The effect of intracardiac mechanical stress on fetal heart maturation in mammals

• Project/Area Number: 19K08343
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: National Center for Child Health and Development
• 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, (非)研究員 (70626697)
• Co-Investigator(Kenkyū-buntansha): 細田 洋司 国立研究開発法人国立循環器病研究センター, 研究所, 客員研究員 (40359807)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 胎児心不全 / 先天性心疾患 / 心筋成熟 / 小動物用高解像度超音波イメージングシステム / 胎児胎盤循環 / 遺伝子発現解析 / 胎盤病理 / 胎児心疾患 / 心臓成熟 / 小動物用超音波高解像度イメージング / PDE5阻害剤 / マウス / 心臓発生 / 超音波イメージング

Outline of Research at the Start

本研究では、小動物用高解像度超音波イメージングシステムによる血行動態解析法及び組織学的な心筋の分化・成熟の評価法を確立し、心臓発生において心形態異常や心機能低下による心室へのメカニカルストレスの変化が心筋細胞の増殖及び分化に与える影響や分子機構を明らかにする。さらに胎児心機能改善薬に対する心室機能の反応性について、網羅的遺伝子発現解析を行い、心臓の分化・成熟に関わる分子または分子機構を探索する。

Outline of Final Research Achievements

We examined two different model mice of fetal cardiac dysfunction that cause cardiac malformation or decreased contractility during the fetal period. Fetal heart failure and decrease in the number of ventricular cardiomyocytes were observed only in mice with cardiac malformation. Therefore, mechanical stress associated with cardiac morphogenesis seems to be more important for fetal heart development.
In human placenta, microscopic analysis showed that the frequency and severity of premature and edematous villi and increased nucleated red blood cells in villous vessels were greater in cases of fetal heart failure. Changes in cytokine-related genes specific to fetal heart failure were also observed, suggesting fetoplacental association.

Academic Significance and Societal Importance of the Research Achievements

小動物用高解像度超音波イメージングシステムを用いて胎生期から血行動態をリアルタイムに観察することで、胎児心不全モデルマウスを同定し、胎児心不全の評価系を確立することが可能であった。組織学的解析の結果、心腔内メカニカルストレスの変化に伴って、心筋細胞の増殖抑制による低形成及び収縮機能の低下、それに対して代償性に細胞増殖期が延長することが示唆された。
胎児心不全時のヒト胎盤において、二次的に組織学的変化及び遺伝子発現変化が生じることが確認された。胎児・胎盤の臓器連関を裏付ける結果であり、胎児心不全の病態解明、さらには胎児心不全のバイオマーカー開発につながると考えている。

Research Products

• [Journal Article] Abnormal Microscopic Findings in the Placenta Correlate With the Severity of Fetal Heart Failure (2023)
  • Author(s): Miyoshi Takekazu、Matsuyama Taka-aki、Nakai Michikazu、Miyazato Mikiya、Yoshimatsu Jun、Hatakeyama Kinta、Hosoda Hiroshi
  • Journal Title: Circulation Journal Volume: 87 Issue: 4 Pages: 560-568
  • DOI: 10.1253/circj.CJ-22-0568
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2023-03-24
  • Peer Reviewed / Open Access
• [Journal Article] Neurodevelopmental outcome after antenatal therapy for fetal supraventricular tachyarrhythmia: 3‐year follow‐up of multicenter trial (2023)
  • Author(s): Miyoshi T.、Maeno Y.、Matsuda T.、Ito Y.、Inamura N.、Kim K.‐S.、Shiraishi I.、Kurosaki K.、Ikeda T.、Sago H.、Horigome H.、Yoda H.、Tsukahara S.、Teramachi Y.、Takahashi K.、Toyoshima K.、Nakai M.、Katsuragi S.、Collaborators、Japan?Fetal Arrhythmia Group
  • Journal Title: Ultrasound in Obstetrics & Gynecology Volume: 61 Issue: 1 Pages: 49-58
  • DOI: 10.1002/uog.26113
  • Peer Reviewed
• [Journal Article] Public attitudes in the clinical application of genome editing on human embryos in Japan: a cross-sectional survey across multiple stakeholders (2022)
  • Author(s): Kobayashi Shinobu、Miyoshi Takekazu、Kobayashi Tohru、Hayakawa Itaru、Urayama Kevin Y.、Uchiyama Masato、Muto Kaori、Takeuchi Yasuto、Taira Masaki、Sago Haruhiko、Takehara Kenji
  • Journal Title: Journal of Human Genetics Volume: 67 Issue: 9 Pages: 541-546
  • DOI: 10.1038/s10038-022-01042-z
  • Peer Reviewed
• [Journal Article] Utility of perinatal natriuretic peptide for predicting neonatal heart failure (2022)
  • Author(s): Miyoshi Takekazu、Hosoda Hiroshi、Miyake Akira、Sakaguchi Heima、Kitano Masataka、Kurosaki Ken‐ichi、Shiraishi Isao、Nakai Michikazu、Nishimura Kunihiro、Miyazato Mikiya、Kangawa Kenji、Yoshimatsu Jun、Minamino Naoto
  • Journal Title: Pediatrics International Volume: 64 Issue: 1
  • DOI: 10.1111/ped.15231
  • Peer Reviewed / Open Access
• [Journal Article] 学術講演会シンポジウム：胎児心不全の診断マーカー及び新規治療法の開発 (2022)
  • Author(s): 三好剛一
  • Journal Title: 日本産科婦人科学会誌 Volume: 74 Pages: 1678-1691
• [Journal Article] 学術奨励賞：胎児頻脈性不整脈の臨床試験および胎児心不全バイオマーカーの開発 (2022)
  • Author(s): 三好剛一
  • Journal Title: 日本産科婦人科学会誌 Volume: 74 Pages: 1383-1396
• [Journal Article] Pediatric Medical Devices ― Survey of Pediatric Cardiologists and Cardiovascular Surgeons in Japan ― (2021)
  • Author(s): Miyoshi T, Kato A, Yasukochi S, Takahashi S, Ho M, Yamamoto H, Inuzuka R, Kim SH, Sakamoto K, Kobayashi T.
  • Journal Title: Circulation Reports Volume: 3 Issue: 3 Pages: 153-160
  • DOI: 10.1253/circrep.CR-20-0136
  • NAID: 130007996755
  • ISSN: 2434-0790
  • Year and Date: 2021-03-10
  • Peer Reviewed / Open Access
• [Journal Article] Significance of Atrial and Brain Natriuretic Peptide Measurements in Fetuses With Heart Failure (2021)
  • Author(s): Miyoshi Takekazu、Hosoda Hiroshi、Minamino Naoto
  • Journal Title: Frontiers in Physiology Volume: 12 Pages: 65435-65435
  • DOI: 10.3389/fphys.2021.654356
  • 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
  • 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 & Therapeutics Volume: 9 Pages: 456-456
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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 / Open Access
• [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 / 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 Pages: 456-456
  • Peer Reviewed / Int'l Joint Research
• [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
  • 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 (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
  • Journal Title: Journal of the American College of Cardiology Volume: 74 Issue: 7 Pages: 874-885
  • DOI: 10.1016/j.jacc.2019.06.024
  • 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
  • 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
  • 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: J Matern Fetal Neonatal Med Volume: 32 Issue: 15 Pages: 2463-8
  • 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 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
  • 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): 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
  • 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: Am J Obstet Gynecol Volume: 220 Issue: 1 Pages: 104.e1-104.e15
  • 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 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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 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: J Cardiol Volume: 73 Issue: 3 Pages: 247-54
  • DOI: 10.1016/j.jjcc.2018.11.007
  • Peer Reviewed
• [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
  • 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: J Comput Assist Tomogr Volume: 43 Issue: 1 Pages: 104-8
  • DOI: 10.1097/rct.0000000000000781
  • Peer Reviewed
• [Presentation] 胎児不整脈に対する胎児治療 (2023)
  • Author(s): 三好剛一
  • Organizer: 第29回日本胎児心臓病学会
• [Presentation] 胎児心不全バイオマーカー (2022)
  • Author(s): 三好剛一
  • Organizer: 第1回日本産婦人科超音波研究会
  • Invited
• [Presentation] 胎児心不全の診断マーカー及び新規治療法の開発 (2022)
  • Author(s): 三好剛一
  • Organizer: 第74回日本産科婦人科学会
• [Presentation] 胎児頻脈性不整脈の臨床試験および胎児心不全バイオマーカーの開発 (2022)
  • Author(s): 三好剛一
  • Organizer: 第74回日本産科婦人科学会
  • Invited
• [Presentation] 胎児心不全の診断 (2022)
  • Author(s): 三好剛一
  • Organizer: 第58回日本超音波医学会 中国地方会学術集会
  • Invited
• [Presentation] 胎児胎盤循環におけるナトリウム利尿ペプチドの代謝 (2021)
  • Author(s): 三好剛一、細田洋司、吉松 淳、南野直人
  • Organizer: 第27回日本胎児心臓病学会
• [Presentation] Metabolism of atrial and brain natriuretic peptides in the fetoplacental circulation of fetuses with congenital heart diseases (2021)
  • Author(s): Miyoshi T, Hosoda H, Yoshimatsu J, Minamino N
  • Organizer: 第73回日本産科婦人科学会
• [Presentation] 胎児胎盤循環におけるナトリウム利尿ペプチドの分子型及び代謝 (2021)
  • Author(s): 三好剛一、細田洋司、吉松 淳、南野直人
  • Organizer: 第57回日本周産期・新生児医学会
• [Presentation] CVPスコアおよびBPスコアを用いた胎児先天性心疾患の予後予測 (2020)
  • Author(s): 三好剛一、根木玲子、吉松 淳
  • Organizer: 第93回日本超音波医学会学術集会
• [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] ガイドラインに基づく胎児心エコーテキスト 精査・臨床編 (2023)
  • Author(s): 三好剛一 他（稲村昇 編集）
  • Total Pages: 239
  • Publisher: 金芳堂
• [Book] 特集：画像！―エキスパート直伝 産婦人科画像診断― (2021)
  • Author(s): 三好剛一
  • Total Pages: 300
  • Publisher: 診断と治療社
• [Book] 国立成育医療研究センター 新産科実践ガイド (2021)
  • Author(s): 三好剛一、左合治彦
  • Total Pages: 240
  • Publisher: 診断と治療社
• [Book] CTGエボリューション 胎児生理学からコンピュータ判読まで (2021)
  • Author(s): 三好剛一、池田智明
  • Total Pages: 200
  • Publisher: 中外医学社
• [Book] 特集：画像！―エキスパート直伝 産婦人科画像診断 (2021)
  • Author(s): 三好剛一
  • Total Pages: 496
  • Publisher: 診断と治療社
• [Book] 特集:周産期の薬 (2020)
  • Author(s): 三好剛一
  • Total Pages: 732
  • Publisher: 東京医学社
• [Book] 特集:周産期と循環管理 (2020)
  • Author(s): 三好剛一
  • Total Pages: 120
  • Publisher: 東京医学社
• [Book] 産婦人科処方のすべて2020－最新投薬マニュアル産科編 (2020)
  • Author(s): 三好剛一
  • Total Pages: 600
  • Publisher: 医学書院
• [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