Elucidating the importance of endothelium-dependent hyperpolarization in the pathogenesis of microvascular angina

• Project/Area Number: 17K15983
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular medicine
• Research Institution: Tohoku University
• Principal Investigator: Shiroto Takashi 東北大学, 大学病院, 特任准教授 (40647567)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 内皮機能障害 / 微小血管狭心症 / 内皮由来弛緩因子 / 内皮由来過分極因子 / EDHF / 分子心臓学

Outline of Final Research Achievements

Vascular endothelium produces endothelium-derived relaxing factors (EDRFs) that modulates vascular tone. Among EDRFs, endothelium-derived hyperpolarization factor (EDHF) is mainly responsible for physiological regulation in microvessels. Thus, present study explored the hypothesis that impaired EDHF-mediated relaxation is involved in the pathogenesis of microvascular angina (MVA).
In patients with MVA, endothelium-dependent vasodilatation of fingertip arterioles to bradykinin was almost absent as assesed by peripheral arterial tonometry (Endo-PAT). Mechanistically, among EDRFs, both nitric oxide (NO)-mediated and EDHF-mediated digital vasodilatations were markedly impared in MVA patients. The results of the present study suggest that MVA is a cardiac manifestation of the systemic small artery disease.

Academic Significance and Societal Importance of the Research Achievements

心臓の表面を走行する冠動脈に器質的及び機能的狭窄を有さない微小血管狭心症は未だ有効な治療法が確立されていないことから、患者の生活の質の低下だけでなく、社会医療経済学的にも問題となっている。
本研究は、微小血管狭心症患者で指尖細動脈における血管拡張因子を介した内皮依存性拡張反応が著明に低下しており、末梢微小血管障害を起こしていることを明らかにした 。
本研究は、微小血管狭心症患者における末梢微小血管の内皮機能障害を世界で初めて明らかにした重要な報告であり、微小血管狭心症患者に対する新たな治療方法への応用へとつながると期待される。

Research Products

• [Journal Article] Marked Impairment of Endothelium-Dependent Digital Vasodilatations in Patients with Microvascular Angina -Evidence for Systemic Small Artery Disease- (2020)
  • Author(s): Shoko Ohura-Kajitani, Takashi Shiroto, Shigeo Godo, Yosuke ikumi, Akiyo Ito, Shuhei Tanaka, Koichi Sato, Jun Sugisawa, Satoshi Tsuchiya, Akira Suda, Tomohiko Shindo, Shohei Ikeda, Kiyotaka Hao, Yoku Kikuchi, Kotaro Nochioka, Yasuharu Matsumoto, Jun Takahashi, Satoshi Miyata, Hiroaki Shimokawa.
  • Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology. Volume: - Issue: 5 Pages: 1400-1412
  • DOI: 10.1161/atvbaha.119.313704
  • Peer Reviewed / Open Access
• [Presentation] Marked Impairment of Endothelium-dependent Digital Vasodilatations in Patients with Microvascular Angina -Possible Manifestation of Systemic Small Artery Disease- (2019)
  • Author(s): Shoko Kajitani, Takashi Shiroto, Shigeo Godo, Akiyo Ito, Yosuke Ikumi, Koichi Sato, Jun Sugisawa, Satoshi Tsuchiya, Akira Suda, Tomohiko Shindo, Shohei Ikeda, Kiyotaka Hao, Yoku Kikuchi, Kotaro Nochioka, Yasuharu Matsumoto, Jun Takahashi, Hiroaki Shimokawa
  • Organizer: AHA Scientific Sessions 2019
  • Int'l Joint Research
• [Presentation] Marked impairment of endothelium-dependent digital vasodilatations in patients with microvascular angina compared with those with vasospastic angina (2019)
  • Author(s): Shoko Kajitani, Takashi Shiroto, Shigeo Godo, Akiyo Ito, Yosuke Ikumi, Koichi Sato, Jun Sugisawa, Satoshi Tsuchiya, Akira Suda, Tomohiko Shindo, Shohei Ikeda, Kiyotaka Hao, Yoku Kikuchi, Kotaro Nochioka, Yasuharu Matsumoto, Jun Takahashi, Hiroaki Shimokawa
  • Organizer: ESC Congress 2019
  • Int'l Joint Research
• [Presentation] Marked impairment of endothelium-dependent digital vasodilatations in patients with microvascular angina compared with those with vasospastic angina (2019)
  • Author(s): Shoko Kajitani, Takashi Shiroto, Shigeo Godo, Akiyo Ito, Yosuke Ikumi, Koichi Sato, Jun Sugisawa, Satoshi Tsuchiya, Akira Suda, Tomohiko Shindo, Shohei Ikeda, Kiyotaka Hao, Yoku Kikuchi, Kotaro Nochioka, Yasuharu Matsumoto, Jun Takahashi, Hiroaki Shimokawa
  • Organizer: 13th International Symposium on Mechanisms Of VasoDilatation, 7th International Symposium on Endothelium-Dependent Hyperpolarization
  • Int'l Joint Research
• [Presentation] 微小血管狭心症患者における抵抗血管内皮依存性血管拡張の著明な障害―冠攣縮性狭心症患者との比較検討― (2019)
  • Author(s): 梶谷 翔子、白戸 崇、神戸 茂雄、須田 彬、池田 尚平、羽尾 清貴、菊地 翼、松本 泰治、高橋 潤、下川 宏明
  • Organizer: 第１９回日本NO学会学術集会
• [Presentation] Marked impairment of endothelium-dependent digital vasodilatations in patients with microvascular angina compared with those with vasospastic angina (2019)
  • Author(s): Shoko Kajitani, Takashi Shiroto, Shigeo Godo, Akiyo Ito, Yosuke Ikumi, Koichi Sato, Jun Sugisawa, Satoshi Tsuchiya, Akira Suda, Tomohiko Shindo, Shohei Ikeda, Kiyotaka Hao, Yoku Kikuchi, Kotaro Nochioka, Yasuharu Matsumoto, Jun Takahashi, Hiroaki Shimokawa
  • Organizer: 第83回日本循環器学会学術集会
• [Remarks] 指先から見えた微小血管狭心症患者の新たな病態 - 全身の微小血管の機能障害を反映 -
  • URL: https://www.tohoku.ac.jp/japanese/2020/04/press20200416-01-finger.html