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Monoclonal hematopoiesis in heart failure

Research Project

Project/Area Number 19K08523
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53020:Cardiology-related
Research InstitutionFukushima Medical University

Principal Investigator

Takeishi Yasuchika  福島県立医科大学, 医学部, 教授 (40272067)

Co-Investigator(Kenkyū-buntansha) 三阪 智史  福島県立医科大学, 医学部, 助教 (50793080)
横川 哲朗  福島県立医科大学, 医学部, 助教 (80748773)
池田 和彦  福島県立医科大学, 医学部, 教授 (90381392)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywordsclonal hematopoiesis / JAK2V617F / pulmonary hypertension / ACVRL1 / ALK1 / Pulmonary hypertension / JAK2変異 / JAK2 / heart failure / monoclonal hematopoiesis
Outline of Research at the Start

クローン性造血が心血管疾患のリスク因子となることが報告されたが、心血管疾患症例において、JAK2V617F変異を有する頻度や臨床病態との関連については明らかではない。本研究では、JAK2V617Fクローン性造血細胞が心疾患、とくに心不全の病態にどのように関与するのか、ヒト血液検体、マウスモデル、培養細胞を用いて、臨床から基礎まで一貫して分子病態を解明し、心不全の新たな治療戦略を確立することを目指す。

Outline of Final Research Achievements

Clonal hematopoiesis is a risk factor for cardiovascular diseases. We identified JAK2V617F-positive clonal hematopoiesis in patients with pulmonary hypertension. JAK2V617F exacerbated hypoxia-induced pulmonary hypertension and pulmonary arterial remodeling in mice. JAK2V617F progressively upregulated Acvrl1 (encoding ALK1) during the differentiation from bone marrow stem/progenitor cells into mature lung neutrophils, and the ALK1 inhibition blocked the development of pulmonary hypertension. Clonal hematopoiesis with JAK2V617F may be a novel therapeutic target for pulmonary hypertension.

Academic Significance and Societal Importance of the Research Achievements

加齢に伴って造血幹細胞に突然変異が生じると、単一クローンに由来する血液細胞の増殖が末梢血中に観察される。これは加齢と心血管疾患を結ぶ現象として注目される。ALK1阻害薬がJAK2変異クローン性造血を有する肺高血圧症に有効な治療戦略となる可能性がある。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (36 results)

All 2022 2021 2020 2019

All Journal Article (14 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 14 results,  Open Access: 12 results) Presentation (15 results) (of which Int'l Joint Research: 15 results,  Invited: 2 results) Book (7 results)

  • [Journal Article] Clonal hematopoiesis with JAK2V617F promotes pulmonary hypertension with ALK1 upregulation in lung neutrophils2021

    • Author(s)
      Kimishima Yusuke、Misaka Tomofumi、Yokokawa Tetsuro、Wada Kento、Ueda Koki、Sugimoto Koichi、Minakawa Keiji、Nakazato Kazuhiko、Ishida Takafumi、Oshima Motohiko、Koide Shuhei、Shide Kotaro、Shimoda Kazuya、Iwama Atsushi、Ikeda Kazuhiko、Takeishi Yasuchika
    • Journal Title

      Nature Communications

      Volume: 12 Issue: 1 Pages: 6177-6177

    • DOI

      10.1038/s41467-021-26435-0

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] NT-proBNP for risk prediction in heart failure: Identification of optimal cutoffs across body mass index categories.2021

    • Author(s)
      Vergaro G, Gentile F, Meems LM, Aimo A, Richards AM, Lam CS, Latini R, Staszewsky L, Anand IS, Cohn JN, Ueland T, Gullestad L, Aukrus P, Rocca HP, Bayes-Genis A, Yoshihisa A, Takeishi Y, et al.
    • Journal Title

      JACC Heart Failure

      Volume: 9 Issue: 9 Pages: 653-663

    • DOI

      10.1016/j.jchf.2021.05.014

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Significance of contact force on esophageal thermal injury during relative high-power short-duration ablation of atrial fibrillation.2021

    • Author(s)
      Kaneshiro T, Amami K, Hijioka N, Nodera M, Yamada S, Yokokawa T, Misaka T, Hikichi T, Yoshihisa A, Takeishi Y.
    • Journal Title

      Circulation Arrhythmia Electrophysiology

      Volume: 14 Issue: 6

    • DOI

      10.1161/circep.121.009897

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Crucial role of hematopoietic JAK2V617F in the development of aortic aneurysms.2021

    • Author(s)
      Yokokawa T, Misaka T, Kimishima Y, Wada K, Minakawa K, Sugimito K, Ishida T, Morishita S, Komatsu N, Ikeda K, Takeishi Y.
    • Journal Title

      Haematologica

      Volume: - Issue: 7 Pages: 1910-1922

    • DOI

      10.3324/haematol.2020.264085

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Blood-based epigenetic markers of FKBP5 gene methylation in patients with dilated cardiomyopathy.2021

    • Author(s)
      Wada K, Misaka T, Yokokawa T, Kimishima Y, Kaneshiro T, Oikawa M, Yoshihisa A, Takeishi Y.
    • Journal Title

      Journal of American Heart Association

      Volume: 10 Issue: 21

    • DOI

      10.1161/jaha.121.021101

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Clonal hematopoiesis and JAK2V617F mutations in patients with cardiovascular disease.2021

    • Author(s)
      Yokokawa T, Misaka T, Kimishima Y, Wada K, Minakawa K, Kaneshiro T, Yoshihisa A, Ikeda K, Takeishi Y.
    • Journal Title

      JACC: CardioOncology

      Volume: 3 Pages: 134-136

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Intrarenal Doppler ultrasonography reflects hemodynamics and predicts prognosis in patients with heart failure.2020

    • Author(s)
      Yoshihisa A, Watanabe K, Sato Y, Ishibashi S, Matsuda M, Yamadera Y, Ichijo Y, Yokokawa T, Misaka T, Oikawa M, Kobayashi A, Takeishi Y.
    • Journal Title

      Scientific Report

      Volume: 10 Issue: 1 Pages: 22257-22257

    • DOI

      10.1038/s41598-020-79351-6

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Clinical implications of hepatic hemodynamic evaluation by abdominal ultrasonographic imaging in patients with heart failure.2020

    • Author(s)
      Yoshihisa A, Ishibashi S, Matsuda M, Yamadera Y, Ichijo Y, Sato Y, Yokokawa T, Misaka T, Oikawa M, Kobayashi A, Yamaki T, Kunii H, Takeishi Y.
    • Journal Title

      Journal of American Heart Association

      Volume: 9 Issue: 15

    • DOI

      10.1161/jaha.120.016689

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Atrial fibrillation is associated with impaired exercise capacity and adverse prognosis in patients with heart failure with mid-range ejection fraction.2020

    • Author(s)
      Sato Y, Yoshihisa A, Kimishima Y, Yokokawa T, Abe S, Shimizu T, Misaka T, Yamada S, Sato T, Kaneshiro T, Oikawa M, Kobayashi A, Yamaki T, Kunii H, Takeishi Y.
    • Journal Title

      European Journal of Preventive Cardiology

      Volume: 27 Issue: 19 Pages: 2322-2325

    • DOI

      10.1177/2047487319894106

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Associations of benzodiazepine with adverse prognosis in heart failure patients with insomnia.2020

    • Author(s)
      Sato Y, Yoshihisa A, Hotsuki Y, Watanabe K, Kimishima Y, Kiko T, Kanno Y, Yokokawa T, Abe S, Misaka T, Sato T, Oikawa M, Kobayashi A, Yamaki T, Kunii H, Nakazato K, Ishida T, Takeishi Y
    • Journal Title

      J Am Heart Assoc

      Volume: 9 Issue: 7

    • DOI

      10.1161/jaha.119.013982

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Impaired frontal brain activity in patients with heart failure assessed by near-infrared spectroscopy.2020

    • Author(s)
      Ichijo Y, Kono S, Yoshihisa A, Misaka T, Kaneshiro T, Oikawa M, Miura I, Yabe H, Takeishi Y
    • Journal Title

      J Am Heart Assoc

      Volume: 9 Issue: 3

    • DOI

      10.1161/jaha.119.014564

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Crucial role of NLRP3 inflammasome in a murine model of Kawasaki disease.2020

    • Author(s)
      4)Anzai F, Watanabe S, Kimura H, Kamata R, Karasawa T, Komada T, Nakamura J, Nagi-Miura N, Ohno N, Takeishi Y, Takahashi M
    • Journal Title

      J Mol Cell Cardiol

      Volume: 138 Pages: 185-196

    • DOI

      10.1016/j.yjmcc.2019.11.158

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] High-sensitivity troponin T, NT-proBNP and glomerular filtration rate: A multimarker strategy for risk stratification in chronic heart failure2019

    • Author(s)
      Aimo Alberto、Yoshihisa Akiomi、Takeishi Yasuchika、Egstrup Michael、Gustafsson Ida、Gaggin Hanna K.、Eggers Kai M.、Huber Kurt、Tentzeris Ioannis、Wilson Tang W.H.、Grodin Justin L.、Passino Claudio、Emdin Michele
    • Journal Title

      International Journal of Cardiology

      Volume: 277 Pages: 166-172

    • DOI

      10.1016/j.ijcard.2018.10.079

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Revisiting the obesity paradox in heart failure: Per cent body fat as predictor of biomarkers and outcome.2019

    • Author(s)
      Aimo A, Januzzi JL, Vergaro G, Clerico A, Latini R, Meessen J, Anand IS, Cohn JN, Gravning J, Ueland T, Nymo SH, Rocca HP, Bayes-Genis A, Lupón J, Boer RA, Yoshihisa A, Takeishi Y, Egstrup M, Gustafsson I, Gaggin HK, Eggers KM, Huber K, Tentzeris I, Ripoli A, Passino C, Emdin M
    • Journal Title

      Eur J Prev Cardiol

      Volume: 26 Issue: 16 Pages: 1751-1759

    • DOI

      10.1177/2047487319852809

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] Hematopoietic calr frameshift mutation exacerbates hypoxia-induced pulmonary hypertension in mice.2021

    • Author(s)
      Yokokawa T, Misaka T, Kimishima Y, Minakawa K, Sugimoto K, Nakazato K, Ikeda K, Takeishi Y.
    • Organizer
      American Heart Association Scientific Sessions
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Small hematopoietic clones with jak2v617f causally lead to pulmonary hypertension through neutrophil selective migration and maturation from the precursors in the lungs.2021

    • Author(s)
      Kimishima Y, Misaka T, Yokokawa T, Wada K, Sugimoto K, Minakawa K, Ikeda K, Nakazato K, Takeishi Y.
    • Organizer
      American Heart Association Scientific Sessions
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Serum level of membrane type 1-matrix metalloproteinase inversely corelates with right ventricular systolic pressure and mean pulmonary artery pressure in pulmonary hypertension.2021

    • Author(s)
      Sugimoto K, Misaka T, Yoshihisa A, Nakazato K, Ishida T, Takeishi Y.
    • Organizer
      American Heart Association Scientific Sessions
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Resting energy expenditure is important factor to predict cardiac mortality in chronic heart failure.2021

    • Author(s)
      Sato T, Yoshihisa A, Ishida T, Takeishi Y.
    • Organizer
      American Heart Association Scientific Sessions
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Prognostic value of relative flow reserve by hybrid 13N-ammonia positron emission tomography/magnetic resonance imaging in coronary artery disease.2021

    • Author(s)
      Endo K, Kiko T, Shimizu T, Yamaki T, Kunii H, Nakazato K, Takeishi Y.
    • Organizer
      American Heart Association Scientific Sessions
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] An increase in circulating cardiomyocyte-specific cell-free DNA in heart failure.2020

    • Author(s)
      Misaka T, Yokokawa T, Kimishima Y, Shimizu T, Kaneshiro T, Takeishi Y.
    • Organizer
      American Heart Association Scientific Session
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] Clinical significance of clonal hematopoiesis with JAK2V617F in patients with cardiovascular diseases.2020

    • Author(s)
      Wada K, Misaka T, Yokokawa T, Kimishima Y, Minakawa K, Kaneshiro T, Yoshihisa A, Ikeda K, Takeishi Y.
    • Organizer
      American Heart Association Scientific Session
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] Clonal hematopoiesis with JAK2V617F promotes pulmonary hypertension through ALK1.2020

    • Author(s)
      Kimishima Y, Misaka T, Yokokawa T, Wada K, Ueda K, Sugimoto K, Minakawa K, Nakazato K, Ishida T, Oshima M, Koide S, Shide K, Shimoda K, Iwama A, Ikeda K, Takeishi Y.
    • Organizer
      American Heart Association Scientific Session
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] Crucial role of Jak2V617f-positive myeloproliferative neoplasm in the development of aortic aneurysm.2020

    • Author(s)
      Yokokawa T, Misaka T, Kimishima Y, Wada K, Minakawa K, Sugimoto K, Ishida T, Ikeda K, Takeishi Y.
    • Organizer
      American Heart Association Scientific Session
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] Endothelin-1 increases ACVRL-1 expression at the transcriptional and post-transcriptional levels in human pulmonary arterial endothelial cells via Gi, RhoA and Rho kinase pathway with involvement of Sp-1.2020

    • Author(s)
      Sugimoto K, Yokokawa T, Misaka T, Yokokawa S, Nakazato K, Ishida T, Takeishi Y.
    • Organizer
      American Heart Association Scientific Session
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] Cardiac PET/MRI imaging in heart failure.2019

    • Author(s)
      Takeishi Y.
    • Organizer
      The 49th Annual Convention & Scientific Session of the Taiwan Society of Cardiology
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Fibrosis and cardiac dysfunction.2019

    • Author(s)
      Takeishi Y.
    • Organizer
      XXIII ISHR World Congress
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Janus activating kinase 2 V617F mutation promotes hypoxia induced pulmonary hypertension in mice.2019

    • Author(s)
      Kimishima Y, Misaka T, Yokokawa T, Sugimoto K, Minakawa K, Ishida T, Ikeda K, Takeishi Y
    • Organizer
      Scientific Sessions of American Heart Association
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Atrial fibrillation is associated with impaired exercise capacity and adverse prognosis in heart failure patients with mid-range ejection fraction.2019

    • Author(s)
      Sato Y, Yoshihisa A, Hotsuki Y, Watanabe K, Kimishima Y, Kiko T, Kanno Y, Yokokawa T, Abe S, Misaka T, Sato T, Oikawa M, Kobayashi A, Yamaki T, Kunii H, Nakazato K, Ishida T, Takeishi Y
    • Organizer
      Scientific Sessions of American Heart Association
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Clinical implications of intrarenal hemodynamic evaluation by ultrasonography in patients with heart failure.2019

    • Author(s)
      Misaka T, Yoshihisa A, Ichijo Y, Kimishima Y, Kanno Y, Yokokawa T, Abe S, Sato T, Oikawa M, Kobayashi A, Yamaki T, Kunii H, Nakazato K, Ishida T, Takeishi Y
    • Organizer
      Scientific Sessions of American Heart Association
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Book] 今日の治療指針 2022年版2022

    • Author(s)
      竹石恭知
    • Total Pages
      2224
    • Publisher
      医学書院
    • ISBN
      9784260047760
    • Related Report
      2021 Annual Research Report
  • [Book] 循環器疾患最新の治療 2022-20232022

    • Author(s)
      義久精臣、竹石恭知
    • Total Pages
      520
    • Publisher
      南江堂
    • ISBN
      9784524229956
    • Related Report
      2021 Annual Research Report
  • [Book] 令和の心不全治療ガイド2022

    • Author(s)
      義久精臣、市村祥平、竹石恭知
    • Total Pages
      314
    • Publisher
      文光堂
    • ISBN
      9784830619694
    • Related Report
      2021 Annual Research Report
  • [Book] 今日の治療指針 2021年版2021

    • Author(s)
      竹石恭知
    • Total Pages
      2192
    • Publisher
      医学書院
    • ISBN
      9784260042826
    • Related Report
      2021 Annual Research Report
  • [Book] 腫瘍循環器診療ハンドブック2020

    • Author(s)
      喜古崇豊, 竹石恭知
    • Total Pages
      231
    • Publisher
      メジカルビュー社
    • Related Report
      2020 Research-status Report
  • [Book] 今日の治療指針 2020年版2020

    • Author(s)
      竹石恭知
    • Total Pages
      2192
    • Publisher
      医学書院
    • Related Report
      2020 Research-status Report
  • [Book] 今日の治療指針2019年版2019

    • Author(s)
      竹石恭知
    • Total Pages
      1859
    • Publisher
      医学書院
    • Related Report
      2019 Research-status Report

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Published: 2019-04-18   Modified: 2023-01-30  

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