Research activity information

• Stress-induced stenotic vascular remodeling via reduction of plasma omega-3 fatty acid metabolite 4-oxoDHA by noradrenaline.

  Makoto Nishimori, Naomi Hayasaka, Kazunori Otsui, Nobutaka Inoue, Junko Asakura, Manabu Nagao, Ryuji Toh, Tatsuro Ishida, Ken-Ichi Hirata, Tomoyuki Furuyashiki, Masakazu Shinohara

  Stress has garnered significant attention as a prominent risk factor for inflammation-related diseases, particularly cardiovascular diseases (CVDs). However, the precise mechanisms underlying stress-driven CVDs remain elusive, thereby impeding the development of preventive and therapeutic strategies. To explore the correlation between plasma lipid metabolites and human depressive states, liquid chromatography-mass spectrometry (LC/MS) based analysis of plasma and the self-rating depression (SDS) scale questionnaire were employed. We also used a mouse model with restraint stress to study its effects on plasma lipid metabolites and stenotic vascular remodeling following carotid ligation. In vitro functional and mechanistic studies were performed using macrophages, endothelial cells, and neutrophil cells. We revealed a significant association between depressive state and reduced plasma levels of 4-oxoDHA, a specific omega-3 fatty acid metabolite biosynthesized by 5-lipoxygenase (LO), mainly in neutrophils. In mice, restraint stress decreased plasma 4-oxoDHA levels and exacerbated stenotic vascular remodeling, ameliorated by 4-oxoDHA supplementation. 4-oxoDHA enhanced Nrf2-HO-1 pathways, exerting anti-inflammatory effects on endothelial cells and macrophages. One of the stress hormones, noradrenaline, reduced 4-oxoDHA and the degraded 5-LO in neutrophils through the proteasome system, facilitated by dopamine D2-like receptor activation. Our study proposed circulating 4-oxoDHA levels as a stress biomarker and supplementation of 4-oxoDHA as a novel therapeutic approach for controlling stress-related vascular inflammation.

  Feb. 2024, Scientific reports, 14(1) (1), 4178 - 4178, English, International magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Investigations into the Pathomechanism of thrombotic Disorders with an Ex Vivo Global Test Performed from Non-Anticoagulated Blood: From Animal Experiments to Bedside Application

  Junichiro Yamamoto, Wataru Shioyama, Hideo Ikarugi, Yoshinobu Ijiri, Muneshige Shimizu, Tomoya Takashima, Hiroyuki Kikukawa, Masahiro Murakami, Kazunori Otsui, Jaap Jan Zwaginga, Kjell S Sakariassen

  Acta Scientific Publications Pvt. Ltd., Jul. 2023, Acta Scientifci Nutritional Health, 7(7) (7), 119 - 127, English

  [Refereed][Invited]

  Scientific journal


• Glucocorticoid in Combination with a TNF-α Inhibitor: Treatment of Deep Vein Thrombosis in a Patient with Behçet's Disease.

  Mitsumasa Okano, Katsuhiko Yoneda, Yoshihide Ichise, Sentaro Kusuhara, Naokazu Muramae, Kenta Mori, Kazunori Otsui, Kazuhiko Sakaguchi

  A 38-year-old man with deep vein thrombosis associated with Behçet's disease (BD) was admitted to our hospital due to worsening symptoms despite the initiation of direct oral anticoagulants (DOACs). Administration of oral prednisolone and an intravenous anti-tumor necrosis factor-alpha (TNF-α) monoclonal antibody dramatically improved his symptoms. In addition, he was incidentally diagnosed with autosomal dominant polycystic kidney disease, which increases the risk of aortic aneurysms. BD also increases the risk of aortic aneurysms. This case suggests that immunosuppressive treatment is effective in patients with inflammation-related DOAC-refractory venous thrombosis who also suffer from BD.

  Jul. 2023, Internal medicine (Tokyo, Japan), 62(13) (13), 2009 - 2012, English, Domestic magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Distinct hypoglycemic effect of different formulations of a fixed ratio of basal insulin plus glucagon-like peptide-1 receptor agonist in a patient with pancreatic diabetes.

  Tomoko Yamada, Shun-Ichiro Asahara, Maki Kimura-Koyanagi, Yoshikazu Tamori, Naokazu Muramae, Kenta Mori, Mitsumasa Okano, Kazunori Otsui, Kazuhiko Sakaguchi

  UNLABELLED: Fixed-ratio combination injection therapy (FRC) is a fixed-ratio mixture containing basal insulin and glucagon-like peptide-1 receptor agonist (GLP-1 RA) in a single injection for the treatment of patients with type 2 diabetes. The two types of FRC products contain different concentrations and mixing ratios of basal insulin and GLP-1 RA. Both products demonstrated satisfactory blood glucose control throughout the day, with less hypoglycemia and weight gain. However, few studies have examined the differences in the actions of the two formulations. Herein, we present a case of a 71-year-old man with pancreatic diabetes and significantly impaired intrinsic insulin secretion capacity, who demonstrated a marked difference in glycemic control following treatment with two different FRC formulations. Treatment with IDegLira, an FRC product, demonstrated suboptimal glucose control in the patient. However, after a change in therapy to another FRC product, IGlarLixi, his glucose control markedly improved, even with a decrease in the injection dose. This difference could have been due to lixisenatide, a short-acting GLP-1RA contained in IGlarLixi, which exerts a postprandial hypoglycemic effect irrespective of intrinsic insulin secretion capacity. In conclusion, IGlarLixi has the potential to achieve good fasting and postprandial glucose control with a once-daily injection, even in patients with type 2 diabetes who have a reduced intrinsic insulin secretion capacity. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13340-023-00621-5.

  Jul. 2023, Diabetology international, 14(3) (3), 294 - 297, English, Domestic magazine


• Panhypopituitarism Mimicking Acute Coronary Syndrome.

  Yoshito Sugi, Kenta Mori, Takashi Kobayashi, Naoki Arai, Mitsumasa Okano, Naokazu Muramae, Toshihiko Oshita, Kazunori Otsui, Kazuhiko Sakaguchi

  A 59-year-old man suspected of having myocardial infarction with sinus bradycardia, a decreased blood pressure, and ST-change on an electrocardiogram was referred to our hospital's emergency department. Emergent coronary angiography revealed no significant findings. However, the patient experienced shock and required intensive care. Curiosity rose when his urination volume was not disturbed; we suspected hormonal abnormalities. A hormonal examination and imaging analysis revealed panhypopituitarism caused by a Rathke's cyst. Appropriate hormonal replacement therapy improved his symptoms and led to normalization of his electrocardiogram findings. Acute coronary syndrome (ACS) is a fatal disease; however, clinicians must not discount panhypopituitarism, as it may mimic ACS symptoms.

  Feb. 2023, Internal medicine (Tokyo, Japan), 62(4) (4), 559 - 564, English, Domestic magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Hemophagocytic Syndrome-Like Tuberculosis-Immune Reconstitution Inflammatory Syndrome After the Initiation of Hepatic Tuberculosis Treatment.

  Serina Nakamura, Naokazu Muramae, Akira Fujisawa, Noriaki Yasuda, Mitsumasa Okano, Kenta Mori, Kazunori Otsui, Kazuhiko Sakaguchi

  A 25-year-old Nepalese woman was referred to our hospital because of fever and intermittent abdominal pain with inguinal lymphadenopathy, which had lasted for several months. A liver biopsy of the positron emission tomography-positive lesion led to a diagnosis of hepatic tuberculosis. After the initiation of antituberculosis treatment, her symptoms resolved. However, 11 days after treatment initiation, chest and back pain, high-grade fever, and vomiting appeared and gradually worsened. She developed anemia and her serum ferritin level was elevated. Hemophagocytic syndrome due to the initial deterioration of tuberculosis was suspected and steroid therapy was initiated with the continuation of the antituberculosis drugs. Thereafter, the patient's condition improved remarkably.

  May 2022, Cureus, 14(5) (5), e24644, English, International magazine

  Link to Kobe Univ. Repository (Kernel)


• Acute Onset of Remitting Seronegative Symmetrical Synovitis With Pitting Edema (RS3PE) Two Weeks After COVID-19 Vaccination With mRNA-1273 With Possible Activation of Parvovirus B19: A Case Report With Literature Review.

  Hiroto Arino, Naokazu Muramae, Mitsumasa Okano, Kenta Mori, Kazunori Otsui, Kazuhiko Sakaguchi

  Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is a rare clinical entity characterized by "remitting," "seronegative," and "symmetrical" synovitis with pitting edema on the dorsum of the hands and feet. Although rheumatic or malignant diseases are diseases that are known to coexist with RS3PE, other factors such as medication, infection, and vaccination have been reported to be associated with RS3PE. Here, we present a case of RS3PE syndrome that satisfied all four diagnostic criteria of RS3PE (pitting edema in the limbs, acute onset, age ≥ 50 years, and/or rheumatoid factor negativity) after mRNA-1273 SARS-CoV-2 vaccination.

  May 2022, Cureus, 14(5) (5), e24952, English, International magazine

  Link to Kobe Univ. Repository (Kernel)


• Global thrombosis test for assessing thrombotic status and efficacy of antithrombotic diet and other conditions

  Masahiro Murakami, Kazunori Otsui, Yoshinobu Ijiri, Muneshige Shimizu, Hideo Ikarugi, Wataru Shioyama, Junichiro Yamamoto, Kjell S Sakariassen

  Because of the high mortality from myocardial infarction and stroke, there is a great demand for finding novel methods of diagnosis, prevention and treatment of these diseases. Most of the current tests measure important determinants of thrombosis such as platelet function, coagulation and fibrinolysis in isolation; therefore, a global test measuring the actual thrombotic status would be more useful in clinical conditions. We obtained considerable experience by using the global thrombosis test, which determines the actual thrombotic status by taking into account the measured platelet reactivity, coagulation and fibrinolytic activities. In animal experiments, we found significant correlation between the ex vivo global thrombosis test measurements and the in vivo thrombotic status. The published evidence for the benefit of an antithrombotic diet with regular physical exercise is also described.

  Future Science Ltd, Mar. 2022, Future Science OA, 8(3) (3)

  Scientific journal


• Focal Hepatic Steatosis Caused by Metastatic Malignant Insulinoma

  Naokazu Muramae, Takashi Kobayashi, Kazunori Otsui, Kazuhiko Sakaguchi

  Japanese Society of Internal Medicine, Feb. 2021, Internal Medicine, 60(4) (4), 653 - 654

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Thrombotic Profile and Oral Anticoagulation in Asian and Non-Asian Patients With Nonvalvular Atrial Fibrillation

  Ying X. Gue, Nobutaka Inoue, Nikolaos Spinthakis, Asumi Takei, Hiroyuki Takahara, Kazunori Otsui, Gregory Y.H. Lip, Diana A. Gorog

  Elsevier BV, Dec. 2019, Journal of the American College of Cardiology, 74(22) (22), 2822 - 2824, English

  Scientific journal


• 慢性偽性腸閉塞症に対する経腸栄養療法中に非閉塞性腸管虚血を合併した一例

  井之上 杏奈, 森 健太, 村前 直和, 森 寛行, 乙井 一典, 坂口 一彦

  症例は77歳、男性。過去に腸閉塞に対して外科手術を受けたことがあった。5ヵ月前から下痢、腹部膨満感、食欲不振が出現し徐々に症状悪化した。2ヵ月前から近医に入退院を繰り返したが、改善せず、胸腹水と下肢浮腫が出現し、当院へ転院した。腹部単純CT検査では小腸優位に広範囲の著明な腸管拡張を認めたが、上下部内視鏡検査では内腔に有意な所見がなく、経過から慢性偽性腸閉塞症(Chronic Intestinal Pseudo-Obstruction:CIPO)と考えられた。中心静脈栄養療法を行っていたが、カテーテル関連血流感染症を併発し、経腸栄養療法へ変更した。経腸栄養開始後8日目(第32病日)に比較的多量の下痢を認め、9日目(第33病日)に血便、その翌日(第34病日)に血圧低下を来たした。造影CTで門脈内ガスと消化管壁内気腫を認め、非閉塞性腸管虚血(Non-Occlusive Mesenteric Ischemia:NOMI)と考えられた。同日死亡した。本症例より、CIPOにおける経腸栄養療投与速度や増量スピードは、NOMI合併のリスクと示唆された。(著者抄録)

  (一社)日本病院総合診療医学会, Sep. 2019, 日本病院総合診療医学会雑誌, 15(5) (5), 451 - 455, Japanese


• A point-of-care global thrombosis test measuring occlusion time and endogenous lysis time may indicate thrombotic status.

  Junichiro Yamamoto, Nobutaka Inoue, Kazunori Otsui, Hideo Ikarugi, Muneshige Shimizu, Shinji Yamamoto, Masahiro Murakami, Yoshinobu Ijiri, Kjell S Sakariassen

  Jul. 2019, Future science OA, 5(6) (6), FSO402, English, International magazine


• Prevention of thrombotic disorders by antithrombotic diet and exercise: evidence by using global thrombosis tests.

  Junichiro Yamamoto, Yoshinobu Ijiri, Hideo Ikarugi, Kazunori Otsui, Nobutaka Inoue, Kjell S Sakariassen

  Prevention of thrombotic disorders has priority over treatment. There are only two pathologically relevant tests which are suitable for measuring the overall thrombotic status both in experimental conditions and in humans. The Global Thrombosis Test (GTT) and the Global Parallel-Plate Thrombosis Test can detect the pathologically relevant global thrombotic status. These tests have been successfully used for monitoring the effect of antithrombotic drugs and for developing novel antithrombotic agents. By using GTT, varieties of fruits, vegetables, and regular physical exercise have been tested for the effect on global thrombotic status. This review discusses the published evidence for the benefit of diet of selected fruit and vegetable varieties and doing regular physical exercise on improving thrombotic status. Future clinical trials monitored by GTT or Global Parallel-Plate Thrombosis Test could decide on the effectiveness of an experimentally proven antithrombotic diet with regular physical exercise in the prevention of thrombotic diseases.

  Apr. 2018, Future science OA, 4(4) (4), FSO285, English, International magazine

  [Refereed]

  Scientific journal


• Overwork accelerates thrombotic reaction: implications for the pathogenesis of Karoshi.

  Kazunori Otsui, Junichiro Yamamoto, Nobutaka Inoue

  Work-related stressors are potential causes of cardiovascular diseases (CVDs) and stroke; however, the pathophysiological mechanisms by which occupational stress induces and exacerbates CVDs remain unclear. The global thrombosis test (GTT) is a novel in vitro assay for evaluating both thrombotic reactions and subsequent thrombolysis. The time required to form an occlusive thrombus with the GTT, called as the occlusion time (OT), and the time to lyse the thrombus, the lysis time (LT), are markers of thrombotic and thrombolytic reactions, respectively. We investigated the impact of work-related stress on the thrombotic and thrombolytic reactions in 46 healthy medical residents. Off-duty or on-duty blood samples were collected on the mornings of non-work days or after the night duty on the emergent room respectively. The duration of sleep was significantly shorter during night duty than during off-duty nights [2.25 (1.0, 3.0) h vs. 6.0 (5.0, 7.0) h; p < 0.001]. Baseline OT was 310.3 (260.9, 437.7) s. whereas the on-duty OT was significantly shortened [284.2 (230.5, 355.8) s; p < 0.01]. LT was significantly prolonged during overwork conditions compared with off-duty conditions [1547 (1346, 1908) s vs. 1470 (1219, 1692) s; p < 0.05]. Overwork accelerates the thrombotic reactions. These reactions might explain the pathogenesis of overwork-related CVDs. The GTT is a good tool for evaluating of the level of fatigue.

  Springer New York LLC, Feb. 2018, Journal of thrombosis and thrombolysis, 45(2) (2), 222 - 224, English, International magazine

  [Refereed]

  Scientific journal


• 心臓リハビリテーション施行症例における骨格筋と運動耐容能の関係 Body Muscle Indexの意義

  平山 園子, 高原 宏之, 白木 宏明, とう 皓之, 吉岡 隆之, 乙井 一典, 岩田 幸代, 小澤 徹, 武居 明日美, 稲本 真也, 井上 信孝

  (一社)日本心臓病学会, Sep. 2016, 日本心臓病学会学術集会抄録, 64回, P - 314, Japanese


• 超高齢者虚血性心疾患症例における、脂質異常症の管理実態の検討

  吉岡隆之, 小澤徹, Otsui Kazunori, 白木宏明, 高原宏之, とう皓之, 平山園子, 岩田幸代, 武居明日美, 稲本真也, 井上信孝

  背景:わが国では、今後、さらなる人口の超高齢化が予想されている。この超高齢化社会の到来により、動脈硬化を基盤とする心血管病患者が一層増加することが予想され、高齢心血管病患者に対する治療戦略の確立がより重要なものとなる。今回われわれは、当院での現状を把握するために、冠動脈疾患の既往のある高齢患者の冠動脈危険因子のうち、脂質異常症の管理実態について検討した。対象と方法:検討対象は、当院において2011年6月から2014年5月の期間に、狭心症あるいは心筋梗塞と診断され、かつ冠動脈造影検査が施行された患者325名のうち、冠動脈疾患の既往のある二次予防対象患者76名とし、脂質異常症の各指標の管理実態について評価を行った。結果:これら二次予防対象患者において、約半数は、LDL-Cの管理目標値「100mg/dL未満」を達成できておらず、また、80歳以上の超高齢患者の中で、冠動脈造影検査の結果、冠動脈疾患の再発のあった群では、再発のなかった群と比べLDL-Cの達成率が低かった。結語:超高齢者の脂質異常症管理については、エビデンスの蓄積が乏しいのが現状であるが、二次予防対象患者において、80歳以上の超高齢者においても、LDL-Cの厳格な管理が重要であると推察された。(著者抄録)

  (公財)日本心臓財団, Aug. 2016, 心臓, 48(8) (8), 923 - 930, Japanese

  [Refereed]

  Scientific journal


• 経時的変化を考慮した脂質異常症の検討 脂質年変動面積を用いた検討

  福山 和恵, 吉岡 隆之, 高原 宏之, 乙井 一典, とう 皓之, 小澤 徹, 岩田 幸代, 武居 明日美, 井上 信孝

  (一社)日本動脈硬化学会, Jun. 2016, 日本動脈硬化学会総会プログラム・抄録集, 48回, 215 - 215, Japanese


• 冠動脈疾患患者におけるEPA/AA比、MDA-LDLの易血栓性への影響

  乙井 一典, 吉岡 隆之, 平山 園子, 小澤 徹, 岩田 幸代, 武居 明日美, 稲本 真也, 井上 信孝

  (一社)日本内科学会, Feb. 2016, 日本内科学会雑誌, 105(Suppl.) (Suppl.), 154 - 154, Japanese


• A Simultaneous Evaluation of Occupational Stress and Depression in Patients with Lifestyle-related Diseases.

  Nobutaka Inoue, Kazunori Otsui, Takayuki Yoshioka, Atsushi Suzuki, Toru Ozawa, Sachiyo Iwata, Asumi Takei

  Objective Karoshi, which is the Japanese term for death from over-work, is usually the extreme result of cardiovascular diseases, and occupational stress plays a pivotal role in the pathogenesis. Depression is closely associated with atherosclerotic cardiovascular disease. The present study was undertaken to examine the relationship between occupational stress and depression. Methods We enrolled 231 consecutive outpatients with lifestyle-related diseases such as diabetes, hyperlipidemia and hypertension were enrolled. Occupational stress was measured by qualitative constructs assessing job control, job demands, and worksite social support using a job content questionnaire (JCQ). The job strain index measured by the ratio of job demands to job control was used as an indicator of the occupational stress. Depression was evaluated by the Self-rating Depression Scale (SDS). Results A univariate linear regression analysis showed the SDS scores to be positively correlated with job demands and the job strain index and negatively correlated with job control and worksite social support. Multiple regression analyses to predict the SDS scores demonstrated that job demands were positively associated with SDS scores and job control and worksite social support were negatively associated with SDS scores after controlling for other variables. The job strain index was positively related to SDS scores. Conclusion Occupational stress expressed as the job strain index was strongly associated with depression. By simultaneously using the SDS and JCQ, the health conditions of patients could be classified based on occupational stress and mental stress, and this classification could help to promote a healthy work environment and guide individual workers.

  JAPAN SOC INTERNAL MEDICINE, 2016, Internal medicine (Tokyo, Japan), 55(9) (9), 1071 - 5, English, Domestic magazine

  [Refereed]

  Scientific journal


• 生活習慣病症例における職業性ストレスと精神的ストレスとの関連

  乙井 一典, 吉岡 隆之, 小澤 徹, 岩田 幸代, 武居 明日美, 井上 信孝

  (一社)日本職業・災害医学会, Nov. 2015, 日本職業・災害医学会会誌, 63(臨増) (臨増), 別94 - 別94, Japanese


• ST上昇心筋梗塞患者では線溶活性能が低下し、抗血小板療法が減弱する

  乙井 一典, 吉岡 隆之, 平山 園子, 小澤 徹, 岩田 幸代, 武居 明日美, 稲本 真也, 井上 信孝

  (一社)日本脈管学会, Oct. 2015, 脈管学, 55(Suppl.) (Suppl.), S164 - S164, Japanese


• Vasospastic Angina in Identical Twins.

  Takayuki Yoshioka, Kazunori Otsui, Atsushi Suzuki, Toru Ozawa, Sachiyo Iwata, Asumi Takei, Nobutaka Inoue

  BACKGROUND: The clinical conditions of various diseases, including coronary artery disease, are determined by genetics and the environment. Previous investigations noted the significance of genetic mutations and polymorphisms in cases of coronary spasm. CASE REPORT: We report on monozygotic identical twins who almost simultaneously presented with vasospastic angina. The 58-year-old younger twin was admitted to our hospital because of persistent chest pain. An electrocardiogram showed an inverted T wave in the left precordial leads. Coronary angiographies revealed a short left main trunk (LMT) and 50% stenosis at the proximal portion of the left anterior descending artery (LAD). Infusion of acetylcholine to his left coronary artery caused marked vasoconstriction associated with a sensation of chest oppression. Nitroglycerine completely reversed this response. Based on these findings, we diagnosed Twin A with vasospastic angina. At nearly the same time, his identical twin brother was diagnosed with vasospastic angina at another hospital. Comparison of both coronary angiograms indicated similar structure of coronary vessels, including short LMT and mild stenosis at the proximal portion of LAD. CONCLUSIONS: These 2 cases highlight the importance of genetic factors in the pathogenesis of vasospastic angina. It may be important for individuals to receive medical attention if their identical twin presents with vasospastic angina.

  Sep. 2015, The American journal of case reports, 16, 598 - 602, English, International magazine

  Scientific journal


• 孤立性腹部内臓動脈解離の臨床的検討

  白木 宏明, 乙井 一典, とう 皓之, 吉岡 隆之, 平山 園子, 小澤 徹, 岩田 幸代, 武居 明日美, 稲本 真也, 井上 信孝

  (一社)日本心臓病学会, Sep. 2015, 日本心臓病学会学術集会抄録, 63回, 553 - 553, Japanese


• Coconut atrium in long-standing rheumatic valvular heart disease.

  Takahisa Onishi, Yuka Idei, Kazunori Otsui, Sachiyo Iwata, Atsushi Suzuki, Toru Ozawa, Koji Domoto, Asumi Takei, Shinya Inamoto, Nobutaka Inoue

  BACKGROUND: Complete calcification of the left atrium (LA) is called "coconut atrium", which decreases the compliance of LA, leading to the elevation of LA pressure that is transmitted to the right-side of the heart. The pathogenesis of LA calcification in patients with rheumatic heart disease is unknown; however, possible mechanisms include chronic strain force in the atrial wall and inflammation. We report here a patient with long-standing rheumatic valvular heart disease with coconut atrium. CASE REPORT: A 76-year-old man presented with breathlessness and leg edema due to right-sided heart failure. He was diagnosed with rheumatic fever at 8 years of age. Mitral commissurotomy and the mitral and aortic valve replacement were previously performed to treat mitral and aortic valvular stenosis. The profile view of the chest X-ray indicated a diffuse calcified outline of the LA wall. A transthoracic echocardiogram revealed pulmonary hypertension and dilatation of both atria. Moreover, computed tomography showed nearly circumferential calcification of the LA wall. Despite intense medical treatment, he succumbed to heart failure. An autopsy demonstrated that the LA was markedly dilated, its wall was calcified, and its appearance was similar to the surface of an atherosclerotic aorta. Microscopic examination revealed intensive calcification in the endocardium. Minimal accumulation of inflammatory cells was noted. Although slight fibrosis was observed, the cardiac musculature was preserved. CONCLUSIONS: To the best of our knowledge, this is the first report that identifies the histological changes of LA calcification associated with long-standing rheumatic valvular heart disease.

  Mar. 2015, The American journal of case reports, 16, 191 - 5, English, International magazine

  Scientific journal


• A super-elderly case of abdominal aortic aneurysm associated with chronic disseminated intravascular coagulation.

  Kazunori Otsui, Mai Yamamoto, Humiaki Aoki, Toru Ozawa, Koji Domoto, Atsushi Suzuki, Sachiyo Iwata, Asumi Takei, Shinya Inamoto, Nobutaka Inoue

  Chronic disseminated intravascular coagulation (DIC) is a well-known complication of aortic aneurysm. A 91-year-old Japanese woman was admitted to our hospital because of massive purpura of the lower limbs. The presence of abdominal aortic aneurysm (AAA) had been pointed out from the age of 80 years, and its diameter had gradually increased. The AAA was composed of two portions, that is, a large upper and a small lower portion, and a large mural thrombosis was observed in the lower portion. The laboratory data led to the diagnosis of DIC, and AAA was the only identifiable cause of coagulopathy. The time course of exacerbation of AAA was consistent with the progression of thrombocytopenia and purpura. Therefore, we concluded that AAA was the underlying cause of DIC. Since DIC in aortic aneurysms is associated with excessive fibrinolysis, tranexamic acid was administered as anti-fibrinolytic therapy. After that, coagulopathy was drastically improved. Our patient responded successfully to anti-fibrinolytic therapy for coagulopathy. The present case illustrates the importance of evaluation of the diameter of an aneurysm as well as intraluminal thrombosis, which may play an important role in coagulopathy including DIC. It is necessary to monitor coagulation and fibrinolysis for the follow-up of patients with AAA. .

  Feb. 2015, Journal of cardiology cases, 11(2) (2), 48 - 51, English, Domestic magazine


• 著明な心筋壁肥厚と心膜液貯留を呈しながら、ステロイド無投与で改善した急性好酸球性心筋炎の1例

  羽渓 優, 森野 加帆里, 乙井 一典, 小澤 徹, 堂本 康治, 岩田 幸代, 武居 明日美, 稲本 真也, 大西 一男, 出射 由香, 井上 信孝

  症例は20歳代女性。主訴:発熱、胸痛。現病歴:38℃の熱発を認め、翌日から胸痛を自覚し近医受診。この際、心電図異常を指摘され本院紹介。入院時現症:意識清明、血圧84/54mmHg、脈拍数122/分、整。心音:3音gallop。呼吸音:清。心電図:洞性頻脈、低電位、aVR以外の誘導で、STの軽度上昇を認めた。胸部X線:心陰影は軽度拡大。血液検査:RBC437×10^4/mm3、WBC 16880/mm3(好中球76%、リンパ球11%、好酸球5%)。心エコー図にて、左室壁運動の低下、左室壁の浮腫状の肥厚、全周性の心膜液貯留を認め、急性心筋炎と診断。一時、収縮期血圧が70mmHgと低下し、ドブタミンによる循環動態の支持を必要とした。心筋生検にて、心筋細胞の断裂、間質の浮腫、好酸球の高度な浸潤を認め、急性好酸球性心筋炎と診断。経過中、末梢血好酸球の増多を認めた。その後、ステロイド無投与にても心筋壁運動の改善、心筋壁肥厚の軽減を認め、退院となった。心筋炎自体の急性期死亡率は38%と報告されているが、好酸球性心筋炎では7%程度であるとされている。好酸球性心筋炎に対して免疫抑制薬の有効性を前向きに検討した臨床研究の報告はなくステロイドの有効性に関しては確立されていないが、高度な心機能障害や、重篤な不整脈をきたす場合は、ステロイド療法も検討すべきであるとされている。今回、ステロイド無投与にても心機能の改善を認めた1例を経験した。好酸球性心筋炎は多彩な病状を呈することが示唆された。(著者抄録)

  (公財)日本心臓財団, Jan. 2015, 心臓, 47(1) (1), 42 - 48, Japanese


• Global Thrombosis Test - a possible monitoring system for the effects and safety of dabigatran.

  Kazunori Otsui, Diana A Gorog, Junichiro Yamamoto, Takayuki Yoshioka, Sachiyo Iwata, Atsushi Suzuki, Toru Ozawa, Asumi Takei, Nobutaka Inoue

  BACKGROUND: Dabigatran is an alternative to warfarin (WF) for the thromboprophylaxis of stroke in patients with non-valvular atrial fibrillation (NVAF). The advantage of dabigatran over WF is that monitoring is not required; however, a method to monitor the effect and the safety of dabigatran is not currently available. The Global Thrombosis Test (GTT) is a novel method to assess both clot formation and lysis activities under physiological conditions. OBJECTIVE: The aim of this study was to evaluate whether treatment with dabigatran might affect shear-induced thrombi (occlusion time [OT], sec) by the GTT, and to investigate the possibility that the GTT could be useful as a monitoring system for dabigatran. PATIENTS/METHODS: The study population consisted of 50 volunteers and 43 NVAF patients on WF therapy, who were subsequently switched to dabigatran. Using the GTT, the thrombotic status was assessed one day before and 1 month after switching anticoagulation from WF to dabigatran. RESULTS: The OT was 524.9 ± 17.0 sec in volunteers whereas that of NVAF patients on WF therapy was 581.7 ± 26.3 sec. The switch from WF to dabigatran significantly prolonged OT (784.5 ± 19.3 sec). One patient on WF therapy and 12 patients on dabigatran therapy were shown to have OT > 900 sec. CONCLUSION: The GTT could be used to assess the risk of dabigatran-related bleeding complications.

  2015, Thrombosis journal, 13, 39 - 39, English, International magazine

  Scientific journal


• 心不全合併大動脈弁狭窄症の臨床的検討

  吉岡 隆之, 乙井 一典, 白木 宏明, とう 皓之, 鈴木 敦, 小澤 徹, 堂本 康治, 稲本 真也, 岩田 幸代, 武居 明日美, 井上 信孝

  (一社)日本心臓病学会, Sep. 2014, 日本心臓病学会学術集会抄録, 62回, O - 385, Japanese


• Serum myeloperoxidase/paraoxonase 1 ratio as potential indicator of dysfunctional high-density lipoprotein and risk stratification in coronary artery disease.

  Yoko Haraguchi, Ryuji Toh, Minoru Hasokawa, Hideto Nakajima, Tomoyuki Honjo, Kazunori Otsui, Kenta Mori, Maki Miyamoto-Sasaki, Masakazu Shinohara, Kunihiro Nishimura, Tatsuro Ishida, Ken-Ichi Hirata

  OBJECTIVE: Granular leukocyte-derived myeloperoxidase (MPO) promotes oxidation of lipoproteins, while paraoxonase 1 (PON1) has antioxidant properties for high-density lipoprotein (HDL). We evaluated their effects on coronary risk stratification and function of lipoproteins. METHODS AND RESULTS: A total 158 patients who had previously undergone percutaneous coronary intervention and who had been hospitalized for coronary re-angiography were enrolled. Coronary lesions (restenosis or de novo lesion) were observed in 84 patients but not associated with conventional lipid profile. In contrast, serum MPO levels and PON1 activities were significantly associated with the prevalence of coronary lesions. The high MPO/PON1 ratio, when cutoff values were set at 1.59, was independently correlated with restenosis (odds ratio 6.4, 95% CI 2.2-19.3, P = 0.001) and de novo lesions (odds ratio 3.5, 95% CI 1.3-9.4, P = 0.014). We isolated HDL from patients with high or low MPO/PON1 ratio, and compared anti-inflammatory properties of HDL. Human umbilical vein endothelial cells were stimulated with inflammatory cytokine, and the expression of vascular cell adhesion molecule-1 (VCAM-1) was evaluated. HDL isolated from patients with low serum MPO/PON1 ratio inhibited VCAM-1 expression significantly greater than that with high MPO/PON1 ratio. We also demonstrated that the cholesterol efflux capacity of apolipoprotein B-depleted serum from patients with high MPO/PON1 ratio was significantly decreased than that with low MPO/PON1 ratio. CONCLUSIONS: MPO/PON1 ratio could be a useful marker for secondary prevention of coronary artery disease through modulation of HDL function.

  ELSEVIER IRELAND LTD, Jun. 2014, Atherosclerosis, 234(2) (2), 288 - 94, English, International magazine

  [Refereed]

  Scientific journal


• アスピリン・クロピトグレル・ワーファリンの3剤内服に対する臨床的意義の検討

  小澤 徹, 井上 信孝, 緒方 俊介, 工藤 宏計, 乙井 一典, 堂本 康治, 岩田 幸代, 武居 明日美, 稲本 真也, 大西 一男

  (一社)日本内科学会, Feb. 2014, 日本内科学会雑誌, 103(Suppl.) (Suppl.), 143 - 143, Japanese


• 脂質異常症患者における血栓準備状態の臨床的検討 Global Thrombosis Test(GTT)を用いて

  乙井 一典, 井上 信孝, 工藤 宏計, 小澤 徹, 堂本 康治, 岩田 幸代, 武居 明日美, 稲本 真也, 大西 一男, 山本 順一郎

  (一社)日本内科学会, Feb. 2014, 日本内科学会雑誌, 103(Suppl.) (Suppl.), 159 - 159, Japanese


• PCI後、DAPTにワーファリン内服を加えることに対する臨床的意義の検討

  小澤 徹, 井上 信孝, 緒方 俊介, 羽溪 優, 工藤 宏計, 乙井 一典, 堂本 康治, 岩田 幸代, 武居 明日美, 稲本 真也, 大西 一男

  (一社)日本心臓病学会, Sep. 2013, 日本心臓病学会誌, 8(Suppl.I) (Suppl.I), 395 - 395, Japanese


• 冠動脈疾患患者における血栓準備状態の臨床的検討 Global Thrombosis Test(GTT)を用いて

  乙井 一典, 井上 信孝, 小澤 徹, 堂本 康治, 岩田 幸代, 武居 明日美, 稲本 真也, 大西 一男, 山本 順一郎

  (一社)日本内科学会, Feb. 2013, 日本内科学会雑誌, 102(Suppl.) (Suppl.), 255 - 255, Japanese


• A case of mitochondrial cardiomyopathy with restrictive transmitral filling pattern.

  Kazunori Otsui, Nobutaka Inoue, Anna Tamagawa, Kazuo Onishi

  A 61-year-old diabetic woman with a mitochondrial A3243G mutation was hospitalized for evaluation of breathlessness, general fatigue, and leg edema. Chest radiography revealed cardiomegaly with massive pleural effusion. Serum lactate, pyruvate, and brain natriuretic peptide concentrations were elevated. Transthoracic echocardiography revealed a restrictive pattern of transmitral flow, although systolic function of the left ventricle was only mildly impaired. Based on these findings and her clinical course, the patient was diagnosed with right-sided heart failure caused by mitochondrial cardiomyopathy associated with a restrictive transmitral filling pattern. Treatment with furosemide, enalapril, and eplerenone was effective, and improvement in her symptoms was associated with amelioration of transthoracic echocardiographic findings and a reduction in serum brain natriuretic peptide levels. Previous reports have indicated heterogeneity in the clinical features of mitochondrial cardiomyopathy in patients carrying the A3243G mutation; the present case highlights the substantial variability in the clinical features of this disease.

  2012, International medical case reports journal, 5, 19 - 22, English, International magazine


• Erratum: Calcium-dependent platelet aggregation through the interaction between phosphatidylserine and LOX-1 (Cardiovascular Research)

  Kazunori Otsui, Makoto Kakutani, Koji Yuasa, Atushi Nakano, Chang-Ping Hu, Akemi Kakino, Yuko Sato, Yoshiko Fujita, Yosuke Kawase, Kou-Ichi Jishage, Hiroshi Suzuki, Jawahar L. Mehta, Mitsuhiro Yokoyama, Ken-Ichi Hirata, Nobutaka Inoue, Tatsuya Sawamura

  Dec. 2010, Cardiovascular Research, 88(3) (3), 547, English

  [Refereed]

  Scientific journal


• LOX-1 mediates vascular lipid retention under hypertensive state.

  Atushi Nakano, Nobutaka Inoue, Yuko Sato, Norihisa Nishimichi, Kenji Takikawa, Yoshiko Fujita, Akemi Kakino, Kazunori Otsui, Saburo Yamaguchi, Haruo Matsuda, Tatsuya Sawamura

  OBJECTIVES: Hypertension is a powerful independent risk factor for atherosclerotic cardiovascular diseases; however, the precise molecular mechanisms whereby hypertension promotes atherosclerotic formation remain to be determined. The interaction between oxidized low-density lipoprotein (oxLDL) and its receptor lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) plays a critical role in atherogenesis. To clarify how hypertension promotes atherosclerosis, we investigated specific roles of LOX-1 in acceleration of lipid deposition under a hypertensive state. METHODS: We employed a model of stroke-prone spontaneously hypertensive rats (SHR-SP) that exhibits acute lipid deposition in mesenteric artery induced by high fat and salt loading. These vascular lipid deposition lesions share similar characteristics with the initial lesions of human atherosclerosis. RESULTS: The enhanced LOX-1 expression in SHR-SP was associated with oxidized LDL deposited in vascular wall. Anti-LOX-1 neutralizing antibody dramatically suppressed the lipid deposition in vivo in SHR-SP. Vitamin E decreased serum oxLDL-like LOX-1 ligands, and suppressed the vascular lipid deposition. The vascular permeability, evaluated by the leakage of Evans blue, was markedly enhanced by pretreatment of oxLDL. The enhancement of vascular permeability induced by oxLDL was suppressed by anti-LOX-1 antibody. CONCLUSION: The enhanced expression and activation of LOX-1 mediated the enhancement of vascular permeability, which contributed to the vascular lipid accumulation under hypertensive states.

  Jun. 2010, Journal of hypertension, 28(6) (6), 1273 - 80, English, International magazine

  Scientific journal


• LOX index, a novel predictive biochemical marker for coronary heart disease and stroke.

  Nobutaka Inoue, Tomonori Okamura, Yoshihiro Kokubo, Yoshiko Fujita, Yuko Sato, Mamoru Nakanishi, Kazuki Yanagida, Akemi Kakino, Shin Iwamoto, Makoto Watanabe, Sayoko Ogura, Kazunori Otsui, Haruo Matsuda, Kagehiro Uchida, Ryo Yoshimoto, Tatsuya Sawamura

  BACKGROUND: Lectin-like oxidized LDL receptor 1 (LOX-1) is implicated in atherothrombotic diseases. Activation of LOX-1 in humans can be evaluated by use of the LOX index, obtained by multiplying the circulating concentration of LOX-1 ligands containing apolipoprotein B (LAB) times that of the soluble form of LOX-1 (sLOX-1) [LOX index = LAB x sLOX-1]. This study aimed to establish the prognostic value of the LOX index for coronary heart disease (CHD) and stroke in a community-based cohort. METHODS: An 11-year cohort study of 2437 residents age 30-79 years was performed in an urban area located in Japan. Of these, we included in the analysis 1094 men and 1201 women without history of stroke and CHD. We measured LAB and sLOX-1 using ELISAs with recombinant LOX-1 and monoclonal anti-apolipoprotein B antibody and with 2 monoclonal antibodies against LOX-1, respectively. RESULTS: During the follow-up period, there were 68 incident cases of CHD and 91 cases of stroke (with 60 ischemic strokes). Compared with the bottom quartile, the hazard ratio (HR) of the top quartile of LOX index was 1.74 (95% CI 0.92-3.30) for stroke and 2.09 (1.00-4.35) for CHD after adjusting for sex, age, body mass index, drinking, smoking, hypertension, diabetes, non-HDL cholesterol, and use of lipid-lowering agents. Compared with the bottom quartile of LOX index, the fully adjusted HRs for ischemic stroke were consistently high from the second to the top quartile: 3.39 (95% CI 1.34-8.53), 3.15 (1.22-8.13) and 3.23 (1.24-8.37), respectively. CONCLUSIONS: Higher LOX index values were associated with an increased risk of CHD. Low LOX index values may be protective against ischemic stroke.

  Apr. 2010, Clinical chemistry, 56(4) (4), 550 - 8, English, International magazine

  Scientific journal


• C-reactive protein uptake by macrophage cell line via class-A scavenger receptor.

  Yoshiko Fujita, Akemi Kakino, Mariko Harada-Shiba, Yuko Sato, Kazunori Otsui, Ryo Yoshimoto, Tatsuya Sawamura

  BACKGROUND: C-reactive protein (CRP) increases in response to inflammation and is purported to be a risk factor for atherogenesis. We recently demonstrated that a scavenger receptor, lectin-like oxidized LDL receptor (LOX-1), is a receptor for CRP. In light of the overlapping ligand spectrum of scavenger receptors such as modified LDL, bacteria, and advanced glycation end products, we examined whether other scavenger receptors recognize CRP. METHODS: We analyzed the uptake of fluorescently labeled CRP in COS-7 cells expressing a series of scavenger receptors and in a monocytic cell line, THP-1, differentiated into macrophage with phorbol 12-myristate 13-acetate (PMA). We applied small interfering RNA (siRNA) against class-A scavenger receptor (SR-A) to THP-1 cells to suppress the expression of SR-A. We also analyzed the binding of nonlabeled CRP to immobilized recombinant LOX-1 and SR-A in vitro using anti-CRP antibody. RESULTS: COS-7 cells expressing LOX-1 and SR-A internalized fluorescently labeled CRP in a dose-dependent manner, but cells expressing CD36, SR-BI, or CD68 did not. The recombinant LOX-1 and SR-A proteins recognized nonlabeled purified CRP and native CRP in serum in vitro. THP-1 cells differentiated into macrophage-like cells by treatment with PMA-internalized fluorescently labeled CRP. siRNA against SR-A significantly and concomitantly inhibited the expression of SR-A (P < 0.01) and CRP uptake (P < 0.01), whereas control siRNA did not. CONCLUSIONS: CRP is recognized by SR-A as well as LOX-1 and taken up via SR-A in a macrophage-like cell line. This process might be of significance in the pathogenesis of atherosclerotic disease.

  Mar. 2010, Clinical chemistry, 56(3) (3), 478 - 81, English, International magazine

  Scientific journal


• Lox-1: the multifunctional receptor underlying cardiovascular dysfunction.

  Sayoko Ogura, Akemi Kakino, Yuko Sato, Yoshiko Fujita, Shin Iwamoto, Kazunori Otsui, Ryo Yoshimoto, Tatsuya Sawamura

  Oxidatively modified low-density lipoprotein (oxLDL) is implicated in the pathogenesis of atherosclerosis. Endothelial dysfunction is the initial change in the vascular wall that induces morphological changes for atheroma-formation. Lectin-like oxidized LDL receptor-1 (LOX-1) was identified as the receptor for oxLDL that was thought to be a major cause of endothelial dysfunction. LOX-1 has been demonstrated to contribute not only to endothelial dysfunction, but also to atherosclerotic-plaque formation, myocardial infarction and intimal thickening after balloon injury. Recent findings on the genetics of LOX-1 and the methodology to detect it and its ligands would further facilitate the examination of the receptor's pathophysiological contribution in atherosclerosis. Furthermore, LOX-1-related tools might open new gateways from diagnosis to therapeutics for cardiovascular diseases.

  Nov. 2009, Circulation journal : official journal of the Japanese Circulation Society, 73(11) (11), 1993 - 9, English, Domestic magazine

  Scientific journal


• Impact of NAD(P)H oxidase-derived reactive oxygen species on coronary arterial remodeling: a comparative intravascular ultrasound and histochemical analysis of atherosclerotic lesions.

  Mitsuyasu Terashima, Yoshitaka Ohashi, Hiroshi Azumi, Kazunori Otsui, Hideaki Kaneda, Kojiro Awano, Seiichi Kobayashi, Tomoyuki Honjo, Takahiko Suzuki, Kazumi Maeda, Mitsuhiro Yokoyama, Nobutaka Inoue

  BACKGROUND: Coronary arterial remodeling, which is a response to the growth of atherosclerotic plaques, is associated with plaque vulnerability. Oxidative stress induced by reactive oxygen species (ROS) via NAD(P)H oxidase in the vasculature also plays a crucial role in the pathogenesis of atherosclerosis-based cardiovascular disease. In this study, the relationship between coronary arterial remodeling and ROS generation was examined by comparing preinterventional intravascular ultrasound findings of atherosclerotic lesions to the histochemical findings of corresponding specimens obtained by directional coronary atherectomy. METHODS AND RESULTS: Predirectional coronary atherectomy intravascular ultrasound images of 49 patients were analyzed. The remodeling index was calculated by dividing the target-lesion external elastic membrane cross-sectional area by the reference-segment external elastic membrane cross-sectional area. Expansive remodeling was defined as a remodeling index of >1.0. ROS generation and NAD(P)H oxidase p22(phox) expression in directional coronary atherectomy specimens were evaluated using the dihydroethidium staining method and immunohistochemistry as the ratio of the positive area to the total surface area in each specimen, respectively. ROS generation and p22(phox) expression were significantly greater in lesions with expansive remodeling than in lesions without remodeling (0.18+/-0.12 versus 0.03+/-0.02, P<0.0001, 0.10+/-0.08 versus 0.04+/-0.05, P=0.0039, respectively). Both ROS generation and p22(phox) expression significantly correlated with the intravascular ultrasound-derived remodeling index (r=0.77, P<0.0001, r=0.53, P<0.0001, respectively). CONCLUSIONS: Simultaneous examination with intravascular ultrasound and immunohistochemistry analyses suggests that NAD(P)H oxidase-derived ROS is related to the coronary arterial remodeling process associated with plaque vulnerability.

  Jun. 2009, Circulation. Cardiovascular interventions, 2(3) (3), 196 - 204, English, International magazine

  Scientific journal


• Enhanced expression of TLR4 in smooth muscle cells in human atherosclerotic coronary arteries.

  Kazunori Otsui, Nobutaka Inoue, Seiichi Kobayashi, Rio Shiraki, Tomoyuki Honjo, Motonori Takahashi, Ken-Ichi Hirata, Seinosuke Kawashima, Mitsuhiro Yokoyama

  Toll-like receptors (TLRs) play an essential role in innate immunity as components of the primary defense system against microbial infections. It has become evident that TLRs are also involved in the pathogenesis of various cardiovascular diseases. However, the expression patterns of TLRs in the human coronary arteries of coronary artery disease (CAD) patients and the regulatory mechanisms of their expression remain unknown. The TLR4 expression patterns were invstigated by immunohistochemical analysis of coronary specimens obtained from autopsy cases or CAD patients by using directional coronary atherectomy. In atherosclerotic coronary arteries (n = 8), TLR4 immunoreactivity was colocalized with infiltrating inflammatory cells. Interestingly, vascular smooth muscle cells of atherosclerotic coronary arteries intensely expressed TLR4 even in the regions that had few inflammatory cells. In contrast, TLR4 expression was barely detected in the vascular smooth muscle cells of nonatherosclerotic coronary arteries (n = 4). Furthermore, intense expression of smooth muscle TLR4 was observed in the coronary arteries of CAD patients (n = 52). Stimulation with tumor necrosis factor alpha and angiotensin II increased the expression of TLR4 mRNA in cultured human vascular smooth muscle cells. Candesartan, an antagonist of the angiotensin II type 1 receptor (AT1), and N-acetylcystine inhibited angiotensin II-induced TLR4 mRNA expression in these cells. These findings suggest that the vascular smooth muscle cells of atherosclerotic coronary arteries may be activated to express TLR4. Furthermore, proinflammatory cytokines and oxidative stress in the inflammatory lesions might contribute to the enhanced expression of TLR4 in vascular smooth muscle cells of atherosclerotic arteries.

  Nov. 2007, Heart and vessels, 22(6) (6), 416 - 22, English, Domestic magazine

  Scientific journal


• Toll-like receptor 4 expressions on peripheral blood monocytes were enhanced in coronary artery disease even in patients with low C-reactive protein.

  Rio Shiraki, Nobutaka Inoue, Seiichi Kobayashi, Junya Ejiri, Kazunori Otsui, Tomoyuki Honjo, Motonori Takahashi, Ken-ichi Hirata, Mitsuhiro Yokoyama, Seinosuke Kawashima

  Toll-like receptors (TLRs) play important roles in the pathogenesis of atherosclerosis. On the other hand, serum high sensitivity C-reactive protein (hsCRP) is known as an independent coronary risk factor, but cardiovascular events do occur even in low hsCRP levels. We investigated whether the TLR4 expression levels on human peripheral blood monocytes were associated with serum hsCRP levels or the occurrence of coronary artery diseases (CAD). One hundred CAD patients and 100 non-CAD subjects were enrolled. There were 72 non-CAD subjects and 53 CAD patients with low serum hsCRP levels. Among the low-hsCRP subjects, the TLR4 expression levels were higher in CAD patients than in non-CAD subjects (P < 0.05, after being adjusted for other risk factors). Moreover, TLR4 expression levels in stable angina pectoris (SAP) patients were elevated compared with those in non-CAD subjects (P < 0.05), and those in acute coronary syndrome patients were higher than SAP patients even in low-hsCRP subjects (P < 0.01). In conclusion, the TLR4 expression levels on peripheral blood monocytes in CAD patients were higher than those in non-CAD subjects and correlated with disease activity, even in low-hsCRP subjects. The combined measurement of serum hsCRP and the TLR4 expression on peripheral blood monocytes, especially among low-hsCRP subjects, may become a new coronary risk marker.

  Dec. 2006, Life sciences, 80(1) (1), 59 - 66, English, International magazine

  Scientific journal


• Endothelial urocortin has potent antioxidative properties and is upregulated by inflammatory cytokines and pitavastatin.

  Tomoyuki Honjo, Nobutaka Inoue, Rio Shiraki, Seiichi Kobayashi, Kazunori Otsui, Motonori Takahashi, Ken-Ichi Hirata, Seinosuke Kawashima, Hiroshi Yokozaki, Mitsuhiro Yokoyama

  BACKGROUND: Urocortin, a neuropeptide discovered in the midbrain, is a member of the corticotropin-releasing factor family and is expressed in heart tissues. Urocortin exerts potent cardioprotective effects under various pathological conditions including ischemia/reperfusion. However, the regulation and function of vascular urocortin are unknown. METHODS AND RESULTS: Immunohistochemistry showed definitive expression of urocortin in endothelial cells of coronary large arteries and microvessels from autopsied hearts. RT-PCR confirmed the expression of urocortin in human umbilical vein endothelial cells (HUVECs). Urocortin (10(-8) M) potently suppressed the generation of angiotensin II-induced reactive oxygen species (ROS) in HUVECs. Tumor necrosis factor-alpha and interferon-gamma increased the urocortin mRNA levels and its release from HUVECs. Incubation with pitavastatin (0.1-3.0 microM) significantly increased the urocortin mRNA levels and its release from HUVECs. Furthermore, treatment with pitavastatin (2 mg/day) for 4 weeks increased the serum urocortin level from 11.0 +/- 6.5 to 16.4 +/- 7.3 ng/ml in healthy volunteers. CONCLUSION: Endothelial urocortin was upregulated by inflammatory cytokines and pitavastatin and suppressed ROS production in endothelial cells. Treatment with pitavastatin increased the serum urocortin level in human subjects. Thus, endothelial urocortin might protect cardiomyocytes in inflammatory lesions. Urocortin might partly explain the mechanisms of various pleiotropic effects of statins.

  2006, Journal of vascular research, 43(2) (2), 131 - 8, English, International magazine

  Scientific journal


• Possible role of brain-derived neurotrophic factor in the pathogenesis of coronary artery disease.

  Junya Ejiri, Nobutaka Inoue, Seiichi Kobayashi, Rio Shiraki, Kazunori Otsui, Tomoyuki Honjo, Motonori Takahashi, Yoshitaka Ohashi, Shinobu Ichikawa, Mitsuyasu Terashima, Takao Mori, Kojiro Awano, Toshiro Shinke, Junya Shite, Ken-ichi Hirata, Hiroshi Yokozaki, Seinosuke Kawashima, Mitsuhiro Yokoyama

  BACKGROUND: The neurotrophin (NT) family, including nerve growth factor NT-3 and brain-derived neurotrophic factor (BDNF), has a critical role in the survival, growth, maintenance, and death of central and peripheral neurons. NTs and their receptors are expressed in atherosclerotic lesions; however, their significance in cardiovascular disease remains unclear. METHODS AND RESULTS: To clarify the role of NTs in the pathogenesis of coronary artery disease, NT plasma levels in the aorta, coronary sinus, and peripheral veins of patients with unstable angina (n=38), stable effort angina (n=45), and non-coronary artery disease (n=24) were examined. In addition, regional expression of BDNF in coronary arteries was examined in autopsy cases and patients with angina pectoris by directional coronary atherectomy. The difference in BDNF levels, but not NT-3, between the coronary sinus and aorta was significantly greater in the unstable angina group compared with the stable effort angina and non-coronary artery disease groups. Immunohistochemical investigations demonstrated BDNF expression in the atheromatous intima and adventitia in atherosclerotic coronary arteries. BDNF expression was enhanced in macrophages and smooth muscle cells in atherosclerotic coronary arteries. Stimulation with recombinant BDNF significantly enhanced NAD(P)H oxidase activity and the generation of reactive oxygen species in cultured human coronary artery smooth muscle cells. CONCLUSIONS: BDNF has an important role in atherogenesis and plaque instability via the activation of NAD(P)H oxidase.

  Oct. 2005, Circulation, 112(14) (14), 2114 - 20, English, International magazine

  Scientific journal

• 【診断と治療のABC[138]高TG血症】 (第4章)管理・治療 高TG血症の管理と治療 治療薬剤 多価不飽和脂肪酸

  森健太, 乙井一典, Hirata Ken-ichi

  Sep. 2018, 最新医学, (別冊高TG血症) (別冊高TG血症), 133 - 142, Japanese

  [Invited]

  Introduction commerce magazine


• 心房細動アブレーションにより30年来の洞不全症候群が改善し,ペースメーカー移植術を回避した1例

  高原宏之, 武居明日美, 吉岡隆之, 乙井一典, 平山園子, 小澤徹, 岩田幸代, 井上信孝

  2015, 日本循環器学会近畿地方会(Web), 120th


• ST上昇心筋梗塞患者では線溶活性能が低下し,抗血小板療法が減弱する

  乙井一典, 吉岡隆之, 平山園子, 小澤徹, 岩田幸代, 武居明日美, 稲本真也, 井上信孝

  2015, 脈管学(Web), 55(supplement) (supplement)


• 中心臓静脈内の限局性リエントリー性心房頻拍の一例

  堀晋也, 武居明日美, 岩田幸代, 小澤徹, 乙井一典, 鈴木敦, 吉岡隆之, 白木宏明, トウ皓之, 井上信孝

  2014, 日本循環器学会近畿地方会(Web), 118th


• 著明な左房石灰化を呈した2症例

  大西貴久, 乙井一典, 小澤徹, 堂本康治, 岩田幸代, 稲本真也, 武居明日美, 井上信孝

  2014, 日本循環器学会近畿地方会(Web), 117th


• A Case of Acute Coronary Syndrome Associated with Depression in the Course of Evaluation for Cardioneurosis

  井上 信孝, 岩田 幸代, 乙井 一典

  日本心臓病学会, Jun. 2013, 日本心臓病学会誌 : Journal of cardiology. Japanese edition, 8(2) (2), 158 - 162, Japanese


• 当院における心不全を呈した大動脈弁狭窄症の臨床的検討

  白木宏明, 工藤宏計, 緒方俊介, 羽溪優, 乙井一典, 小澤徹, 堂本康治, 岩田幸代, 武居明日美, 稲本真也, 井上信孝, 大西一男

  2013, 日本循環器学会近畿地方会(Web), 116th


• LOX-1 Binds to CRP, Activating Complement System and Deteriorating Myocardial Infarction

  Yoshiko Fujita, Akemi Kakino, Kazunori Otsui, Saburo Yamaguchi, Yuko Sato, Tatsuya Sawamura

  INFORMA HEALTHCARE, 2011, CLINICAL AND EXPERIMENTAL HYPERTENSION, 33(1) (1), 9 - 9, English

  Summary international conference


• Serum Myeloperoxidase/Paraoxonase 1 Ratio Is an Independent Predictor for Repeat Revascularization After Percutaneous Coronary Intervention

  Yoko Haraguchi, Ryuji Toh, Minoru Hasokawa, Hideto Nakajima, Tomoyuki Honjo, Kazunori Otsui, Kunihiro Nishimura, Tatsuro Ishida, Ken-ichi Hirata

  LIPPINCOTT WILLIAMS & WILKINS, Nov. 2010, CIRCULATION, 122(21) (21), English

  Summary international conference


• Response [2]

  Nobutaka Inoue, Junya Ejiri, Seiichi Kobayashi, Rio Shiraki, Kazunori Otsui, Tomoyuki Honjo, Motonori Takahashi, Toshiro Shinke, Junya Shite, Ken-Ichi Hirata, Seinosuke Kawashima, Mitsuhiro Yokoyama, Hiroshi Yokozaki, Takao Mori, Yoshitaka Ohashi, Shinobu Ichikawa, Mitsuyasu Terashima, Kojiro Awano

  Apr. 2006, Circulation, 113(16) (16), e724 - e725, English

  Report scientific journal

• 最新醫學 診断と治療のABC 138 高TG血症 / 高TG血症の管理と治療 3．治療薬剤 2）多価不飽和脂肪酸

  森健太, Otsui Kazunori, 平田健一

  Others, 最新醫學別冊, Sep. 2018, Japanese

  Scholarly book

• 低Na血症を認め、無菌性髄膜炎を伴うリンパ球性下垂体炎と診断した1例

  馬 艶, 德永 俊太郎, 南地 克洋, 笠松 朗, 三好 園子, Mori Hiroyuki, Otsui Kazunori, Fukuoka Hidenori, Sakaguchi Kazuhiko, Ogawa Wataru

  第215回日本内科学会近畿地方会, Mar. 2017, Japanese, 日本内科学会近畿地方会, 神戸, Domestic conference

  Oral presentation


• 急速に進行する低Na血症を契機に診断できた無菌性髄膜炎を伴うリンパ球性下垂体炎の1例

  馬 艶, 徳永俊太郎, 南地克洋, 笠松 朗, 三好園子, Mori Hiroyuki, Otsui Kazunori, Sakaguchi Kazuhiko

  第215回日本内科学会近畿地方会, Mar. 2017, Japanese, 日本内科学会, 兵庫, Domestic conference

  Oral presentation


• Over workMightAccelerateThromboticReaction

  Otsui Kazunori

  第81回日本循環器学会学術集会, Mar. 2017, Japanese, 日本循環器学会, 石川, Domestic conference

  Poster presentation


• 腹部大動脈瘤による消費性凝固障害にステントグラフト内挿術が有用であった高齢者の1例

  丸口勇人, 徳永俊太郎, 南地克洋, 笠松朗, 三好園子, Mori Hiroyuki, Otsui Kazunori, 安田尚史, Sakaguchi Kazuhiko, Ogawa Wataru

  第214回日本内科学会近畿地方会, Dec. 2016, Japanese, 日本内科学会, 大阪, Domestic conference

  Oral presentation


• 第64回日本職業・災害医学会学術大会

  Otsui Kazunori, 福山和枝, 井上信孝

  第64回日本職業・災害医学会学術大会, Oct. 2016, Japanese, 日本職業・災害医学会, 宮城, Domestic conference

  Oral presentation


• 頚部痛を主訴に受診した若年発症急性心筋梗塞の1例

  村上 慎吾, Mori Hiroyuki, 南地 克洋, 德永 俊太郎, 笠松 朗, 三好 園子, Otsui Kazunori, Sakaguchi Kazuhiko, Ogawa Wataru

  第213回日本内科学会近畿地方会, Sep. 2016, Japanese, 日本内科学会近畿地方会, 大阪, Domestic conference

  Oral presentation


• クリプトコッカス髄膜炎の再燃時にクリプトコッカス骨髄炎を合併した1例

  谷藤 貴紀, 南地 克洋, 德永 俊太郎, 笠松 朗, 三好 園子, Mori Hiroyuki, Otsui Kazunori, Sakaguchi Kazuhiko, Ogawa Wataru

  第212回日本内科学会近畿地方会, Jun. 2016, Japanese, 大阪, Domestic conference

  Oral presentation


• グルコースクランプ法を用いて検討した原発性アルドステロン症の手術前後の病態変化

  Otsui Kazunori, 吉岡隆之, 平山園子, 小澤徹, 岩田幸代, 武居明日美, 稲本真也, 井上信孝

  第113回日本内科学会総会, Apr. 2016, Japanese, 日本内科学会, 東京, Domestic conference

  Oral presentation


• he Direct Factor Xa Inhibitors Have a Differential Effect on Endogenous Thrombolysis Compared with Warfarin

  Otsui Kazunori, T. Yoshioka, S. Hirayama, T. Ozawa, S. Iwata, A. Takei, S. Inamoto, N. Inoue

  第80回日本循環器学会学術集会, Mar. 2016, Japanese, 日本循環器学会, 宮城, Domestic conference

  Poster presentation