Monoclonal hematopoiesis in heart failure

• Project/Area Number: 19K08523
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Fukushima 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: ¥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)
• Keywords: clonal 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。

Research Products

• [Journal Article] Clonal hematopoiesis with JAK2V617F promotes pulmonary hypertension with ALK1 upregulation in lung neutrophils (2021)
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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 failure (2019)
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • Int'l Joint Research / Invited
• [Presentation] Fibrosis and cardiac dysfunction. (2019)
  • Author(s): Takeishi Y.
  • Organizer: XXIII ISHR World Congress
  • 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
  • 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
  • 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
  • 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
• [Book] 循環器疾患最新の治療 2022-2023 (2022)
  • Author(s): 義久精臣、竹石恭知
  • Total Pages: 520
  • Publisher: 南江堂
  • ISBN: 9784524229956
• [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
• [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
• [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
• [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
• [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