心外膜脂肪の線維化を検出し心房細動ハイリスク患者を同定するCT画像診断法

• Project/Area Number: 21K19658
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 58:Society medicine, nursing, and related fields
• Research Institution: Oita University
• Principal Investigator: 高橋 尚彦 大分大学, 医学部, 教授 (30263239)
• Project Period (FY): 2021-07-09 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2022: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2021: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 心房細動 / 心外膜脂肪 / CT値減衰度

Outline of Research at the Start

心房細動患者は数百万人にのぼり脳梗塞を高率に発症する。申請者は心房細動に関する基礎研究を15年以上にわたって行ってきた。最近では心臓手術時に得られた59例の心房細動患者の左心耳切片を検討し“心外膜脂肪そのものの線維化が顕著であるほど，隣接する心房筋に炎症性心房線維化が強く生じる”という新事実を明らかにし，これを“Fibrotic EAT”と名付けた。このFibrotic EATには悪玉サイトカイン（IL-6，MCP-1，TNF-α）が多く含まれ心房細動を進行させることも突き止めた。本研究の目的は，このFibrotic EATを検出可能な新たなCT画像診断テクノロジーを開発することである。

Outline of Annual Research Achievements

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce epicardial adipose tissue (EAT) in humans, enhancing cardioprotective effects on heart failure and atrial fibrillation. We investigated the direct effect of the SGLT2 inhibitor empagliflozin on human primary epicardial adipocytes and preadipocytes. SGLT2 is primarily expressed in human preadipocytes in the EAT. The expression levels of SGLT2 significantly diminished when the preadipocytes were terminally differentiated. Adipogenesis of preadipocytes was attenuated by empagliflozin treatment without affecting cell proliferation. The messenger RNA levels and secreted protein levels of interleukin 6 and monocyte chemoattractant protein 1 were significantly decreased in empagliflozin-treated adipocytes. Coculture of human induced pluripotent stem cell-derived atrial cardiomyocytes and adipocytes pretreated with or without empagliflozin revealed that empagliflozin significantly suppressed reactive oxygen species. IL6 messenger RNA expression in human EAT showed significant clinically relevant associations. Empagliflozin suppresses human epicardial preadipocyte differentiation/maturation, likely inhibiting epicardial adipogenesis and improving the paracrine secretome profile of EAT, particularly by regulating IL6 expression.

Research Products

• [Journal Article] Empagliflozin Suppresses the Differentiation/Maturation of Human Epicardial Preadipocytes and Improves Paracrine Secretome Profile (2023)
  • Author(s): Takano Masayuki、Kondo Hidekazu、Harada Taisuke、Takahashi Masaki、Ishii Yumi、Yamasaki Hirochika、Shan Tong、Akiyoshi Kumiko、Shuto Takashi、Teshima Yasushi、Wada Tomoyuki、Yufu Kunio、Sako Hidenori、Anai Hirofumi、Miyamoto Shinji、Takahashi Naohiko
  • Journal Title: JACC: Basic to Translational Science Volume: 8 Issue: 9 Pages: 1081-1097
  • DOI: 10.1016/j.jacbts.2023.05.007
  • Peer Reviewed / Open Access
• [Journal Article] Histological validation of atrial structural remodelling in patients with atrial fibrillation (2023)
  • Author(s): Yuya Takahashi, Takanori Yamaguchi, Toyokazu Otsubo, Kana Nakashima, Kodai Shinzato, Ryosuke Osako, Shigeki Shichida, Yuki Kawano, Akira Fukui, Atsushi Kawaguchi, Shinichi Aishima, Tsunenori Saito, Naohiko Takahashi, Koichi Node
  • Journal Title: European Heart Journal Volume: 44 Issue: 35 Pages: 3339-3353
  • DOI: 10.1093/eurheartj/ehad396
  • Peer Reviewed / Open Access
• [Journal Article] Role of epicardial adipose tissue in human atrial fibrillation (2023)
  • Author(s): Naohiko Takahashi, Ichitaro Abe, Shintaro Kira, Yumi Ishii
  • Journal Title: Journal of Arrhythmia Volume: Feb 19;39(2) Issue: 2 Pages: 93-110
  • DOI: 10.1002/joa3.12825
  • Peer Reviewed / Open Access
• [Journal Article] Detection of fibrotic remodeling of epicardial adipose tissue in patients with atrial fibrillation: Imaging approach based on histological observation (2021)
  • Author(s): Ishii Yumi、Abe Ichitaro、Kira Shintaro、Harada Taisuke、Takano Masayuki、Oniki Takahiro、Kondo Hidekazu、Teshima Yasushi、Yufu Kunio、Shuto Takashi、Wada Tomoyuki、Nakagawa Mikiko、Shimada Tatsuo、Asayama Yoshiki、Miyamoto Shinji、Takahashi Naohiko
  • Journal Title: Heart Rhythm O2 Volume: 2 Issue: 4 Pages: 311-323
  • DOI: 10.1016/j.hroo.2021.05.006
  • Peer Reviewed / Open Access
• [Presentation] Promotion of Atrial Lymphangiogenesis Attenuates AngiotensinII-Induced Atrial Fibrosis and Fibrillation (2024)
  • Author(s): Takahashi M, et al.
  • Organizer: 日本循環器学会学術大会
  • Int'l Joint Research
• [Presentation] Novel Role of Human Epicardial Adipocyte-derived SPARCL1 in Patients with Postoperative (2024)
  • Author(s): Harada M, et al.
  • Organizer: 日本循環器学会学術大会
  • Int'l Joint Research
• [Presentation] Qualitative alteration of Epicardial adipose tissue and Atrial myocardial fibrosis as a substrate of Atrial fibrillation (2023)
  • Author(s): Takahashi N
  • Organizer: 第86回日本循環器学会学術集会
  • Int'l Joint Research
• [Presentation] Detecting Fibrotic Remodeling of Epicardial Adipose Tissue in Patients with Atrial Fibrillation (2021)
  • Author(s): Ishii Y, Abe I, harada T, Takano M, Kira S, Kondo H, Teshima Y, yufu K, Nakagawa M, Shimada T, Miyamoto S, Takahashi N.
  • Organizer: 第85回日本循環器学会学術集会 3.26-28,2021. 横浜web
  • Int'l Joint Research