Novel variants in chronic theromboembolic pulmonary hypertension

• Project/Area Number: 17K15982
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular medicine
• Research Institution: Tohoku University
• Principal Investigator: Yaoita Nobuhiro 東北大学, 医学系研究科, 非常勤講師 (00735368)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 慢性血栓塞栓性肺高血圧症 / 急性肺塞栓症 / 一塩基変異多型 / 一塩基多型 / 一塩基変異多形 / 循環器・高血圧

Outline of Final Research Achievements

Chronic thromboembolic pulmonary hypertension (CTEPH) is a fatal disease entity of pulmonary hypertension (PH) characterized by obstruction of the major pulmonary arteries by organized thrombus and pulmonary vascular remodeling. The genetic background of CTEPH was not revealed so far. We checked the single nucelotide polimrphisms(SNPs) in CTEPH patients, which was related to idiopathic pulmonary arterial hypertension (IPAH) or acute pulmonary embolism (APE).it was revealed that CTEPH patients did not have any non-synonymous SNPs related to IPAH, but they had non-synonymous SNPs related with APE such as F5, MTHFR and THBD. Moreover, in CTEPH patients who did not have ha history of APE,SNPs of THBD was significantly higher than in healthy subjects. Furthermore, thrombin-activated fibrinolysis inhibitor was activated in CTEPH patients who had the SNPs of THBDs. Taken together, CTEPH patients had SNPs related to APE, even though CTEPH patients did not have history of APE.

Academic Significance and Societal Importance of the Research Achievements

肺動脈内に生じた器質化血栓により生じる慢性血栓塞栓性肺高血圧症(CTEPH)は予後の悪い難病である。急性肺塞栓症(APE)の合併症と考えられるが、APEの既往のないCTEPH患者も多い。このためCTEPHの病態がAPEと似ているのか不明であった。本研究では、世界で初めてCTEPH患者の遺伝的背景を解析し、CTEPH患者にはAPEの危険因子となる遺伝的背景があることがわかった。また、APEの既往のないCTEPH患者もAPEの危険因子となる遺伝的背景があることがわかった。このことからCTEPHとAPEが類似した病態である可能性が示唆された。

Research Products

• [Int'l Joint Research] Charite Universitasmedizin/Institute of Physiology(ドイツ)
• [Int'l Joint Research] Charite Universitasmedizin/Institute of Physiology(ドイツ)
• [Journal Article] Selenoprotein P Promotes the Development of Pulmonary Arterial Hypertension. (2018)
  • Author(s): Kikuchi N, Satoh K, Kurosawa R, Yaoita N, Elias-Al-Mamun M, Siddique MAH, Omura J, Satoh T, Nogi M, Sunamura S, Miyata S, Saito Y, Hoshikawa Y, Okada Y, Shimokawa H.
  • Journal Title: Circulation Volume: 138 Issue: 6 Pages: 600-623
  • DOI: 10.1161/circulationaha.117.033113
  • Peer Reviewed / Open Access
• [Journal Article] Sex differences in hemodynamic responses and long-term survival to optimal medical therapy in patients with pulmonary arterial hypertension. (2018)
  • Author(s): Kozu K, Sugimura K, Aoki T, Tatebe S, Yamamoto S, Yaoita N, Shimizu T, Nochioka K, Sato H, Konno R, Satoh K, Miyata S, Shimokawa H.
  • Journal Title: Heart Vessels. Volume: in press Issue: 8 Pages: 939-947
  • DOI: 10.1007/s00380-018-1140-6
  • Peer Reviewed / Open Access
• [Journal Article] Comprehensive evaluation of the effectiveness and safety of balloon pulmonary angioplasty for inoperable chronic thrombo-embolic pulmonary hypertension: long-term effects and procedure-related complications. (2017)
  • Author(s): Aoki T, Sugimura K, Tatebe S, Miura M, Yamamoto S, Yaoita N, Suzuki H, Sato H, Kozu K, Konno R, Miyata S, Nochioka K, Satoh K, Shimokawa H.
  • Journal Title: Eur Heart J. Volume: 7 Issue: 42 Pages: 3152-3159
  • DOI: 10.1093/eurheartj/ehx530
  • Peer Reviewed / Open Access
• [Journal Article] Activated TAFI Promotes the Development of Chronic Thromboembolic Pulmonary Hypertension: A Possible Novel Therapeutic Target. (2017)
  • Author(s): Satoh T, Satoh K, Yaoita N, Kikuchi N, Omura J, Kurosawa R, Numano K, Al-Mamun E, Siddique MA, Sunamura S, Nogi M, Suzuki K, Miyata S, Morser J, Shimokawa H
  • Journal Title: Circ Res. Volume: 14 Pages: 1246-1262
  • Peer Reviewed / Open Access
• [Journal Article] The Efficacy of a Genetic Analysis of the BMPR2 Gene in a Patient with Severe Pulmonary Arterial Hypertension and an Atrial Septal Defect Treated with Bilateral Lung Transplantation. (2017)
  • Author(s): Tatebe S, Sugimura K, Aoki T, Yamamoto S, Yaoita N, Suzuki H, Sato H, Kozu K, Konno R, Satoh K, Fukuda K, Adachi O, Saito R, Nakanishi N, Morisaki H, Oyama K, Saiki Y, Okada Y, Shimokawa H
  • Journal Title: Intern Med. Volume: 1 Pages: 3193-3197
  • NAID: 130006235510
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic Impacts of Plasma Levels of Cyclophilin A in Patients With Coronary Artery Disease. (2017)
  • Author(s): Ohtsuki T, Satoh K, Omura J, Kikuchi N, Satoh T, Kurosawa R, Nogi M, Sunamura S, Yaoita N, Aoki T, Tatebe S, Sugimura K, Takahashi J, Miyata S, Shimokawa H.
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 37 Pages: 685-693
  • Peer Reviewed / Open Access
• [Journal Article] The effect of heart rate reduction in pulmonary arterial hypertension. (2017)
  • Author(s): Yaoita N, Shimokawa H.
  • Journal Title: Am J Physiol Heart Circ Physiol. Volume: 15
  • Peer Reviewed / Open Access