Faculty Profiles - AKAGI Satoshi

Papers - AKAGI Satoshi

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In vivo tracking transplanted cardiomyocytes derived from human induced pluripotent stem cells using nuclear medicine imaging. Reviewed International journal

Yukihiro Saito, Naoko Nose, Toshihiro Iida, Kaoru Akazawa, Takayuki Kanno, Yuki Fujimoto, Takanori Sasaki, Masaru Akehi, Takahiro Higuchi, Satoshi Akagi, Masashi Yoshida, Toru Miyoshi, Hiroshi Ito, Kazufumi Nakamura

Frontiers in cardiovascular medicine 10 1261330 - 1261330 2023

Language：English Publishing type：Research paper (scientific journal)

INTRODUCTION: Transplantation of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) is a promising treatment for heart failure. Information on long-term cell engraftment after transplantation is clinically important. However, clinically applicable evaluation methods have not yet been established. METHODS: In this study, to noninvasively assess transplanted cell engraftment, human SLC5A5, which encodes a sodium/iodide symporter (NIS) that transports radioactive tracers such as 125I, 18F-tetrafluoroborate (TFB), and 99mTc-pertechnetate (99mTcO4-), was transduced into human induced pluripotent stem cells (iPSCs), and nuclear medicine imaging was used to track engrafted human iPSC-CMs. RESULTS: To evaluate the pluripotency of NIS-expressing human iPSCs, they were subcutaneously transplanted into immunodeficient rats. Teratomas were detected by 99mTcO4- single photon emission computed tomography (SPECT/CT) imaging. NIS expression and the uptake ability of 125I were maintained in purified human iPSC-CMs. NIS-expressing human iPSC-CMs transplanted into immunodeficient rats could be detected over time using 99mTcO4- SPECT/CT imaging. Unexpectedly, NIS expression affected cell proliferation of human iPSCs and iPSC-derived cells. DISCUSSION: Such functionally designed iPSC-CMs have potential clinical applications as a noninvasive method of grafted cell evaluation, but further studies are needed to determine the effects of NIS transduction on cellular characteristics and functions.

DOI： 10.3389/fcvm.2023.1261330

Use of the index of pulmonary vascular disease for predicting long-term outcome of pulmonary arterial hypertension associated with congenital heart disease. Reviewed International journal

Ayako Chida-Nagai, Naoki Masaki, Kay Maeda, Konosuke Sasaki, Hiroki Sato, Jun Muneuchi, Yoshie Ochiai, Hiroomi Murayama, Masahiro Tahara, Atsuko Shiono, Atsushi Shinozuka, Fumihiko Kono, Daisuke Machida, Shinichi Toyooka, Seiichiro Sugimoto, Kazufumi Nakamura, Satoshi Akagi, Maiko Kondo, Shingo Kasahara, Yasuhiro Kotani, Junichi Koizumi, Katsuhiko Oda, Masako Harada, Daisuke Nakajima, Akira Murata, Hazumu Nagata, Koichi Yatsunami, Tomio Kobayashi, Yoshikiyo Matsunaga, Takahiro Inoue, Hiroyuki Yamagishi, Naomi Nakagawa, Katsuki Ohtani, Masaki Yamamoto, Yushi Ito, Tatsunori Hokosaki, Yuta Kuwahara, Satoshi Masutani, Koji Nomura, Tsutomu Wada, Hirofumi Sawada, Masayuki Abiko, Tatsunori Takahashi, Yuichi Ishikawa, Seigo Okada, Atsushi Naitoh, Takako Toda, Tatsuya Ando, Akihiro Masuzawa, Shinsuke Hoshino, Masaaki Kawada, Yuichi Nomura, Kentaro Ueno, Naoki Ohashi, Tsuyoshi Tachibana, Yuchen Cao, Hideaki Ueda, Sadamitsu Yanagi, Masaaki Koide, Norie Mitsushita, Kouji Higashi, Yoshihiro Minosaki, Tomohiro Hayashi, Takashi Okamoto, Kenji Kuraishi, Eiji Ehara, Hidekazu Ishida, Hitoshi Horigome, Takashi Murakami, Kohta Takei, Taku Ishii, Gen Harada, Yasutaka Hirata, Jun Maeda, Shunsuke Tatebe, Chiharu Ota, Yasunobu Hayabuchi, Hisanori Sakazaki, Takashi Sasaki, Keiichi Hirono, Sayo Suzuki, Masahiro Yasuda, Atsuhito Takeda, Madoka Sawai, Kagami Miyaji, Atsushi Kitagawa, Yosuke Nakai, Nobuyuki Kakimoto, Kouta Agematsu, Atsushi Manabe, Yoshikatsu Saiki

Frontiers in cardiovascular medicine 10 1212882 - 1212882 2023

Language：English Publishing type：Research paper (scientific journal)

AIMS: Limited data exist on risk factors for the long-term outcome of pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD-PAH). We focused on the index of pulmonary vascular disease (IPVD), an assessment system for pulmonary artery pathology specimens. The IPVD classifies pulmonary vascular lesions into four categories based on severity: (1) no intimal thickening, (2) cellular thickening of the intima, (3) fibrous thickening of the intima, and (4) destruction of the tunica media, with the overall grade expressed as an additive mean of these scores. This study aimed to investigate the relationship between IPVD and the long-term outcome of CHD-PAH. METHODS: This retrospective study examined lung pathology images of 764 patients with CHD-PAH aged <20 years whose lung specimens were submitted to the Japanese Research Institute of Pulmonary Vasculature for pulmonary pathological review between 2001 and 2020. Clinical information was collected retrospectively by each attending physician. The primary endpoint was cardiovascular death. RESULTS: The 5-year, 10-year, 15-year, and 20-year cardiovascular death-free survival rates for all patients were 92.0%, 90.4%, 87.3%, and 86.1%, respectively. The group with an IPVD of ≥2.0 had significantly poorer survival than the group with an IPVD <2.0 (P = .037). The Cox proportional hazards model adjusted for the presence of congenital anomaly syndromes associated with pulmonary hypertension, and age at lung biopsy showed similar results (hazard ratio 4.46; 95% confidence interval: 1.45-13.73; P = .009). CONCLUSIONS: The IPVD scoring system is useful for predicting the long-term outcome of CHD-PAH. For patients with an IPVD of ≥2.0, treatment strategies, including choosing palliative procedures such as pulmonary artery banding to restrict pulmonary blood flow and postponement of intracardiac repair, should be more carefully considered.

DOI： 10.3389/fcvm.2023.1212882

Fulminant Myocarditis for Non-small-cell Carcinoma of the Lung with Nivolumab and Ipilimumab Plus Chemotherapy: A Case Report. Reviewed

Tomoka Nishimura, Kiichiro Ninomiya, Mitsutaka Nakashima, Satoshi Akagi, Tadahiro Kuribayashi, Hisao Higo, Katsuyuki Hotta, Yoshinobu Maeda, Hiroshi Ito, Katsuyuki Kiura

Internal medicine (Tokyo, Japan) 62 ( 9 ) 1319 - 1322 2022.9

Language：English Publishing type：Research paper (scientific journal)

A 59-year-old man with a high level of antinuclear antibody received nivolumab and ipilimumab plus chemotherapy for lung cancer. Two weeks after the second course, he was admitted with a fever and severe fatigue. Laboratory studies showed elevated markers of myocardial damage, and a myocardial biopsy showed inflammatory cell infiltration, damaged myocardial fibers. Myocarditis was diagnosed as an immune-related adverse event (irAE), and high-dose corticosteroids were initiated. However, his cardiac function rapidly worsened, and he died on the fifth day after admission. There is no established treatment strategy for fulminant myocarditis as an irAE, and the further exploration of viable treatment strategies is required.

DOI： 10.2169/internalmedicine.0505-22

Effects of luseogliflozin and voglibose on high-risk lipid profiles and inflammatory markers in diabetes patients with heart failure. Reviewed International journal

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

Scientific reports 12 ( 1 ) 15449 - 15449 2022.9

Language：English Publishing type：Research paper (scientific journal)

Sodium-glucose cotransporter 2 inhibitors could reduce cardiovascular events in patients with heart failure irrespective of diabetes status. In this prespecified sub-analysis of randomised-controlled trial, we investigated the efficacy of luseogliflozin (2.5 mg daily), a sodium-glucose cotransporter 2 inhibitor, with that of voglibose (0.6 mg daily), an alpha-glucosidase inhibitor, on high-risk lipid profile and inflammatory markers in patients with type-2 diabetes and heart failure. Among the 157 patients studied, there were no significant differences in the mean malondialdehyde LDL or small-dense LDL cholesterol levels between the luseogliflozin and voglibose groups (percent change: 0.2% vs. - 0.6%, p = 0.93; - 1.7% vs. - 8.6%, p = 0.21) after 12 weeks in comparison to levels at the baseline. No significant difference was observed between the two groups in the adiponectin and high-sensitivity C-reactive protein levels after 12 weeks compared to the baseline levels (percent change, - 1.6% vs. - 4.0% and 22.5% vs. 10.0%; p = 0.52 and p = 0.55, respectively). In conclusion, in patients with type-2 diabetes and heart failure, compared to voglibose, luseogliflozin did not significantly improve the high-risk lipoprotein profile including malondialdehyde LDL and small-dense LDL cholesterol or the levels of inflammatory markers, including adiponectin and high-sensitivity C-reactive protein.Trial registration: Trial number: UMIN-CTR, UMIN000018395; Registered 23 July 2015; URL: https://www.umin.ac.jp/ctr/index.htm .

DOI： 10.1038/s41598-022-19371-6

Overview of the 86th Annual Scientific Meeting of the Japanese Circulation Society - Cardiology Spreading Its Wings. Invited

Kazufumi Nakamura, Toru Miyoshi, Satoshi Akagi, Norihisa Toh, Yukihiro Saito, Yoichi Takaya, Masatoki Yoshida, Koji Nakagawa, Satoshi Kawada, Hironobu Toda, Takashi Miki, Rie Nakayama, Fumi Yokohama, Keishi Ichikawa, Masashi Yoshida, Makiko Taniyama, Nobuhiro Nishii, Teiji Akagi, Hiroshi Morita, Hiroshi Ito

Circulation journal : official journal of the Japanese Circulation Society 86 ( 8 ) 1312 - 1318 2022.7

Language：English Publishing type：Research paper (scientific journal)

The 86thAnnual Scientific Meeting of the Japanese Circulation Society was held in a web-based format on March 11-13, 2022. In accordance with the internationalization policy of the JCS, the meeting was held with the Asian Pacific Society of Cardiology Congress 2022. The main theme was "Cardiology Spreading its Wings". The number of patients with heart failure and other cardiovascular diseases is increasing dramatically, and the fields dealt with by cardiovascular medicine are also greatly expanding. This conference was both intellectually satisfying and exciting for all participants, who numbered over 14,900. The meeting was completed with great success, and the enormous amount of cooperation and support from all involved was greatly appreciated.

DOI： 10.1253/circj.CJ-22-0349

Impact of shear wave dispersion slope analysis for assessing the severity of myocarditis. Reviewed International journal

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

Scientific reports 12 ( 1 ) 8776 - 8776 2022.5

Language：English Publishing type：Research paper (scientific journal)

This study aimed to elucidate the utility of a novel ultrasound-based technique, shear wave dispersion slope (SWDS) analysis, which estimates tissue viscosity, for evaluating the severity of myocardial inflammation. Experimental autoimmune myocarditis (EAM) at different disease phases [3-week (acute phase): n = 10, 5-week (subacute phase): n = 9, and 7-week (late phase): n = 11] were developed in male Lewis rats. SWDS was measured in the right and the left ventricular free walls (RVFW and LVFW) under a retrograde perfusion condition. Histological myocardial inflammation was evaluated by CD68 staining. The accumulation of CD68-positive cells was severe in the myocardium of the EAM 3-week group. The median (interquartile range) SWDS of RVFW was significantly higher in the EAM 3-week group [9.9 (6.5-11.0) m/s/kHz] than in the control group [5.4 (4.5-6.8) m/s/kHz] (P = 0.034). The median SWDS of LVFW was also significantly higher in the EAM 3-week group [8.1 (6.4-11.0) m/s/kHz] than in the control group [4.4 (4.2-4.8) m/s/kHz] (P = 0.003). SWDS and the percentage of CD68-positive area showed a significant correlation in RVFW (R2 = 0.64, P < 0.001) and LVFW (R2 = 0.73, P < 0.001). This study showed that SWDS was elevated in ventricular walls with acute inflammation and also significantly correlated with the degree of myocardial inflammation. These results suggest the potential of SWDS in estimating the histological severity of acute myocarditis.

DOI： 10.1038/s41598-022-12935-6

Quantification of Lung Perfusion Blood Volume in Dual-Energy Computed Tomography in Patients with Pulmonary Hypertension. Reviewed International journal

Satoko Ugawa, Satoshi Akagi, Kentaro Ejiri, Kazufumi Nakamura, Hiroshi Ito

Life (Basel, Switzerland) 12 ( 5 ) 2022.5

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

Dual-energy computed tomography (DECT) is a promising technique for the assessment of the lung perfused blood volume (LPBV) in the lung parenchyma. This study was performed to compare the LPBV by DECT of patients with pulmonary hypertension (PH) and controls and to evaluate the association between the LPBV and the perfusion ratio derived by lung perfusion scintigraphy. This study involved 45 patients who underwent DECT (25 patients with PH and 20 controls). We measured the total LPBV and distribution of the LPBV in each lung. The total LPBV was significantly lower in the PH group than the control group (38 ± 9 vs. 45 ± 8 HU, p = 0.024). Significant differences were observed between the LPBV of the upper lung of the PH and control groups (34 ± 10 vs. 47 ± 10, p = 0.021 and 37 ± 10 vs. 47 ± 8, p < 0.001). A significant correlation was observed between the LPBV and the lung perfusion scintigraphy. A lower total LPBV and lower LPBV of the upper lung as detected by DECT might be specific findings of PH.

DOI： 10.3390/life12050684

Enhancement of pacing function by HCN4 overexpression in human pluripotent stem cell-derived cardiomyocytes. Reviewed International journal

Yukihiro Saito, Kazufumi Nakamura, Masashi Yoshida, Hiroki Sugiyama, Satoshi Akagi, Toru Miyoshi, Hiroshi Morita, Hiroshi Ito

Stem cell research & therapy 13 ( 1 ) 141 - 141 2022.4

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The number of patients with bradyarrhythmia and the number of patients with cardiac pacemakers are increasing with the aging population and the increase in the number of patients with heart diseases. Some patients in whom a cardiac pacemaker has been implanted experience problems such as pacemaker infection and inconvenience due to electromagnetic interference. We have reported that overexpression of HCN channels producing a pacemaker current in mouse embryonic stem cell-derived cardiomyocytes showed enhanced pacing function in vitro and in vivo. The aim of this study was to determine whether HCN4 overexpression in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) can strengthen the pacing function of the cells. METHODS: Human HCN4 was transduced in the AAVS1 locus of human induced pluripotent stem cells by nucleofection and HCN4-overexpressing iPSC-CMs were generated. Gene expression profiles, frequencies of spontaneous contraction and pacing abilities of HCN4-overexpressing and non-overexpressing iPSC-CMs in vitro were compared. RESULTS: HCN4-overexpressing iPSC-CMs showed higher spontaneous contraction rates than those of non-overexpressing iPSC-CMs. They responded to an HCN channel blocker and β adrenergic stimulation. The pacing rates against parent iPSC line-derived cardiomyocytes were also higher in HCN4-overexpressing iPSC-CMs than in non-overexpressing iPSC-CMs. CONCLUSIONS: Overexpression of HCN4 showed enhancement of If current, spontaneous firing and pacing function in iPSC-CMs. These data suggest this transgenic cell line may be useful as a cardiac pacemaker.

DOI： 10.1186/s13287-022-02818-y

Pathophysiology and Treatment of Diabetic Cardiomyopathy and Heart Failure in Patients with Diabetes Mellitus Reviewed International journal

Kazufumi Nakamura, Toru Miyoshi, Masashi Yoshida, Satoshi Akagi, Yukihiro Saito, Kentaro Ejiri, Naoaki Matsuo, Keishi Ichikawa, Keiichiro Iwasaki, Takanori Naito, Yusuke Namba, Masatoki Yoshida, Hiroki Sugiyama, Hiroshi Ito

International Journal of Molecular Sciences 23 ( 7 ) 3587 - 3587 2022.3

Language：English Publishing type：Research paper (scientific journal) Publisher：MDPI AG

There is a close relationship between diabetes mellitus and heart failure, and diabetes is an independent risk factor for heart failure. Diabetes and heart failure are linked by not only the complication of ischemic heart disease, but also by metabolic disorders such as glucose toxicity and lipotoxicity based on insulin resistance. Cardiac dysfunction in the absence of coronary artery disease, hypertension, and valvular disease is called diabetic cardiomyopathy. Diabetes-induced hyperglycemia and hyperinsulinemia lead to capillary damage, myocardial fibrosis, and myocardial hypertrophy with mitochondrial dysfunction. Lipotoxicity with extensive fat deposits or lipid droplets is observed on cardiomyocytes. Furthermore, increased oxidative stress and inflammation cause cardiac fibrosis and hypertrophy. Treatment with a sodium glucose cotransporter 2 (SGLT2) inhibitor is currently one of the most effective treatments for heart failure associated with diabetes. However, an effective treatment for lipotoxicity of the myocardium has not yet been established, and the establishment of an effective treatment is needed in the future. This review provides an overview of heart failure in diabetic patients for the clinical practice of clinicians.

DOI： 10.3390/ijms23073587

LCZ696 ameliorates doxorubicin-induced cardiomyocyte toxicity in rats. Reviewed International journal

Toru Miyoshi, Kazufumi Nakamura, Naofumi Amioka, Omer F Hatipoglu, Tomoko Yonezawa, Yukihiro Saito, Masashi Yoshida, Satoshi Akagi, Hiroshi Ito

Scientific reports 12 ( 1 ) 4930 - 4930 2022.3

Language：English Publishing type：Research paper (scientific journal)

Doxorubicin (DOX)-based chemotherapy induces cardiotoxicity, which is considered the main bottleneck for its clinical application. In this study, we investigated the potential benefit of LCZ696, an angiotensin receptor-neprilysin inhibitor against DOX-induced cardiotoxicity in rats and H9c2 cells and determined whether the mechanism underlying any such effects involves its antioxidant activity. Male Sprague-Dawley rats were randomly separated into four groups, each consisting of 15 rats (DOX (1.5 mg/kg/day intraperitoneally for 10 days followed by non-treatment for 8 days); DOX + valsartan (31 mg/kg/day by gavage from day 1 to day 18); DOX + LCZ696 (68 mg/kg/day by gavage from day 1 to day 18); and control (saline intraperitoneally for 10 days). DOX-induced elevation of cardiac troponin T levels on day 18 was significantly reduced by LCZ696, but not valsartan. The DOX-induced increase in myocardial reactive oxygen species (ROS) levels determined using dihydroethidium was significantly ameliorated by LCZ696, but not valsartan, and was accompanied by the suppression of DOX-induced increase in p47phox. LCZ696 recovered the DOX-induced decrease in phosphorylation of adenosine monophosphate-activated protein kinase and increased the ratio of Bax and Bcl-2. In H9c2 cardiomyocytes, LCZ696 reduced DOX-induced mitochondrial ROS generation and improved cell viability more than valsartan. Our findings indicated that LCZ696 ameliorated DOX-induced cardiotoxicity in rat hearts in vivo and in vitro, possibly by mediating a decrease in oxidative stress.

DOI： 10.1038/s41598-022-09094-z

Effects of luseogliflozin on estimated plasma volume in patients with heart failure with preserved ejection fraction. Reviewed International journal

Mitsutaka Nakashima, Toru Miyoshi, Kentaro Ejiri, 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

ESC heart failure 9 ( 1 ) 712 - 720 2022.2

Language：English Publishing type：Research paper (scientific journal)

AIMS: Sodium glucose co-transporter 2 inhibitors have diuretic effects in both patients with glycosuria and with natriuresis. We sought to assess the effect of luseogliflozin on estimated plasma volume (ePV) in patients with type 2 diabetes and heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: This study was a post-hoc analysis of the MUSCAT-HF trial (UMIN000018395), a multicentre, prospective, open-label, randomized controlled trial that assessed the effect of 12 weeks of luseogliflozin (2.5 mg, once daily, n = 83) as compared with voglibose (0.2 mg, three times daily, n = 82) on the reduction in brain natriuretic peptide (BNP) in patients with type 2 diabetes and HFpEF. The analysis compared the change in ePV calculated by the Straus formula from baseline to Weeks 4, 12, and 24, using a mixed-effects model for repeated measures. We also estimated the association between changes in ePV and changes in other clinical parameters, including BNP levels. Luseogliflozin significantly reduced ePV as compared to voglibose at Week 4 {adjusted mean group-difference -6.43% [95% confidence interval (CI): -9.11 to -3.74]}, at Week 12 [-8.73% (95%CI: -11.40 to -6.05)], and at Week 24 [-11.02% (95%CI: -13.71 to -8.33)]. The effect of luseogliflozin on these parameters was mostly consistent across various patient clinical characteristics. The change in ePV at Week 12 was significantly associated with log-transformed BNP (r = 0.197, P = 0.015) and left atrial volume index (r = 0.283, P = 0.019). CONCLUSIONS: Luseogliflozin significantly reduced ePV in patients with type 2 diabetes and HFpEF, as compared with voglibose. The reduction of intravascular volume by luseogliflozin may provide clinical benefits to patients with type 2 diabetes and HFpEF.

DOI： 10.1002/ehf2.13683

Pemafibrate Prevents Rupture of Angiotensin II-Induced Abdominal Aortic Aneurysms. Reviewed International journal

Naofumi Amioka, Toru Miyoshi, Tomoko Yonezawa, Megumi Kondo, Satoshi Akagi, Masashi Yoshida, Yukihiro Saito, Kazufumi Nakamura, Hiroshi Ito

Frontiers in cardiovascular medicine 9 904215 - 904215 2022

Language：English Publishing type：Research paper (scientific journal)

Background: Abdominal aortic aneurysm (AAA) is a life-threatening disease that lacks effective preventive therapies. This study aimed to evaluate the effect of pemafibrate, a selective peroxisome proliferator-activated receptor alpha (PPARα) agonist, on AAA formation and rupture. Methods: Experimental AAA was induced by subcutaneous angiotensin II (AngII) infusion in ApoE - / - mice for 4 weeks. Pemafibrate (0.1 mg/kg/day) was administered orally. Dihydroethidium staining was used to evaluate the reactive oxygen species (ROS). Results: The size of the AngII-induced AAA did not differ between pemafibrate- and vehicle-treated groups. However, a decreased mortality rate due to AAA rupture was observed in pemafibrate-treated mice. Pemafibrate ameliorated AngII-induced ROS and reduced the mRNA expression of interleukin-6 and tumor necrosis factor-α in the aortic wall. Gelatin zymography analysis demonstrated significant inhibition of matrix metalloproteinase-2 activity by pemafibrate. AngII-induced ROS production in human vascular smooth muscle cells was inhibited by pre-treatment with pemafibrate and was accompanied by an increase in catalase activity. Small interfering RNA-mediated knockdown of catalase or PPARα significantly attenuated the anti-oxidative effect of pemafibrate. Conclusion: Pemafibrate prevented AAA rupture in a murine model, concomitant with reduced ROS, inflammation, and extracellular matrix degradation in the aortic wall. The protective effect against AAA rupture was partly mediated by the anti-oxidative effect of catalase induced by pemafibrate in the smooth muscle cells.

DOI： 10.3389/fcvm.2022.904215

Efficacy of shear wave elasticity for evaluating myocardial hypertrophy in hypertensive rats. Reviewed 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

Language：English Publishing type：Research paper (scientific journal)

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

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 79 ( 3 ) 446 - 452 2021.11

Language：English Publishing type：Research paper (scientific journal)

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

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

Language：English

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

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

Language：English Publishing type：Research paper (scientific journal)

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

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

Language：English Publishing type：Research paper (scientific journal)

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

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

Language：English Publishing type：Research paper (scientific journal)

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

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

Language：English Publishing type：Research paper (scientific journal)

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

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

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

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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