Development of new heart failure treatment that takes into account cardiorenal syndrome

• Project/Area Number: 26461134
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Meiji University of Integrative Medicine (2016); Kyoto Prefectural University of Medicine (2014-2015)
• Principal Investigator: Asanuma Hiroshi 明治国際医療大学, 医学教育研究センター, 教授 (20416217)
• Co-Investigator(Kenkyū-buntansha): 北風 政史 国立研究開発法人国立循環器病研究センター, 研究開発基盤センター, 部長 (20294069) ; 朝倉 正紀 兵庫医科大学, 医学部, 准教授 (80443505) ; 長谷川 拓也 国立研究開発法人国立循環器病研究センター, 病院, 医師 (10602584)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 心不全 / 心腎連関 / トランスレーショナル研究 / インドキシル硫酸

Outline of Final Research Achievements

Renal dysfunction is associated with cardiovascular toxicity through the action of indoxyl sulfate (IS). The levels of IS can be reduced by the spherical carbon adsorbent AST-120. Because heart failure (HF) causes renal dysfunction by low cardiac output and renal edema, the removal of IS could be cardioprotective. Therefore, we examined whether plasma IS levels increase in HF, and whether AST-120 can reduce those levels and improve HF in the canine pacing induced HF. In the untreated dogs, plasma IS levels increased and cardiac function deteriorated. In contrast, plasma IS levels in the treated dogs decreased to baseline levels and cardiac function improved when compared with untreated dogs. These effects were observed even after the onset of HF. Finally, plasma IS levels increased in patients with HF compared with those in healthy subjects, and the treatment with AST-120 improved cardiac dysfunction in patients with HF. Thus, AST-120 could be a novel candidate for the treatment of HF.

Research Products

• [Journal Article] Translational Study of Hydrogen Gas Inhalation as Adjuncts to Reperfusion Therapy for Acute Myocardial Infarction. (2017)
  • Author(s): Asanuma H, Kitakaze M.
  • Journal Title: Circ J. Volume: 印刷中
  • NAID: 130006887067
  • Peer Reviewed / Open Access
• [Journal Article] Use of serum fibroblast growth factor 23 vs. plasma B-type natriuretic peptide levels in assessing the pathophysiology of patients with heart failure. (2017)
  • Author(s): Imazu M, Takahama H, Amaki M, Sugano Y, Ohara T, Hasegawa T, Kanzaki H, Anzai T, Mochizuki N, Asanuma H, Asakura M, Kitakaze M.
  • Journal Title: Hypertens Res. Volume: 40 Issue: 2 Pages: 181-188
  • DOI: 10.1038/hr.2016.130
  • Peer Reviewed / Open Access
• [Journal Article] Targeted Therapy for Acute Autoimmune Myocarditis with Nano-Sized Liposomal FK506 in Rats. (2017)
  • Author(s): Okuda K, Fu HY, Matsuzaki T, Araki R, Tsuchida S, Thanikachalam PV, Fukuta T, Asai T, Yamato M, Sanada S, Asanuma H, Asano Y, Asakura M, Hanawa H, Hao H, Oku N, Takashima S, Kitakaze M, Sakata Y, Minamino T.
  • Journal Title: PLoS One. Volume: 11 Issue: 8 Pages: e0160944-e0160944
  • DOI: 10.1371/journal.pone.0160944
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Non-linear Equation using Plasma Brain Natriuretic Peptide Levels to Predict Cardiovascular Outcomes in Patients with Heart Failure. (2016)
  • Author(s): Fukuda H, Suwa H, Nakano A, Sakamoto M, Imazu M, Hasegawa T, Takahama H, Amaki M, Kanzaki H, Anzai T, Mochizuki N, Ishii A, Asanuma H, Asakura M, Washio T, Kitakaze M.
  • Journal Title: Sci Rep. Volume: 6 Issue: 1
  • DOI: 10.1038/srep37073
  • Peer Reviewed / Open Access
• [Journal Article] Identification of the Mtus1 Splice Variant as a Novel Inhibitory Factor Against Cardiac Hypertrophy. (2016)
  • Author(s): Ito S, Asakura M, Liao Y, Min KD, Takahashi A, Shindo K, Yamazaki S, Tsukamoto O, Asanuma H, Mogi M, Horiuchi M, Asano Y, Sanada S, Minamino T, Takashima S, Mochizuki N, Kitakaze M.
  • Journal Title: J Am Heart Assoc. Volume: 5 Issue: 7
  • DOI: 10.1161/jaha.116.003521
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A Chemical Endoplasmic Reticulum Chaperone Alleviates Doxorubicin-Induced Cardiac Dysfunction. (2016)
  • Author(s): Fu HY, Sanada S, Matsuzaki T, Liao Y, Okuda K, Yamato M, Tsuchida S, Araki R, Asano Y, Asanuma H, Asakura M, French BA, Sakata Y, Kitakaze M, Minamino T.
  • Journal Title: Circ Res. Volume: 118 Issue: 5 Pages: 798-809
  • DOI: 10.1161/circresaha.115.307604
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Development of Nucleic Chromatin Measurements as a New Prognostic Marker for Severe Chronic Heart Failure. (2016)
  • Author(s): Kanzaki M, Asano Y, Ishibashi-Ueda H, Oiki E, Nishida T, Asanuma H, Kato H, Oka T, Ohtani T, Tsukamoto O, Higo S, Kioka H, Matsuoka K, Sawa Y, Komuro I, Kitakaze M, Takashima S, Sakata Y.
  • Journal Title: PLoS One. Volume: 11 Issue: 2 Pages: e0148209-e0148209
  • DOI: 10.1371/journal.pone.0148209
  • Peer Reviewed / Open Access
• [Journal Article] An Interaction between GLP-1 and Adenosine Contributes to Cardioprotection of a Dipeptidyl Peptidase 4 Inhibitor from Myocardial Ischemia/Reperfusion Injury. (2015)
  • Author(s): Ihara M, Asanuma H, Yamazaki S , Kato H, Asano Y, Shinozaki Y, Mori H, Minamino T, Asakura M, Sugimachi M, Mochizuki N, Kitakaze M.
  • Journal Title: American Journal of Physiology. Volume: 308
  • Peer Reviewed
• [Journal Article] Impact of Either GLP-1 Agonists or DPP-4 Inhibitors on Pathophysiology of Heart Failure (2015)
  • Author(s): Takahashi A, Ihara M, Yamazaki S(○), Asanuma H, Asakura M, Kitakaze M
  • Journal Title: International Heart Journal Volume: 56 Issue: 4 Pages: 372-376
  • DOI: 10.1536/ihj.15-028
  • NAID: 130005087570
  • ISSN: 1349-2365, 1349-3299
  • Peer Reviewed / Open Access
• [Journal Article] Plasma B-type natriuretic peptide is a useful tool for assessing coronary heart disease risk in a Japanese general population. (2015)
  • Author(s): Hasegawa T, Asakura M, Eguchi K, Asanuma H, Ohara T, Kanzaki H, Hashimura K, Tomoike H, Kim J, Kitakaze M.
  • Journal Title: Hypertens Res. Volume: 38 Issue: 1 Pages: 74-79
  • DOI: 10.1038/hr.2014.123
  • Peer Reviewed / Open Access
• [Journal Article] Higdla is a oositive regulaator of cytochrome c oxidase (2015)
  • Author(s): T. Hayashi, Y. Asano, Y. Shintani, H. Aoyama, H. Kioka, O. Tsukamoto, M. Hikita, K. Shinzawa-Itoh, K. Takajuji, S. Higo, H. Kato, S. Yamazaki, K. Matsuoka, A. Nakano, H. Asanuma, M. Asakura, T. Minamino, Y. Goto, T. Ogura, M. Kitakaze, I. Komuro, Y. Sakata, T. Tsukihara, S. Yoshikawa, S. Takashima
  • Journal Title: Proc. Nat. Acad. Sci. U.S.A. Volume: 112 Issue: 5 Pages: 1553-1558
  • DOI: 10.1073/pnas.1419767112
  • Peer Reviewed / Open Access
• [Journal Article] Noninvasive and quantitative live imaging reveals a potential stress-responsive enhancer in the failing heart. (2014)
  • Author(s): Matsuoka K, Asano Y, Higo S, Tsukamoto O, Yan Y, Yamazaki S, Matsuzaki T, Kioka H, Kato H, Uno Y, Asakura M, Asanuma H, Minamino T, Aburatani H, Kitakaze M, Komuro I, Takashima S.
  • Journal Title: FASEB J. Volume: 28(4) Issue: 4 Pages: 1870-9
  • DOI: 10.1096/fj.13-245522
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Carperitide induces coronary vasodilation and limits infarct size in canine ischemic hearts: Role of NO. (2014)
  • Author(s): Asanuma H, Sanada S, Asakura M, Asano Y, Kim J, Shinozaki Y, Mori H, Minamino T, Takashima S,Kitakaze M.
  • Journal Title: Hypertens Res. Volume: 37(8) Issue: 8 Pages: 716-23
  • DOI: 10.1038/hr.2014.70
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Pathophysiological impact of serum fibroblast growth factor 23 in patients with nonischemic cardiac disease and early chronic kidney disease. (2014)
  • Author(s): Imazu M, Takahama H, Asanuma H, Funada A, Sugano Y, Ohara T, Hasegawa T, Asakura M, Kanzaki H, Anzai T, Kitakaze M.
  • Journal Title: Am J Physiol Heart Circ Physiol. Volume: 307(10) Issue: 10 Pages: H1504-H1511
  • DOI: 10.1152/ajpheart.00331.2014
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Development of Large Animal Models Relevant to Heart Failure in Clinical Settings for Better Understanding of Its Physiology and Pathophysiology. (2017)
  • Author(s): Asanuma H, Takahama H, Takahama H, Asakura M, Kitakaze M.
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 金沢
  • Year and Date: 2017-03-17
  • Invited
• [Presentation] Mtus1A Variant Suppresses Cardiac Hypertrophy through the Inhibition of ERK Signaling Activated by ROS Production. (2016)
  • Author(s): Ito S, Asakura M, Min KD, Shindo K, Imazu M, Fukuda H, Chung H, Yamazaki Y, Asanuma H, Kitakaze M.
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 仙台
  • Year and Date: 2016-03-18
• [Presentation] Subclinical Left Ventricular Dysfunction in Stage A Subjects in a Community-based Population. (2016)
  • Author(s): Hasegawa T, Asakura M, Kanzaki H, Sakamoto M, Asanuma H, Takashio S, Amaki M, Takahama H, Ohhara T, Sugano Y, Yasuda S, Ogawa H, Anzai T, Kitakaze M.
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 仙台
  • Year and Date: 2016-03-18
• [Presentation] AST-120, an Adsorbent of Uremic Toxins Improves the Pathophysiology of Heart Failure in Conscious Dogs. (2015)
  • Author(s): Asanuma H, Chung H, Ito S, Min K, Takahama H, Imazu M, Asakura M, Kitakaze M.
  • Organizer: 第32回 ISHR日本部会総会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-10
• [Presentation] AST-120, an adsorbent of uremic toxins improved the cardiac function by suppressing apoptosis and ERK phosphorylation in heart failure dogs. (2015)
  • Author(s): Chung H, Asanuma H, Ito S, Min KD, Shindo K, Imazu M, Asakura M, Kitakaze M.
  • Organizer: 第32回 ISHR日本部会総会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-10
• [Presentation] Proteomic analysis of canine failing hearts induced by rapid pacing: relationship between mitochondrial dysfunction and LV Function. (2015)
  • Author(s): Fukuda H, Min KD, Imazu M, Shindo K, Ito S, Asanuma H, Asakura M, Kitakaze M.
  • Organizer: 第32回 ISHR日本部会総会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-10
• [Presentation] AST-120, An Adsorbent of Uremic Toxins Improved the Cardioprotective Signaling in Pacing-induced Heart Failure Dog. (2015)
  • Author(s): Chung H, Asanuma H, Ito S, Min KD, Shindo K, Imazu M, Fukuda H, Takahama H, Asakura M, Kitakaze M.
  • Organizer: 第19回日本心不全学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2015-10-22
• [Presentation] Proteomic Analysis of Failing Hearts: Relationship between Mitochondrial Dysfunction and Left Ventricular Ejection Fraction. (2015)
  • Author(s): Fukuda H, Min KD, Imazu M, Shindo K, Ito S, Tomonaga T, Minamino N, Asanuma H, Asakura M, Kitakaze M.
  • Organizer: 第19回日本心不全学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2015-10-22
• [Presentation] Proteomic analysis of canine failing hearts induced by rapid pacing: evidence for the elevation of the protein levels related to either mitochondrial dysfunction or acute phase response signaling. (2015)
  • Author(s): Fukuda H, Min KD, Asanuma H, Ito S, Shindo K, Imazu M, Tomonaga T, Minamino N, Asakura M, Kitakaze M.
  • Organizer: European Society of Cardiology Congress 2016
  • Place of Presentation: イギリス・ロンドン
  • Year and Date: 2015-08-29
  • Int'l Joint Research
• [Presentation] 血液透析濾過の心機能に及ぼす効果の検討～血液透析との比較～ (2015)
  • Author(s): 浅沼博司、田中雅登、松原弘和、岡崎英俊、松原博、田中正己
  • Organizer: 第60回 日本透析医学会学術集会・総会
  • Place of Presentation: 横浜
  • Year and Date: 2015-06-26
• [Presentation] Development of New Heart Failure Treatment in Consideration of Cardiorenal Syndrome. (2014)
  • Author(s): Asanuma H, Takahama H, Imazu M, Sasaki H, Ihara M, Minamino T, Takashima S, Sugimachi M, Asakura M, Kitakaze M.
  • Organizer: 第18回 日本心不全学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-10-10 – 2014-10-12
  • Invited
• [Presentation] Dipeptidyl- Peptidase 4 Inhibitor Alogliptin Attenuates Myocardial Ischemia/Reperfusion Infury Via an Adenosine- dependent Mechanism. (2014)
  • Author(s): Ihara M, Yamazaki S, Asanuma H, Kitakaze M.
  • Organizer: 第18回 日本心不全学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-10-10 – 2014-10-12
• [Presentation] Relationship between Indoxyl Sulfate and Fibroblast Growth Factor 23 in Heart Failure Patients with Preserved Renal Function. (2014)
  • Author(s): Imazu M, Asakura M, Takahama H, Asanuma H, Funada A, Sugano Y, Ohara T, Hasegawa T, Kanzaki H, Anzai T, Kitakaze M.
  • Organizer: 第18回 日本心不全学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-10-10 – 2014-10-12
• [Presentation] 心エコードプラ法を用いた左室拡張機能障害評価の問題点 分類不能例の存在とその重症度評価について (2014)
  • Author(s): 長谷川拓也、神崎秀明、朝倉正紀、浅沼博司、舟田晃、大原貴裕、菅野康夫、安田聡、小川久雄、安斉俊久、北風政史
  • Organizer: 第62回 日本心臓病学会学術集会
  • Place of Presentation: 仙台
  • Year and Date: 2014-09-26 – 2014-09-28
• [Presentation] Mtus1 splice variant inhibits cardiac hypertrophy and exacerbates heart failure. (2014)
  • Author(s): Ito S, Asakura M, Min K, Imazu M, Shindo K, Asanuma H, Kitakaze M.
  • Organizer: ヨーロッパ心臓病学会2014
  • Place of Presentation: スペイン・バルセロナ
  • Year and Date: 2014-08-30 – 2014-09-03
• [Presentation] Pressure overload to the heart induces pulmonary up-regulation of genes coding secretory proteins involved in the cardiovascular diseases. (2014)
  • Author(s): Min K, Asakura M, Ito S, Shindo K,Imazu M, Asanuma H, Kitakaze M.
  • Organizer: ヨーロッパ心臓病学会2014
  • Place of Presentation: スペイン・バルセロナ
  • Year and Date: 2014-08-30 – 2014-09-03
• [Book] ここが知りたい 重症心不全の患者さんが来ました (2016)
  • Author(s): 浅沼博司、北風政史
  • Total Pages: 564
  • Publisher: 中外医学社
• [Book] ここが知りたい 強心薬のさじ加減 (2016)
  • Author(s): 浅沼博司、北風政史
  • Total Pages: 456
  • Publisher: 中外医学社
• [Book] 心不全診療Q＆A エキスパート105人からの回答 改訂2版 (2015)
  • Author(s): 浅沼博司、北風政史
  • Total Pages: 459
  • Publisher: 中外医学社
• [Book] 救急医学 (2014)
  • Author(s): 浅沼博司、伊原まどか、北風政史
  • Total Pages: 124
  • Publisher: へるす出版
• [Book] ここが知りたい 利尿薬の選び方, 使い方 (2014)
  • Author(s): 浅沼博司、北風政史
  • Total Pages: 328
  • Publisher: 中外医学社