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

2019 Fiscal Year Annual Research Report

• Project/Area Number: 17K16316
• Research Institution: National Center for Child Health and Development
• Principal Investigator: 三好 剛一 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
• 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 / PDE5阻害剤 / マウス

Outline of Annual Research Achievements

本研究では、小動物用超音波高解像度イメージングシステムを用いて、胎児心疾患モデルマウスを胎生期から評価することによって、胎内での循環動態の解明及び胎仔心不全への治療法の開発を目的とした。
小動物用超音波イメージングシステム（Vevo2100, VisualSonics）を用いてHey2欠損マウスの胎生期の心形態及び循環動態を検討したところ、ホモ接合型欠損マウスにおいて心室中隔欠損症及び右室低形成を呈し、胎齢と共に左室拡大の進行、両心室の収縮能の低下を認め、一部で胸水貯留が確認された。以上より、胎児心不全モデルマウスとして応用が可能と考えられた。
同マウスを用いて、PDE5阻害剤の経胎盤的投与による胎仔胎盤循環への効果を検討した。PDE5阻害剤投与によって、胎仔の左室拡張末期面積及び拡張能に変化はなかったが、左室収縮能の有意な改善を認めた。左室心筋緻密化層は野生型マウスの約2/3に菲薄化していたが、PDE5阻害剤投与による変化は認めなかった。また、胎児胎盤重量及び胎盤循環にも変化を認めなかった。以上より、PDE5阻害剤の胎仔心筋への直接作用が示唆された。また、治療効果はPDE5阻害剤の低用量群のみで確認され、有効な治療域があることが推察された。
小動物用超音波イメージングシステムにより、従来困難であったマウス胎仔心臓の機能的評価がリアルタイムに可能であった。さらに胎児心不全モデルマウスにおいて、PDE5阻害剤の経胎盤的投与により、胎仔の左室収縮能改善効果が示された。胎児心不全に対する新しい治療法の開発につながる知見と考えられる。

Remarks

2020年3月2日　国立循環器病研究センターより研究成果をプレスリリース

Research Products

• [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.
  • Peer Reviewed
• [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 Pages: －
  • 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.
  • Peer Reviewed
• [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: － Pages: －
  • DOI: 10.1080/14767058.2019.1651271.
  • 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: International Journal of Hematology Volume: 110 Pages: 550-558
  • DOI: 10.1007/s12185-019-02712-z.
  • 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
  • Peer Reviewed
• [Journal Article] Antenatal therapy for fetal supraventricular tachyarrhythmias: multicenter trial. (2019)
  • 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; the Japan Fetal Arrhythmia Group.
  • Journal Title: Journal of the American College of Cardiology Volume: 74 Pages: 874-885
  • DOI: 10.1016/j.jacc.2019.06.024
  • Peer Reviewed
• [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 Pages: 347-352
  • DOI: 10.1016/j.jjcc.2019.04.002.
  • 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 Pages: 183-187
  • DOI: 10.1016/j.tjog.2019.01.002.
  • Peer Reviewed
• [Journal Article] Prediction of postnatal arrhythmia in fetuses with cardiac rhabdomyoma. (2019)
  • Author(s): Ide T, Miyoshi T, Katsuragi S, Neki R, Kurosaki K, Shiraishi I, Yoshimatsu J, Ikeda T.
  • Journal Title: The Journal of Maternal-Fetal & Neonatal Medicine Volume: 32 Pages: 2463-2468
  • DOI: 10.1080/14767058.2018.1438402.
  • Peer Reviewed
• [Journal Article] Cardiovascular profile and biophysical profile scores predict short-term prognosis in infants with congenital heart defect. (2019)
  • Author(s): Miyoshi T, Katsuragi S, Neki R, Kurosaki K, Shiraishi I, Nakai M, Nishimura K, Yoshimatsu J, Ikeda T.
  • Journal Title: Journal of Obstetrics and Gynaecology Research Volume: 45 Pages: 1268-1276
  • DOI: 10.1111/jog.13970
  • Peer Reviewed
• [Journal Article] 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.
  • Journal Title: International Journal of Hematology Volume: 109 Pages: 641-649
  • DOI: 10.1007/s12185-019-02633-x.
  • Peer Reviewed
• [Journal Article] Maternal biomarkers for fetal heart failure in fetuses with congenital heart defects or arrhythmias. (2019)
  • Author(s): Miyoshi T, Hosoda H, Nakai M, Nishimura K, Miyazato M, Kangawa K, Ikeda T, Yoshimatsu J, Minamino N.
  • Journal Title: American Journal of Obstetrics & Gynecology Volume: 220 Pages: 104.e1-15
  • DOI: 10.1016/j.ajog.2018.09.024.
  • 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 R, Umekawa T, Yoshikawa K, Owa T, Magawa S, Furuhashi F, Tsuji M, Maki S, Shimada K, Kaneda MK, Nii M, Tanaka H, Tanaka K, Kamimoto Y, Kondo E, Kato I, Ikemura K, Okuda M, Ma N, Miyoshi T, Hosoda H, Endoh M, Kimura T, Ikeda T.
  • Journal Title: Scientific Reports Volume: 9 Pages: 234
  • DOI: 10.1038/s41598-018-36084-x.
  • Peer Reviewed / Open Access
• [Journal Article] Safety and Efficacy of a 52-mg Levonorgestrel-releasing Intrauterine System in Women with Cardiovascular Disease. (2019)
  • Author(s): Ueda Y, Kamiya CA, Horiuchi C, Miyoshi T, Hazama R, Tsuritani M, Iwanaga N, Neki R, Ikeda T, Yoshimatsu J.
  • Journal Title: Journal of Obstetrics and Gynaecology Research Volume: 45 Pages: 382-388
  • DOI: 10.1111/jog.13828.
  • Peer Reviewed
• [Journal Article] Pregnancy Outcomes and Mid-term Prognosis in Women after Arterial Switch Operation for Dextro - transposition of the Great Arteries -Experiences in a tertiary hospital and review of literature-. (2019)
  • 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: Journal of Cardiology Volume: 73 Pages: 247-254
  • DOI: 10.1016/j.jjcc.2018.11.007.
  • Peer Reviewed
• [Journal Article] Fetal Cardiac Functional Assessment by Fetal Heart Magnetic Resonance Imaging. (2019)
  • Author(s): Tsuritani M, Morita Y, Miyoshi T, Kurosaki K, Yoshimatsu J.
  • Journal Title: Journal of Computer Assisted Tomography Volume: 43 Pages: 104-108
  • DOI: 10.1097/RCT.0000000000000781.
  • 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
• [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
• [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
  • 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
• [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
  • 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
• [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
• [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
• [Book] Maternal and Fetal Cardiovascular Disease 1st ed, (2019)
  • Author(s): Miyoshi T.
  • Total Pages: 30
  • Publisher: Springer Japan
• [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