Study on diagnosis and treatment effect evaluation of pulmonary hypertension by biomarker and imaging modality

• Project/Area Number: 17K09516
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Fukushima Medical University
• Principal Investigator: Nakazato Kazuhiko 福島県立医科大学, 医学部, 准教授 (90363762)
• Co-Investigator(Kenkyū-buntansha): 杉本 浩一 福島県立医科大学, 医学部, 准教授 (30404867) ; 小林 淳 福島県立医科大学, 医学部, 助教 (20448640) ; 鈴木 聡 福島県立医科大学, 医学部, 助教 (60536944)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 肺高血圧症 / 治療効果判定 / 予後予測 / バイオマーカー / 生理検査 / 臨床診断 / 画像診断 / 右心機能評価 / 心臓超音波検査 / 循環器

Outline of Final Research Achievements

We searched for biomarkers and laboratory findings useful for diagnosing pulmonary hypertension and for determining the therapeutic effect.
We reported that the complication of pulmonary hemorrhage of balloon pulmonary angioplasty (BPA) for chronic pulmonary thromboembolic pulmonary hypertension (CTEPH) correlates with pulmonary artery diameter measurable by CT. We also reported that when the pulmonary arterial pressure was gradually decreased by BPA, the abnormal 12-lead ECG waveform (right heart load) was also gradually improved.
We found that the presence of diabetes mellitus was an independent prognostic factor for pulmonary hypertension in patients with chronic respiratory disease including chronic obstructive pulmonary disease (COPD). Furthermore, it was revealed that the blood level of neprilysin, which breaks down vasoactive peptide such as BNP, is not related to the prognosis of patients with pulmonary hypertension.

Academic Significance and Societal Importance of the Research Achievements

難病である肺高血圧症の診断と治療は近年大きく進歩しつつあるが、その診断や治療効果の判定、さらには予後予測に関する有効な指標の確立が望まれている。
４群肺高血圧症に対する有効な治療法として普及しつつあるバルーン肺動脈形成術（BPA）について、合併症の予測や治療効果判定に関するCTや心電図所見についての新たな知見を得て発表した。
近年、糖尿病と肺高血圧症の関係が基礎研究を中心に注目されているが、慢性肺疾患患者群において、糖尿病の合併が３群肺高血圧症の独立した危険因子であることを証明した。また、可溶性ネプリライシンの血中濃度は予測に反して、肺高血圧症患者の生命予後と相関しないことを見出した。

Research Products

• [Journal Article] Senescence Marker Protein 30 Deficiency Exacerbates Pulmonary Hypertension in Hypoxia-Exposed Mice (2019)
  • Author(s): Sugimoto Koichi、Yokokawa Tetsuro、Misaka Tomofumi、Nakazato Kazuhiko、Ishida Takafumi、Takeishi Yasuchika
  • Journal Title: International Heart Journal Volume: 60 Issue: 6 Pages: 1430-1434
  • DOI: 10.1536/ihj.19-190
  • NAID: 130007753858
  • ISSN: 1349-2365, 1349-3299
  • Year and Date: 2019-11-30
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Fibrosis-4 Index Is Useful for Predicting Mortality in Patients with Pulmonary Hypertension due to Left Heart Disease (2019)
  • Author(s): Tetsuro Yokokawa, Koichi Sugimoto, Akiomi Yoshihisa, Takuya Goto, Tomofumi Misaka, Masayoshi Oikawa, Atsushi Kobayashi, Takayoshi Yamaki, Hiroyuki Kunii, Kazuhiko Nakazato, Takafumi Ishida, Yasuchika Takeishi
  • Journal Title: International Heart Journal Volume: 60 Issue: 5 Pages: 1147-1153
  • DOI: 10.1536/ihj.19-034
  • NAID: 130007719002
  • ISSN: 1349-2365, 1349-3299
  • Year and Date: 2019-09-27
  • Peer Reviewed / Open Access
• [Journal Article] Electrocardiographic Criteria of Right Ventricular Hypertrophy in Patients with Chronic Thromboembolic Pulmonary Hypertension after Balloon Pulmonary Angioplasty (2019)
  • Author(s): Yokokawa Tetsuro、Sugimoto Koichi、Nakazato Kazuhiko、Misaka Tomofumi、Oikawa Masayoshi、Kobayashi Atsushi、Yoshihisa Akiomi、Yamaki Takayoshi、Kunii Hiroyuki、Ishida Takafumi、Takeishi Yasuchika
  • Journal Title: Internal Medicine Volume: 58 Issue: 15 Pages: 2139-2144
  • DOI: 10.2169/internalmedicine.2320-18
  • NAID: 130007686856
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2019-08-01
  • Peer Reviewed / Open Access
• [Journal Article] Soluble neprilysin does not correlate with prognosis in pulmonary hypertension (2019)
  • Author(s): Yoshihisa Akiomi、Yokokawa Tetsuro、Misaka Tomofumi、Oikawa Masayoshi、Kobayashi Atsushi、Yamaki Takayoshi、Sugimoto Koichi、Kunii Hiroyuki、Nakazato Kazuhiko、Takeishi Yasuchika
  • Journal Title: ESC Heart Failure Volume: 6 Issue: 2 Pages: 291-296
  • DOI: 10.1002/ehf2.12404
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Liver fibrosis marker, 7S domain of collagen type IV, in patients with pre-capillary pulmonary hypertension (2018)
  • Author(s): 8.Yoshihisa A, Kimishima Y, Kiko T, Sato Y, Watanabe S, Kanno Y, Abe S, Miyata-Tatsumi M, Sato T, Suzuki S, Oikawa M, Kobayashi A, Yamaki T, Sugimoto K, Kunii H, Nakazato K, Suzuki H, Ishida T, Takeishi Y
  • Journal Title: Int J Cardiol Volume: 258 Pages: 269-274
  • DOI: 10.1016/j.ijcard.2018.01.138
  • Peer Reviewed / Open Access
• [Presentation] JAK2 V617F mutation promotes hypoxia-induced pulmonary hypertension in mice (2019)
  • Author(s): Yusuke Kimishima, Tomofumi Misaka, Tetsuro Yokokawa, Keiji Minakawa, Koichi Sugimoto, Takafumi Ishida, Kazuhiko Ikeda, Yasuchika Takeishi
  • Organizer: XXIII ISHR World Congress
  • Int'l Joint Research
• [Presentation] Endothelin-1 upregulates activin receptor-like kinase-1 (ALK-1) expression through Gi-RhoA dependent pathway in human pulmonary arterial endothelial cells (2019)
  • Author(s): Koichi Sugimoto, Tetsuro Yokokawa, Tomofumi Misaka, Kazuhiko Nakazato, Takafumi Ishida, Yasuchika Takeishi
  • Organizer: 第83回 日本循環器学会学術集会
• [Presentation] Relationship between treatment effect of riociguat and methemoglobin in patients with pulmonary hypertension (2019)
  • Author(s): Koichi Sugimoto, Akiomi Yoshihisa, Kazuhiko Nakazato, Masayoshi Oikawa, Atsushi Kobayashi, Takayoshi Yamaki, Hiroyuki Kunii, Takafumi Ishida, Yasuchika Takeishi
  • Organizer: 第83回 日本循環器学会学術集会
• [Presentation] 治療に難渋しているcombined post- and pre-capillary PHの一例 (2019)
  • Author(s): 中里和彦, 天海一明, 喜古崇豊, 菅野優紀, 山田慎哉, 及川雅啓, 杉本浩一, 竹石恭知
  • Organizer: 第4回 日本肺高血圧・肺循環学会学術集会
• [Presentation] Effect of endothelin-1 stimulation in the expression of activin receptor-like kinase-1 (ALK-1) in human pulmonary arterial endothelial cells (2018)
  • Author(s): Sugimoto K, Kimishima Y, Misaka T, Nakazato K, Ishida T, Takeishi Y
  • Organizer: International Society for Heart Research
  • Int'l Joint Research
• [Presentation] Balloon pulmonary angioplasty improves electrocardiographic remodeling of the right ventricle in patients with chronic thromboembolic pulmonary hypertension (2018)
  • Author(s): Yokokawa T, Sugimoto K, Nakazato K, Oikawa M, Kobayashi A, Yoshihisa A, Yamaki T, Kunii H, Ishida T, Takeishi Y
  • Organizer: Scientific Sessions of American Heart Association 2018, Chicago, USA
  • Int'l Joint Research
• [Presentation] The fibrosis-4 index predicts the mortality of patients with pulmonary hypertension due to left sided-heart disease (2018)
  • Author(s): Sugimoto K, Yoshihisa A, Goto T, Yokokawa T, Oikawa M, Kobayashi A, Nakazato K, Ishida T, Takeishi Y
  • Organizer: Scientific Sessions of American Heart Association 2018, Chicago, USA
  • Int'l Joint Research
• [Presentation] Impact of combined post capillary pulmonary hypertension based on upcoming diagnostic criteria on the prognosis of pulmonary hypertension due to left-sided heart disease (2018)
  • Author(s): Sugimoto K, Yoshihisa A, Yokokawa T, Misaka T, Oikawa M, Kobayashi A, Yamaki T, Kunii H, Nakazato K, Ishida T, Takeishi Y
  • Organizer: Scientific Sessions of American Heart Association 2018, Chicago, USA
  • Int'l Joint Research
• [Presentation] Senescence marker protein 30 affects phosphorylation of endothelial nitric oxide synthase in hypoxia-induced pulmonary hypertension in mice (2018)
  • Author(s): Sugimoto K, Sato A, Suzuki S, Yokokawa T, Misaka T, Nakazato K, Ishida T, Takeishi Y
  • Organizer: Scientific Sessions of American Heart Association 2018, Chicago, USA
  • Int'l Joint Research