Updated on 2022/06/30

写真a

 
AKAGI Satoshi
 
Organization
Faculty of Medicine, Dentistry and Pharmaceutical Sciences Assistant Professor
Position
Assistant Professor
External link

Degree

  • 博士(医学) ( 2009.4   岡山大学 )

  • 博士

 

Papers

  • Efficacy of shear wave elasticity for evaluating myocardial hypertrophy in hypertensive rats. International journal

    Yoichi Takaya, Kazufumi Nakamura, Rie Nakayama, Hiroaki Ohtsuka, Naofumi Amioka, Megumi Kondo, Kaoru Akazawa, Yuko Ohno, Keishi Ichikawa, Yukihiro Saito, Satoshi Akagi, Masashi Yoshida, Toru Miyoshi, Hiroshi Ito

    Scientific reports   11 ( 1 )   22812 - 22812   2021.11

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    Shear wave (SW) imaging is a novel ultrasound-based technique for assessing tissue characteristics. SW elasticity may be useful to assess the severity of hypertensive left ventricular (LV) hypertrophy. This study aimed to evaluate the efficacy of SW elasticity for assessing the degree of myocardial hypertrophy using hypertensive rats. Rats were divided into hypertension group and control group. SW elasticity was measured on the excised heart. Myocardial hypertrophy was assessed histologically. LV weight was greater in hypertension group. An increase in interventricular septum and LV free wall thicknesses was observed in hypertension group. SW elasticity was significantly higher in hypertension group than in control group (14.6 ± 4.3 kPa vs. 6.5 ± 1.1 kPa, P < 0.01). The cross-sectional area of cardiomyocytes was larger in hypertension group than in control group (397 ± 50 μm2 vs. 243 ± 14 μm2, P < 0.01), and SW elasticity was positively correlated with the cross-sectional area of cardiomyocytes (R = 0.96, P < 0.01). This study showed that SW elasticity was higher in hypertensive rats and was closely correlated with the degree of myocardial hypertrophy, suggesting the efficacy of SW elasticity for estimating the severity of hypertensive LV hypertrophy.

    DOI: 10.1038/s41598-021-02271-6

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  • Fragmented QRS as a predictor of cardiac events in patients with cardiac sarcoidosis. Reviewed International journal

    Soichiro Ogura, Kazufumi Nakamura, Hiroshi Morita, Koji Nakagawa, Nobuhiro Nishii, Satoshi Akagi, Norihisa Toh, Yoichi Takaya, Masashi Yoshida, Toru Miyoshi, Atsuyuki Watanabe, Hiroshi Ito

    Journal of cardiology   2021.11

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    BACKGROUND: Multiple spikes within the QRS complex, known as fragmented QRS (fQRS), are associated with the occurrences of ventricular arrhythmic events (VAEs) in patients with Brugada syndrome and hypertrophic cardiomyopathy. However, the association between fQRS and occurrence of VAEs in patients with cardiac sarcoidosis (CS) has not been elucidated. METHODS: We evaluated the associations between fQRS and cardiac events including VAEs [non-sustained ventricular tachycardia (NSVT), sustained ventricular tachycardia (VT), and ventricular fibrillation (VF)], hospitalization for heart failure, and all-cause death in 68 patients with CS (30 patients with fQRS vs. 38 patients without fQRS) over a 5-year period. RESULTS: Cardiac events occurred in 22 patients with fQRS and 18 patients without fQRS (73% vs. 47%, p=0.009). Of the cardiac events that occurred in CS patients, VAEs occurred more frequently in patients with fQRS than in patients without fQRS (VAEs: 70% vs. 45%, p=0.017; NSVT: 70% vs. 45%, p=0.010; VT: 43% vs. 18%, p=0.011, and VF: 6.7% vs. 2.6%, p=0.34), whereas there was no significant difference in hospitalization for heart failure or all-cause death between patients with and those without fQRS (hospitalization for heart failure: 6.7% vs. 5.3%, p=0.75; all-cause death: 6.7% vs. 5.3%, p=0.64). Multivariate analysis showed that fQRS in the baseline electrocardiogram was independently associated with VAEs (hazard ratio: 2.21, 95% confidence interval: 1.15-4.25, p=0.017). CONCLUSION: fQRS is a predictor of VAEs in patients with CS.

    DOI: 10.1016/j.jjcc.2021.10.022

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  • A case of a middle-aged patient with a ventricular septal defect complicated by severe pulmonary hypertension-stepwise surgical repair with pulmonary vasodilators. Reviewed

    Anna Kanai, Norimichi Koitabashi, Satoshi Akagi, Hidemi Sorimachi, Yohei Ishibashi, Takashi Nagasaka, Noriaki Takama, Katsura Soma, Atsushi Yao, Shingo Kasahara, Masahiko Kurabayashi

    Journal of cardiology cases   24 ( 3 )   131 - 135   2021.9

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    We report a case of ventricular septal defect (VSD) in which we attempted to treat pulmonary arterial hypertension (PAH) with the goal of VSD closure in an adult with suspected Eisenmenger syndrome in childhood. Four years previously (age 41 years), she was referred to our department due to repeated hemoptysis requiring further treatment of PAH. We started combination therapy with several pulmonary vasodilators. Two years later, her pulmonary vascular resistance (PVR) was improved but still not at the level where VSD closure was possible. To control the increased PA flow resulting from intensive PAH treatment and to reduce the risk of hemoptysis, we performed pulmonary artery banding (PAB). As the risk of hemoptysis decreased, a prostacyclin analog was introduced, and the dose was increased. More than 1 year after PAB, active vasoactivity testing became positive, suggesting that the pulmonary vascular lesion was now "reversible". We performed VSD closure and atrial septal defect creation even though her PVR was still high. After the operation, her exercise capacity was remarkably improved. We suggest that stepwise surgical repair with pulmonary vasodilators is an important treatment option for select patients with VSD with severe PAH. <Learning objective: Advances in pulmonary arterial hypertension (PAH) treatment have led to the use of a "treat-and-repair" strategy to close the intracardiac shunt after PAH treatment in select patients with adult congenital heart disease. In our case, ventricular septal defect (VSD) closure was achieved with stepwise surgical repair and a combination of pulmonary vasodilators, even though long-standing severe PAH with persistent hemoptysis remained. Even after a long period of exposure to high blood flow, this strategy may reduce pulmonary vascular resistance and permit eventual closure of the VSD.>.

    DOI: 10.1016/j.jccase.2021.02.013

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  • Pathological and clinical effects of interleukin-6 on human myocarditis. Reviewed International journal

    Naofumi Amioka, Kazufumi Nakamura, Tomonari Kimura, Keiko Ohta-Ogo, Takehiro Tanaka, Tomohiro Toji, Satoshi Akagi, Koji Nakagawa, Norihisa Toh, Masashi Yoshida, Toru Miyoshi, Nobuhiro Nishii, Atsuyuki Watanabe, Ryotaro Asano, Takeshi Ogo, Yoshikazu Nakaoka, Hiroshi Morita, Hiroyuki Yanai, Hiroshi Ito

    Journal of cardiology   78 ( 2 )   157 - 165   2021.8

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    BACKGROUND: Numerous basic studies have shown a relationship between interleukin-6 (IL-6) and the development or severity of myocarditis. However, there has been no study in which the effect of IL-6 levels in patients with myocarditis was evaluated. METHODS: We enrolled control patients (n = 12) and consecutive patients with acute myocarditis (n = 13), including lymphocytic, eosinophilic, and giant cell myocarditis, and investigated the pathological and clinical effects of IL-6 on human myocarditis. RESULTS: The serum IL-6 level in patients with myocarditis (16.7 [9.9, 103.8] pg/mL) was significantly higher than that in the control patients (1.4 [1.0, 1.9] pg/mL) (P<0.001). Immunohistochemical analysis showed that IL-6 was expressed in infiltrating inflammatory cells of endomyocardial biopsy samples from all patients with myocarditis. Moreover, the log-transformed value of serum IL-6 level showed significant positive correlations with serum creatine kinase (CK) level, CK-MB level, peak CK level, peak CK-MB level and C-reactive protein level (all P ≤ 0.005) and a negative correlation with the left ventricular (LV) ejection fraction (p = 0.014). We divided the patients with myocarditis into a low IL-6 group (9.9 [4.5, 14.2] pg/dL, n = 7) and a high IL-6 group (108.9 [51.1, 130.9] pg/dL, n = 6). The degree of infiltration of IL-6-expressing inflammatory cells in myocardial samples obtained from patients in the high IL-6 group was significantly more severe than that in samples obtained from patients in the low IL-6 group. Furthermore, patients in the high IL-6 group significantly more frequently received catecholamine therapy (P = 0.005), venoarterial extracorporeal membrane oxygenation (P = 0.029), and artificial respirator support (P = 0.021) in the acute phase of myocarditis. CONCLUSION: The results suggest that there is a strong impact of IL-6 on cardiac injury and dysfunction in patients with myocarditis.

    DOI: 10.1016/j.jjcc.2021.03.003

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  • Serum and pulmonary uric acid in pulmonary arterial hypertension. Reviewed International journal

    Laurent Savale, Satoshi Akagi, Ly Tu, Amélie Cumont, Raphaël Thuillet, Carole Phan, Benjamin Le Vely, Nihel Berrebeh, Alice Huertas, Xavier Jaïs, Vincent Cottin, Ari Chaouat, Cécile Tromeur, Athénaïs Boucly, Etienne Marie Jutant, Olaf Mercier, Elie Fadel, David Montani, Olivier Sitbon, Marc Humbert, Yuichi Tamura, Christophe Guignabert

    The European respiratory journal   58 ( 2 )   2021.8

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    Previous studies have suggested an association between uric acid (UA) and the severity of pulmonary arterial hypertension (PAH), but it is unknown whether UA contributes to disease pathogenesis.The aim of this study was to determine the prognostic value of circulating UA in the era of current management of PAH and to investigate the role of UA in pulmonary vascular remodelling.Serum UA levels were determined in idiopathic, heritable or anorexigen PAH at baseline and first re-evaluation in the French Pulmonary Hypertension Network. We studied protein levels of xanthine oxidase (XO) and the voltage-driven urate transporter 1 (URATv1) in lungs of control and PAH patients and of monocrotaline (MCT) and Sugen/hypoxia (SuHx) rats. Functional studies were performed using human pulmonary artery smooth muscle cells (PA-SMCs) and two animal models of pulmonary hypertension (PH).High serum UA levels at first follow-up, but not at baseline, were associated with a poor prognosis. Both the generating enzyme XO and URATv1 were upregulated in the wall of remodelled pulmonary arteries in idiopathic PAH patients and MCT and SuHx rats. High UA concentrations promoted a mild increase in cell growth in idiopathic PAH PA-SMCs, but not in control PA-SMCs. Consistent with these observations, oxonic acid-induced hyperuricaemia did not aggravate MCT-induced PH in rats. Finally, chronic treatment of MCT and SuHx rats with benzbromarone mildly attenuated pulmonary vascular remodelling.UA levels in idiopathic PAH patients were associated with an impaired clinical and haemodynamic profile and might be used as a non-invasive indicator of clinical prognosis during follow-up. Our findings also indicate that UA metabolism is disturbed in remodelled pulmonary vascular walls in both experimental and human PAH.

    DOI: 10.1183/13993003.00332-2020

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  • Inhibitory effects of RAGE-aptamer on development of monocrotaline-induced pulmonary arterial hypertension in rats. Reviewed International journal

    Kazufumi Nakamura, Satoshi Akagi, Kentaro Ejiri, Masashi Yoshida, Toru Miyoshi, Masakiyo Sakaguchi, Naofumi Amioka, Luh Oliva Saraswati Suastika, Megumi Kondo, Rie Nakayama, Yoichi Takaya, Yuichiro Higashimoto, Kei Fukami, Hiromi Matsubara, Hiroshi Ito

    Journal of cardiology   78 ( 1 )   12 - 16   2021.7

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    BACKGROUND: The receptor for advanced glycation end products (RAGE), a transmembrane receptor belonging to the immunoglobulin superfamily, is overexpressed in pulmonary artery smooth muscle cells (PASMCs) in patients with pulmonary arterial hypertension (PAH) and is implicated in the etiology of PAH. Recently, we reported that RAGE-aptamer, a short and single-stranded DNA directed against RAGE, inhibited an inappropriate increase in cultured PASMCs in PAH. The aim of this study was to determine the efficacy of RAGE-aptamer in monocrotaline-induced PAH in rats. METHODS AND RESULTS: Rats were assigned to either an untreated control group, a group that received continuous subcutaneous administration of RAGE-aptamer immediately after monocrotaline injection, or a group that received control-aptamer immediately after monocrotaline injection. All rats survived 21 days after injection of monocrotaline and control-aptamer or RAGE-aptamer. Injection of monocrotaline with continuous subcutaneous delivery of control-aptamer resulted in higher right ventricular systolic pressure compared with controls. This increase was attenuated by continuous subcutaneous delivery of RAGE-aptamer. The proportion of small pulmonary arteries with full muscularization was greater in the monocrotaline and control-aptamer group than in the control group. Continuous subcutaneous delivery of RAGE-aptamer significantly reduced the percentage of small pulmonary arteries with full muscularization. CONCLUSIONS: Continuous subcutaneous delivery of RAGE-aptamer suppresses development of monocrotaline-induced PAH in rats. Inhibition of RAGE ameliorates muscularization of small pulmonary arteries. Treatment with RAGE-aptamer might be a new therapeutic option for PAH.

    DOI: 10.1016/j.jjcc.2020.12.009

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  • Efficacy of shear wave elastography for evaluating right ventricular myocardial fibrosis in monocrotaline-induced pulmonary hypertension rats. Reviewed International journal

    Rie Nakayama, Yoichi Takaya, Kazufumi Nakamura, Megumi Kondo, Kaoru Kobayashi, Yuko Ohno, Naofumi Amioka, Satoshi Akagi, Masashi Yoshida, Toru Miyoshi, Hiroshi Ito

    Journal of cardiology   78 ( 1 )   17 - 23   2021.7

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    BACKGROUND: Right ventricular (RV) function is important for outcomes in pulmonary hypertension. Evaluation of RV myocardial characteristics is useful to assess the disease severity. Shear wave elastography (SWE) provides information of shear wave (SW) elasticity, which is related to tissue hardness, and SW dispersion slope, which reflects tissue viscosity. This study aimed to test the hypothesis that SW elasticity is increased and SW dispersion slope is decreased in the right ventricle of monocrotaline (MCT)-induced pulmonary hypertension rats. METHODS: Rats were divided into MCT-induced pulmonary hypertension group (n = 10) and control group (n = 10). SW elasticity and SW dispersion slope were measured on excised hearts. Myocardial fibrosis was evaluated histologically. RESULTS: RV hypertrophy was observed in the MCT group. SW elasticity of right ventricle was higher in the MCT group than in the control group (3.5 ± 0.9 kPa vs. 2.5 ± 0.4 kPa, p < 0.01). SW dispersion slope of right ventricle was lower in the MCT group than in the control group (5.3 ± 1.7 m/s/kHz vs. 7.7 ± 1.5 m/s/kHz, p < 0.01). The fibrosis area of right ventricle was increased in MCT group compared with control group (18 ± 5% vs. 8 ± 3%, p < 0.01), and was positively related to SW elasticity and negatively related to SW dispersion slope. CONCLUSIONS: Higher SW elasticity and lower SW dispersion slope were observed in the fibrotic myocardium of right ventricle in MCT-induced pulmonary hypertension rats. SWE may have the potential to evaluate RV function by assessing myocardial characteristics.

    DOI: 10.1016/j.jjcc.2021.01.015

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  • Effects of Dual Initial Combination Therapy With Macitentan Plus Riociguat or Macitentan Plus Selexipag on Hemodynamics in Patients With Pulmonary Arterial Hypertension (SETOUCHI-PH Study) - Protocol of a Multicenter Randomized Control Trial. Reviewed

    Satoshi Akagi, Yoshihiro Dohi, Kaori Ishikawa, Kayoko Kubota, Koshin Horimoto, Shusuke Yagi, Tetsuo Hirata, Eiichiro Yamamoto, Hiroshi Ito, Kazufumi Nakamura

    Circulation reports   3 ( 2 )   105 - 109   2021.1

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    Background: The latest guideline from the European Society of Cardiology and European Respiratory Society recommends initial combination therapy with oral pulmonary arterial hypertension (PAH)-specific drugs in PAH patients with World Health Organization functional class (WHO-FC) II or III. However, whether this initial combination therapy improves hemodynamics and clinical failure events regardless of the combination of PAH-specific drugs remains unknown. This study was designed to evaluate whether the initial combination therapy with macitentan plus riociguat or macitentan plus selexipag showed equal efficacy in reducing pulmonary vascular resistance (PVR) 8 months after administration. Methods and Results: This study is a multicenter randomized control trial. PAH subjects with WHO-FC II or III will be randomized (1 : 1) into initial combination therapy with either macitentan plus riociguat or macitentan plus selexipag, and will be observed 8 months after the initiation of treatment. The primary endpoint will be the difference in the change ratio of PVR from baseline to after 8 months of treatment. Conclusions: The SETOUCHI-PH study will clarify whether initial combination therapy with macitentan plus riociguat or macitentan plus selexipag results in equal reductions in PVR 8 months after administration.

    DOI: 10.1253/circrep.CR-20-0133

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  • Effect of Luseogliflozin on Heart Failure With Preserved Ejection Fraction in Patients With Diabetes Mellitus. Reviewed International journal

    Kentaro Ejiri, Toru Miyoshi, Hajime Kihara, Yoshiki Hata, Toshihiko Nagano, Atsushi Takaishi, Hironobu Toda, Seiji Nanba, Yoichi Nakamura, Satoshi Akagi, Satoru Sakuragi, Taro Minagawa, Yusuke Kawai, Nobuhiro Nishii, Soichiro Fuke, Masaki Yoshikawa, Kazufumi Nakamura, Hiroshi Ito

    Journal of the American Heart Association   9 ( 16 )   e015103   2020.8

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    Background Effects of sodium-glucose cotransporter 2 inhibitors on reducing hospitalization for heart failure have been reported in randomized controlled trials, but their effects on patients with heart failure with preserved ejection fraction (HFpEF) are unknown. This study aimed to evaluate the drug efficacy of luseogliflozin, a sodium-glucose cotransporter 2 inhibitor, in patients with type 2 diabetes mellitus and HFpEF. Methods and Results We performed a multicenter, open-label, randomized, controlled trial for comparing luseogliflozin 2.5 mg once daily with voglibose 0.2 mg 3 times daily in patients with type 2 diabetes mellitus suffering from HFpEF (left ventricular ejection fraction >45% and BNP [B-type natriuretic peptide] concentrations ≥35 pg/mL) in a 1:1 randomization fashion. The primary outcome was the difference from baseline in BNP levels after 12 weeks of treatment between the 2 drugs. A total of 173 patients with diabetes mellitus and HFpEF were included. Of these, 83 patients were assigned to receive luseogliflozin and 82 to receive voglibose. There was no significant difference in the reduction in BNP concentrations after 12 weeks from baseline between the 2 groups. The ratio of the mean BNP value at week 12 to the baseline value was 0.79 in the luseogliflozin group and 0.87 in the voglibose group (percent change, -9.0% versus -1.9%; ratio of change with luseogliflozin versus voglibose, 0.93; 95% CI, 0.78-1.10; P=0.26). Conclusion In patients with type 2 diabetes mellitus and HFpEF, there is no significant difference in the degree of reduction in BNP concentrations after 12 weeks between luseogliflozin and voglibose. Registration URL: https://www.umin.ac.jp/ctr/index.htm; Unique identifier: UMIN000018395.

    DOI: 10.1161/JAHA.119.015103

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  • Medical and surgical management of a pulmonary hypertensive adult patient with unrepaired complex congenital heart disease: a case report Reviewed

    Akagi Satosshi, Kasahara Shingo, Akagi Teiji, Nakamura Kazufumi, Ito Hiroshi

    2020.7

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  • Deficiency of CD44 prevents thoracic aortic dissection in a murine model. Reviewed International journal

    Omer F Hatipoglu, Toru Miyoshi, Tomoko Yonezawa, Megumi Kondo, Naofumi Amioka, Masashi Yoshida, Satoshi Akagi, Kazufumi Nakamura, Satoshi Hirohata, Hiroshi Ito

    Scientific reports   10 ( 1 )   6869 - 6869   2020.4

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    Thoracic aortic dissection (TAD) is a life-threatening vascular disease. We showed that CD44, a widely distributed cell surface adhesion molecule, has an important role in inflammation. In this study, we examined the role of CD44 in the development of TAD. TAD was induced by the continuous infusion of β-aminopropionitrile (BAPN), a lysyl oxidase inhibitor, and angiotensin II (AngII) for 7 days in wild type (WT) mice and CD44 deficient (CD44-/-) mice. The incidence of TAD in CD44-/- mice was significantly reduced compared with WT mice (44% and 6%, p < 0.01). Next, to evaluate the initial changes, aortic tissues at 24 hours after BAPN/AngII infusion were examined. Neutrophil accumulation into thoracic aortic adventitia in CD44-/- mice was significantly decreased compared with that in WT mice (5.7 ± 0.3% and 1.6 ± 0.4%, p < 0.01). In addition, BAPN/AngII induced interleukin-6, interleukin-1β, matrix metalloproteinase-2 and matrix metalloproteinase-9 in WT mice, all of which were significantly reduced in CD44-/- mice (all p < 0.01). In vitro transmigration of neutrophils from CD44-/- mice through an endothelial monolayer was significantly decreased by 18% compared with WT mice (p < 0.01). Our findings indicate that CD44 has a critical role in TAD development in association with neutrophil infiltration into adventitia.

    DOI: 10.1038/s41598-020-63824-9

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  • Successful Transition From Phosphodiesterase-5 Inhibitors to Riociguat Without a Washout Period in Patients With Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: A Pilot Cohort Study. Reviewed International journal

    Kazuhiro Kuroda, Satoshi Akagi, Kazufumi Nakamura, Toshihiro Sarashina, Kentaro Ejiri, Hiroshi Ito

    Heart, lung & circulation   29 ( 3 )   331 - 336   2020.3

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    BACKGROUND: Transition to pulmonary arterial hypertension (PAH)-specific drugs is considered in patients with PAH and chronic thromboembolic pulmonary hypertension who do not respond to combination therapy or who experience side effects to the combination drugs. Riociguat directly stimulates soluble guanylate cyclase independently of nitric oxide. Therefore, transition from a phosphodiesterase type 5 inhibitor (PDE5i), which requires nitric oxide to exert its effects, to riociguat might be effective. The length of time of washout periods for transition is important because haemodynamic instability sometimes occurs during these periods or during transition with no washout period. METHOD: We investigated the feasibility of transitioning from a PDE5i to riociguat without washout periods by monitoring haemodynamics under right heart catheterisation in six patients with PAH and one with chronic thromboembolic pulmonary hypertension who had already received dual- or triple-combination therapy. RESULTS: Reasons for transition were headache caused by a PDE5i in three patients, and an inadequate response to combination therapy in four. Transition was successful in all patients, with no haemodynamic instability observed. Pulmonary vascular resistance (from 797 ± 241 to 518 ± 230 dyne/s/cm-5) and systemic blood pressure (from 121 ± 13 to 100 ± 15 mmHg) were significantly reduced immediately after transition. There were no significant differences in the tricuspid regurgitation pressure gradient or systemic blood pressure during the post-transition and follow-up periods. Headaches caused by a PDE5i were diminished after transition to riociguat. CONCLUSIONS: Transition from a PDE5i to riociguat without a washout period is safe. This transition may be a viable option for patients with headaches caused by a PDE5i, or who have an inadequate response to combination therapy that includes a PDE5i.

    DOI: 10.1016/j.hlc.2019.01.013

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  • Chemotherapy Improved Pulmonary Arterial Hypertension in a Patient with Chronic-Active Epstein-Barr Virus Infection.

    Satoshi Akagi, Takashi Miki, Yasuhisa Sando, Nobuharu Fujii, Toshihiro Sarashina, Kazufumi Nakamura, Hiroshi Ito

    International heart journal   61 ( 1 )   191 - 194   2020.1

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    Chronic-active Epstein-Barr virus infection (CAEBV) is a rare disease that can lead to pulmonary arterial hypertension (PAH). However, the treatment for CAEBV-associated PAH has not been established. We discuss a case of improved pulmonary hypertension after chemotherapy in a patient with CAEBV-associated PAH. A 44-year old man was admitted to our hospital because of an abnormal electrocardiogram and liver dysfunction detected by annual medical examination. Echocardiography showed a dilated right ventricle and an estimated right ventricular systolic pressure of 92 mmHg. Right heart catheterization revealed a mean pulmonary arterial pressure of 45 mmHg and pulmonary vascular resistance of 9.8 Wood units. Laboratory examination showed granular lymphocytes and 91% natural killer cells in lymphocyte subsets in peripheral blood. We diagnosed the patient as having CAEBV-associated PAH. After two cycles of chemotherapy without PAH-specific drugs, echocardiography showed improvement in the dilated right ventricle and an estimated right ventricular systolic pressure of 59 mmHg. Right heart catheterization revealed a mean pulmonary arterial pressure of 27 mmHg and pulmonary vascular resistance of 2.4 Wood units. Chemotherapy may improve pulmonary hypertension in patients with CAEBV-associated PAH.

    DOI: 10.1536/ihj.19-419

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  • Marked Reduction of Pulmonary Artery Pressure After Registration for Lung Transplantation Is Associated With Long-Term Survival in Patients With Pulmonary Arterial Hypertension - Cohort Study.

    Satoshi Akagi, Hiromi Matsubara, Kazufumi Nakamura, Takahiro Oto, Kentaro Ejiri, Hiroshi Ito

    Circulation journal : official journal of the Japanese Circulation Society   84 ( 2 )   245 - 251   2020.1

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    BACKGROUND: The waiting period for lung transplantation (LT) is approximately 3 years in Japan. The prognosis of patients with pulmonary arterial hypertension (PAH) awaiting LT is poor without LT. Patients at the present center often survive in the long term after registration for LT. The aim of this study was to elucidate why some patients survive in the long term by investigating changes in pulmonary artery pressure (PAP) after registration, and medication used.Methods and Results:This study involved 57 patients with PAH who were enrolled in a registry for LT at Okayama University Hospital. We divided patients into 3 groups according to outcome: LT (n=27); death without LT (n=21); and survival without LT (n=9). The median interval from PAH diagnosis to epoprostenol treatment was shorter in the survival group (58 days) than in the LT group (378 days) and death group (545 days). Eight patients in the survival group, 13 in the LT group, and 13 in the death group underwent right heart catheterization after registration. Percent change in mean PAP after registration was significantly greater in the survival group (-32%) than in the LT group (-13%) and death group (1%; P<0.01). CONCLUSIONS: Even after LT registration, patients who received epoprostenol infusion soon after diagnosis of PAH often had marked reduction in PAP and long-term survival without LT.

    DOI: 10.1253/circj.CJ-19-0784

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  • 肺高血圧症に合併した肺動脈瘤の経過と転機について

    江尻 健太郎, 赤木 達, 中村 一文, 笠原 真悟, 伊藤 浩

    日本心臓病学会学術集会抄録   67回   P - 196   2019.9

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  • Crucial role of RAGE in inappropriate increase of smooth muscle cells from patients with pulmonary arterial hypertension. Reviewed International journal

    Kazufumi Nakamura, Masakiyo Sakaguchi, Hiromi Matsubara, Satoshi Akagi, Toshihiro Sarashina, Kentaro Ejiri, Kaoru Akazawa, Megumi Kondo, Koji Nakagawa, Masashi Yoshida, Toru Miyoshi, Takeshi Ogo, Takahiro Oto, Shinichi Toyooka, Yuichiro Higashimoto, Kei Fukami, Hiroshi Ito

    PloS one   13 ( 9 )   e0203046   2018.9

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    BACKGROUND: Pulmonary vascular remodeling of pulmonary arterial hypertension (PAH) is characterized by an inappropriate increase of vascular cells. The receptor for advanced glycation end products (RAGE) is a type I single-pass transmembrane protein belonging to the immunoglobulin superfamily and is involved in a broad range of hyperproliferative diseases. RAGE is also implicated in the etiology of PAH and is overexpressed in pulmonary artery smooth muscle cells (PASMCs) in patients with PAH. We examined the role of RAGE in the inappropriate increase of PASMCs in patients with PAH. METHODS AND RESULTS: PASMCs were obtained from 12 patients with PAH including 9 patients with idiopathic PAH (IPAH) and 3 patients with heritable PAH (HPAH) (2 patients with BMPR2 mutation and one patient with SMAD9 mutation) who underwent lung transplantation. Western blot analysis and immunofluorescence staining revealed that RAGE and S100A8 and A9, ligands of RAGE, were overexpressed in IPAH and HPAH-PASMCs in the absence of any external growth stimulus. PDGF-BB (10 ng/mL) up-regulated the expression of RAGE in IPAH and HPAH-PASMCs. PAH-PASMCs are hyperplastic in the absence of any external growth stimulus as assessed by 3H-thymidine incorporation. This result indicates overgrowth characterized by continued growth under a condition of no growth stimulation in PAH-PASMCs. PDGF-BB stimulation caused a higher growth rate of PAH-PASMCs than that of non-PAH-PASMCs. AS-1, an inhibitor of TIR domain-mediated RAGE signaling, significantly inhibited overgrowth characterized by continued growth under a condition of no growth stimulation in IPAH and HPAH-PASMCs (P<0.0001). Furthermore, AS-1 significantly inhibited PDGF-stimulated proliferation of IPAH and HPAH-PASMCs (P<0.0001). CONCLUSIONS: RAGE plays a crucial role in the inappropriate increase of PAH-PASMCs. Inhibition of RAGE signaling may be a new therapeutic strategy for PAH.

    DOI: 10.1371/journal.pone.0203046

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  • Treat-and-repair strategy is a feasible therapeutic choice in adult patients with severe pulmonary arterial hypertension associated with a ventricular septal defect: case series. Reviewed International journal

    Satoshi Akagi, Shingo Kasahara, Toshihiro Sarashina, Kazufumi Nakamura, Hiroshi Ito

    European heart journal. Case reports   2 ( 2 )   yty033   2018.6

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    Introduction: Recent advances in pulmonary arterial hypertension (PAH)-specific drugs have dramatically changed the therapeutic strategy for PAH. A strategy that includes 'treatment' with PAH-specific drugs initially and then 'repair' by closure of the cardiac defect (i.e. 'treat and repair') was devised, and has been attempted, in patients with PAH associated with a cardiac defect. Case presentation: We present three cases of severe PAH associated with a ventricular septal defect (VSD) in adult patients who were initially treated with PAH-specific drugs followed by VSD closure. Two of the patients were treated with a combination of an endothelin receptor antagonist (ERA), phosphodiesterase type 5 inhibitor, and intravenous prostacyclin before VSD closure. The third patient was treated with an ERA and pulmonary artery banding before VSD closure. After 12 months of anti-PAH treatment, the pulmonary vascular resistance index and the ratio of the pulmonary vascular index to the systemic vascular resistance index decreased to levels that allowed VSD closure. At the mid- and long-term follow-up measurements after surgical closure of the VSD, the mean pulmonary artery pressure had markedly decreased. Discussion: Our case series suggests that the treat-and-repair strategy is a promising approach for adult patients with severe PAH associated with VSD.

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  • Progression of pulmonary artery dilatation in patients with pulmonary hypertension coexisting with a pulmonary artery aneurysm. Reviewed International journal

    Satoshi Akagi, Kazufumi Nakamura, Toshihiro Sarashina, Kentaro Ejiri, Shingo Kasahara, Hiroshi Ito

    Journal of cardiology   71 ( 5 )   517 - 522   2018.5

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    BACKGROUND: Pulmonary artery (PA) dilatation is usually observed in patients with pulmonary hypertension (PH), but a PA aneurysm (PA diameter > 40mm) is rare. The difference between characteristics of patients with and those without progression of PA diameter remains poorly understood. We assessed the changes in PA diameter in patients with PH coexisting with and without a PA aneurysm. METHODS: We investigated the changes in PA diameter by multi-detector computed tomography performed twice with an interval of more than one year in 44 patients with PH. Seventeen patients had a PA aneurysm and 27 patients did not have a PA aneurysm at baseline. RESULTS: The median follow-up period was 3.6 years. All patients received medical or invasive treatment for PH. At baseline, main PA diameters were 52±15mm in patients with a PA aneurysm and 33±3mm in patients without a PA aneurysm. Mean PA pressure was higher in patients with a PA aneurysm than in those without a PA aneurysm (61±15mmHg vs. 51±16mmHg, p=0.04). At follow-up, mean PA pressure significantly decreased in both patients with a PA aneurysm (44±11mmHg) and patients without a PA aneurysm (41±18mmHg). Main PA diameter significantly increased in patients with a PA aneurysm (65±28mm, change ratio: 23.3%), while it did not increase in patients without a PA aneurysm (32±3mm, change ratio: -3.1%). CONCLUSIONS: PA dilatation progressed in patients with a PA aneurysm despite treatment of PH. The progression of PA dilatation is independent of reduction of PA pressure by PH treatment.

    DOI: 10.1016/j.jjcc.2017.11.005

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  • Suppression of Wnt Signaling and Osteogenic Changes in Vascular Smooth Muscle Cells by Eicosapentaenoic Acid. Reviewed International journal

    Yukihiro Saito, Kazufumi Nakamura, Daiji Miura, Kei Yunoki, Toru Miyoshi, Masashi Yoshida, Norifumi Kawakita, Tomonari Kimura, Megumi Kondo, Toshihiro Sarashina, Satoshi Akagi, Atsuyuki Watanabe, Nobuhiro Nishii, Hiroshi Morita, Hiroshi Ito

    Nutrients   9 ( 8 )   17574 - 17582   2017.8

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    Vascular medial calcification is often observed in patients with arteriosclerosis. It is also associated with systolic hypertension, wide pulse pressure, and fluctuation of blood pressure, which results in cardiovascular events. Eicosapentaenoic acid (EPA) has been shown to suppress vascular calcification in previous animal experiments. We investigated the inhibitory effects of EPA on Wnt signaling, which is one of the important signaling pathways involved in vascular calcification. Intake of food containing 5% EPA resulted in upregulation of the mRNA expression of Klotho, an intrinsic inhibitor of Wnt signaling, in the kidneys of wild-type mice. Expression levels of β-catenin, an intracellular signal transducer in the Wnt signaling pathway, were increased in the aortas of Klotho mutant (kl/kl) mice compared to the levels in the aortas of wild-type mice. Wnt3a or BIO, a GSK-3 inhibitor that activates β-catenin signaling, upregulated mRNA levels of AXIN2 and LEF1, Wnt signaling marker genes, and RUNX2 and BMP4, early osteogenic genes, in human aorta smooth muscle cells. EPA suppressed the upregulation of AXIN2 and BMP4. The effect of EPA was cancelled by T0070907, a PPARγ inhibitor. The results suggested that EPA could suppress vascular calcification via the inhibition of Wnt signaling in osteogenic vascular smooth muscle cells via PPARγ activation.

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  • High Frequency of Acute Adverse Cardiovascular Events After Lung Transplantation in Patients With Pulmonary Arterial Hypertension Receiving Preoperative Long-Term Intravenous Prostacyclin. Reviewed

    Satoshi Akagi, Takahiro Oto, Motomu Kobayashi, Kentaroh Miyoshi, Seiichiro Sugimoto, Masaomi Yamane, Kazufumi Nakamura, Toshihiro Sarashina, Shinichiro Miyoshi, Hiroshi Ito

    International heart journal   58 ( 4 )   557 - 561   2017.8

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    Adverse cardiovascular events after lung transplantation (LT) increase the mortality in patients with pulmonary arterial hypertension (PAH). Long-term intravenous prostacyclin is the usual treatment in severe patients with PAH, but it may increase the risk of hemorrhage due to its antiplatelet aggregation effect or thrombocytopenia. We investigated the impact of length of intravenous prostacyclin therapy on acute adverse cardiovascular events including hemorrhagic complication after LT. We retrospectively compared the incidence of adverse events (death, intrathoracic hematoma and bleeding, cardiac congestion or shock, cerebral infarction and pulmonary embolism) within 30 days after LT between no/short-term (median 0.6 years, n = 13) and long-term (median 3.7 years, n = 15) intravenous prostacyclin groups. There were no differences in the dose of intravenous prostacyclin and pulmonary artery pressure between the two groups. Among 22 adverse events (0.8 ± 1.1 events/patient), 4 events occurred in the no/short-term intravenous prostacyclin group and 18 occurred in the long-term intravenous prostacyclin group. The event rate per patient in the long-term intravenous prostacyclin group (1.2 ± 1.3 events/patient) was significantly higher than that in the no/short-term intravenous prostacyclin group (0.3 ± 0.5 events/patient) (P < 0.05). Intrathoracic hematoma and bleeding was the most frequent adverse event (9 events, 41%). Preoperative long-term intravenous prostacyclin therapy increases acute adverse cardiovascular events after LT in patients with PAH.

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  • Reverse Right Ventricular Remodeling After Lung Transplantation in Patients With Pulmonary Arterial Hypertension Under Combination Therapy of Targeted Medical Drugs. Reviewed

    Toshihiro Sarashina, Kazufumi Nakamura, Satoshi Akagi, Takahiro Oto, Hiroki Oe, Kentaro Ejiri, Koji Nakagawa, Nobuhiro Nishii, Hiromi Matsubara, Motomu Kobayashi, Hiroshi Morimatsu, Shinichiro Miyoshi, Hiroshi Ito

    Circulation journal : official journal of the Japanese Circulation Society   81 ( 3 )   383 - 390   2017.2

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    BACKGROUND: Patients with pulmonary arterial hypertension (PAH) are currently treated with combination therapy of PAH-targeted drugs. Reverse right ventricular (RV) remodeling after lung transplantation (LTx) in patients with end-stage PAH despite combination therapy of PAH-targeted drugs has not been fully elucidated.Methods and Results:A total of 136 patients, including 32 with PAH, underwent LTx from 1998 to 2014. We enrolled 12 consecutive patients with PAH treated with combination therapy of PAH-targeted drugs who underwent LTx and retrospectively analyzed the temporal and serial changes in hemodynamics and echocardiography before LTx and at 3 and 12 months after LTx. Before LTx, the RV was markedly dilated with substantially reduced RV fractional area change (RVFAC). At 3 months after LTx, pulmonary artery pressure, pulmonary vascular resistance and RV stroke work index were significantly decreased, while left ventricular stroke work index was increased. RV size assessed by echocardiography also significantly decreased and RVFAC improved. At 12 months after LTx, RVFAC was further increased and RV wall thickness was decreased significantly. CONCLUSIONS: Although severe RV dysfunction and dilation were observed in patients with end-stage PAH despite combination therapy of PAH-targeted drugs, RV function and morphology were improved after reduction of RV pressure load by LTx.

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  • Feasibility of Repairing Defects Followed by Treatment with Pulmonary Hypertension-specific Drugs (Repair and Treat) in Patients with Pulmonary Hypertension Associated with Atrial Septal Defect: Study Protocol for Interventional Trial. Reviewed

    Satoshi Akagi, Kazufumi Nakamura, Teiji Akagi, Koji Nakagawa, Yoichi Takaya, Toshihiro Sarashina, Kentaro Ejiri, Hiroshi Ito

    Acta medica Okayama   70 ( 5 )   397 - 400   2016.10

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    A treatment strategy for patients with pulmonary hypertension (PH) and atrial septal defect (ASD) remains unclear. This study was designed to evaluate the effects of initial repair of ASD followed by treatment with PH-specific drugs in patients with PH and ASD. Eligible patients receive transcatheter ASD closure followed by treatment with bosentan and sildenafil. Right heart catheterization is performed at baseline and at 12, 24 and 48 weeks. The primary endpoint is change in pulmonary artery pressure and pulmonary vascular resistance from baseline to follow-up. This study should provide valuable information to establish a therapeutic strategy for PH and ASD.

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  • Translational research on pulmonary hypertension Reviewed

    Kazufumi Nakamura*,Satoshi Akagi*

    Respiration and Circulation   64 ( 6 )   582 - 587   2016.6

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  • Intratracheal Administration of Prostacyclin Analogue-incorporated Nanoparticles Ameliorates the Development of Monocrotaline and Sugen-Hypoxia-induced Pulmonary Arterial Hypertension. Reviewed International journal

    Satoshi Akagi, Kazufumi Nakamura, Hiromi Matsubara, Megumi Kondo, Daiji Miura, Tetsuya Matoba, Kensuke Egashira, Hiroshi Ito

    Journal of cardiovascular pharmacology   67 ( 4 )   290 - 8   2016.4

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    Nanoparticles (NPs) have been used as novel drug delivery systems. Drug-incorporated NPs for local delivery might optimize the efficacy and minimize the side effects of drugs. Intravenous prostacyclin improves long-term survival in patients with pulmonary arterial hypertension (PAH), but it causes serious side effects such as catheter-related infections. We investigated the efficacy and safety of intratracheal administration of a prostacyclin analogue, beraprost (BPS), incorporated NPs in Sugen-hypoxia-normoxia and monocrotaline rat models of PAH and in human PAH pulmonary arterial smooth muscle cells (PASMCs). After a single administration, BPS NPs significantly decreased right ventricular pressure, right ventricular hypertrophy, and pulmonary artery muscularization in the 2 rat models. BPS NPs significantly improved the survival rate in the monocrotaline rat model. No infiltration of inflammatory cells, hemorrhage, or fibrosis was found in the liver, kidney, spleen, and heart after the administration of BPS NPs. No liver or kidney dysfunction was found in the blood examinations. BPS and BPS NPs significantly inhibited the proliferation of human PAH PASMCs after 24 hours of treatment. BPS NPs significantly continued to inhibit the proliferation of human PAH PASMCs at 24 hours after the removal of BPS NPs. BPS NPs significantly induced apoptosis in PAH PASMCs compared to that in non-PAH PASMCs. Intratracheal administration of BPS NPs ameliorates pulmonary hypertension in PAH rat models by a sustained antiproliferative effect and a proapoptotic effect on PAH PASMCs.

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  • Treat and Repair Strategy in Patients With Atrial Septal Defect and Significant Pulmonary Arterial Hypertension. Reviewed

    Yasufumi Kijima, Teiji Akagi, Yoichi Takaya, Satoshi Akagi, Koji Nakagawa, Kengo Kusano, Shunji Sano, Hiroshi Ito

    Circulation journal : official journal of the Japanese Circulation Society   80 ( 1 )   227 - 34   2016

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    BACKGROUND: A therapeutic strategy in patients with atrial septal defect (ASD) and significant pulmonary arterial hypertension (PAH) remains controversial. This study aimed to assess the effect of PAH-specific medications and subsequent transcatheter shunt closure (ie, a treat and repair strategy) in these patients. METHODS AND RESULTS: Among 646 patients with ASD, 22 patients (mean age of 56±20 years) who had PAH [mean pulmonary artery pressure ≥25 mmHg and pulmonary vascular resistance (PVR) ≥3 Wood units] underwent successful transcatheter ASD closure. Prior to the procedure, 8 patients received PAH-specific medications (PHM group) and 14 patients did not (non-PHM group). Initially, the PHM group had higher PVR compared with non-PHM group (9.6±3.8 vs. 4.2±1.0 Wood units, P<0.01). After treatment with PAH-specific medications, PVR in this group decreased to 4.0±0.8 Wood units (P<0.01). No adverse events were observed in either the PHM or non-PHM group during or after the transcatheter procedure. In the PHM group, during a treatment period of 52±48 months, the World Health Organization Functional Classification significantly improved (3.0±0.5 to 2.0±0.0, P<0.01), as well as in the non-PHM group (2.1±0.6 to 1.5±0.5, P<0.01). CONCLUSIONS: Treat and repair strategy provided substantial improvement and no worsening of the WHO-FC, even in patients with ASD and significant PAH. Long-term hemodynamic follow-up is mandatory to evaluate the ultimate efficacy and safety of this new strategy.

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  • Epoprostenol Therapy for Pulmonary Arterial Hypertension. Invited Reviewed

    Satoshi Akagi, Kazufumi Nakamura, Hiromi Matsubara, Aiko Ogawa, Toshihiro Sarashina, Kentaro Ejiri, Hiroshi Ito

    Acta medica Okayama   69 ( 3 )   129 - 36   2015.8

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    Pulmonary arterial hypertension (PAH) is characterized by elevation of pulmonary artery pressure caused by pulmonary vasoconstriction and vascular remodeling, which leads to right heart failure and death. Epoprostenol (prostaglandin I2) has a potent short-acting vasodilator property, and intravenous continuous epoprostenol is therefore used for treatment of PAH. Here we review evidence for the usefulness of intravenous continuous epoprostenol therapy in patients with PAH. Epoprostenol therapy is effective in idiopathic PAH patients and in patients with PAH associated with connective tissue disease, portal hypertension or congenital heart diseases, but it is not effective in patients with pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis. High-dose epoprostenol therapy markedly improved hemodynamics in some patients with PAH, possibly due to reverse remodeling of pulmonary arteries. This therapy has several side effects and complications such as headache, hypotension and catheter-related infections. Intravenous continuous epoprostenol is an effective treatment, but there are still some problems to be resolved.

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  • Reverse remodeling of pulmonary arteries by high-dose prostaglandin I2 therapy: A case report. Reviewed

    Satoshi Akagi, Kazufumi Nakamura, Hiromi Matsubara, Keiko Ohta-Ogo, Chikao Yutani, Katsumasa Miyaji, Aiko Ogawa, Kengo Kusano, Takahiro Oto, Hatsue Ishibashi-Ueda, Hiroshi Ito

    Journal of cardiology cases   9 ( 5 )   173 - 176   2014.5

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    Idiopathic pulmonary arterial hypertension (IPAH) is characterized by pulmonary vascular remodeling. We have reported that high-dose prostaglandin I2 (PGI2) therapy markedly improved hemodynamics in IPAH patients and that PGI2 induced apoptosis of pulmonary artery smooth muscle cells obtained from IPAH patients. PGI2 is thought to have reverse remodeling effects, although it has not been histologically confirmed. In a case series, we examined the reverse pulmonary vascular remodeling effects of PGI2 in lung tissues obtained from an IPAH patient treated with high-dose PGI2 and an IPAH patient not treated with PGI2. Apoptotic cells were detected in small pulmonary arteries of the IPAH patient treated with high-dose PGI2 but not in those from the IPAH patient not treated with PGI2. Media of peripheral pulmonary arteries were thick in the IPAH patient not treated with PGI2. On the other hand, media of peripheral pulmonary arteries were thin in the IPAH patient treated with high-dose PGI2. The single case report suggested that high-dose PGI2 therapy has the potential for reverse pulmonary vascular remodeling by induction of apoptosis and reduction of medial hypertrophy. Accumulation of cases is needed for the application to generalized effect of high-dose PGI2. <Learning objective: Reverse pulmonary vascular remodeling would provide further improvement in patients with IPAH. High-dose PGI2 therapy has the potential for reverse pulmonary vascular remodeling in patients with IPAH.>.

    DOI: 10.1016/j.jccase.2013.12.011

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  • [Treatment with imatinib for refractory PAH].

    Kazufumi Nakamura, Satoshi Akagi, Toshihiro Sarashina, Aiko Ogawa, Hiromi Matsubara, Hiroshi Ito

    Nihon yakurigaku zasshi. Folia pharmacologica Japonica   143 ( 4 )   173 - 7   2014.4

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  • Different sizes of centrilobular ground-glass opacities in chest high-resolution computed tomography of patients with pulmonary veno-occlusive disease and patients with pulmonary capillary hemangiomatosis. Reviewed

    Cardiovasc Pathol   2013.8

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  • Prostaglandin I2 induces apoptosis via upregulation of Fas ligand in pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension. Reviewed International journal

    Satoshi Akagi, Kazufumi Nakamura, Hiromi Matsubara, Kengo Fukushima Kusano, Noriyuki Kataoka, Takahiro Oto, Katsumasa Miyaji, Aya Miura, Aiko Ogawa, Masashi Yoshida, Hatsue Ueda-Ishibashi, Chikao Yutani, Hiroshi Ito

    International journal of cardiology   165 ( 3 )   499 - 505   2013.5

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    BACKGROUND: Pulmonary vascular remodeling with idiopathic pulmonary arterial hypertension (IPAH) is associated with impaired apoptosis of pulmonary artery smooth muscle cells (PASMCs). We have reported that high-dose prostaglandin I2 (PGI2) therapy markedly improved hemodynamics in IPAH patients. The therapy is thought to reverse vascular remodeling, though the mechanism is unclear. The aim of this study is to assess proapoptotic effects of PGI2 on PASMCs obtained from IPAH patients. METHODS: We investigated proapoptotic effects of PGI2 in PAH-PASMCs by TUNEL assays, caspase-3,-7 assays and transmission electron microscopy. We examined the expression of Fas ligand (FasL), an apoptosis-inducing member of the TNF cytokine family, in PAH-PASMCs. We measured the serum FasL levels in IPAH patients treated with PGI2. RESULTS: TUNEL-positive, caspase-3, 7-active cells and fragmentation of the nucleus were detected in PAH-PASMCs treated with PGI2. The percentage of apoptotic cells induced by PGI2 at a high concentration was higher than that induced by PGI2 at a low concentration. PCR-array analysis revealed that PGI2 upregulated the FasL gene in PAH-PASMCs, and we measured the FasL expression by quantitative RT-PCR and Western blotting. PGI2 significantly increased the mRNA level of FasL by 3.98 fold and the protein level of FasL by 1.70 fold. An IP receptor antagonist inhibited the induction of apoptosis, elevation of cyclic AMP and upregulation of FasL by PGI2. Serum FasL level had a significant positive correlation with PGI2 dose in IPAH patients treated with PGI2. CONCLUSIONS: PGI2 has proapoptotic effects on PAH-PASMCs via the IP receptor and upregulation of FasL.

    DOI: 10.1016/j.ijcard.2011.09.004

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  • Acute vasoreactivity testing with nicardipine in patients with pulmonary arterial hypertension. Reviewed

    Yukihiro Saito, Kazufumi Nakamura, Katsumasa Miyaji, Satoshi Akagi, Hiroki Mizoguchi, Aiko Ogawa, Soichiro Fuke, Hideki Fujio, Takahiko Kiyooka, Satoshi Nagase, Kunihisa Kohno, Hiroshi Morita, Kengo F Kusano, Hiromi Matsubara, Tohru Ohe, Hiroshi Ito

    Journal of pharmacological sciences   120 ( 3 )   206 - 12   2012.10

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    Acute vasoreactivity testing for patients with pulmonary arterial hypertension (PAH) has been reported to be useful to identify patients with sustained beneficial response to oral calcium-channel blockers (CCBs), but there is a risk of exacerbation during the testing with oral CCBs. Therefore, we developed a testing method utilizing intravenous nicardipine, a short-acting CCB, and examined the safety and usefulness of acute vasoreactivity testing with nicardipine in PAH patients. Acute vasoreactivity testing with nicardipine was performed in 65 PAH patients. Nicardipine was administered by short-time continuous infusion (1 μg·kg⁻¹·min⁻¹ for 5 min and 2 μg·kg⁻¹·min⁻¹ for 5 min) followed by bolus injection (5 μg/kg). Hemodynamic responses were continuously measured using a right heart catheter. Acute responders were defined as patients who showed a decrease in mean pulmonary artery pressure of at least 10 mmHg to an absolute level below 40 mmHg with preserved or increased cardiac output. Two acute responders and sixty-three non-acute responders were identified. There was no hemodynamic instability requiring additional inotropic agents or death during the testing. Acute responders had good responses to long-term oral CCBs. The acute vasoreactivity testing with nicardipine might be safe and useful for identifying CCB responders in PAH patients.

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  • Pro-apoptotic effects of imatinib on PDGF-stimulated pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension. Reviewed International journal

    Kazufumi Nakamura, Satoshi Akagi, Aiko Ogawa, Kengo F Kusano, Hiromi Matsubara, Daiji Miura, Soichiro Fuke, Nobuhiro Nishii, Satoshi Nagase, Kunihisa Kohno, Hiroshi Morita, Takahiro Oto, Ryutaro Yamanaka, Fumio Otsuka, Aya Miura, Chikao Yutani, Tohru Ohe, Hiroshi Ito

    International journal of cardiology   159 ( 2 )   100 - 6   2012.8

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    BACKGROUND: Remodeling of the pulmonary artery by an inappropriate increase of pulmonary artery smooth muscle cells (PASMCs) is problematic in the treatment of idiopathic pulmonary arterial hypertension (IPAH). Effective treatment that achieves reverse remodeling is required. The aim of this study was to assess the pro-apoptotic effects of imatinib, a platelet-derived growth factor (PDGF)-receptor tyrosine kinase inhibitor, on PASMCs obtained from patients with IPAH. METHODS: PASMCs were obtained from 8 patients with IPAH undergoing lung transplantation. Cellular proliferation was assessed by (3)H-thymidine incorporation. Pro-apoptotic effects of imatinib were examined using TUNEL and caspase-3,7 assays and using transmission electron microscopy. RESULTS: Treatment with imatinib (0.1 to 10 μg/mL) significantly inhibited PDGF-BB (10 ng/mL)-induced proliferation of PASMCs from IPAH patients. Imatinib (1 μg/mL) did not induce apoptosis in quiescent IPAH-PASMCs, but it had a pro-apoptotic effect on IPAH-PASMCs stimulated with PDGF-BB. Imatinib did not induce apoptosis in normal control PASMCs with or without PDGF-BB stimulation. PDGF-BB induced phosphorylation of Akt at 15 min, and Akt phosphorylation was inhibited by imatinib in IPAH-PASMCs. Akt-I-1/2 (1 μmol/L), an Akt inhibitor, in the presence of PDGF-BB significantly increased apoptotic cells compared with the control condition. Thus, Akt-I-1/2 could mimic the effects of imatinib on PASMCs. CONCLUSION: Imatinib has anti-proliferative and pro-apoptotic effects on IPAH-PASMCs stimulated with PDGF. The inhibitory effect of imatinib on Akt phosphorylation induced by PDGF plays an important role in the pro-apoptotic effect.

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  • Intermittent arm ischemia induces vasodilatation of the contralateral upper limb. Reviewed

    Kenki Enko, Kazufumi Nakamura, Kei Yunoki, Toru Miyoshi, Satoshi Akagi, Masashi Yoshida, Norihisa Toh, Mutsuko Sangawa, Nobuhiro Nishii, Satoshi Nagase, Kunihisa Kohno, Hiroshi Morita, Kengo F Kusano, Hiroshi Ito

    The journal of physiological sciences : JPS   61 ( 6 )   507 - 13   2011.11

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    Intermittent arm ischemia before percutaneous coronary intervention induces remote ischemic preconditioning (RIPC) and attenuates myocardial injury in patients with myocardial infarction. Several studies have shown that intermittent arm ischemia increases coronary flow and is related to autonomic nerve system. The aim of this study was to determine whether intermittent arm ischemia induces vasodilatation of other arteries and to assess changes in the autonomic nerve system during intermittent arm ischemia in humans. We measured change in the right brachial artery diameter during intermittent left arm ischemia through three cycles of 5-min inflation (200 mmHg) and 5-min deflation of a blood-pressure cuff using a 10-MHz linear array transducer probe in 20 healthy volunteers. We simultaneously performed power spectral analysis of heart rate. Ischemia-reperfusion of the left arm significantly dilated the right brachial artery time-dependently, resulting in a 3.2 ± 0.4% increase after the 3rd cycle. In the power spectral analysis of heart rate, the high-frequency domain (HF), which is a marker of parasympathetic activity, was significantly higher after the 3rd cycle of ischemia-reperfusion than baseline HF (P = 0.02). Intermittent arm ischemia was accompanied by vasodilatation of another artery and enhancement of parasympathetic activity. Those effects may play an important role in the mechanism of RIPC.

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  • Usefulness of acute pulmonary vasoreactivity test of sildenafil in treatment of portopulmonary hypertension. A case report. Reviewed

    Satoshi Akagi, Kazufumi Nakamura, Soichiro Fuke, Kengo Fukushima Kusano, Hiroshi Ito

    Journal of cardiology cases   4 ( 1 )   e31-e33   2011.8

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    A 50-year-old man diagnosed with liver cirrhosis type C was referred to our hospital because of right heart failure with pulmonary hypertension. Echocardiography revealed enlargement of the right atrium and ventricle with severe tricuspid regurgitation. The peak flow velocity of tricuspid regurgitation by continuous wave Doppler echocardiography was 452 cm/s. Right heart catheterization demonstrated severe pulmonary hypertension [pulmonary arterial pressure (PAP) systolic/diastolic/mean = 73/20/41 mmHg and pulmonary vascular resistance (PVR) = 509 dyn s cm-5] with portal hypertension. We diagnosed the patient as having portopulmonary hypertension (PoPH). Although we treated the patient with a prostacyclin analog, tricuspid regurgitation velocity was increased to 480 cm/s four years after the start of the therapy. To select drugs for the treatment of PoPH, we performed an acute vasoreactivity test of sildenafil during right heart catheterization. Since single administration of sildenafil (20 mg) decreased PAP (93/30/55-77/27/44 mmHg) and PVR (908-833 dyn s cm-5), we added sildenafil (20 mg, t.i.d.) to the prostacyclin analog. Tricuspid regurgitation velocity decreased to 403 cm/s one year after the addition of sildenafil. An acute vasoreactivity test of sildenafil during right heart catheterization was useful for the decision of the drug to be used in the treatment of PoPH.

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  • Circulating KCNH2 current-activating factor in patients with heart failure and ventricular tachyarrhythmia. Reviewed International journal

    Hiroki Sugiyama, Kazufumi Nakamura, Hiroshi Morita, Satoshi Akagi, Yoshinori Tani, Yusuke Katayama, Nobuhiro Nishii, Toru Miyoshi, Satoshi Nagase, Kunihisa Kohno, Kengo Fukushima Kusano, Tohru Ohe, Junko Kurokawa, Tetsushi Furukawa, Hiroshi Ito

    PloS one   6 ( 5 )   e19897   2011.5

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    BACKGROUND: It is estimated that approximately half of the deaths in patients with HF are sudden and that the most likely causes of sudden death are lethal ventricular tachyarrhythmias such as ventricular tachycardia (VT) or fibrillation (VF). However, the precise mechanism of ventricular tachyarrhythmias remains unknown. The KCNH2 channel conducting the delayed rectifier K(+) current (I(Kr)) is recognized as the most susceptible channel in acquired long QT syndrome. Recent findings have revealed that not only suppression but also enhancement of I(Kr) increase vulnerability to major arrhythmic events, as seen in short QT syndrome. Therefore, we investigated the existence of a circulating KCNH2 current-modifying factor in patients with HF. METHODOLOGY/PRINCIPAL FINDINGS: We examined the effects of serum of HF patients on recombinant I(Kr) recorded from HEK 293 cells stably expressing KCNH2 by using the whole-cell patch-clamp technique. Study subjects were 14 patients with non-ischemic HF and 6 normal controls. Seven patients had a history of documented ventricular tachyarrhythmias (VT: 7 and VF: 1). Overnight treatment with 2% serum obtained from HF patients with ventricular arrhythmia resulted in a significant enhancement in the peaks of I(Kr) tail currents compared to the serum from normal controls and HF patients without ventricular arrhythmia. CONCLUSIONS/SIGNIFICANCE: Here we provide the first evidence for the presence of a circulating KCNH2 channel activator in patients with HF and ventricular tachyarrhythmias. This factor may be responsible for arhythmogenesis in patients with HF.

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  • Marked hemodynamic improvements by high-dose epoprostenol therapy in patients with idiopathic pulmonary arterial hypertension. Reviewed

    Satoshi Akagi, Kazufumi Nakamura, Katsumasa Miyaji, Aiko Ogawa, Kengo Fukushima Kusano, Hiroshi Ito, Hiromi Matsubara

    Circulation journal : official journal of the Japanese Circulation Society   74 ( 10 )   2200 - 5   2010.10

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    BACKGROUND: The appropriate dose range of epoprostenol is thought to be 25-40 ng · kg(-1) · min(-1) based on the results of previous studies showing that epoprostenol therapy reduced mean pulmonary artery pressure (mPAP) by 12-22% and pulmonary vascular resistance (PVR) by 32-53% compared with baseline values in patients with idiopathic pulmonary arterial hypertension (IPAH). However, the efficacy of treatment of IPAH patients with epoprostenol >40 ng · kg(-1) · min(-1) has not been determined and this was the aim of the present study. METHODS AND RESULTS: The study group comprised 16 consecutive patients, none of whom died; 2 dropped out because they could not be titrated up as needed to the highest effective epoprostenol dose. Hemodynamics were evaluated in 14 IPAH patients who received high-dose epoprostenol monotherapy. The mean epoprostenol dosage was 107 ± 40 ng · kg(-1) · min(-1) (range, 54-190 ng · kg(-1) · min(-1)) and the mean duration of high-dose epoprostenol therapy was 1,355 ± 627 days (range, 582-2,410 days). Significant decreases from baseline values were seen in mPAP (from 66 ± 16 to 47 ± 12 mmHg, P<0.001) and PVR (from 21.6 ± 8.3 to 6.9 ± 2.9 Wood units, P<0.001). Compared with the baseline state, high-dose epoprostenol therapy reduced mPAP by 30% and PVR by 68%. CONCLUSIONS: The present study suggests high-dose epoprostenol therapy is a new treatment strategy for IPAH.

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  • Three-dimensional structure of pulmonary capillary vessels in patients with pulmonary hypertension. Reviewed International journal

    Aya Miura, Kazufumi Nakamura, Kengo F Kusano, Hiromi Matsubara, Aiko Ogawa, Satoshi Akagi, Takahiro Oto, Takuro Murakami, Aiji Ohtsuka, Chikao Yutani, Tohru Ohe, Hiroshi Ito

    Circulation   121 ( 19 )   2151 - 3   2010.5

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    DOI: 10.1161/CIR.0b013e3181e037c1

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  • Inhibitory effects of simvastatin on platelet-derived growth factor signaling in pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension. Reviewed International journal

    Tetsuya Ikeda, Kazufumi Nakamura, Satoshi Akagi, Kengo Fukushima Kusano, Hiromi Matsubara, Hideki Fujio, Aiko Ogawa, Aya Miura, Daiji Miura, Takahiro Oto, Ryutaro Yamanaka, Fumio Otsuka, Hiroshi Date, Tohru Ohe, Hiroshi Ito

    Journal of cardiovascular pharmacology   55 ( 1 )   39 - 48   2010.1

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    Idiopathic pulmonary arterial hypertension (IPAH) is a progressive disease characterized by inappropriate increase of pulmonary artery smooth muscle cells (PASMCs) leading to occlusion of pulmonary arterioles. Inhibition of platelet-derived growth factor (PDGF) signaling is starting to garner attention as a targeted therapy for IPAH. We assessed the inhibitory effects of simvastatin, a 3-hydroxy-3-methylglutanyl coenzyme A reductase inhibitor, on PDGF-induced proliferation and migration of PASMCs obtained from 6 patients with IPAH who underwent lung transplantation. PDGF stimulation caused a significantly higher growth rate of PASMCs from patients with IPAH than that of normal control PASMCs as assessed by (3)H-thymidine incorporation. Simvastatin (0.1 micromol/L) significantly inhibited PDGF-induced cell proliferation of PASMCs from patients with IPAH but did not inhibit proliferation of normal control cells at the same concentration. Western blot analysis revealed that simvastatin significantly increased the expression of cell cycle inhibitor p27. PDGF significantly increased the migration distance of IPAH-PASMCs compared with that of normal PASMCs, and simvastatin (1 micromol/L) significantly inhibited PDGF-induced migration. Immunofluorescence staining revealed that simvastatin (1 micromol/L) inhibited translocation of Rho A from the cytoplasm to membrane and disorganized actin fibers in PASMCs from patients with IPAH. In conclusion, simvastatin had inhibitory effects on inappropriate PDGF signaling in PASMCs from patients with IPAH.

    DOI: 10.1097/FJC.0b013e3181c0419c

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  • Intravenous administration of nicorandil immediately before percutaneous coronary intervention can prevent slow coronary flow phenomenon. Reviewed International journal

    Yusuke Kawai, Kenichi Hisamatsu, Hiromi Matsubara, Kazuhiro Dan, Satoshi Akagi, Katsumasa Miyaji, Mitsuru Munemasa, Yoshihisa Fujimoto, Kengo F Kusano, Tohru Ohe

    European heart journal   30 ( 7 )   765 - 72   2009.4

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    AIMS: To determine the effect of intravenous administration of nicorandil on slow coronary flow (SCF) phenomenon in patients undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS: In a preliminary study, 6 mg of nicorandil showed optimal efficacy for vasodilatation without causing significant haemodynamic instability. In the main study, a total of 408 patients were randomly assigned to receive intravenous administration of 6 mg of nicorandil immediately before PCI. The number of patients in the nicorandil group was 206 [acute coronary syndrome (ACS): 47, non-ACS: 159] and that in the control group was 202 (ACS: 61, non-ACS: 141). Nicorandil significantly decreased the incidence of post-procedural SCF phenomenon in both the ACS and non-ACS groups. The rate of target vessel revascularization (TVR) was significantly lower in the nicorandil group than in the control group in ACS patients. CONCLUSION: Our simple procedure prevented SCF phenomenon not only in patients with ACS but also in patients with non-ACS without any adverse effect. Additionally our procedure reduced the rate of TVR in patients with ACS.

    DOI: 10.1093/eurheartj/ehp077

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  • [Anticoagulation therapy in pulmonary arterial hypertension].

    Satoshi Akagi, Kengo Fukushima Kusano

    Nihon rinsho. Japanese journal of clinical medicine   66 ( 11 )   2174 - 8   2008.11

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    Vascular thrombosis implicates in the pathogenesis of pulmonary arterial hypertension (PAH). Anticoagulation therapy (warfarin) has been recommended by many experts in the treatment of PAH. However, the long-term effectiveness of anticoagulation therapy remains controversial. Because of the various drugs, such as epoprostenol, bosentan, and sildenafil, for the treatment of PAH recently, warfarin alone is not a realistic therapy for PAH. Accordingly we reviewed the previous manuscript regarding anticoagulation therapy for PAH, and looked at the current role of anticoagulation therapy in Japan.

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  • Epoprostenol infusion therapy changes angiographic findings of pulmonary arteries in patients with idiopathic pulmonary arterial hypertension. Reviewed

    Masahito Sakuma, Jun Demachi, Jun Nawata, Jun Suzuki, Tohru Takahashi, Hiromi Matsubara, Satoshi Akagi, Kunio Shirato

    Circulation journal : official journal of the Japanese Circulation Society   72 ( 7 )   1147 - 51   2008.7

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    BACKGROUND: The pulmonary vascular changes induced by epoprostenol in patients with idiopathic pulmonary artery hypertension (IPAH) have not been reported by a clinical study. METHODS AND RESULTS: Analysis 1 compared the wedged pulmonary angiography (PAG) findings prior to initiation of epoprostenol therapy (n=24) with those after initiation (n=16). Analysis 2 compared the PAG findings prior to and after initiation of epoprostenol therapy (n=9) in the same pulmonary arteries in the same subjects. In analysis 1, a "cotton grass-like" stain originating from the peripheral pulmonary vessels (each vessel could not be distinguished on angiography) was not observable in any of 24 cases before initiation of epoprostenol therapy, but was visible in 13 of 16 cases after (p<0.0001). In analysis 2, the diameter of subsegmental arteries changed from 3.0+/-0.9 mm (mean +/- standard deviation) to 3.7+/-1.2 mm (p=0.004) between the 2 time periods. Cotton grass-like stain was not found in any cases before epoprostenol, but in all 9 cases after chronic use (p=0.004). CONCLUSIONS: After initiating epoprostenol therapy, cotton grass-like stain appeared in most patients with IPAH. The possible reason for this is release of severe vasoconstriction and/or emergence of neovascularization.

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  • Additional effects of bosentan in patients with idiopathic pulmonary arterial hypertension already treated with high-dose epoprostenol. Reviewed

    Satoshi Akagi, Hiromi Matsubara, Katsumasa Miyaji, Etsuko Ikeda, Kazuhiro Dan, Naoto Tokunaga, Kenichi Hisamatsu, Mitsuru Munemasa, Yoshihisa Fujimoto, Tohru Ohe

    Circulation journal : official journal of the Japanese Circulation Society   72 ( 7 )   1142 - 6   2008.7

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    BACKGROUND: Combination therapy has been proposed in treatment algorithms for idiopathic pulmonary arterial hypertension (IPAH), so the additional effects of bosentan in IPAH patients already treated with high-dose epoprostenol (EPO) was evaluated in the present study. METHODS AND RESULTS: Bosentan (62.5 mg twice daily) was administered to 8 IPAH patients already being treated with high-dose EPO (average dose 99.6+/-43.4 ng . kg(-1) . min(-1)). Hemodynamics were assessed at baseline and at 2 days and then 1 year after the initiation of bosentan. Because a remarkable elevation of mixed venous oxygen saturation was observed at the initiation of bosentan, the dosage of EPO was reduced in 7 patients (from 99.6+/-43.4 to 82.8+/-31.3 ng . kg(-1) . min(-1), p<0.05). There was a significant decrease from the baseline value for systolic pulmonary artery pressure (80.1+/-19.3 to 66.8+/-16.5 mmHg, p<0.05). These effects were maintained for 1 year without progression of PAH in 6 patients whose condition had been stabilized at baseline. CONCLUSIONS: The additional use of bosentan for IPAH patients whose condition has been stabilized by high-dose EPO is safe and effective.

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  • Prevention of catheter-related infections using a closed hub system in patients with pulmonary arterial hypertension. Reviewed

    Satoshi Akagi, Hiromi Matsubara, Aiko Ogawa, Yusuke Kawai, Kenichi Hisamatsu, Katsumasa Miyaji, Mitsuru Munemasa, Yoshihisa Fujimoto, Kengo Fukushima Kusano, Tohru Ohe

    Circulation journal : official journal of the Japanese Circulation Society   71 ( 4 )   559 - 64   2007.4

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    BACKGROUND: Most of the patients with pulmonary arterial hypertension (PAH) receiving intravenous epoprostenol have experienced catheter-related infections during long-term treatment. Catheter hub was reported to be the most important source of catheter-related infections. To prevent the catheter-related infections, we have introduced a closed hub system and compared the incidence of catheter-related infections with that in patients using a non-closed hub system. METHODS AND RESULTS: We evaluated the results obtained on 24 occasions in 20 patients with PAH between June 1999 and December 2005. On 11 occasions, a non-closed hub system was used and on 13 cases a closed hub system. We classified the catheter-related infection into a catheter-related bloodstream infection (CRBSI) group or a tunnel infection group based on the pathway of bacteria. The CRBSI rate was 0.89 per 1,000 catheter days in the non-closed hub system group vs 0.10 per 1,000 catheter days in the closed hub system group. Kaplan-Meier analysis showed that the risk of CRBSI significantly decreased in the closed hub system group. None of the patients died as a direct consequence of catheter-related infection during the study period. CONCLUSIONS: We successfully prevented CRBSI by using a closed hub system.

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  • Images in cardiovascular medicine. Right-sided heart failure due to compression of the right atrium by remarkable ascending aortic elongation. Reviewed International journal

    Satoshi Akagi, Eiji Taguchi, Kazuhiro Dan, Yoko Ikeda, Yusuke Kawai, Kenichi Hisamatsu, Mitsuru Munemasa, Yoshihisa Fujimoto, Hiromi Matsubara, Hiroshi Mikouchi

    Circulation   112 ( 14 )   e252   2005.10

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  • [A case of splenic hemorrhage in the course of malignant mesothelioma]. Reviewed

    Satoshi Akagi, Shinji Ozaki, Takumi Kishimoto

    Nihon Kokyuki Gakkai zasshi = the journal of the Japanese Respiratory Society   42 ( 3 )   253 - 6   2004.3

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    A 56-year-old man was admitted to our hospital because of mass lesions at the levels of the right upper and lower lung regions on a chest plain radiograph. Chest computed tomography showed tumors which projected from the pleura of the right upper and lower lung fields. One particular point of interest was the complete separation of the tumors from each other. Malignant mesothelioma was diagnosed by biopsy of the pleura via echogram. Both chemotherapy and radiotherapy were administered because of brain metastasis and direct rib invasion. Under this combined therapy, sudden anemia and hypotension appeared due to splenic hemorrhage, which suggested splenic metastasis of the malignant mesothelioma. Multiple metastases in, for example, the spleen, brain, lung, liver, duodenum, small intestine, kidney, adrenal gland, vertebra, thyroid gland, and lymph nodes were confirmed by autopsy. Distant metastasis is rare for malignant mesothelioma, and we report here a case of splenic metastasis with splenic hemorrhage in malignant mesothelioma.

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  • 化学療法が著効した心悪性リンパ腫の1例 Reviewed

    心臓   2003.8

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Research Projects

  • 心血管メカノセンサーTRPV2の低酸素誘発性肺高血圧症への関与解明と治療法開発

    Grant number:21K08108  2021.04 - 2024.03

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    中村 一文, 鵜殿 平一郎, 片野坂 友紀, 赤木 達

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    Grant amount:\4030000 ( Direct expense: \3100000 、 Indirect expense:\930000 )

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  • 特発性肺動脈性肺高血圧症由来肺動脈平滑筋細胞のエネルギー代謝の解明と治療薬の開発

    Grant number:20K08424  2020.04 - 2023.03

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    赤木 達, 中村 一文, 吉田 賢司, 伊藤 浩

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    Grant amount:\4290000 ( Direct expense: \3300000 、 Indirect expense:\990000 )

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  • 尿毒素による心不全発症・再発の病態解明と新規治療戦略の基盤構築

    Grant number:19K08558  2019.04 - 2022.03

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    伊藤 浩, 中村 一文, 赤木 達, 三好 亨

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    Grant amount:\4290000 ( Direct expense: \3300000 、 Indirect expense:\990000 )

    高齢化に伴い心不全患者は増加の一途をたどっており、その予後は収縮障害・拡張障害ともに不良である。心不全発症において心 腎 連 関 が 近年注目されるようになり、腎機能低下が心不全に悪影響を及ぼすことが多く報告されるようになってきたが、心腎連関の病態進展の分子機構は未だ不明な点が多い。慢性腎臓病では、全身的な代謝変化および尿中への代謝産物の排泄障害にともない様々な尿毒素が体内に蓄積する。これまでに約90種類の尿毒素質が報告されているが、その一つであるインドキシル硫酸は腸内細菌によってつくられたインドールが肝臓で代謝されて合成さる。基礎研究においてインドキシル硫酸は心肥大、心筋線維化を促進すること(Eur Heart J. 2010 Jul;31(14):1771-9、PLoS One. 2012;7(7):e41281)、また、臨床研究においては少数例ではあるが非透析の拡張型心筋症患者の予後とインドキシル硫酸濃度が関連すること (Circ J. 2013;77(2):390-6)、が報告されている。また臨床面では申請者らによるパイロット研究で、血中インドキシル硫酸増加が心不全再入院の予測因子であることが示唆されている。本研究では、基礎研究として、尿毒素が心不全発症に関与する分子病態を動物実験にて明らかにし、心臓における心腎連関の新規標的分子の探索を行う。同時に、臨床研究として血中インドキシル硫酸と心不全発症の関連を前向きの多施設レジストリーにて検証する。このように、基礎と臨床の両面からインドキシル硫酸の心臓への影響を明らかにし、心不全に対する新規治療戦略の基盤を構築する。

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  • Development of new treatments with RAGE-aptamer-incorporated nanoparticles for pulmonary arterial hypertension

    Grant number:18K08037  2018.04 - 2021.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    中村 一文, 赤木 達, 阪口 政清, 三好 亨, 深水 圭, 伊藤 浩

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    Grant amount:\4420000 ( Direct expense: \3400000 、 Indirect expense:\1020000 )

    1. 肺高血圧モデルラットにおけるRAGE特異的DNA-aptamer封入ナノ粒子の効果の検討
    モノクロタリン誘発性高血圧モデルラットにおいてモノクロタリンと同時に終末糖化産物受容体RAGE特異的 DNA aptamerの持続皮下注を行ったところ、右室収縮期圧の上昇を有意に抑制した。すなわち肺高血圧症の発症を抑制することができた。さらに肺動脈病理像を検討したところRAGE特異的 DNA aptamerにおいて中膜平滑筋層の肥厚がモノクロタリン群にくらべ有意に抑制されていた。すなわちRAGE特異的 DNA aptamerの肺動脈リモデリングの発生抑制効果を認めた。この結果を現在論文投稿準備しつつ, RAGE特異的DNA-aptamer封入ナノ粒子の作成を検討中である。また我々の検討を含む様々なナノ粒子の肺高血圧症への治療効果をまとめた総説が英文雑誌に掲載された (Nakamura et al. Int J Mol Sci. 2019)。
    2. 肺動脈性肺高血圧症(PAH)患者肺動脈の細胞におけるRAGE特異的DNA-aptamer封入ナノ粒子による過剰増殖・アポトーシス抵抗性・異常遊走・炎症に対する効果の検討
    培養したPAH患者の肺動脈平滑筋細胞において,血小板由来増殖因子(PDGF)刺激にてRAGEの発現は増加した。PAH肺動脈平滑筋細胞の増殖はPDGF刺激のいずれの状態においてもPAHのない対照controlの肺動脈平滑筋細胞より亢進しており,AS-1 (TIR/BB-loop類似構造体(mimetic))にてTIRAP機能抑制を介してRAGE signaling を抑制してみると, PDGF刺激による増殖反応を抑制した。さらにPAH肺動脈平滑筋細胞においてPDGF刺激による増殖をRAGE特異的DNA aptamerも有意に抑制した。

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  • Characteristics of cardiomyocyte from idiopathic pulmonary arterial hypertension and newly developed treatment

    Grant number:17K09498  2017.04 - 2020.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    Akagi Satoshi

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    Grant amount:\4550000 ( Direct expense: \3500000 、 Indirect expense:\1050000 )

    Idiopathic pulmonary arterial hypertension (IPAH) has characteristics with remarkable elevation of pulmonary artery pressure and dysfunction of right ventricular. Drugs for IPAH targets pulmonary arteries but did not directly target right ventricle. In this study we successfully created iPS cells from fibroblast obtained from patient with IPAH. Next, we successfully induced cardiomyocyte. Cardiomyocyte from IPAH patient had characteristic that energy metabolism depends on glycolysis under both normoxia and hypoxia.

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  • Development of new treatments with suppression of RAGE signal for pulmonary hypertension

    Grant number:15K09158  2015.04 - 2018.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    NAKAMURA Kazufumi

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    Grant amount:\4940000 ( Direct expense: \3800000 、 Indirect expense:\1140000 )

    1.After a single administration, imatinib or beraprost-nanoparticles significantly decreased right ventricular pressure and right ventricular hypertrophy in rat models of pulmonary arterial hypertension (PAH).
    2.Pulmonary artery smooth muscle cells of PAH (PAH-PASMCs) were hyperplastic. AS-1, an inhibitor of TIR domain-mediated RAGE signaling, significantly inhibited overgrowth in PAH-PASMCs.

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  • New therapy for pulmonary hypertension using prostaglandin I2 incorporated nanoparticles

    Grant number:26860563  2014.04 - 2016.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)  Grant-in-Aid for Young Scientists (B)

    AKAGI Satoshi

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    Grant amount:\3770000 ( Direct expense: \2900000 、 Indirect expense:\870000 )

    We prepare the beraprost incorporated nanoparticles (BPS-NPs) and investigated the effects on pulmonary hypertension in Sugen-hypoxia and monocrotaline rat models of pulmonary arterial hypertension (PAH). We examined the right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVH) and pulmonary vascular remodeling 2 weeks after the intratracheal administration of PBS, FITC incorporated nanoparticle (FITC-NPs) and BPS-NPs. BPS-NPs significantly decreased RVSP, RVH and pulmonary vascular remodeling compared with PBS and FITC-NPs in Sugen-hypoxia and monocrotaline rat models. Furthermore, BPS-NPs significantly improved survival rate compared with PBS and FITC-NPs in monocrotaline rat models.

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Class subject in charge

  • Cardiovascular Medicine(Core Clinical Practice) (2021academic year) special  - その他

  • Cadiovascular Disease (2021academic year) special  - その他

  • Cardiovascular Medicine(Core Clinical Practice) (2020academic year) special  - その他

  • Cadiovascular Disease (2020academic year) special  - その他