivity to N-type channel-specific blockers in electrocardiography, blood pressure, and echocardiography. In contrast, cardiac atria of the beta3-Tg mice revealed normal contractility to isoproterenol. Furthermore, their cardiac myocytes showed normal calcium channel currents, indicating unchanged calcium influx through VDCCs. Langendorff heart perfusion analysis revealed enhanced sensitivity to electric field stimulation in the beta3-Tg mice, whereas beta3-null and Cav2.2-null showed decreased responsiveness. The plasma epinephrine and norepinephrine levels in the beta3-Tg mice were significantly increased in the basal state, indicating enhanced sympathetic tone. Electrophysiological analysis in SCG neurons of beta3-Tg mice revealed increased calcium channel currents, especially N- and L-type currents. These results identify a determining role for the beta3 subunit in the N-type channel population in SCG and a major role in sympathetic nerve regulation.

DOI PubMed

TRP channel and cardiovascular disease.

Hiroyuki Watanabe, Manabu Murakami, Takayoshi Ohba, Yoichiro Takahashi, Hiroshi Ito

Pharmacology & therapeutics   118 ( 3 ) 337 - 51   2008年06月  [査読有り]

研究論文（学術雑誌）  

The transient receptor potential (TRP) channel superfamily consists of 28 mammalian cation channels and is expressed in almost every tissue, including the heart and vasculature; most TRP channels are permeable to Ca(2+) and are prime molecular candidates for store-operated channels (SOCs), receptor-operated channels (ROCs), ligand-gated channels (LGCs) and stretch-activated channels (SACs). As these channels act as multifunctional cellular sensors and are involved in several fundamental cell functions such as contraction, proliferation and cell death, investigation of their roles in human disease is very important. This review presents an overview of current knowledge about the pathological role of TRP channels in cardiovascular diseases and highlights some TRP channels for which a role in the diseases can be anticipated. Evidences suggest that up-regulation of TRPC channels is involved in the development of cardiac hypertrophy and heart failure; TRPM4 participates in some features of cardiac arrhythmias; increased expression of TRPC channels is associated with vascular remodeling and pulmonary hypertension; reduced expression or activity of TRPV4 impairs endothelium-dependent vasorelaxation; TRPC3/C4 and TRPM2 act as endothelial redox sensors; and TRPC1, -C4, -C6, -V4, and -M2, have been implicated in endothelial barrier dysfunction. Ultimately, TRP channels will become important novel pharmacological targets for the treatment of human cardiovascular diseases.

DOI PubMed

Amlodipine inhibits cell proliferation via PKD1-related pathway.

Takayoshi Ohba, Hiroyuki Watanabe, Manabu Murakami, Milena Radovanovic, Kenji Iino, Masaru Ishida, Shinya Tosa, Kyoichi Ono, Hiroshi Ito

Biochemical and biophysical research communications   369 ( 2 ) 376 - 81   2008年05月  [査読有り]

研究論文（学術雑誌）  

Human coronary artery smooth muscle cell (hCASMC) proliferation is involved in the progression of coronary artery disease. Amlodipine, a widely used antihypertensive drug, exerts antiproliferative effects by increasing the expression of p21((Waf1/Cip1)). Polycystic kidney disease 1 (PKD1) is also involved in cell cycle inhibition via p21((Waf1/Cip1)) up-regulation. We clarified the involvement of PKD1-related signaling on hCASMCs. Cultured hCASMCs, which constitutively express PKD1, were stimulated with 5% serum. Amlodipine increased p21((Waf1/Cip1)) expression in a dose- and time-dependent manner, resulting in reduced hCASMC proliferation. The inhibitory effect of amlodipine was mimicked by overexpression of PKD1 and was reversed by a dominant-negative version of PKD1 (R4227X). Immunoblot analysis showed that phosphorylated JAK2 was increased by amlodipine treatment or PKD1 overexpression. A luciferase assay revealed that the overexpression of PKD1 induced STAT1 enhancer activity. These data suggest that PKD1 contributes to the antiproliferative effect of amlodipine on hCASMCs via JAK/STAT signaling and p21((Waf1/Cip1)) up-regulation.

DOI PubMed

Functional role of stromal interaction molecule 1 (STIM1) in vascular smooth muscle cells.

Yoichiro Takahashi, Hiroyuki Watanabe, Manabu Murakami, Kyoichi Ono, Yoshiko Munehisa, Takashi Koyama, Kiyoshi Nobori, Toshihiko Iijima, Hiroshi Ito

Biochemical and biophysical research communications   361 ( 4 ) 934 - 40   2007年10月  [査読有り]

研究論文（学術雑誌）  

We investigated the functional role of STIM1, a Ca(2+) sensor in the endoplasmic reticulum (ER) that regulates store-operated Ca(2+) entry (SOCE), in vascular smooth muscle cells (VSMCs). STIM1 was mainly localized at the ER and plasma membrane. The knockdown of STIM1 expression by small interfering (si) RNA drastically decreased SOCE. In contrast, an EF-hand mutant of STIM1, STIM1(E87A), produced a marked increase in SOCE, which was abolished by co-transfection with siRNA to transient receptor potential canonical 1 (TRPC1). In addition, transfection with siRNA against STIM1 suppressed phosphorylation of cAMP-responsive element binding protein (CREB) and cell growth. These results suggest that STIM1 is an essential component of SOCE and that it is involved in VSMC proliferation.

PubMed

Successful outcome in a pregnant woman with isolated noncompaction of the left ventricular myocardium.

Yoshiko Munehisa, Hiroyuki Watanabe, Toshimitsu Kosaka, Akinori Kimura, Hiroshi Ito

Internal medicine (Tokyo, Japan)   46 ( 6 ) 285 - 9   2007年06月  [査読有り]

研究論文（学術雑誌）  

A 24-year-old pregnant woman was referred to our hospital for the evaluation of her cardiac function. An electrocardiogram showed Wolff-Parkinson-White syndrome. Echocardiography revealed prominent trabeculation and deep intertrabecular recesses at the left ventricular apex and mid-portion of the inferior and lateral wall, with an impaired ejection fraction. She was diagnosed as having an isolated noncompaction of the ventricular myocardium (INVM). As the pregnancy progressed, severe restrictive hemodynamics became apparent. In consideration of the fetal growth, we decided to deliver the fetus by cesarean section at 32 weeks gestation; the patient successfully delivered a female infant. Interestingly, echocardiography demonstrated INVM in both the child and mother. This report is the first description of a successful pregnancy in a patient with familial INVM.

PubMed

Essential role of the N-terminus of murine Orai1 in store-operated Ca2+ entry.

Yoichiro Takahashi, Manabu Murakami, Hiroyuki Watanabe, Hitoshi Hasegawa, Takayoshi Ohba, Yoshiko Munehisa, Kiyoshi Nobori, Kyoichi Ono, Toshihiko Iijima, Hiroshi Ito

Biochemical and biophysical research communications   356 ( 1 ) 45 - 52   2007年04月  [査読有り]

研究論文（学術雑誌）  

Store-operated Ca(2+) entry (SOCE) is a physiologically important process that is triggered by intracellular Ca(2+) depletion. Recently, human Orai1 (the channel-forming subunit) and STIM1 (the calcium sensor) were identified as essential molecules for SOCE. Here, we report the cloning and functional analysis of three murine orthologs of Orai1, termed Orai1, 2, and 3. Among the genes identified, Orai1 contains a distinctive proline- and arginine-rich N-terminal cytoplasmic sequence. Co-expression of STIM1 with Orai1 produced a marked effect on SOCE, while co-expression with Orai2 or Orai3 had little effect. Expression of Orai1 without its N-terminal tail had a marginal effect on SOCE, while chimeric Orai2 containing the Orai1 N-terminus produced a marked increase in SOCE. In addition, a truncated version of Orai1 containing the N-terminus without the pore-forming transmembrane domain had a dominant negative effect on SOCE. These results reveal the essential role of Orai1 and its N-terminal sequence in SOCE.

PubMed

Modified sympathetic regulation in N-type calcium channel null-mouse.

Manabu Murakami, Takayoshi Ohba, Tsai-Wen Wu, Susumu Fujisawa, Takashi Suzuki, Yoichiro Takahashi, Eiki Takahashi, Hiroyuki Watanabe, Ichiro Miyoshi, Kyoichi Ono, Hironobu Sasano, Hiroshi Ito, Toshihiko Iijima

Biochemical and biophysical research communications   354 ( 4 ) 1016 - 20   2007年03月  [査読有り]

研究論文（学術雑誌）  

To elucidate the physiological importance of neuronal (N)-type calcium channels in sympathetic controls, we analyzed N-type channel-deficient (NKO) mice. Immunoprecipitation analysis revealed increased interaction between beta3 (a major accessory subunit of N-type channels) and R-type channel-forming CaV2.3 in NKO mice. R-R intervals in NKO ECG recordings were elongated and fluctuating, suggesting disturbed sympathetic tonus. N-type channel inhibitors elongated the R-R interval in control mice, whereas R-type channel blocking with SNX-482 significantly affected NKO but not control mice, indicating a compensatory role for R-type channels. Echocardiography and Langendorff heart analysis confirmed a major role for R-type channels in NKO mice. Combined, our biochemical and physiological analyses strongly suggest that the remaining sympathetic tonus in NKO mice is dependent on R-type calcium channels.

PubMed

Upregulation of TRPC1 in the development of cardiac hypertrophy

Ohba T， Watanabe H et. Al

JMCC   42 ( 3 ) 498 - 507   2007年03月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Involvement of transient receptor potential canonical 1 (TRPC1) in angiotensin II-induced vascular smooth muscle cell hypertrophy

Takahashi Y， Watanabe H et. Al

Atherosclerosis     2007年01月  [査読有り]

研究論文（学術雑誌）   国内共著

Regulatory role of neuron-restrictive silencing factor in expression of TRPC1.

Takayoshi Ohba, Hiroyuki Watanabe, Yoichiro Takahashi, Takashi Suzuki, Ichiro Miyoshi, Shinnsuke Nakayama, Eisaku Satoh, Kenji Iino, Hironobu Sasano, Yasuo Mori, Sadao Kuromitsu, Keiichi Imagawa, Yoshihiko Saito, Toshihiko Iijima, Hiroshi Ito, Manabu Murakami

Biochemical and biophysical research communications   351 ( 3 ) 764 - 70   2006年12月  [査読有り]

研究論文（学術雑誌）  

Neuron-restrictive silencer factor (NRSF) binds its consensus element to repress the transcription of various genes. The dominant-negative form (dnNRSF) has a hypertrophic effect on cardiogenesis through an unidentified mechanism. We examined the involvement of transient receptor potential (TRP) channel proteins, using transgenic mice overexpressing dnNRSF (dnNRSF mice). Electrophoretic mobility-shift assays revealed an interaction between NRSF and a neuron-restrictive silencer element-like sequence in intron 4 of TRPC1 genomic DNA. According to RT-PCR and Western analyses, TRPC1 was up-regulated in dnNRSF mouse heart. Transient overexpression of TRPC1 in HEK 293T cells increased the activity of the nuclear factor in activated T cells (NFAT) promoter and stimulated store-operated Ca(2+) channel (SOCC)-mediated Ca(2+) entry. Transfection of TRPC1 into primary cardiomyocytes increased NFAT activity, indicating a major role for TRPC1 in NFAT activation. Our findings strongly suggest that NRSF regulates TRP1 gene expression and causes changes in the levels of calcium entry through SOCCs.

PubMed

Identification of a cardiac isoform of the murine calcium channel alpha1C (Cav1.2-a) subunit and its preferential binding with the beta2 subunit.

Manabu Murakami, Takayoshi Ohba, Yoichiro Takahashi, Hiroyuki Watanabe, Ichiro Miyoshi, Shinsuke Nakayama, Kyoichi Ono, Hiroshi Ito, Toshihiko Iijima

Journal of molecular and cellular cardiology   41 ( 1 ) 115 - 25   2006年07月  [査読有り]

研究論文（学術雑誌）  

We describe a cardiac muscle isoform of the voltage-dependent calcium channel alpha1 subunit, which corresponds to the rabbit ortholog of alpha1C-a (Cav1.2a). We also cloned smooth muscle isoforms alpha1C-b (Cav1.2b) and alpha1C-d (Cav1.2d). Differences among these three isoforms lie within the N-terminal region (exon 1A or 1B), the sixth transmembrane segment of domain I (exon 8A or 8B), and the use of exon 10, which forms the intracellular loop between transmembrane domains I and II. Two-hybrid analysis revealed interactions among the three alpha1 isoforms and beta subunits. In vitro overlay and immunoprecipitation analyses revealed preferential binding between alpha1C-a and beta2, which is also expressed at a high level in the heart.

PubMed

Increased expression of transient receptor potential C1 in rats with hypertensive hypertrophy

Takayoshi Ohba, Hiroyuki Watanabe, Manabu Murakami,Yoichiro Tkahashi,Hiroshi Ito

秋田医学   32   201 - 207   2006年03月  [査読有り]

研究論文（学術雑誌）  

The effect of Unoprostone on store operated Ca entry in human aortic smooth muscle cells

Watanabe Akiko, Watanabe Hiroyuki, Ono Kyoichi, Ohba Takayoshi, Murakami Manabu, Hasegawa Hitoshi, Sasaki Masahiro, Iijima Toshihiko, Yoshitomi Takeshi, Ito Hiroshi

秋田医学   32 ( 1 ) 7 - 14   2005年05月  [査読有り]

研究論文（学術雑誌）  

Genomic organization and functional analysis of murine PKD2L1.

Manabu Murakami, Takayoshi Ohba, Feng Xu, Seiji Shida, Eisaku Satoh, Kyoichi Ono, Ichiro Miyoshi, Hiroyuki Watanabe, Hiroshi Ito, Toshihiko Iijima

The Journal of biological chemistry   280 ( 7 ) 5626 - 35   2005年02月  [査読有り]

研究論文（学術雑誌）  

Mutations in genes that encode polycystins 1 or 2 cause polycystic kidney disease (PKD). Here, we report the genomic organization and functional expression of murine orthologue of human polycystin-2L1 (PKD2L1). The murine PKD2L1 gene comprises 15 exons in chromosome 19C3. Coexpression of PKD2L1 together with polycystin-1 (PKD1) resulted in the expression of PKD2L1 channels on the cell surface, whereas PKD2L1 expressed alone was retained within the endoplasmic reticulum (ER). This suggested that interaction between PKD1 and PKD2L1 is essential for PKD2L1 trafficking and channel formation. Deletion analysis at the cytoplasmic tail of PKD2L1 revealed that the coiled-coil domain was important for trafficking by PKD1. Mutagenesis within two newly identified ER retention signal-like amino acid sequences caused PKD2L1 to be expressed at the cell surface. This indicated that the coiled-coil domain was responsible for retaining PKD2L1 within the ER. Functional analysis of murine PKD2L1 expressed in HEK 293 cells was undertaken using calcium imaging. Coexpression of PKD1 and PKD2L1 resulted in the formation of functional cation channels that were opened by hypo-osmotic stimulation, whereas neither molecule formed functional channels when expressed alone. We conclude that PKD2L1 forms functional cation channels on the plasma membrane by interacting with PKD1. These findings raise the possibility that PKD2L1 represents the third genetic locus that is responsible for PKD.

PubMed

Low Molecular Weight Heparin Prevents Cardiovascular Remodeling Induced by the Long-Term Inhibition of Nitric Oxide Synthase with N-Nitro-L-Arginine Methyl Ester in Rat Hearts

HASEGAWA Hitoshi,SAITO Takashi,FUJIWARA Yoshimasa,KUROKAWA Fukiko,WATANABE hiroyuki

秋田医学   31   221 - 230   2004年12月  [査読有り]

研究論文（学術雑誌）  

To evaluate the effect of low molecular weight heparin (LMWH) oncardiovascular remodeling induced by long term inhibition of nitric oxide synthase withN-nitro-L-arginine methyl ester (L-NAME), 40 male Sprague-Dawley rats were randomlydivided into four groups: the control group (n=10) that received 0.9% saltsolution; the L-NAME group (n=10) that received 30 mg/kg/day of L-NAME, theLMWH3000 group (n=10) that received 30 mg/kg/day of L-NAME and 4 mg/kg/dayof LMWH (molecular weight (M.W.) of 3000) and the LMWH6000 group (n= 10)that received 30 mg/kg/day of L-NAME and 4 mg/kg/day of LMWH (M.W. 6000).All agents, including saline, were administered intraperitoneally by implantation ofosmotic mini pumps. Systolic blood pressure was measured by the tail-cuff method ontreatment days 1,7, 14, and 28, and histological examination of harvested cardiac tissueand coronary arteries was performed on day 28. Systolic blood pressure was greater inthe L-NAME, LMWH3000 and LMWH6000 groups when compared with the controlgroup. There were no significant differences in activated coagulation time (ACT)when comparing the four groups. Medial smooth muscle cell proliferation and hypertrophyand increases in perivascular and myocardial fibrosis were observed in the L-NAMEgroup compared with the control group. Further, these changes were inhibited by thecoadministration of LMWH3000 or LWMH6000. This study demonstrates that LMWHprevents cardiovascular remodeling induced by L-NAME in rat hearts independent of itsanticoagulant activity. Low molecular weight heparin prevents cardiovascular remodeling

Determinants of severity in dilated cardiomyopathy: The gap of tricuspid and mitral valve opening

IZUMI Manabu,KIBIRA Satoshi,WATANABE Hiroyuki,TSUYA Hiroyuki

秋田医学   31   201 - 209   2004年12月  [査読有り]

研究論文（学術雑誌）  

Objectives: The purpose of this study is to analyze factors that influence the gap of
opening timing between the mitral valve (MV) and the tricuspid valve (TV) in
patients with dilated cardiomyopathy (DCM).
Background: The DCM patients with heart failure often show shorter left ventricular
(LV) isovolumic relaxation time (IRT) and longer right ventricular (RV) IRT, which
may influence the gap of opening timing between TV and MV.
Method: We evaluated consecutive 34 patients with DCM. The time between QRS
initial and TV opening (Q-T time), and that between QRS initial and MV opening (QM
time) were measured by pulsed Doppler recording of each ventricular inflow. The
time interval between MV and TV opening (M-T time) was determined by subtracting
Q-M time from Q-T time. In addition, the other Doppler time intervals including preejectional
period, ejection time, IRT were determined. We analyzed the relation
between Doppler time intervals and factors including NYHA classification and rightsided
cardiac pressure.
Result: There is significant relationship (p <0.001) between M-T time and PCWP
(r=0.65), and NYHA (rs=0.67), respectively. The Ll IRT determined by subtraction
of LV IRT from RV IRT, correlated significantly with M-T time (r=0.83, p<O.OOl),
however, the difference between LV and RV in PEP and ET did not correlated
significantly with M-T time.
Conclusion: The gap of opening timing between TV and MV, determined as M-T time,
correlates strongly with LlIRT and also the severity of congestive heart failure in DCM
patients.

Cell swelling， heat and chemical agonists use distinet pathways for the activation of the cation channel TRPV4

Vriens J， Watanabe H et. Al

Proc Natl Acad Sci USA 2004   101 ( 1 ) 396 - 401   2004年01月  [査読有り]

研究論文（学術雑誌）   国内共著

Reduction of ST elevation in repeated coronary occlusion model depends on both altered metabolic response and conduction property.

Takashi Saito, Hiroto Miura, Yutaka Kimura, Hiroyuki Watanabe, Akira Nakagomi, Yoshikazu Tamura, Hitoshi Hasegawa, Satoshi Kibira, Mamoru Miura

International journal of cardiology   92 ( 2-3 ) 219 - 27   2003年12月  [査読有り]

研究論文（学術雑誌）  

The aim of this study was to elucidate the mechanisms of altered electrical response to ischemia in repeated coronary occlusion model. To test its dependence on metabolic response, extracellular K+ concentration (eKC), myocardial pH and PCO2 were simultaneously measured with epicardial ECG during three consecutive 4 min of left anterior descending coronary artery (LAD) occlusion separated by 15 min of reperfusion in canine hearts. ECG changes induced by infusion of high K+-buffer (10 mM) into the coronary arterial bed via carotid artery-LAD bypass (referred to as high K+-challenges: HKC) were also tested prior to (the first HKC), and during each reperfusion period (the second to the fourth HKC). ST elevation was significantly reduced in subsequent occlusions (3.14 +/- 0.48 and 2.98 +/- 0.47 mV in the second and third occlusion, both P<0.05, compared to 4.91 +/- 0.78 mV in the first). This was accompanied by significant attenuation of the changes in eKC, tissue pH and PCO2. ST elevation induced by HKC also significantly reduced after repeated occlusion (4.09 +/- 0.79 mV in the fourth HKC vs. 5.64 +/- 0.68 mV in the first, P<0.05) in spite of the identical changes in eKC during HKC. This progressive decrease in ST changes by HKC was rather consistent with augmented conduction delay (86.4 +/- 7.1% increase in activation time in the fourth vs. 54.3 +/- 3.4% in the first, P<0.01). These findings indicate that repeated ischemia induces altered electrical response to subsequent ischemia based on both attenuated metabolic response and altered conduction property.

PubMed

Pitavastatin inhibits upregulation of intermediate conductance calcium-activated potassium channels and coronary arteriolar remodeling induced by long-term blockade of nitric oxide synthesis.

Yutaka Terata, Takashi Saito, Yoshimasa Fujiwara, Hitoshi Hasegawa, Hiroto Miura, Hiroyuki Watanabe, Yoshikatsu Chiba, Satoshi Kibira, Mamoru Miura

Pharmacology   68 ( 4 ) 169 - 76   2003年08月  [査読有り]

研究論文（学術雑誌）  

UNLABELLED: We have reported that intermediate conductance Ca(2+)-activated K(+) channels (ImK) showed augmented expression in angiotensin II (AII) type 1 receptor-dependent manner in post-ischemic rat heart. ImK has tyrosine phosphorylation sequence in the C-terminus and motifs for NFkappaB and AP1 in the promoter. While statin inhibits AII-mediated vascular remodeling via anti-inflammatory effect independent of cholesterol lowering. To test the possible effect of statin on expression of ImK, Wistar-Kyoto rats received L-nitro-arginine methyl ester (LNAME: 1 mg/ml in drinking water) for 4 weeks in group L. While in L+P group, rats received both LNAME and pitavastatin (PTV: 1 mg/kg/day in drinking water). Temporal profile of ImK mRNA was examined by RT-PCR using specific primers for ImK. RESULTS: Long-term LNAME administration produced significant hypertension and resulted in marked microvascular remodeling characterized by medial thickening and perivascular fibrosis of coronary arterioles (100-200 microm in diameter). RT-PCR revealed significant up-regulation of ImK mRNA with two distinct peaks in L group in the early phase (days 3-7) and the late phase (4 weeks). PTV partially inhibited a rise in systolic blood pressure, but completely abolished the first peak of ImK upregulation (0.76 +/- 0.04 vs. 3.96 +/- 1.43 folds at day 7, p < 0.001). Co-treatments with PTV also significantly inhibited medial thickening and perivascular fibrosis. These findings indicate that statin inhibits microvascular remodeling induced by chronic inhibition of NO synthesis through the action independent of cholesterol lowering.

PubMed

The TRPV4 channel: structure-function relationship and promiscuous gating behaviour.

Bernd Nilius, Hiroyuki Watanabe, Joris Vriens

Pflugers Archiv : European journal of physiology   446 ( 3 ) 298 - 303   2003年06月  [査読有り]

研究論文（学術雑誌）  

Transient receptor potential (TRP) channels provide an enormous variability of Ca(2+) influx mechanisms triggered by a wide range of stimuli. In this review, we discuss the activation properties of the Ca(2+)- and Mg(2+)-permeable TRP channel of the vanilloid subfamily TRPV4. This channel is activated by various physical and chemical stimuli, such as cell swelling, heat, phorbols and, probably, by endogenous ligands, which are able to induce Ca(2+) entry. Not much is known about the regulation of this channel. We will refer only to a mechanism of Ca(2+)-dependent inhibition of TRPV4. Possible functional roles of this channel will be correlated with its observed expression pattern. Finally, we discuss the structural determinants of TRPV4 channel function.

PubMed

Modulation of TRPV4 gating by intra- and extracellular Ca2+.

Hiroyuki Watanabe, Joris Vriens, Annelies Janssens, Robert Wondergem, Guy Droogmans, Bernd Nilius

Cell calcium   33 ( 5-6 ) 489 - 95   2003年05月  [査読有り]

研究論文（学術雑誌）  

We have studied the modulation of gating properties of the Ca2+-permeable, cation channel TRPV4 transiently expressed in HEK293 cells. The phorbol ester 4alphaPDD transiently activated a current through TRPV4 in the presence of extracellular Ca2+. Increasing the concentration of extracellular Ca2+ ([Ca2+](e)) reduced the current amplitude and accelerated its decay. This decay was dramatically delayed in the absence of [Ca2+](e). It was also much slower in the presence of [Ca2+](e) in a mutant channel, obtained by a point mutation in the 6th transmembrane domain, F707A. Mutant channels, containing a single mutation in the C-terminus of TRPV4 (E797), were constitutively open. In conclusion, gating of the 4alphaPDD-activated TRPV4 channel depends on both extra- and intracellular Ca2+, and is modulated by mutations of single amino acid residues in the 6th transmembrane domain and the C-terminus of the TRPV4 protein.

PubMed

TNF-alpha rapidly antagonizes the beta-adrenergic responses of the chloride current in guinea-pig ventricular myocytes.

Kenji Iino, Hiroyuki Watanabe, Takashi Saito, Satoshi Kibira, Toshihiko Iijima, Mamoru Miura

Circulation journal : official journal of the Japanese Circulation Society   67 ( 4 ) 347 - 53   2003年04月  [査読有り]

研究論文（学術雑誌）  

The purpose of this study was to test the hypothesis that tumor necrosis factor-alpha (TNF-alpha) rapidly antagonizes the beta-adrenergic responses of the chloride current and to clarify the intracellular mechanisms responsible for the anti-adrenergic action. The whole-cell patch-clamp technique was used to monitor the anti-adrenergic effects of TNF-alpha on the cAMP-dependent chloride current (I(Cl)) recorded from isolated guinea-pig ventricular myocytes. Ramp pulses (+/-120 mV; dv/dt = +/-0.4 V/s) were applied from the holding potential of -40 mV. TNF-alpha rapidly (<15 min) inhibited the isoproterenol (Iso, 0.1 micromol/L)-induced I(Cl) in a concentration-dependent manner (30-1,000 U/ml, IC (50) = 144 U/ml, n=30). The inhibitory action of TNF-alpha was also observed when I(Cl) had been previously stimulated by 1 micromol/L forskolin (n=5). Prior exposure of myocytes to 5 microg/ml pertussis toxin (PTX) hardly affected the anti-adrenergic action of TNF-alpha (n=4). However, when I(Cl) was induced by both 8-bromo-cAMP (100 micromol/L) and isobutylmethylxanthine (0.1 mmol/L), TNF-alpha (1,000 U/ml) failed to decrease I(Cl) amplitude (n=5). Prior exposure of myocytes to 5 mg/ml pertussis toxin (PTX) hardly affected the anti-adrenergic action of TNF-alpha (n=4). Furthermore, despite of the presence of nitro-L-arginine methyl ester (0.1 mmol/L), a nitric oxide synthase (NOS) inhibitor, TNF-alpha reversed the Iso-induced increase in I(Cl) (n=5). These results suggest that TNF-alpha rapidly antagonizes the beta-adrenergic responses of I(Cl) by reducing cAMP concentration. This anti-adrenergic action is mediated by neither the PTX-sensitive G proteins regulatory pathway nor constitutive NOS activation.

PubMed

Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels

Watanabe H et. Al

Nature   424 ( 6947 ) 434 - 438   2003年01月  [査読有り]

研究論文（学術雑誌）   国内共著

Beneficial effect of dual-chamber pacing for a left mid-ventricular obstruction with apical aneurysm.

Hiroyuki Watanabe, Satoshi Kibira, Takashi Saito, Hiroshi Shimizu, Toyohiko Abe, Ichirota Nakajima, Kenji Iino, Mamoru Miura

Circulation journal : official journal of the Japanese Circulation Society   66 ( 10 ) 981 - 4   2002年10月  [査読有り]

研究論文（学術雑誌）  

Sustained ventricular tachycardia (VT) developed in a 63-year-old woman. The 2-dimensional echocardiogram revealed left mid-ventricular obstructive hypertrophy and a discrete apical chamber. A continuous wave Doppler signal across the mid-ventricular narrowing exhibited early systolic ejection flow and diastolic paradoxical jet flow from the apex to the basal chamber, implying a significant systolic and diastolic intraventricular gradient with a high apical pressure. The left ventriculogram confirmed a mid-ventricular obstruction with an apical aneurysm. Invasive assessment of intraventricular pressure showed a peak-to-peak gradient greater than 100 mmHg. Treatment with antiarrhythmic agents could not prevent the VT, but dual-chamber pacing reduced the intraventricular pressure gradient and suppressed the VT completely. Continuous wave Doppler showed that the early systolic ejection flow from the apex had disappeared, that there was isovolumetric relaxation flow toward the apex and that there was attenuation of the diastolic paradoxical jet flow toward the basal chamber. Such findings by continuous wave Doppler can be useful in pacing therapy for evaluating changes in the severity of mid-ventricular obstruction.

PubMed

Molecular determinants of permeation through the cation channel TRPV4.

Thomas Voets, Jean Prenen, Joris Vriens, Hiroyuki Watanabe, Annelies Janssens, Ulrich Wissenbach, Matthias Bödding, Guy Droogmans, Bernd Nilius

The Journal of biological chemistry   277 ( 37 ) 33704 - 10   2002年09月  [査読有り]

研究論文（学術雑誌）  

We have studied the molecular determinants of ion permeation through the TRPV4 channel (VRL-2, TRP12, VR-OAC, and OTRPC4). TRPV4 is characterized by both inward and outward rectification, voltage-dependent block by Ruthenium Red, a moderate selectivity for divalent versus monovalent cations, and an Eisenman IV permeability sequence. We identify two aspartate residues, Asp(672) and Asp(682), as important determinants of the Ca(2+) sensitivity of the TRPV4 pore. Neutralization of either aspartate to alanine caused a moderate reduction of the relative permeability for divalent cations and of the degree of outward rectification. Neutralizing both aspartates simultaneously caused a much stronger reduction of Ca(2+) permeability and channel rectification and additionally altered the permeability order for monovalent cations toward Eisenman sequence II or I. Moreover, neutralizing Asp(682) but not Asp(672) strongly reduces the affinity of the channel for Ruthenium Red. Mutations to Met(680), which is located at the center of a putative selectivity filter, strongly reduced whole cell current amplitude and impaired Ca(2+) permeation. In contrast, neutralizing the only positively charged residue in the putative pore region, Lys(675), had no obvious effects on the properties of the TRPV4 channel pore. Our findings delineate the pore region of TRPV4 and give a first insight into the possible architecture of its permeation pathway.

PubMed

L-nitro-arginine inhibits increase in endothelin binding sites induced by ischemia and reperfusion.

Takashi Saito, Etsuko Fushimi, Toshiko Tamura, Yoshimasa Fujiwara, Hiroto Miura, Hiroyuki Watanabe, Satoshi Kibira, Hitoshi Hasegawa, Mamoru Miura

Journal of molecular and cellular cardiology   34 ( 8 ) 1041 - 7   2002年08月  [査読有り]

研究論文（学術雑誌）  

We have demonstrated that ischemia and reperfusion promoted augmented contractile response to endothelin-1 (ET) in coronary arteries in the presence of polymorphonuclear leukocytes (PMN). It has been also reported that ischemia and reperfusion increase ET binding sites in cardiac membrane in isolated rat heart perfused by blood cell-free system. To determine the role of PMN and L-arginine to nitric oxide (NO) pathway in these phenomena, isolated perfused rabbit hearts were subjected to 30 min of global ischemia followed by 30 min of reflow in the absence or presence of PMN and 10(-5)M of L-nitro-arginine (LNA). PMN was prepared with Percoll density gradients from peritoneal exudate elicited by glycogen. PMN activated with 10(-6)M of phorbol myristate acetate or their supernatant were infused into the coronary perfusion circuit after 5 min of reflow. LNA was added to perfusate also after reflow. The effect of superoxide dismutase (SOD: 50 IU/ml) was also determined. After the end of protocols, membrane fraction was isolated from the hearts for (125)I-ET-1 binding assay. ET-1 binding (Bmax) showed a significant increase by ischemia and reperfusion (P<0.01 vs control). That was markedly augmented with addition of activated PMN or their supernatant (both P<0.01), but abolished either by LNA or SOD (P<0.01 and P<0.05, respectively). These results indicate that increase in ET-receptor by ischemia and reperfusion is mediated by free radicals generated via L-arginine to NO pathway.

PubMed

The intracellular tyrosine residues of the ATP-gated P2X(1) ion channel are essential for its function.

Emese Toth-Zsamboki, Cecile Oury, Hiroyuki Watanabe, Bernd Nilius, Jos Vermylen, Marc F Hoylaerts

FEBS letters   524 ( 1-3 ) 15 - 9   2002年07月  [査読有り]

研究論文（学術雑誌）  

The four highly conserved intracellular tyrosine residues of the P2X(1) ion channel were mutated into phenylalanine. Simultaneous electrophysiological and calcium measurements in transfected human embryonic kidney (HEK 293) cells indicated that Y362F and Y370F mutants were non-functional, despite their proper plasma membrane expression. The Y16F and Y363F mutants retained 2.2% and 26% of the wild-type P2X(1) activity, respectively. However, no tyrosine phosphorylation was detected on Western blots of P2X(1) immunoprecipitates derived either from HEK 293 cell lysates or from human platelets, expressing P2X(1) endogenously. Thus, Y16, Y362, Y363 and Y370 are required for the appropriate three-dimensional structure and function of the intracellular P2X(1) domains.

PubMed

ATP and nitric oxide modulate a Ca(2+)-activated non-selective cation current in macrovascular endothelial cells.

Suk H Suh, Hiroyuki Watanabe, Guy Droogmans, Bernd Nilius

Pflugers Archiv : European journal of physiology   444 ( 3 ) 438 - 45   2002年06月  [査読有り]

研究論文（学術雑誌）  

We have studied the properties of a non-selective cation current (NSC(Ca)) in macrovascular endothelial cells derived from human umbilical vein (EA cells) that is activated by an increase of intracellular Ca(2+) concentration, [Ca(2+)](i). Current-voltage relationships are linear and the kinetics of the current is time-independent. Current-[Ca(2+)](i) relationships were fitted to a Ca(2+) binding site model with a concentration for half-maximal activation of 417 +/- 76 nM, a Hill coefficient of 2.3 +/- 0.8 and a maximum current of -23.9 +/- 2.7 pA/pF at -50 mV. The Ca(2+)-activated channel is more permeable to Na(+) than for Cs(+) ( P(Cs)/ P(Na)=0.58, n=7), but virtually impermeable to Ca(2+). Current activation was transient if ATP was omitted from the pipette solution. The maximal currents at 300 and 500 nM [Ca(2+)](i) were smaller than in the absence of ATP, but were not significantly different at 2 microM. The intracellular Ca(2+) concentration for half-maximal activation of the Ca(2+)-activated current was shifted to 811 +/- 12 nM in the absence of ATP. Substitution of ATP by the non-hydrolysable ATP analogue adenylylimidodiphosphate (AMP-PNP) did not affect current activation. Sodium nitroprusside (SNP) decreased NSC(Ca) in a concentration-dependent manner. The nitric oxide (NO) donors S-nitroso- N-acetylpenicillamine (SNAP) and 3-morpholinosydnonimine (SIN-1) also inhibited NSC(Ca). In contrast, nitro- L-arginine (NLA), which inhibits all NO-synthases, potentiated NSC(Ca), whereas superoxide dismutase (SOD), which inhibits the breakdown of NO, inhibited NSC(Ca). It is concluded that the Ca(2+)-activated non-selective action channel in EA cells is modulated by the metabolic state of the cell and by NO.

PubMed

Ca2+ overload evokes a transient outward current in guinea-pig ventricular myocytes.

Ichirota Nakajima, Hiroyuki Watanabe, Kenji Iino, Takashi Saito, Mamoru Miura

Circulation journal : official journal of the Japanese Circulation Society   66 ( 1 ) 87 - 92   2002年01月  [査読有り]

研究論文（学術雑誌）  

There are 2 types of transient outward currents (Ito) in the hearts of various mammals: a 4-aminopyridine (4-AP) sensitive K+ current and a 4-AP resistant Ca2+ activated current, carried by Cl-, (referred to as I(to1) and I(to2), respectively). However, the I(to) has been considered to be absent in guinea-pig ventricular myocytes and so this study tested the hypothesis that I(to1) is generally absent in guinea-pig ventricular myocytes, but I(to2) appears under the condition of Ca2+ overload. Membrane currents were recorded by the whole-cell patch-clamp technique and Ca2+ overload was achieved by adding internal, and eliminating external, Na+ with subsequent enhancement of Ca2+ influx via the Na+-Ca2+ exchange. Under physiological conditions, I(to) could not be elicited by 300 ms-test pulse from -70 mV to 0 mV (n=32). However, under Ca2+ overload, a biphasic current resulting from the overlap of the L-type Ca2+ channel current and Ito was elicited (n=38). This I(to) was resistant to 4-AP (3 mmol/L, n=30) but sensitive to both anthrancene-9-carboxylic acid (9-AC, 3 mmol/L, n=8) and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (100 micromol/L, n=3). Replacing K+ with Cs+ on both sides of the membrane failed to abolish I(to) (n=38). I(to) disappeared by lowering the external Cl- (n=3). The amplitude of I(to) was dependent on that of the L-type Ca2+ channel current (n=4). Because Ca2+ release from the sarcoplasmic reticulum was prevented by caffeine (5 mmol/L), I(to) was negligible (n=6). These results suggest that I(to1) is absent, but Ca2+ overload evokes I(to2) in guinea-pig ventricular myocytes.

PubMed

Activation of TRPV4 channels(hVRL2/mTRP12) by phorbol derivatives.

Watanabe H et. Al

J Biol Chem   277 ( 16 ) 13569 - 13577   2002年01月  [査読有り]

研究論文（学術雑誌）   国内共著

Heat-evoked activation of TRPV4 channels in a HEK293 cell expression system and in native mouse aorta endothelial cells.

Watanabe H et. al

J Biol Chem   277 ( 49 ) 47044 - 47051   2002年01月  [査読有り]

研究論文（学術雑誌）   国内共著

CaT1 and the Calcium Release-activated Calcium Channel Manifest Distinct Pore Properties

Thomas Voets, Jean Prenen, Andrea Fleig, Rudi Vennekens, Hiroyuki Watanabe, Joost G.J. Hoenderop,René J.M. Bindels,Guy Droogmans, Reinhold Penner, Bernd Nilius

JOURNAL OF BIOLOGICAL CHEMISTRY   276 ( 51 ) 47767 - 47770   2001年12月  [査読有り]

研究論文（学術雑誌）  

The calcium release-activated calcium channel (CRAC) is a highly Ca2+-selective ion channel that is activated on depletion of inositol triphosphate (IP3)-sensitive intracellular Ca2+ stores. It was recently reported that CaT1, a member of the TRP family of cation channels, exhibits the unique biophysical properties of CRAC, which led to the conclusion that CaT1 comprises all or part of the CRAC pore (Yue, L., Peng, J. B., Hediger, M. A., and Clapham, D. E. (2001) Nature 410, 705–709). Here, we directly compare endogenous CRAC with heterologously expressed CaT1 and show that they manifest several clearly distinct properties. CaT1 can be distinguished from CRAC in the following features: sensitivity to store-depleting agents; inward rectification in the absence of divalent cations; relative permeability to Na+ and Cs+; effect of 2-aminoethoxydiphenyl borate (2-APB). Moreover, CaT1 displays a mode of voltage-dependent gating that is fully absent in CRAC and originates from the voltage-dependent binding/unbinding of Mg2+ inside the channel pore. Our results imply that the pores of CaT1 and CRAC are not identical and indicate that CaT1 is a Mg2+-gated channel not directly related to CRAC.

DOI

Congestive Heart Failure Associated with Portasystemic Shunt by Small-Bowel Varices

KIBIRA Satoshi, ISHIDA Hideaki, WATANABE Hiroyuki, IZUMI Chikako, OOMOTO Naoki, OGAWA Yasuhiko, SAITO Takashi, MIURA Mamoru

日本臨床生理学会雑誌   30 ( 1 ) 59 - 64   2000年02月  [査読有り]

研究論文（学術雑誌）  

Validity of the right ventricular Doppler index for assessment of severity of congestive heart failure in patients with dilated cardiomyopathy

C Izumi

Heart and vessels   14 ( 5 ) 232 - 239   1999年09月  [査読有り]

研究論文（学術雑誌）  

DOI

Calcium channel blocking properties of NKY-722, a highly hydrophilic dihydropyridine derivative, in single ventricular cells of guinea-pig hearts

Watanabe H, Nishio M, Iijima T

Japanese Heart Journal   35   451 - 452   1994年  [査読有り]

研究論文（学術雑誌）