The role of inflammatory signal in pulmonary arterial and right ventricular remodeling of congenital heart disease

• Project/Area Number: 18K15880
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Soma Katsura 東京大学, 医学部附属病院, 特任助教 (90755696)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 成人先天性心疾患 / 肺高血圧 / 右室リモデリング / 血管リモデリング / 炎症細胞 / 低酸素 / シャント性心疾患 / マクロファージ / 先天性心疾患 / 右心不全 / 成人先生心疾患 / 肺血管リモデリング

Outline of Final Research Achievements

Although the prognosis of adult congenital heart disease (ACHD) has improved, the prognosis of ACHD with right ventricular dysfunction and pulmonary hypertension (PH) remains poor. Increased pulmonary blood flow in shunt disease causes significant pulmonary vascular / right ventricular remodeling, but its pathological mechanism has not been elucidated. We constructed and analyzed a mouse pathological model with increased pulmonary blood flow and hypoxia. In particular, we focused on macrophages that accumulate during the proliferative phase of vascular smooth muscle cells, and examined the functional role of this macrophage subpopulation in a shunt disease model. In this study, we showed that control of inflammation contributes to the treatment of pulmonary hypertension through analysis of the mechanism by which inflammatory cell infiltration due to hypoxic stress exacerbates pulmonary vascular remodeling.

Academic Significance and Societal Importance of the Research Achievements

診断治療技術の進歩により成人先天性心疾患の予後は改善しているが、一部、低酸素や肺高血圧、右室機能不全を呈する成人先天性心疾患患者の予後は悪いがその機序が明らかでない。右心不全研究においては、これまで低酸素誘導性の肺高血圧モデル、あるいは、肺動脈縮窄による圧負荷モデルが使用されてきたが、先天性心疾患で特徴的な容量負荷や肺血流増加による右室機能低下をきたす病態モデルは存在しなかった。本研究では既存の右室圧負荷モデルのみでなく、肺血流量増加による肺高血圧症と低酸素血症を合併したシャント性心疾患モデルを使用し、炎症制御が肺高血圧、右室リモデリング制御の鍵となることを明らかにした点に意義がある。

Research Products

• [Journal Article] Symptomatic Right Ventricular Outflow Tract Obstruction Due to Sinus of Valsalva Aneurysm (2020)
  • Author(s): Saito Akihito、Soma Katsura、Masuzawa Akihiro、Hatsuse Satoshi、Nakayama Yukiteru、Amiya Eisuke、Yao Atsushi、Hirata Yasutaka、Komuro Issei
  • Journal Title: Circulation Journal Volume: 84 Issue: 12 Pages: 2324
  • DOI: 10.1253/circj.CJ-20-0554
  • NAID: 130007942490
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2020-11-25
  • Peer Reviewed
• [Journal Article] Fractional exhaled nitric oxide in adult congenital heart disease. Nitric Oxide (2020)
  • Author(s): Saito A, Amiya E, Soma K, Inaba T, Maki H, Hatano M, Yao A, Morita H, Komuro I.
  • Journal Title: Nitric Oxide Volume: 100 Pages: 45-49
  • DOI: 10.1016/j.niox.2020.05.001
  • Peer Reviewed
• [Journal Article] Successful angioplasties using high pressure large balloons in a patient with severe anastomotic pulmonary artery stenosis soon after single-lung transplantation (2020)
  • Author(s): Shiraga Kazuhiro、Hirata Yoichiro、Saito Akihito、Ozcelik Nazire、Asakai Hiroko、Inuzuka Ryo、Soma Katsura、Sato Masaaki、Hirata Yasutaka、Oka Akira
  • Journal Title: Journal of Cardiology Cases Volume: 22 Issue: 1 Pages: 22-25
  • DOI: 10.1016/j.jccase.2020.03.008
  • Peer Reviewed
• [Journal Article] Soluble VCAM-1 promotes gemcitabine resistance via macrophage infiltration and predicts therapeutic response in pancreatic cancer (2020)
  • Author(s): Takahashi Ryota、Ijichi Hideaki、Sano Makoto、Miyabayashi Koji、Mohri Dai、Kim Jinsuk、Kimura Gen、Nakatsuka Takuma、Fujiwara Hiroaki、Yamamoto Keisuke、Kudo Yotaro、Tanaka Yasuo、Tateishi Keisuke、Nakai Yousuke、Morishita Yasuyuki、Soma Katsura、Takeda Norihiko、Moses Harold L.、Isayama Hiroyuki、Koike Kazuhiko
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 1-13
  • DOI: 10.1038/s41598-020-78320-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Murine Model of Pulmonary Artery Overflow Vasculopathy Revealed Macrophage Accumulation in the Lung (2019)
  • Author(s): Minatsuki Shun、Takeda Norihiko、Soma Katsura、Katoh Manami、Maki Hisataka、Hatano Masaru、Takimoto Eiki、Manabe Ichiro、Komuro Issei
  • Journal Title: International Heart Journal Volume: 60 Issue: 2 Pages: 451-456
  • DOI: 10.1536/ihj.18-281
  • NAID: 130007617444
  • ISSN: 1349-2365, 1349-3299
  • Year and Date: 2019-03-30
  • Peer Reviewed / Open Access
• [Journal Article] Combination Therapy of Fenestrated-Fontan Procedure with Medication Improved Double-outlet Right Ventricle in Adulthood. (2019)
  • Author(s): Sassa T, Nakayama A, Saito A, Soma K, Inuzuka R, Hirata Y, Komuro I.
  • Journal Title: J Cardiovasc Imaging. Volume: 27 Issue: 4 Pages: 288-289
  • DOI: 10.4250/jcvi.2019.27.e40
  • Peer Reviewed
• [Journal Article] Therapeutic targeting of mitochondrial ROS ameliorates murine model of volume overload cardiomyopathy. (2019)
  • Author(s): Okamura K, Nakagama Y, Takeda N, Soma K, Sato T, Isagawa T, Kido Y, Sakamoto M, Manabe I, Hirata Y, Komuro I, Ono M
  • Journal Title: Journal of Pharmacological Sciences Volume: 141 Issue: 1 Pages: 56-63
  • DOI: 10.1016/j.jphs.2019.09.005
  • Peer Reviewed / Open Access
• [Journal Article] Macrophage hypoxia signaling regulates cardiac fibrosis via Oncostatin M. (2019)
  • Author(s): Abe H, Takeda N, Isagawa T, Semba H, Nishimura S, Morioka MS, Nakagama Y, Sato T, Soma K, Koyama K, Wake M, Katoh M, Asagiri M, Neugent ML, Kim JW, Stockmann C, Yonezawa T, Inuzuka R, Hirota Y, Maemura K, Yamashita T, Otsu K, Manabe I, Nagai R, Komuro I.
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 2824-2833
  • DOI: 10.1038/s41467-019-10859-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of liver fibrosis using the hepatic vein waveform in patients with Fontan circulation. (2019)
  • Author(s): Nakatsuka T, Soroida Y, Nakagawa H, Shindo T, Sato M, Soma K, Nakagomi R, Kobayashi T, Endo M, Hikita H, Sato M, Gotoh H, Iwai T, Yasui M, Shinozaki-Ushiku A, Shiraga K, Asakai H, Hirata Y, Fukayama M, Ikeda H, Yatomi Y, Tateishi R, Inuzuka R, Koike K.
  • Journal Title: Hepatol Res. Volume: 49 Issue: 3 Pages: 304-313
  • DOI: 10.1111/hepr.13248
  • Peer Reviewed
• [Journal Article] 心房中隔欠損シャント性肺動脈性肺高血圧に対するTreat and Repairの適用 (2019)
  • Author(s): 八尾厚史，相馬桂，稲葉俊郎
  • Journal Title: 日本成人先天性心疾患学会誌 Volume: 8 Pages: 12-24
  • Peer Reviewed
• [Journal Article] Diastolic Tricuspid Regurgitation Related to Atrial Systole With a Bileaflet Mechanical Valve (2018)
  • Author(s): Saito Akihito、Soma Katsura、Kojima Toshiya、Inaba Toshiro、Yao Atsushi、Komuro Issei
  • Journal Title: Circulation Journal Volume: 82 Issue: 11 Pages: 2921-2922
  • DOI: 10.1253/circj.CJ-18-0219
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2018-10-25
  • Peer Reviewed
• [Journal Article] Regular Treatment Strategy with a Large Amount of Carvedilol for Heart Failure Improves Biventricular Systolic Failure in a Patient with Repaired Tetralogy of Fallot (2018)
  • Author(s): Soma Katsura、Yao Atsushi、Saito Akihito、Inaba Toshiro、Ishikawa Yuichi、Hirata Yasutaka、Komuro Issei
  • Journal Title: International Heart Journal Volume: 59 Issue: 5 Pages: 1169-1173
  • DOI: 10.1536/ihj.17-525
  • NAID: 130007490553
  • ISSN: 1349-2365, 1349-3299
  • Year and Date: 2018-09-01
  • Peer Reviewed
• [Journal Article] Challenge to Shunt-Related Pulmonary Arterial Hypertension in Adult Congenital Heart Disease (2018)
  • Author(s): Soma Katsura、Yao Atsushi
  • Journal Title: ICUとCCU Volume: 42 Pages: 517-523
• [Presentation] Deep Learning-based Approach for Screening Atrial Septal Defect on Chest Radiographs (2020)
  • Author(s): Ryo Matsuoka , Hiroshi Akazawa , Satoshi Kodera , Katsura Soma , Hiroki Yagi, Masahiko Umei , Hiroshi Kadowaki , Junichi Ishida , Hiroki Shinohara, Susumu Katsushika, Hirotaka Ieki, Toshihiro Yamaguchi, Yasutomi Higashikuni, Katsuhito Fujiu , Kaoru Ito, Atsushi Yao, Issei Komuro
  • Organizer: 第85回日本循環器学会学術集会
• [Presentation] 成人期チアノーゼ性心疾患の評価と管理 (2019)
  • Author(s): 相馬桂
  • Organizer: 第21回成人先天性心疾患学会
  • Invited
• [Presentation] シャント閉鎖後のPAHの治療戦略と注意点 (2019)
  • Author(s): 相馬桂 八尾厚史
  • Organizer: 第21回成人先天性心疾患学会
• [Presentation] 成人先天性心疾患にみられる全身合併症―成人先天性心疾患にみられる呼吸機能障害 (2019)
  • Author(s): 相馬桂
  • Organizer: 第67回心臓病学会
• [Presentation] 成人期チアノーゼ性心疾患の評価と管理 (2019)
  • Author(s): 相馬桂
  • Organizer: 第21回日本成人先天性心疾患学会
  • Invited
• [Presentation] シャント閉鎖後のPAHと治療戦略と注意点 (2019)
  • Author(s): 相馬桂
  • Organizer: 第21回日本成人先天性心疾患学会
  • Invited
• [Presentation] ACHD Services and Training System of ACHD Specialists in Japan (2018)
  • Author(s): 相馬桂
  • Organizer: 7th Congress Of ASIA PACIFIC PEDIATRIC CARDIAC SOCIETY
  • Int'l Joint Research / Invited
• [Presentation] 成人先天性心疾患治療の現在と将来への展望 (2018)
  • Author(s): 相馬桂
  • Organizer: 第66回日本心不全学会
  • Invited
• [Book] 心疾患合併妊娠と心エコー 肺高血圧症を合併した妊娠での管理と注意点 (2019)
  • Author(s): 相馬桂
  • Publisher: 文光堂