2024/06/19 更新

写真a

ユアサ シンスケ
湯浅 慎介
Shinsuke Yuasa
所属
医歯薬学域 教授
職名
教授
外部リンク

学位

  • 医学博士 ( 2005年9月   慶應義塾大学 )

研究分野

  • ライフサイエンス / 循環器内科学

委員歴

  • 日本再生医療学会   代議員  

    2022年11月   

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    団体区分:学協会

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  • European Society of Cardiology   Fellow  

    2021年   

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    団体区分:学協会

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  • 心不全学会   代議員  

    2020年4月   

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    団体区分:学協会

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  • American Heart Association   Fellow  

    2020年   

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    団体区分:学協会

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  • 心臓病学会   代議員  

    2019年4月   

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    団体区分:学協会

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  • 国際心臓研究学会(ISHR)日本部会   評議員  

    2014年   

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    団体区分:学協会

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▼全件表示

 

論文

  • A deep learning-based automated diagnosis system for SPECT myocardial perfusion imaging. 国際誌

    Dai Kusumoto, Takumi Akiyama, Masahiro Hashimoto, Yu Iwabuchi, Toshiomi Katsuki, Mai Kimura, Yohei Akiba, Hiromune Sawada, Taku Inohara, Shinsuke Yuasa, Keiichi Fukuda, Masahiro Jinzaki, Masaki Ieda

    Scientific reports   14 ( 1 )   13583 - 13583   2024年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Images obtained from single-photon emission computed tomography for myocardial perfusion imaging (MPI SPECT) contain noises and artifacts, making cardiovascular disease diagnosis difficult. We developed a deep learning-based diagnosis support system using MPI SPECT images. Single-center datasets of MPI SPECT images (n = 5443) were obtained and labeled as healthy or coronary artery disease based on diagnosis reports. Three axes of four-dimensional datasets, resting, and stress conditions of three-dimensional reconstruction data, were reconstructed, and an AI model was trained to classify them. The trained convolutional neural network showed high performance [area under the curve (AUC) of the ROC curve: approximately 0.91; area under the recall precision curve: 0.87]. Additionally, using unsupervised learning and the Grad-CAM method, diseased lesions were successfully visualized. The AI-based automated diagnosis system had the highest performance (88%), followed by cardiologists with AI-guided diagnosis (80%) and cardiologists alone (65%). Furthermore, diagnosis time was shorter for AI-guided diagnosis (12 min) than for cardiologists alone (31 min). Our high-quality deep learning-based diagnosis support system may benefit cardiologists by improving diagnostic accuracy and reducing working hours.

    DOI: 10.1038/s41598-024-64445-2

    PubMed

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  • Artificial intelligence–enabled assessment of right ventricular to pulmonary artery coupling in patients undergoing transcatheter tricuspid valve intervention

    Vera Fortmeier, Mark Lachmann, Lukas Stolz, Jennifer von Stein, Matthias Unterhuber, Mohammad Kassar, Muhammed Gerçek, Anne R Schöber, Thomas J Stocker, Hazem Omran, Maria I Körber, Amelie Hesse, Gerhard Harmsen, Kai Peter Friedrichs, Shinsuke Yuasa, Tanja K Rudolph, Michael Joner, Roman Pfister, Stephan Baldus, Karl-Ludwig Laugwitz, Stephan Windecker, Fabien Praz, Philipp Lurz, Jörg Hausleiter, Volker Rudolph

    European Heart Journal - Cardiovascular Imaging   2023年11月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Oxford University Press (OUP)  

    Abstract

    Aims

    Right ventricular to pulmonary artery (RV-PA) coupling has been established as a prognostic marker in patients with severe tricuspid regurgitation (TR) undergoing transcatheter tricuspid valve interventions (TTVI). RV-PA coupling assesses right ventricular systolic function related to pulmonary artery pressure levels, which are ideally measured by right heart catheterization. This study aimed to improve the RV-PA coupling concept by relating tricuspid annular plane systolic excursion (TAPSE) to mean pulmonary artery pressure (mPAP) levels. Moreover, instead of right heart catheterization, this study sought to employ an extreme gradient boosting (XGB) algorithm to predict mPAP levels based on standard echocardiographic parameters.

    Methods and results

    This multicentre study included 737 patients undergoing TTVI for severe TR; among them, 55 patients from one institution served for external validation. Complete echocardiography and right heart catheterization data were available from all patients. The XGB algorithm trained on 10 echocardiographic parameters could reliably predict mPAP levels as evaluated on right heart catheterization data from external validation (Pearson correlation coefficient R: 0.68; P value: 1.3 × 10−8). Moreover, predicted mPAP (mPAPpredicted) levels were superior to echocardiographic systolic pulmonary artery pressure (sPAPechocardiography) levels in predicting 2-year mortality after TTVI [area under the curve (AUC): 0.607 vs. 0.520; P value: 1.9 × 10−6]. Furthermore, TAPSE/mPAPpredicted was superior to TAPSE/sPAPechocardiography in predicting 2-year mortality after TTVI (AUC: 0.633 vs. 0.586; P value: 0.008). Finally, patients with preserved RV-PA coupling (defined as TAPSE/mPAPpredicted > 0.617 mm/mmHg) showed significantly higher 2-year survival rates after TTVI than patients with reduced RV-PA coupling (81.5% vs. 58.8%, P < 0.001). Moreover, independent association between TAPSE/mPAPpredicted levels and 2-year mortality after TTVI was confirmed by multivariate regression analysis (P value: 6.3 × 10−4).

    Conclusion

    Artificial intelligence–enabled RV-PA coupling assessment can refine risk stratification prior to TTVI without necessitating invasive right heart catheterization. A comparison with conservatively treated patients is mandatory to quantify the benefit of TTVI in accordance with RV-PA coupling.

    DOI: 10.1093/ehjci/jead324

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  • Endothelial-fibroblast interactions during Scarb1 accelerate heart failure

    Toshiomi Katsuki, Dai Kusumoto, Yohei Akiba, Mai Kimura, Jin Komuro, Takahiro Nakamura, Hisayuki Hashimoto, Thukaa Kuoka, Yutaka Suzuki, Yoshiaki Kubota, Keiichi Fukuda, Shinsuke Yuasa, Masaki Ieda

    2023年9月

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    出版者・発行元:Cold Spring Harbor Laboratory  

    Summary

    Endothelial cells (ECs) maintain cardiac homeostasis and EC dysfunction causes heart failure progression. Moreover, pathological changes occur via interactions between multiple cells, including ECs. Here, we conducted single-cell RNA-seq analysis of non-cardiomyocytes in mouse hearts during heart failure progression to elucidate the pathological changes in ECs and fibroblasts (FBs) mediated by cell-cell interactions. We show that capillary and arterial ECs exhibit mesenchymal gene expression changes with heart failure progression, indicating that endothelial-to-mesenchymal transition (EndMT) is a major pathological alteration in ECs. We also found that the interaction between ECs and FBs was enriched during heart failure, particularly when involving Scavenger Receptor Class B Member 1 (Scarb1) in ECs. FBs induce mesenchymal gene alterations in ECs in the EC-FB co-culture system, which is inhibited by blocking SCARB1. RNA-seq analysis showed that administration of a SCARB1 inhibitor blocked mesenchymal gene expression, and inflammatory changes, suggesting that the EC-FB interaction via Scarb1 is important for EndMT induction in ECs. Systemic administration of a SCARB1 inhibitor attenuated heart failure progression and cardiac fibrosis. EC-specificScarb1knockout mouse showed improved cardiac function, suggesting a crucial role of Scarb1 in heart failure progression. Our results suggest that Scarb1 is a promising candidate for novel heart failure treatments that target ECs.

    DOI: 10.1101/2023.09.15.557661

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  • 巨大深部静脈血栓症および肺血栓塞栓症を発症した生体肺移植後妊娠の一例

    海井 智彦, 平出 貴裕, 小柳 喬幸, 醍醐 恭平, 岸野 喜一, 北方 博規, 白石 泰之, 湯浅 慎介, 福島 裕之, 山岸 敬幸, 福田 恵一

    日本心臓病学会学術集会抄録   71回   P - 2   2023年9月

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    記述言語:日本語   出版者・発行元:(一社)日本心臓病学会  

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  • Machine learning in cardiology: Clinical application and basic research

    Jin Komuro, Dai Kusumoto, Hisayuki Hashimoto, Shinsuke Yuasa

    Journal of Cardiology   82 ( 2 )   128 - 133   2023年8月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier BV  

    DOI: 10.1016/j.jjcc.2023.04.020

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  • Perspectives of hospitalized heart failure patients: preferred and perceived participation roles in treatment decisions

    Otoya Sekine, Hiroki Kitakata, Shun Kohsaka, Daisuke Fujisawa, Naomi Nakano, Yasuyuki Shiraishi, Yoshikazu Kishino, Yoshinori Katsumata, Shinsuke Yuasa, Keiichi Fukuda, Takashi Kohno

    Heart and Vessels   38 ( 10 )   1244 - 1255   2023年6月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    DOI: 10.1007/s00380-023-02275-4

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    その他リンク: https://link.springer.com/article/10.1007/s00380-023-02275-4/fulltext.html

  • Genetic Testing Enables the Diagnosis of Familial Hypercholesterolemia Underdiagnosed by Clinical Criteria: Analysis of Japanese Early-Onset Coronary Artery Disease Patients

    Hiroshi Miyama, Yoshinori Katsumata, Mizuki Momoi, Genki Ichihara, Taishi Fujisawa, Jin Endo, Takashi Kawakami, Masaharu Kataoka, Shinsuke Yuasa, Motoaki Sano, Kazuki Sato, Keiichi Fukuda

    Cardiology Research and Practice   2023   1 - 7   2023年4月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Hindawi Limited  

    Definitive diagnosis of familial hypercholesterolemia (FH) is paramount for the risk management of patients and their relatives. The present study aimed to investigate the frequency of gene variants contributing to low-density lipoprotein cholesterol (LDL-C) metabolism and their clinical relevance in patients with early-onset coronary artery disease (EOCAD). Among 63 consecutive patients with EOCAD (men <55 years or women <65 years) who underwent percutaneous coronary intervention (PCI) from 2013 to 2019 at Keio University Hospital, 52 consented to participate in this retrospective study. Targeted sequencing of LDLR, PCSK9, APOB, and LDLRAP1 was performed. Of the 52 patients enrolled (42 men; mean age: 50 ± 6 years), one (LDLR, c.1221_1222delCGinsT) harbored a pathogenic mutation, and one (APOB, c.10591A>G) harbored variants of uncertain significance. Both the patients harboring the variants were male, showing no history of diabetes mellitus or chronic kidney disease, no family history of EOCAD, and no physical findings of FH (i.e., tendon xanthomas or Achilles tendon thickening). Patients harboring the LDLR variant had three-vessel disease, were on a statin prescription at baseline, and had stable LDL-C levels; however, the case showed a poor response to the intensification of medication after PCI. Approximately 3.8% of patients with EOCAD harbored variants of gene related to LDL-C metabolism; there were no notable indicators in the patients’ background or clinical course to diagnose FH. Given the difficulty in diagnosing FH based on clinical manifestations and family history, genetic testing could enable the identification of hidden risk factors and provide early warnings to their relatives.

    DOI: 10.1155/2023/2236422

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    その他リンク: http://downloads.hindawi.com/journals/crp/2023/2236422.xml

  • Epiphenomenon or Prognostically Relevant Interventional Target? A Novel Proportionality Framework for Severe Tricuspid Regurgitation

    Vera Fortmeier, Mark Lachmann, Matthias Unterhuber, Lukas Stolz, Mohammad Kassar, Laurin Ochs, Muhammed Gerçek, Anne R. Schöber, Thomas J. Stocker, Hazem Omran, Maria I. Körber, Amelie Hesse, Kai Peter Friedrichs, Shinsuke Yuasa, Tanja K. Rudolph, Michael Joner, Roman Pfister, Stephan Baldus, Karl‐Ludwig Laugwitz, Fabien Praz, Stephan Windecker, Jörg Hausleiter, Philipp Lurz, Volker Rudolph

    Journal of the American Heart Association   12 ( 6 )   2023年3月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Ovid Technologies (Wolters Kluwer Health)  

    Background

    <p lang="en">Tricuspid regurgitation (TR) frequently develops in patients with long‐standing pulmonary hypertension, and both pathologies are associated with increased morbidity and mortality. This study aimed to improve prognostic assessment in patients with severe TR undergoing transcatheter tricuspid valve intervention (TTVI) by relating the extent of TR to pulmonary artery pressures.

    </p> Methods and Results

    <p lang="en"> In this multicenter study, we included 533 patients undergoing TTVI for moderate‐to‐severe or severe TR. The proportionality framework was based on the ratio of tricuspid valve effective regurgitant orifice area to mean pulmonary artery pressure. An optimal threshold for tricuspid valve effective regurgitant orifice area/mean pulmonary artery pressure ratio was derived on 353 patients with regard to 2‐year all‐cause mortality and externally validated on 180 patients. Patients with a tricuspid valve effective regurgitant orifice area/mean pulmonary artery pressure ratio ≤1.25 mm 2 /mm Hg (defining proportionate TR) featured significantly lower 2‐year survival rates after TTVI than patients with disproportionate TR (56.6% versus 69.6%; P =0.005). In contrast with patients with disproportionate TR (n=398), patients with proportionate TR (n=135) showed more pronounced mPAP levels (37.9±9.06 mm Hg versus 27.9±8.17 mm Hg; P &lt;2.2×10 −16 ) and more severely impaired right ventricular function (tricuspid annular plane systolic excursion: 16.0±4.11 versus 17.0±4.64 mm; P =0.012). Moreover, tricuspid valve effective regurgitant orifice area was smaller in patients with proportionate TR when compared with disproportionate TR (0.350±0.105 cm 2 versus 0.770±0.432 cm 2 ; P &lt;2.2×10 −16 ). Importantly, proportionate TR remained a significant predictor for 2‐year mortality after adjusting for demographic and clinical variables (hazard ratio, 1.7; P =0.006).

    </p> Conclusions

    <p lang="en">The proposed proportionality framework promises to improve future risk stratification and clinical decision‐making by identifying patients who benefit the most from TTVI (disproportionate TR). As a next step, randomized controlled studies with a conservative treatment arm are needed to quantify the net benefit of TTVI in patients with proportionate TR.

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    DOI: 10.1161/jaha.122.028737

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  • Machine learning identifies pathophysiologically and prognostically informative phenotypes among patients with mitral regurgitation undergoing transcatheter edge-to-edge repair

    Teresa Trenkwalder, Mark Lachmann, Lukas Stolz, Vera Fortmeier, Héctor Alfonso Alvarez Covarrubias, Elena Rippen, Friederike Schürmann, Antonia Presch, Moritz von Scheidt, Celine Ruff, Amelie Hesse, Muhammed Gerçek, N Patrick Mayr, Ilka Ott, Tibor Schuster, Gerhard Harmsen, Shinsuke Yuasa, Sebastian Kufner, Petra Hoppmann, Christian Kupatt, Heribert Schunkert, Adnan Kastrati, Karl-Ludwig Laugwitz, Volker Rudolph, Michael Joner, Jörg Hausleiter, Erion Xhepa

    European Heart Journal - Cardiovascular Imaging   24 ( 5 )   574 - 587   2023年2月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Oxford University Press (OUP)  

    Abstract

    Aims

    Patients with mitral regurgitation (MR) present with considerable heterogeneity in cardiac damage depending on underlying aetiology, disease progression, and comorbidities. This study aims to capture their cardiopulmonary complexity by employing a machine-learning (ML)-based phenotyping approach.

    Methods and results

    Data were obtained from 1426 patients undergoing mitral valve transcatheter edge-to-edge repair (MV TEER) for MR. The ML model was developed using 609 patients (derivation cohort) and validated on 817 patients from two external institutions. Phenotyping was based on echocardiographic data, and ML-derived phenotypes were correlated with 5-year outcomes. Unsupervised agglomerative clustering revealed four phenotypes among the derivation cohort: Cluster 1 showed preserved left ventricular ejection fraction (LVEF; 56.5 ± 7.79%) and regular left ventricular end-systolic diameter (LVESD; 35.2 ± 7.52 mm); 5-year survival in Cluster 1, hereinafter serving as a reference, was 60.9%. Cluster 2 presented with preserved LVEF (55.7 ± 7.82%) but showed the largest mitral valve effective regurgitant orifice area (0.623 ± 0.360 cm2) and highest systolic pulmonary artery pressures (68.4 ± 16.2 mmHg); 5-year survival ranged at 43.7% (P-value: 0.032). Cluster 3 was characterized by impaired LVEF (31.0 ± 10.4%) and enlarged LVESD (53.2 ± 10.9 mm); 5-year survival was reduced to 38.3% (P-value: &amp;lt;0.001). The poorest 5-year survival (23.8%; P-value: &amp;lt;0.001) was observed in Cluster 4 with biatrial dilatation (left atrial volume: 312 ± 113 mL; right atrial area: 46.0 ± 8.83 cm2) although LVEF was only slightly reduced (51.5 ± 11.0%). Importantly, the prognostic significance of ML-derived phenotypes was externally confirmed.

    Conclusion

    ML-enabled phenotyping captures the complexity of extra-mitral valve cardiac damage, which does not necessarily occur in a sequential fashion. This novel phenotyping approach can refine risk stratification in patients undergoing MV TEER in the future.

    DOI: 10.1093/ehjci/jead013

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  • Confidence in self-care after heart failure hospitalization

    Shun Hashimoto, Hiroki Kitakata, Shun Kohsaka, Daisuke Fujisawa, Yasuyuki Shiraishi, Naomi Nakano, Otoya Sekine, Yoshikazu Kishino, Yoshinori Katsumata, Shinsuke Yuasa, Keiichi Fukuda, Takashi Kohno

    Journal of Cardiology   81 ( 1 )   42 - 48   2023年1月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier BV  

    DOI: 10.1016/j.jjcc.2022.10.001

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  • A genetic and developmental biological approach for a family with complex congenital heart diseases-evidence of digenic inheritance. 国際誌

    Yu Yoshida, Keiko Uchida, Kazuki Kodo, Reina Ishizaki-Asami, Jun Maeda, Yoshinori Katsumata, Shinsuke Yuasa, Keiichi Fukuda, Kenjiro Kosaki, Yusuke Watanabe, Osamu Nakagawa, Hiroyuki Yamagishi

    Frontiers in cardiovascular medicine   10   1135141 - 1135141   2023年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: Congenital heart disease (CHD) is caused by cardiovascular developmental defects and has a global prevalence of ∼1%. The etiology of CHD is multifactorial and remains generally unknown, despite advances in analytical techniques based on next-generation sequencing (NGS). The aim of our study was to elucidate the multi-genetic origin and pathogenesis of an intriguing familial case with complex CHD. METHODS: We performed an original trio-based gene panel analysis using NGS of the family, including two siblings with CHD of single ventricular phenotype, and their unaffected parents. The pathogenicity of the detected rare variants was investigated in silico, and the functional effects of the variants were confirmed in vitro using luciferase assays. The combinatorial effect of gene alterations of the putative responsible genes was tested in vivo using genetically engineered mutant mice. RESULTS: NGS-based gene panel analyses revealed two heterozygous rare variants in NODAL and in TBX20 common to the siblings and to just one of parents. Both variants were suspected pathogenic in silico, and decreased transcriptional activities of downstream signaling pathways were observed in vitro. The analyses of Nodal and Tbx20 double mutant mice demonstrated that Nodal+/-Tbx20-/- embryos showed more severe defects than Nodal+/+Tbx20-/- embryos during early heart development. The expression of Pitx2, a known downstream target of Nodal, was downregulated in Tbx20-/- mutants. CONCLUSIONS: Two rare variants on NODAL and TBX20 genes detected in this family were considered to be loss-of-function mutations. Our results suggest that NODAL and TBX20 may be complementary for the cardiac development, and a combinatorial loss-of-function of NODAL and TBX20 could be implicated in digenic inherence as the etiology of complex CHD associated with single ventricle defects in this family.

    DOI: 10.3389/fcvm.2023.1135141

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  • Development of non-bias phenotypic drug screening for cardiomyocyte hypertrophy by image segmentation using deep learning

    Jin Komuro, Yuta Tokuoka, Tomohisa Seki, Dai Kusumoto, Hisayuki Hashimoto, Toshiomi Katsuki, Takahiro Nakamura, Yohei Akiba, Thukaa Kuoka, Mai Kimura, Takahiro Yamada, Keiichi Fukuda, Akira Funahashi, Shinsuke Yuasa

    Biochemical and Biophysical Research Communications   632   181 - 188   2022年12月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier BV  

    DOI: 10.1016/j.bbrc.2022.09.108

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  • Social Isolation and Implementation of Advanced Care Planning Among Hospitalized Patients With Heart Failure

    Hiroki Kitakata, Takashi Kohno, Shun Kohsaka, Daisuke Fujisawa, Naomi Nakano, Otoya Sekine, Yasuyuki Shiraishi, Yoshikazu Kishino, Yoshinori Katsumata, Shinsuke Yuasa, Keiichi Fukuda

    Journal of the American Heart Association   11 ( 21 )   2022年11月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Ovid Technologies (Wolters Kluwer Health)  

    Background

    <p lang="en">The implementation of advance care planning (ACP) in heart failure management is insufficient. Social isolation (SI) could be a barrier to ACP initiation, albeit the relationship between SI and patients' preference for ACP or end‐of‐life care remains unknown.

    </p> Methods and Results

    <p lang="en"> We conducted a questionnaire survey, including assessments of SI using the 6‐item Lubben Social Network Scale as well as patients' perspectives on ACP and end‐of‐life care. Of the 160 patients approached by our multidisciplinary heart failure team during admission, 120 patients (75.0%) completed the survey (median age, 73.0 years; men, 74.2%). A Cox proportional hazard model was constructed to elucidate the short‐term (180‐day) prognostic impact of SI. Overall, 28.3% of participants were at high risk for SI (6‐item Lubben Social Network Scale score &lt;12). High‐risk patients had more negative attitudes toward ACP than those without (61.8% versus 80.2%; P =0.035). The actual performance of ACP conversation in patients with and without high risk were 20.6% and 30.2%, respectively. Regarding preference in end‐of‐life care, “Saying what one wants to tell loved ones” (73.5% versus 90.6%; P =0.016) and “Spending enough time with family” (58.8% versus 77.9%; P =0.035) were less important in high‐risk patients. High risk for SI was associated with higher 180‐day risk‐adjusted all‐cause mortality (hazard ratio, 7.89 [95% CI, 1.53–40.75]).

    </p> Conclusions

    <p lang="en">In hospitalized patients with heart failure, high risk for SI was frequently observed. High‐risk patients were associated with a negative attitude toward ACP, despite higher mortality. Further research is required to establish an ideal approach to provide ACP in socially vulnerable patients.

    </p>

    DOI: 10.1161/jaha.122.026645

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  • Artificial intelligence-enabled phenotyping of patients with severe aortic stenosis: on the recovery of extra-aortic valve cardiac damage after transcatheter aortic valve replacement

    Mark Lachmann, Elena Rippen, Tibor Schuster, Erion Xhepa, Moritz von Scheidt, Teresa Trenkwalder, Costanza Pellegrini, Tobias Rheude, Amelie Hesse, Anja Stundl, Gerhard Harmsen, Shinsuke Yuasa, Heribert Schunkert, Adnan Kastrati, Karl-Ludwig Laugwitz, Michael Joner, Christian Kupatt

    Open Heart   9 ( 2 )   e002068 - e002068   2022年10月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:BMJ  

    Objective

    A novel artificial intelligence-based phenotyping approach to stratify patients with severe aortic stenosis (AS) prior to transcatheter aortic valve replacement (TAVR) has been proposed, based on echocardiographic and haemodynamic data. This study aimed to analyse the recovery of extra-aortic valve cardiac damage in accordance with this novel stratification system following TAVR.

    Methods

    The proposed phenotyping approach was previously established employing data from 366 patients with severe AS from a bicentric registry. For this consecutive study, echocardiographic follow-up data, obtained on day 147±75.1 after TAVR, were available from 247 patients (67.5%).

    Results

    Correction of severe AS by TAVR significantly reduced the proportion of patients suffering from concurrent severe mitral regurgitation (from 9.29% to 3.64%, p value: 0.0015). Moreover, pulmonary artery pressures were ameliorated (estimated systolic pulmonary artery pressure: from 47.2±15.8 to 43.3±15.1 mm Hg, p value: 0.0079). However, right heart dysfunction as well as the proportion of patients with severe tricuspid regurgitation remained unchanged. Clusters with persistent right heart dysfunction ultimately displayed 2-year survival rates of 69.2% (95% CI 56.6% to 84.7%) and 74.6% (95% CI 65.9% to 84.4%), which were significantly lower compared with clusters with little or no persistent cardiopulmonary impairment (88.3% (95% CI 83.3% to 93.5%) and 85.5% (95% CI 77.1% to 94.8%)).

    Conclusions

    This phenotyping approach preprocedurally identifies patients with severe AS, who will not recover from extra-aortic valve cardiac damage following TAVR and whose survival is therefore significantly reduced. Importantly, not the degree of pulmonary hypertension at initial presentation, but the irreversibility of right heart dysfunction determines prognosis.

    DOI: 10.1136/openhrt-2022-002068

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  • The complement C3-complement factor D-C3a receptor signalling axis regulates cardiac remodelling in right ventricular failure. 国際誌

    Shogo Ito, Hisayuki Hashimoto, Hiroyuki Yamakawa, Dai Kusumoto, Yohei Akiba, Takahiro Nakamura, Mizuki Momoi, Jin Komuro, Toshiomi Katsuki, Mai Kimura, Yoshikazu Kishino, Shin Kashimura, Akira Kunitomi, Mark Lachmann, Masaya Shimojima, Gakuto Yozu, Chikaaki Motoda, Tomohisa Seki, Tsunehisa Yamamoto, Yoshiki Shinya, Takahiro Hiraide, Masaharu Kataoka, Takashi Kawakami, Kunimichi Suzuki, Kei Ito, Hirotaka Yada, Manabu Abe, Mizuko Osaka, Hiromi Tsuru, Masayuki Yoshida, Kenji Sakimura, Yoshihiro Fukumoto, Michisuke Yuzaki, Keiichi Fukuda, Shinsuke Yuasa

    Nature communications   13 ( 1 )   5409 - 5409   2022年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Failure of the right ventricle plays a critical role in any type of heart failure. However, the mechanism remains unclear, and there is no specific therapy. Here, we show that the right ventricle predominantly expresses alternative complement pathway-related genes, including Cfd and C3aR1. Complement 3 (C3)-knockout attenuates right ventricular dysfunction and fibrosis in a mouse model of right ventricular failure. C3a is produced from C3 by the C3 convertase complex, which includes the essential component complement factor D (Cfd). Cfd-knockout mice also show attenuation of right ventricular failure. Moreover, the plasma concentration of CFD correlates with the severity of right ventricular failure in patients with chronic right ventricular failure. A C3a receptor (C3aR) antagonist dramatically improves right ventricular dysfunction in mice. In summary, we demonstrate the crucial role of the C3-Cfd-C3aR axis in right ventricular failure and highlight potential therapeutic targets for right ventricular failure.

    DOI: 10.1038/s41467-022-33152-9

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  • Sleep-disordered breathing is independently associated with elevated natriuretic peptide levels in patients with cardiovascular diseases.

    Kohei Sugiura, Takashi Kohno, Shun Kohsaka, Yasuyuki Shiraishi, Yoshinori Katsumata, Kentaro Hayashida, Shinsuke Yuasa, Seiji Takatsuki, Keiichi Fukuda

    Heart and vessels   37 ( 6 )   994 - 1002   2022年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Sleep disorders and sleep duration have attracted considerable attention as potential modifiable risk factors for the development and progression of heart failure (HF). However, whether these sleep behaviors could aggravate the underlying cardiac condition remains ambiguous. We evaluated the associations between the levels of plasma B-type natriuretic peptide (BNP) and sleep-disordered breathing (SDB), sleep quality and quantity, or daytime sleepiness in cardiovascular diseases (CVD) patients. A total of 1717 consecutive patients with CVD [median age, 66 years (55-74 years); female, 27.5%] were enrolled. SDB was screened by nocturnal pulse oximetry; sleep quality and quantity were determined by Pittsburg Sleep Quality Index, and daytime sleepiness was examined by Epworth Sleepiness Scale. The median plasma BNP level was 54.9 pg/ml (23.5-146.4 pg/ml). Multiple regression analyses showed that the BNP level in the highest quintile (BNP > 181.8 pg/ml) was associated with SDB (severe: OR, 5.88; 95% CI 3.17-10.88; moderate: OR, 3.62; 95% CI 2.17-6.02; mild: OR, 2.22: 95% CI 1.42-3.47). There were no significant associations between other sleep parameters and higher BNP levels. The relationship between SDB and BNP levels was unchanged regardless of the previous history of symptomatic HF. SDB was independently associated with the elevated plasma BNP level in patients with a variety of CVD.

    DOI: 10.1007/s00380-021-01998-6

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  • Recent Technological Innovations to Promote Cardiovascular Research

    Shinsuke Yuasa

    Circulation Journal   86 ( 6 )   919 - 922   2022年5月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Japanese Circulation Society  

    DOI: 10.1253/circj.cj-21-0978

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  • Induced Pluripotent Stem Cell-Based Drug Screening by Use of Artificial Intelligence

    Dai Kusumoto, Shinsuke Yuasa, Keiichi Fukuda

    Pharmaceuticals   15 ( 5 )   562 - 562   2022年4月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:MDPI AG  

    Induced pluripotent stem cells (iPSCs) are terminally differentiated somatic cells that differentiate into various cell types. iPSCs are expected to be used for disease modeling and for developing novel treatments because differentiated cells from iPSCs can recapitulate the cellular pathology of patients with genetic mutations. However, a barrier to using iPSCs for comprehensive drug screening is the difficulty of evaluating their pathophysiology. Recently, the accuracy of image analysis has dramatically improved with the development of artificial intelligence (AI) technology. In the field of cell biology, it has become possible to estimate cell types and states by examining cellular morphology obtained from simple microscopic images. AI can evaluate disease-specific phenotypes of iPS-derived cells from label-free microscopic images; thus, AI can be utilized for disease-specific drug screening using iPSCs. In addition to image analysis, various AI-based methods can be applied to drug development, including phenotype prediction by analyzing genomic data and virtual screening by analyzing structural formulas and protein–protein interactions of compounds. In the future, combining AI methods may rapidly accelerate drug discovery using iPSCs. In this review, we explain the details of AI technology and the application of AI for iPSC-based drug screening.

    DOI: 10.3390/ph15050562

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  • Harnessing feature extraction capacities from a pre-trained convolutional neural network (VGG-16) for the unsupervised distinction of aortic outflow velocity profiles in patients with severe aortic stenosis

    Mark Lachmann, Elena Rippen, Daniel Rueckert, Tibor Schuster, Erion Xhepa, Moritz von Scheidt, Costanza Pellegrini, Teresa Trenkwalder, Tobias Rheude, Anja Stundl, Ruth Thalmann, Gerhard Harmsen, Shinsuke Yuasa, Heribert Schunkert, Adnan Kastrati, Michael Joner, Christian Kupatt, Karl Ludwig Laugwitz

    European Heart Journal - Digital Health   3 ( 2 )   153 - 168   2022年4月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Oxford University Press (OUP)  

    Abstract

    Aims

    Hypothesizing that aortic outflow velocity profiles contain more valuable information about aortic valve obstruction and left ventricular contractility than can be captured by the human eye, features of the complex geometry of Doppler tracings from patients with severe aortic stenosis (AS) were extracted by a convolutional neural network (CNN).

    Methods and results

    After pre-training a CNN (VGG-16) on a large data set (ImageNet data set; 14 million images belonging to 1000 classes), the convolutional part was employed to transform Doppler tracings to 1D arrays. Among 366 eligible patients [age: 79.8 ± 6.77 years; 146 (39.9%) women] with pre-procedural echocardiography and right heart catheterization prior to transcatheter aortic valve replacement (TAVR), good quality Doppler tracings from 101 patients were analysed. The convolutional part of the pre-trained VGG-16 model in conjunction with principal component analysis and k-means clustering distinguished two shapes of aortic outflow velocity profiles. Kaplan–Meier analysis revealed that mortality in patients from Cluster 2 (n = 40, 39.6%) was significantly increased [hazard ratio (HR) for 2-year mortality: 3; 95% confidence interval (CI): 1–8.9]. Apart from reduced cardiac output and mean aortic valve gradient, patients from Cluster 2 were also characterized by signs of pulmonary hypertension, impaired right ventricular function, and right atrial enlargement. After training an extreme gradient boosting algorithm on these 101 patients, validation on the remaining 265 patients confirmed that patients assigned to Cluster 2 show increased mortality (HR for 2-year mortality: 2.6; 95% CI: 1.4–5.1, P-value: 0.004).

    Conclusion

    Transfer learning enables sophisticated pattern recognition even in clinical data sets of limited size. Importantly, it is the left ventricular compensation capacity in the face of increased afterload, and not so much the actual obstruction of the aortic valve, that determines fate after TAVR.

    DOI: 10.1093/ehjdh/ztac004

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    その他リンク: https://academic.oup.com/ehjdh/article-pdf/3/2/153/47117014/ztac004.pdf

  • Recurrence of Myopericarditis Following mRNA COVID-19 Vaccination in a Male Adolescent. 国際誌

    Tomohiko C Umei, Yoshikazu Kishino, Keiko Watanabe, Yasuyuki Shiraishi, Taku Inohara, Shinsuke Yuasa, Keiichi Fukuda

    CJC open   4 ( 3 )   350 - 352   2022年3月

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    記述言語:英語  

    COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease has spread worldwide, resulting in health and economic crises. Vaccination against SARS-CoV-2 infection is considered a valid prevention measure to control this pandemic. There have been reports of cases of myopericarditis following mRNA COVID-19 vaccination. We present a case of a 20-year-old man with recurrent myopericarditis following an initial episode of influenza virus-induced myopericarditis and after a second dose of the mRNA-1273 Moderna COVID-19 vaccine. Careful attention should be paid to patients with a history of myocarditis following COVID-19 vaccination.

    DOI: 10.1016/j.cjco.2021.12.002

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  • Clinical course of the longest-lived man in the world: A case report 査読

    Ryo Shikimoto, Yasumichi Arai, Shinsuke Yuasa, Yasuyuki Gondo, Saori Yasumoto, Yukiko Abe, Nobuyoshi Hirose

    Experimental Gerontology   159   111679 - 111679   2022年3月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier BV  

    DOI: 10.1016/j.exger.2021.111679

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  • Solving the Pulmonary Hypertension Paradox in Patients With Severe Tricuspid Regurgitation by Employing Artificial Intelligence

    Vera Fortmeier, Mark Lachmann, Maria I. Körber, Matthias Unterhuber, Moritz von Scheidt, Elena Rippen, Gerhard Harmsen, Muhammed Gerçek, Kai Peter Friedrichs, Fabian Roder, Tanja K. Rudolph, Shinsuke Yuasa, Michael Joner, Karl-Ludwig Laugwitz, Stephan Baldus, Roman Pfister, Philipp Lurz, Volker Rudolph

    JACC: Cardiovascular Interventions   15 ( 4 )   381 - 394   2022年2月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier BV  

    DOI: 10.1016/j.jcin.2021.12.043

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  • Editorial: Induced Pluripotent Stem Cell-Based Disease Modeling and Drug Discovery: Can We Recapitulate Cardiovascular Disease on a Culture Dish?

    Shinsuke Yuasa, Masayuki Yazawa, Jong-Kook Lee

    Frontiers in Cell and Developmental Biology   9   2022年1月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Frontiers Media SA  

    DOI: 10.3389/fcell.2021.831304

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  • Sex differences in sleep and psychological disturbances among patients admitted for cardiovascular diseases. 国際誌

    Yuichi Jono, Takashi Kohno, Shun Kohsaka, Hiroki Kitakata, Yasuyuki Shiraishi, Yoshinori Katsumata, Kentaro Hayashida, Shinsuke Yuasa, Seiji Takatsuki, Keiichi Fukuda

    Sleep & breathing = Schlaf & Atmung   2022年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Understanding sex differences is critical for improving outcomes in patients with cardiovascular conditions. Sleep and psychological disturbances contribute to the development and progression of cardiovascular diseases, and important sex differences persist in their incidence and association with clinical outcomes. METHODS: Sex-based variation in sleep and psychological disturbances were assessed in consecutive patients with cardiovascular diseases in a single university hospital. The prevalence of insomnia, sleep disordered breathing (SDB), anxiety, and depression was assessed using the Pittsburgh Sleep Quality Index (PSQI), nocturnal pulse oximeter, and the Hospital Anxiety and Depression Scale (HADS). The effect of sex on the prevalence of sleep and psychological disturbances as well as their associations was quantified using multivariate logistic regression models. RESULTS: Among 1,233 patients (mean age 63.6 years, 25% women), women were significantly less likely than men to experience SDB (17.5% vs 31.5%, p < 0.001), but more likely to report an increased burden of insomnia (54.7% vs 43.3%, p = 0.001) and depression (23.9% vs 16.7%, p = 0.004). Insomnia was associated with depression, which was more remarkable among women (p value for interaction: 0.039). SDB was associated with anxiety among women but not men (p value for interaction: 0.003). There was no significant difference in the prevalence of anxiety between women and men. CONCLUSIONS: Among patients with cardiovascular disease, women reported an increased burden of insomnia and depression compared to men. The association between sleep and psychological disturbances may be more pronounced in women, suggesting that cardiologists should increase efforts for identification of such comorbidities and administer corresponding treatment, especially in women.

    DOI: 10.1007/s11325-021-02544-4

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  • Upregulation of neuropeptide Y in cardiac sympathetic nerves induces stress (Takotsubo) cardiomyopathy. 国際誌

    Takahide Arai, Hideaki Kanazawa, Kensuke Kimura, Masahito Munakata, Hiroyuki Yamakawa, Ken Shinmura, Shinsuke Yuasa, Motoaki Sano, Keiichi Fukuda

    Frontiers in neuroscience   16   1013712 - 1013712   2022年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Substantial emotional or physical stress may lead to an imbalance in the brain, resulting in stress cardiomyopathy (SC) and transient left ventricular (LV) apical ballooning. Even though these conditions are severe, their precise underlying mechanisms remain unclear. Appropriate animal models are needed to elucidate the precise mechanisms. In this study, we established a new animal model of epilepsy-induced SC. The SC model showed an increased expression of the acute phase reaction protein, c-Fos, in the paraventricular hypothalamic nucleus (PVN), which is the sympathetic nerve center of the brain. Furthermore, we observed a significant upregulation of neuropeptide Y (NPY) expression in the left stellate ganglion (SG) and cardiac sympathetic nerves. NPY showed neither positive nor negative inotropic and chronotropic effects. On the contrary, NPY could interrupt β-adrenergic signaling in cardiomyocytes when exposure to NPY precedes exposure to noradrenaline. Moreover, its elimination in the left SG via siRNA treatment tended to reduce the incidence of SC. Thus, our results indicated that upstream sympathetic activation induced significant upregulation of NPY in the left SG and cardiac sympathetic nerves, resulting in cardiac dysfunctions like SC.

    DOI: 10.3389/fnins.2022.1013712

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  • Anti-senescent drug screening by deep learning-based morphology senescence scoring

    Dai Kusumoto, Tomohisa Seki, Hiromune Sawada, Akira Kunitomi, Toshiomi Katsuki, Mai Kimura, Shogo Ito, Jin Komuro, Hisayuki Hashimoto, Keiichi Fukuda, Shinsuke Yuasa

    Nature Communications   12 ( 1 )   2021年12月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    <title>Abstract</title>Advances in deep learning technology have enabled complex task solutions. The accuracy of image classification tasks has improved owing to the establishment of convolutional neural networks (CNN). Cellular senescence is a hallmark of ageing and is important for the pathogenesis of ageing-related diseases. Furthermore, it is a potential therapeutic target. Specific molecular markers are used to identify senescent cells. Moreover senescent cells show unique morphology, which can be identified. We develop a successful morphology-based CNN system to identify senescent cells and a quantitative scoring system to evaluate the state of endothelial cells by senescence probability output from pre-trained CNN optimised for the classification of cellular senescence, Deep Learning-Based Senescence Scoring System by Morphology (Deep-SeSMo). Deep-SeSMo correctly evaluates the effects of well-known anti-senescent reagents. We screen for drugs that control cellular senescence using a kinase inhibitor library by Deep-SeSMo-based drug screening and identify four anti-senescent drugs. RNA sequence analysis reveals that these compounds commonly suppress senescent phenotypes through inhibition of the inflammatory response pathway. Thus, morphology-based CNN system can be a powerful tool for anti-senescent drug screening.

    DOI: 10.1038/s41467-020-20213-0

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    その他リンク: http://www.nature.com/articles/s41467-020-20213-0

  • Preferences on advance care planning and end-of-life care in patients hospitalized for heart failure. 国際誌

    Hiroki Kitakata, Takashi Kohno, Shun Kohsaka, Daisuke Fujisawa, Naomi Nakano, Yasuyuki Shiraishi, Yoshinori Katsumata, Yuji Nagatomo, Shinsuke Yuasa, Keiichi Fukuda

    ESC heart failure   8 ( 6 )   5102 - 5111   2021年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    AIMS: Early engagement in advance care planning (ACP) is recommended in heart failure (HF) management. We investigated the preferences of patients with HF regarding ACP and end-of-life (EOL) care, including their desired timing of ACP initiation. METHODS AND RESULTS: Data were collected using a 92-item questionnaire survey, which was directly distributed to hospitalized patients by dedicated physicians and nurses in a university hospital setting. One-hundred eighty-seven patients agreed to participate (response rate: 92.6%), and 171 completed the survey [valid response rate: 84.7%; men: 67.3%; median age: 73.0 (63.0-81.0) years]. Logistic regression analyses were conducted to identify the predictors of positive attitudes towards ACP. Most recognized ACP as important for their care (n = 127, 74.3%), 48.1% stated that ACP should be initiated after repeated HF hospitalizations in the past year, and 29.0% preferred ACP to begin during the first or second HF hospitalization. Only 21.7% of patients had previously engaged in ACP conversations during HF management. Positive attitudes towards ACP were associated with lower depressive symptoms [two-item Patient Health Questionnaire; odds ratio (OR): 0.75, 95% confidence interval (CI): 0.61-0.92, P-value: 0.006], marriage (OR: 2.53, 95% CI: 1.25-5.12, P-value: 0.010), and a high educational level (OR: 2.66, 95% CI: 1.28-5.56, P-value: 0.009), but not with severity of HF (represented by Seattle Heart Failure Model risk score). Regarding EOL care, while 'Saying what one wants to tell loved ones' (83.4%), 'Dying a natural death' (81.8%), and 'Being able to stay at one's favorite place' (75.6%) were the three most important factors for patients, preferences for 'Receiving sufficient treatment' (56.5%) and 'Knowing what to expect about future condition' (50.3%) were divergent. CONCLUSIONS: Despite patients' preferences for ACP conversations, there was a discrepancy between preference and engagement in ACP among patients hospitalized for HF. Patients' preferences regarding EOL care may differ; physicians need to consider the appropriate ACP approach to align with patients' care goals.

    DOI: 10.1002/ehf2.13578

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  • Subphenotyping of Patients With Aortic Stenosis by Unsupervised Agglomerative Clustering of Echocardiographic and Hemodynamic Data

    Mark Lachmann, Elena Rippen, Tibor Schuster, Erion Xhepa, Moritz von Scheidt, Costanza Pellegrini, Teresa Trenkwalder, Tobias Rheude, Anja Stundl, Ruth Thalmann, Gerhard Harmsen, Shinsuke Yuasa, Heribert Schunkert, Adnan Kastrati, Karl-Ludwig Laugwitz, Christian Kupatt, Michael Joner

    JACC: Cardiovascular Interventions   14 ( 19 )   2127 - 2140   2021年10月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier BV  

    DOI: 10.1016/j.jcin.2021.08.034

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  • Predictors of New-Onset Atrial Tachyarrhythmias After Transcatheter Atrial Septal Defect Closure in Adults. 国際誌

    Kotaro Miura, Mai Kimura, Atsushi Anzai, Takahide Arai, Takashi Kawakami, Shinsuke Yuasa, Kentaro Hayashida, Jin Endo, Hikaru Tsuruta, Yuji Itabashi, Akio Kawamura, Keiichi Fukuda, Hideaki Kanazawa

    Heart, lung & circulation   30 ( 9 )   1406 - 1413   2021年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: New-onset atrial tachyarrhythmia (ATA) often develops after atrial septal defect (ASD) closure. Its development raises some potential concerns such as stroke and bleeding complications caused by anticoagulant therapy and limited access to the left atrium for catheter ablation. Although it is essential to identify the risk factors of new-onset ATA, few studies have examined these factors. This study investigated unknown risk factors for the development of new-onset ATA after transcatheter ASD closure in patients without a history of ATA. METHODS: A total of 238 patients without a history of ATA, aged ≥18 years and who underwent transcatheter ASD closure at the current hospital were reviewed. Patient characteristics were compared between the groups with and without new-onset ATA. The factors associated with new-onset ATA were examined using univariate and multivariable analyses. RESULTS: Thirteen (13) (5.5%) patients experienced ATA during follow-up (mean, 21±14 months). Compared with patients without new-onset ATA, patients with new-onset ATA were older (48±18 vs 66±11 years; p<0.001) and had high brain natriuretic peptide (BNP) levels (36±36 vs 177±306 pg/mL; p<0.001). On multivariable analysis, BNP ≥40 pg/mL before ASD closure was associated with new-onset ATA after adjusting for age (OR, 4.91; 95% CI, 1.22-19.8; p=0.025). CONCLUSION: Patients with BNP levels >40 pg/mL before transcatheter ASD closure may have a higher risk of developing new-onset ATA.

    DOI: 10.1016/j.hlc.2021.02.018

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  • Transcatheter Mitral Valve Repair Effective and Safe for Refractory Eclipsed Mitral Regurgitation-Induced Cardiogenic Shock: A Case Report. 国際誌

    Tomohiko C Umei, Yasuyuki Shiraishi, Hikaru Tsuruta, Kentaro Hayashida, Shohei Imaeda, Toshinobu Ryuzaki, Sosuke Myojin, Yusuke Kobari, Tetsuya Saito, Nobuhiro Yoshijima, Yuji Itabashi, Yoshikazu Kishino, Yoshinori Katsumata, Shinsuke Yuasa, Keiichi Fukuda

    Circulation. Cardiovascular imaging   14 ( 7 )   e012641   2021年7月

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  • Prognostic Understanding and Preference for the Communication Process with Physicians in Hospitalized Heart Failure Patients. 国際誌

    Hiroki Kitakata, Takashi Kohno, Shun Kohsaka, Daisuke Fujisawa, Naomi Nakano, Yasuyuki Shiraishi, Yoshinori Katsumata, Shinsuke Yuasa, Keiichi Fukuda

    Journal of cardiac failure   27 ( 3 )   318 - 326   2021年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Heart failure (HF) is a highly prevalent, heterogeneous, and life-threatening condition. Precise prognostic understanding is essential for effective decision making, but little is known about patients' attitudes toward prognostic communication with their physicians. METHODS AND RESULTS: We conducted a questionnaire survey, consisting of patients' prognostic understanding, preferences for information disclosure, and depressive symptoms, among hospitalized patients with HF (92 items in total). Individual 2-year survival rates were calculated using the Seattle Heart Failure Model, and its agreement level with patient self-expectations of 2-year survival were assessed. A total of 113 patients completed the survey (male 65.5%, median age 75.0 years, interquartile range 66.0-81.0 years). Compared with the Seattle Heart Failure Model prediction, patient expectation of 2-year survival was matched only in 27.8% of patients; their agreement level was low (weighted kappa = 0.11). Notably, 50.9% wished to know "more," although 27.7% felt that they did not have an adequate prognostic discussion. Compared with the known prognostic variables (eg, age and HF severity), logistic regression analysis demonstrated that female and less depressive patients were associated with patients' preference for "more" prognostic discussion. CONCLUSIONS: Patients' overall prognostic understanding was suboptimal. The communication process requires further improvement for patients to accurately understand their HF prognosis and be involved in making a better informed decision.

    DOI: 10.1016/j.cardfail.2020.10.009

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  • Factors related to instrumental activities of daily living in persons with chronic thromboembolic pulmonary hypertension

    Tatsuya Iwasawa, Shogo Fukui, Michiyuki Kawakami, Takashi Kawakami, Masaharu Kataoka, Shinsuke Yuasa, Keiichi Fukuda, Toshiyuki Fujiwara, Tetsuya Tsuji

    Chronic Respiratory Disease   18   147997312110466 - 147997312110466   2021年1月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:SAGE Publications  

    Instrumental activities of daily living (IADL) are significantly related to quality of life and mortality among individuals with heart disease. However, few reports have examined IADL in persons with chronic thromboembolic pulmonary hypertension (CTEPH). The aim of this study was to clarify factors related to IADL in persons with CTEPH. This retrospective, observational study enrolled 163 persons with CTEPH (mean ± standard deviation age = 65 ± 13 years; 68% female) admitted to the Department of Cardiology at Keio University Hospital between January 2015 and July 2019. The Frenchay Activities Index (FAI) was used to assess IADL. Age, sex, body mass index, World Health Organization functional class (WHO-FC), cardiac function (mean pulmonary arterial pressure, mean right atrial pressure, pulmonary capillary wedge pressure, and cardiac index), pulmonary function (percentage vital capacity, percentage forced expiratory volume in 1 s, diffusion capacity of carbon monoxide (DLCO)/alveolar volume (VA)), physical function (knee extension strength and walking speed), and 6-min walking distance (6MWD) were assessed. Multiple regression analysis was performed to identify factors significantly associated with FAI. Mean FAI was 25 ± 8. Univariate analysis showed that sex, WHO-FC, DLCO/VA, walking speed, and 6MWD were correlated with FAI. Multiple regression analysis showed that 6MWD (sβ = 0.338, 95% CI 0.014–0.034, p &lt; .001), sex (sβ = 0.268, 95% CI 2.238–7.165, p &lt; .001), and DLCO/VA (sβ = 0.257, 95% CI 1.011–3.528, p &lt; .001) were significantly correlated with FAI ( R2 = 0.261). IADL were associated with exercise tolerance, sex, and DLCO/VA in persons with CTEPH. In the future, more details of IADL are expected to be clarified by analyzing individual components of IADL and investigating social background characteristics, including living environment.

    DOI: 10.1177/14799731211046634

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    その他リンク: http://journals.sagepub.com/doi/full-xml/10.1177/14799731211046634

  • Thyroid Hormone Plays an Important Role in Cardiac Function: From Bench to Bedside. 国際誌

    Hiroyuki Yamakawa, Tomoko S Kato, Jaeduk Yoshimura Noh, Shinsuke Yuasa, Akio Kawamura, Keiichi Fukuda, Yoshiyasu Aizawa

    Frontiers in physiology   12   606931 - 606931   2021年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Thyroid hormones (THs) are synthesized in the thyroid gland, and they circulate in the blood to regulate cells, tissues, and organs in the body. In particular, they exert several effects on the cardiovascular system. It is well known that THs raise the heart rate and cardiac contractility, improve the systolic and diastolic function of the heart, and decrease systemic vascular resistance. In the past 30 years, some researchers have studied the molecular pathways that mediate the role of TH in the cardiovascular system, to better understand its mechanisms of action. Two types of mechanisms, which are genomic and non-genomic pathways, underlie the effects of THs on cardiomyocytes. In this review, we summarize the current knowledge of the action of THs in the cardiac function, the clinical manifestation and parameters of their hemodynamics, and treatment principles for patients with hyperthyroid- or hypothyroid-associated heart disease. We also describe the cardiovascular drugs that induce thyroid dysfunction and explain the mechanism underlying the thyroid toxicity of amiodarone, which is considered the most effective antiarrhythmic agent. Finally, we discuss the recent reports on the involvement of thyroid hormones in the regulation of myocardial regeneration and metabolism in the adult heart.

    DOI: 10.3389/fphys.2021.606931

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  • Psychological disturbances and their association with sleep disturbances in patients admitted for cardiovascular diseases. 国際誌

    Risa Matsuda, Takashi Kohno, Shun Kohsaka, Yasuyuki Shiraishi, Yoshinori Katsumata, Kentaro Hayashida, Shinsuke Yuasa, Seiji Takatsuki, Keiichi Fukuda

    PloS one   16 ( 1 )   e0244484   2021年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Depression and anxiety are common mental health problems that are strongly associated with sleep disturbances, according to community-based researches. However, this association has not been investigated among patients admitted for cardiovascular diseases (CVDs). We examined the prevalence of depression and anxiety in inpatients with various CVDs and their association with sleep disturbances. MATERIALS AND METHODS: This cross-sectional study included 1294 patients hospitalized for CVDs in a Japanese university hospital were evaluated for their mental status using the Hospital Anxiety and Depression Scale (HADS), for sleep-disordered breathing (SDB) using pulse oximetry, and for sleep quality using the Pittsburgh Sleep Quality Index (PSQI). RESULTS: Patient characteristics were as below: mean age, 63.9±14.7 years; 25.7% female. Overall, 18.9% had depression (HADS-depression≥8) and 17.1% had anxiety (HADS-anxiety≥8). The presence of depression was associated with female sex, older age, higher plasma brain natriuretic peptide level, lower estimated glomerular filtration rate, and the prevalence of heart failure. Overall, 46.5% patients were categorized as having a poor sleep quality (PSQI>5), and 28.5% patients had SDB (3% oxygen desaturation index>15). Although depression and anxiety were not associated with SDB, they were independently associated with poor sleep quality (OR = 3.09, 95% CI 2.19-4.36; OR = 3.93, 95% CI 2.71-5.69, respectively). CONCLUSIONS: Depression and anxiety were not uncommon in patients with CVDs. Poor sleep quality could be an important risk factor linked to psychological disturbances.

    DOI: 10.1371/journal.pone.0244484

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  • Frequent nightmares and its associations with psychological and sleep disturbances in hospitalized patients with cardiovascular diseases. 国際誌

    Haruaki Horie, Takashi Kohno, Shun Kohsaka, Hiroki Kitakata, Yasuyuki Shiraishi, Yoshinori Katsumata, Kentaro Hayashida, Shinsuke Yuasa, Seiji Takatsuki, Keiichi Fukuda

    European journal of cardiovascular nursing : journal of the Working Group on Cardiovascular Nursing of the European Society of Cardiology   20 ( 5 )   421 - 427   2020年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    AIMS: Frequent nightmares can pose a serious clinical problem, especially in association with sleep and psychological disturbances, in the general population. However, this association has not been investigated in inpatients with cardiovascular (CV) diseases. Furthermore, whether CV medications could induce iatrogenic nightmares remains unknown. In a cross-sectional designed study, we evaluated the prevalence and determinants of frequent nightmares and its association with sleep and psychological disturbances among hospitalized CV patients. METHODS AND RESULTS: A total of 1233 patients (mean age, 64 ± 15 years; 25.1% female) hospitalized for various CV diseases in a single university hospital were enrolled. We assessed nightmares and sleep characteristics using the Pittsburgh Sleep Quality Index (PSQI), sleep-disordered breathing (SDB) using nocturnal pulse oximetry, and psychological disturbances using Hospital Anxiety and Depression Scale (HADS). Overall, 14.8% and 3.6% of the patients had at least one nightmare per month and per week (frequent nightmares), respectively. In this cohort, 45.9% had insomnia (modified PSQI > 5), 28.0% had SDB (3% oxygen desaturation index > 15), 18.5% had depression (HADS-depression ≥ 8), and 16.9% had anxiety (HADS-anxiety ≥ 8). Frequent nightmares were not associated with CV medications and SDB but were associated with depression [odds ratio (OR) = 4.61, 95% confidence interval (CI) = 2.03-10.48], anxiety (OR = 5.32, 95% CI = 2.36-12.01), and insomnia (OR = 7.15, 95% CI = 2.41-21.22). CONCLUSIONS: Frequent nightmares were not uncommon in patients hospitalized for CV diseases. Although the cause-effect relationship is unclear, frequent nightmares were associated with psychological disturbances and insomnia, but not iatrogenic factors, among hospitalized CV patients. Cardiologists should be more conscientious to nightmare complaints with respect to screening for psychological disturbances and insomnia.

    DOI: 10.1093/eurjcn/zvaa016

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  • Successful Percutaneous Abscess Drainage and Irrigation for the Treatment of Infected Aortic Aneurysm Post-Thoracic Endovascular Aortic Repair. 国際誌

    Ippei Tsuzuki, Yoshikazu Kishino, Yasuyuki Shiraishi, Yoshinori Katsumata, Shinsuke Yuasa, Nobutake Ito, Masanori Inoue, Tsutomu Ito, Hideyuki Shimizu, Keiichi Fukuda

    CJC open   2 ( 6 )   735 - 738   2020年11月

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    記述言語:英語  

    Infected aortic aneurysm (IAA) is a rare, life-threatening disease with rapid progression and a high mortality rate. An 84-year-old man developed IAA caused by urosepsis owing to extended-spectrum β-lactamase-producing Escherichia coli infection. Considering surgical risk and perioperative mortality, the patient underwent computed tomography-guided percutaneous abscess drainage and continuous irrigation with optimal antibiotic therapy. We controlled his systemic inflammation without surgery; thus, he was discharged. Six months later, we confirmed that the abscess had almost disappeared in the follow-up computed tomography scan. Percutaneous abscess drainage and irrigation may be an effective therapeutic option for surgical high-risk patients with IAA.

    DOI: 10.1016/j.cjco.2020.08.008

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  • Left ventricular thrombus with COVID-19 complication in a patient with dilated cardiomyopathy. 国際誌

    Shohei Imaeda, Hiroki Kabata, Yasuyuki Shiraishi, Hirofumi Kamata, Hikaru Tsuruta, Shinsuke Yuasa, Makoto Ishii, Keiichi Fukuda, Koichi Fukunaga

    CJC open   3 ( 1 )   124 - 126   2020年9月

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    記述言語:英語  

    Thrombosis, especially venous thromboembolism, is a complication often associated with COVID-19. However, there have been relatively few reports of arterial thrombosis. Here, we describe a case of non-severe COVID-19 in a patient with dilated cardiomyopathy. After admission, symptoms, laboratory data, and imaging findings improved, but D-dimer levels gradually increased. Contrast computed tomography (CT) and echocardiography revealed a left ventricular thrombus. Anti-coagulant treatment diminished the thrombus, and the patient recovered and was discharged. Although a left ventricular thrombus is a rare COVID-19 complication, performing appropriate diagnostic tests could improve COVID-19 mortality in patients with dilated cardiomyopathy.

    DOI: 10.1016/j.cjco.2020.09.014

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  • Independent and cumulative association of clinical and morphological heart failure with long-term outcome after percutaneous coronary intervention. 国際誌

    Mai Kimura, Takashi Kohno, Mitsuaki Sawano, Paul A Heidenreich, Ikuko Ueda, Toshiyuki Takahashi, Takashi Matsubara, Koji Ueno, Kentaro Hayashida, Shinsuke Yuasa, Takahiro Ohki, Keiichi Fukuda, Shun Kohsaka

    Journal of cardiology   2020年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Heart failure (HF) is a risk factor for adverse post-procedural outcome after revascularization; however, it is unclear how left ventricular systolic dysfunction (LVSD) and clinical HF symptoms affect percutaneous coronary intervention (PCI) outcomes. We investigated the characteristics and long-term outcomes of patients with clinical HF or LVSD after PCI. METHODS: This was a Japanese multicenter registry study of adult patients receiving PCI. Among 4689 consecutive patients who underwent PCI at 15 hospitals from January 2009 to December 2012, we analyzed 2634 (56.2%) with documented left ventricular ejection fraction (LVEF). They were divided into four groups based on clinical HF (symptoms or HF hospitalization) and LVEF [≥35% and <35% (HF due to LVSD)]. The primary outcome was major adverse cardiovascular events (MACE), comprising all-cause death, acute coronary syndrome, HF hospitalization, performance of coronary artery bypass grafting, and stroke within 2 years after the initial PCI. RESULTS: Our findings revealed 354 patients (13.4%) with HF (clinical HF, n = 173, 48.9%; LVSD, n = 132, 37.3%; both, n = 49; 13.8%). The incidence of MACE was higher in patients with clinical HF or LVSD, and was largely due to higher non-cardiac death and HF hospitalization. After adjustment, clinical HF (hazard ratio 2.16, 95% confidence interval; 1.49-3.14) and lower LVEF (per 10%, hazard ratio 0.89, 95% confidence interval; 0.81-0.99) were independently associated with higher MACE risk. CONCLUSIONS: Clinical HF and LVSD were independently associated with adverse long-term clinical outcomes, particularly with non-cardiac death and HF readmission, in patients treated with PCI.

    DOI: 10.1016/j.jjcc.2020.06.014

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  • Associations of cardiovascular biomarkers and plasma albumin with exceptional survival to the highest ages. 国際誌

    Takumi Hirata, Yasumichi Arai, Shinsuke Yuasa, Yukiko Abe, Michiyo Takayama, Takashi Sasaki, Akira Kunitomi, Hiroki Inagaki, Motoyoshi Endo, Jun Morinaga, Kimio Yoshimura, Tetsuo Adachi, Yuichi Oike, Toru Takebayashi, Hideyuki Okano, Nobuyoshi Hirose

    Nature communications   11 ( 1 )   3820 - 3820   2020年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Supercentenarians (those aged ≥110 years) are approaching the current human longevity limit by preventing or surviving major illness. Identifying specific biomarkers conducive to exceptional survival might provide insights into counter-regulatory mechanisms against aging-related disease. Here, we report associations between cardiovascular disease-related biomarkers and survival to the highest ages using a unique dataset of 1,427 oldest individuals from three longitudinal cohort studies, including 36 supercentenarians, 572 semi-supercentenarians (105-109 years), 288 centenarians (100-104 years), and 531 very old people (85-99 years). During follow-up, 1,000 participants (70.1%) died. Overall, N-terminal pro-B-type natriuretic peptide (NT-proBNP), interleukin-6, cystatin C and cholinesterase are associated with all-cause mortality independent of traditional cardiovascular risk factors and plasma albumin. Of these, low NT-proBNP levels are statistically associated with a survival advantage to supercentenarian age. Only low albumin is associated with high mortality across age groups. These findings expand our knowledge on the biology of human longevity.

    DOI: 10.1038/s41467-020-17636-0

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  • Zero-Contrast Transcatheter Closure of Patent Ductus Arteriosus Guided by Multiple Imaging Modalities. 査読 国際誌

    Kotaro Miura, Hideaki Kanazawa, Mai Kimura, Takahide Arai, Takashi Kawakami, Shinsuke Yuasa, Kentaro Hayashida, Keiichi Fukuda

    The Canadian journal of cardiology   2020年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.cjca.2020.03.052

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  • Exploring Triaging and Short-Term Outcomes of Early Invasive Strategy in Non-ST Segment Elevation Acute Coronary Syndrome: A Report from Japanese Multicenter Registry. 査読 国際誌

    Nobuhiro Ikemura, Yasuyuki Shiraishi, Mitsuaki Sawano, Ikuko Ueda, Yohei Numasawa, Shigetaka Noma, Masahiro Suzuki, Yukihiko Momiyama, Kentaro Hayashida, Shinsuke Yuasa, Hiroaki Miyata, Keiichi Fukuda, Shun Kohsaka

    Journal of clinical medicine   9 ( 4 )   2020年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    This observational study aimed to examine the extent of early invasive strategy (EIS) utilization in patients with non-ST elevation acute coronary syndrome (NSTE-ACS) according to the National Cardiovascular Data Registry (NCDR) CathPCI risk score, and its association with clinical outcomes. Using a prospective multicenter Japanese registry, 2968 patients with NSTE-ACS undergoing percutaneous coronary intervention within 72 hours of hospital arrival were analyzed. Multivariable logistic regression analyses were performed to determine predictors of EIS utilization. Additionally, adverse outcomes were compared between patients treated with and without EIS. Overall, 82.1% of the cohort (n = 2436) were treated with EIS, and the median NCDR CathPCI risk score was 22 (interquartile range: 14-32) with an expected 0.3-0.6% in-hospital mortality. Advanced age, peripheral artery disease, chronic kidney disease or patients without elevation of cardiac biomarkers were less likely to be treated with EIS. EIS utilization was not associated with a risk of in-hospital mortality; yet, it was associated with an increased risk of acute kidney injury (AKI) (adjusted odds ratio: 1.42; 95% confidence interval: 1.02-2.01) regardless of patients' in-hospital mortality risk. Broader use of EIS utilization comes at the cost of increased AKI development risk; thus, the pre-procedural risk-benefit profile of EIS should be reassessed appropriately in patients with lower mortality risk.

    DOI: 10.3390/jcm9041106

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  • Successful Surgical Treatment Combined With Infliximab in a Patient With Acute Aortic Regurgitation Caused by Behçet Disease. 査読 国際誌

    Yumiko Kawakubo, Yoshinori Katsumata, Jin Komuro, Yasuyuki Shiraishi, Shinsuke Yuasa, Yuji Itabashi, Takashi Kohno, Keiichi Fukuda

    The Canadian journal of cardiology   36 ( 7 )   1161.e3-1161.e5   2020年3月

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    記述言語:英語  

    Standard aortic valve replacement for aortic regurgitation caused by Behçet disease (BD) is frequently complicated by postoperative recurrent prosthetic valve detachment. Tumour necrosis factor (TNF) α is known to be associated with higher inflammation activities. Therefore, the concomitant use of immunomodulatory agents with TNFα inhibitors may be the key to a better outcome. This is a case report of a 46-year-old woman with severe acute aortic regurgitation due to BD. Immunosuppressive therapy including the TNFα inhibitor infliximab, which has not been reported for perioperative use to date, resulted in the prompt remission of inflammation, leading to the success of Bentall surgery.

    DOI: 10.1016/j.cjca.2020.03.029

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  • Stem Cell Aging in Skeletal Muscle Regeneration and Disease. 査読 国際誌

    Hiroyuki Yamakawa, Dai Kusumoto, Hisayuki Hashimoto, Shinsuke Yuasa

    International journal of molecular sciences   21 ( 5 )   2020年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Skeletal muscle comprises 30-40% of the weight of a healthy human body and is required for voluntary movements in humans. Mature skeletal muscle is formed by multinuclear cells, which are called myofibers. Formation of myofibers depends on the proliferation, differentiation, and fusion of muscle progenitor cells during development and after injury. Muscle progenitor cells are derived from muscle satellite (stem) cells (MuSCs), which reside on the surface of the myofiber but beneath the basement membrane. MuSCs play a central role in postnatal maintenance, growth, repair, and regeneration of skeletal muscle. In sedentary adult muscle, MuSCs are mitotically quiescent, but are promptly activated in response to muscle injury. Physiological and chronological aging induces MuSC aging, leading to an impaired regenerative capability. Importantly, in pathological situations, repetitive muscle injury induces early impairment of MuSCs due to stem cell aging and leads to early impairment of regeneration ability. In this review, we discuss (1) the role of MuSCs in muscle regeneration, (2) stem cell aging under physiological and pathological conditions, and (3) prospects related to clinical applications of controlling MuSCs.

    DOI: 10.3390/ijms21051830

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  • Poor outcomes in carriers of the RNF213 variant (p.Arg4810Lys) with pulmonary arterial hypertension. 査読 国際誌

    Takahiro Hiraide, Masaharu Kataoka, Hisato Suzuki, Yuki Aimi, Tomohiro Chiba, Sarasa Isobe, Yoshinori Katsumata, Shinichi Goto, Kohsuke Kanekura, Yoshitake Yamada, Hidenori Moriyama, Hiroki Kitakata, Jin Endo, Shinsuke Yuasa, Yasumichi Arai, Nobuyoshi Hirose, Toru Satoh, Yoji Hakamata, Motoaki Sano, Shinobu Gamou, Kenjiro Kosaki, Keiichi Fukuda

    The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation   39 ( 2 )   103 - 112   2020年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: A variant of c.14429G>A (p.Arg4810Lys, rs112735431) in the ring finger protein 213 gene (RNF213; NM_001256071.2) has been recently identified as a risk allele for pulmonary arterial hypertension (PAH). PAH can be added as a new member of RNF213-associated vascular diseases, which include Moyamoya disease and peripheral pulmonary stenosis. Our aim was to identify the clinical features and outcomes of PAH patients with this variant. METHODS: Whole-exome sequencing was performed in 139 idiopathic (or possibly heritable) PAH patients. RESULTS: The RNF213 p.Arg4810Lys variant was identified in a heterozygous state in 11 patients (7.9%). Time-course changes in hemodynamics after combination therapy in the patients with the RNF213 p.Arg4810Lys variant were significantly poorer compared with those carrying the bone morphogenic protein receptor type 2 (BMPR2) mutation (n = 36) (comparison of changes in mean pulmonary arterial pressure, p = 0.007). The event-free rate of death or lung transplantation was significantly poorer in RNF213 p.Arg4810Lys variant carriers than in BMPR2 mutation carriers (5-year event-free rate since the introduction of prostaglandin I2 infusion, 0% vs 93%, respectively; p < 0.001). CONCLUSIONS: Idiopathic PAH patients with the RNF213 p.Arg4810Lys variant are associated with poor clinical outcomes even in recent times. Earlier consideration of lung transplantation might be required for RNF213 p.Arg4810Lys variant carriers who are developing PAH. Documentation of the RNF213 p.Arg4810Lys variant, as well as already known pathogenic genes, such as BMPR2, can provide clinically relevant information for therapeutic strategies, leading to a personalized approach for the treatment of PAH.

    DOI: 10.1016/j.healun.2019.08.022

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  • たこつぼ型心筋症に下膵十二指腸動脈瘤破裂を合併した1例

    長尾 元太, 中村 貴裕, 白石 泰之, 岸野 喜一, 勝俣 良紀, 山川 裕之, 湯浅 慎介, 伊東 伸剛, 井上 政則, 福田 恵一

    日本内科学会関東地方会   657回   62 - 62   2020年2月

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    記述言語:日本語   出版者・発行元:日本内科学会-関東地方会  

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  • Peripheral pulmonary stenosis with Noonan syndrome treated by balloon pulmonary angioplasty

    Seien Ko, Jin Komuro, Yoshinori Katsumata, Yasuyuki Shiraishi, Takashi Kawakami, Yoshitake Yamada, Shinsuke Yuasa, Takashi Kohno, Kenjiro Kosaki, Keiichi Fukuda

    Pulmonary Circulation   10 ( 4 )   2020年

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    掲載種別:研究論文(学術雑誌)  

    © The Author(s) 2020. Noonan syndrome is known to have various cardiovascular defects, which include pulmonary artery stenosis. Pulmonary artery stenosis is characterized by obstruction of pulmonary artery blood flow that can cause elevated pulmonary artery pressure and ventilation-perfusion inequality, which can cause dyspnea on exertion and eventually, heart failure. Although the etiology of pulmonary artery stenosis related to congenital diseases is still unknown, balloon pulmonary angioplasty has being reported to be effective to selected patients with Alagille and Williams syndromes, but not from Noonan syndrome despite of modest prevalence of pulmonary artery stenosis. Here, we report the first Noonan syndrome patient with pulmonary artery stenosis who underwent successful balloon pulmonary angioplasty. The strategy used in balloon pulmonary angioplasty was planned with careful morphologic evaluation by computed tomographic angiography, and performed with scoring balloons in a graded approach with multiple sessions. After balloon pulmonary angioplasty, we confirmed maintained dilation of lesions and symptom alleviation, suggesting that balloon pulmonary angioplasty can be performed safely on pulmonary artery stenosis in a Noonan syndrome patient.

    DOI: 10.1177/2045894020954310

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  • Incidence, Clinical Characteristics, and Long-term Outcome of the Dilated Phase of Hypertrophic Cardiomyopathy. 査読

    Yoshiyasu Aizawa, Yoko Tanimoto, Yoshiko Hirata, Taishi Fujisawa, Ryoma Fukuoka, Kazuaki Nakajima, Yoshinori Katsumata, Takahiko Nishiyama, Takehiro Kimura, Shinsuke Yuasa, Takashi Kohno, Shun Kohsaka, Mitsushige Murata, Yuichiro Maekawa, Yoshiko Furukawa, Seiji Takatsuki, Keiichi Fukuda

    The Keio journal of medicine   68 ( 4 )   87 - 94   2019年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Some patients with hypertrophic cardiomyopathy (HCM) develop systolic dysfunction, called the dilated phase of HCM (d-HCM), which is associated with increased morbidity and mortality. We conducted a retrospective study using an HCM database to clarify the incidence, clinical characteristics, and long-term outcomes of d-HCM. We analyzed an HCM cohort consisting of 434 patients (273 with apical HCM and 161 with non-apical HCM; 18 had obstructive HCM, 16 had dilated HCM, and 127 had other HCM) diagnosed by echocardiography in our hospital between 1991 and 2010. The follow-up period was 8.4 ± 6.7 years. The mean age at final follow-up was 67 ± 14 years, and 304 patients (70%) were men. The mean age of the 16 d-HCM patients at the initial visit was 45 ± 17 years, the age at final follow-up was 59 ± 18 years, and 13 were men. Thirteen d-HCM patients developed atrial fibrillation and six patients developed ischemic stroke. Twelve d-HCM patients were implanted with cardiac devices: one pacemaker, nine implantable cardioverter-defibrillators, and two cardiac resynchronization therapy with defibrillator. Five patients died of progressive heart failure at the age of 61 ± 23 years. The age at the initial visit and final follow-up were lower and the NYHA class, brain natriuretic peptide levels, and left ventricular function at initial evaluation were worse in the d-HCM group. Univariate analysis demonstrated that a lower age at the initial visit was associated with d-HCM (hazard ratio 0.955/1 year increase; 95% CI 0.920-0.991, P = 0.015). In our HCM cohort, the incidence of d-HCM was 4%. A high prevalence of atrial fibrillation and cerebral infarction and poor prognosis were noted in this group, despite patients undergoing medication and device implantation.

    DOI: 10.2302/kjm.2018-0004-OA

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  • TEVAR術後の感染性胸部大動脈瘤に対して抗菌薬および経皮的ドレナージによる保存的治療が奏功した1例

    安藤 裕子, 都築 一平, 岸野 喜一, 白石 泰之, 勝俣 良紀, 湯浅 慎介, 伊東 伸剛, 井上 政則, 志水 秀行, 福田 恵一

    日本内科学会関東地方会   656回   34 - 34   2019年12月

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    記述言語:日本語   出版者・発行元:日本内科学会-関東地方会  

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  • 経皮的中隔心筋焼灼術施行後に左室流出路狭窄が再燃し再焼灼にて治療し得た閉塞性肥大型心筋症の1症例

    松本 龍門, 三山 寛司, 秋田 敬太郎, 白石 泰之, 勝俣 良紀, 板橋 裕史, 荒井 隆秀, 鶴田 ひかる, 湯浅 慎介, 河野 隆志, 前川 裕一郎, 村田 光繁, 福田 恵一

    心臓   51 ( 10 )   1072 - 1076   2019年10月

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    記述言語:日本語   出版者・発行元:(公財)日本心臓財団  

    症例は84歳女性。2011年に閉塞性肥大型心筋症(HOCM)を偶発的に指摘され近医通院を開始した。その後2016年8月頃より労作時胸痛が出現し増悪傾向を認め、同年11月に当院循環器内科を紹介受診した。経胸壁心エコーにて最大圧較差119mmHgの左室潤出路狭窄を認め、シベンゾリン、ビソプロロール導入後も改善に乏しく、2017年1月に経皮的中隔心筋焼灼術(PTSMA)を施行した。心室中隔基部を灌流する合計4本の中隔枝に対しアルコール焼灼を施行し、術中にエコー上で最大圧較差19mmHgまで軽減を確認した。術後は症状も消失したため問題なく退院となったが、2ヵ月後の2017年3月頃より労作時胸痛が再燃し、心エコーで最大圧較差96mmHgと流出路狭窄の再増悪を認め、PTSMA再施行目的に同年4月に入院となった。冠動脈造影では初回治療時にアルコール焼灼した4本の中隔枝のうち最も近位部の枝に再灌流を認め、同枝に対し再度アルコール焼灼を施行した。術後心エコーで最大圧較差15mmHgまで改善を認め、症状も消失し、1年半後の現在も再燃なく経過している。今回、初回PTSMA施行後の遠隔期に有症候性の流出路狭窄が再燃し、2回目のPTSMAで治療し得た閉塞性肥大型心筋症の1例を経験したので文献的考察を交えて報告する。(著者抄録)

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    その他リンク: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J00679&link_issn=&doc_id=20191018140013&doc_link_id=10.11281%2Fshinzo.51.1072&url=https%3A%2F%2Fdoi.org%2F10.11281%2Fshinzo.51.1072&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

  • Discrepancy between patient-reported quality of life and the prognostic assessment of Japanese patients hospitalized with acute heart failure. 査読

    Satoshi Shoji, Yasuyuki Shiraishi, Mitsuaki Sawano, Yoshinori Katsumata, Shinsuke Yuasa, Takashi Kohno, Keiichi Fukuda, John A Spertus, Shun Kohsaka

    Heart and vessels   34 ( 9 )   1464 - 1470   2019年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Patient-reported quality of life (PRQL) is a primary therapeutic target for patients with chronic heart failure (HF) and is associated with long-term prognosis. However, its utility in hospitalized HF (HHF) patients in the acute setting remains unclear. We aimed to assess the utility of PRQL (the Kansas City Cardiomyopathy Questionnaire [KCCQ]) in HHF patients and its association with long-term prognosis as well as with the clinical risk score (Get With The Guidelines-Heart Failure [GWTG-HF] risk score). PRQL was evaluated using the KCCQ in consecutive 114 HHF patients. Its association with the composite outcome of all-cause mortality or HF readmission within the first year after discharge was analyzed. Furthermore, its distribution by the clinical risk score (GWTG-HF) was evaluated using Pearson's correlation coefficient. The median KCCQ was 34.9, but was widely distributed (interquartile range 23.7-56.8). After adjustment for known prognostic indicators, the KCCQ was not an independent predictor of the composite outcome within the first year (group with high vs. low KCCQ scores: hazard ratio, 0.67; 95% confidence interval 0.26-1.71). There was no significant correlation between the KCCQ and the GWTG-HF risk score. In conclusion, PRQL during the acute phase of HF was significantly impaired and also varied widely, irrespective of patient characteristics or severity. PRQL assessment and risk prediction for HHF patients in the acute setting seemed to provide two distinct types of information for health care providers.

    DOI: 10.1007/s00380-019-01378-1

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  • 補体副経路を標的とした右心不全および心室性不整脈に対する新たな治療法の開発

    伊藤 章吾, 湯浅 慎介, 小室 仁, 勝木 俊臣, 木村 舞, 岸野 喜一, 楠本 大, 橋本 寿之, 鈴木 邦道, 柚崎 通介, 福田 恵一

    補体   56 ( 1 )   55 - 56   2019年7月

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    記述言語:日本語   出版者・発行元:(一社)日本補体学会  

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  • A tale of two sisters with hypertrophic cardiomyopathy and recurrent embolism: When is the optimal timing of the intervention for left atrial appendage?

    Mai Kimura, Takashi Kohno, Shinji Makino, Shigeo Okuda, Kan Nawata, Ryo Yanagisawa, Hidenori Kojima, Takahiko Nishiyama, Yoshiyasu Aizawa, Shinsuke Yuasa, Mitsushige Murata, Yuichiro Maekawa, Kazuma Okamoto, Hideyuki Shimizu, Keiichi Fukuda

    Heart & Lung   48 ( 3 )   198 - 200   2019年5月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier BV  

    DOI: 10.1016/j.hrtlng.2018.08.010

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  • SPEG, an Indispensable Kinase of SERCA2a for Calcium Homeostasis. 査読 国際誌

    Dai Kusumoto, Shinsuke Yuasa, Keiichi Fukuda

    Circulation research   124 ( 5 )   668 - 670   2019年3月

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  • Shortening Hospital Stay Is Feasible and Safe in Patients With Chronic Thromboembolic Pulmonary Hypertension Treated With Balloon Pulmonary Angioplasty. 査読 国際誌

    Mai Kimura, Takashi Kohno, Takashi Kawakami, Masaharu Kataoka, Takahiro Hiraide, Hidenori Moriyama, Sarasa Isobe, Toshimitsu Tsugu, Yuji Itabashi, Mitsushige Murata, Shinsuke Yuasa, Keiichi Fukuda

    The Canadian journal of cardiology   35 ( 2 )   193 - 198   2019年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: There is no consensus on the length of hospital stay (LOHS) and post-interventional management after balloon pulmonary angioplasty (BPA) in patients with chronic thromboembolic pulmonary hypertension (CTEPH). We examined temporal trends with respect to LOHS and requirement for intensive care for BPA and their relationship with the incidence of BPA-related complications. METHODS: From November 2012 to September 2017, a total of 123 consecutive patients with CTEPH who underwent BPA were enrolled (age: 66.0 [54.0 to 74.0], World Health Organization [WHO] functional class II/III/IV; 27/88/8). Patients were divided for analysis into 3 groups according to the date of their first BPA: early-, middle-, and late-phase groups. RESULTS: Mean pulmonary arterial pressure decreased from 36.0 (29.0 to 45.0) to 20.0 (16.0 to 22.0) mm Hg after BPA (P < 0.001). The LOHS was 41.0 (31.0 to 54.0) days in total including all sessions and 6.6 (6.0 to 7.9) days/session. Despite no significant differences in age, baseline hemodynamics, and laboratory data among the 3 groups, there was a significant reduction in LOHS (7.9 [7.0 to 9.5], 6.5 [6.1 to 7.3], 6.0 [5.3 to 6.5] days/session, P < 0.001) and use of intensive/high care unit (100%, 93%, 46%, P < 0.001). The reduction in LOHS and intensive/high care unit use did not affect the occurrence of BPA-related complications. CONCLUSIONS: Increasing experience with BPA was associated with a reduction in LOHS and the use of intensive/high care unit, but no change was noted in the rate of BPA-related complications. These findings suggest that the reduction in both LOHS and use of the intensive care unit for BPA is feasible and does not jeopardize the safety of the procedure.

    DOI: 10.1016/j.cjca.2018.12.001

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  • The application of convolutional neural network to stem cell biology. 査読 国際誌

    Dai Kusumoto, Shinsuke Yuasa

    Inflammation and regeneration   39   14 - 14   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Induced pluripotent stem cells (iPSC) are one the most prominent innovations of medical research in the last few decades. iPSCs can be easily generated from human somatic cells and have several potential uses in regenerative medicine, disease modeling, drug screening, and precision medicine. However, further innovation is still required to realize their full potential. Machine learning is an algorithm that learns from large datasets for pattern formation and classification. Deep learning, a form of machine learning, uses a multilayered neural network that mimics human neural circuit structure. Deep neural networks can automatically extract features from an image, although classical machine learning methods still require feature extraction by a human expert. Deep learning technology has developed recently; in particular, the accuracy of an image classification task by using a convolutional neural network (CNN) has exceeded that of humans since 2015. CNN is now used to address several tasks including medical issues. We believe that CNN would also have a great impact on the research of stem cell biology. iPSCs are utilized after their differentiation to specific cells, which are characterized by molecular techniques such as immunostaining or lineage tracing. Each cell shows a characteristic morphology; thus, a morphology-based identification system of cell type by CNN would be an alternative technique. The development of CNN enables the automation of identifying cell types from phase contrast microscope images without molecular labeling, which will be applied to several researches and medical science. Image classification is a strong field among deep learning tasks, and several medical tasks will be solved by deep learning-based programs in the future.

    DOI: 10.1186/s41232-019-0103-3

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  • Stroke After Percutaneous Coronary Intervention in the Era of Transradial Intervention. 査読 国際誌

    Satoshi Shoji, Shun Kohsaka, Hiraku Kumamaru, Mitsuaki Sawano, Yasuyuki Shiraishi, Ikuko Ueda, Shigetaka Noma, Masahiro Suzuki, Yohei Numasawa, Kentaro Hayashida, Shinsuke Yuasa, Hiroaki Miyata, Keiichi Fukuda

    Circulation. Cardiovascular interventions   11 ( 12 )   e006761   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Periprocedural stroke is a rare but life-threatening complication of percutaneous coronary intervention (PCI). Transradial intervention (TRI) is more beneficial than transfemoral intervention for periprocedural bleeding and acute kidney injuries, but its effect on periprocedural stroke has not been fully investigated. Our study aimed to assess risk predictors of periprocedural stroke according to PCI access site. METHODS AND RESULTS: Between 2008 and 2016, 17 966 patients undergoing PCI were registered in a prospective multicenter database. Periprocedural stroke was defined as loss of neurological function caused by an ischemic or hemorrhagic event with residual symptoms lasting at least 24 hours after onset. Periprocedural stroke was observed in 42 patients (0.3%). Stroke patients were older and had a higher incidence of chronic kidney disease, peripheral artery disease, and acute coronary syndrome but were less likely to undergo TRI. Multivariable logistic regression analysis revealed TRI (odds ratio; 0.33; 95% CI, 0.16-0.71; P=0.004) was significantly associated with a lower occurrence of periprocedural stroke. Finally, propensity score-matching analysis showed that TRI was associated with a reduced risk of periprocedural stroke compared with transfemoral intervention (0.1% versus 0.4%; P=0.014). According to our sensitivity analysis, this finding was robust to the presence of an unmeasured confounder in almost all plausible scenarios. CONCLUSIONS: TRI was associated with a reduced risk of periprocedural stroke compared with transfemoral intervention. Increased TRI use may reduce overall PCI complications and should be recommended as the optimal access site for both urgent/emergent and elective PCIs.

    DOI: 10.1161/CIRCINTERVENTIONS.118.006761

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  • 拡張型心筋症に伴う重症機能性僧帽弁逆流症に対して経皮的僧帽弁修復術を施行した1例

    明神 聡介, 白石 泰之, 林田 健太郎, 鶴田 ひかる, 板橋 裕史, 吉島 信宏, 勝俣 良紀, 湯浅 慎介, 河野 隆志, 福田 恵一

    日本内科学会関東地方会   647回   33 - 33   2018年12月

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    記述言語:日本語   出版者・発行元:日本内科学会-関東地方会  

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  • 非結核性抗酸菌によるペースメーカー感染の1例

    井合 渉, 白石 泰之, 藤澤 大志, 中嶋 一晶, 勝俣 良紀, 湯浅 慎介, 河野 隆志, 高月 誠司, 福田 恵一, 上蓑 義典

    日本内科学会関東地方会   646回   28 - 28   2018年11月

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    記述言語:日本語   出版者・発行元:日本内科学会-関東地方会  

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  • Excessive Daytime Sleepiness Is Associated With Depression Scores, But Not With Sleep-Disordered Breathing in Patients With Cardiovascular Diseases. 査読

    Mikiko Ohashi, Takashi Kohno, Shun Kohsaka, Ryoma Fukuoka, Kentaro Hayashida, Shinsuke Yuasa, Motoaki Sano, Seiji Takatsuki, Keiichi Fukuda

    Circulation journal : official journal of the Japanese Circulation Society   82 ( 8 )   2175 - 2183   2018年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Excessive daytime sleepiness (EDS) is a significant public health concern, with sleep-disordered breathing (SDB) being a common cause. However, their precise relationship in patients with cardiovascular disease (CVD) is unclear. Furthermore, whether comorbid psychological disorders could contribute to EDS remains unknown. We aimed to assess the prevalence of EDS and its related factors, including SDB and depression, in patients with CVD.Methods and Results:We analyzed data from 1,571 patients admitted for various CVDs in a single university hospital (median age, 67 [56-76] years; 29.6% women). We assessed EDS using the Japanese version of the Epworth Sleepiness Scale (ESS; median 6.0 [4.0-9.0]). The presence of EDS (ESS >10, n=297 [18.9%]) did not differ between patients with and without SDB, which was screened with nocturnal pulse oximetry. In contrast, the patients with EDS had higher depression scores (Hospital Anxiety and Depression Scale subscore for depression [HADS-D] and Patient Healthcare Questionnaire [PHQ]-9). The depression scores, measured by HADS-D (odds ratio [OR] 1.14; 95% confidence interval [CI], 1.07-1.22) and PHQ-9 (OR, 1.14; 95% CI, 1.07-1.20) were independent determinants of EDS. These relationships among EDS, SDB, and depression were consistent among the subgroups with cardiovascular comorbidities. CONCLUSIONS: The presence of EDS is associated with depressive symptoms, but not with SDB, in patients with CVD, suggesting that these patients should be thoroughly assessed for psychological disturbances.

    DOI: 10.1253/circj.CJ-17-1395

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  • ベーチェット病に伴う急性重度大動脈弁閉鎖不全症に対し免疫抑制療法後に大動脈基部置換術を施行した1例

    大畑 孝憲, 川久保 裕美子, 小室 仁, 勝俣 良紀, 白石 泰之, 湯浅 慎介, 河野 隆志, 福田 恵一, 志水 秀行, 竹内 勤

    日本内科学会関東地方会   643回   33 - 33   2018年7月

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    記述言語:日本語   出版者・発行元:日本内科学会-関東地方会  

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  • Automated Deep Learning-Based System to Identify Endothelial Cells Derived from Induced Pluripotent Stem Cells. 査読 国際誌

    Dai Kusumoto, Mark Lachmann, Takeshi Kunihiro, Shinsuke Yuasa, Yoshikazu Kishino, Mai Kimura, Toshiomi Katsuki, Shogo Itoh, Tomohisa Seki, Keiichi Fukuda

    Stem cell reports   10 ( 6 )   1687 - 1695   2018年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Deep learning technology is rapidly advancing and is now used to solve complex problems. Here, we used deep learning in convolutional neural networks to establish an automated method to identify endothelial cells derived from induced pluripotent stem cells (iPSCs), without the need for immunostaining or lineage tracing. Networks were trained to predict whether phase-contrast images contain endothelial cells based on morphology only. Predictions were validated by comparison to immunofluorescence staining for CD31, a marker of endothelial cells. Method parameters were then automatically and iteratively optimized to increase prediction accuracy. We found that prediction accuracy was correlated with network depth and pixel size of images to be analyzed. Finally, K-fold cross-validation confirmed that optimized convolutional neural networks can identify endothelial cells with high performance, based only on morphology.

    DOI: 10.1016/j.stemcr.2018.04.007

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  • Improvement in the electrocardiograms associated with right ventricular hypertrophy after balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension. 査読 国際誌

    Takahiko Nishiyama, Seiji Takatsuki, Takashi Kawakami, Yoshinori Katsumata, Takehiro Kimura, Masaharu Kataoka, Hikaru Tsuruta, Yuji Itabashi, Mitsushige Murata, Shinsuke Yuasa, Yoshiyasu Aizawa, Keiichi Fukuda

    International journal of cardiology. Heart & vasculature   19   75 - 82   2018年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Balloon pulmonary angioplasty (BPA) is a treatment option for patients with chronic thromboembolic pulmonary hypertension (CTEPH). Methods and results: In 60 patients with CTEPH, we examined the hemodynamic data before and after BPA. In addition, the sequential ECG findings for right ventricular hypertrophy (RVH) were assessed. The mean pulmonary arterial pressure (mPAP) decreased from 38 ± 11 to 20 ± 4 mm Hg (p < 0.05). The ROC analysis showed that the S waves in V5, R waves in V1 + S waves in V5, S waves in I, and QRS axis were significant predictors of an mPAP ≧ 30 mm Hg (AUC > 0.75, p < 0.01). The predictive values for the mPAP before the BPA were the S and R waves in lead V6, and P waves in lead II (33.417 + 0.078 × P in II - 0.10 × R in V6 + 0.012 × S in V6). The change in the mPAP (ΔmPAP) correlated with the change in the amplitudes of the ECGs: ΔS wave in lead I (R = 0.544, p < 0.001), ΔR in V1 + S in V5 (R = 0.476, p < 0.001), and ΔP wave in II (R = 0.511, p < 0.001). At 6 months of follow-up, the improvement in an R in V1 + S in V5 of ≧10 mm implied a better functional status. Conclusion: BPA therapy reduced the pulmonary arterial pressure in patients with CTEPH and was associated with an improvement in the ECG findings related to RVH.

    DOI: 10.1016/j.ijcha.2018.05.003

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  • Selective modulation of local linkages between active transcription and oxidative demethylation activity shapes cardiomyocyte-specific gene-body epigenetic status in mice. 査読 国際誌

    Mayumi Oda, Shunichi Wakabayashi, N Ari Wijetunga, Shinsuke Yuasa, Hirokazu Enomoto, Ruri Kaneda, Sung Han Yoon, Nishant Mittal, Qiang Jing, Masako Suzuki, John M Greally, Keiichi Fukuda, Shinji Makino

    BMC genomics   19 ( 1 )   349 - 349   2018年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Cell-type-specific genes exhibit heterogeneity in genomic contexts and may be subject to different epigenetic regulations through different gene transcriptional processes depending on the cell type involved. The gene-body regions (GBRs) of some cardiomyocyte (CM)-specific genes are long and highly hypomethylated in CMs. To explore the cell-type specificities of epigenetic patterns and functions, multiple epigenetic modifications of GBRs were compared among CMs, liver cells and embryonic stem cells (ESCs). RESULTS: We found that most genes show a moderately negative correlation between transcript levels and gene lengths. As CM-specific genes are generally longer than other cell-type-specific genes, we hypothesized that the gene-body epigenetic features of CMs may support the transcriptional regulation of CM-specific genes. We found gene-body DNA hypomethylation in a CM-specific gene subset co-localized with rare gene-body marks, including RNA polymerase II (Pol II) and p300. Interestingly, 5-hydroxymethylcytosine (5hmC) within the gene body marked cell-type-specific genes at neonatal stages and active gene-body histone mark H3K36 trimethylation declined and overlapped with cell-type-specific gene-body DNA hypomethylation and selective Pol II/p300 accumulation in adulthood. Different combinations of gene-body epigenetic modifications were also observed with genome-wide scale cell-type specificity, revealing the occurrence of dynamic epigenetic rearrangements in GBRs across different cell types. CONCLUSIONS: As 5hmC enrichment proceeded to hypomethylated GBRs, we considered that hypomethylation may not represent a static state but rather an equilibrium state of turnover due to the balance between local methylation linked to transcription and Tet oxidative modification causing demethylation. Accordingly, we conclude that demethylation in CMs can be a used to establish such cell-type-specific epigenetic domains in relation to liver cells. The establishment of cell-type-specific epigenetic control may also change genomic contexts of evolution and may contribute to the development of cell-type-specific transcriptional coordination.

    DOI: 10.1186/s12864-018-4752-4

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  • Characteristics and in-hospital outcomes in young patients presenting with acute coronary syndrome treated by percutaneous coronary intervention. 査読

    Yukiho Hirota, Mitsuaki Sawano, Yohei Numasawa, Ikuko Ueda, Shigetaka Noma, Masahiro Suzuki, Kentaro Hayashida, Shinsuke Yuasa, Yuichiro Maekawa, Shun Kohsaka, Keiichi Fukuda

    Cardiovascular intervention and therapeutics   33 ( 2 )   154 - 162   2018年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    There is a growing interest in the optimizing care of acute coronary syndrome (ACS) in young patients, largely owing to their potential for longer life expectancy. Herein, we aimed to investigate the clinical characteristics and outcome of young ACS patients (e.g. under 60 year old) from a Japanese multicenter percutaneous coronary intervention (PCI) registry (KiCS-PCI). KiCS-PCI registered consecutive ACS patients from 15 institutions, and 1560 (24.0%) out of 6499 ACS-related PCI involved patients aged <60 years. In this group, prevalence of dyslipidemia, smoking and family history of premature coronary artery disease (CAD) was higher, while the other classical risk factors were lower when compared to the old patients. After adjustment for known confounders, presentation with cardiogenic shock (CS) before PCI (OR 32.57, 95% CI 12.06-87.97), culprit lesion of LMT (OR 7.53, 95% CI 1.26-44.98), multi-vessel disease (OR 3.82, 95% CI 1.37-10.63) and higher body mass index (OR 1.12, 95% CI 1.00-1.24) showed association with higher in-hospital mortality in young patients. Multi-vessel disease (OR 4.1, 95% CI 1.9-8.9) and chronic kidney disease (OR 3.56, 95% CI 2.26-5.68) were associated with CS presentation. CS presentation was inversely associated with classical risk factors such as hypertension (OR 0.61, 95% CI 0.38-0.96), family history of CAD (OR 0.49, 95% CI 0.25-0.96), and dyslipidemia (OR 0.45, 95% CI 0.29-0.71) and culprit lesion of RCA (OR 0.60, 95% CI 0.37-0.94). Overall, ACS in the younger population was observed frequently, accounting for a quarter of ACS-related PCI. CS was a harbinger for in-hospital mortality in these patients.

    DOI: 10.1007/s12928-017-0471-z

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  • Patient confidence regarding secondary lifestyle modification and knowledge of 'heart attack' symptoms following percutaneous revascularisation in Japan: a cross-sectional study. 査読 国際誌

    Hiroki Kitakata, Takashi Kohno, Shun Kohsaka, Junko Fujino, Naomi Nakano, Ryoma Fukuoka, Shinsuke Yuasa, Yuichiro Maekawa, Keiichi Fukuda

    BMJ open   8 ( 3 )   e019119   2018年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: To assess patient perspectives on secondary lifestyle modification and knowledge of 'heart attack' after percutaneous coronary intervention (PCI) for coronary artery disease (CAD). DESIGN: Observational cross-sectional study. SETTING: A single university-based hospital centre in Japan. PARTICIPANTS: In total, 236 consecutive patients with CAD who underwent PCI completed a questionnaire (age, 67.4±10.1 years; women, 14.8%; elective PCI, 75.4%). The survey questionnaire included questions related to confidence levels about (1) lifestyle modification at the time of discharge and (2) appropriate recognition of heart attack symptoms and reactions to these symptoms on a four-point Likert scale (1=not confident to 4=completely confident). PRIMARY OUTCOME MEASURE: The primary outcome assessed was the patients' confidence level regarding lifestyle modification and the recognition of heart attack symptoms. RESULTS: Overall, patients had a high level of confidence (confident or completely confident,>75%) about smoking cessation, alcohol restriction and medication adherence. However, they had a relatively low level of confidence (<50%) about the maintenance of blood pressure control, healthy diet, body weight and routine exercise (≥3 times/week). After adjustment, male sex (OR 3.61, 95% CI 1.11 to 11.8) and lower educational level (OR 3.25; 95% CI 1.70 to 6.23) were identified as factors associated with lower confidence levels. In terms of confidence in the recognition of heart attack, almost all respondents answered 'yes' to the item 'I should go to the hospital as soon as possible when I have a heart attack'; however, only 28% of the responders were confident in their ability to distinguish between heart attack symptoms and other conditions. CONCLUSIONS: There were substantial disparities in the confidence levels associated with lifestyle modification and recognition/response to heart attack. These gaps need to be studied further and disseminated to improve cardiovascular care.

    DOI: 10.1136/bmjopen-2017-019119

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  • 日本人急性心不全患者では低い患者報告QOLは退院後の長期予後不良と関連しない(Lower Patient-Reported Quality of Life is not Associated with Worse Post-Discharge Long-term Outcomes in Japanese Acute Heart Failure Patients)

    Shoji Satoshi, Shiraishi Yasuyuki, Kohsaka Shun, Sawano Mitsuaki, Ikemura Nobuhiro, Katsumata Yoshinori, Yuasa Shinsuke, Kohno Takashi, Fukuda Keiichi

    日本循環器学会学術集会抄録集   82回   PE021 - 6   2018年3月

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    記述言語:英語   出版者・発行元:(一社)日本循環器学会  

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  • 非ST上昇型急性冠症候群患者における早期侵襲的戦略の適用と腎転帰に対するその関連性(Application of Early Invasive Strategies in Non-ST Segment Elevation Acute Coronary Syndrome Patients and Its Relation to Renal Outcomes)

    Ikemura Nobuhiro, Shiraishi Yasuyuki, Sawano Mitsuaki, Ueda Ikuko, Numasawa Yohei, Noma Shigetaka, Suzuki Masahiro, Yuasa Shinsuke, Hayashida Kentaro, Momiyama Yukihiko, Fukuda Keiichi, Kohsaka Shun

    日本循環器学会学術集会抄録集   82回   PE121 - 5   2018年3月

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    記述言語:英語   出版者・発行元:(一社)日本循環器学会  

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  • Percutaneous Occlusion of Patent Ductus Arteriosus for an Elderly Patient With Refractory Congestive Heart Failure. 査読 国際誌

    Satoshi Shoji, Hideaki Kanazawa, Ryo Yanagisawa, Makoto Tanaka, Ryoma Fukuoka, Keitaro Akita, Mai Kimura, Takahide Arai, Takashi Kawakami, Kentaro Hayashida, Shinsuke Yuasa, Hikaru Tsuruta, Yuji Itabashi, Mitsushige Murata, Takahiko Nishiyama, Takashi Kohno, Yuichiro Maekawa, Keiichi Fukuda

    Circulation. Heart failure   11 ( 2 )   e004764   2018年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1161/CIRCHEARTFAILURE.117.004764

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  • 重症ARによるうっ血性心不全を来しBentall手術を要した大動脈炎症候群の1例

    筋野 朝陽, 福田 芽森, 白石 泰之, 稲葉 佑, 梶尾 暢彦, 勝俣 良紀, 河野 隆志, 湯浅 慎介, 福田 恵一

    日本内科学会関東地方会   639回   70 - 70   2018年2月

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    記述言語:日本語   出版者・発行元:日本内科学会-関東地方会  

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  • 骨盤内腫瘍による腫瘍塞栓性肺高血圧症を肺動脈血吸引細胞診にて診断しえた1例

    島田 史恵, 三浦 光太郎, 勝俣 良紀, 白石 泰之, 河野 隆志, 湯浅 慎介, 福田 恵一, 清河 駿樹, 同前 愛, 野村 弘行

    日本内科学会関東地方会   639回   67 - 67   2018年2月

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    記述言語:日本語   出版者・発行元:日本内科学会-関東地方会  

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  • Impact of catheter-induced iatrogenic coronary artery dissection with or without postprocedural flow impairment: A report from a Japanese multicenter percutaneous coronary intervention registry. 査読 国際誌

    Takahiro Hiraide, Mitsuaki Sawano, Yasuyuki Shiraishi, Ikuko Ueda, Yohei Numasawa, Shigetaka Noma, Kouji Negishi, Takahiro Ohki, Shinsuke Yuasa, Kentaro Hayashida, Hiroaki Miyata, Keiichi Fukuda, Shun Kohsaka

    PloS one   13 ( 9 )   e0204333   2018年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Despite the ever-increasing complexity of percutaneous coronary intervention (PCI), the incidence, predictors, and in-hospital outcomes of catheter-induced coronary artery dissection (CICAD) is not well defined. In addition, there are little data on whether persistent coronary flow impairment after CICAD will affect clinical outcomes. We evaluated 17,225 patients from 15 participating hospitals within the Japanese PCI registry from January 2008 to March 2016. Associations between CICAD and in-hospital adverse cardiovascular events were evaluated using multivariate logistic regression. Outcomes of patients with CICAD with or without postprocedural flow impairment (TIMI flow ≤ 2 or 3, respectively) were analyzed. The population was predominantly male (79.4%; mean age, 68.2 ± 11.0 years); 35.6% underwent PCI for complex lesions (eg. chronic total occlusion or a bifurcation lesion.). CICAD occurred in 185 (1.1%), and its incidence gradually decreased (p < 0.001 for trend); postprocedural flow impairment was observed in 43 (23.2%). Female sex, complex PCI, and target lesion in proximal vessel were independent predictors (odds ratio [OR], 2.18; 95% confidence interval [CI], 1.53-3.10; OR, 2.19; 95% CI, 1.58-3.04; and OR, 1.55; 95% CI, 1.06-2.28, respectively). CICAD was associated with an increased risk of in-hospital adverse events (composite of new-onset cardiogenic shock and new-onset heart failure) regardless of postprocedural flow impairment (OR, 10.9; 95% CI, 5.30-22.6 and OR, 2.27; 95% CI, 1.20-4.27, respectively for flow-impaired and flow-recovered CICAD). In conclusion, CICAD occurred in roughly 1% of PCI cases; female sex, complex PCI, and proximal lesion were its independent risk factors. CICAD was associated with adverse in-hospital cardiovascular events regardless of final flow status. Our data implied that the appropriate selection of PCI was necessary for women with complex lesions.

    DOI: 10.1371/journal.pone.0204333

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  • Prognostic significance of repeated brain natriuretic peptide measurements after percutaneous transluminal septal myocardial ablation in patients with drug-refractory hypertrophic obstructive cardiomyopathy. 査読 国際誌

    Keitaro Akita, Hikaru Tsuruta, Shinsuke Yuasa, Mitsushige Murata, Keiichi Fukuda, Yuichiro Maekawa

    Open heart   5 ( 1 )   e000786   2018年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Objectives: To evaluate whether repeated brain natriuretic peptide (BNP) measurements after percutaneous transluminal septal myocardial ablation (PTSMA) provide prognostic information regarding the response to PTSMA in patients with drug-refractory hypertrophic obstructive cardiomyopathy (HOCM). Background: Plasma BNP levels are associated with clinical outcomes in patients with HOCM. However, the prognostic value of plasma BNP level changes before and after PTSMA remains unclear. Methods: We measured the plasma BNP levels serially before and after PTSMA, and evaluated the relationship between the changes in plasma BNP levels and clinical improvement in 47 patients. The patients were assigned to two groups based on the reduction in the New York Heart Association class ≥1 (good responder) or <1 (poor responder) before and after PTSMA. The Kansas City Cardiomyopathy Questionnaire (KCCQ) was used to measure health status. Results: The plasma BNP levels gradually decreased after PTSMA, although the levels plateaued 3 months until 12 months after PTSMA. Although the plasma BNP levels and resting left ventricular outflow tract peak pressure gradient before PTSMA were comparable between the groups, the ratio of the BNP levels before and after PTSMA in the good responder group was significantly lower than that in the poor responder group (0.43 (range, 0.24-0.68) vs 0.78 (range, 0.62-0.93), p=0.002). The KCCQ score changes in the good responder group were significantly higher than those in the poor responder group. Conclusions: The plasma BNP level ratio was associated with long-term clinical improvement of heart failure after PTSMA for drug-refractory HOCM.

    DOI: 10.1136/openhrt-2018-000786

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  • Predictors of high cost after percutaneous coronary intervention: A review from Japanese multicenter registry overviewing the influence of procedural complications. 査読 国際誌

    Taku Inohara, Yohei Numasawa, Takahiro Higashi, Ikuko Ueda, Masahiro Suzuki, Kentaro Hayashida, Shinsuke Yuasa, Yuichiro Maekawa, Keiichi Fukuda, Shun Kohsaka

    American heart journal   194   61 - 72   2017年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Percutaneous coronary intervention (PCI) is widely used; however, factors of high-cost care after PCI have not been thoroughly investigated. We sought to evaluate the in-hospital costs related to PCI and identify predictors of high costs. METHODS: We extracted 2,354 consecutive PCI cases (1,243 acute cases, 52.8%) from 3 Japanese cardiovascular centers from 2011 to 2015. In-hospital complications were predefined under consensus definitions (eg, acute kidney injury [AKI]). We extracted the facility cost data for each patient's resource under the universal Japanese insurance system. We classified the patients into total cost quartiles and identified predictors for the highest quartile ("high-cost" group). In addition, incremental costs for procedure-related complications were calculated. RESULTS: During the study period, a total of 401 cases (17.0%) experienced procedure-related complications. The in-hospital acute and elective PCI costs per case were US $14,840 (interquartile range [IQR] 11,370-20,070) and US $11,030 (IQR 8929-14,670), respectively. After adjusting for baseline differences, any of the procedure-related complications remained an independent predictor of high costs (acute: odds ratio 1.66, 95% CIs 1.13-2.43; elective: odds ratio 3.73, 95% CIs 1.96-7.11). Notably, incremental costs were mainly attributed to AKI, which accounted for 37.5% of all incremental costs; it increased by US $9,840 for each AKI event, and the total cost increase reached US $2,588,035. CONCLUSIONS: Procedure-related complications, particularly postprocedural AKI, were associated with higher costs in PCI. Further studies are required to evaluate prospectively whether the preventive strategy with a personalized risk stratification for AKI could save costs.

    DOI: 10.1016/j.ahj.2017.08.008

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  • 脊椎側彎症を合併した末梢性肺動脈狭窄症の1例

    岡田 真彦, 高 聖淵, 白石 泰之, 勝俣 良紀, 川上 崇史, 湯浅 慎介, 河野 隆志, 福田 恵一

    日本内科学会関東地方会   636回   30 - 30   2017年10月

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    記述言語:日本語   出版者・発行元:日本内科学会-関東地方会  

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  • 循環器疾患を合併する閉塞性睡眠時無呼吸症例におけるCPAP治療アドヒアランスの実態および抑うつ不安・睡眠の質に及ぼす効果

    松田 理沙, 河野 隆志, 福岡 良磨, 白石 泰之, 勝俣 良紀, 湯浅 慎介, 佐野 元昭, 福田 恵一

    日本心臓病学会学術集会抄録   65回   P - 313   2017年9月

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    記述言語:日本語   出版者・発行元:(一社)日本心臓病学会  

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  • Epigenetic barrier against the propagation of fluctuating gene expression in embryonic stem cells. 査読 国際誌

    Yuki Saito, Akira Kunitomi, Tomohisa Seki, Shugo Tohyama, Dai Kusumoto, Makoto Takei, Shin Kashimura, Hisayuki Hashimoto, Gakuto Yozu, Chikaaki Motoda, Masaya Shimojima, Toru Egashira, Mayumi Oda, Keiichi Fukuda, Shinsuke Yuasa

    FEBS letters   591 ( 18 )   2879 - 2889   2017年9月

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    記述言語:英語  

    The expression of pluripotency genes fluctuates in a population of embryonic stem (ES) cells and the fluctuations in the expression of some pluripotency genes correlate. However, no correlation in the fluctuation of Pou5f1, Zfp42, and Nanog expression was observed in ES cells. Correlation between Pou5f1 and Zfp42 fluctuations was demonstrated in ES cells containing a knockout in the NuRD component Mbd3. ES cells containing a triple knockout in the DNA methyltransferases Dnmt1, Dnmt3a, and Dnmt3b showed correlation between the fluctuation of Pou5f1, Zfp42, and Nanog gene expression. We suggest that an epigenetic barrier is key to preventing the propagation of fluctuating pluripotency gene expression in ES cells.

    DOI: 10.1002/1873-3468.12791

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  • 冠動脈造影中に側副血行路の出現と消失を認めた、重症冠攣縮性狭心症の一例

    秋田 敬太郎, 前川 裕一郎, 八島 史明, 田野崎 翔, 荒井 隆秀, 川上 崇史, 林田 健太郎, 金澤 英明, 湯浅 慎介, 福田 恵一

    日本心血管インターベンション治療学会抄録集   26回   MP151 - MP151   2017年7月

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    記述言語:英語   出版者・発行元:(一社)日本心血管インターベンション治療学会  

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  • Barriers Associated With Door-to-Balloon Delay in Contemporary Japanese Practice. 査読

    Nobuhiro Ikemura, Mitsuaki Sawano, Yasuyuki Shiraishi, Ikuko Ueda, Hiroaki Miyata, Yohei Numasawa, Shigetaka Noma, Masahiro Suzuki, Yukihiko Momiyama, Taku Inohara, Kentaro Hayashida, Shinsuke Yuasa, Yuichiro Maekawa, Keiichi Fukuda, Shun Kohsaka

    Circulation journal : official journal of the Japanese Circulation Society   81 ( 6 )   815 - 822   2017年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Door-to-balloon (DTB) time ≤90 min is an important quality indicator in the management of ST-elevation myocardial infarction (STEMI), but a considerable number of patients still do not meet this goal, particularly in countries outside the USA and Europe.Methods and Results:We analyzed 2,428 STEMI patients who underwent primary PCI ≤12 h of symptom onset who were registered in an ongoing prospective multicenter database (JCD-KiCS registry), between 2008 and 2013. We analyzed both the time trend in DTB time within this cohort in the registry, and independent predictors of delayed DTB time >90 min. Median DTB time was 90 min (IQR, 68-115 min) during the study period and there were no significant changes with year. Predictors for delay in DTB time included peripheral artery disease, prior revascularization, off-hour arrival, age >75 years, heart failure at arrival, and use of IABP or VA-ECMO. Notably, high-volume PCI-capable institutions (PCI ≥200/year) were more adept at achieving shorter DTB time compared with low-volume institutions (PCI <200/year). CONCLUSIONS: Half of the present STEMI patients did not achieve DTB time ≤90 min. Targeting the elderly and patients with multiple comorbidities, and PCI performed in off-hours may aid in its improvement.

    DOI: 10.1253/circj.CJ-16-0905

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  • Emerin plays a crucial role in nuclear invagination and in the nuclear calcium transient. 査読 国際誌

    Masaya Shimojima, Shinsuke Yuasa, Chikaaki Motoda, Gakuto Yozu, Toshihiro Nagai, Shogo Ito, Mark Lachmann, Shin Kashimura, Makoto Takei, Dai Kusumoto, Akira Kunitomi, Nozomi Hayashiji, Tomohisa Seki, Shugo Tohyama, Hisayuki Hashimoto, Masaki Kodaira, Toru Egashira, Kenshi Hayashi, Chiaki Nakanishi, Kenji Sakata, Masakazu Yamagishi, Keiichi Fukuda

    Scientific reports   7   44312 - 44312   2017年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Alteration of the nuclear Ca2+ transient is an early event in cardiac remodeling. Regulation of the nuclear Ca2+ transient is partly independent of the cytosolic Ca2+ transient in cardiomyocytes. One nuclear membrane protein, emerin, is encoded by EMD, and an EMD mutation causes Emery-Dreifuss muscular dystrophy (EDMD). It remains unclear whether emerin is involved in nuclear Ca2+ homeostasis. The aim of this study is to elucidate the role of emerin in rat cardiomyocytes by means of hypertrophic stimuli and in EDMD induced pluripotent stem (iPS) cell-derived cardiomyocytes in terms of nuclear structure and the Ca2+ transient. The cardiac hypertrophic stimuli increased the nuclear area, decreased nuclear invagination, and increased the half-decay time of the nuclear Ca2+ transient in cardiomyocytes. Emd knockdown cardiomyocytes showed similar properties after hypertrophic stimuli. The EDMD-iPS cell-derived cardiomyocytes showed increased nuclear area, decreased nuclear invagination, and increased half-decay time of the nuclear Ca2+ transient. An autopsied heart from a patient with EDMD also showed increased nuclear area and decreased nuclear invagination. These data suggest that Emerin plays a crucial role in nuclear structure and in the nuclear Ca2+ transient. Thus, emerin and the nuclear Ca2+ transient are possible therapeutic targets in heart failure and EDMD.

    DOI: 10.1038/srep44312

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  • Flecainide ameliorates arrhythmogenicity through NCX flux in Andersen-Tawil syndrome-iPS cell-derived cardiomyocytes. 査読 国際誌

    Yusuke Kuroda, Shinsuke Yuasa, Yasuhide Watanabe, Shogo Ito, Toru Egashira, Tomohisa Seki, Tetsuhisa Hattori, Seiko Ohno, Masaki Kodaira, Tomoyuki Suzuki, Hisayuki Hashimoto, Shinichiro Okata, Atsushi Tanaka, Yoshiyasu Aizawa, Mitsushige Murata, Takeshi Aiba, Naomasa Makita, Tetsushi Furukawa, Wataru Shimizu, Itsuo Kodama, Satoshi Ogawa, Norito Kokubun, Hitoshi Horigome, Minoru Horie, Kaichiro Kamiya, Keiichi Fukuda

    Biochemistry and biophysics reports   9   245 - 256   2017年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Andersen-Tawil syndrome (ATS) is a rare inherited channelopathy. The cardiac phenotype in ATS is typified by a prominent U wave and ventricular arrhythmia. An effective treatment for this disease remains to be established. We reprogrammed somatic cells from three ATS patients to generate induced pluripotent stem cells (iPSCs). Multi-electrode arrays (MEAs) were used to record extracellular electrograms of iPSC-derived cardiomyocytes, revealing strong arrhythmic events in the ATS-iPSC-derived cardiomyocytes. Ca2+ imaging of cells loaded with the Ca2+ indicator Fluo-4 enabled us to examine intracellular Ca2+ handling properties, and we found a significantly higher incidence of irregular Ca2+ release in the ATS-iPSC-derived cardiomyocytes than in control-iPSC-derived cardiomyocytes. Drug testing using ATS-iPSC-derived cardiomyocytes further revealed that antiarrhythmic agent, flecainide, but not the sodium channel blocker, pilsicainide, significantly suppressed these irregular Ca2+ release and arrhythmic events, suggesting that flecainide's effect in these cardiac cells was not via sodium channels blocking. A reverse-mode Na+/Ca2+exchanger (NCX) inhibitor, KB-R7943, was also found to suppress the irregular Ca2+ release, and whole-cell voltage clamping of isolated guinea-pig cardiac ventricular myocytes confirmed that flecainide could directly affect the NCX current (INCX). ATS-iPSC-derived cardiomyocytes recapitulate abnormal electrophysiological phenotypes and flecainide suppresses the arrhythmic events through the modulation of INCX.

    DOI: 10.1016/j.bbrep.2017.01.002

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  • An RyR2 mutation found in a family with a short-coupled variant of torsade de pointes. 査読 国際誌

    Mai Kimura, Taishi Fujisawa, Yoshiyasu Aizawa, Noritaka Matsuhashi, Shogo Ito, Kazuaki Nakajima, Shin Kashimura, Akira Kunitomi, Yoshinori Katsumata, Takahiko Nishiyama, Takehiro Kimura, Nobuhiro Nishiyama, Shinsuke Yuasa, Seiji Takatsuki, Kenjiro Kosaki, Keiichi Fukuda

    International journal of cardiology   227   367 - 369   2017年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.ijcard.2016.11.052

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  • Nocturnal intermittent hypoxia and short sleep duration are independently associated with elevated C-reactive protein levels in patients with coronary artery disease. 査読 国際誌

    Ryoma Fukuoka, Takashi Kohno, Shun Kohsaka, Ryo Yanagisawa, Takashi Kawakami, Kentaro Hayashida, Hideaki Kanazawa, Shinsuke Yuasa, Yuichiro Maekawa, Motoaki Sano, Keiichi Fukuda

    Sleep medicine   29   29 - 34   2017年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Sleep-disordered breathing (SDB) or short sleep duration and coronary artery disease (CAD) are related, yet, the prevalence of SDB and short sleep duration as well as their mechanism remain unknown. Enhanced vascular inflammation is also implicated as one of the pathophysiologic mechanisms in CAD. The aims of this study were to evaluate the prevalence of patients with SDB and short sleep duration, and to examine their relationship with serum C-reactive protein (CRP) level in CAD patients. METHODS AND RESULTS: We evaluated 161 CAD patients who underwent percutaneous coronary intervention, using nocturnal pulse oximetry, a non-invasive screening method for nocturnal intermittent hypoxia. Based on three percent oxygen desaturation index (3% ODI), the patients were divided into nocturnal intermittent hypoxia (3% ODI ≥ 15; n = 45) and control groups (3% ODI < 15, n = 116). The nocturnal intermittent hypoxia group had higher body mass index and serum CRP level compared with the control group. Short sleep duration (<6 h, n = 45) was also associated with increased CRP level compared with the control group (≥6 h, n = 116). In multiple regression analysis, nocturnal intermittent hypoxia (β = 0.332, 95% confidence interval [CI] 0.102-0.562, P = 0.005) and short sleep duration (β = 0.311, 95% CI 0.097-0.526, P = 0.005) were both independent determinants for log serum CRP level. CONCLUSIONS: Nocturnal intermittent hypoxia and short sleep duration were independently associated with elevated serum CRP level in CAD patients, suggesting that both SDB and sleep shortage are associated with enhanced inflammation in CAD patients. SDB and sleep duration may be important modifiable factors in the clinical management of patients with CAD.

    DOI: 10.1016/j.sleep.2016.09.012

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  • Disease Characterization of Long QT Syndrome Using iPS Cell-Derived Cardiomyocytes 査読

    Keiichi Fukuda, Toru Egashira, Tomohisa Seki, Shinsuke Yuasa

    journal of arrhythmia   27 ( 4 )   246   2017年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Long QT Syndrome (LQTS) is well characterized inheritable, life threatening disease, and often related to large pedigrees of family history. The present study established induced pluripotent stem cell (iPSC) from the patients with LQTS, and investigated whether the LQTS patient-derived iPSCs can be utilized for disease characterization, and drug response. We reprogrammed patient somatic cells, differentiated cardiomyocytes and examined electrophysiological properties. Genotype analysis showed the heterozygote mutation in KCNQ1 gene, 1893delC, indicating that this patient was type 1 LQTS. Drug response examination using multielectrode analysis (MEA) revealed the LQTS-iPSC-derived cardiomyocytes revealed IKs disturbance, but not IKr. Electrophysiological recording confirmed 1893delC has a dominant negative role in IKs channel function by trafficking defect. Isoproterenol induced ventricular tachycardia-like arrhythmia. This study provides the evidences that iPSCs can be utilized for characterization, drug response, and diagnosis for patients with LQTS to conduct medical therapies. © 2011, Japanese Heart Rhythm Society. All rights reserved.

    DOI: 10.4020/jhrs.27.PL

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  • Treating Aging Model of Werner Syndrome Specific Induced Pluripotent Stem Cells by Crisper/cas9 Systems 査読

    Gakuto Yozu, Shinsuke Yuasa, Hiroyuki Daida, Keiichi Fukuda

    CIRCULATION   134   2016年11月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Treating Aging Model of Werner Syndrome Specific Induced Pluripotent Stem Cells by Crisper/cas9 Systems 査読

    Gakuto Yozu, Shinsuke Yuasa, Hiroyuki Daida, Keiichi Fukuda

    CIRCULATION   134   2016年11月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Embryonic type Na+ channel β-subunit, SCN3B masks the disease phenotype of Brugada syndrome. 査読 国際誌

    Shinichiro Okata, Shinsuke Yuasa, Tomoyuki Suzuki, Shogo Ito, Naomasa Makita, Tetsu Yoshida, Min Li, Junko Kurokawa, Tomohisa Seki, Toru Egashira, Yoshiyasu Aizawa, Masaki Kodaira, Chikaaki Motoda, Gakuto Yozu, Masaya Shimojima, Nozomi Hayashiji, Hisayuki Hashimoto, Yusuke Kuroda, Atsushi Tanaka, Mitsushige Murata, Takeshi Aiba, Wataru Shimizu, Minoru Horie, Kaichiro Kamiya, Tetsushi Furukawa, Keiichi Fukuda

    Scientific reports   6   34198 - 34198   2016年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    SCN5A is abundant in heart and has a major role in INa. Loss-of-function mutation in SCN5A results in Brugada syndrome (BrS), which causes sudden death in adults. It remains unclear why disease phenotype does not manifest in the young even though mutated SCN5A is expressed in the young. The aim of the present study is to elucidate the timing of the disease manifestation in BrS. A gain-of-function mutation in SCN5A also results in Long QT syndrome type 3 (LQTS3), leading to sudden death in the young. Induced pluripotent stem cells (iPSCs) were generated from a patient with a mixed phenotype of LQTS3 and BrS with the E1784K SCN5A mutation. Here we show that electrophysiological analysis revealed that LQTS3/BrS iPSC-derived cardiomyocytes recapitulate the phenotype of LQTS3 but not BrS. Each β-subunit of the sodium channel is differentially expressed in embryonic and adult hearts. SCN3B is highly expressed in embryonic hearts and iPSC-derived cardiomyocytes. A heterologous expression system revealed that INa of mutated SCN5A is decreased and SCN3B augmented INa of mutated SCN5A. Knockdown of SCN3B in LQTS3/BrS iPSC-derived cardiomyocytes successfully unmasked the phenotype of BrS. Isogenic control of LQTS3/BrS (corrected-LQTS3/BrS) iPSC-derived cardiomyocytes gained the normal electrophysiological properties.

    DOI: 10.1038/srep34198

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  • 透析中のショックを繰り返す左室流出路狭窄に対して経皮的中隔心筋焼灼術(PTSMA)を施行した一例

    秋田 敬太郎, 前川 裕一郎, 庄司 聡, 西山 崇比古, 河野 隆志, 田中 誠, 柳澤 亮, 木村 舞, 八島 史明, 荒井 隆秀, 川上 崇史, 金澤 英明, 林田 健太郎, 湯浅 慎介, 福田 恵一

    日本心臓病学会学術集会抄録   64回   O - 023   2016年9月

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    記述言語:日本語   出版者・発行元:(一社)日本心臓病学会  

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  • Intensive statin therapy stabilizes C-reactive protein, but not chemokine in stable coronary artery disease treated with an everolimus-eluting stent. 査読 国際誌

    Hiroaki Sukegawa, Yuichiro Maekawa, Shinsuke Yuasa, Atsushi Anzai, Masaki Kodaira, Makoto Takei, Fumiya Sano, Ikuko Ueda, Takashi Kawakami, Kentaro Hayashida, Takashi Kohno, Shun Kohsaka, Takayuki Abe, Keiichi Fukuda

    Coronary artery disease   27 ( 5 )   405 - 11   2016年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Besides its potent plasma cholesterol-lowering activity, statin treatment has several other important effects, including lowering high-sensitive C-reactive protein (hs-CRP), levels, and stabilizing risk factors of atherosclerosis, thereby reducing the risk of cardiovascular events. Our aim in this study was to identify how intensive statin therapy can affect plasma levels of inflammatory markers over the long term. METHODS AND RESULTS: We used a prospective, randomized, open blinded-endpoint design. A total of 30 patients with stable coronary artery disease treated with everolimus-eluting stent implantation were randomized to receive rosuvastatin 2.5 (standard therapy group) or 10 mg (intensive therapy group) for 12 months. Plasma levels of hs-CRP, pentraxin-3, monocyte chemoattractant protein-1, and CXC chemokine ligand 4 were measured after a percutaneous coronary intervention, at 1, 3, 6, 9, and 12 months. Levels of LDL cholesterol (LDL-C) and HDL cholesterol were also measured. We investigated short-term and long-term clinical outcomes. After 12 months of therapy, the intensive therapy group had lower levels of LDL-C than the standard therapy group. Plasma levels of hs-CRP largely fluctuated in the standard therapy group, whereas they were stable in the intensive therapy group during the follow-up period. There were no significant differences in serum pentraxin-3, monocyte chemoattractant protein-1, and CXC chemokine ligand 4 levels, or in the incidence of any clinical adverse events, between the standard and the intensive therapy groups. CONCLUSION: Intensive rosuvastatin therapy stabilizes hs-CRP levels, but not chemokine levels, besides lowering LDL-C levels. Thus, this therapy may inhibit the progression of atherosclerosis by stably inhibiting the inflammatory cascade.

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  • 成人動脈管開存に対する2種類のデバイスを用いた経カテーテル的閉鎖術の比較検討

    金澤 英明, 河村 朗夫, 木村 舞, 八島 史明, 荒井 隆秀, 川上 崇史, 林田 健太郎, 湯浅 慎介, 前川 裕一郎, 福田 恵一

    心臓   48 ( 8 )   913 - 920   2016年8月

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    記述言語:日本語   出版者・発行元:(公財)日本心臓財団  

    動脈管開存(PDA)に対する経カテーテル的閉鎖術には、大きく分けて2種類のデバイスを用いた治療法が行われている。従来より標準的治療法として行われてきたコイル閉鎖術とAMPLAZERTM Duct Occluder(ADO;St.Jude Medical、St.Paul、MN、USA)を用いた閉鎖術である。アンプラッツァー閉鎖術は、その安全性と有用性が評価され、世界的に広く普及してきたが、成人PDA症に対するコイル閉鎖術とアンプラッツァー閉鎖術を比較検討した報告は少ない。そこで、今回われわれは、成人PDAに対するコイル閉鎖術とアンプラッツァー閉鎖術の有効性、安全性についての比較検討を行った。対象は、経カテーテル的閉鎖術を施行した成人PDA患者連続24症例(コイル群11例、アンプラッツァー群13例)。その結果、PDAに対する経カテーテル的閉鎖術は、コイル群、アンプラッツァー群ともに高い成功率(91%vs100%、p=ns)が得られたが、コイル群で残存シャントに関連した溶血を2例に認め、また2例に永続的な残存シャントを認めた。一方、アンプラッツァー群では、全例で完全閉鎖が得られ、溶血をはじめとした合併症は認めなかった。以上より、成人PDAに対する経カテーテル的閉鎖術はいずれの治療法も高い成功率と安全性が得られたが、わが国でもADOが使用可能となった現在では、最小動脈管径が2mm以上のPDAに対しては、ADOを用いたアンプラッツァー閉鎖術が第一選択になり得ると考えられた。(著者抄録)

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    その他リンク: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J00679&link_issn=&doc_id=20160822330004&doc_link_id=%2Fah2sinzd%2F2016%2F004808%2F007%2F0913-0920%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fah2sinzd%2F2016%2F004808%2F007%2F0913-0920%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

  • [Regenerative Therapy of the Cardiovascular Area Using iPS Cells].

    Keiichi Fukuda, Shugo Tohyama, Tomohisa Seki, Shinsuke Yuasa, Kenichiro Shimoji, Jun Fujita

    Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine   105 ( 7 )   1287 - 95   2016年7月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • 重症肺高血圧症を伴う薬剤抵抗性閉塞性肥大型心筋症に対して、経皮的中隔心筋焼灼術を施行し著明な症状改善を認めた一例

    秋田 敬太郎, 前川 裕一郎, 鶴田 ひかる, 福岡 良磨, 田中 誠, 柳澤 亮, 八島 史明, 木村 舞, 川上 崇史, 金澤 英明, 林田 健太郎, 湯浅 慎介, 村田 光繁, 福田 恵一

    日本心血管インターベンション治療学会抄録集   25回   MO570 - MO570   2016年7月

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    記述言語:英語   出版者・発行元:(一社)日本心血管インターベンション治療学会  

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  • 薬物療法抵抗性閉塞性肥大型心筋症症例に対するPTSMAの効果MDCTによる左房容積評価の検討

    前川 裕一郎, 秋田 敬太郎, 鶴田 ひかる, 柳澤 亮, 田中 誠, 木村 舞, 八島 史明, 荒井 隆秀, 川上 崇史, 金澤 英明, 林田 健太郎, 湯浅 慎介, 村田 光繁, 福田 恵一

    日本心血管インターベンション治療学会抄録集   25回   MO399 - MO399   2016年7月

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    記述言語:英語   出版者・発行元:(一社)日本心血管インターベンション治療学会  

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  • H1foo Has a Pivotal Role in Qualifying Induced Pluripotent Stem Cells. 査読 国際誌

    Akira Kunitomi, Shinsuke Yuasa, Fumihiro Sugiyama, Yuki Saito, Tomohisa Seki, Dai Kusumoto, Shin Kashimura, Makoto Takei, Shugo Tohyama, Hisayuki Hashimoto, Toru Egashira, Yoko Tanimoto, Saori Mizuno, Shoma Tanaka, Hironobu Okuno, Kazuki Yamazawa, Hideo Watanabe, Mayumi Oda, Ruri Kaneda, Yumi Matsuzaki, Toshihiro Nagai, Hideyuki Okano, Ken-Ichi Yagami, Mamoru Tanaka, Keiichi Fukuda

    Stem cell reports   6 ( 6 )   825 - 833   2016年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Embryonic stem cells (ESCs) are a hallmark of ideal pluripotent stem cells. Epigenetic reprogramming of induced pluripotent stem cells (iPSCs) has not been fully accomplished. iPSC generation is similar to somatic cell nuclear transfer (SCNT) in oocytes, and this procedure can be used to generate ESCs (SCNT-ESCs), which suggests the contribution of oocyte-specific constituents. Here, we show that the mammalian oocyte-specific linker histone H1foo has beneficial effects on iPSC generation. Induction of H1foo with Oct4, Sox2, and Klf4 significantly enhanced the efficiency of iPSC generation. H1foo promoted in vitro differentiation characteristics with low heterogeneity in iPSCs. H1foo enhanced the generation of germline-competent chimeric mice from iPSCs in a manner similar to that for ESCs. These findings indicate that H1foo contributes to the generation of higher-quality iPSCs.

    DOI: 10.1016/j.stemcr.2016.04.015

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  • Electrophysiological properties of iPS cell-derived cardiomyocytes from a patient with long QT syndrome type 1 harboring the novel mutation M437V of KCNQ1. 査読 国際誌

    Tatsufumi Sogo, Kumi Morikawa, Yasutaka Kurata, Peili Li, Takafumi Ichinose, Shinsuke Yuasa, Daizou Nozaki, Junichiro Miake, Haruaki Ninomiya, Wataru Shimizu, Keiichi Fukuda, Kazuhiro Yamamoto, Yasuaki Shirayoshi, Ichiro Hisatome

    Regenerative therapy   4   9 - 17   2016年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Introduction: Long QT syndrome type 1 (LQT1) is caused by mutations in KCNQ1 coding slowly-activating delayed-rectifier K+ channels. We identified the novel missense mutation M437V of KCNQ1 in a LQT1 patient. Here, we employed iPS cell (iPSC)-derived cardiomyocytes to investigate electrophysiological properties of the mutant channel and LQT1 cardiomyocytes. Methods: To generate iPSCs from the patient and a healthy subject, peripheral blood T cells were reprogrammed by Sendai virus vector encoding human OCT3/4, SOX2, KLF4, and c-MYC. Cardiomyocytes were prepared from iPSCs and human embryonic stem cells using a cytokine-based two-step differentiation method and were subjected to patch clamp experiments. Results: LQT1 iPSC-derived cardiomyocytes exhibited prolongation of action potential duration (APD), which was due to a reduction of the KCNQ1-mediated current IKs; Na+, Ca2+ and other K+ channel currents were comparable. When expressed in HEK293 and COS7 cells, the mutant KCNQ1 was normally expressed in the plasma membrane but generated smaller currents than the wild type. Isoproterenol significantly prolonged APDs of LQT1 cardiomyocytes, while shortening those of healthy ones. A mathematical model for IKs-reduced human ventricular myocytes reproduced APD prolongation and generation of early afterdepolarizations (EADs) under β-adrenergic stimulation. Conclusions: QT prolongation of the LQT1 patient with the mutation M437V of KCNQ1 was caused by IKs reduction, which may render the patient vulnerable to generation of EADs and arrhythmias.

    DOI: 10.1016/j.reth.2015.12.001

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  • Glutamine Oxidation Is Indispensable for Survival of Human Pluripotent Stem Cells. 査読 国際誌

    Shugo Tohyama, Jun Fujita, Takako Hishiki, Tomomi Matsuura, Fumiyuki Hattori, Rei Ohno, Hideaki Kanazawa, Tomohisa Seki, Kazuaki Nakajima, Yoshikazu Kishino, Marina Okada, Akinori Hirano, Takuya Kuroda, Satoshi Yasuda, Yoji Sato, Shinsuke Yuasa, Motoaki Sano, Makoto Suematsu, Keiichi Fukuda

    Cell metabolism   23 ( 4 )   663 - 74   2016年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Human pluripotent stem cells (hPSCs) are uniquely dependent on aerobic glycolysis to generate ATP. However, the importance of oxidative phosphorylation (OXPHOS) has not been elucidated. Detailed amino acid profiling has revealed that glutamine is indispensable for the survival of hPSCs. Under glucose- and glutamine-depleted conditions, hPSCs quickly died due to the loss of ATP. Metabolome analyses showed that hPSCs oxidized pyruvate poorly and that glutamine was the main energy source for OXPHOS. hPSCs were unable to utilize pyruvate-derived citrate due to negligible expression of aconitase 2 (ACO2) and isocitrate dehydrogenase 2/3 (IDH2/3) and high expression of ATP-citrate lyase. Cardiomyocytes with mature mitochondria were not able to survive without glucose and glutamine, although they were able to use lactate to synthesize pyruvate and glutamate. This distinguishing feature of hPSC metabolism allows preparation of clinical-grade cell sources free of undifferentiated hPSCs, which prevents tumor formation during stem cell therapy.

    DOI: 10.1016/j.cmet.2016.03.001

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  • A Novel Wire-Assisted Technique for Closing Large Atrial Septal Defects: New Concepts of Closure Mechanism. 査読 国際誌

    Hideaki Kanazawa, Akio Kawamura, Mai Kimura, Keitaro Akita, Fumiaki Yashima, Takahide Arai, Takashi Kawakami, Kentaro Hayashida, Hikaru Tsuruta, Shinsuke Yuasa, Yuji Itabashi, Mitsushige Murata, Yuichiro Maekawa, Keiichi Fukuda

    JACC. Cardiovascular interventions   9 ( 6 )   e59-61   2016年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.jcin.2015.12.016

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  • In-Stent Dissection Causes No Flow During Percutaneous Coronary Intervention. 査読 国際誌

    Fumiaki Yashima, Shinsuke Yuasa, Yuichiro Maekawa, Mai Kimura, Keitaro Akita, Ryo Yanagisawa, Makoto Tanaka, Kentaro Hayashida, Takashi Kawakami, Hideaki Kanazawa, Jun Fujita, Keiichi Fukuda

    JACC. Cardiovascular interventions   9 ( 1 )   102 - 103   2016年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.jcin.2015.09.025

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  • "Moving left ventricular obstruction" due to stress cardiomyopathy in a patient with hypertrophic obstructive cardiomyopathy treated with percutaneous transluminal septal myocardial ablation. 査読 国際誌

    Keitaro Akita, Yuichiro Maekawa, Hikaru Tsuruta, Shigeo Okuda, Ryo Yanagisawa, Toshimi Kageyama, Takashi Kawakami, Hideaki Kanazawa, Kentaro Hayashida, Shinsuke Yuasa, Mitsushige Murata, Masahiro Jinzaki, Keiichi Fukuda

    International journal of cardiology   202   194 - 5   2016年1月

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  • Recent improvements and emerging issues in iPSC generation for the modeling of disease 査読

    Tomohisa Seki, Shinsuke Yuasa, Keiichi Fukuda

    Human iPS Cells in Disease Modelling   1 - 9   2016年1月

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    記述言語:英語   掲載種別:論文集(書籍)内論文   出版者・発行元:Springer Japan  

    Recently, induced pluripotent stem cells (iPSCs) have attracted attention as a novel tool for the modeling of disease because of their potential to reveal new insights that have not been elucidated using animal models. Since iPSC generation was first reported, there have been many efforts to improve the method of generating iPSCs for clinical applications. To date, many methods for iPSC generation have been reported. Each has advantages and disadvantages for the modeling of disease, and thus the most appropriate method differs depending on the intended use of the iPSCs. Additionally, as the study of disease modeling with human iPSCs has progressed, the need to remove uncertainties due to variations in iPSCs cell lines has increasingly focused researchers’ attention on attaining experimental accuracy. Recognition of these uncertainties is important for the advancement of disease modeling studies with iPSCs.

    DOI: 10.1007/978-4-431-55966-5_1

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  • Cardiac arrhythmia modelling using iPS cells 査読

    Shinsuke Yuasa

    Human iPS Cells in Disease Modelling   45 - 51   2016年1月

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    記述言語:英語   掲載種別:論文集(書籍)内論文   出版者・発行元:Springer Japan  

    Innovation in stem cell biology has greatly impacted on medical researches. The generation of induced pluripotent stem cell (iPSC) established the novel concept not only in regenerative medicine but also disease modelling. There are several reports that disease-specific iPSC-derived cells have recapitulated cellular phenotypes of wide varieties of diseases. The disease-specific iPSCs are utilised to understand unknown pathogenesis by in vitro examination of disease-specific iPSC-derived cells. It is also shown that disease-specific iPSC-derived cells can be applied to high throughput screening for new drugs. Early reports about disease modelling using iPSCs focused on various types of cardiac arrhythmia because it is difficult to model human arrhythmia in animal models such as a genetically engineered mouse and it is relatively clear to show the phenotypes of cardiac arrhythmia in iPSC-derived cardiomyocyte such as abnormal electrophysiological activities. In this chapter, we focus on the conceptual and practical issues about cardiac arrhythmia modelling using disease-specific iPSCs and discuss the future directions.

    DOI: 10.1007/978-4-431-55966-5_4

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  • Patient-Specific Induced Pluripotent Stem Cell Models: Characterization of iPS Cell-Derived Cardiomyocytes. 査読 国際誌

    Toru Egashira, Shinsuke Yuasa, Shugo Tohyama, Yusuke Kuroda, Tomoyuki Suzuki, Tomohisa Seki, Keiichi Fukuda

    Methods in molecular biology (Clifton, N.J.)   1353   343 - 53   2016年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Despite significant advances in medical treatment, cardiovascular disease is still a major cause of morbidity and mortality in advanced countries. To improve the outcome, the further promotion of basic cardiovascular science has a pivotal role for the developing novel therapeutic approach. However, due to the inaccessibility of human heart tissue, we couldn't obtain the sufficient amount of patient's heart tissues. The discovery of human-induced pluripotent stem cells (iPSCs) is highly expected to provide the breakthrough to this obstruction. Through the patient-specific iPSCs-derived cardiomyocytes, we could analyze the patient-specific heart diseases directly and repetitively. Herein we introduce the outline of creation for cardiac disease modeling using patient-specific iPSCs. Within several topics, we present the actual representative methodologies throughout the process from the derivation of cardiomyocytes to those of functional analysis.

    DOI: 10.1007/7651_2014_165

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  • Significant reduction of left atrial volume concomitant with clinical improvement after percutaneous transluminal septal myocardial ablation for drug-refractory hypertrophic obstructive cardiomyopathy, and its precise detection with multidetector CT. 査読 国際誌

    Yuichiro Maekawa, Keitaro Akita, Hikaru Tsuruta, Yoshitake Yamada, Kentaro Hayashida, Shinsuke Yuasa, Mitsushige Murata, Masahiro Jinzaki, Keiichi Fukuda

    Open heart   3 ( 1 )   e000359   2016年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: In patients with hypertrophic obstructive cardiomyopathy (HOCM), left atrial (LA) volume measurement is very important to provide prognostic information. Recent studies demonstrated that multidetector CT (MDCT) is useful to assess the changes in LA volume. Our aim was to examine the utility of a follow-up cardiac MDCT for long-term evaluation of the effect of percutaneous transluminal septal myocardial ablation (PTSMA) on LA volume. METHODS: We studied a consecutive cohort of 20 patients with drug-refractory symptomatic HOCM after PTSMA. We evaluated LA volume analyses with cardiac MDCT on patients who underwent PTSMA as compared to echocardiography. RESULTS: Before PTSMA, 75% of all patients had heart failure-associated symptoms in the New York Heart Association functional class III/IV. All patients experienced relief from heart failure-associated symptoms after PTSMA. Cardiac MDCT showed significant reduction in the index of maximum LA volume during follow-up compared to before PTSMA in the same way as in echocardiography (93.6±34.1 mL/m(2) vs 82.6±35.3 mL/m(2), p=0.035). A Bland-Altman plot showed small mean differences and limits of agreement in the measurements of the index of maximum LA volume before and after PTSMA between echocardiography and MDCT. CONCLUSIONS: The follow-up cardiac MDCT was a useful tool to evaluate the effectiveness of PTSMA on reduction of LA volume. Cardiac MDCT might provide comparable measurements of the LA volume in patients with drug-refractory symptomatic HOCM before and after PTSMA compared to echocardiography.

    DOI: 10.1136/openhrt-2015-000359

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  • Generation of Induced Pluripotent Stem Cells from Human Peripheral T Cells Using Sendai Virus in Feeder-free Conditions. 査読 国際誌

    Yoshikazu Kishino, Tomohisa Seki, Shinsuke Yuasa, Jun Fujita, Keiichi Fukuda

    Journal of visualized experiments : JoVE   ( 105 )   2015年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Recently, iPSCs have attracted attention as a new source of cells for regenerative therapies. Although the initial method for generating iPSCs relied on dermal fibroblasts obtained by invasive biopsy and retroviral genomic insertion of transgenes, there have been many efforts to avoid these disadvantages. Human peripheral T cells are a unique cell source for generating iPSCs. iPSCs derived from T cells contain rearrangements of the T cell receptor (TCR) genes and are a source of antigen-specific T cells. Additionally, T cell receptor rearrangement in the genome has the potential to label individual cell lines and distinguish between transplanted and donor cells. For safe clinical application of iPSCs, it is important to minimize the risk of exposing newly generated iPSCs to harmful agents. Although fetal bovine serum and feeder cells have been essential for pluripotent stem cell culture, it is preferable to remove them from the culture system to reduce the risk of unpredictable pathogenicity. To address this, we have established a protocol for generating iPSCs from human peripheral T cells using Sendai virus to reduce the risk of exposing iPSCs to undefined pathogens. Although handling Sendai virus requires equipment with the appropriate biosafety level, Sendai virus infects activated T cells without genome insertion, yet with high efficiency. In this protocol, we demonstrate the generation of iPSCs from human peripheral T cells in feeder-free conditions using a combination of activated T cell culture and Sendai virus.

    DOI: 10.3791/53225

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  • Lesion morphological classification by OCT to predict therapeutic efficacy after balloon pulmonary angioplasty in CTEPH. 査読 国際誌

    Taku Inohara, Takashi Kawakami, Masaharu Kataoka, Masanori Yamamoto, Mai Kimura, Hideaki Kanazawa, Shinsuke Yuasa, Kentaro Hayashida, Yuichiro Maekawa, Keiichi Fukuda

    International journal of cardiology   197   23 - 5   2015年10月

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  • "Protruding Myocardium" as a Target for Percutaneous Transluminal Septal Myocardial Ablation in a Case of Hypertrophic Obstructive Cardiomyopathy. 査読 国際誌

    Yuichiro Maekawa, Keitaro Akita, Hikaru Tsuruta, Fumiaki Yashima, Mai Kimura, Yoshitake Yamada, Takashi Kawakami, Hideaki Kanazawa, Kentaro Hayashida, Shinsuke Yuasa, Mitsushige Murata, Masahiro Jinzaki, Keiichi Fukuda

    JACC. Cardiovascular interventions   8 ( 12 )   e201-2   2015年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.jcin.2015.05.029

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  • Analysis of cardiomyocyte movement in the developing murine heart. 査読 国際誌

    Hisayuki Hashimoto, Shinsuke Yuasa, Hidenori Tabata, Shugo Tohyama, Tomohisa Seki, Toru Egashira, Nozomi Hayashiji, Fumiyuki Hattori, Dai Kusumoto, Akira Kunitomi, Makoto Takei, Shin Kashimura, Gakuto Yozu, Masaya Shimojima, Chikaaki Motoda, Naoto Muraoka, Kazunori Nakajima, Asako Sakaue-Sawano, Atsushi Miyawaki, Keiichi Fukuda

    Biochemical and biophysical research communications   464 ( 4 )   1000 - 1007   2015年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The precise assemblage of several types of cardiac precursors controls heart organogenesis. The cardiac precursors show dynamic movement during early development and then form the complicated heart structure. However, cardiomyocyte movements inside the newly organized mammalian heart remain unclear. We previously established the method of ex vivo time-lapse imaging of the murine heart to study cardiomyocyte behavior by using the Fucci (fluorescent ubiquitination-based cell cycle indicator) system, which can effectively label individual G1, S/G2/M, and G1/S-transition phase nuclei in living cardiomyocytes as red, green, and yellow, respectively. Global analysis of gene expression in Fucci green positive ventricular cardiomyocytes confirmed that cell cycle regulatory genes expressed in G1/S, S, G2/M, and M phase transitions were upregulated. Interestingly, pathway analysis revealed that many genes related to the cell cycle were significantly upregulated in the Fucci green positive ventricular cardiomyocytes, while only a small number of genes related to cell motility were upregulated. Time-lapse imaging showed that murine proliferating cardiomyocytes did not exhibit dynamic movement inside the heart, but stayed on site after entering the cell cycle.

    DOI: 10.1016/j.bbrc.2015.07.036

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  • Cardiovascular Disease Modeling Using Patient-Specific Induced Pluripotent Stem Cells. 査読 国際誌

    Atsushi Tanaka, Shinsuke Yuasa, Koichi Node, Keiichi Fukuda

    International journal of molecular sciences   16 ( 8 )   18894 - 922   2015年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The generation of induced pluripotent stem cells (iPSCs) has opened up a new scientific frontier in medicine. This technology has made it possible to obtain pluripotent stem cells from individuals with genetic disorders. Because iPSCs carry the identical genetic anomalies related to those disorders, iPSCs are an ideal platform for medical research. The pathophysiological cellular phenotypes of genetically heritable heart diseases such as arrhythmias and cardiomyopathies, have been modeled on cell culture dishes using disease-specific iPSC-derived cardiomyocytes. These model systems can potentially provide new insights into disease mechanisms and drug discoveries. This review focuses on recent progress in cardiovascular disease modeling using iPSCs, and discusses problems and future perspectives concerning their use.

    DOI: 10.3390/ijms160818894

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  • Erratum: G-CSF supports long-term muscle regeneration in mouse models of muscular dystrophy. 査読 国際誌

    Nozomi Hayashiji, Shinsuke Yuasa, Yuko Miyagoe-Suzuki, Mie Hara, Naoki Ito, Hisayuki Hashimoto, Dai Kusumoto, Tomohisa Seki, Shugo Tohyama, Masaki Kodaira, Akira Kunitomi, Shin Kashimura, Makoto Takei, Yuki Saito, Shinichiro Okata, Toru Egashira, Jin Endo, Toshikuni Sasaoka, Shin'ichi Takeda, Keiichi Fukuda

    Nature communications   6   7295 - 7295   2015年6月

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    記述言語:英語  

    DOI: 10.1038/ncomms8295

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  • Fractured mobile flap in pulmonary artery: One of possible mechanisms for residual or recurrent pulmonary hypertension after pulmonary endarterectomy. 査読 国際誌

    Takahide Arai, Takashi Kawakami, Masaharu Kataoka, Shinsuke Yuasa, Yuichiro Maekawa, Keiichi Fukuda

    International journal of cardiology   185   129 - 30   2015年4月

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  • G-CSF supports long-term muscle regeneration in mouse models of muscular dystrophy. 査読 国際誌

    Nozomi Hayashiji, Shinsuke Yuasa, Yuko Miyagoe-Suzuki, Mie Hara, Naoki Ito, Hisayuki Hashimoto, Dai Kusumoto, Tomohisa Seki, Shugo Tohyama, Masaki Kodaira, Akira Kunitomi, Shin Kashimura, Makoto Takei, Yuki Saito, Shinichiro Okata, Toru Egashira, Jin Endo, Toshikuni Sasaoka, Shin'ichi Takeda, Keiichi Fukuda

    Nature communications   6   6745 - 6745   2015年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Duchenne muscular dystrophy (DMD) is a chronic and life-threatening disease that is initially supported by muscle regeneration but eventually shows satellite cell exhaustion and muscular dysfunction. The life-long maintenance of skeletal muscle homoeostasis requires the satellite stem cell pool to be preserved. Asymmetric cell division plays a pivotal role in the maintenance of the satellite cell pool. Here we show that granulocyte colony-stimulating factor receptor (G-CSFR) is asymmetrically expressed in activated satellite cells. G-CSF positively affects the satellite cell population during multiple stages of differentiation in ex vivo cultured fibres. G-CSF could be important in developing an effective therapy for DMD based on its potential to modulate the supply of multiple stages of regenerated myocytes. This study shows that the G-CSF-G-CSFR axis is fundamentally important for long-term muscle regeneration, functional maintenance and lifespan extension in mouse models of DMD with varying severities.

    DOI: 10.1038/ncomms7745

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  • Prognostic implications of optimal medical therapy in patients undergoing percutaneous coronary intervention for acute coronary syndrome in octogenarians. 査読

    Atsushi Anzai, Yuichiro Maekawa, Masaki Kodaira, Satoshi Mogi, Takahide Arai, Takashi Kawakami, Hideaki Kanazawa, Kentaro Hayashida, Shinsuke Yuasa, Akio Kawamura, Keiichi Fukuda

    Heart and vessels   30 ( 2 )   186 - 92   2015年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The proportion of elderly acute coronary syndrome (ACS) patients who receive optimal medical therapy (OMT) after percutaneous coronary intervention (PCI) and whether OMT affects their long-term outcomes remain unclear. We retrospectively investigated 405 ACS patients who underwent stent implantation between 2005 and 2009, and compared the outcomes between patients <80 years of age vs. ≥80 years of age. The prescription rate of the recommended medical agents for ACS in both groups during hospitalization and 2 years after admission was also retrieved. Among the enrolled study population, 75 patients (19%) were aged ≥80 years. These elderly patients had a higher 2-year mortality compared with patients aged <80 years group. The prescription rate of beta-blockers, angiotensin-blocking drugs, and statins tended to be lower in patients aged ≥80 years than in those aged <80 years. Furthermore, among patients ≥80 years of age, those who received OMT had better clinical outcome of 2-year mortality compared to those without OMT. Elderly patients with ACS treated by PCI are at substantially higher risk of adverse events than younger patients. However, they are less likely to receive OMT. PCI with OMT might improve the clinical outcomes of elderly ACS patients.

    DOI: 10.1007/s00380-014-0474-y

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  • Improved renal function in a patient with hypertrophic obstructive cardiomyopathy after multidetector computed tomography-guided percutaneous transluminal septal myocardial ablation. 査読 国際誌

    Yuichiro Maekawa, Masahiro Jinzaki, Hikaru Tsuruta, Keitaro Akita, Yoshitake Yamada, Takashi Kawakami, Kentaro Hayashida, Shinsuke Yuasa, Mitsushige Murata, Keiichi Fukuda

    International journal of cardiology   181   349 - 50   2015年2月

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  • HTRA1 (high temperature requirement A serine peptidase 1) gene is transcriptionally regulated by insertion/deletion nucleotides located at the 3' end of the ARMS2 (age-related maculopathy susceptibility 2) gene in patients with age-related macular degeneration. 査読 国際誌

    Daisuke Iejima, Takeshi Itabashi, Yuich Kawamura, Toru Noda, Shinsuke Yuasa, Keiichi Fukuda, Chio Oka, Takeshi Iwata

    The Journal of biological chemistry   290 ( 5 )   2784 - 97   2015年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Dry age-related macular degeneration (AMD) accounts for over 85% of AMD cases in the United States, whereas Japanese AMD patients predominantly progress to wet AMD or polypoidal choroidal vasculopathy. Recent genome-wide association studies have revealed a strong association between AMD and an insertion/deletion sequence between the ARMS2 (age-related maculopathy susceptibility 2) and HTRA1 (high temperature requirement A serine peptidase 1) genes. Transcription regulator activity was localized in mouse retinas using heterozygous HtrA1 knock-out mice in which HtrA1 exon 1 was replaced with β-galactosidase cDNA, thereby resulting in dominant expression of the photoreceptors. The insertion/deletion sequence significantly induced HTRA1 transcription regulator activity in photoreceptor cell lines but not in retinal pigmented epithelium or other cell types. A deletion construct of the HTRA1 regulatory region indicated that potential transcriptional suppressors and activators surround the insertion/deletion sequence. Ten double-stranded DNA probes for this region were designed, three of which interacted with nuclear extracts from 661W cells in EMSA. Liquid chromatography-mass spectrometry (LC-MS/MS) of these EMSA bands subsequently identified a protein that bound the insertion/deletion sequence, LYRIC (lysine-rich CEACAM1 co-isolated) protein. In addition, induced pluripotent stem cells from wet AMD patients carrying the insertion/deletion sequence showed significant up-regulation of the HTRA1 transcript compared with controls. These data suggest that the insertion/deletion sequence alters the suppressor and activator cis-elements of HTRA1 and triggers sustained up-regulation of HTRA1. These results are consistent with a transgenic mouse model that ubiquitously overexpresses HtrA1 and exhibits characteristics similar to those of wet AMD patients.

    DOI: 10.1074/jbc.M114.593384

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  • The Role of Circadian Rhythms in Fatal Arrhythmias and the Potential Impact of Intervention for Sleep-Disordered Breathing. 査読 国際誌

    Yoshiyasu Aizawa, Takashi Kohno, Shinsuke Yuasa, Keiichi Fukuda

    Current pharmaceutical design   21 ( 24 )   3512 - 22   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    There exist circadian patterns in the occurrence of sudden cardiac death. The suprachiasmatic nuclei is the 'master clock' in mammalian bodies. Furthermore, several circadian genes have been successfully isolated in basic studies and a huge variety of key players form the human circadian rhythm. Obvious circadian patterns are present in the occurrence of critical events, but those characteristics differ greatly according to each disease. In this review we summarized the current understanding of the basic mechanism and association with specific cardiovascular diseases that demonstrate a circadian onset of fatal events. We also summarized the recent deep understanding of sleep-disordered breathing. The close relationship between sleep-disordered breathing and cardiovascular diseases may provide us with the possibility of a novel intervention against sudden cardiac death.

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  • Impaired respiratory function in MELAS-induced pluripotent stem cells with high heteroplasmy levels. 査読 国際誌

    Masaki Kodaira, Hideyuki Hatakeyama, Shinsuke Yuasa, Tomohisa Seki, Toru Egashira, Shugo Tohyama, Yusuke Kuroda, Atsushi Tanaka, Shinichiro Okata, Hisayuki Hashimoto, Dai Kusumoto, Akira Kunitomi, Makoto Takei, Shin Kashimura, Tomoyuki Suzuki, Gakuto Yozu, Masaya Shimojima, Chikaaki Motoda, Nozomi Hayashiji, Yuki Saito, Yu-Ichi Goto, Keiichi Fukuda

    FEBS open bio   5   219 - 25   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Mitochondrial diseases are heterogeneous disorders, caused by mitochondrial dysfunction. Mitochondria are not regulated solely by nuclear genomic DNA but by mitochondrial DNA. It is difficult to develop effective therapies for mitochondrial disease because of the lack of mitochondrial disease models. Mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is one of the major mitochondrial diseases. The aim of this study was to generate MELAS-specific induced pluripotent stem cells (iPSCs) and to demonstrate that MELAS-iPSCs can be models for mitochondrial disease. We successfully established iPSCs from the primary MELAS-fibroblasts carrying 77.7% of m.3243A>G heteroplasmy. MELAS-iPSC lines ranged from 3.6% to 99.4% of m.3243A>G heteroplasmy levels. The enzymatic activities of mitochondrial respiratory complexes indicated that MELAS-iPSC-derived fibroblasts with high heteroplasmy levels showed a deficiency of complex I activity but MELAS-iPSC-derived fibroblasts with low heteroplasmy levels showed normal complex I activity. Our data indicate that MELAS-iPSCs can be models for MELAS but we should carefully select MELAS-iPSCs with appropriate heteroplasmy levels and respiratory functions for mitochondrial disease modeling.

    DOI: 10.1016/j.fob.2015.03.008

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  • A massive suspension culture system with metabolic purification for human pluripotent stem cell-derived cardiomyocytes. 査読 国際誌

    Natsuko Hemmi, Shugo Tohyama, Kazuaki Nakajima, Hideaki Kanazawa, Tomoyuki Suzuki, Fumiyuki Hattori, Tomohisa Seki, Yoshikazu Kishino, Akinori Hirano, Marina Okada, Ryota Tabei, Rei Ohno, Chihana Fujita, Tomoko Haruna, Shinsuke Yuasa, Motoaki Sano, Jun Fujita, Keiichi Fukuda

    Stem cells translational medicine   3 ( 12 )   1473 - 83   2014年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Cardiac regenerative therapy with human pluripotent stem cells (hPSCs), such as human embryonic stem cells and induced pluripotent stem cells, has been hampered by the lack of efficient strategies for expanding functional cardiomyocytes (CMs) to clinically relevant numbers. The development of the massive suspension culture system (MSCS) has shed light on this critical issue, although it remains unclear how hPSCs could differentiate into functional CMs using a MSCS. The proliferative rate of differentiating hPSCs in the MSCS was equivalent to that in suspension cultures using nonadherent culture dishes, although the MSCS provided more homogeneous embryoid bodies (EBs), eventually reducing apoptosis. However, pluripotent markers such as Oct3/4 and Tra-1-60 were still expressed in EBs 2 weeks after differentiation, even in the MSCS. The remaining undifferentiated stem cells in such cultures could retain a strong potential for teratoma formation, which is the worst scenario for clinical applications of hPSC-derived CMs. The metabolic purification of CMs in glucose-depleted and lactate-enriched medium successfully eliminated the residual undifferentiated stem cells, resulting in a refined hPSC-derived CM population. In colony formation assays, no Tra-1-60-positive colonies appeared after purification. The nonpurified CMs in the MSCS produced teratomas at a rate of 60%. However, purified CMs never induced teratomas, and enriched CMs showed proper electrophysiological properties and calcium transients. Overall, the combination of a MSCS and metabolic selection is a highly effective and practical approach to purify and enrich massive numbers of functional CMs and provides an essential technique for cardiac regenerative therapy with hPSC-derived CMs.

    DOI: 10.5966/sctm.2014-0072

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  • Endothelin-1 induces myofibrillar disarray and contractile vector variability in hypertrophic cardiomyopathy-induced pluripotent stem cell-derived cardiomyocytes. 査読 国際誌

    Atsushi Tanaka, Shinsuke Yuasa, Giulia Mearini, Toru Egashira, Tomohisa Seki, Masaki Kodaira, Dai Kusumoto, Yusuke Kuroda, Shinichiro Okata, Tomoyuki Suzuki, Taku Inohara, Takuro Arimura, Shinji Makino, Kensuke Kimura, Akinori Kimura, Tetsushi Furukawa, Lucie Carrier, Koichi Node, Keiichi Fukuda

    Journal of the American Heart Association   3 ( 6 )   e001263   2014年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Despite the accumulating genetic and molecular investigations into hypertrophic cardiomyopathy (HCM), it remains unclear how this condition develops and worsens pathologically and clinically in terms of the genetic-environmental interactions. Establishing a human disease model for HCM would help to elucidate these disease mechanisms; however, cardiomyocytes from patients are not easily obtained for basic research. Patient-specific induced pluripotent stem cells (iPSCs) potentially hold much promise for deciphering the pathogenesis of HCM. The purpose of this study is to elucidate the interactions between genetic backgrounds and environmental factors involved in the disease progression of HCM. METHODS AND RESULTS: We generated iPSCs from 3 patients with HCM and 3 healthy control subjects, and cardiomyocytes were differentiated. The HCM pathological phenotypes were characterized based on morphological properties and high-speed video imaging. The differences between control and HCM iPSC-derived cardiomyocytes were mild under baseline conditions in pathological features. To identify candidate disease-promoting environmental factors, the cardiomyocytes were stimulated by several cardiomyocyte hypertrophy-promoting factors. Interestingly, endothelin-1 strongly induced pathological phenotypes such as cardiomyocyte hypertrophy and intracellular myofibrillar disarray in the HCM iPSC-derived cardiomyocytes. We then reproduced these phenotypes in neonatal cardiomyocytes from the heterozygous Mybpc3-targeted knock in mice. High-speed video imaging with motion vector prediction depicted physiological contractile dynamics in the iPSC-derived cardiomyocytes, which revealed that self-beating HCM iPSC-derived single cardiomyocytes stimulated by endothelin-1 showed variable contractile directions. CONCLUSIONS: Interactions between the patient's genetic backgrounds and the environmental factor endothelin-1 promote the HCM pathological phenotype and contractile variability in the HCM iPSC-derived cardiomyocytes.

    DOI: 10.1161/JAHA.114.001263

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  • Successful second attempt multidetector computed tomography-guided percutaneous transluminal septal myocardial ablation for an octogenarian with hypertrophic obstructive cardiomyopathy. 査読 国際誌

    Yuichiro Maekawa, Masahiro Jinzaki, Atsushi Anzai, Hikaru Tsuruta, Keisuke Matsumura, Yoshitake Yamada, Ryota Tabei, Takashi Kawakami, Kentaro Hayashida, Shinsuke Yuasa, Mitsushige Murata, Masahiro Suzuki, Sachio Kuribayashi, Keiichi Fukuda

    International journal of cardiology   176 ( 3 )   e131-2   2014年10月

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  • Time-lapse imaging of cell cycle dynamics during development in living cardiomyocyte. 査読 国際誌

    Hisayuki Hashimoto, Shinsuke Yuasa, Hidenori Tabata, Shugo Tohyama, Nozomi Hayashiji, Fumiyuki Hattori, Naoto Muraoka, Toru Egashira, Shinichiro Okata, Kojiro Yae, Tomohisa Seki, Takahiko Nishiyama, Kazunori Nakajima, Asako Sakaue-Sawano, Atsushi Miyawaki, Keiichi Fukuda

    Journal of molecular and cellular cardiology   72   241 - 9   2014年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Mammalian cardiomyocytes withdraw from the cell cycle shortly after birth, although it remains unclear how cardiomyocyte cell cycles behave during development. Compared to conventional immunohistochemistry in static observation, time-lapse imaging can reveal comprehensive data in hard-to-understand biological phenomenon. However, there are no reports of an established protocol of successful time-lapse imaging in mammalian heart. Thus, it is valuable to establish a time-lapse imaging system to enable the observation of cell cycle dynamics in living murine cardiomyocytes. This study sought to establish time-lapse imaging of murine heart to study cardiomyocyte cell cycle behavior. The Fucci (fluorescent ubiquitination-based cell cycle indicator) system can effectively label individual G1, S/G2/M, and G1/S-transition phase nuclei red, green and yellow, respectively, in living mammalian cells, and could therefore be useful to visualize the real-time cell cycle transitions in living murine heart. To establish a similar system for time-lapse imaging of murine heart, we first developed an ex vivo culture system, with the culture conditions determined in terms of sample state, serum concentration, and oxygen concentration. The optimal condition (slice culture, oxygen concentration 20%, serum concentration 10%) successfully mimicked physiological cardiomyocyte proliferation in vivo. Time-lapse imaging of cardiac slices from E11.5, E14.5, E18.5, and P1 Fucci-expressing transgenic mice revealed an elongated S/G2/M phase in cardiomyocytes during development. Our time-lapse imaging of murine heart revealed a gradual elongation of the S/G2/M phase during development in living cardiomyocytes.

    DOI: 10.1016/j.yjmcc.2014.03.020

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  • Coexistence of two distinct fascinating cardiovascular disorders: heterotaxy syndrome with left ventricular non-compaction and vasospastic angina. 査読 国際誌

    Toru Egashira, Shinsuke Yuasa, Mai Kimura, Mitsuaki Sawano, Atsushi Anzai, Kentaro Hayashida, Akio Kawamura, Takehiro Kimura, Nobuhiro Nishiyama, Yoshiyasu Aizawa, Seiji Takatsuki, Hikaru Tsuruta, Mitsushige Murata, Yoshitake Yamada, Takashi Kohno, Yuichiro Maekawa, Motoaki Sano, Kenjiro Kosaki, Keiichi Fukuda

    International journal of cardiology   174 ( 2 )   e54-6   2014年6月

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  • "Phantom vessel" running parallel to the culprit artery in a case of acute myocardial infarction. 査読 国際誌

    Atsushi Anzai, Shinsuke Yuasa, Hideaki Kanazawa, Masaki Kodaira, Takahide Arai, Takashi Kawakami, Kentaro Hayashida, Yuichiro Maekawa, Akio Kawamura, Keiichi Fukuda

    JACC. Cardiovascular interventions   7 ( 6 )   e51-2   2014年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.jcin.2013.08.020

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  • Utility of the reverse wire technique in multidetector computed tomography-guided percutaneous transluminal septal myocardial ablation. 査読 国際誌

    Yuichiro Maekawa, Masahiro Jinzaki, Atsushi Anzai, Keisuke Matsumura, Hikaru Tsuruta, Takashi Kawakami, Kentaro Hayashida, Shinsuke Yuasa, Mitsushige Murata, Masahiro Suzuki, Sachio Kuribayashi, Keiichi Fukuda

    International journal of cardiology   173 ( 3 )   e33-4   2014年5月

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  • 肥大型心筋症iPS細胞由来の心筋細胞においてEndothelin-1は収縮変動を誘発する(Endothelin-1 Induces Contraction Variability in Hypertrophic Cardiomyopathy-iPS Cell-derived Cardiomyocytes)

    Tanaka Atsushi, Yuasa Shinsuke, Egashira Toru, Seki Tomohisa, Kodaira Masaki, Kusumoto Dai, Yae Kojiro, Kuroda Yusuke, Okata Shinichiro, Suzuki Tomoyuki, Arimura Takuro, Kimura Kensuke, Furukawa Tetsushi, Kimura Akinori, Node Koichi, Fukuda Keiichi

    Circulation Journal   78 ( Suppl.I )   7 - 8   2014年3月

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    記述言語:英語   出版者・発行元:(一社)日本循環器学会  

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  • Endogenous prostaglandin D2 and its metabolites protect the heart against ischemia-reperfusion injury by activating Nrf2. 査読 国際誌

    Yoshinori Katsumata, Ken Shinmura, Yuki Sugiura, Shugo Tohyama, Tomohiro Matsuhashi, Hideyuki Ito, Xiaoxiang Yan, Kentaro Ito, Shinsuke Yuasa, Masaki Ieda, Yoshihiro Urade, Makoto Suematsu, Keiichi Fukuda, Motoaki Sano

    Hypertension (Dallas, Tex. : 1979)   63 ( 1 )   80 - 7   2014年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We recently demonstrated that glucocorticoids markedly upregulate the expression of cyclooxygenase-2 in cardiomyocytes and protect hearts from ischemia-reperfusion (I/R) injury by activating lipocalin-type prostaglandin D (PGD) synthase (L-PGDS)-derived PGD(2) biosynthesis. We examined a downstream mechanism of cardioprotection elicited by PGD(2) biosynthesis. Acute PGD(2) treatment did not protect hearts against I/R injury. We then speculated that PGD(2) and its metabolite 15-deoxy-Δ12,14-PGJ(2) activate gene expression networks to mediate the glucocorticoid-mediated cardioprotection. Using an unbiased approach, we identified that glucocorticoids induce a number of well-known erythroid-derived 2-like 2 (Nrf2) target genes in the heart in an L-PGDS-dependent manner and that the cardioprotective effect of glucocorticoids against I/R injury was not seen in Nrf2-knockout hearts. We showed relatively low expression of PGD(2) receptors (ie, DP1 and DP2) in the heart but abundant expression of PGF(2α) receptor (FP), which binds PGF(2α) and PGD(2) with equal affinity. Glucocorticoids also failed to induce the expression of L-PGDS-dependent Nrf2 target genes in FP-knockout hearts. PGD(2) acted through its metabolite 15-deoxy-Δ12,14-PGJ(2) in the heart as evidenced by the glucocorticoid-mediated activation of peroxisome proliferator-activated receptor-γ. In turn, glucocorticoids failed to induce the expression of L-PGDS-dependent Nrf2 target genes in hearts pretreated with peroxisome proliferator-activated receptor-γ antagonist GW9662, and glucocorticoid-mediated cardioprotection against I/R injury was compromised in FP-knockout mice and GW9662-treated mice. In conclusion, PGD(2) protects heart against I/R injury by activating Nrf2 predominantly via FP receptor. In addition, we propose activation of peroxisome proliferator-activated receptor-γ by the dehydrated metabolite of PGD(2) (15-deoxy-Δ12,14-PGJ(2)) as another mechanism by which glucocorticoids induce cardioprotection.

    DOI: 10.1161/HYPERTENSIONAHA.113.01639

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  • Anatomical variations affect radial artery spasm and procedural achievement of transradial cardiac catheterization. 査読

    Yohei Numasawa, Akio Kawamura, Shun Kohsaka, Masashi Takahashi, Ayaka Endo, Takahide Arai, Yohei Ohno, Shinsuke Yuasa, Yuichiro Maekawa, Keiichi Fukuda

    Heart and vessels   29 ( 1 )   49 - 57   2014年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Transradial cardiac catheterization (TRCC) has unique technical challenges such as access difficulty related to anatomical variations and/or radial artery (RA) spasm. We sought to evaluate the incidence of anatomical variations of the RA and whether they would affect RA spasm and procedural achievement of TRCC. A total of 744 consecutive patients who underwent TRCC were analyzed by routine radial arteriography. Anatomical variations were defined as abnormal origin of the RA and/or radioulnar loop and/or tortuous configuration. RA spasm was defined as >75 % stenosis at first radial arteriography. Overall, anatomical variations were noted in 68 patients (9.1 %), including 39 cases of abnormal origin (5.2 %), 11 cases of radioulnar loop (1.5 %), and 42 cases of tortuous configuration (5.6 %). Transradial procedures failed in 26 patients (3.5 %), and more frequently in patients with anatomical variation than in those with normal anatomy (23.5 % vs 1.5 %, P < 0.001). Importantly, on multivariate analysis the presence of anatomical variation was a distinct predictor of transradial procedure failure (odds ratio (OR) 17.80; 95 % CI 7.55-43.73; P < 0.001). RA spasm was observed in 83 patients (11.2 %), and more frequently in patients with anatomical variation than in those with normal anatomy (35.3 % vs 8.7 %, P < 0.001). Anatomical variation (OR 4.74; 95 % CI 2.61-8.47; P < 0.001) and female gender (OR 2.23; 95 % CI 1.01-4.73; P = 0.041) were distinct predictors of RA spasm. Anatomical variations were observed in 9.1 % of the patients, and strongly correlated with RA spasm and procedural achievement of TRCC.

    DOI: 10.1007/s00380-013-0324-3

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  • Reprogramming suppresses premature senescence phenotypes of Werner syndrome cells and maintains chromosomal stability over long-term culture. 査読 国際誌

    Akira Shimamoto, Harunobu Kagawa, Kazumasa Zensho, Yukihiro Sera, Yasuhiro Kazuki, Mitsuhiko Osaki, Mitsuo Oshimura, Yasuhito Ishigaki, Kanya Hamasaki, Yoshiaki Kodama, Shinsuke Yuasa, Keiichi Fukuda, Kyotaro Hirashima, Hiroyuki Seimiya, Hirofumi Koyama, Takahiko Shimizu, Minoru Takemoto, Koutaro Yokote, Makoto Goto, Hidetoshi Tahara

    PloS one   9 ( 11 )   e112900   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Werner syndrome (WS) is a premature aging disorder characterized by chromosomal instability and cancer predisposition. Mutations in WRN are responsible for the disease and cause telomere dysfunction, resulting in accelerated aging. Recent studies have revealed that cells from WS patients can be successfully reprogrammed into induced pluripotent stem cells (iPSCs). In the present study, we describe the effects of long-term culture on WS iPSCs, which acquired and maintained infinite proliferative potential for self-renewal over 2 years. After long-term cultures, WS iPSCs exhibited stable undifferentiated states and differentiation capacity, and premature upregulation of senescence-associated genes in WS cells was completely suppressed in WS iPSCs despite WRN deficiency. WS iPSCs also showed recapitulation of the phenotypes during differentiation. Furthermore, karyotype analysis indicated that WS iPSCs were stable, and half of the descendant clones had chromosomal profiles that were similar to those of parental cells. These unexpected properties might be achieved by induced expression of endogenous telomerase gene during reprogramming, which trigger telomerase reactivation leading to suppression of both replicative senescence and telomere dysfunction in WS cells. These findings demonstrated that reprogramming suppressed premature senescence phenotypes in WS cells and WS iPSCs could lead to chromosomal stability over the long term. WS iPSCs will provide opportunities to identify affected lineages in WS and to develop a new strategy for the treatment of WS.

    DOI: 10.1371/journal.pone.0112900

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  • Multidetector computed tomography-guided percutaneous transluminal septal myocardial ablation in a Noonan syndrome patient with hypertrophic obstructive cardiomyopathy. 査読 国際誌

    Yuichiro Maekawa, Masahiro Jinzaki, Hikaru Tsuruta, Yoshitake Yamada, Yoshikazu Kishino, Takashi Kawakami, Kentaro Hayashida, Shinsuke Yuasa, Mitsushige Murata, Akio Kawamura, Motoaki Sano, Sachio Kuribayashi, Keiichi Fukuda

    International journal of cardiology   172 ( 1 )   e79-81   2014年

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  • Generation and characterization of functional cardiomyocytes derived from human T cell-derived induced pluripotent stem cells. 査読 国際誌

    Tomohisa Seki, Shinsuke Yuasa, Dai Kusumoto, Akira Kunitomi, Yuki Saito, Shugo Tohyama, Kojiro Yae, Yoshikazu Kishino, Marina Okada, Hisayuki Hashimoto, Makoto Takei, Toru Egashira, Masaki Kodaira, Yusuke Kuroda, Atsushi Tanaka, Shinichiro Okata, Tomoyuki Suzuki, Mitsushige Murata, Jun Fujita, Keiichi Fukuda

    PloS one   9 ( 1 )   e85645   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Induced pluripotent stem cells (iPSCs) have been proposed as novel cell sources for genetic disease models and revolutionary clinical therapies. Accordingly, human iPSC-derived cardiomyocytes are potential cell sources for cardiomyocyte transplantation therapy. We previously developed a novel generation method for human peripheral T cell-derived iPSCs (TiPSCs) that uses a minimally invasive approach to obtain patient cells. However, it remained unknown whether TiPSCs with genomic rearrangements in the T cell receptor (TCR) gene could differentiate into functional cardiomyocyte in vitro. To address this issue, we investigated the morphology, gene expression pattern, and electrophysiological properties of TiPSC-derived cardiomyocytes differentiated by floating culture. RT-PCR analysis and immunohistochemistry showed that the TiPSC-derived cardiomyocytes properly express cardiomyocyte markers and ion channels, and show the typical cardiomyocyte morphology. Multiple electrode arrays with application of ion channel inhibitors also revealed normal electrophysiological responses in the TiPSC-derived cardiomyocytes in terms of beating rate and the field potential waveform. In this report, we showed that TiPSCs successfully differentiated into cardiomyocytes with morphology, gene expression patterns, and electrophysiological features typical of native cardiomyocytes. TiPSCs-derived cardiomyocytes obtained from patients by a minimally invasive technique could therefore become disease models for understanding the mechanisms of cardiac disease and cell sources for revolutionary cardiomyocyte therapies.

    DOI: 10.1371/journal.pone.0085645

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  • Derivation of transgene-free human induced pluripotent stem cells from human peripheral T cells in defined culture conditions. 査読 国際誌

    Yoshikazu Kishino, Tomohisa Seki, Jun Fujita, Shinsuke Yuasa, Shugo Tohyama, Akira Kunitomi, Ryota Tabei, Kazuaki Nakajima, Marina Okada, Akinori Hirano, Hideaki Kanazawa, Keiichi Fukuda

    PloS one   9 ( 5 )   e97397   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Recently, induced pluripotent stem cells (iPSCs) were established as promising cell sources for revolutionary regenerative therapies. The initial culture system used for iPSC generation needed fetal calf serum in the culture medium and mouse embryonic fibroblast as a feeder layer, both of which could possibly transfer unknown exogenous antigens and pathogens into the iPSC population. Therefore, the development of culture systems designed to minimize such potential risks has become increasingly vital for future applications of iPSCs for clinical use. On another front, although donor cell types for generating iPSCs are wide-ranging, T cells have attracted attention as unique cell sources for iPSCs generation because T cell-derived iPSCs (TiPSCs) have a unique monoclonal T cell receptor genomic rearrangement that enables their differentiation into antigen-specific T cells, which can be applied to novel immunotherapies. In the present study, we generated transgene-free human TiPSCs using a combination of activated human T cells and Sendai virus under defined culture conditions. These TiPSCs expressed pluripotent markers by quantitative PCR and immunostaining, had a normal karyotype, and were capable of differentiating into cells from all three germ layers. This method of TiPSCs generation is more suitable for the therapeutic application of iPSC technology because it lowers the risks associated with the presence of undefined, animal-derived feeder cells and serum. Therefore this work will lead to establishment of safer iPSCs and extended clinical application.

    DOI: 10.1371/journal.pone.0097397

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  • Induced pluripotent stem cells: New advances in cardiac regenerative medicine 査読

    Shinsuke Yuasa, Mitsushige Murata, Keiichi Fukuda

    Emerging Trends in Cell and Gene Therapy   225 - 249   2013年12月

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    記述言語:英語   掲載種別:論文集(書籍)内論文   出版者・発行元:Humana Press Inc.  

    To bring the notion of cardiac regenerative medicine to fruition, researchers have tried to determine which stem cells, embryonic stem (ES) cells or somatic stem cells, are most suitable. Thus far, there is no clear indication which is better, because both have their own advantages and disadvantages. In 2006, murine induced pluripotent stem (iPS) cells were first established. Since then, basic research into the properties of iPS cells has continued apace. Originally, human iPS cells were generated from dermal fibroblasts by retrovirus-mediated gene transfer. Although this technique is sophisticated and easy to perform, the skin biopsy is accompanied by some bleeding and pain, and there may be some damage to the host genome because of retrovirus-mediated transgene integration. However, methods of producing iPS cells have improved steadily. For clinical application in the cardiovascular field, efficient methods that produce pluripotent stem cells that can differentiate into cardiomyocytes need to be developed. Existing methods for ES cells can be applied to iPS cells to obtain cardiomyocyte differentiation. In addition, existing purification methods can be used to obtain pure cardiomyocytes from a population of mixed cells. These techniques have themselves been the subject of extensive research, and continued advances are now making the clinical application of pluripotent stem cells a reality. We are at the forefront of medical innovations in the cardiovascular field based on the use of pluripotent stem cells.

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  • Aortic aneurysm: an independent predictor of a looped brachiocephalic trunk in patients undergoing transradial coronary angiography. 査読 国際誌

    Satoshi Mogi, Yuichiro Maekawa, Masaki Kodaira, Atsushi Anzai, Takahide Arai, Takashi Kawakami, Kentaro Hayashida, Shinsuke Yuasa, Akio Kawamura, Keiichi Fukuda

    Coronary artery disease   24 ( 7 )   602 - 5   2013年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: A looped brachiocephalic trunk may cause transradial coronary angiography (TRA) failure with a right radial approach. The prevalences of aortic aneurysm (AA) and a looped brachiocephalic trunk are closely related to increased age. OBJECTIVE: The aim of this study was to clarify the relationship between AA and a looped brachiocephalic trunk. PATIENTS AND METHODS: A total of 1306 consecutive patients who underwent TRA through the right radial artery at Keio University Hospital between January 2007 and December 2011 were examined retrospectively. A looped brachiocephalic trunk was defined as the presence of a full 360° loop in the 45° left anterior oblique view requiring a change in the access site to the left radial or femoral artery. RESULTS: Of the 1306 patients who underwent TRA at Keio University Hospital between January 2007 and December 2011, 137 had AA. The patients were divided into two groups: patients with a looped brachiocephalic trunk and those without it. Patients in the looped brachiocephalic group were older and had a higher BMI. The prevalence of hypertension was higher in the looped brachiocephalic trunk group. Creatinine clearance was lower in patients with a looped brachiocephalic trunk than in those without a looped brachiocephalic trunk. Multivariate analysis showed that AA was an independent predictor of a looped brachiocephalic trunk. CONCLUSION: AA is a predictor of a looped brachiocephalic trunk that should be considered in patients undergoing TRA.

    DOI: 10.1097/MCA.0b013e3283650254

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  • Erratum: Incidence of periprocedural myocardial infarction and cardiac biomarker testing after percutaneous coronary intervention in Japan: Results from a multicenter registry (Heart Vessels DOI 10.1007/s00380-012-0314-x) 査読

    Takahide Arai, Shinsuke Yuasa, Hiroaki Miyata, Akio Kawamura, Yuichiro Maekawa, Shiro Ishikawa, Shigetaka Noma, Soushin Inoue, Yuji Sato, Shun Kohsaka, Keiichi Fukuda

    Heart and Vessels   28 ( 6 )   720   2013年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1007/s00380-013-0364-8

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  • Incidence of periprocedural myocardial infarction and cardiac biomarker testing after percutaneous coronary intervention in Japan: results from a multicenter registry. 査読

    Takahide Arai, Shinsuke Yuasa, Hiroaki Miyata, Akio Kawamura, Yuichiro Maekawa, Shiro Ishikawa, Shigetaka Noma, Soushin Inoue, Yuji Sato, Shun Kohsaka, Keiichi Fukuda

    Heart and vessels   28 ( 6 )   714 - 9   2013年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Periprocedural myocardial infarction (pMI) is an important complication associated with percutaneous coronary intervention (PCI). However, data on the frequency of biomarker testing and the incidence of pMI remain unclear. Using the multicenter Japan Cardiovascular Database, we identified 2182 patients who underwent PCI without preprocedural cardiac biomarker elevation (silent ischemia, stable angina, or unstable angina without biomarker elevation) from September 2008 to August 2011. Of these, 550 patients (25.2 %) underwent cardiac biomarker testing within 6-24 h after PCI. The incidence of pMI was 2.7 % among all identified patients and 7.5 % among those who underwent cardiac marker testing. Of note, cardiac biomarker testing was performed more frequently than no testing in patients with a higher risk profile such as unstable angina (32.7 vs 24.7 %, P < 0.001), higher symptom scaling (28.2 vs 22.5 %, P = 0.008), urgent or emergent procedures (19.3 vs 15.0 %, P = 0.022 or 4.2 vs 1.0 %, P < 0.001, respectively), and type C lesion (31.3 vs 25.2 %, P = 0.006). Presentation with silent ischemia (odds ratio = 1.51, 95 % confidence interval (CI) 1.16-1.97) and nonemergent PCIs (odds ratio = 3.45, 95 % CI 1.79-6.67) were associated with no postprocedural cardiac biomarker testing. The real-world multicenter PCI registry in Japan revealed an incidence of 2.7 % for pMI; however, cardiac biomarkers were assessed in only 25.2 % of patients after PCI. The results suggest an underuse of postprocedural biomarker testing and room for procedural quality improvement, particularly in cases of silent ischemia and nonemergent cases.

    DOI: 10.1007/s00380-012-0314-x

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  • Intracardiac echocardiography for percutaneous closure of atrial septal defects: initial experiences in Japan. 査読

    Sayaka Shimizu, Akio Kawamura, Takahide Arai, Yohei Ohno, Satoshi Mogi, Masaki Kodaira, Atsushi Anzai, Takashi Kawakami, Hideaki Kanazawa, Kentaro Hayashida, Shinsuke Yuasa, Yuichiro Maekawa, Keiichi Fukuda

    Cardiovascular intervention and therapeutics   28 ( 4 )   368 - 73   2013年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Transcatheter closure of secundum atrial septal defect (ASD) has been widely performed as a less invasive alternative to surgery with zero mortality so far in Japan. In the US and Europe, intracardiac echocardiography (ICE) has replaced transesophageal echocardiography (TEE) as a primary imaging tool during percutaneous ASD closure. However, the experience of ICE in ASD closure is limited in Japan. Consecutive 51 patients underwent percutaneous ASD closure with ICE guidance. Clinical results were compared to those of 41 patients who underwent ASD closure with TEE guidance. Pediatric patients and patients with multiple ASDs who were expected to need multiple devices were excluded. Success rate was similar in both groups (ICE 96.1 %, TEE 92.7 %). Catheterization laboratory time was significantly shortened with ICE than with TEE (131 vs. 155 min, p = 0.0003). There were no complications related to the use of ICE. ICE-guided ASD closure is feasible in most adult patients. ICE is superior to TEE in shortening catheterization laboratory time and eliminating general anesthesia, and can potentially replace TEE as the primary image guide during percutaneous ASD closure.

    DOI: 10.1007/s12928-013-0187-7

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  • Enhanced optineurin E50K-TBK1 interaction evokes protein insolubility and initiates familial primary open-angle glaucoma. 査読 国際誌

    Yuriko Minegishi, Daisuke Iejima, Hiroaki Kobayashi, Zai-Long Chi, Kazuhide Kawase, Tetsuya Yamamoto, Tomohisa Seki, Shinsuke Yuasa, Keiichi Fukuda, Takeshi Iwata

    Human molecular genetics   22 ( 17 )   3559 - 67   2013年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Glaucoma is the leading cause for blindness affecting 60 million people worldwide. The optineurin (OPTN) E50K mutation was first identified in familial primary open-angle glaucoma (POAG), the onset of which is not associated with intraocular pressure (IOP) elevation, and is classified as normal-tension glaucoma (NTG). Optineurin (OPTN) is a multifunctional protein and its mutations are associated with neurodegenerative diseases such as POAG and amyotrophic lateral sclerosis (ALS). We have previously described an E50K mutation-carrying transgenic (E50K-tg) mouse that exhibited glaucomatous phenotypes of decreased retinal ganglion cells (RGCs) and surrounding cell death at normal IOP. Further phenotypic analysis of these mice revealed persistent reactive gliosis and E50K mutant protein deposits in the outer plexiform layer (OPL). Over-expression of E50K in HEK293 cells indicated accumulation of insoluble OPTN in the endoplasmic reticulum (ER). This phenomenon was consistent with the results seen in neurons derived from induced pluripotent stem cells (iPSCs) from E50K mutation-carrying NTG patients. The E50K mutant strongly interacted with TANK-binding kinase 1 (TBK1), which prohibited the proper oligomerization and solubility of OPTN, both of which are important for OPTN intracellular transition. Treatment with a TBK1 inhibitor, BX795, abrogated the aberrant insolubility of the E50K mutant. Here, we delineated the intracellular dynamics of the endogenous E50K mutant protein for the first time and demonstrated how this mutation causes OPTN insolubility, in association with TBK1, to evoke POAG.

    DOI: 10.1093/hmg/ddt210

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  • Testosterone induces cardiomyocyte differentiation from embryonic stem cells. 査読 国際誌

    Hisayuki Hashimoto, Shinsuke Yuasa

    Journal of molecular and cellular cardiology   62   69 - 71   2013年9月

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  • 心房中隔欠損の経皮的閉鎖の観察のための心腔内心エコー法 日本における最初の経験(Intracardiac Echocardiography for Percutaneous Closure of Atrial Septal Defects: Initial Experiences in Japan) 査読

    河村 朗夫, 清水 清香, 荒井 隆秀, 茂木 聡, 小平 真幸, 安西 淳, 川上 崇, 林田 健太郎, 金澤 英明, 湯浅 慎介, 前川 裕一郎, 福田 恵一

    日本心臓病学会誌   8 ( Suppl.I )   385 - 385   2013年9月

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    記述言語:英語   出版者・発行元:(一社)日本心臓病学会  

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  • 肥大型閉塞性心筋症を併発したヌーナン症候群患者におけるPTSMA(PTSMA in a patient with Noonan syndrome accompanied by hypertrophic obstructive cardiomyopathy) 査読

    前川 裕一郎, 安西 淳, 湯浅 慎介, 荒井 隆秀, 小平 真幸, 茂木 聡, 林田 健太郎, 河村 朗夫, 佐野 元昭, 福田 恵一

    日本心臓病学会誌   8 ( Suppl.I )   684 - 684   2013年9月

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    記述言語:英語   出版者・発行元:(一社)日本心臓病学会  

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  • Induction of human cardiomyocyte-like cells from fibroblasts by defined factors. 査読 国際誌

    Rie Wada, Naoto Muraoka, Kohei Inagawa, Hiroyuki Yamakawa, Kazutaka Miyamoto, Taketaro Sadahiro, Tomohiko Umei, Ruri Kaneda, Tomoyuki Suzuki, Kaichiro Kamiya, Shugo Tohyama, Shinsuke Yuasa, Kiyokazu Kokaji, Ryo Aeba, Ryohei Yozu, Hiroyuki Yamagishi, Toshio Kitamura, Keiichi Fukuda, Masaki Ieda

    Proceedings of the National Academy of Sciences of the United States of America   110 ( 31 )   12667 - 72   2013年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Heart disease remains a leading cause of death worldwide. Owing to the limited regenerative capacity of heart tissue, cardiac regenerative therapy has emerged as an attractive approach. Direct reprogramming of human cardiac fibroblasts (HCFs) into cardiomyocytes may hold great potential for this purpose. We reported previously that induced cardiomyocyte-like cells (iCMs) can be directly generated from mouse cardiac fibroblasts in vitro and vivo by transduction of three transcription factors: Gata4, Mef2c, and Tbx5, collectively termed GMT. In the present study, we sought to determine whether human fibroblasts also could be converted to iCMs by defined factors. Our initial finding that GMT was not sufficient for cardiac induction in HCFs prompted us to screen for additional factors to promote cardiac reprogramming by analyzing multiple cardiac-specific gene induction with quantitative RT-PCR. The addition of Mesp1 and Myocd to GMT up-regulated a broader spectrum of cardiac genes in HCFs more efficiently compared with GMT alone. The HCFs and human dermal fibroblasts transduced with GMT, Mesp1, and Myocd (GMTMM) changed the cell morphology from a spindle shape to a rod-like or polygonal shape, expressed multiple cardiac-specific proteins, increased a broad range of cardiac genes and concomitantly suppressed fibroblast genes, and exhibited spontaneous Ca(2+) oscillations. Moreover, the cells matured to exhibit action potentials and contract synchronously in coculture with murine cardiomyocytes. A 5-ethynyl-2'-deoxyuridine assay revealed that the iCMs thus generated do not pass through a mitotic cell state. These findings demonstrate that human fibroblasts can be directly converted to iCMs by defined factors, which may facilitate future applications in regenerative medicine.

    DOI: 10.1073/pnas.1304053110

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  • 経カテーテル心房中隔欠損症治療における心腔内超音波の安全性の検討 査読

    清水 清香, 安西 淳, 小平 真幸, 茂木 聡, 荒井 隆秀, 川上 崇史, 林田 健太郎, 湯浅 慎介, 前川 裕一郎, 河村 朗夫

    日本心血管インターベンション治療学会誌   5 ( Suppl.I )   740 - 740   2013年5月

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    記述言語:日本語   出版者・発行元:(一社)日本心血管インターベンション治療学会  

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  • IVUS断線の予測因子 当院における検証 査読

    清水 清香, 茂木 聡, 安西 淳, 小平 真幸, 荒井 隆秀, 川上 崇史, 林田 健太郎, 湯浅 慎介, 前川 裕一郎, 河村 朗夫

    日本心血管インターベンション治療学会誌   5 ( Suppl.I )   717 - 717   2013年5月

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    記述言語:日本語   出版者・発行元:(一社)日本心血管インターベンション治療学会  

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  • The generation of induced pluripotent stem cells from a patient with KCNH2 G603D, without LQT2 disease associated symptom. 査読

    Shinichiro Okata, Shinsuke Yuasa, Teiichi Yamane, Tetsushi Furukawa, Keiichi Fukuda

    Journal of medical and dental sciences   60 ( 1 )   17 - 22   2013年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The long QT syndrome type 2 (LQT2) is inheritable life threatening arrhythmic disorder and one of the most common genetic variants in long QT syndrome. There are some indications for treatment of the patients with LQT2 but it is impossible to completely prevent fatal arrhythmia. To develop novel therapy for the patients with LQT2, it has been desired to generate diseasespecific and patient-specific disease model. Human induced pluripotent stem (iPS) cells are somatic cell-derived pluripotent stem cells with infinite proliferation ability and multipotency. Patient-specific iPS cells can be derived from patient somatic cells, have all genomic information encoded in patient's genome including mutation and all SNPs, and can be ideal disease models of the patients. To generate disease model for LQT2 by iPS cells, we should firstly generate iPS cells from the patient with LQT2 and confirm the genomic mutation in iPS cells. In this study, we showed the successful generation of iPS cells from a patient with KCNH2 G603D mutation. The patient specific iPS cells properly expressed stem cell markers, such as NANOG and OCT3/4. We also confirmed that the KCNH2 G603D (G1808A) mutation was taken over in patient specific iPS cells. These patient-specific iPS cells may contribute to the future analysis for disease pathogenesis and drug innovation.

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  • Distinct metabolic flow enables large-scale purification of mouse and human pluripotent stem cell-derived cardiomyocytes. 査読 国際誌

    Shugo Tohyama, Fumiyuki Hattori, Motoaki Sano, Takako Hishiki, Yoshiko Nagahata, Tomomi Matsuura, Hisayuki Hashimoto, Tomoyuki Suzuki, Hiromi Yamashita, Yusuke Satoh, Toru Egashira, Tomohisa Seki, Naoto Muraoka, Hiroyuki Yamakawa, Yasuyuki Ohgino, Tomofumi Tanaka, Masatoshi Yoichi, Shinsuke Yuasa, Mitsushige Murata, Makoto Suematsu, Keiichi Fukuda

    Cell stem cell   12 ( 1 )   127 - 37   2013年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Heart disease remains a major cause of death despite advances in medical technology. Heart-regenerative therapy that uses pluripotent stem cells (PSCs) is a potentially promising strategy for patients with heart disease, but the inability to generate highly purified cardiomyocytes in sufficient quantities has been a barrier to realizing this potential. Here, we report a nongenetic method for mass-producing cardiomyocytes from mouse and human PSC derivatives that is based on the marked biochemical differences in glucose and lactate metabolism between cardiomyocytes and noncardiomyocytes, including undifferentiated cells. We cultured PSC derivatives with glucose-depleted culture medium containing abundant lactate and found that only cardiomyocytes survived. Using this approach, we obtained cardiomyocytes of up to 99% purity that did not form tumors after transplantation. We believe that our technological method broadens the range of potential applications for purified PSC-derived cardiomyocytes and could facilitate progress toward PSC-based cardiac regenerative therapy.

    DOI: 10.1016/j.stem.2012.09.013

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  • Acute coronary syndrome or apical ballooning syndrome? 査読

    Yuichiro Maekawa, Akio Kawamura, Shinsuke Yuasa, Yohei Ohno, Takahide Arai, Keiichi Fukuda

    Heart and vessels   28 ( 1 )   130 - 3   2013年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Apical ballooning syndrome (ABS) is uniquely characterized by the acute onset of transient extensive kinesis of the apical and mid portions of the left ventricle without significant epicardial coronary artery stenosis, accompanied by chest symptoms and electrocardiogram changes similar to those of acute coronary syndrome. We report a case of ABS with severe coronary artery stenosis presenting as acute coronary syndrome after emotional stress. ABS should be considered a cause of left ventricular wall motion abnormalities even if a coronary arteriogram shows severe coronary artery stenosis.

    DOI: 10.1007/s00380-012-0242-9

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  • Application of iPS cells for cardiovascular medicine 査読

    Keiichi Fukuda, Tomohisa Seki, Shugo Tohyama, Shinsuke Yuasa

    JOURNAL OF PHARMACOLOGICAL SCIENCES   121   4P - 4P   2013年

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    記述言語:英語   出版者・発行元:JAPANESE PHARMACOLOGICAL SOC  

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  • Novel insights into disease modeling using induced pluripotent stem cells. 査読

    Toru Egashira, Shinsuke Yuasa, Keiichi Fukuda

    Biological & pharmaceutical bulletin   36 ( 2 )   182 - 8   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Induced pluripotent stem cell (iPSC) technology has great potential to establish novel therapeutic approaches in regenerative medicine and disease analysis. Although cell therapy using iPSC-derived cells still has many hurdles to overcome before clinical applications, disease analysis using patient-specific iPSCs may be of practical use in the near future. There are several reports that patient-specific iPSC-derived cells have recapitulated the apparent cellular phenotypes of a wide variety of diseases. Moreover, some studies revealed that it could be possible to discover effective new drugs and to clarify disease pathogenesis by examination of patient-specific iPSC-derived cells in vitro. We have recently reported that iPSCs can be a diagnostic tool in a patient with a novel mutation. For definitive diagnosis in a patient with long QT syndrome who had an uncharacterized genetic mutation, we succeeded in clarifying the patient's cellular electrophysiologic characteristics and the molecular mechanism underlying the disease phenotype through the multifaceted analyses of patient-specific iPSC-derived cardiomyocytes. In this review, we focus on the conceptual and practical issues in disease modeling using patient-specific iPSCs and discuss future directions in this research field.

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  • Distinct iPS Cells Show Different Cardiac Differentiation Efficiency. 査読 国際誌

    Yohei Ohno, Shinsuke Yuasa, Toru Egashira, Tomohisa Seki, Hisayuki Hashimoto, Shugo Tohyama, Yuki Saito, Akira Kunitomi, Kenichiro Shimoji, Takeshi Onizuka, Toshimi Kageyama, Kojiro Yae, Tomofumi Tanaka, Ruri Kaneda, Fumiyuki Hattori, Mitsushige Murata, Kensuke Kimura, Keiichi Fukuda

    Stem cells international   2013   659739 - 659739   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Patient-specific induced pluripotent stem (iPS) cells can be generated by introducing transcription factors that are highly expressed in embryonic stem (ES) cells into somatic cells. This opens up new possibilities for cell transplantation-based regenerative medicine by overcoming the ethical issues and immunological problems associated with ES cells. Despite the development of various methods for the generation of iPS cells that have resulted in increased efficiency, safety, and general versatility, it remains unknown which types of iPS cells are suitable for clinical use. Therefore, the aims of the present study were to assess (1) the differentiation potential, time course, and efficiency of different types of iPS cell lines to differentiate into cardiomyocytes in vitro and (2) the properties of the iPS cell-derived cardiomyocytes. We found that high-quality iPS cells exhibited better cardiomyocyte differentiation in terms of the time course and efficiency of differentiation than low-quality iPS cells, which hardly ever differentiated into cardiomyocytes. Because of the different properties of the various iPS cell lines such as cardiac differentiation efficiency and potential safety hazards, newly established iPS cell lines must be characterized prior to their use in cardiac regenerative medicine.

    DOI: 10.1155/2013/659739

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  • Loss of Function of Heat Shock Protein 60 (hsp60) Increases Susceptibility to Atrioventricular (av) Block 査読

    Hirokazu Enomoto, Shinji Makino, Yuta Higashikuse, Takuro Arimura, Sung H. Yoon, Toshimi Kageyama, Mayumi Oda, Motoaki Sano, Shinsuke Yuasa, Ruri Kaneda, Mitsushige Murata, Fumiyuki Hattori, Atsushi Kawakami, Akira Kudo, Akinori Kimura, Takayuki Inomata, Keiichi Fukuda

    CIRCULATION   126 ( 21 )   2012年11月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • miR-142-3p is essential for hematopoiesis and affects cardiac cell fate in zebrafish. 査読 国際誌

    Takahiko Nishiyama, Ruri Kaneda, Tomohiko Ono, Shugo Tohyama, Hisayuki Hashimoto, Jin Endo, Hikaru Tsuruta, Shinsuke Yuasa, Masaki Ieda, Shinji Makino, Keiichi Fukuda

    Biochemical and biophysical research communications   425 ( 4 )   755 - 61   2012年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    MicroRNAs (miRNAs) play a pivotal role during embryonic development and are required for proper organogenesis, including hematopoiesis. Recent studies suggest that, in the early mesoderm, there is an interaction between the hematopoietic and cardiac lineages. However, whether miRNAs can affect other lineages remains unknown. Therefore, we investigated whether hematopoietic miR-142-3p modulated the mesoderm formation. We report that knockdown (KD) of miR-142-3p, a hematopoietic-specific miRNA, in zebrafish resulted in loss of hematopoiesis during embryonic development. Intriguingly, we observed abnormal cardiac phenotypes and insufficiency of somitegenesis in KD-morphants. In the early developmental stage, a tiny heart, contractile dysfunction in the ventricle, cardiac arrhythmia (e.g. a 2:1 ratio of atrial:ventricular beating), and bradycardia were consistently observed. Histological examination revealed severe hypoplasia of the ventricle and disrupted muscle alignment. To determine the mechanism, we performed DNA microarray analysis. The results revealed that the expression of several mesodermal genes essential for the formation of cardiac and somatic mesoderm, such as no tail, T-box gene 16, mesoderm posterior a, one eye pinhead, and rho-associated, coiled-coil containing protein kinase (Rock2a), were increased in miR-142-3p KD-morphants. The luciferase reporter assay revealed that miR-142-3p repressed luciferase activity on the Rock2a 3'-UTR. The findings of the present study indicate that miR-142-3p plays a critical role in hematopoiesis, cardiogenesis, and somitegenesis in the early stage of mesoderm formation via regulation of Rock2a.

    DOI: 10.1016/j.bbrc.2012.07.148

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  • Disease characterization using LQTS-specific induced pluripotent stem cells. 査読 国際誌

    Toru Egashira, Shinsuke Yuasa, Tomoyuki Suzuki, Yoshiyasu Aizawa, Hiroyuki Yamakawa, Tomohiro Matsuhashi, Yohei Ohno, Shugo Tohyama, Shinichiro Okata, Tomohisa Seki, Yusuke Kuroda, Kojiro Yae, Hisayuki Hashimoto, Tomofumi Tanaka, Fumiyuki Hattori, Toshiaki Sato, Shunichiro Miyoshi, Seiji Takatsuki, Mitsushige Murata, Junko Kurokawa, Tetsushi Furukawa, Naomasa Makita, Takeshi Aiba, Wataru Shimizu, Minoru Horie, Kaichiro Kamiya, Itsuo Kodama, Satoshi Ogawa, Keiichi Fukuda

    Cardiovascular research   95 ( 4 )   419 - 29   2012年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    AIMS: Long QT syndrome (LQTS) is an inheritable and life-threatening disease; however, it is often difficult to determine disease characteristics in sporadic cases with novel mutations, and more precise analysis is necessary for the successful development of evidence-based clinical therapies. This study thus sought to better characterize ion channel cardiac disorders using induced pluripotent stem cells (iPSCs). METHODS AND RESULTS: We reprogrammed somatic cells from a patient with sporadic LQTS and from controls, and differentiated them into cardiomyocytes through embryoid body (EB) formation. Electrophysiological analysis of the LQTS-iPSC-derived EBs using a multi-electrode array (MEA) system revealed a markedly prolonged field potential duration (FPD). The IKr blocker E4031 significantly prolonged FPD in control- and LQTS-iPSC-derived EBs and induced frequent severe arrhythmia only in LQTS-iPSC-derived EBs. The IKs blocker chromanol 293B did not prolong FPD in the LQTS-iPSC-derived EBs, but significantly prolonged FPD in the control EBs, suggesting the involvement of IKs disturbance in the patient. Patch-clamp analysis and immunostaining confirmed a dominant-negative role for 1893delC in IKs channels due to a trafficking deficiency in iPSC-derived cardiomyocytes and human embryonic kidney (HEK) cells. CONCLUSIONS: This study demonstrated that iPSCs could be useful to characterize LQTS disease as well as drug responses in the LQTS patient with a novel mutation. Such analyses may in turn lead to future progress in personalized medicine.

    DOI: 10.1093/cvr/cvs206

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  • A case of severe aortic stenosis with severe coronary artery disease that was successfully treated by balloon aortic valvuloplasty and percutaneous coronary intervention. 査読

    Yuichiro Maekawa, Akio Kawamura, Akira Furuta, Shinsuke Yuasa, Keiichi Fukuda

    Heart and vessels   27 ( 5 )   528 - 31   2012年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We describe an 85-year-old woman with severe aortic stenosis, who also had severe coronary artery disease. She suffered from dyspnea on exertion and frequent syncope. Echocardiography revealed an immobile and heavily calcified aortic valve, and coronary angiography revealed two-vessel disease including chronic total occlusion. Open-heart surgery was refused and she was referred to our department. She underwent percutaneous coronary intervention (PCI) for the right coronary artery and left anterior descending artery. Following PCI, percutaneous balloon aortic valvuloplasty (BAV) was performed on the same day. We chose balloons of 15 × 60 mm, 18 × 60 mm, and 20 × 60 mm, respectively. Improvement in the mean aortic valve pressure gradient (PG) and calculated aortic valve area (mean PG 48-23 mmHg, 0.8-1.2 cm(2), respectively) was observed after the final balloon dilatation. No significant complications occurred. The combination of BAV with PCI may be a useful treatment for relief of the associated symptoms of severe aortic stenosis and coronary artery disease, though it does not improve the long-term prognosis.

    DOI: 10.1007/s00380-011-0208-3

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  • 家族性WPW症候群の1家系における臨床像の検討

    稲川 浩平, 相澤 義泰, 高月 誠司, 勝俣 良紀, 西山 崇比古, 木村 雄弘, 西山 信大, 福本 耕太郎, 谷本 陽子, 谷本 耕司郎, 湯浅 慎介, 西森 健雄, 稲垣 雅行, 有村 卓朗, 木村 彰方, 三田村 秀雄, 福田 恵一

    心電図   32 ( Suppl.5 )   S - 155   2012年9月

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    記述言語:日本語   出版者・発行元:(一社)日本不整脈心電学会  

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  • 心房中隔欠損に対する血管内閉鎖術中の心腔内超音波AcuNav パイロットスタディ(Intra-Cardiac Ultrasound AcuNav in Endovascular Closure of Atrial Septal Defect: Pilot Study) 査読

    河村 朗夫, 河野 一樹, 茂木 聡, 安西 淳, 小平 真幸, 荒井 隆秀, 鶴田 ひかる, 村田 光繁, 湯浅 慎介, 前川 裕一郎, 福田 恵一

    日本心臓病学会誌   7 ( Suppl.I )   367 - 367   2012年8月

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    記述言語:英語   出版者・発行元:(一社)日本心臓病学会  

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  • ステント留置後の長期管理 ステント留置を行った急性冠症候群症例における高齢者の薬物療法の現況 査読

    前川 裕一郎, 湯浅 慎介, 荒井 隆秀, 大野 洋平, 高橋 賢至, 茂木 聡, 小平 真幸, 安西 淳, 河村 朗夫, 福田 恵一

    日本心臓病学会誌   7 ( Suppl.I )   156 - 156   2012年8月

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    記述言語:日本語   出版者・発行元:(一社)日本心臓病学会  

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  • 心房中隔欠損閉鎖術後5ヶ月目のAmplatzer心房中隔欠損閉鎖栓の不完全な内皮化(Incomplete Endothelialization of Amplatzer Septal Occluder Device at 5 Months After Closure of Atrial Septal Defect) 査読

    河村 朗夫, 氣賀澤 秀明, 佐藤 徹, 前川 裕一郎, 湯浅 慎介, 荒井 隆秀, 大野 洋平, 高橋 賢至, 茂木 聡, 安西 淳, 小平 真幸, 菅間 博, 福田 恵一

    日本心臓病学会誌   7 ( Suppl.I )   282 - 282   2012年8月

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    記述言語:英語   出版者・発行元:(一社)日本心臓病学会  

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  • Successful percutaneous coil embolization of coronary-pulmonary, -carotid, and -internal mammary artery fistulas. 査読

    Yohei Numasawa, Akio Kawamura, Subaru Hashimoto, Ayaka Endo, Shinsuke Yuasa, Yuichiro Maekawa, Sachio Kuribayashi, Keiichi Fukuda

    Heart and vessels   27 ( 3 )   331 - 6   2012年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We herein describe a 57-year-old man with coronary-pulmonary artery fistulas that had abnormal connections between the left common carotid artery and the left internal mammary artery. The patient was treated with percutaneous coil embolization using antegrade (via the coronary artery) and retrograde (via the pulmonary artery) approaches. Coronary artery fistulas have diverse anatomical variations, and it is important to thoroughly evaluate the anatomy before beginning any mode of treatment, surgical or endovascular. In the case reported herein, multislice computed tomography played a pivotal role in the preprocedure evaluation.

    DOI: 10.1007/s00380-011-0172-y

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  • Successful coronary intervention of chronic total occlusion of the right coronary artery by ipsilateral injection via an isolated conus artery. 査読

    Takahide Arai, Akio Kawamura, Shinsuke Yuasa, Yuichiro Maekawa, Keiichi Fukuda

    Heart and vessels   27 ( 3 )   327 - 30   2012年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A conus artery is sometimes a good collateral source for the left anterior descending coronary artery and the right coronary artery (RCA). In some cases, the conus artery arises independently of the RCA from a separate orifice, which is called an isolated conus artery. The conus artery is often missed by angiography for RCA if a catheter is deeply engaged. This case report describes a percutaneous coronary intervention of chronic total occlusion of the proximal RCA with good collateral circulation from an isolated conus artery by super-selective ipsilateral injection via the artery.

    DOI: 10.1007/s00380-011-0170-0

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  • Effect of preoperative evaluation by multidetector computed tomography in percutaneous coronary interventions of chronic total occlusions. 査読 国際誌

    Koji Ueno, Akio Kawamura, Takeshi Onizuka, Takashi Kawakami, Yuji Nagatomo, Kentaro Hayashida, Shinsuke Yuasa, Yuichiro Maekawa, Toshihisa Anzai, Masahiro Jinzaki, Sachio Kuribayashi, Satoshi Ogawa

    International journal of cardiology   156 ( 1 )   76 - 9   2012年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: The prevalence of success of percutaneous coronary interventions (PCIs) of chronic total occlusions (CTOs) remains relatively low. We determined the effect of preoperative multidetector computed tomography coronary angiography (CTCA) in PCIs of CTOs. METHODS: The study population was 100 consecutive patients who underwent PCIs of CTOs from January 2005 to December 2007 at Keio University School of Medicine. They were divided into two groups according to the absence (non-CT group, n=60) or presence (CT group, n=40) of preoperative CTCA. The effect of preoperative CTCA was assessed in the prevalence of success of the procedure, prevalence of complications, irradiation time, and the dose of contrast agents. RESULTS: The prevalence of procedural success was similar in both groups (non-CT group vs CT group 80.0% vs 77.5%, p=0.76). Irradiation time and the dose of contrast agents were also similar between these groups. The prevalence of complications was significantly reduced in the CT group (23.3% vs 7.5%, p=0.039), especially coronary perforations, which required treatment only in the non-CT group (10.0% vs 0.0%, p=0.039). Multiple logistic regression analysis revealed that use of a rotablator (odds ratio [OR]: 4.40, 95% confidence interval [CI]: 1.19-16.27, p=0.027) and absence of preoperative CTCA (OR: 4.26, 95% CI: 1.04-17.49, p=0.044) were independent determinants of complications. CONCLUSION: Preoperative CTCA does not affect the prevalence of procedural success, irradiation time and the dose of contrast agents, but may be useful to reduce the prevalence of complications during PCIs of CTOs.

    DOI: 10.1016/j.ijcard.2010.10.026

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  • Generation of induced pluripotent stem cells from a small amount of human peripheral blood using a combination of activated T cells and Sendai virus. 査読 国際誌

    Tomohisa Seki, Shinsuke Yuasa, Keiichi Fukuda

    Nature protocols   7 ( 4 )   718 - 28   2012年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Induced pluripotent stem cells (iPSCs) have become important cell sources for genetic disease models, and they have the potential to be cell sources for future clinical therapies. However, invasive tissue sampling reduces the number of candidates who consent to donate cells for iPSC generation. In addition, integrated transgenes can potentially insert at inappropriate points in the genome, and in turn have a direct oncogenic effect. Technical modifications using a combination of activated T cells and a temperature-sensitive mutant of Sendai virus (SeV) can avoid invasive tissue sampling and residual transgene issues in generating iPSCs. Such advances may increase the number of consenting patients for cell donations. Here we present a detailed protocol for the generation of iPSCs from a small amount of human peripheral blood using a combination of activated T cells and mutant SeV encoding human OCT3/4, SOX2, KLF4 and c-MYC; T cell-derived iPSCs can be generated within 1 month of blood sampling.

    DOI: 10.1038/nprot.2012.015

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  • RESIDUAL TRANSGENE EXPRESSION OF YAMANAKA FACTORS DETERMINE QUALITY AND DIFFERENTIATION EFFICIENCY OF CARDIOMYOCYTES DERIVED FROM MOUSE INDUCED PLURIPOTENT STEM CELL LINES 査読

    Yohei Ohno, Shinsuke Yuasa, Toru Egashira, Tomohisa Seki, Hisayuki Hashimoto, Shugo Tohyama, Masaki Kodaira, Dai Kusumoto, Fumiyuki Hattori, Kojiro Yae, Mitsushige Murata, Keiichi Fukuda

    JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY   59 ( 13 )   E1001 - E1001   2012年3月

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    記述言語:英語   出版者・発行元:ELSEVIER SCIENCE INC  

    DOI: 10.1016/S0735-1097(12)61002-X

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  • Wnt2 accelerates cardiac myocyte differentiation from ES-cell derived mesodermal cells via non-canonical pathway. 査読 国際誌

    Takeshi Onizuka, Shinsuke Yuasa, Dai Kusumoto, Kenichiro Shimoji, Toru Egashira, Yohei Ohno, Toshimi Kageyama, Tomofumi Tanaka, Fumiyuki Hattori, Jun Fujita, Masaki Ieda, Kensuke Kimura, Shinji Makino, Motoaki Sano, Akira Kudo, Keiichi Fukuda

    Journal of molecular and cellular cardiology   52 ( 3 )   650 - 9   2012年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The efficient induction of cardiomyocyte differentiation from embryonic stem (ES) cells is crucial for cardiac regenerative medicine. Although Wnts play important roles in cardiac development, complex questions remain as to when, how and what types of Wnts are involved in cardiogenesis. We found that Wnt2 was strongly up-regulated during cardiomyocyte differentiation from ES cells. Therefore, we investigated when and how Wnt2 acts in cardiogenesis during ES cell differentiation. Wnt2 was strongly expressed in the early developing murine heart. We applied this embryonic Wnt2 expression pattern to ES cell differentiation, to elucidate Wnt2 function in cardiomyocyte differentiation. Wnt2 knockdown revealed that intrinsic Wnt2 was essential for efficient cardiomyocyte differentiation from ES cells. Moreover, exogenous Wnt2 increased cardiomyocyte differentiation from ES cells. Interestingly, the effects on cardiogenesis of intrinsic Wnt2 knockdown and exogenous Wnt2 addition were temporally restricted. During cardiomyocyte differentiation from ES cells, Wnt2 didn't activate canonical Wnt pathway but utilizes JNK/AP-1 pathway which is required for cardiomyocyte differentiation from ES cells. Therefore we conclude that Wnt2 plays strong positive stage-specific role in cardiogenesis through non-canonical Wnt pathway in murine ES cells.

    DOI: 10.1016/j.yjmcc.2011.11.010

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  • 成人心房中隔欠損患者のAmplatzer Septal Occluder術前の心電図所見の特徴(Electrocardiographic Findings of Adult Patients with Atrial Septal Defect Referred for Amplatzer Septal Occluder)

    河村 朗夫, 前川 裕一郎, 湯浅 慎介, 大野 洋平, 荒井 隆秀, 田村 雄一, 村田 光繁, 鶴田 ひかる, 高橋 賢至, 四津 良平, 福田 恵一

    日本成人先天性心疾患学会雑誌   1 ( 1 )   74 - 74   2012年1月

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    記述言語:英語   出版者・発行元:日本成人先天性心疾患学会  

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  • Direct comparison of Takotsubo cardiomyopathy between Japan and USA: 3-year follow-up study. 査読

    Yuichiro Maekawa, Akio Kawamura, Shinsuke Yuasa, Richard W Nesto, Keiichi Fukuda

    Internal medicine (Tokyo, Japan)   51 ( 3 )   257 - 62   2012年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: Takotsubo cardiomyopathy (TC) mimics myocardial infarction and is well defined and known to not only Japan but also western countries. However, whether or not there are differences in the characteristics of TC between Japan and USA remains unknown. PATIENTS: Data for patients who had undergone urgent left heart catheterization for suspected acute coronary syndrome were retrospectively retrieved from Keio University School of Medicine (KUSM) database in Japan and Lahey Clinic Medical Center (LCMC) database in USA between 2002 and 2007. RESULTS: During the study period, 626 coronary angiographies were performed in KUSM and 1,880 coronary angiographies were performed in LCMC. Twelve patients in Japan and 34 patients in USA met the inclusion criteria. Mean age of patients in Japan was 75 years where 92% were women, compared to 67 years and 94% women in USA. Although the prevalence of hypertension, dyslipidemia and diabetes mellitus were similar between Japan and USA, there was a trend towards fewer patients in Japan displaying a history of coronary revascularization. Surprisingly, a family history of premature coronary artery disease (CAD) was present in 21% of USA patients, whereas no patients were present in Japan. There were no differences in the incidence of readmission for heart failure, cardiac death and TC recurrence during the follow-up period. CONCLUSION: Patients with TC in Japan have fewer prior overt CAD and fewer family history of premature CAD, but no significant differences were found in the long-term prognosis and the recurrence rate between patients in Japan and USA.

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  • Effect of fulvic acid on ultraviolet induced skin aging: The effect of fulvic acid on fibroblasts and matrix metalloproteinase 査読

    Hisako Kinoshita, Masayoshi Kinoshita, Akiyo Takahashi, Shinsuke Yuasa, Keiichi Fukuda

    Nishinihon Journal of Dermatology   74 ( 4 )   427 - 431   2012年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    Since skin is the most superficial organ, skin aging is a complex process resulting from not only intrinsic factors (passage of time and genetic factors) but also extrinsic factors (UV irradiation and environmental pollutants). Important reasons for skin aging, such as wrinkling, sagging, and laxity, are a decreased number of fibroblasts and decreased synthesis of extracellular proteins in the dermis, as well as increased degradation of the collagenous matrix from UV irradiation and other environmental stresses. Fulvic acid is derived from humic substances, which are formed naturally during the decay of plant and animal residues. Fulvic acid has been shown to have chelating activity, to act as buffer solution, to have antimicrobial activity in vitro and to have an effect in treatment of eczema in vivo. We investigated the effect of fulvic acid on fibroblasts and matrix metalloproteinases (MMPs), which are responsible for degradation of collagen. Normal adult fibroblasts and calcein-AM were used in a cell viability study, and FITC-labeled collagen was used to evaluate MMP activity and inhibitory effect of fulvic acid. A concentration of 1% fulvic acid increased cell viability by 26.1% when compared with a control, and 5% fulvic acid did not show any cytotoxicity. In the presence of 0.25 units of MMP-8, the inhibition of collagen degradation was 47% in 1% fulvic acid (P &lt
    0.01) and 61% in 5% fulvic acid (P &lt
    0.01), and in the presence of 0.5 units of MMP-8, the inhibition of collagen degradation was 23% in 1% fulvic acid (P &lt
    0.01) and 56% in 5% fulvic acid (P &lt
    0.01). Our study suggests the possibility of an anti-aging effect of fulvic acid due to an increase in fibroblast viability and a prevention of collagen degradation.

    DOI: 10.2336/nishinihonhifu.74.427

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  • Outcomes of intravascular ultrasound-guided percutaneous coronary intervention with drug-eluting stents versus bare metal stents for acute coronary syndrome in octogenarians. 査読 国際誌

    Yuichiro Maekawa, Akio Kawamura, Shinsuke Yuasa, Yohei Ohno, Takahide Arai, Yohei Numasawa, Ayaka Endo, Keiichi Fukuda

    Angiology   62 ( 8 )   620 - 4   2011年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The number of percutaneous coronary interventions (PCI) performed for octogenarians with acute coronary syndrome (ACS) continue to increase. The short- and long-term outcomes of intravascular ultrasound (IVUS)-guided PCI with drug-eluting stents (DES) or bare metal stents (BMS) for ACS in octogenarians, however, remain largely unknown. We analyzed clinical outcomes of octogenarians undergoing IVUS-guided PCI for ACS with either DES or BMS. During the study period, a total of 776 patients with ACS underwent IVUS-guided PCI and 75 of them were octogenarians. In-hospital mortality tended to be lower in the DES group than in the BMS group. Between 6 months and 1 year of follow up, treatment with DES compared with BMS tended to result in fewer target lesion revascularizations. Major adverse cardiac events were similar between patients receiving DES and BMS. In octogenarians with ACS treated with IVUS-guided PCI, DES appears as safe as BMS, providing similar short- and long-term outcomes.

    DOI: 10.1177/0003319711403733

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  • Derivation of induced pluripotent stem cells from human peripheral circulating T cells. 査読 国際誌

    Tomohisa Seki, Shinsuke Yuasa, Keiichi Fukuda

    Current protocols in stem cell biology   Chapter 4   Unit4A.3   2011年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    This unit describes a protocol for the generation of induced pluripotent stem (iPS) cells from human peripheral circulating T cells. Initially, human dermal fibroblasts and retroviral vectors were used to generate human iPS cells. Invasive approaches, such as skin biopsy, and genomic insertion of transgenes into the host genome are not appropriate for routine clinical application. Peripheral circulating T cells are readily available from blood samples of patients and healthy volunteers. For the efficient generation of human iPS cells, efficient introduction of the transgene into host cells is necessary. Using a combination of activated T cell culture and Sendai virus allows for the easy and efficient introduction of transgenes into activated T cells and the generation of human iPS cells without genomic integration of extrinsic genes. The T cell-derived iPS (TiPS) cells exhibit monoclonal T cell receptor (TCR) rearrangement in their genome, a hallmark of mature terminally differentiated T cells.

    DOI: 10.1002/9780470151808.sc04a03s18

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  • G-CSF influences mouse skeletal muscle development and regeneration by stimulating myoblast proliferation. 査読 国際誌

    Mie Hara, Shinsuke Yuasa, Kenichiro Shimoji, Takeshi Onizuka, Nozomi Hayashiji, Yohei Ohno, Takahide Arai, Fumiyuki Hattori, Ruri Kaneda, Kensuke Kimura, Shinji Makino, Motoaki Sano, Keiichi Fukuda

    The Journal of experimental medicine   208 ( 4 )   715 - 27   2011年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    After skeletal muscle injury, neutrophils, monocytes, and macrophages infiltrate the damaged area; this is followed by rapid proliferation of myoblasts derived from muscle stem cells (also called satellite cells). Although it is known that inflammation triggers skeletal muscle regeneration, the underlying molecular mechanisms remain incompletely understood. In this study, we show that granulocyte colony-stimulating factor (G-CSF) receptor (G-CSFR) is expressed in developing somites. G-CSFR and G-CSF were expressed in myoblasts of mouse embryos during the midgestational stage but not in mature myocytes. Furthermore, G-CSFR was specifically but transiently expressed in regenerating myocytes present in injured adult mouse skeletal muscle. Neutralization of endogenous G-CSF with a blocking antibody impaired the regeneration process, whereas exogenous G-CSF supported muscle regeneration by promoting the proliferation of regenerating myoblasts. Furthermore, muscle regeneration was markedly impaired in G-CSFR-knockout mice. These findings indicate that G-CSF is crucial for skeletal myocyte development and regeneration and demonstrate the importance of inflammation-mediated induction of muscle regeneration.

    DOI: 10.1084/jem.20101059

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  • Neural crest-derived stem cells migrate and differentiate into cardiomyocytes after myocardial infarction. 査読 国際誌

    Yuichi Tamura, Keisuke Matsumura, Motoaki Sano, Hidenori Tabata, Kensuke Kimura, Masaki Ieda, Takahide Arai, Yohei Ohno, Hideaki Kanazawa, Shinsuke Yuasa, Ruri Kaneda, Shinji Makino, Kazunori Nakajima, Hideyuki Okano, Keiichi Fukuda

    Arteriosclerosis, thrombosis, and vascular biology   31 ( 3 )   582 - 9   2011年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: We recently demonstrated that primitive neural crest-derived (NC) cells migrate from the cardiac neural crest during embryonic development and remain in the heart as dormant stem cells, with the capacity to differentiate into various cell types, including cardiomyocytes. Here, we examined the migration and differentiation potential of these cells on myocardial infarction (MI). METHODS AND RESULTS: We obtained double-transgenic mice by crossing protein-0 promoter-Cre mice with Floxed-enhanced green fluorescent protein mice, in which the NC cells express enhanced green fluorescent protein. In the neonatal heart, NC stem cells (NCSCs) were localized predominantly in the outflow tract, but they were also distributed in a gradient from base to apex throughout the ventricular myocardium. Time-lapse video analysis revealed that the NCSCs were migratory. Some NCSCs persisted in the adult heart. On MI, NCSCs accumulated at the ischemic border zone area (BZA), which expresses monocyte chemoattractant protein-1 (MCP-1). Ex vivo cell migration assays demonstrated that MCP-1 induced NCSC migration and that this chemotactic effect was significantly depressed by an anti-MCP-1 antibody. Small NC cardiomyocytes first appeared in the BZA 2 weeks post-MI and gradually increased in number thereafter. CONCLUSIONS: These results suggested that NCSCs migrate into the BZA via MCP-1/CCR2 signaling and contribute to the provision of cardiomyocytes for cardiac regeneration after MI.

    DOI: 10.1161/ATVBAHA.110.214726

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  • メダカおよびヒトではtitinのMバンド領域におけるミスセンス変異が拡張型心筋症の原因となる(Missense Mutation in the M-band Region of titin Leads to Hypertrophic Cardiomyopathy in Medaka Fish and Human)

    Higashikuse Yuta, Makino Shinji, Yoon Sung Han, Oda Mayumi, Kageyama Toshimi, Yuasa Shinsuke, Kaneda Ruri, Murata Mitsushige, Sano Motoaki, Kudo Akira, Kawakami Atsushi, Kimura Akinori, Arimura Takuro, Morizane Shintaro, Suzuki Takeshi, Fukuda Keiichi

    Circulation Journal   75 ( Suppl.I )   127 - 127   2011年3月

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    記述言語:英語   出版者・発行元:(一社)日本循環器学会  

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  • Simple autogeneic feeder cell preparation for pluripotent stem cells. 査読 国際誌

    Weizhen Li, Hiromi Yamashita, Fumiyuki Hattori, Hao Chen, Shugo Tohyama, Yusuke Satoh, Erika Sasaki, Shinsuke Yuasa, Shinji Makino, Motoaki Sano, Keiichi Fukuda

    Stem cell research   6 ( 1 )   83 - 9   2011年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Mouse embryonic fibroblasts (MEFs) are the most commonly used feeder cells for pluripotent stem cells. However, autogeneic feeder (AF) cells have several advantages such as no xenogeneic risks and reduced costs. In this report, we demonstrate that common marmoset embryonic stem (cmES) cells can be maintained on common marmoset AF (cmAF) cells. These cmES cells were maintained on cmAF cells for 6 months, retaining their morphology, normal karyotype, and expression patterns for the pluripotent markers Oct-3/4, Nanog, SSEA-3, SSEA-4, TRA-1-60, and TRA-1-81, as well as their ability to differentiate into cardiac and neural cells. Antibody array analysis revealed equivalent protein expression profiles between cmES cells maintained on cmAF cells and MEFs. In addition, similarly prepared human embryonic stem (hES) and induced pluripotent stem (hiPS) cell-derived AF cells supported the growth of and maintained the morphology and pluripotent marker expressions of hES and hiPS cells, respectively. DNA microarray analysis revealed that these hES and hiPS cells had mRNA expression profiles similar to those of hES and hiPS cells maintained on MEFs, respectively. Taken together, these findings imply that AF cells can replace MEFs in the routine maintenance of primate pluripotent stem cells.

    DOI: 10.1016/j.scr.2010.09.003

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  • Induced pluripotent stem cells in cardiovascular medicine. 査読 国際誌

    Toru Egashira, Shinsuke Yuasa, Keiichi Fukuda

    Stem cells international   2011   348960 - 348960   2011年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Induced pluripotent stem (iPS) cells are generated by reprogramming human somatic cells through the forced expression of several embryonic stem (ES) cell-specific transcription factors. The potential of iPS cells is having a significant impact on regenerative medicine, with the promise of infinite self-renewal, differentiation into multiple cell types, and no problems concerning ethics or immunological rejection. Human iPS cells are currently generated by transgene introduction principally through viral vectors, which integrate into host genomes, although the associated risk of tumorigenesis is driving research into nonintegration methods. Techniques for pluripotent stem cell differentiation and purification to yield cardiomyocytes are also advancing constantly. Although there remain some unsolved problems, cardiomyocyte transplantation may be a reality in the future. After those problems will be solved, applications of human iPS cells in human cardiovascular regenerative medicine will be envisaged for the future. Furthermore, iPS cell technology has generated new human disease models using disease-specific cells. This paper summarizes the progress of iPS cell technology in cardiovascular research.

    DOI: 10.4061/2011/348960

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  • The Overexpression of S105N Mutant Rad Leads Intracellular Ca2+ Overload Via Up-Regulation of Cardiac Ryanodine Receptor Activity 査読

    Hiroyuki Yamakawa, Mitsushige Murata, Hirotaka Yada, Mika Mizusawa, Shugo Tohyama, Yasuyuki Ohgino, Shinsuke Yuasa, Shinji Makino, Motoaki Sano, Keiichi Fukuda, Tomoyuki Suzuki, Kaichiro Kamiya

    journal of arrhythmia   27 ( 4 )   275   2011年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: The ras-related small G-protein Rad was originally identified from skeletal muscle of patients with type 2 diabetes mellitus. We have recently reported that Rad plays a critical role in generating arrhythmias. The study was aimed to elucidate the role of Rad in intracellular calcium homeostasis. Methods and Reslts: We developed the transgenic mice that overexpress S105N mutant Rad driven by α-myosin heavy chain promoter. We mesure intracellular Ca concentration ([Ca2+]I) from isolated cardiomyocytes by confocal microscopy. The amplitude of [Ca2+]I transient was significantly increased in S105N-Rad-TG cardiomyocytes, compared with littermate. Furthermore, the Ca2+ sparks and the spontaneous Ca2+ waves occurred with greater frequency in S105N-Rad-TG cells, implicating the enhanced activity of SERCA. We recorded L-type calcium currents (ICa-L) and action potentials (APs) from isolated cardiomyocytes using whole cell patch-clamp technique. The peak ICa-L was dramatically larger in the S105N-Rad-TG cells than in littermate. Early afterdepolarization (EAD) and delayed afterdepolarization (DAD) were frequently observed in S105N-Rad-TG. Then, the phosphorylation of RYR2 at Ser2809 and PKA was significantly enhanced in S105N-Rad-TG by Western blot. Conclusions: Our results provided the first evidence that Rad might regulate RYR2 activity possibly via downstream of PKA signaling pathway. © 2011, Japanese Heart Rhythm Society. All rights reserved.

    DOI: 10.4020/jhrs.27.OP32_5

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  • Application of Human iPS Cell-Technologies to Arrhythmia Researches 査読

    Mitsushige Murata, Toru Egashira, Kojiro Yae, Shinsuke Yuasa, Keiichi Fukuda

    Journal of Arrhythmia   27   2011年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The possibility of modeling human diseases has been a potential in regenerative medicine. Disease modeling especially using human induced pluripotent stem (hiPS) cell is highly applicable for the novel approaches to analyze genetic cardiovascular diseases. Although the inherited fatal arrhythmogenic diseases including long QT syndrome (LQTs) have been characterized by their clinical as well as genomic phenotypes, further investigations for elucidation of pathogenesis and development of tailor-maid therapy are highly desired. We generated hiPS cells from healthy volunteers or patients with LQTs by transfecting 4 reprogmming genes such as Oct3/4, Sox2, Klf4, and c-Myc. Stable iPS colonies were screened by immunostaining and RT-PCR of the various stem cell markers, and cardiac differentiation of hiPS cells were made by formation of embryoid bodies. Molecular characterization of hiPS-derived cardiomyocytes was investigated, and action potential was recorded using conventional microelectrode technique. Furthermore, drug sensitivity test was also performed by multi-electrode array systems. HiPS-derived cardiomyocytes of normal volunteers showed the similar characteristics to native cardiomyocytes on expression of cardiac specific-marker genes and electrophysiologic phenotypes. Notably, LQTs model using patient-specific iPS-derived cardiomyocytes showed the characteristic LQTs phenotype, comparing to healthy control, implicating that disease modeling using hiPS cells may play a crucial role for arrhythmia researches including disease mechanisms as well as development of new therapies. © 2011, Japanese Heart Rhythm Society. All rights reserved.

    DOI: 10.4020/jhrs.27.SY15_5

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  • 循環器疾患特異的iPS細胞研究の展開

    湯浅 慎介, 福田 恵一

    心臓   43 ( 1 )   10 - 13   2011年

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    記述言語:日本語   出版者・発行元:Japan Heart Foundation  

    DOI: 10.11281/shinzo.43.10

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    その他リンク: http://search.jamas.or.jp/link/ui/2011136804

  • ヒトiPS細胞由来心筋細胞の電気生理学―パッチクランプ実験―:―パッチクランプ実験―

    古川 哲史, 黒川 洵子, 大方 信一郎, 遠山 周吾, 湯浅 慎介, 村田 光繁, 福田 恵一

    心電図   31 ( 3 )   325 - 328   2011年

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    記述言語:日本語   出版者・発行元:The Japanese Society of Electrocardiology  

    心臓電気生理・不整脈の研究は,従来ヒト以外の生物種の心筋細胞を用いるか,ヒトイオンチャネル遺伝子を心筋以外の細胞株に異所性に発現させて行われてきたが,これらの方法はヒト心筋細胞とは異なる環境下での検討であるということが課題として指摘されていた.ヒトiPS細胞から分化誘導した心筋細胞の樹立により,この問題の克服が期待されている.今回,ヒトiPS細胞から分化誘導した心筋細胞の電気生理学的特性を検討した.ヒト心筋型イオンチャネルmRNAの発現,ヒト心筋型イオン電流記録,自律神経応答,イオンチャネルブロッカーの作用などが確認された.ヒトiPS細胞から分化誘導した心筋様細胞は心筋細胞に近い特性が獲得されているが,結節型,心房筋型,心室筋型が混在すると考えられた.

    DOI: 10.5105/jse.31.325

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    その他リンク: http://search.jamas.or.jp/link/ui/2011331786

  • Generation and clinical application of human T cell-derived induced pluripotent stem cells

    Seki Tomohisa, Yuasa Shinsuke, Fukuda Keiichi

    Inflammation and Regeneration   31 ( 5 )   393 - 398   2011年

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    記述言語:英語   出版者・発行元:The Japanese Society of Inflammation and Regeneration  

    Pluripotent stem (iPS) cells are a very promising cell source for models of human genetic diseases and revolutionary new therapies. Successful reprogramming of human blood cells has been reported and is likely to advance the clinical application of iPS cells. In terms of a patient's own somatic cells, generating iPS cells from peripheral blood cells has advantages for clinical applications because these cells are an easily accessible cell source. Of the human peripheral blood cells, T cells can be readily cultured in vitro and proliferate rapidly. Furthermore, only a small amount of peripheral blood is needed to generate iPS cells from T cells, thus increasing the number of patients in whom the technique can be used. iPS cells that contain T-cell receptor (TCR) rearrangements in their genome also have the potential to be traceable markers when establishing novel transplantation therapies. The present review summarizes recent progress in the methods used to generate iPS cells and the future potential of human T cell-derived iPS cells.

    DOI: 10.2492/inflammregen.31.393

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  • 4-hydroxy-2-nonenal protects against cardiac ischemia-reperfusion injury via the Nrf2-dependent pathway. 査読 国際誌

    Yan Zhang, Motoaki Sano, Ken Shinmura, Kayoko Tamaki, Yoshinori Katsumata, Tomohiro Matsuhashi, Shintaro Morizane, Hideyuki Ito, Takako Hishiki, Jin Endo, Heping Zhou, Shinsuke Yuasa, Ruri Kaneda, Makoto Suematsu, Keiichi Fukuda

    Journal of molecular and cellular cardiology   49 ( 4 )   576 - 86   2010年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Reactive oxygen species (ROS) attack polyunsaturated fatty acids of the membrane and trigger lipid peroxidation, which results in the generation of alpha,beta-unsaturated aldehydes, such as 4-hydroxy-2-nonenal (4-HNE). There is compelling evidence that high concentrations of aldehydes are responsible for much of the damage elicited by cardiac ischemia-reperfusion injury, while sublethal concentrations of aldehydes stimulate stress resistance pathways, to achieve cardioprotection. We investigated the mechanism of cardioprotection mediated by 4-HNE. For cultured cardiomyocytes, 4-HNE was cytotoxic at higher concentrations (>or=20 microM) but had no appreciable cytotoxicity at lower concentrations. Notably, a sublethal concentration (5muM) of 4-HNE primed cardiomyocytes to become resistant to cytotoxic concentrations of 4-HNE. 4-HNE induced nuclear translocation of transcription factor NF-E2-related factor 2 (Nrf2), and enhanced the expression of gamma-glutamylcysteine ligase (GCL) and the core subunit of the Xc(-) high-affinity cystine transporter (xCT), thereby increasing 1.45-fold the intracellular GSH levels. Cardiomyocytes treated with either Nrf2-specific siRNA or the GCL inhibitor l-buthionine sulfoximine (BSO) were less tolerant to 4-HNE. Moreover, the cardioprotective effect of 4-HNE pretreatment against subsequent glucose-free anoxia followed by reoxygenation was completely abolished in these cells. Intravenous administration of 4-HNE (4 mg/kg) activated Nrf2 in the heart and increased the intramyocardial GSH content, and consequently improved the functional recovery of the left ventricle following ischemia-reperfusion in Langendorff-perfused hearts. This cardioprotective effect of 4-HNE was not observed for Nrf2-knockout mice. In summary, 4-HNE activates Nrf2-mediated gene expression and stimulates GSH biosynthesis, thereby conferring on cardiomyocytes protection against ischemia-reperfusion injury.

    DOI: 10.1016/j.yjmcc.2010.05.011

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  • CK値の変動から評価した疾患、検査・治療方法による心筋障害の検討

    貞廣 威太郎, 香坂 俊, 高橋 賢至, 遠藤 彩佳, 茂木 聡, 沼澤 洋平, 大野 洋平, 荒井 隆秀, 湯浅 慎介, 前川 裕一郎, 河村 朗夫, 吉川 勉, 福田 恵一

    日本心臓病学会誌   5 ( Suppl.I )   397 - 397   2010年8月

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    記述言語:日本語   出版者・発行元:(一社)日本心臓病学会  

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  • PCI施行後の無症候性再狭窄 冠動脈危険因子と慢性腎臓病の寄与の比較

    貞廣 威太郎, 香坂 俊, 高橋 賢至, 遠藤 彩佳, 茂木 聡, 沼澤 洋平, 大野 洋平, 荒井 隆秀, 湯浅 慎介, 前川 裕一郎, 河村 朗夫, 吉川 勉, 福田 恵一

    日本心臓病学会誌   5 ( Suppl.I )   380 - 380   2010年8月

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    記述言語:日本語   出版者・発行元:(一社)日本心臓病学会  

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  • Generation of induced pluripotent stem cells from human terminally differentiated circulating T cells. 査読 国際誌

    Tomohisa Seki, Shinsuke Yuasa, Mayumi Oda, Toru Egashira, Kojiro Yae, Dai Kusumoto, Hikari Nakata, Shugo Tohyama, Hisayuki Hashimoto, Masaki Kodaira, Yohei Okada, Hiroyuki Seimiya, Noemi Fusaki, Mamoru Hasegawa, Keiichi Fukuda

    Cell stem cell   7 ( 1 )   11 - 4   2010年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.stem.2010.06.003

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  • Zac1 is an essential transcription factor for cardiac morphogenesis. 査読 国際誌

    Shinsuke Yuasa, Takeshi Onizuka, Kenichiro Shimoji, Yohei Ohno, Toshimi Kageyama, Sung Han Yoon, Toru Egashira, Tomohisa Seki, Hisayuki Hashimoto, Takahiko Nishiyama, Ruri Kaneda, Mitsushige Murata, Fumiyuki Hattori, Shinji Makino, Motoaki Sano, Satoshi Ogawa, Owen W J Prall, Richard P Harvey, Keiichi Fukuda

    Circulation research   106 ( 6 )   1083 - 91   2010年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    RATIONALE: The transcriptional networks guiding heart development remain poorly understood, despite the identification of several essential cardiac transcription factors. OBJECTIVE: To isolate novel cardiac transcription factors, we performed gene chip analysis and found that Zac1, a zinc finger-type transcription factor, was strongly expressed in the developing heart. This study was designed to investigate the molecular and functional role of Zac1 as a cardiac transcription factor. METHODS AND RESULTS: Zac1 was strongly expressed in the heart from cardiac crescent stages and in the looping heart showed a chamber-restricted pattern. Zac1 stimulated luciferase reporter constructs driven by ANF, BNP, or alphaMHC promoters. Strong functional synergy was seen between Zac1 and Nkx2-5 on the ANF promoter, which carries adjacent Zac1 and Nkx2-5 DNA-binding sites. Zac1 directly associated with the ANF promoter in vitro and in vivo, and Zac1 and Nkx2-5 physically associated through zinc fingers 5 and 6 in Zac1, and the homeodomain in Nkx2-5. Zac1 is a maternally imprinted gene and is the first such gene found to be involved in heart development. Homozygous and paternally derived heterozygous mice carrying an interruption in the Zac1 locus showed decreased levels of chamber and myofilament genes, increased apoptotic cells, partially penetrant lethality and morphological defects including atrial and ventricular septal defects, and thin ventricular walls. CONCLUSIONS: Zac1 plays an essential role in the cardiac gene regulatory network. Our data provide a potential mechanistic link between Zac1 in cardiogenesis and congenital heart disease manifestations associated with genetic or epigenetic defects in an imprinted gene network.

    DOI: 10.1161/CIRCRESAHA.109.214130

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  • G-CSF promotes the proliferation of developing cardiomyocytes in vivo and in derivation from ESCs and iPSCs. 査読 国際誌

    Kenichiro Shimoji, Shinsuke Yuasa, Takeshi Onizuka, Fumiyuki Hattori, Tomofumi Tanaka, Mie Hara, Yohei Ohno, Hao Chen, Toru Egasgira, Tomohisa Seki, Kojiro Yae, Uichi Koshimizu, Satoshi Ogawa, Keiichi Fukuda

    Cell stem cell   6 ( 3 )   227 - 37   2010年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    During a screen for humoral factors that promote cardiomyocyte differentiation from embryonic stem cells (ESCs), we found marked elevation of granulocyte colony-stimulating factor receptor (G-CSFR) mRNA in developing cardiomyocytes. We confirmed that both G-CSFR and G-CSF were specifically expressed in embryonic mouse heart at the midgestational stage, and expression levels were maintained throughout embryogenesis. Intrauterine G-CSF administration induced embryonic cardiomyocyte proliferation and caused hyperplasia. In contrast, approximately 50% of csf3r(-/-) mice died during late embryogenesis because of the thinning of atrioventricular walls. ESC-derived developing cardiomyocytes also strongly expressed G-CSFR. When extrinsic G-CSF was administered to the ESC- and human iPSC-derived cardiomyocytes, it markedly augmented their proliferation. Moreover, G-CSF-neutralizing antibody inhibited their proliferation. These findings indicated that G-CSF is critically involved in cardiomyocyte proliferation during development, and may be used to boost the yield of cardiomyocytes from ESCs for their potential application to regenerative medicine.

    DOI: 10.1016/j.stem.2010.01.002

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  • Nongenetic method for purifying stem cell-derived cardiomyocytes. 査読 国際誌

    Fumiyuki Hattori, Hao Chen, Hiromi Yamashita, Shugo Tohyama, Yu-Suke Satoh, Shinsuke Yuasa, Weizhen Li, Hiroyuki Yamakawa, Tomofumi Tanaka, Takeshi Onitsuka, Kenichiro Shimoji, Yohei Ohno, Toru Egashira, Ruri Kaneda, Mitsushige Murata, Kyoko Hidaka, Takayuki Morisaki, Erika Sasaki, Takeshi Suzuki, Motoaki Sano, Shinji Makino, Shinzo Oikawa, Keiichi Fukuda

    Nature methods   7 ( 1 )   61 - 6   2010年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Several applications of pluripotent stem cell (PSC)-derived cardiomyocytes require elimination of undifferentiated cells. A major limitation for cardiomyocyte purification is the lack of easy and specific cell marking techniques. We found that a fluorescent dye that labels mitochondria, tetramethylrhodamine methyl ester perchlorate, could be used to selectively mark embryonic and neonatal rat cardiomyocytes, as well as mouse, marmoset and human PSC-derived cardiomyocytes, and that the cells could subsequently be enriched (>99% purity) by fluorescence-activated cell sorting. Purified cardiomyocytes transplanted into testes did not induce teratoma formation. Moreover, aggregate formation of PSC-derived cardiomyocytes through homophilic cell-cell adhesion improved their survival in the immunodeficient mouse heart. Our approaches will aid in the future success of using PSC-derived cardiomyocytes for basic and clinical applications.

    DOI: 10.1038/nmeth.1403

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  • Creating frog heart as an organ: in vitro-induced heart functions as a circulatory organ in vivo. 査読 国際誌

    Masayoshi Kinoshita, Takashi Ariizumi, Shinsuke Yuasa, Shunichirou Miyoshi, Shinji Komazaki, Keiichi Fukuda, Makoto Asashima

    The International journal of developmental biology   54 ( 5 )   851 - 6   2010年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Cardiomyocytes have been induced from various pluripotent cells, such as embryonic stem cells and myeloid stem cells; however, the generation of cardiac tissues beyond two-dimensional cell-sheets has not been reported. Creating higher order, three-dimensional structures that are unique to heart is the long-awaited next step in realizing cardiac regenerative medicine. We have previously shown that cardiomyocytes can be induced in vitro from undifferentiated cells (animal caps) excised from Xenopus embryos. Cardiomyocytes were induced by first dissociating the animal caps and then reaggregating them following treatment with activin. Here, we describe an interesting method for creating a complete ectopic heart in vivo, involving the introduction of in vitro-created tissue during early embryogenesis. Thus, animal cap reaggregates were transplanted into the abdomen of late-neurula-stage embryos, resulting in two-chambered hearts being formed. The dual-heart larvae matured into adult animals with transplanted hearts intact. Involvement of transplanted hearts in systemic circulation was demonstrated. Moreover, the ectopic hearts possessed higher order structures such as atrium and ventricle, and were morphologically, histologically, and electrophysiologically identical to original hearts. This system should facilitate the study of heart organogenesis and may promote a shift from tissue to organ engineering for clinical applications.

    DOI: 10.1387/ijdb.093036mk

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  • 高度屈曲を伴う二本の冠動脈肺動脈瘻に対し、冠動脈側及び肺動脈側からコイル塞栓術を施行した1例

    沼澤 洋平, 河村 朗夫, 橋本 統, 香坂 俊, 遠藤 彩佳, 長友 祐司, 湯浅 慎介, 村田 光繁, 前川 裕一郎, 吉川 勉

    日本内科学会関東地方会   568回   29 - 29   2009年12月

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    記述言語:日本語   出版者・発行元:日本内科学会-関東地方会  

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  • Omentopexy enhances graft function in myocardial cell sheet transplantation. 査読 国際誌

    Ryo Suzuki, Fumiyuki Hattori, Yuji Itabashi, Masatoyo Yoshioka, Shinsuke Yuasa, Haruko Manabe-Kawaguchi, Mitsushige Murata, Shinji Makino, Kiyokazu Kokaji, Ryohei Yozu, Keiichi Fukuda

    Biochemical and biophysical research communications   387 ( 2 )   353 - 9   2009年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Myocardial cell sheets (MCS) are a potentially valuable tool for tissue engineering aimed at heart regeneration. Several methods have recently been established for the fabrication of MCS. However, the lack of a sufficient blood supply has inhibited functional recovery of the MCS. To address this challenge, we combined MCS transplantation with omentopexy (OP), which utilizes omental tissue as a surgical flap. Rats were divided into five groups: sham, myocardial infarction (MI), MCS transplantation, OP, and MCS+OP. Histologic analysis revealed that MCS+OP drastically reversed MI-induced cardiac remodeling. Echocardiography revealed that MCS increased cardiac function, while OP had a synergistic beneficial effect with MCS transplantation. Immunofluorescence imaging showed that OP increased the survival of transplanted cardiomyocytes, and increased the blood supply through enhancement of angiogenesis and migration of small arteries into the MCS. Taken together, we concluded that OP is a promising strategy for the enhancement of graft function in MCS transplantation.

    DOI: 10.1016/j.bbrc.2009.07.024

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  • In vitro pharmacologic testing using human induced pluripotent stem cell-derived cardiomyocytes. 査読 国際誌

    Tomofumi Tanaka, Shugo Tohyama, Mitsushige Murata, Fumimasa Nomura, Tomoyuki Kaneko, Hao Chen, Fumiyuki Hattori, Toru Egashira, Tomohisa Seki, Yohei Ohno, Uichi Koshimizu, Shinsuke Yuasa, Satoshi Ogawa, Shinya Yamanaka, Kenji Yasuda, Keiichi Fukuda

    Biochemical and biophysical research communications   385 ( 4 )   497 - 502   2009年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The lethal ventricular arrhythmia Torsade de pointes (TdP) is the most common reason for the withdrawal or restricted use of many cardiovascular and non-cardiovascular drugs. The lack of an in vitro model to detect pro-arrhythmic effects on human heart cells hinders the development of new drugs. We hypothesized that recently established human induced pluripotent stem (hiPS) cells could be used in an in vitro drug screening model. In this study, hiPS cells were driven to differentiate into functional cardiomyocytes, which expressed cardiac markers including Nkx2.5, GATA4, and atrial natriuretic peptide. The hiPS-derived cardiomyocytes (hiPS-CMs) were analyzed using a multi electrode assay. The application of ion channel inhibitors resulted in dose-dependent changes to the field potential waveform, and these changes were identical to those induced in the native cardiomyocytes. This study shows that hiPS-CMs represent a promising in vitro model for cardiac electrophysiologic studies and drug screening.

    DOI: 10.1016/j.bbrc.2009.05.073

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  • Glucocorticoid protects rodent hearts from ischemia/reperfusion injury by activating lipocalin-type prostaglandin D synthase-derived PGD2 biosynthesis. 査読 国際誌

    Satori Tokudome, Motoaki Sano, Ken Shinmura, Tomohiro Matsuhashi, Shintaro Morizane, Hidenori Moriyama, Kayoko Tamaki, Kentaro Hayashida, Hiroki Nakanishi, Noritada Yoshikawa, Noriaki Shimizu, Jin Endo, Takaharu Katayama, Mitsushige Murata, Shinsuke Yuasa, Ruri Kaneda, Kengo Tomita, Naomi Eguchi, Yoshihiro Urade, Koichiro Asano, Yasunori Utsunomiya, Takeshi Suzuki, Ryo Taguchi, Hirotoshi Tanaka, Keiichi Fukuda

    The Journal of clinical investigation   119 ( 6 )   1477 - 88   2009年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Lipocalin-type prostaglandin D synthase (L-PGDS), which was originally identified as an enzyme responsible for PGD2 biosynthesis in the brain, is highly expressed in the myocardium, including in cardiomyocytes. However, the factors that control expression of the gene encoding L-PGDS and the pathophysiologic role of L-PGDS in cardiomyocytes are poorly understood. In the present study, we demonstrate that glucocorticoids, which act as repressors of prostaglandin biosynthesis in most cell types, upregulated the expression of L-PGDS together with cytosolic calcium-dependent phospholipase A2 and COX2 via the glucocorticoid receptor (GR) in rat cardiomyocytes. Accordingly, PGD2 was the most prominently induced prostaglandin in vivo in mouse hearts and in vitro in cultured rat cardiomyocytes after exposure to GR-selective agonists. In isolated Langendorff-perfused mouse hearts, dexamethasone alleviated ischemia/reperfusion injury. This cardioprotective effect was completely abrogated by either pharmacologic inhibition of COX2 or disruption of the gene encoding L-PGDS. In in vivo ischemia/reperfusion experiments, dexamethasone reduced infarct size in wild-type mice. This cardioprotective effect of dexamethasone was markedly reduced in L-PGDS-deficient mice. In cultured rat cardiomyocytes, PGD2 protected against cell death induced by anoxia/reoxygenation via the D-type prostanoid receptor and the ERK1/2-mediated pathway. Taken together, these results suggest what we believe to be a novel interaction between glucocorticoid-GR signaling and the cardiomyocyte survival pathway mediated by the arachidonic acid cascade.

    DOI: 10.1172/JCI37413

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  • Recent advances in cardiovascular regenerative medicine: the induced pluripotent stem cell era. 査読 国際誌

    Shinsuke Yuasa, Keiichi Fukuda

    Expert review of cardiovascular therapy   6 ( 6 )   803 - 10   2008年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Induced pluripotent stem (iPS) cells have recently been established by transfecting mouse and human fibroblasts with the transcription factors Oct3/4, Sox2, Klf4 and c-Myc, known to be expressed at high levels in embryonic stem (ES) cells. These cells have great potential in regenerative medicine as they have the capacity to differentiate into all three germ layer-derived cells and are syngeneic. The differentiation of ES cells into cardiomyocytes mimics the early processes involved in heart development. Recent studies describe the contribution of various growth factors and corresponding inhibitors to heart development during embryogenesis. Bone morphogenetic proteins, Wnt protein and Notch signals play critical roles in heart development in a context- and time-dependent manner. Consistent with ES cells, the exposure of iPS cells to such growth factors is hypothesized to augment differentiation into cardiomyocytes. The combination of iPS cells and appropriate developmental signal information has the potential for providing the foundations for future regenerative medicine.

    DOI: 10.1586/14779072.6.6.803

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  • Common marmoset embryonic stem cell can differentiate into cardiomyocytes. 査読 国際誌

    Hao Chen, Fumiyuki Hattori, Mitsushige Murata, Weizhen Li, Shinsuke Yuasa, Takeshi Onizuka, Kenichiro Shimoji, Yohei Ohno, Erika Sasaki, Kensuke Kimura, Daihiko Hakuno, Motoaki Sano, Shinji Makino, Satoshi Ogawa, Keiichi Fukuda

    Biochemical and biophysical research communications   369 ( 3 )   801 - 6   2008年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Common marmoset monkeys have recently attracted much attention as a primate research model, and are preferred to rhesus and cynomolgus monkeys due to their small bodies, easy handling and efficient breeding. We recently reported the establishment of common marmoset embryonic stem cell (CMESC) lines that could differentiate into three germ layers. Here, we report that our CMESC can also differentiate into cardiomyocytes and investigated their characteristics. After induction, FOG-2 was expressed, followed by GATA4 and Tbx20, then Nkx2.5 and Tbx5. Spontaneous beating could be detected at days 12-15. Immunofluorescent staining and ultrastructural analyses revealed that they possessed characteristics typical of functional cardiomyocytes. They showed sinus node-like action potentials, and the beating rate was augmented by isoproterenol stimulation. The BrdU incorporation assay revealed that CMESC-derived cardiomyocytes retained a high proliferative potential for up to 24 weeks. We believe that CMESC-derived cardiomyocytes will advance preclinical studies in cardiovascular regenerative medicine.

    DOI: 10.1016/j.bbrc.2008.02.141

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  • Cardiac regenerative medicine. 査読

    Shinsuke Yuasa, Keiichi Fukuda

    Circulation journal : official journal of the Japanese Circulation Society   72 Suppl A   A49-55   2008年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Severe heart failure is associated with damage to the myocardium that is irreversible with current medical therapies. Recent experimental and clinical studies, however, have opened the possibility of solving many of the associated problems, making this an exciting and tangible goal. There are many potential cell sources for regenerative cardiac medicine, including bone marrow stem cells, endothelial progenitor cells, skeletal myocytes, adult cardiac stem cells, and embryonic stem (ES) cells. Although ES cells are highly proliferative and suitable for mass production, they are not autologous, and an efficient protocol is yet to be established to ensure selective cardiomyocyte induction. Recent studies have successfully established inducible pluripotent stem (iPS) cells from mouse and human fibroblasts by the gene transfer of 4 transcription factors that are strongly expressed in ES cells: Oct3/4, Sox2, Klf4 and c-Myc. iPS cells can differentiate into all 3 germ layer-derived cells and are syngeneic, indicating that they can become an ideal cell source for regenerative medicine. Despite these successes, the accumulating evidence from fields as diverse as developmental biology, stem cell biology and tissue engineering must be integrated to achieve the full potential of cardiac regenerative medicine.

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  • Administration of granulocyte colony-stimulating factor after myocardial infarction enhances the recruitment of hematopoietic stem cell-derived myofibroblasts and contributes to cardiac repair. 査読 国際誌

    Jun Fujita, Mitsuharu Mori, Hiroshi Kawada, Yasuyo Ieda, Mitsuyo Tsuma, Yumi Matsuzaki, Haruko Kawaguchi, Takashi Yagi, Shinsuke Yuasa, Jin Endo, Tomomitsu Hotta, Satoshi Ogawa, Hideyuki Okano, Ryohei Yozu, Kiyoshi Ando, Keiichi Fukuda

    Stem cells (Dayton, Ohio)   25 ( 11 )   2750 - 9   2007年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The administration of granulocyte colony-stimulating factor (G-CSF) after myocardial infarction (MI) improves cardiac function and survival rates in mice. It was also reported recently that bone marrow (BM)-derived c-kit(+) cells or macrophages in the infarcted heart are associated with improvement of cardiac remodeling and function. These observations prompted us to examine whether BM-derived hematopoietic cells mobilized by G-CSF administration after MI play a beneficial role in the infarct region. A single hematopoietic stem cell from green fluorescent protein (GFP)-transgenic mice was used to reconstitute hematopoiesis in each experimental mouse. MI was then induced, and the mice received G-CSF for 10 days. In the acute phase, a number of GFP(+) cells showing the elongated morphology were found in the infarcted area. Most of these cells were positive for vimentin and alpha-smooth muscle actin but negative for CD45, indicating that they were myofibroblasts. The number of these cells was markedly enhanced by G-CSF administration, and the enhanced myofibroblast-rich repair was considered to lead to improvements of cardiac remodeling, function, and survival rate. Next, G-CSF-mobilized monocytes were harvested from the peripheral blood of GFP-transgenic mice and injected intravenously into the infarcted mice. Following this procedure, GFP(+) myofibroblasts were observed in the infarcted myocardium. These results indicate that cardiac myofibroblasts are hematopoietic in origin and could arise from monocytes/macrophages. MI leads to the recruitment of monocytes, which differentiate into myofibroblasts in the infarct region. Administration of G-CSF promotes this recruitment and enhances cardiac protection.

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  • Bone marrow derived cells are involved in the pathogenesis of cardiac hypertrophy in response to pressure overload. 査読 国際誌

    Jin Endo, Motoaki Sano, Jun Fujita, Kentaro Hayashida, Shinsuke Yuasa, Naoki Aoyama, Yuji Takehara, Osamu Kato, Shinji Makino, Satoshi Ogawa, Keiichi Fukuda

    Circulation   116 ( 10 )   1176 - 84   2007年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Bone marrow (BM) cells possess broad differentiation potential and can form various cell lineages in response to pathophysiological cues. The present study investigated whether BM-derived cells contribute to the pathogenesis of cardiac hypertrophy, as well as the possible cellular mechanisms involved in such a role. METHODS AND RESULTS: Lethally irradiated wild-type mice were transplanted with BM cells from enhanced green fluorescent protein-transgenic mice. The chimeric mice were subjected to either prolonged hypoxia or transverse aortic constriction. BM-derived enhanced green fluorescent protein-expressing cardiomyocytes increased in number over time, emerging predominantly in the pressure-overloaded ventricular myocardium, although they constituted <0.01% of recipient cardiomyocytes. To determine whether BM-derived cardiomyocytes were derived from cell fusion or transdifferentiation at the single-cell level, lethally irradiated Cre mice were transplanted with BM cells from the double-conditional Cre reporter mouse line Z/EG. BM-derived cardiomyocytes were shown to arise from both cell fusion and transdifferentiation. Interestingly, BM-derived myofibroblasts expressing both vimentin and alpha-smooth muscle actin were concentrated in the perivascular fibrotic area. These cells initially expressed MAC-1/CD14 but lost expression of these markers during the chronic phase, which suggests that they were derived from monocytes. A similar phenomenon occurred in cultured human monocytes, most of which ultimately expressed vimentin and alpha-smooth muscle actin. CONCLUSIONS: We found that BM-derived cells were involved in the pathogenesis of cardiac hypertrophy via the dual mechanisms of cell fusion and transdifferentiation. Moreover, the present results suggest that BM-derived monocytes accumulating in the perivascular space might play an important role in the formation of perivascular fibrosis via direct differentiation into myofibroblasts.

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  • Intramolecular control of protein stability, subnuclear compartmentalization, and coactivator function of peroxisome proliferator-activated receptor gamma coactivator 1alpha. 査読 国際誌

    Motoaki Sano, Satori Tokudome, Noriaki Shimizu, Noritada Yoshikawa, Chie Ogawa, Kousuke Shirakawa, Jin Endo, Takaharu Katayama, Shinsuke Yuasa, Masaki Ieda, Shinji Makino, Fumiyuki Hattori, Hirotoshi Tanaka, Keiichi Fukuda

    The Journal of biological chemistry   282 ( 35 )   25970 - 80   2007年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Peroxisome proliferator-activated receptor gamma coactivator (PGC)-1 is a critical transcriptional regulator of energy metabolism. Here we found that PGC-1alpha is a short lived and aggregation-prone protein. PGC-1alpha localized throughout the nucleoplasm and was rapidly destroyed via the ubiquitin-proteasome pathway. Upon proteasome inhibition, PGC-1alpha formed insoluble polyubiquitinated aggregates. Ubiquitination of PGC-1alpha depended on the integrity of the C terminus-containing arginine-serine-rich domains and an RNA recognition motif. Interestingly, ectopically expressed C-terminal fragment of PGC-1alpha was autonomously ubiquitinated and aggregated with promyelocytic leukemia protein. Cooperation of the N-terminal region containing two PEST-like motifs was required for prevention of aggregation and targeting of the polyubiquitinated PGC-1alpha for degradation. This region thereby negatively controlled the aggregation properties of the C-terminal region to regulate protein turnover and intranuclear compartmentalization of PGC-1alpha. Exogenous expression of the PGC-1alpha C-terminal fragment interfered with degradation of full-length PGC-1alpha and enhanced its coactivation properties. We concluded that PGC-1alpha function is critically regulated at multiple steps via intramolecular cooperation among several distinct structural domains of the protein.

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  • Dominant negative suppression of Rad leads to QT prolongation and causes ventricular arrhythmias via modulation of L-type Ca2+ channels in the heart. 査読 国際誌

    Hirotaka Yada, Mitsushige Murata, Kouji Shimoda, Shinsuke Yuasa, Haruko Kawaguchi, Masaki Ieda, Takeshi Adachi, Mitsuru Murata, Satoshi Ogawa, Keiichi Fukuda

    Circulation research   101 ( 1 )   69 - 77   2007年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Disorders of L-type Ca2+ channels can cause severe cardiac arrhythmias. A subclass of small GTP-binding proteins, the RGK family, regulates L-type Ca2+ current (I(Ca,L)) in heterologous expression systems. Among these proteins, Rad (Ras associated with diabetes) is highly expressed in the heart, although its role in the heart remains unknown. Here we show that overexpression of dominant negative mutant Rad (S105N) led to an increase in I(Ca,L) and action potential prolongation via upregulation of L-type Ca2+ channel expression in the plasma membrane of guinea pig ventricular cardiomyocytes. To verify the in vivo physiological role of Rad in the heart, a mouse model of cardiac-specific Rad suppression was created by overexpressing S105N Rad, using the alpha-myosin heavy chain promoter. Microelectrode studies revealed that action potential duration was significantly prolonged with visible identification of a small plateau phase in S105N Rad transgenic mice, when compared with wild-type littermate mice. Telemetric electrocardiograms on unrestrained mice revealed that S105N Rad transgenic mice had significant QT prolongation and diverse arrhythmias such as sinus node dysfunction, atrioventricular block, and ventricular extrasystoles, whereas no arrhythmias were observed in wild-type mice. Furthermore, administration of epinephrine induced frequent ventricular extrasystoles and ventricular tachycardia in S105N Rad transgenic mice. This study provides novel evidence that the suppression of Rad activity in the heart can induce ventricular tachycardia, suggesting that the Rad-associated signaling pathway may play a role in arrhythmogenesis in diverse cardiac diseases.

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  • E-cadherin-coated plates maintain pluripotent ES cells without colony formation. 査読 国際誌

    Masato Nagaoka, Uichi Koshimizu, Shinsuke Yuasa, Fumiyuki Hattori, Hao Chen, Tomofumi Tanaka, Masaru Okabe, Keiichi Fukuda, Toshihiro Akaike

    PloS one   1 ( 1 )   e15   2006年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Embryonic stem (ES) cells cultured on gelatin-coated plates or feeder layers form tight aggregated colonies by the E-cadherin-mediated cell-cell adhesions. Here we show that murine ES cells do not make cell-cell contacts or form colonies when cultured on the plate coated with a fusion protein of E-cadherin and IgG Fc domain. The cells in culture retain all ES cell features including pluripotency to differentiate into cells of all three germ layers and germ-line transmission after extended culture. Furthermore, they show a higher proliferative ability, lower dependency on LIF, and higher transfection efficiency than colony-forming conditions. Our results suggest that aggregated colony formation might inhibit diffusion of soluble factors and increase cell-cell communication, which may result in a heterogeneous environment within and between surrounding cells of the colony. This method should enable more efficient and scalable culture of ES cells, an important step towards the clinical application of these cells.

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  • Contribution of bone marrow-derived cells on pressure overload-induced cardiac hypertrophy and perivascular fibrosis in mice 査読

    Endo Jin, Sano Motoaki, Fujita Jun, Hayashida Kentaro, Yuasa Shinsuke, Makino Shinji, Fukuda Keiichi, Ogawa Satoshi

    CIRCULATION   114 ( 18 )   165   2006年10月

  • Chondromodulin-I maintains cardiac valvular function by preventing angiogenesis. 査読 国際誌

    Masatoyo Yoshioka, Shinsuke Yuasa, Keisuke Matsumura, Kensuke Kimura, Takayuki Shiomi, Naritaka Kimura, Chisa Shukunami, Yasunori Okada, Makio Mukai, Hankei Shin, Ryohei Yozu, Masataka Sata, Satoshi Ogawa, Yuji Hiraki, Keiichi Fukuda

    Nature medicine   12 ( 10 )   1151 - 9   2006年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The avascularity of cardiac valves is abrogated in several valvular heart diseases (VHDs). This study investigated the molecular mechanisms underlying valvular avascularity and its correlation with VHD. Chondromodulin-I, an antiangiogenic factor isolated from cartilage, is abundantly expressed in cardiac valves. Gene targeting of chondromodulin-I resulted in enhanced Vegf-A expression, angiogenesis, lipid deposition and calcification in the cardiac valves of aged mice. Echocardiography showed aortic valve thickening, calcification and turbulent flow, indicative of early changes in aortic stenosis. Conditioned medium obtained from cultured valvular interstitial cells strongly inhibited tube formation and mobilization of endothelial cells and induced their apoptosis; these effects were partially inhibited by chondromodulin-I small interfering RNA. In human VHD, including cases associated with infective endocarditis, rheumatic heart disease and atherosclerosis, VEGF-A expression, neovascularization and calcification were observed in areas of chondromodulin-I downregulation. These findings provide evidence that chondromodulin-I has a pivotal role in maintaining valvular normal function by preventing angiogenesis that may lead to VHD.

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  • Stem cells as a source of regenerative cardiomyocytes. 査読 国際誌

    Keiichi Fukuda, Shinsuke Yuasa

    Circulation research   98 ( 8 )   1002 - 13   2006年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The realization of regenerative cardiac medicine depends on the availability of cardiomyocytes in sufficient numbers for transplantation of cardiac tissue and the accompanying blood vessels. Embryonic stem (ES) cells, bone marrow (BM) stem cells, and tissue-derived stem cells are all potential cell sources. Although ES cells are highly proliferative and suitable for mass production, an efficient protocol is yet to be established to ensure selective cardiomyocyte induction using these cells. Recent advances in developmental biology have clarified the involvement of critical factors in cardiomyocyte differentiation, including bone morphogenic protein and Wnt signaling proteins, and such factors have the potential to improve the efficiency of stem cell induction. Initial studies of the intracoronary administration of BM mononuclear cells after myocardial infarction has yielded promising results; however, intensive investigation of the underlying molecular mechanisms at play as well as double-blinded clinical trials will be necessary to establish the extent of both migration of the BM stem cells into the damaged cardiac tissue and their differentiation into cardiomyocytes. Several types of cardiac tissue stem cells have also been reported, but an accurate and extensive comparison of these cells with regard to their characteristics and multipotency remains to be done. An integrative study involving developmental biology, stem cell biology, and tissue engineering is required to achieve the full potential of cardiac regeneration.

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  • Analysis of the electrophysiological properties and arrhythmias in directly contacted skeletal and cardiac muscle cell sheets. 査読 国際誌

    Yuji Itabashi, Shunichiro Miyoshi, Shinsuke Yuasa, Jun Fujita, Tatsuya Shimizu, Teruo Okano, Keiichi Fukuda, Satoshi Ogawa

    Cardiovascular research   67 ( 3 )   561 - 70   2005年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: Autologous skeletal muscle cell (SM) transplantation into the in vivo heart sometimes induces serious arrhythmias. The purpose of this study was to investigate the electrophysiology of cardiomyocyte (CM) and SM in direct contact and to study the mechanism underlying the cause of arrhythmia using the recently developed cell sheet engineering technique. METHODS: Primary cultured rat neonatal SM and CM were prepared, and cell sheets were fabricated using temperature-responsive culture dishes. The action potential was recorded by a conventional microelectrode. Intracellular calcium concentration and optical mapping image of the action potential were recorded using Fluo-3 and di-4-ANEPPS, respectively. A video motion-detecting system was used for the detection of arrhythmias. RESULTS: SM myotubes occasionally displayed automaticity. SM sheets did not display synchronized contraction, but instead groups of myotubes contracted independently. The action potential of SM, induced by artificial pacing, did not expand to the entire sheet but was limited within a restricted, small area around the electrode, and it was unfeasible to generate an electrical connection or propagate an action potential between CM and SM sheets. SM sheets, in which some of the myotubes displayed automaticity, caused fibrillation-like contraction in the co-cultured CM sheets, and this arrhythmia was specifically blocked by the stretch-activated channel blocker GsMTx-4. CONCLUSIONS: These findings show that SM sheets do not contract synchronously or generate functional syncytia with the surrounding CM sheets and that stretch-induced arrhythmias due to spontaneous contraction of SM may occur in the CM sheet.

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  • Transient inhibition of BMP signaling by Noggin induces cardiomyocyte differentiation of mouse embryonic stem cells. 査読 国際誌

    Shinsuke Yuasa, Yuji Itabashi, Uichi Koshimizu, Tomofumi Tanaka, Keijiro Sugimura, Masayoshi Kinoshita, Fumiyuki Hattori, Shin-ichi Fukami, Takuya Shimazaki, Satoshi Ogawa, Hideyuki Okano, Keiichi Fukuda

    Nature biotechnology   23 ( 5 )   607 - 11   2005年5月

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    記述言語:英語  

    Embryonic stem (ES) cells are a promising source of cardiomyocytes, but clinical application of ES cells has been hindered by the lack of reliable selective differentiation methods. Differentiation into any lineage is partly dependent on the regulatory mechanisms of normal early development. Although several signals, including bone morphogenetic protein (BMP), Wnt and FGF, are involved in heart development, scarce evidence is available about the exact signals that mediate cardiomyocyte differentiation. While investigating the involvement of BMP signaling in early heart formation in the mouse, we found that the BMP antagonist Noggin is transiently but strongly expressed in the heart-forming region during gastrulation and acts at the level of induction of mesendoderm to establish conditions conducive to cardiogenesis. We applied this finding to develop an effective protocol for obtaining cardiomyocytes from mouse ES cells by inhibition of BMP signaling.

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  • A new method for manufacturing cardiac cell sheets using fibrin-coated dishes and its electrophysiological studies by optical mapping. 査読 国際誌

    Yuji Itabashi, Shunichiro Miyoshi, Haruko Kawaguchi, Shinsuke Yuasa, Kojiro Tanimoto, Akira Furuta, Tatsuya Shimizu, Teruo Okano, Keiichi Fukuda, Satoshi Ogawa

    Artificial organs   29 ( 2 )   95 - 103   2005年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We developed a novel simple method for making functional myocardial cell sheets that may be used as transplants. Polymerized human fibrin-coated dishes were prepared with fibrinogen monomers mixed with thrombin. Neonatal rat cardiomyocytes cultured on these dishes formed myocardial cell sheets within 4 days. These cell sheets were easily dissociated intact from the polymerized fibrin layer, because the fibrin had been digested by intrinsic protease. Two overlaid myocardial cell sheets exhibited synchronized spontaneous beating and captured artificial pacing. Optical mapping confirmed that the conduction of the action potential between two partially overlaid myocardial cell sheets was established, and the action potential propagated across the junction without any delay. Transplanted three-layered myocardial cell sheets exhibited strong spontaneous beating and showed well-differentiated striations and an increase in cell size. This simple method of cell sheet engineering may also be applicable for various other cell types.

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  • 血管新生抑制因子chondromodulin-1の心臓における発現

    吉岡 正豊, 潮見 隆之, 岡田 保典, 開 祐司, 湯浅 慎介, 松村 圭祐, 遠藤 仁, 鬼塚 岳志, 福田 恵一, 小川 聡

    脈管学   44 ( 9 )   442 - 442   2004年9月

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    記述言語:日本語   出版者・発行元:(一社)日本脈管学会  

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  • Cardiomyocytes undergo cells division following myocardial infarction is a spatially and temporally restricted event in rats. 査読 国際誌

    Shinsuke Yuasa, Keiichi Fukuda, Yuichi Tomita, Jun Fujita, Masaki Ieda, Satoko Tahara, Yuji Itabashi, Takashi Yagi, Haruko Kawaguchi, Yasuyo Hisaka, Satoshi Ogawa

    Molecular and cellular biochemistry   259 ( 1-2 )   177 - 81   2004年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Dividing cardiomyocytes are observed in autopsied human hearts following recent myocardial infarction, however there is a lack of information in the literature on the division of these cells. In this study we used a rat model to investigate how and when adult mammalian cardiomyocytes proliferate by cell division after myocardial infarction. Myocardial infarction was induced in Wistar rats by ligation of the left coronary artery. The rats were sacrificed periodically up to 28 days following induced myocardial infarction, and the hearts subjected to microscopic investigation. Cardiomyocytes entering the cell cycle were assayed by observation of nuclear morphology and measuring expression of Ki-67, a proliferating cell marker. Ki-67 positive cardiomyocytes and dividing nuclei were observed initially after 1 day. After 2 days dividing cells gradually increased in number at the ischemic border zone, reaching a peak increase of 1.12% after 3 days, then gradually decreasing in number. Dividing nuclei increased at the ischemic border zone after 3 days, peaked by 0.14% at day 5, and then decreased. In contrast, Ki-67 positive cells and dividing nuclei were limited in number in the non-ischemic area throughout all experiments. In conclusion, mitogenic cardiomyocytes are present in the adult rat heart following myocardial infarction, but were spatially and temporally restricted.

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  • A case of systemic lupus erythematosus presenting with rectal ulcers as the initial clinical manifestation of disease 査読

    Shinsuke Yuasa, Akira Suwa, Michito Hirakata, Norifumi Hibi, Yasushi Iwao, Koichi Koizumi, Tsuneyo Mimori, Yasuo Ikeda

    Clinical and Experimental Rheumatology   20 ( 3 )   407 - 410   2002年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Gastrointestinal involvement is often seen in patients with systemic lupus erythematosus (SLE). All parts of the gastrointestinal tract may be affected. However, rectal involvement at onset is rare. We describe here a case of SLE in which rectal ulcers due to vasculitis occurred as the initial manifestation of the disease without involvement of any other organ. The ulcers worsened, along with the appearance of lupus nephritis 5 years later. When steroid therapy was initiated, there was rapid clinical and radiographic improvement. Our case suggests that rectal ulcer is a rare but important complication of SLE and can represent the initial and sole clinical manifestation of the disease.

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MISC

  • 巨大深部静脈血栓症および肺血栓塞栓症を発症した生体肺移植後妊娠の一例

    海井 智彦, 平出 貴裕, 小柳 喬幸, 醍醐 恭平, 岸野 喜一, 北方 博規, 白石 泰之, 湯浅 慎介, 福島 裕之, 山岸 敬幸, 福田 恵一

    日本心臓病学会学術集会抄録   71回   P - 2   2023年9月

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    記述言語:日本語   出版者・発行元:(一社)日本心臓病学会  

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  • バルーン肺動脈形成術後の急性肺血栓塞栓症に対して抗凝固療法の変更が有効であった慢性血栓塞栓性肺高血圧症の1例

    梅井 智彦, 岸野 喜一, 川上 崇史, 平出 貴裕, 白石 泰之, 猪原 拓, 湯浅 慎介, 福田 恵一

    心臓   55 ( 7 )   743 - 748   2023年7月

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    記述言語:日本語   出版者・発行元:(公財)日本心臓財団  

    症例は65歳男性で、労作時呼吸困難を主訴とした。リバーロキサバンによる抗凝固療法中の慢性血栓塞栓性肺高血圧症に対し、バルーン肺動脈形成(BPA)目的で入院した。BPA治療後、労作時息切れ症の改善を認めたが、2ヵ月後に再増悪を認めた。肺動脈造影では左A10に血栓を疑う造影欠損を認め、肺高血圧症も認めた。吸引とバルーン拡張を繰り返したが、造影欠損の完全な消失は得られなかった。赤色血栓が吸引されたため、亜急性期新鮮血栓を疑い、ヘパリン持続静注治療後にワルファリンに切り替えた。肺高血圧症にはリオシグアトを導入した。血栓は完全に消失し、血流も良好で、労作時息切れ症状も改善した。現在まで再燃なく経過良好である。

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  • 補体C3-D因子-C3a受容体のシグナル経路は右室不全における心臓リモデリングを制御する

    伊藤 章吾, 湯浅 慎介, 片岡 雅晴, 福本 義弘, 福田 恵一

    日本肺高血圧・肺循環学会学術集会抄録集   8回   20 - 20   2023年6月

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    記述言語:日本語   出版者・発行元:日本肺高血圧・肺循環学会  

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  • ステロイド漸減中に肺高血圧症の増悪を認めたサルコイドーシスの1例

    佐藤 正幸, 新屋 貴章, 平出 貴裕, 北方 博規, 岸野 喜一, 白石 泰之, 湯浅 慎介, 福田 恵一

    日本内科学会関東地方会   686回   46 - 46   2023年5月

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    記述言語:日本語   出版者・発行元:日本内科学会-関東地方会  

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  • 機械学習を用いた循環器疾患創薬基盤技術の開発

    湯浅 慎介

    先進医薬研究振興財団研究成果報告集   2022年度   238 - 239   2023年3月

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    記述言語:日本語   出版者・発行元:(公財)先進医薬研究振興財団  

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  • 【循環器病学の未来-基本計画から考える循環器病学のグランドデザイン】AI・数理モデルによる循環器疾患診療・研究の変貌 人工知能の循環器基礎研究への応用と展望

    湯浅 慎介

    医学のあゆみ   283 ( 14 )   1359 - 1362   2022年12月

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    記述言語:日本語   出版者・発行元:医歯薬出版(株)  

    近年の人工知能(AI)の進歩は著しく,さまざまな分野では社会実装されている.これまでの基礎研究におけるAIの利用は,網羅的遺伝子発現解析におけるクラスタリングやゲノム解析などに用いられてきた.AIによる画像認識は顔認識や自動運転など日常生活に広く取り入れられているが,基礎研究においてはあまり用いられてこなかった.基礎研究においては細胞を用いたさまざまな研究がなされており,細胞の種類,形体や状態は主に免疫染色を用いて顕微鏡により観察されている.一方,位相差顕微鏡によっても細胞の特徴を描出することは可能であるが,免疫染色などを用いないと人間が詳細な情報を得ることは困難である.しかし機械学習を用いることにより,位相差顕微鏡画像から多能性幹細胞に由来する分化細胞の種類を自動認識することや,病的細胞の自動判別系を確立することが可能である.これらの技術は今後ますます発展していくことが想定され,AIを用いることで循環器基礎研究も飛躍的に発展していくことが期待される.(著者抄録)

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    その他リンク: https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J00060&link_issn=&doc_id=20221228010027&doc_link_id=issn%3D0039-2359%26volume%3D283%26issue%3D14%26spage%3D1359&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0039-2359%26volume%3D283%26issue%3D14%26spage%3D1359&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

  • Single cell解析に基づく心不全特異的な線維芽細胞集団を標的とした心不全の新規治療戦略

    小室 仁, 橋本 寿之, 勝木 俊臣, 楠本 大, 湯浅 慎介, 福田 恵一

    心臓   54 ( 12 )   1405 - 1405   2022年12月

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    記述言語:日本語   出版者・発行元:(公財)日本心臓財団  

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  • 重症右心不全を合併する慢性血栓塞栓性肺高血圧症に対するバルーン肺動脈形成術の効果と安全性

    井合 渉, 川上 崇史, 木村 舞, 片岡 雅晴, 荒井 隆秀, 林田 健太郎, 金澤 英明, 湯浅 慎介, 福田 恵一

    日本心臓病学会学術集会抄録   70回   O - 3   2022年9月

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    記述言語:日本語   出版者・発行元:(一社)日本心臓病学会  

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  • 右心不全マウスモデルを用いた右心不全特異的な治療法の創出

    伊藤 章吾, 湯浅 慎介, 山川 裕之, 矢田 浩崇, 伊藤 桂, 片岡 雅晴, 福本 義弘, 福田 恵一

    日本心臓病学会学術集会抄録   70回   O - 1   2022年9月

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    記述言語:日本語   出版者・発行元:(一社)日本心臓病学会  

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  • 終末期医療を考える:アドバンス・ケア・プランニングの導入における現状と課題 心不全患者でのアドバンス・ケア・プランニング導入における社会的孤立の重要性

    北方 博規, 河野 隆志, 香坂 俊, 中野 直美, 関根 乙矢, 白石 泰之, 岸野 喜一, 勝俣 良紀, 湯浅 慎介, 福田 恵一

    日本心臓病学会学術集会抄録   70回   P1 - 2   2022年9月

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    記述言語:日本語   出版者・発行元:(一社)日本心臓病学会  

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  • 高安動脈炎に伴う重度大動脈弁閉鎖不全症に対して免疫抑制療法先行後に外科的大動脈弁置換術を実施した一例

    秋葉 庸平, 岸野 喜一, 白石 泰之, 勝俣 良紀, 湯浅 慎介, 近藤 泰, 伊藤 努, 福田 恵一

    日本心臓病学会学術集会抄録   70回   C - 5   2022年9月

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    記述言語:日本語   出版者・発行元:(一社)日本心臓病学会  

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  • Whipple病による血液培養陰性感染性心内膜炎と診断した1例

    遠藤 洵之介, 中村 貴裕, 北方 博規, 白石 泰之, 岸野 喜一, 香坂 俊, 猪原 拓, 湯浅 慎介, 福田 恵一

    日本内科学会関東地方会   679回   29 - 29   2022年7月

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    記述言語:日本語   出版者・発行元:日本内科学会-関東地方会  

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  • 補体副経路を標的とした右心不全に対する新規治療法の開発

    伊藤 章吾, 湯浅 慎介, 伊藤 桂, 矢田 浩崇, 大坂 瑞子, 吉田 雅幸, 桃井 瑞生, 片岡 雅晴, 福本 義弘

    血管   45 ( 1 )   42 - 42   2022年6月

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    記述言語:日本語   出版者・発行元:日本心脈管作動物質学会  

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  • リジュベネーションを目指した老化研究 機械学習を用いた老化治療薬の探索

    湯浅 慎介

    日本老年医学会雑誌   59 ( Suppl. )   16 - 16   2022年5月

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    記述言語:日本語   出版者・発行元:(一社)日本老年医学会  

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  • iPS細胞を用いた遺伝性不整脈・心筋疾患研究の最前線

    湯浅 慎介

    循環器内科   91 ( 3 )   386 - 390   2022年3月

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    記述言語:日本語   出版者・発行元:(有)科学評論社  

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  • Single cell解析に基づく心不全特異的な線維芽細胞集団を標的とした心不全の新規治療戦略

    小室 仁, 橋本 寿之, 楠本 大, 湯浅 慎介

    大和証券ヘルス財団研究業績集   ( 45 )   36 - 41   2022年3月

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    記述言語:日本語   出版者・発行元:(公財)大和証券ヘルス財団  

    心臓線維芽細胞に発現する転写因子c-Mycの心臓における役割を、single cell解析に基づいて調べ、心臓線維芽細胞が心不全の治療標的となり得るか検証した。心不全時に特異的に出現する心臓線維芽細胞集団を見つけ、その細胞集団ではc-Mycが特徴的に発現していることを見出した。さらに、その線維芽細胞においてc-Mycは心不全の進行に寄与していることが示唆された。一方、c-Mycを心臓線維芽細胞で過剰発現させ、その遺伝子発現を網羅的に解析したところ、その細胞自体は炎症や線維化に関連した遺伝子の発現が低下しており、心不全の進行を抑制する働きが予想された。これらのことから、in vivoではc-Myc陽性心不全特異的心臓線維芽細胞は別の細胞と相互作用することにより、心不全の進行に寄与しているという仮説が立てられた。

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  • mRNA-1273 COVID-19ワクチン接種後の心筋炎の再発(Recurrence of Myopericarditis following mRNA-1273 COVID-19 Vaccination)

    渡邊 桂子, 梅井 智彦, 都築 一平, 岸野 喜一, 白石 泰之, 猪原 拓, 湯浅 慎介, 福田 恵一

    日本循環器学会学術集会抄録集   86回   CRRP2 - 7   2022年3月

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    記述言語:英語   出版者・発行元:(一社)日本循環器学会  

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  • 右心不全に対する治療方法の開発に向けて

    湯浅 慎介

    循環器内科   91 ( 2 )   226 - 227   2022年2月

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    記述言語:日本語   出版者・発行元:(有)科学評論社  

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  • 2種のASD閉鎖デバイス間におけるASDの解剖学的特徴と術後臨床成績の比較

    三浦 光太郎, 金澤 英明, 木村 舞, 荒井 隆秀, 川上 崇史, 湯浅 慎介, 林田 健太郎, 品田 慶太郎, 鶴田 ひかる, 福田 恵一

    日本成人先天性心疾患学会雑誌   11 ( 1 )   187 - 187   2022年1月

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    記述言語:日本語   出版者・発行元:(一社)日本成人先天性心疾患学会  

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  • 拡張型心筋症の経過中に腹水貯留による腹部コンパートメント症候群を来した1例

    渡邊 桂子, 梅井 智彦, 岸野 喜一, 遠山 周吾, 白石 泰之, 猪原 拓, 湯浅 慎介, 須永 将梧, ちょ 柏松, 福田 恵一

    日本内科学会関東地方会   673回   45 - 45   2021年11月

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    記述言語:日本語   出版者・発行元:日本内科学会-関東地方会  

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  • Preferences and Attitudes Toward Advance Care Planning and End-of-life Care of Patients Hospitalized for Heart Failure

    Hiroki Kitakata, Takashi Kohno, Shun Kohsaka, Daisuke Fujisawa, Yasuyuki Shiraishi, Yoshinori Katsumata, Shinsuke Yuasa, Keiichi Fukuda

    CIRCULATION   140   2019年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • 原因不明の470症例の心筋症患者に対し、次世代シークエンスによる心筋症遺伝子解析施行し、心Fabry病が発見された一例

    山川 裕之, 相澤 義泰, 湯浅 慎介, 佐野 元昭, 福田 恵一

    日本心臓病学会学術集会抄録   67回   O - 016   2019年9月

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    記述言語:日本語   出版者・発行元:(一社)日本心臓病学会  

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  • サルコメアにおける顆粒球コロニー刺激因子受容体の発現とその作用

    林地 のぞみ, 赤松 和土, 湯浅 慎介, 福田 恵一, 平澤 恵理, 島田 和典

    日本筋学会学術集会プログラム・抄録集   5回   134 - 134   2019年8月

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    記述言語:日本語   出版者・発行元:日本筋学会  

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  • Nightmares and Insomnia Are Independently Associated With Depression and Anxiety in Patients Hospitalized With Cardiovascular Diseases

    Haruaki Horie, Takashi Kohno, Yasuyuki Shiraishi, Yoshinori Katsumata, Kentaro Hayashida, Shinsuke Yuasa, Shun Kohsaka, Seiji Takatsuki, Keiichi Fukuda

    CIRCULATION   138   2018年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Sex Differences in Prevalence and Association of Sleep and Psychological Disturbances in Patients Hospitalized With Cardiovascular Diseases

    Yuichi Jono, Takashi Kohno, Hiroki Kitakata, Ryoma Fukuoka, Yasuyuki Shiraishi, Yoshinori Katsumata, Kentaro Hayashida, Shinsuke Yuasa, Shun Kohsaka, Seiji Takatsuki, Keiichi Fukuda

    CIRCULATION   138   2018年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Application and Procedure-Related Outcome of Early Invasive Strategy in Non-ST Segment Elevation Acute Coronary Syndrome in Relation to the Pre-Procedural Risk Assessment

    Nobuhiro Ikemura, Yasuyuki Shiraishi, Mitsuaki Sawano, Ikuko Ueda, Yohei Numasawa, Shigetaka Noma, Masahiro Suzuki, Kentaro Hayashida, Shinsuke Yuasa, Yukihiko Momiyama, Hiroaki Miyata, Keiichi Fukuda, Shun Kohsaka

    CIRCULATION   138   2018年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Unroofed coronary sinusを伴った二次孔型心房中隔欠損症に対して経皮的心房中隔閉鎖術を行った一例

    三浦 光太郎, 金澤 英明, 荒井 隆秀, 川上 崇史, 湯浅 慎介, 林田 健太郎, 山田 祥岳, 陣崎 雅弘, 福田 恵一

    日本心血管インターベンション治療学会抄録集   27回   MP253 - MP253   2018年8月

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    記述言語:日本語   出版者・発行元:(一社)日本心血管インターベンション治療学会  

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  • Unroofed coronary sinusを伴った二次孔型心房中隔欠損症に対して経皮的心房中隔閉鎖術を行った一例

    三浦 光太郎, 金澤 英明, 荒井 隆秀, 川上 崇史, 湯浅 慎介, 林田 健太郎, 山田 祥岳, 陣崎 雅弘, 福田 恵一

    日本心血管インターベンション治療学会抄録集   27回   MP253 - MP253   2018年8月

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    記述言語:英語   出版者・発行元:(一社)日本心血管インターベンション治療学会  

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  • 補体副経路を標的とした右室起源致死性不整脈に対する新たな治療法の開発

    伊藤 章吾, 関 倫久, 湯浅 慎介, 小室 仁, 勝木 俊臣, 木村 舞, 岸野 喜一, 楠本 大, 鈴木 邦道, 柚崎 通介, 福田 恵一

    補体   55 ( 1 )   48 - 49   2018年8月

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    記述言語:日本語   出版者・発行元:(一社)日本補体学会  

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  • EFFICACY AND SAFETY OF PRE-PROCEDURAL PRASUGREL IN ASIANS UNDERGOING PERCUTANEOUS CORONARY INTERVENTION FOR ACUTE CORONARY SYNDROME: A REPORT FROM A JAPANESE MULTICENTER REGISTRY

    Satoshi Shoji, Mitsuaki Sawano, Yasuyuki Shiraishi, Nobuhiro Ikemura, Ikuko Ueda, Yohei Numasawa, Shigetaka Noma, Masahiro Suzuki, Kentaro Hayashida, Shinsuke Yuasa, Keiichi Fukuda, Shun Kohsaka

    JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY   71 ( 11 )   170 - 170   2018年3月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ELSEVIER SCIENCE INC  

    DOI: 10.1016/S0735-1097(18)30711-3

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  • 臨床応用前夜となったヒトiPS細胞を用いた心臓再生医療

    福田 恵一, 遠山 周吾, 関 倫久, 中嶋 一晶, 湯浅 慎介, 金澤 英明, 藤田 淳

    医工学治療   30 ( Suppl. )   47 - 47   2018年3月

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    記述言語:日本語   出版者・発行元:(NPO)日本医工学治療学会  

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  • 患者特異的iPSCを用いた進行性心臓伝導障害の研究(Studying Progressive Cardiac Conduction Disturbance with Patient-specific iPSCs)

    元田 親章, 湯浅 慎介, 中野 由紀子, 福田 恵一, 木原 康樹

    日本循環器学会学術集会抄録集   82回   PJ016 - 2   2018年3月

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    記述言語:英語   出版者・発行元:(一社)日本循環器学会  

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  • Werner症候群のモデルにおいてRhoキナーゼ活性は老化表現型を調節する(Rho kinase activity regulates aging phenotype in the model of Werner syndrome)

    四津 学人, 湯浅 慎介, 代田 浩之, 福田 恵一

    日本心臓病学会学術集会抄録   65回   YIA - 4   2017年9月

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    記述言語:英語   出版者・発行元:(一社)日本心臓病学会  

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  • 心筋再生医療 前臨床研究から臨床応用へ向けた課題とその克服

    福田 恵一, 遠山 周吾, 國富 晃, 湯浅 慎介, 中嶋 一晶, 関 倫彦, 藤田 淳

    糖尿病   60 ( Suppl.1 )   S - 5   2017年4月

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    記述言語:日本語   出版者・発行元:(一社)日本糖尿病学会  

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  • Irx6はRXRシグナルを均衡させて心臓の炎症を制御する(Irx6 Regulates Cardiac Inflammation by Balancing RXR Signals)

    元田 親章, 湯浅 慎介, 木原 康樹, 福田 恵一

    日本循環器学会学術集会抄録集   81回   PJ - 175   2017年3月

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    記述言語:英語   出版者・発行元:(一社)日本循環器学会  

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  • 経皮的冠動脈インターベンション中の医原性冠動脈解離の発生率と予測因子 現代多施設共同PCIレジストリからの報告(Incidence and Predictors of Iatrogenic Coronary Artery Dissection during Percutaneous Coronary Intervention: A Report from Contemporary Multicenter PCI Registry)

    平出 貴裕, 香坂 俊, 植田 育子, 澤野 充明, 池村 修寛, 勝木 俊臣, 庄司 聡, 前川 裕一郎, 湯浅 慎介, 林田 健太郎, 鈴木 雅裕, 沼澤 洋平, 宮田 裕章, 福田 恵一

    日本循環器学会学術集会抄録集   81回   PJ - 084   2017年3月

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    記述言語:英語   出版者・発行元:(一社)日本循環器学会  

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  • 20年後の再生医療を予測する 循環器領域へのiPS細胞の臨床応用の現状

    福田 恵一, 遠山 周吾, 関 倫久, 湯浅 慎介, 藤田 淳

    循環器専門医   24 ( 2 )   242 - 251   2016年8月

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    記述言語:日本語   出版者・発行元:(一社)日本循環器学会  

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  • iPS細胞を用いた循環器領域の再生医療

    福田恵一, 遠山周吾, 関倫久, 湯浅慎介, 下地顕一郎, 藤田淳

    日本内科学会雑誌   105 ( 7 )   1287‐1295   2016年7月

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    記述言語:日本語  

    DOI: 10.2169/naika.105.1287

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  • Large ASDに対するワイヤーアシストテクニックを用いたデバイス留置術

    金澤 英明, 河村 朗夫, 木村 舞, 荒井 隆秀, 川上 崇史, 林田 健太郎, 湯浅 慎介, 前川 裕一郎, 鶴田 ひかる, 板橋 裕史, 村田 光繁, 福田 恵一

    日本心血管インターベンション治療学会抄録集   25回   MO378 - MO378   2016年7月

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    記述言語:英語   出版者・発行元:(一社)日本心血管インターベンション治療学会  

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  • The Modeling of Werner Syndrome by Induced Pluripotent Stem Cells

    Gakuto Yozu, Shinsuke Yuasa, Chikaaki Motoda, Dai Kusumoto, Akira Kunitomi, Shin Kashimura, Makoto Takei, Masaya Shimojima, Nozomi Hayashiji, Tomohisa Seki, Shugo Tohyama, Koutaro Yokote, Hiroyuki Daita, Keiichi Fukuda

    CIRCULATION   132   2015年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • MDCTガイド下経皮的中隔心筋焼灼術後腎機能の著しい改善を認めた重症閉塞性肥大型心筋症の一例(Improved renal function in a patient with HOCM after multidetector computed tomographyguided PTSMA)

    Maekawa Yuichiro, Akita Keitaro, Tsuruta Hikaru, Yashima Fumiaki, Inohara Taku, Kimura Mai, Yamada Yoshitake, Kawakami Takashi, Kanazawa Hideaki, Hayashida Kentaro, Yuasa Shinsuke, Murata Mitsushige, Jinzaki Masahiro, Fukuda Keiichi

    日本心血管インターベンション治療学会抄録集   24回   1641 - 1641   2015年7月

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    記述言語:英語   出版者・発行元:(一社)日本心血管インターベンション治療学会  

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  • 薬物療法抵抗性閉塞性肥大型心筋症に対するMDCTガイド下経皮的中隔心筋焼灼術の左心房容積に対する効果(Significant reduction of LA volume after MDCT-guided PTSMA for drug-refractory HOCM)

    Maekawa Yuichiro, Akita Keitaro, Tsuruta Hikaru, Yamada Yoshitake, Kimura Mai, Inohara Taku, Yashima Fumiaki, Kawakami Takashi, Kanazawa Hideaki, Hayashida Kentaro, Yuasa Shinsuke, Murata Mitsushige, Jinzaki Masahiro, Fukuda Keiichi

    日本心血管インターベンション治療学会抄録集   24回   1642 - 1642   2015年7月

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    記述言語:英語   出版者・発行元:(一社)日本心血管インターベンション治療学会  

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  • Uncontrolled Endothelial Migration In Hereditary Hemorrhagic Telangiectasia: Disease Modeling With Ips Cell

    Makoto Takei, Shinsuke Yuasa, Dai Kusumoto, Akira Kunitomi, Shin Kashiumura, Gakuto Yodu, Masaya Shimojima, Chikaaki Motoda, Atsushi Tanaka, Yusuke Kuroda, Shugo Tohyama, Tomohisa Seki, Keiichi Fukuda

    CIRCULATION RESEARCH   117   2015年7月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Andersen-Tawil症候群iPS細胞に由来する心筋細胞において逆モードNa+/Ca2+交換輸送体阻害薬は不整脈原性基質を抑制する(Reverse-mode Na+/Ca2+ Exchanger Inhibitor Suppresses an Arrhythmogenic Substrate in Andersen-Tawil Syndrome-induced Pluripotent Stem Cell-derived Cardiomyocytes)

    黒田 裕介, 湯浅 慎介, 堀江 稔, 堀米 仁志, 神谷 香一郎, 福田 恵一

    日本心臓病学会学術集会抄録   62回   YIA - 3   2014年9月

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    記述言語:英語   出版者・発行元:(一社)日本心臓病学会  

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  • Novel Pathological Detection System of Induced Pluripotent Stem Cell-Derived Cardiomyocytes Using T-Cell Receptor Gene Locus for Cell Transplantation Therapy

    Yoshikazu Kishino, Tomohisa Seki, Shugo Tohyama, Shinsuke Yuasa, Jun Fujita, Motoaki Sano, Keiichi Fukuda

    CIRCULATION   128 ( 22 )   2013年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • 心サルコイドーシスの診断、治療におけるFDG-PET検査の有用性についての検討

    藤田 淳, 中原 理紀, 香坂 俊, 猪原 拓, 田村 雄一, 河野 隆志, 江頭 徹, 西山 信大, 湯浅 慎介, 前川 裕一郎, 村田 光繁, 牧野 伸司, 高月 誠司, 佐野 元昭, 栗林 幸夫, 福田 恵一

    日本心臓病学会誌   8 ( Suppl.I )   547 - 547   2013年9月

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    記述言語:日本語   出版者・発行元:(一社)日本心臓病学会  

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  • 慢性腎臓病を合併した慢性肺血栓塞栓性肺高血圧症に対してバルーン肺動脈形成術を施行した一例

    宗形 昌儒, 川上 崇史, 田村 雄一, 林田 健太郎, 金澤 英明, 湯浅 慎介, 前川 裕一郎, 河村 朗夫, 福田 恵一

    日本心臓病学会誌   8 ( Suppl.I )   694 - 694   2013年9月

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    記述言語:日本語   出版者・発行元:(一社)日本心臓病学会  

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  • 計6回のバルーン肺動脈形成術(BPA)により肺動脈圧が正常域まで改善できた慢性肺血栓塞栓性肺高血圧症の一例

    宗形 昌儒, 川上 崇史, 田村 雄一, 林田 健太郎, 金澤 英明, 湯浅 慎介, 前川 裕一郎, 河村 朗夫, 福田 恵一

    日本心臓病学会誌   8 ( Suppl.I )   695 - 695   2013年9月

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    記述言語:日本語   出版者・発行元:(一社)日本心臓病学会  

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  • iPS細胞を用いた循環器疾患モデル構築 (特集 致死性不整脈診療の最前線) -- (致死性不整脈疾患への新たなアプローチ法)

    湯浅 慎介

    最新医学   68 ( 7 )   1525 - 1530   2013年7月

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    記述言語:日本語   出版者・発行元:最新医学社  

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    その他リンク: http://search.jamas.or.jp/link/ui/2013318779

  • iPS細胞を用いた循環器疾患モデル構築とその応用 (第1土曜特集 イオンチャネル病のすべて) -- (イオンチャネル病研究へのアプローチ)

    湯浅 慎介

    医学のあゆみ   245 ( 9 )   704 - 709   2013年6月

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    記述言語:日本語   出版者・発行元:医歯薬出版  

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    その他リンク: http://search.jamas.or.jp/link/ui/2013226911

  • Up-to-Date : Imaging & Therapy : iPS細胞を用いた循環器診療はどこまで進んだか?

    湯浅 慎介

    Circulation up-to-date   8 ( 2 )   188 - 193   2013年4月

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    記述言語:日本語   出版者・発行元:メディカ出版  

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    その他リンク: http://search.jamas.or.jp/link/ui/2013172459

  • Versican Secretion from Endocardium is Required for Chamber Formation via The Recruitment of Cardiac Progenitors

    Sung-Han Yoon, Yuta Higashikuse, Toshimi Kageyama, Mayumi Oda, Ruri Kaneda, Motoaki Sano, Shinsuke Yuasa, Misato Fujita, Atsushi Kawakami, Atsushi Shimizu, Sonoko Hatano, Hideto Watanabe, Akira Kudo, Shinji Makino, Keiichi Fukuda

    CIRCULATION   126 ( 21 )   2012年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Amplatzer心房中隔欠損閉鎖栓と最小侵襲手術の時代における成人心房中隔欠損の管理(Management of Adult Atrial Septal Defect in the Era of Amplatzer Septal Occluder and Minimally Invasive Cardiac Surgery)

    河村 朗夫, 岡本 一真, 鶴田 ひかる, 村田 光繁, 吉武 明弘, 志水 秀行, 工藤 樹彦, 古梶 清和, 饗庭 了, 前川 裕一郎, 湯浅 慎介, 荒井 隆秀, 四津 良平, 福田 恵一

    日本心臓病学会誌   7 ( Suppl.I )   367 - 367   2012年8月

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    記述言語:英語   出版者・発行元:(一社)日本心臓病学会  

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  • 臨床応用へ向けたiPS細胞樹立方法の開発 (特集 iPS細胞を用いた心臓病の診断と治療)

    湯浅 慎介

    呼吸と循環   60 ( 5 )   459 - 463   2012年5月

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    記述言語:日本語   出版者・発行元:医学書院  

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  • 心筋細胞特異的遺伝子のDNAメチル化状態はgene body領域における転写とエピジェネティック状態の関係に影響を及ぼす

    小田真由美, 小田真由美, 牧野伸司, 榎本博一, 八戸宏二朗, 金田るり, 湯浅慎介, 福田恵一

    日本分子生物学会年会プログラム・要旨集(Web)   35th   2012年

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  • Distinct Metabolic Flow Enables Large-Scale Purification of Pluripotent Stem Cell-Derived Cardiomyocytes

    Shugo Tohyama, Fumiyuki Hattori, Motoaki Sano, Takako Hishiki, Yoshiko Nagahata, Tomofumi Tanaka, Shinsuke Yuasa, Makoto Suematsu, Keiichi Fukuda

    CIRCULATION   124 ( 21 )   2011年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • QT延長症候群特異的人工多能性幹細胞を用いた疾患の性質決定(Disease characterization using long QT syndrome-specific induced pluripotent stem cells)

    江頭 徹, 湯浅 慎介, 鈴木 智之, 八戸 宏二郎, 山川 裕之, 相澤 義泰, 村田 光繁, 三好 俊一郎, 神谷 香一郎, 福田 恵一

    日本心臓病学会誌   6 ( Suppl.I )   234 - 234   2011年8月

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    記述言語:英語   出版者・発行元:(一社)日本心臓病学会  

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  • 最新基礎科学 知っておきたい 1滴の血液からiPS細胞

    関倫久, 湯浅慎介, 福田恵一

    臨床整形外科   46 ( 4 )   354 - 357   2011年4月

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    記述言語:日本語   出版者・発行元:医学書院  

    DOI: 10.11477/mf.1408101965

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  • Novel Method 'Fucci' Elucidated the Cardiomyocyte Cell Cycle Dynamics in Various Life Stages

    Hisayuki Hashimoto, Shinsuke Yuasa, Shugo Tohyama, Tomohisa Seki, Toru Egashira, Kojiro Yae, Dai Kusumoto, Masaki Kodaira, Fumiyuki Hattori, Naoto Muraoka, Hidenori Tabata, Kazunori Nakajima, Asako Sakaue-Sawano, Atsushi Miyawaki, Keiichi Fukuda

    CIRCULATION   122 ( 21 )   2010年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Versican is Essential for Chamber Formation by Recruiting Cardiac Progenitor Cells from the Outflow Tract in Medaka Fish

    Sung Han Yoon, Shinji Makino, Atsushi Shimizu, Yuta Higashikuse, Mayumi Oda, Misato Fujita, Atsushi Kawakami, Akira Kudo, Shinsuke Yuasa, Motoaki Sano, Keiichi Fukuda

    CIRCULATION   122 ( 21 )   2010年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • DNA Methylation Changes in the b-MHC Locus Mediate Gene Regulation by Antisense RNA in Mouse Postnatal Cardiomyocyte Development

    Mayumi Oda, Shinji Makino, Shinsuke Yuasa, Sung Han Yoon, Yuta Higashikuse, Kojiro Yae, Ruri Kaneda, Mitsushige Murata, Motoaki Sano, Keiichi Fukuda

    CIRCULATION   122 ( 21 )   2010年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • ヒトiPS由来心筋細胞の電気生理学的特性について

    遠山 周吾, 村田 光繁, 黒川 洵子, Fernando Lopez-Redondo, 服部 文幸, 水澤 美香, 山川 裕之, 橋本 寿之, 江頭 徹, 関 朋久, 扇野 泰行, 八戸 宏二郎, 湯浅 慎介, 福田 恵一

    心電図   30 ( Suppl.4 )   S - 4   2010年9月

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    記述言語:日本語   出版者・発行元:(一社)日本不整脈心電学会  

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  • My Technology G-CSFを用いたES細胞,iPS細胞由来心筋前駆細胞の増殖促進

    湯浅 慎介, 福田 恵一

    細胞工学   29 ( 12 )   1258 - 1261   2010年

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    記述言語:日本語   出版者・発行元:学研メディカル秀潤社  

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  • Molecular Characterization of Induced Pluripotent Stem (iPS) Cell-Derived Cardiomyocytes

    Yohei Ohno, Shinsuke Yuasa, Toru Egashira, Tomohisa Seki, Hisayuki Hashimoto, Shugo Toyama, Sung Han Yoon, Takahide Arai, Chen Hao, Tomofumi Tanaka, Fumiyuki Hattori, Kojiro Yae, Mitsushige Murata, Satoshi Ogawa, Shinya Yamanaka, Keiichi Fukuda

    CIRCULATION   120 ( 18 )   S765 - S765   2009年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Generation of Induced Pluripotent Stem Cells in Healthy Volunteers and Patients With Hereditary Heart Disease

    Toru Egashira, Shinsuke Yuasa, Yohei Ohno, Tomohisa Seki, Hisayuki Hashimoto, Shogo Toyama, Sung H. Yoon, Chen Hao, Tomofumi Tanaka, Fumiyuki Hattori, Kojiro Yae, Mitsushige Murata, Satoshi Ogawa, Keiichi Fukuda

    CIRCULATION   120 ( 18 )   S619 - S619   2009年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Functional Characterization of Human Induced Pluripotent Stem Cell Derived Cardiomyocytes

    Shugo Tohyama, Mitsushige Murata, Fumiyuki Hattori, Tomofumi Tanaka, Hao Chen, Hiromi Yamashita, Yusuke Sato, Toru Egashira, Tomohisa Seki, Hisayuki Hashimoto, Yohei Ohno, Yuichi Tamura, Shinsuke Yuasa, Satoshi Ogawa, Keiichi Fukuda

    CIRCULATION   120 ( 18 )   S723 - S723   2009年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • MicroRNA 142-3p Regulates Heart Development, Somitegenesis and Hematopoiesis in the Stage of Early Mesoderm Formation

    Takahiko Nishiyama, Ruri Kaneda, Sung Han Yoon, Toshimi Kageyama, Takahide Arai, Yuichi Tamura, Kentaro Hayashida, Hiroyuki Mano, Shinsuke Yuasa, Shinji Makino, Keiichi Fukuda

    CIRCULATION   120 ( 18 )   S605 - S605   2009年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • 低分子量G蛋白質Radによる心筋細胞内Ca2+動態の調節機構について

    山川 裕之, 村田 光繁, 矢田 浩崇, 相澤 義泰, 湯浅 慎介, 小川 聡, 村田 満, 牧野 信司, 佐野 元昭, 福田 恵一

    心電図   29 ( Suppl.3 )   S - 3   2009年6月

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    記述言語:日本語   出版者・発行元:(一社)日本不整脈心電学会  

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  • OE-348 DES can be a CABG Buster? : LMT-CYPHER(OE59,Coronary Revascularization, PCI (Complex Lesions) (IHD),Oral Presentation (English),The 73rd Annual Scientific Meeting of The Japanese Circulation Society)

    Hayashida Kentaro, Kawamura Akio, Yamane Masahisa, Asakura Yasushi, Kataoka Masaharu, Matumura Keisuke, Kanazawa Hideaki, Endo Ayaka, Ono Yohei, Arai Takahide, Jo Yusuke, Katayama Takaharu, Koide Kimi, Kageyama Toshimi, Yuasa Shinsuke, Maekawa Yuichiro, Ogawa Satoshi

    Circulation journal : official journal of the Japanese Circulation Society   73   262 - 262   2009年3月

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    記述言語:英語   出版者・発行元:社団法人日本循環器学会  

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  • Multiple roles for BMP signaling in cardiac development

    Shinsuke Yuasa, Keiichi Fukuda

    Drug Discovery Today: Therapeutic Strategies   5 ( 4 )   209 - 214   2008年12月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等  

    The bone morphogenetic protein (BMP) family is the largest subfamily of the transforming growth factor-beta (TGF-β) superfamily. Some BMPs are expressed before cardioblast formation and throughout the late stages of heart development. BMPs have crucial roles in a broad range of biological events, including cellular proliferation, differentiation, migration and apoptosis during organ development. At least six BMPs (BMP2, 4, 5, 6, 7 and 10) are expressed in the heart, where they have both independent and redundant functions. Experiments on genetically modified mice have demonstrated the importance of BMP signaling for heart morphogenesis after the mid-gestation stage. Interestingly, BMPs play a dual role in heart development. Precise regulation of BMP inhibition and BMP stimulation is required for proper heart development during the early stage of cardiomyocyte differentiation. Knowledge of embryogenesis is frequently used in studies of stem cell biology. Through the application of BMP signal regulation in cardiac development, many systems for the differentiation of embryonic stem (ES) cells into cardiomyocytes are developed. These results reveal the crucial role of temporal and spatial regulation of BMPs and BMP antagonists in heart development. © 2009 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.ddstr.2008.12.001

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  • The Potent Angiogenic Factor Periostin Accelerates Degeneration and Sclerosis of the Cardiac Valve Complex

    Daihiko Hakuno, Naritaka Kimura, Tokuhiro Kimura, Shinsuke Yuasa, Mitsushige Murata, Shinji Makino, Motoaki Sano, Yasunori Okada, Ryohei Yozu, Akira Kudo, Satoshi Ogawa, Keiichi Fukuda

    CIRCULATION   118 ( 18 )   S456 - S456   2008年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Imprinting Gene-Modified Parthenogenic ES Cells Can be a Novel Autologous Cell Source for Generating Regenerative Cardiomyocytes

    Toshimi Kageyama, Shinji Makino, Fumiyuki Hattori, Run Kaneda, Shinsuke Yuasa, Takeshi Onizuka, Sonhan Yun, Youhei Ohno, Jin Endo, Kenichirour Shimoji, Takohide Arai, Daihiko Hakuno, Tomofumi Tanaka, Kensuke Kimura, Hayashida Kentaro, Mitsushige Murata, Takaharu Katayama, Motoaki Sano, Tomoyuki Tokunaga, Tomohiro Kono, Satoshi Ogawa, Koichi Fukuda

    CIRCULATION   118 ( 18 )   S491 - S492   2008年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Neural Crest Stem Cells Supply Intrinsic Cardiac Adrenergic Cells and Contribute to Reinnervation after Myocardial Infarction in Mice

    Yuichi Tamura, Masaki Ieda, Keisuke Matsumura, Hideaki Kanazawa, Kensuke Kimura, Yasuyo Ieda, Jin Endo, Takahide Arai, Haruke Kawaguchi-Manabe, Yuichi Tomita, Shinsuke Yuasa, Motoaki Sano, Kazuto Kobayashi, Satoshi Ogawa, Keiichi Fukuda

    CIRCULATION   118 ( 18 )   S395 - S395   2008年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • DEXAMETHASONE INDUCES LATE PHASE OF CARDIOPROTECTION VIA A CYCLOOXYGENASE-2-DEPENDENT MECHANISM

    Kayoko Tamaki, Ken Shinmura, Motoaki Sano, Satori Tokudome, Jin Endo, Takaharu Katayama, Kentaro Hayashida, Shinsuke Yuasa, Ruri Kaneda, Shinji Makino, Keiichi Fukuda

    JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY   45   S32 - S32   2008年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD  

    DOI: 10.1016/j.yjmcc.2008.09.697

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  • Molecular Characterization, Safety and Feasibility of Induced Pluripotent Stem (iPS) Cell Derived Cardiomyocytes for Heart Regenerative Therapy

    Yohei Ohno, Shinsuke Yuasa, Takeshi Onizuka, Toru Egashira, Kenichiro Shimoji, Sung Han Yoon, Takahide Arai, Jin Endo, Toshimi Kageyama, Hao Chan, Tomofumi Tanaka, Fumiyuki Hattori, Satoshi Ogawa, Shinya Yamanaka, Keiichi Fukuda

    CIRCULATION   118 ( 18 )   S429 - S429   2008年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Dominant Negative Suppression of Red Leads to Intracellular Ca2+ Overload via Up-Regulation of Cardiac Ryanodine Receptor Activity

    Mitsushige Murata, Hirotaka Yada, Hiroyuki Yamakawa, Yoshiyasu Aizawa, Shinsuke Yuasa, Daihlko Hakuno, Shinji Makino, Motoaki Sano, Mitsuru Murata, Satoshi Ogawa, Keiichi Fukuda

    CIRCULATION   118 ( 18 )   S523 - S523   2008年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Sublethal Levels of Aldehydes Augmented Cardiac Anti-Oxidant Defense through Activation of elF2 alpha-ATF4 Pathway via GCN2 Kinase

    Takaharu Katayama, Motoaki Sano, Jin Endo, Kentaro Hayashida, Tomohiro Matsuhashi, Satori Tokudome, Toshimi Kageyama, Shinsuke Yuasa, Takeshi Adachi, Makoto Suematsu, Kiyomi Nishimaki, Ikuroh Ohsawa, Shigeo Ohta, Satoshi Ogawa, Keiichi Fukuda

    CIRCULATION   118 ( 18 )   S320 - S320   2008年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Activation of L-serine biosynthesis is indispensable for hormetic effects of aldehydes in the heart

    Jin Endo, Motoaki Sano, Takaharu Katayama, Takeshi Adachi, Kentaro Hayashida, Shinsuke Yuasa, Shinji Makino, Makoto Suematsu, Keiichi Fukuda, Satoshi Ogawai

    JOURNAL OF CARDIAC FAILURE   14 ( 7 )   S149 - S149   2008年9月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS  

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  • PJ-274 Wnt2 plays a key role in cardiac development via a non-canonical pathway(Development and differentiation(02)(M),Poster Session(Japanese),The 72nd Annual Scientific Meeting of the Japanese Circulation Society)

    Onizuka Takeshi, Yuasa Shinsuke, Shimoji Kenichiro, Sano Motoaki, Kimura Kensuke, Makino Shinji, Hakuno Daihiko, Murata Mitsushige, Kanazawa Hideaki, Yada Hirotaka, Hayashida Kentaro, Kageyama Toshimi, Katayama Takaharu, Endoh Jin, Ono Yohei, Arai Takahide, Fukuda Keiichi, Ogawa Satoshi

    Circulation journal : official journal of the Japanese Circulation Society   72   580 - 580   2008年3月

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    記述言語:英語   出版者・発行元:社団法人日本循環器学会  

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  • OE-241 "Re-aggregation Method" Dramatically Improved the Survival of Purified Mouse and Monkey ES Cell-Derived Cardiomyocytes in Grafted Myocardium(Regeneration(angiogenesis/myocardial regeneration)(01)(M),Oral Presentation(English),The 72nd Annual Scientific Meeting of the Japanese Circulation Society)

    Hattori Fumiyuki, Chen Hao, Li Weizhen, Yuasa Shinsuke, Onizuka Takeshi, Shimoji Kenichiro, Murata Mitsushige, Kimura Kensuke, Makino Shinji, Sano Motoaki, Fukuda Keiichi

    Circulation journal : official journal of the Japanese Circulation Society   72   241 - 241   2008年3月

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    記述言語:英語   出版者・発行元:社団法人日本循環器学会  

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  • Inhalation of hydrogen gas protects the heart from ischemic reperfusion injury

    Kekntaro Hayashida, Motoaki Sano, Kensuke Kimura, Jin Endo, Takaharu Katayama, Saori Tokudome, Takeshi Onizuka, Shinsuke Yuasa, Akio Kawamura, Satoshi Ogawa, Keiichi Fukuda

    JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY   51 ( 10 )   A375 - A375   2008年3月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ELSEVIER SCIENCE INC  

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  • Genetic mutation of ALDH2 enhances cardiomyocyte tolerance to oxidative stress as a result of hormetic response to aldehydes

    Jin Endo, Motoaki Sano, Takahanu Katayama, Satori Tokudome, Shinsuke Yuasa, Mitsushige Murata, Shinji Makino, Takeshi Adachi, Makoto Suematsu, Hiroki Nakanishi, Rye Taguchi, Ikurou Ohsawa, Shigeo Ohta, Satoshi Ogawa, Keiichi Fukuda

    CIRCULATION   116 ( 16 )   53 - 53   2007年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Neural crest stem cells supply cardiomyocytes for the physiological turnover and the regeneration after myocardial infarction

    Keisuke Matsumura, Yuichi Tamura, Hideaki Kanazawa, Shinsuke Yuasa, Satoshi Ogawa, Keiichi Fukuda

    CIRCULATION   116 ( 16 )   258 - 258   2007年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Zac1 is an essential cardiac transcription factor

    Shinsuke Yuasa, Takeshi Onizuka, Kenichiro Shimoji, Yohei Ohno, Jin Endo, Hideaki Kanazawa, Hirotaka Yada, Sung H. Yoon, Tomomi Kageyama, Takashi Kawakami, Satoshi Ogawa, Keiichi Fukuda

    CIRCULATION   116 ( 16 )   129 - 129   2007年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • PPARγ coactivator 1αのタンパク質レベルでの量、核内局在、転写活性化作用は、ユビキチン・プロテアソーム系を介する分子内相互作用によって制御されている

    佐野 元昭, 徳留 さとり, 吉川 賢忠, 清水 宣明, 片山 隆晴, 遠藤 仁, 湯浅 慎介, 服部 文幸, 牧野 伸司, 田中 廣壽, 福田 恵一

    日本ヒト細胞学会学術集会プログラム・抄録   25回   78 - 78   2007年8月

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    記述言語:日本語   出版者・発行元:日本ヒト細胞学会  

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  • Zac1は心臓発生における必須の転写因子である

    湯浅 慎介, 鬼塚 岳志, 下地 顕一郎, 大野 洋平, 遠藤 仁, 金澤 英明, 矢田 浩崇, 木村 成卓, 川上 崇史, 影山 智己, 片山 隆晴, 荒井 隆秀, 村田 光繁, 伯野 大彦, 木村 謙介, 牧野 伸司, 佐野 元昭, 小川 聡, 福田 恵一

    日本ヒト細胞学会学術集会プログラム・抄録   25回   85 - 85   2007年8月

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    記述言語:日本語   出版者・発行元:日本ヒト細胞学会  

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  • PE-568 Contribution of Bone Marrow-derived Cells on Pressure Overload-induced Cardiac Hypertrophy and Perivascular Fibrosis in Mice(Regeneration (angiogenesis/myocardial regeneration)-4, The 71st Annual Scientific Meeting of the Japanese Circulation Society)

    Endo Jin, Sano Motoaki, Fujita Jun, Hayashida Kentaro, Yuasa Shinsuke, Makino Shinji, Fukuda Keiichi, Ogawa Satoshi

    Circulation journal : official journal of the Japanese Circulation Society   71   465 - 466   2007年3月

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    記述言語:英語   出版者・発行元:社団法人日本循環器学会  

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  • FRS-035 Pathological Angiogenesis in Human Cardiac Valves is Accompanied by Decreased ChM-I and Augmented VEGF-A and MMP Expression(Pathophysiology of Cardiovascular Disease, The 71st Annual Scientific Meeting of the Japanese Circulation Society)

    Hakuno Daihiko, Yoshioka Masatoyo, Yuasa Shinsuke, Matsumura Keisuke, Kimura Kensuke, Shiomi Takayuki, Kimura Naritaka, Shukunami Chisa, Okada Yasunori, Mukai Makio, Shin Hankei, Yozu Ryohei, Ogawa Satoshi, Hiraki Yuji, Fukuda Keiichi

    Circulation journal : official journal of the Japanese Circulation Society   71   124 - 124   2007年3月

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    記述言語:英語   出版者・発行元:社団法人日本循環器学会  

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  • PJ-402 Disruption of Chondromodulin-I Gene, a Potent Angioinhibitory Factor, Causes Aortic Valve Stenosis in Mice(Valvular herat disease/Pericarditis/Cardiac tumor-3, The 71st Annual Scientific Meeting of the Japanese Circulation Society)

    Kimura Naritaka, Yuasa Shinsuke, Hakuno Daihiko, Kimura Kensuke, Matsumura Keisuke, Yozu Ryohei, Fukuda Keiichi

    Circulation journal : official journal of the Japanese Circulation Society   71   572 - 572   2007年3月

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    記述言語:英語   出版者・発行元:社団法人日本循環器学会  

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  • Disruption of chondromodulin-I gene, a potent angioinhibitory factor, causes aortic valve stenosis in mice

    Naritaka Kimura, Masatoyo Yoshioka, Shinsuke Yuasa, Keisuke Matsumura, Kensuke Kimura, Chisa Shukunami, Yuji Hiraki, Ryohei Yozu, Kelichi Fukuda

    CIRCULATION   114 ( 18 )   326 - 326   2006年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Mitochondrial membrane potential measurement dye is applicable for purification of mouse and marmoset embryonic stem cell-derived cardiomyocytes

    Fumiyuki Hattori, Hao Chen, Weizhen Li, Jun Fujita, Shinsuke Yuasa, Kenichiro Shimoji, Takeshi Onizuka, Erika Sasaki, Shinzo Oikawa, Satoshi Ogawa, Keiichi Fukuda

    CIRCULATION   114 ( 18 )   197 - 197   2006年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • 心臓弁膜症の病因の解明 無血管性維持機構とその破綻

    吉岡 正豊, 湯浅 慎介, 松村 圭祐, 潮見 隆之, 宿南 知沙, 岡田 保典, 向井 万起男, 申 範圭, 四津 良平, 佐田 政隆, 小川 聡, 開 祐司, 福田 恵一

    Journal of Cardiology   47 ( 2 )   100 - 101   2006年2月

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    記述言語:日本語   出版者・発行元:(一社)日本心臓病学会  

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  • A Novel BTB/POZ Protein, RhoBTB3, Negatively Regulates Angiotensin II Induced-cardiac Hypertrophy(Renin-angiotensin-aldosterone System (H), The 69th Annual Scientific Meeting of the Japanese Circulation Society)

    Yuasa Shinsuke, Fukuda Keiichi, Shimoji Kenichiro, Endo Jin, Matsumura Keisuke, Yoshioka Masatoyo, Onitsuka Takeshi, Yata Mitsugu, Kanazawa Hideaki, Yada Hirotaka, Yagi Takashi, Itabashi Yuji, Manabe Tomohiro, Fujita Jun, Murata Mitsushige, Ieda Masaki, Kanki Hideaki, Miyatake Satoshi, Hattori Fumiyuki, Ogawa Satoshi

    Circulation journal : official journal of the Japanese Circulation Society   69   112 - 112   2005年3月

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    記述言語:英語   出版者・発行元:社団法人日本循環器学会  

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  • イヌ心筋梗塞モデルにおいて,G-CSF投与は梗塞部血管再生,細胞密度上昇を促進する

    八木 崇, 福田 恵一, 藤田 淳, 下地 顕一郎, 遠藤 仁, 松村 圭祐, 林田 健太郎, 吉岡 正豊, 湯浅 慎介, 金沢 英明, 矢田 税, 板橋 裕史, 真鍋 知宏, 家田 真樹, 久下 康代, 川口 治子

    脈管学   44 ( 9 )   500 - 500   2004年9月

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    記述言語:日本語   出版者・発行元:(一社)日本脈管学会  

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  • Existence of Side Population Cells in Primary Heart Cell Culture

    Shibuya Isao, Tomita Yuichi, Matuzaki Yumi, Kawaguchi Haruko, Hisaka Yasuyo, Ieda Masaki, Tahara Satoko, Manabe Tomohiro, Fujita Jun, Itabashi Yuji, Yagi Takashi, Yuasa Shinsuke, Kinoshita Masayoshi, Hayashida Kentaro, Yoshioka Masatoyo, Tamura Yuichi, Okano Hideyuki, Fukuda Keiichi

    Circulation journal : official journal of the Japanese Circulation Society   67   306 - 306   2003年3月

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    記述言語:英語   出版者・発行元:社団法人日本循環器学会  

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  • 心・血管疾患と再生医学 成体幹細胞を用いた心筋再生と細胞移植による心不全治療

    福田 恵一, 伯野 大彦, 冨田 雄一, 藤田 淳, 澁谷 功, 鈴木 雄介, 湯浅 慎介, 板橋 裕史, 小川 聡

    炎症・再生   22 ( 4 )   330 - 330   2002年6月

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    記述言語:日本語   出版者・発行元:日本炎症・再生医学会  

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共同研究・競争的資金等の研究

  • SERCA治療介入による心不全患者に投与可能な抗不整脈薬の研究、開発

    研究課題/領域番号:20K08461  2020年04月 - 2023年03月

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    矢田 浩崇, 湯浅 慎介

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    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

    現在はSKI(SERCA C674S mutant Kock-in Mice)マウスに対するアンギオテンシン(ANG)IIとHypoxiaによる研究を行っている.
    AngII負荷においては不整脈誘発の実験を行った。1週間のAngII皮下ポンプ負荷では左室収縮能力は低下しないものの、電気生理学的検査でVTが多く誘発された。Caトランジエント、スパーク、カフェイン実験を行うと、筋小胞体からのCaスパークの増加とSRのCa枯渇、ピークCaトランジエント(F/Fo)の低下を認めていた。SERCA機能不全は左室収縮能と関係なく、Caハンドリング異常を介して不整脈を増加させることが確認でき、欧州不整脈学会(EHRA 2020.4)においてYIA basic research部門に選出され高い評価を受けた。
    また、我々は酸素環境下における、低酸素暴露肺高血圧モデル(HXPH)におけるSKIの右室肥大についても実験を施行しており、4 週間 10% HXPHを行なうと、WT、SKI とも HXPH で同等の右室収縮期圧上昇と肺動脈リモデリングを認めたが、Fulton Index(RV weight/IVS+LV weight)がWTと比較してSKIで高くなっており、HXPH環境下においてよりSKIで右心肥大を認めた。右室単離心筋 CaトランジエントはピークCaトランジエント(F/Fo)の低下およびTime to 50% relaxation (T50)の延長を認めており、Caハンドリング異常による右心不全についても検証しており、以下学会で報告した。
    また、不整脈の解析方法の確立も行っている。オプティカルマッピングの新たな観察方法および解析方法の確立も同時に行っており、ex vivoにおける心室性不整脈の観察をより詳細に解析できるよう研究を継続している。

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  • 右心不全の発症機序の解明と治療方法の開発

    研究課題/領域番号:20H03678  2020年04月 - 2023年03月

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

    湯浅 慎介

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    配分額:17680000円 ( 直接経費:13600000円 、 間接経費:4080000円 )

    重症心不全患者は世界中で増えているが、有効な内科的治療法は限られている。心臓は全身に血液を送る左心室と、肺に血液を送る右心室に分かれるが、これまでは心不全における重要性は左心室が中心と考えられてきた。右心不全は右心室の絶対的/相対的収縮不全や拡張障害に伴う拍出不全であり、全身の鬱血、肝障害、腎障害など様々な臓器障害を生じる。右心不全は肺高血圧症などの純粋な右心不全疾患の予後と相関する重要な因子であることは広く知られていたが、さらに右心不全はあらゆる左心不全に続発して発症し左心不全の予後を規定する重要な因子でもあることも知られてきた。しかし右心不全を焦点に当てた研究は進んでおらず特異的な治療方法も皆無である。
    本研究では右心不全の発症機序の解明と治療方法の開発を目的とする。まず右心室と左心室の分子生物学的な差異に焦点をあて、マウス右心室、左心室、心室中隔を各々分取し、網羅的遺伝子発現解析を行った。その結果、右心室や左心室には、各々特徴的な遺伝子発現を呈していた。さらにgene ontology解析等を行い、右心室の特徴を定義している分子生物学的・細胞生物学的機能に着目した。その結果、免疫に関わる経路が右心室で特徴的に活性化していることが示唆された。同経路の右心不全における役割を明らかにするために、マウス右心不全モデルを作成することとした。肺動脈主幹部に狭窄手術を行うことにより右心室に特異的に圧負荷をかけることで、術後約1~2週間で右心不全に至るモデルになることを確認した。同モデルにおいて、右心不全において先述の経路はさらに活性化することを見出し、同経路が右心不全発症・増悪に関与していることが想定された。同経路のin vivoにおける役割を明らかにするために、同経路に関わる各種分子のノックアウトマウスを作成し機能解析を行ってきた。

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  • 右心不全の発症機序の解明と治療方法の開発

    研究課題/領域番号:20H03678  2020年04月 - 2023年03月

    文部科学省・日本学術振興会  科学研究費助成事業  基盤研究(B)

    湯浅 慎介

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    担当区分:研究代表者  資金種別:競争的資金

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  • 動物モデルとヒトiPS細胞を用いた環境と遺伝子相互作用による心疾患形成機構の解明

    研究課題/領域番号:19H03622  2019年04月 - 2022年03月

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

    山岸 敬幸, 土橋 隆俊, 古道 一樹, 内田 敬子, 湯浅 慎介

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    22q11.2欠失症候群に合併する先天性心疾患の責任遺伝子であるTBX1の発現を遺伝子改変技術で低下させたマウスモデルにおいて、妊娠母マウスに葉酸を投与することにより、胎仔の先天性心疾患表現型を軽症化することに成功し、葉酸によりNOTCHシグナルが活性化され、心臓前駆細胞である神経堤細胞の発生分化異常が救済される機序が示唆された。また、遺伝子改変マウスの交配実験によりTBX1と同じ遺伝子群のTBX20が心臓発生において遺伝的相補性を持って機能することが明らかになり、下流転写因子PITX2の発現を制御することにより心臓ルーピングおよび心室中隔形成に関与すると考えられた。

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  • ヒトiPS細胞を利用した心臓領域特異的心筋細胞および心内膜細胞の誘導法開発

    研究課題/領域番号:17K10151  2017年04月 - 2020年03月

    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)

    古道 一樹, 芝田 晋介, 湯浅 慎介

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    配分額:4550000円 ( 直接経費:3500000円 、 間接経費:1050000円 )

    平成30年度は初年度の計画に引き続き、レポーターiPS細胞株の樹立を目指した。NKX2.5遺伝子を利用した全心臓前駆細胞の選別に加え、二次心臓領域由来前駆細胞に特異的に発現する転写因子ISL1の開始コドン直前にP2A配列を挟んでCre組み換え酵素を、またヒトにおける遺伝子発現のsafety siteであるPPP1R12C遺伝子のイントロン内に、EF1aプロモーター下にCre依存性にEGFPを発現するトランスジーンを挿入するための遺伝子組み換え用ドナーベクターを新たに構築した。前モデルでは、蛍光タンパクと転写因子間をIRES配列を用いて接続したが、転写因子の発現低下につながる可能性が疑われたため、P2A配列を用いた。しかし、前年度に構築したNKX2.5遺伝子の直前にP2A配列を挟んでturboRFPを導入したiPS細胞が、心筋分化過程で心臓前駆細胞に分化する途中一過性のみに赤色蛍光を発現し、その発現が安定しない問題が生じた。P2A配列がうまく作用していない可能性を疑い、再度IRES配列を用いたトランスジーンに計画を変更した。さらにEF1aプロモーターにLoxP配列で挟まれたNeo耐性遺伝子およびEGFP遺伝子を連結したトランスジーンは、HeLa細胞にCre強制発現遺伝子とともに共発現させると、EGFPをCre依存性に発現することが確認されたが、iPS細胞にゲノム編集して導入した後に、Cre強制発現ベクターをトランスフェクションしてもEGFPの発現が認められなかった。原因として、Creタンパクの核内移行の問題、トランスフェクション効率の問題、iPS細胞内でのEF1aプロモーターのサイレンシングなどが疑われており、現在確認中である。心内膜細胞ソートシステムについては、ゲノム編集に必要なドナーベクターおよびCRISPR/Cas9ベクターを構築し、現在ゲノム編集効率を解析中である。

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  • T-box遺伝子ファミリー機能解析による先天性心血管疾患発症機構の解明

    研究課題/領域番号:16H05359  2016年04月 - 2019年03月

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

    山岸 敬幸, 土橋 隆俊, 内田 敬子, 湯浅 慎介, 家田 真樹

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    配分額:17290000円 ( 直接経費:13300000円 、 間接経費:3990000円 )

    22q11.2欠失症候群モデル(Tbx1発現低下)マウスの総動脈幹症の病型が、妊娠母体マウスへの葉酸投与により軽症化した。その機序として、流出路中隔を形成する間葉系細胞の発生障害が、葉酸により救済されることを解明した。そして、心臓の発生および神経堤細胞の遊走・分化を制御する複数の因子の発現が、葉酸により変化することを明らかにした。また、Tbx4が肺間葉系細胞の未分化維持に機能することを明らかにし、その分子機序として、Tbx4が分泌性増殖因子Fgf10の発現を直接制御することを解明した。さらにCRISPR/Cas9システムを用いてTbx20欠損マウスを作製し、Tbx1との遺伝的相補性を検討した。

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  • 様々な疾患モデルを駆使した遺伝性循環器疾患の解明

    研究課題/領域番号:16H05304  2016年04月 - 2019年03月

    文部科学省・日本学術振興会  科学研究費助成事業  基盤研究(B)

    湯浅 慎介

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    担当区分:研究代表者  資金種別:競争的資金

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  • 様々な疾患モデルを駆使した遺伝性循環器疾患の解明

    研究課題/領域番号:16H05304  2016年04月 - 2019年03月

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

    湯浅 慎介

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    配分額:17420000円 ( 直接経費:13400000円 、 間接経費:4020000円 )

    近年のゲノム解析技術の進歩により遺伝性循環器疾患の理解が深まったように思える一方で、より謎が深まった部分も多くある。すなわち健常者や遺伝性疾患患者に、あまりにも多くの変異が存在することが判明し、どの遺伝子変異が、どの程度、疾患表現型に結びついているかは依然として不明である。一方でゲノム編集技術の進歩により、様々な遺伝子改変モデルが簡単に作製可能となり、これまで敷居が高かった遺伝子改変モデルを用いた研究が容易となった。本研究では、これまでに蓄積された遺伝性循環器疾患患者におけるゲノム解析結果をもとに、遺伝子改変ゼブラフィッシュ、遺伝子改変マウス、疾患特異的iPS細胞を用いて、様々な遺伝子改変モデルを駆使して病態解明研究を行ってきた。これまでに候補となる遺伝子変異に関して、in vitroおよびin vivoの疾患モデルの構築をしてきた。
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    これまでに蓄積されてきた遺伝子解析結果から、遺伝性循環器疾患において疾患発症の原因となる候補変異遺伝子の決定を行ってきた。同候補遺伝子の機能解析として、bioinformatics approachによる機能予測解析、培養細胞を用いたin vitro解析、実験動物を用いた機能解析を行ってきた。同遺伝子の機能解析研究においては、野生型遺伝子過剰発現、変異型遺伝子過剰発現および遺伝子機能欠失を、培養細胞や実験動物において導入することにより心臓や血管の変化を観察した。さらに変化をきたした遺伝子機能解析系において、細胞や組織を対象として網羅的遺伝子発現解析等を行うことにより分子機序の探索を行ってきた。それらの解析を通して、疾患発症機序の新たな概念の構築、疾患モデルとしての検証、治療方法開発系の構築、治療方法の開発を行っている。

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  • クロマチンリモデリング因子による高品質iPS細胞の作製方法の確立

    研究課題/領域番号:16H02651  2016年04月 - 2019年03月

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

    福田 恵一, 湯浅 慎介, 國富 晃

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    配分額:47320000円 ( 直接経費:36400000円 、 間接経費:10920000円 )

    人工多能性幹細胞(induced pluripotent stem cell: iPS細胞)は分化細胞に3つまたは4つの転写因子(Oct4,Sox2,Klf4,c-Myc)を導入することにより樹立され、現在iPS細胞を用いた再生医療などが期待されている。しかしながら現状ではマウス、ヒトともに樹立されたiPS細胞の分化能力などの幹細胞の性質・品質は不均一であり、iPS細胞を臨床応用する際に重大な問題点となっている。本研究では卵母細胞特異的に発現し、クロマチンリモデリング因子として知られているリンカーヒストンH1fooをコードしている遺伝子であるH1fooを、上記転写因子とともにマウスおよびヒト分化細胞に導入することで、より質の高いiPS細胞を安定的に効率良く作製する方法を確立する。高品質iPS細胞においては、安定的に高効率の心筋細胞分化が実現され、再生医療の発展に貢献することができる。
    iPS細胞の質に関しては、染色体の安定性、遺伝子変異の有無、分化多能性に関して議論がなされてきた。またマウスES細胞並みの高品質ヒトiPS細胞として、naive iPS細胞に関する研究もなされてきた。本研究においては、再生医療の実現を念頭に置き、通常の体細胞からiPS細胞を作製する方法に導入する遺伝子を追加することにより、iPS細胞の品質向上を行ってきた。マウス体細胞においてレトロウイルスベクターを用いてiPS細胞樹立時にOct4、Sox2、Klf4と共にH1fooを強制発現させてiPS細胞を樹立し、同iPS細胞の高品質の確認を行ってきた。

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  • 老化モデルを用いた老化現象の理解

    2016年04月 - 2019年03月

    文部科学省・日本学術振興会  科学研究費助成事業  挑戦的萌芽研究

    湯浅 慎介

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    担当区分:研究代表者  資金種別:競争的資金

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  • 老化モデルを用いた老化現象の理解

    研究課題/領域番号:16K15415  2016年04月 - 2019年03月

    日本学術振興会  科学研究費助成事業 挑戦的萌芽研究  挑戦的萌芽研究

    湯浅 慎介

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    配分額:3380000円 ( 直接経費:2600000円 、 間接経費:780000円 )

    老化は様々な疾患の基盤となっており、老化制御を介した医療開発を行うためには、老化の分子基盤を理解する必要がある。一これまでに行われてきた老化研究は、細胞老化を中心としたin vitroの細胞を用いた研究、線虫などの短命の実験生物を用いた研究、遺伝子改変を中心としたモデルマウスを用いた研究、サルなどの大動物を用いた長期間の介入研究、遺伝性老化症候群の遺伝子解析研究、そして老化症候群の患者由来iPS細胞を用いた研究がなされてきた。どの実験モデルも長所・短所があり、相互補完的に研究がなされてきた。本研究においては、種々のモデルを用いて老化機序の探索を行った。

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  • 筋衛星細胞の質と量を制御する機構の解明とその制御

    研究課題/領域番号:15H01521  2015年04月 - 2017年03月

    文部科学省・日本学術振興会  科学研究費助成事業  新学術領域研究(研究領域提案型)

    湯浅 慎介

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    担当区分:研究代表者  資金種別:競争的資金

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  • 筋衛星細胞の質と量を制御する機構の解明とその制御

    研究課題/領域番号:15H01521  2015年04月 - 2017年03月

    日本学術振興会  科学研究費助成事業 新学術領域研究(研究領域提案型)  新学術領域研究(研究領域提案型)

    湯浅 慎介

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    配分額:11180000円 ( 直接経費:8600000円 、 間接経費:2580000円 )

    骨格筋の幹細胞である筋衛星細胞は、通常は静止期にあるが筋傷害に反応し活性化・増殖・分化し、筋芽細胞を経て融合し成熟骨格筋細胞となり、筋肉としての機能維持を担っている。本研究においては『筋衛星細胞の質と量を制御する機構を解明し、筋肉におけるステムセルエイジングの制御』を目的とする。骨格筋ステムセルエイジングに伴い骨格筋の再生能の低下や再生骨格筋の機能低下が想定され、骨格筋ステムセルエイジング正しく理解し制御する方法を開発することは、あらゆる骨格筋疾患の治療に繋がり意義のあることである。早期に骨格筋ステムセルエイジングを来すモデルとして、マウス筋ジストロフィーモデルを用いた解析を行った。筋ジストロフィーは慢性の骨格筋傷害の結果、骨格筋再生が常に促されており、早期にステムセルエイジングを来す。筋ジストロフィーモデルにおいて、骨格筋の幹細胞である筋衛星細胞の詳細な解析を行い、筋衛星細胞の老化に伴うステムセルエイジングとG-CSFとの関わりをin vivoにおいて解析し、G-CSFがステムセルエイジングを制御できることを見出した。また筋ジストロフィー治療方法開発へ向けた、G-CSF投与の至適な量や時期等を検討した。さらに加齢に伴いゆるやかにステムセルエイジングに至ることが想定されるが、加齢に伴う筋衛星細胞の老化、骨格筋再生能低下によるサルコペニアにおける筋衛星細胞の数と機能改善へ向けた研究を行った。

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  • iPS細胞を用いたSCVTdP疾患概念の構築と新規治療方法の開発

    研究課題/領域番号:26670408  2014年04月 - 2016年03月

    日本学術振興会  科学研究費助成事業 挑戦的萌芽研究  挑戦的萌芽研究

    湯浅 慎介

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    配分額:3640000円 ( 直接経費:2800000円 、 間接経費:840000円 )

    SCVTdP患者からiPS細胞を作製した。同iPS細胞とコントロールiPS細胞から心筋細胞を分化誘導、精製し、電気生理学的解析、分子生物学的解析を行った。電気生理学的解析として行った細胞外電位解析、活動電位解析、パッチクランプによる解析により、疾患特異的な表現型を同定しえた。詳細な機能解析を続け、治療方法の開発へ繋げていく。

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  • 動物モデルを用いた先天性心臓流出路異常の予防と新たな治療への基礎的研究

    研究課題/領域番号:25293238  2013年04月 - 2016年03月

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

    山岸 敬幸, 土橋 隆俊, 牧野 伸司, 内田 敬子, 湯浅 慎介, 家田 真樹

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    配分額:18460000円 ( 直接経費:14200000円 、 間接経費:4260000円 )

    マウスモデルを用いて、心臓流出路発生における分泌因子Sema3Cの発現が転写因子Foxc1/2に活性化され、二次心臓領域では転写因子Tbx1に直接的に、心臓神経堤細胞ではTbx1の下流分泌因子Fgf8を介して間接的に抑制されることを明らかにした。このダイナミックな発現制御により、心臓神経堤細胞の正常な遊走が誘導され、流出路中隔が形成される。また、IP3R2型の発現部位をLacZで標識するマウスにより中枢から末梢にかけての肺動脈発生の可視化に成功し、このマウスモデルを利用して心臓流出路異常に伴う肺血管発生異常の機序を明らかにし、肺動脈平滑筋に特異的な未知の発現制御配列と制御因子の候補を特定した。

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  • iPS細胞を用いたミトコンドリア病の解析および治療薬開発

    研究課題/領域番号:25860623  2013年04月 - 2015年03月

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    小平 真幸, 湯浅 慎介, 江頭 徹, 橋本 寿之, 楠本 大, 國富 晃, 樫村 晋

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    配分額:4030000円 ( 直接経費:3100000円 、 間接経費:930000円 )

    難治性疾患であるミトコンドリア病の一病型であるMELASの患者より多分化能を有するiPS細胞の樹立に成功した。樹立したiPS細胞では各々のラインで変異率は異なり、低いものは3.6%から高いものは99.4%と広く分布していた。未分化iPS細胞から分化した線維芽細胞について変異率やミトコンドリア機能について解析した。解析した変異率の高いラインでは電子伝達系複合体Ⅰでの機能低下を認めた一方、変異率が低いラインでは機能低下を認めなかった。これはMELAS患者の臨床的特徴として報告されているが、ここまでの研究において我々はMELASにおける病態モデルを構築することに成功した。

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  • 疾患特異的iPS細胞を用いたQT延長症候群のメカニズムの解明と治療への応用

    研究課題/領域番号:25870331  2013年04月 - 2015年03月

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    服部 哲久, 黒田 裕介, 湯浅 慎介

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    配分額:4420000円 ( 直接経費:3400000円 、 間接経費:1020000円 )

    QT延長症候群7型(LQT-7)は、心電図のQT/QU時間延長、周期性四肢麻痺、骨格異常を三徴とした、心室性不整脈の原因となる疾患であり、KCNJ2遺伝子異常が原因である。遺伝子変異の異なるLQT-7患者3名より人工多能性幹(iPS)細胞を樹立し、分化心筋を解析した。単一細胞の活動電位解析では、活動電位持続時間と最大拡張期電位に有意差を認めなかったが、多電極アレイ解析では、LQT-7においてフレカイニドにより不規則な興奮が減少し、イソプロテレノールを投与しても異常な興奮が誘発されず、不整脈予防効果が推測された。本研究により疾患研究や薬剤効果の検討に疾患特異的iPS細胞研究の有用性が示唆された。

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  • 再生現象が制御する炎症調節機構の解明と、その制御

    研究課題/領域番号:24117716  2012年04月 - 2014年03月

    日本学術振興会  科学研究費助成事業 新学術領域研究(研究領域提案型)  新学術領域研究(研究領域提案型)

    湯浅 慎介

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    配分額:9620000円 ( 直接経費:7400000円 、 間接経費:2220000円 )

    慢性炎症は様々な疾患発症の基盤となっているが、発症・維持機構そして収束機転は分かっていない。これらの機序を正しく理解することにより、様々な疾患の基盤となっている慢性炎症を制御することが可能となる。様々な組織において、様々な原因のもとで炎症は起こることが広く知られている。しかしながら多くの場合に、炎症は一時的なもので、自然に消退していく。炎症の発症、治癒機転を詳細に解析すると、最初に組織傷害が起こると、急性炎症が起こり、傷害組織において再生が始まり、炎症が収束し、再生が完成することにより治癒へと向かう。しかしながら、一部は急性炎症から炎症収束に向かわずに慢性炎症に至り、さらなる組織破壊、組織機能障害を伴う慢性疾患に移行する。これらの事象から慢性疾患の発症において重要な転機は、急性組織傷害から炎症収束に続く治癒に向かうものと、急性組織傷害から慢性炎症に移行し慢性疾患となるものの違いであることが分かる。何が慢性炎症疾患を防ぎ、慢性疾患と治癒がどのように分かれていくかは不明である。我々は、本研究により再生現象そのもの、さらには再生組織由来物質が炎症収束起点となることを見出した。同研究により、炎症収束を促し治癒へ向かわせる機構は、組織や臓器特異的な現象ではなく、組織や臓器を超えた統一的な機構があることを見出した。これらの機構を応用することにより、多くのヒト慢性炎症疾患を対象に治療法の開発へ結びつなげることが可能となる。

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  • 転写因子を用いた心筋細胞分化誘導方法の開発

    研究課題/領域番号:22689027  2010年 - 2012年

    日本学術振興会  科学研究費助成事業 若手研究(A)  若手研究(A)

    湯浅 湯浅

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    配分額:25090000円 ( 直接経費:19300000円 、 間接経費:5790000円 )

    iPS細胞は線維芽細胞にES細胞特異的転写因子を導入し樹立される多能性幹細胞である。患者特異的心筋細胞を得るにはiPS細胞を樹立・維持し分化・選別する。また心臓特異的転写因子を線維芽細胞に導入することで直接心筋細胞の分化誘導が可能であると考えられている。心筋特異的転写因子を線維芽細胞に遺伝子導入し、心筋特異的遺伝子発現が上昇することを確認した。これらにより心筋再生医療へ応用されることが期待される

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  • 心臓流出路を形成する細胞の発生分化と相互作用を制御する分子機構

    研究課題/領域番号:22390211  2010年 - 2012年

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

    山岸 敬幸, 内田 敬子, 山岸 千尋, 土橋 隆俊, 古道 一樹, 牧野 伸司, 湯浅 慎介

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    配分額:18590000円 ( 直接経費:14300000円 、 間接経費:4290000円 )

    心臓流出路の発生には、おもに二次心臓領域と心臓神経堤由来の2種類の心臓前駆細胞の働きが必須であるが、これらの細胞の相互作用によって正常な流出路が形成される機序はいまだ明確でない。私たちは、二次心臓領域に発現し、心臓神経堤細胞の遊走に関与する神経血管誘導因子・Sema3Cの発現制御機構を明らかにすることにより、流出路発生における両細胞間相互作用に関与する分子機構を解明した。Sema3CのenhancerにlacZ遺伝子を連結・導入したtransgenicマウスの解析とChIP およびluciferase assayを組み合わせ、Sema3Cの上流直接活性化因子としてFoxc1/c2を、上流抑制因子としてTbx1を特定した。遺伝子改変マウスの解析によって、Tbx1の発現低下によりSema3Cが神経堤細胞に異所性に発現し、その遊走を障害することが示唆された。さらに両細胞間相互作用を担う候補タンパクの検討により、Tbx1のSema3C抑制機構は、心臓神経堤細胞において分泌因子Fgf8を介することが推定された。

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  • 心臓形成に関わる新規転写因子の機能解析

    研究課題/領域番号:20659128  2008年

    日本学術振興会  科学研究費助成事業 萌芽研究  萌芽研究

    福田 恵一, 湯浅 慎介

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    配分額:3200000円 ( 直接経費:3200000円 )

    本研究では、胚性幹細胞が心筋細胞に分化する過程で特異的に発現が増強する遺伝子群をDNAアレイ解析でスクリーニングした結果、Znフィンガーモチーフを6カ所持つ転写因子Zac-1を見出した。Zac-1はいくつかの臓器で発現が観察されたが,胎生期には心臓で特異的に発現が強く、他の臓器ではほとんど発現していなかった。このZac-1の心臓発生、心筋特異的転写制御を解析し、同時にZac-1の遺伝指欠損マウスを作成することにより、心筋発生におけるZac-1の意義を解析した。Zac-1の細胞内の核に局在し、心臓発生に伴い発生早期からどの一生涯心臓に発現していた。心臓特異的構造蛋白あるいは分泌蛋白であるANP、BNP、α-MHC(α-ミオシン重鎖)の発現に関与していた。ANPのプロモーターのNkx2.5の結合部位の近接した部分にZac-1が結合することを同定した。Zac-1は既知のどの転写因子よりもANPの転写活性を常勝させた。Zac-1の種々のdeletion mutantを作成し、DNA結合部位の同定を行った。Zac-1は他の心臓特異的転写因子Nkx2.5、GATA4、MEF2Cとの協調作用を示した。Zac-1のジンクフィンガーモチーフと転写因子Nkx2.5のホメオボックスドメインが両者の結合に関与していた。Zac-1遺伝子を遺伝子ノックアウトした際には心臓は形成されなかった。Nkx2.5遺伝子をノックアウトするとZac-1の発現は低下することから、Nkx2,5の下流にZac-1遺伝子の発現がコントロールされていることが明らかとなった。

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  • 胚性幹細胞を用いた高率心筋細胞誘導法の開発

    研究課題/領域番号:18790513  2006年 - 2007年

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    湯浅 慎介

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    配分額:3400000円 ( 直接経費:3400000円 )

    胚性幹細胞(Embryonic Stem Cell(ES細胞))からの分化誘導は、生理的状況下における発生において重要な因子が同様に関与していると考えられている。そこで我々は、過去に心臓発生に重要とされる因子を検討したが、充分な効果は得られなかった。発生学的観点から見直したところBMP antagonistであるNogginが心臓発生領域で発現し、Nogginを胚性幹細胞に作用させると高率に心筋細胞を誘導できることを見いだした(Yuasa S, et. al. Transient inhibition of BMP signaling by Noggin induces cardiomyocyte diflferentiation of mouse embryonic stem cells. Nature Biotechnology. 2005 May; 23(5):607-611.)。さらなる分化誘導効率の上昇を目的として、発生学的に重要な他の因子も検討していたところ、現在までに数種類の遺伝子(分泌因子)が心臓発生予定領域に発現し、かっ胚性幹細胞の分化誘導効率を上昇させることが判明した。現在は、一つの因子に注目して解析中である。その因子のレセプターは、心臓発生の胎生中期に非常に強く発現している。その因子を胎仔に注射すると胎仔の心筋細胞が増殖することが確認され、新規心筋細胞増殖因子であることが判明した。また、その因子を分化途中のES細胞に添加することにより、心筋細胞を増殖することが判明した。

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  • 心筋細胞移植前臨床にむけたサルおよびヒト幹細胞からの心筋再生と移植法の検討

    研究課題/領域番号:17209029  2005年 - 2007年

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

    福田 恵一, 村田 光繁, 湯浅 慎介, 服部 文幸, 谷岡 功邦, 佐々木 えりか, 吉岡 正豊

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    配分額:49530000円 ( 直接経費:38100000円 、 間接経費:11430000円 )

    本研究ではヒト胚性幹細胞(ES細胞)およびコモンマーモセットサルES細胞を用いて、効率的な心筋細胞の分化誘導法、心筋細胞と残存する未分化な幹細胞を分離する方法、効率的な再生心筋移植法の開発を行った。心筋細胞の誘導法ではES細胞から前方中胚葉への誘導物質としてnogginを同定した(Nature Biotech,2005)。また、前方中胚葉から心筋細胞に分化誘導する因子(X因子)を同定し、投稿中である。さらに分化早期の心筋細胞に強く発現する因子の受容体(Y受容体)を同定し、この受容体のリガンド(Y因子)を作用させることにより、心筋細胞に細胞分裂を惹起する受容体を同定した。このY因子を妊娠マウスの子宮に投与すると心筋細胞数が増加することを見出した。これらの因子を組み合わせることで、サルおよびヒトES細胞を強力に心筋細胞に誘導することに成功した。また、再生心筋細胞と未分化幹細胞を分離する方法としてミトコンドリア法を開発した。心筋細胞は他の細胞に比して圧倒的にミトコンドリア含量が多く、ミトコンドリアに選択的に取り込まれる色素を利用することにより、純度99.9%で心筋細胞を単離することに成功した。この方法で採集した心筋細胞を移植しても奇形腫の形成は認められなかった。再生心筋細胞を効率的に移植する方法として凝集法を開発した。この方法は移植した細胞の生着率を90%以上に増加させることが出来、免疫不全マウス、サルへの移植も成功した。

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