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New approach in rodent model using high-frequency ultrasound imaging systems and development of novel therapies for fetal heart failure

Research Project

Project/Area Number 17K16316
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Embryonic/Neonatal medicine
Research InstitutionNational Center for Child Health and Development (2019)
Mie University (2017-2018)

Principal Investigator

Miyoshi Takekazu  国立研究開発法人国立成育医療研究センター, 臨床研究センター, 上級専門職 (70626697)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywords胎児心不全 / 胎児心疾患 / 胎児治療 / 小動物用超音波高解像度イメージングシステム / PDE5阻害剤 / マウス / 小動物用超音波高解像度イメージング / 先天性心疾患 / 胎児・新生児医学 / 先天異常学 / 遺伝子改変マウス
Outline of Final Research Achievements

We first used an ultra-high-frequency ultrasound imaging systemin utero and demonstrated that Hey2 knockout embryos had worsening right ventricular hypoplasia and marked left ventricular (LV) dilatation as gestation progressed. In both ventricles, fractional shortening was significantly lower in Hey2 knockout embryos than in wild-type embryos, indicating that the embryos can be used as a murine model of fetal heart failure.
Subsequently, we evaluated the effect of tadalafil treatment (0.04 or 0.08 mg/ml; T0.04 or T0.08 groups, respectively) on fetoplacental circulation in Hey2 knockout embryos. LV fractional shortening was significantly higher in the T0.04 group than in control, whereas LV dilation, mitral E/A ratio, and umbilical artery resistance index were not significantly different among all groups. Therefore, our findings suggest that tadalafil is a potential agent to treat impaired fetal ventricular systolic function.

Academic Significance and Societal Importance of the Research Achievements

小動物用超音波高解像度イメージングシステムを応用し、従来困難であったマウス胎仔心臓の機能的評価をリアルタイムに行なうことで、Hey2ホモ接合型欠損マウスが胎児心不全モデルマウスになりうることを初めて示した。本実験系は、様々な遺伝子改変マウスの胎仔心機能や循環動態の観察などに広く応用できると考えられる。
さらに、本実験系を用いて、PDE5阻害剤が胎児心不全に対する新規治療法となりうることを初めて示した。胎仔心臓に対するPDE5阻害剤の作用機序や最適な投与量については更なる検討が必要であるが、胎児水腫への進行を抑制し、在胎期間を延長させることで、胎児心疾患の予後改善に寄与すると考えている。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (47 results)

All 2020 2019 2018 2017 Other

All Journal Article (23 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 23 results,  Open Access: 4 results) Presentation (19 results) (of which Int'l Joint Research: 2 results,  Invited: 5 results) Book (4 results) Remarks (1 results)

  • [Journal Article] Maternal administration of tadalafil improves fetal ventricular systolic function in a Hey2 knockout mouse model of fetal heart failure.2020

    • Author(s)
      Miyoshi T, Hisamitsu T, Ishibashi-Ueda H, Ikemura K, Ikeda T, Miyazato M, Kangawa K, Watanabe Y, Nakagawa O, Hosoda H.
    • Journal Title

      International Journal of Cardiology

      Volume: 302 Pages: 110-116

    • DOI

      10.1016/j.ijcard.2019.12.013

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Induction of Immune Tolerance towards allogeneic cells using fetal directed placental injection in a Murine model.2020

    • Author(s)
      Shimazu Y, Endo M, Miyoshi T, Takahashi K, Hosoda H, Tamai K, Flake AW, Kimura T, Yosimatsu J.
    • Journal Title

      Journal of Stem Cell Research & Therapy

      Volume: 9

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Predictive value of protein S-specific activity and ELISA testing in patients with the protein S K196E mutation.2020

    • Author(s)
      Miyoshi T, Maruyama K, Oku H, Asahara S, Hanada H, Neki R, Yoshimatsu J, Kokame K, Miyata T.
    • Journal Title

      Thrombosis Research

      Volume: 185 Pages: 1-4

    • DOI

      10.1016/j.thromres.2019.10.026

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Plasma natriuretic peptide levels reflect the status of the heart failure in fetuses with arrhythmia.2020

    • Author(s)
      Miyoshi T, Hosoda H, Kurosaki K, Shiraishi I, Nakai M, Nishimura K, Miyazato M, Kangawa K, Ikeda T, Yoshimatsu J, Minamino N.
    • Journal Title

      The Journal of Maternal-Fetal & Neonatal Medicine

      Volume: - Issue: 12 Pages: 1883-1889

    • DOI

      10.1080/14767058.2019.1651271

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A less-intensive anticoagulation protocol of therapeutic unfractionated heparin administration for pregnant patients.2019

    • Author(s)
      Neki R, Mitsuguro M, Okamoto A, Ida K, Miyoshi T, Kamiya C, Iwanaga N, Miyata T, Yoshimatsu J.
    • Journal Title

      Int J Hematol.

      Volume: 110(5) Issue: 5 Pages: 550-558

    • DOI

      10.1007/s12185-019-02712-z

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Metabolism of atrial and brain natriuretic peptides in the fetoplacental circulation of fetuses with congenital heart diseases.2019

    • Author(s)
      Miyoshi T, Hosoda H, Miyazato M, Kangawa K, Yoshimatsu J, Minamino N.
    • Journal Title

      Placenta

      Volume: 83 Pages: 26-32

    • DOI

      10.1016/j.placenta.2019.06.382

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Antenatal Therapy for Fetal Supraventricular Tachyarrhythmias2019

    • Author(s)
      Miyoshi T, Maeno Y, Hamasaki T, Inamura N, Yasukochi S, Kawataki M, Horigome H, Yoda H, Taketazu M, Nii M, Hagiwara A, Kato H, Shimizu W, Shiraishi I, Sakaguchi H, Ueda K, Katsuragi S, Yamamoto H, Sago H, Ikeda T
    • Journal Title

      Journal of the American College of Cardiology

      Volume: 74 Issue: 7 Pages: 874-885

    • DOI

      10.1016/j.jacc.2019.06.024

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Predicting postpartum cardiac events in pregnant women with complete atrioventricular block.2019

    • Author(s)
      Nakashima A, Miyoshi T, Kamiya CA, Nishio M, Horiuchi C, Tsuritani M, Iwanaga N, Katsuragi S, Neki R, Ikeda T, Yoshimatsu J.
    • Journal Title

      Journal of Cardiology

      Volume: 74 Issue: 4 Pages: 347-352

    • DOI

      10.1016/j.jjcc.2019.04.002

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Maternal and fetal outcomes in pregnancy complicated with Eisenmenger syndrome.2019

    • Author(s)
      Katsurahgi S, Kamiya C, Yamanaka K, Neki R, Miyoshi T, Iwanaga N, Horiuchi C, Tanaka H, Yoshimatsu J, Niwa K, Takagi Y, Ogo T, Nakanishi N, Ikeda T.
    • Journal Title

      Taiwanese Journal of Obstetrics & Gynecology

      Volume: 58 Issue: 2 Pages: 183-187

    • DOI

      10.1016/j.tjog.2019.01.002

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Prediction of postnatal arrhythmia in fetuses with cardiac rhabdomyoma2019

    • Author(s)
      Ide T, Miyoshi T, Katsuragi S, Neki R, Kurosaki K, Shiraishi I, Yoshimatsu J, Ikeda T.
    • Journal Title

      J Matern Fetal Neonatal Med

      Volume: 32 Issue: 15 Pages: 2463-8

    • DOI

      10.1080/14767058.2018.1438402

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Cardiovascular profile and biophysical profile scores predict short‐term prognosis in infants with congenital heart defect2019

    • Author(s)
      Miyoshi T, Katsuragi S, Neki R, Kurosaki KI, Shiraishi I, Nakai M, Nishimura K, Yoshimatsu J, Ikeda T.
    • Journal Title

      Journal of Obstetrics and Gynaecology Research

      Volume: 印刷中 Issue: 7 Pages: 1268-1276

    • DOI

      10.1111/jog.13970

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Effects of low-dose combined oral contraceptives and protein S K196E mutation on anticoagulation factors: a prospective observational study2019

    • Author(s)
      Takekazu Miyoshi, Hisato Oku, Saiko Asahara, Akira Okamoto, Koichi Kokame, Michikazu Nakai, Kunihiro Nishimura, Fumiyuki Otsuka, Aya Higashiyama, Jun Yoshimatsu, Toshiyuki Miyata
    • Journal Title

      International Journal of Hematology

      Volume: 印刷中 Issue: 6 Pages: 641-649

    • DOI

      10.1007/s12185-019-02633-x

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Maternal biomarkers for fetal heart failure in fetuses with congenital heart defects or arrhythmias2019

    • Author(s)
      Miyoshi T, Hosoda H, Nakai M, Nishimura K, Miyazato M, Kangawa K, Ikeda T, Yoshimatsu J, Minamino N.
    • Journal Title

      Am J Obstet Gynecol

      Volume: 220 Issue: 1 Pages: 104.e1-104.e15

    • DOI

      10.1016/j.ajog.2018.09.024

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Tadalafil treatment in mice for preeclampsia with fetal growth restriction has neuro-benefic effects in offspring through modulating prenatal hypoxic conditions.2019

    • Author(s)
      Tachibana Ryota, Umekawa Takashi, Yoshikawa Kento, Owa Takao, Magawa Shoichi, Furuhashi Fumi, Tsuji Makoto, Maki Shintaro, Shimada Kyoko, Kaneda K. Michiko, Nii Masafumi, Tanaka Hiroaki, Tanaka Kayo, Kamimoto Yuki, Kondo Eiji, Kato Ineko, Ikemura Kenji, Okuda Masahiro, et al.
    • Journal Title

      Scientific Reports

      Volume: 9 Issue: 1 Pages: 234-234

    • DOI

      10.1038/s41598-018-36084-x

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Safety and efficacy of a 52-mg levonorgestrel-releasing intrauterine system in women with cardiovascular disease.2019

    • Author(s)
      3.Ueda Y, Kamiya CA, Horiuchi C, Miyoshi T, Hazama R, Tsuritani M, Iwanaga N, Neki R, Ikeda T, Yoshimatsu J.
    • Journal Title

      J Obstet Gynaecol Res.

      Volume: 45(2) Issue: 2 Pages: 382-388

    • DOI

      10.1111/jog.13828

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Pregnancy outcomes and mid-term prognosis in women after arterial switch operation for dextro-transposition of the great arteries - Tertiary hospital experiences and review of literature2019

    • Author(s)
      Horiuchi C, Kamiya CA, Ohuchi H, Miyoshi T, Tsuritani M, Iwanaga N, Neki R, Niwa K, Kurosaki K, Ichikawa H, Ikeda T, Yoshimatsu J.
    • Journal Title

      J Cardiol

      Volume: 73 Issue: 3 Pages: 247-54

    • DOI

      10.1016/j.jjcc.2018.11.007

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Fetal cardiac functional assessment by fetal heart magnetic resonance imaging2019

    • Author(s)
      Tsuritani M, Morita Y, Miyoshi T, Kurosaki K, Yoshimatsu J.
    • Journal Title

      J Comput Assist Tomogr

      Volume: 43 Issue: 1 Pages: 104-8

    • DOI

      10.1097/rct.0000000000000781

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Fetal paroxysmal atrial fibrillation during transplacental therapy for supraventricular tachycardia2018

    • Author(s)
      Miyoshi T, Sakaguchi H, Shiraishi I, Yoshimatsu J, Ikeda T.
    • Journal Title

      HeartRhythm Case Reports

      Volume: 5 Issue: 1 Pages: 22-4

    • DOI

      10.1016/j.hrcr.2018.10.004

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Prediction of postnatal arrhythmia in fetuses with cardiac rhabdomyoma.2018

    • Author(s)
      Ide T, Miyoshi T, Katsuragi S, Neki R, Kurosaki KI, Shiraishi I, Yoshimatsu J, Ikeda T.
    • Journal Title

      J Matern Fetal Neonatal Med.

      Volume: 印刷中

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Plasma natriuretic peptide levels in fetuses with congenital heart defect and arrhythmia: a single-center prospective study.2017

    • Author(s)
      Miyoshi T, Umekawa T, Hosoda H, Asada T, Fujiwara A, Kurosaki KI, Shiraishi I, Nakai M, Nishimura K, Miyazato M, Kangawa K, Ikeda T, Yoshimatsu J, Minamino N.
    • Journal Title

      Ultrasound Obstet Gynecol.

      Volume: 印刷中 Issue: 5 Pages: 609-16

    • DOI

      10.1002/uog.18925

    • Related Report
      2018 Research-status Report 2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Tadalafil Improves L-NG-Nitroarginine Methyl Ester-Induced Preeclampsia With Fetal Growth Restriction-Like Symptoms in Pregnant Mice2017

    • Author(s)
      Yoshikawa Kento、Umekawa Takashi、Maki Shintaro、Kubo Michiko、Nii Masafumi、Tanaka Kayo、Tanaka Hiroaki、Osato Kazuhiro、Kamimoto Yuki、Kondo Eiji、Ikemura Kenji、Okuda Masahiro、Katayama Kan、Miyoshi Takekazu、Hosoda Hiroshi、Ma Ning、Yoshida Toshimichi、Ikeda Tomoaki
    • Journal Title

      American Journal of Hypertension

      Volume: 31 Issue: 1 Pages: 89-96

    • DOI

      10.1093/ajh/hpx130

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Cardiovascular profile score as a predictor of acute intrapartum non-reassuring fetal status in infants with congenital heart defects.2017

    • Author(s)
      Miyoshi T, Katsuragi S, Neki R, Kurosaki KI, Shiraishi I, Nakai M, Nishimura K, Yoshimatsu J, Ikeda T.
    • Journal Title

      J Matern Fetal Neonatal Med.

      Volume: 30 Pages: 2831-2837

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Potential utility of pulsed Doppler for prenatal diagnosis of fetal ventricular tachycardia secondary to long QT syndrome.2017

    • Author(s)
      Miyoshi T, Sakaguchi H, Shiraishi I, Yoshimatsu J, Ikeda T.
    • Journal Title

      Ultrasound Obstet Gynecol.

      Volume: 印刷中 Issue: 5 Pages: 697-699

    • DOI

      10.1002/uog.18819

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Presentation] 胎児心不全診断におけるナトリウム利尿ペプチド測定の意義2019

    • Author(s)
      細田洋司、三好剛一、吉松 淳、池田智明、南野直人.
    • Organizer
      日本心血管内分泌代謝学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 母体血清を用いた胎児心不全診断法の開発2019

    • Author(s)
      三好剛一、細田洋司、吉松 淳、池田智明、南野直人.
    • Organizer
      日本胎児治療学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 上室性不整脈の胎児治療2019

    • Author(s)
      三好剛一
    • Organizer
      心臓病胎児診断症例報告会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 胎児心不全における母体血中バイオマーカー2019

    • Author(s)
      三好剛一、細田洋司、吉松 淳、池田智明、南野直人.
    • Organizer
      日本周産期・新生児医学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Effects of low-dose combined oral contraceptives and protein S K196E mutation on anticoagulation factors: a prospective observational study.2019

    • Author(s)
      Miyoshi T, Oku H, Asahara S, Okamoto A, Kokame K, Nakai M, Nishimura K, Otsuka F, Higashiyama A, Yoshimatsu J, Miyata T.
    • Organizer
      Congress of International Society on Thrombosis and Hemostasis
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 胎児頻脈性不整脈に対する経胎盤的抗不整脈薬投与に関する臨床試験-多施設共同試験-2019

    • Author(s)
      三好剛一、稲村 昇、安河内 聰、堀米仁志、与田仁志、竹田津未生、新居正基、左合治彦、前野泰樹、池田智明.
    • Organizer
      日本超音波医学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Maternal biomarkers for fetal heart failure in fetuses with congenital heart disease.2019

    • Author(s)
      Miyoshi T, Yoshimatsu J, Ikeda T.
    • Organizer
      日本産科婦人科学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 胎児頻脈性不整脈に対する経胎盤的抗不整脈薬投与に関する臨床試験:多施設共同介入試験2019

    • Author(s)
      三好剛一、前野泰樹、稲村 昇、安河内 聰、川滝元良、堀米仁志、与田仁志、竹田津未生、新居正基、生水真紀夫、賀藤 均、萩原聡子、清水 渉、坂口平馬、白石 公、上田恵子、桂木真司、濵崎俊光、山本晴子、左合治彦、池田智明.
    • Organizer
      日本胎児心臓病学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 胎児不整脈の経胎盤的治療2018

    • Author(s)
      三好剛一
    • Organizer
      第70回日本産科婦人科学会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] 胎児心疾患モデルマウスに対する経胎盤的PDE5阻害剤投与の有効性2018

    • Author(s)
      三好剛一、細田洋司、久光隆、渡邉裕介、中川修
    • Organizer
      第91回日本超音波医学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] 頻脈性不整脈と胎児治療2018

    • Author(s)
      三好剛一
    • Organizer
      第70回神奈川胎児エコー研究会アドバンス講座
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] 胎児心不全における母体血中バイオマーカーの探索研究2018

    • Author(s)
      三好剛一、細田洋司、吉松 淳、池田智明、南野直人
    • Organizer
      第39回日本妊娠高血圧学会
    • Related Report
      2018 Research-status Report
  • [Presentation] 胎児先天性心疾患及び不整脈症例における羊水中ナトリウム利尿ペプチドの検討2018

    • Author(s)
      三好剛一、細田洋司、吉松 淳、池田智明、南野直人
    • Organizer
      第16回日本胎児治療学会
    • Related Report
      2018 Research-status Report
  • [Presentation] Measurements of natriuretic peptides in amniotic fluid and umbilical cord plasma provide valuable diagnostic information on fetal heart diseases2018

    • Author(s)
      Minamino N, Miyoshi T, Umekawa T, Shiraishi I, Nishimura K, Miyazato M, Kangawa K, Ikeda T, Yoshimatsu J, Hosoda H
    • Organizer
      18th International Congress of Endocrinology
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] 胎児心疾患モデルマウスを用いた胎仔心不全治療法の開発2018

    • Author(s)
      三好剛一、吉松淳、渡邉裕介、中川修、植田初江、宮里幹也、細田洋司
    • Organizer
      第24回日本胎児心臓病学会
    • Related Report
      2017 Research-status Report
  • [Presentation] 胎児不整脈のトピックス2018

    • Author(s)
      三好剛一
    • Organizer
      第21回中部出生前医療研究会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] 小動物用超音波イメージングシステムを用いた胎児心不全モデルマウスの探索2017

    • Author(s)
      三好剛一、根木玲子、吉松淳
    • Organizer
      第90回日本超音波医学会学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] 小動物用超音波高解像度イメージングシステムを用いた胎仔心不全の病態解明2017

    • Author(s)
      三好剛一、吉松淳、池田智明
    • Organizer
      第53回日本周産期・新生児医学会学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] 胎児頻脈性不整脈の鑑別診断と治療2017

    • Author(s)
      三好剛一
    • Organizer
      第19回日本イアンドナルド超音波講座
    • Related Report
      2017 Research-status Report
    • Invited
  • [Book] Maternal and Fetal Cardiovascular Disease 1st ed,2019

    • Author(s)
      Miyoshi T.
    • Total Pages
      30
    • Publisher
      Springer Japan
    • Related Report
      2019 Annual Research Report
  • [Book] 胎児発育不全2018

    • Author(s)
      三好剛一
    • Total Pages
      196
    • Publisher
      中外医学社
    • Related Report
      2018 Research-status Report
  • [Book] 心エコー2018

    • Author(s)
      三好剛一、根木玲子
    • Total Pages
      304
    • Publisher
      文光堂
    • Related Report
      2018 Research-status Report
  • [Book] Fetal & Neonatal Medicine2018

    • Author(s)
      三好剛一
    • Total Pages
      44
    • Publisher
      メディカルレビュー社
    • Related Report
      2018 Research-status Report
  • [Remarks] 胎児心不全に対する新規治療法開発につながる可能性  経母体的タダラフィル投与により胎仔心収縮能が改善

    • URL

      http://www.ncvc.go.jp/pr/release/20200302_press.html

    • Related Report
      2019 Annual Research Report

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Published: 2017-04-28   Modified: 2021-02-19  

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