Establishment of a novel therapeutic strategy for heart failure based on an understanding of metabolic regulation

• Project/Area Number: 15K09081
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Kobe University
• Principal Investigator: Tanaka Hidekazu 神戸大学, 医学研究科, 講師 (20590342)
• Co-Investigator(Kenkyū-buntansha): 杜 隆嗣 神戸大学, 医学研究科, 特命准教授 (50379418)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 心不全 / メタボローム解析 / βヒドロキシ酪酸 / 2-アミノ酪酸 / グルタチオン / 糖尿病 / 肥満 / 左室拡張能 / 心エコー図 / 抗がん剤

Outline of Final Research Achievements

1) A comprehensive quantification of serum metabolites in patients with atrial septal defect revealed that circulating levels of β-hydroxybutyrate (βOHB) and 2-aminobutyric acid (2-AB) reflected hemodynamic changes. We found that βOHB exert cardioprotective effects against oxidative stress. We also revealed that 2-AB modulates glutathione homeostasis. 2) Coexistence of left ventricular (LV) longitudinal myocardial systolic dysfunction with LV diastolic dysfunction could lead to heart failure with preserved ejection fraction (HFpEF). Diabetes mellitus (DM) is known as a significant factor associated with HFpEF. We revealed the impact of overweight on LV longitudinal myocardial systolic function in patients with type II DM.

Research Products

• [Journal Article] Impact of overweight on left ventricular function in type 2 diabetes mellitus (2017)
  • Author(s): Suto Makiko、Tanaka Hidekazu、Mochizuki Yasuhide、Mukai Jun、Takada Hiroki、Soga Fumitaka、Dokuni Kumiko、Hatani Yutaka、Hatazawa Keiko、Matsuzoe Hiroki、Sano Hiroyuki、Shimoura Hiroyuki、Ooka Junichi、Matsumoto Kensuke、Hirota Yushi、Ogawa Wataru、Hirata Ken-ichi
  • Journal Title: Cardiovascular Diabetology Volume: 16 Issue: 1 Pages: 145-145
  • DOI: 10.1186/s12933-017-0632-5
  • NAID: 120006373805
  • Peer Reviewed / Open Access
• [Journal Article] 2-Aminobutyric acid modulates glutathione homeostasis in the myocardium. (2016)
  • Author(s): Irino Y, Toh R, Nagao M, Mori T, Honjo T, Shinohara M, Tsuda S, Nakajima H, Satomi-Kobayashi S, Shinke T, Tanaka H, Ishida T, Miyata O, Hirata KI.
  • Journal Title: Sci Rep. Volume: - Issue: 1 Pages: 36749-36749
  • DOI: 10.1038/srep36749
  • NAID: 120005898711
  • Peer Reviewed / Open Access
• [Journal Article] Bi-ventricular contractile reserve offers an incremental prognostic value for patients with dilated cardiomyopathy. (2015)
  • Author(s): Matsumoto K, Tanaka H, Onishi A, Motoji Y, Tatsumi K, Sawa T, Miyoshi T, Imanishi J, Mochizuki Y, Hirata K.
  • Journal Title: Eur Heart J Cardiovasc Imaging. Volume: 16 Issue: 11 Pages: 1213-1223
  • DOI: 10.1093/ehjci/jev069
  • Peer Reviewed
• [Journal Article] Clinical features of subclinical left ventricular systolic dysfunction in patients with diabetes mellitus. (2015)
  • Author(s): Mochizuki Y, Tanaka H, Matsumoto K, Sano H, Toki H, Shimoura H, Ooka J, Sawa T, Motoji Y, Ryo K, Hirota Y, Ogawa W, Hirata K.
  • Journal Title: Cardiovasc Diabetol. Volume: 14 Issue: 1 Pages: 37-37
  • DOI: 10.1186/s12933-015-0201-8
  • NAID: 120005647287
  • Peer Reviewed
• [Journal Article] Combining passive leg-lifting with transmural myocardial strain profile for enhanced predictive capability for subclinical left ventricular dysfunction in Duchenne muscular dystrophy. (2015)
  • Author(s): Yamamoto T, Tanaka H, Takeshima Y, Hayashi N, Hirata K, Kawano S.
  • Journal Title: J Cardiol. Volume: 66 Issue: 3 Pages: 212-217
  • DOI: 10.1016/j.jjcc.2015.02.003
  • Peer Reviewed
• [Journal Article] Association of peripheral nerve conduction in diabetic neuropathy with subclinical left ventricular systolic dysfunction. (2015)
  • Author(s): Mochizuki Y, Tanaka H, Matsumoto K, Sano H, Toki H, Shimoura H, Ooka J, Sawa T, Motoji Y, Ryo K, Hirota Y, Ogawa W, Hirata K.
  • Journal Title: Cardiovasc Diabetol. Volume: 14 Issue: 1 Pages: 47-47
  • DOI: 10.1186/s12933-015-0213-4
  • NAID: 120005627300
  • Peer Reviewed
• [Journal Article] Right ventricular function and right-heart echocardiographic response to therapy predict long-term outcome in patients with pulmonary hypertension. (2015)
  • Author(s): Sano H, Tanaka H, Motoji Y, Fukuda Y, Sawa T, Mochizuki Y, Ryo K, Matsumoto K, Emoto N, Hirata K.
  • Journal Title: Can J Cardiol. Volume: 31 Issue: 4 Pages: 529-536
  • DOI: 10.1016/j.cjca.2015.01.027
  • Peer Reviewed
• [Presentation] 2-aminobutyric acid as a newly identified modulator of glutathione homeostasis in failing myocardium (2017)
  • Author(s): Manabu Nagao, Ryuji Toh, Yasuhiro Irino, Hidekazu Tanaka, Toshiro Shinke, Tatsuro Ishida, Ken-ichi Hirata
  • Organizer: 第8１回 日本循環器学会 学術集会
  • Place of Presentation: 金沢 日本
  • Year and Date: 2017-03-17
• [Presentation] Elevated beta-hydroxybutyrate due to downregulation of SCOT exerts cardioprotective effects in failing hearts (2016)
  • Author(s): Manabu Nagao, Ryuji Toh, Yasuhiro Irino, Takeshige Mori, Tomoyuki Honjo, Seimi Satomi-Kobayashi, Toshiro Shinke, Hidekazu Tanaka, Tatsuro Ishida, and Ken-ichi Hirata
  • Organizer: 第80回 日本循環器学会 学術集会
  • Place of Presentation: 仙台 日本
  • Year and Date: 2016-03-18
• [Presentation] 2-Aminobutyric acid reflects myocardial redox state in doxorubicin-induced cardiomyopathy (2015)
  • Author(s): Manabu Nagao, Ryuji Toh, Yasuhiro Irino, Takeshige Mori, Tomoyuki Honjo, Seimi Satomi-Kobayashi, Masakazu Shinohara, Toshiro Shinke, Tatsuro Ishida, Ken-ichi Hirata
  • Organizer: 11th International Conference of the Metabolomics Society (Metabolomics 2015)
  • Place of Presentation: サンフランシスコ 米国
  • Year and Date: 2015-06-29
  • Int'l Joint Research
• [Presentation] Feasibility of 2-Aminobutyric acid as a biomarker for early detection of doxorubicin-induced cardiotoxicity (2015)
  • Author(s): Manabu Nagao, Ryuji Toh, Yasuhiro Irino, Takeshige Mori, Tomoyuki Honjo, Seimi Satomi-Kobayashi, Masakazu Shinohara, Toshiro Shinke, Tatsuro Ishida, Ken-ichi Hirata
  • Organizer: 第79回 日本循環器学会 学術集会
  • Place of Presentation: 大阪 日本
  • Year and Date: 2015-04-24
• [Patent(Industrial Property Rights)] 抗酸化誘導剤および抗酸化誘導剤を併用する主治療薬のスクリーニング方法 (2016)
  • Inventor(s): 杜 隆嗣、入野 康宏、平田 健一
  • Industrial Property Rights Holder: 杜 隆嗣、入野 康宏、平田 健一
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2016-136751
  • Filing Date: 2016-07-11