Study of the development of low invasive predictors for the progression of coronary artery diseases in patients with heart transplantation

• Project/Area Number: 19K09256
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55030:Cardiovascular surgery-related
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: Watanabe Takuya 国立研究開発法人国立循環器病研究センター, 病院, 医長 (20627509)
• Co-Investigator(Kenkyū-buntansha): 松本 学 国立研究開発法人国立循環器病研究センター, 病院, 医師 (30408827)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 心臓移植 / 重症心不全 / 移植心冠動脈病変 / 植込型補助人工心臓 / 機械的循環補助装置 / 心臓移植後 / 移植後冠動脈病変 / 移植免疫 / 微小血管 / 移植心冠動脈硬化症 / 心筋病理

Outline of Research at the Start

心臓移植後遠隔期に発症する移植心冠動脈硬化症は心臓移植の遠隔予後に影響する合併症である。移植心冠動脈硬化症の進行の評価のためには、冠動脈血管内超音波検査などの侵襲的な検査が必要であるため、非観血的な移植心冠動脈硬化症の進行の予測法を確立することが重要である。本研究の目的は、移植心冠動脈硬化症の進行を低侵襲に予測する手段としての、（１）心筋生検による微小血管の変化、及び（２）移植心筋組織内の冠動脈血管壁へのレシピエント細胞の迷入の解析、並びに（３）レシピエントの上腕動脈の血流依存性血管拡張反応検査で評価される末梢血管内皮機能検査の有用性検討することである。

Outline of Final Research Achievements

The research questions of this study were to establish a new minimally invasive method to predict the progression of cardiac allograft vasculopathy which is a complication that affects the long-term prognosis after heart transplantation: (1) microvascular changes by myocardial biopsy, and (2) analysis of recipient cell straying into the coronary artery vessel wall within transplant myocardial tissue, and (3) Peripheral vascular endothelial function testing as assessed by flow-mediated vasodilation response testing of the recipient's brachial artery. Regarding the main objective (3), we found that the evaluation of endothelial function by flow-mediated vasodilatation test in the brachial artery in post-heart transplant patients can predict the progression of cardiac allograft vasculopathy in post-heart transplant patients, and we are ready for submission for publication.

Academic Significance and Societal Importance of the Research Achievements

本研究課題を通して、幅広く心臓移植後患者及び心臓移植を要する重症心不全患者の予後予測やリスク因子に関する臨床研究を行い、種々の研究論文の発表を行った。本研究成果を通じて、心臓移植後患者、心臓移植を要し植込み型補助人工心臓を装着するような重症心不全患者の予後を予測し、個別化医療を実践するための礎となる知見が得られた。心臓移植、重症心不全は本邦においては依然として確立した治療方針が明らかではない領域であり、本研究成果が確立した重症心不全治療の促進につながることが期待される。

Research Products

• [Journal Article] Risk Assessment of Neutropenia during Low-Dose Valganciclovir Prophylaxis for Heart Transplant Recipients (2022)
  • Author(s): Mai Otokubo , Kyoichi Wada , Megumi Ikura , Kotoka Hayase , Takaya Uno , Kazuki Nakagita , Naoki Hayakawa , Takuya Watanabe , Osamu Seguchi , Norihide Fukushima , Tsutomu Nakamura
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 45 Issue: 4 Pages: 452-459
  • DOI: 10.1248/bpb.b21-00860
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2022-04-01
  • Peer Reviewed / Open Access
• [Journal Article] Successful recovery from refractory hypoxia due to right-to-left shunting associated with iatrogenic atrial septal defect after catheter ablation in a patient with a left-ventricular assist device: a case report (2022)
  • Author(s): Shotaro Komeyama, Takuya Watanabe, Kenichiro Yamagata, Norihide Fukushima
  • Journal Title: Eur Heart J Case Rep. Volume: 22 Issue: 7
  • DOI: 10.1093/ehjcr/ytac277
  • Peer Reviewed / Open Access
• [Journal Article] Impact of the HeartMate 3 continuous-flow left ventricular assist device in patients with small body size (2022)
  • Author(s): Tonai Kohei、Fukushima Satsuki、Tadokoro Naoki、Kainuma Satoshi、Kawamoto Naonori、Kakuta Takashi、Koga-Ikuta Ayumi、Watanabe Takuya、Seguchi Osamu、Tsukamoto Yasumasa、Fukushima Norihide、Fujita Tomoyuki
  • Journal Title: Interactive CardioVascular and Thoracic Surgery Volume: 34 Issue: 5 Pages: 902-908
  • DOI: 10.1093/icvts/ivac012
  • Peer Reviewed / Open Access
• [Journal Article] Successful bridge to recovery in a patient with fulminant giant cell myocarditis that developed from multiple autoimmune disorders including myasthenia gravis: a case report. (2022)
  • Author(s): Nobuichiro Yagi , Takuya Watanabe , Yoshihiko Ikeda , Norihide Fukushima
  • Journal Title: European heart journal. Case reports Volume: 6 Issue: 2
  • DOI: 10.1093/ehjcr/ytac046
  • Peer Reviewed / Open Access
• [Journal Article] Impact of sleep-disordered breathing on ventricular tachyarrhythmias after left ventricular assist device implantation. (2022)
  • Author(s): Kumai Y, Seguchi O, Mochizuki H, Kimura Y, Iwasaki K, Kuroda K, Nakajima S, Matsumoto Y, Watanabe T, Yanase M, Sata M, Fukushima S, Fujita T, Chikamori T, Kobayashi J, Fukushima N.
  • Journal Title: J Artif Organs Volume: 25 Issue: 3 Pages: 223-230
  • DOI: 10.1007/s10047-021-01307-y
  • Peer Reviewed / Open Access
• [Journal Article] Pulmonary Vascular Reverse Remodeling After Left Ventricular Assist Device Implantation in Patients With Pulmonary Hypertension. (2022)
  • Author(s): Anegawa E, Seguchi O, Mochizuki H, Kuroda K, Doi Nakajima S, Watanabe T, Yanase M, Tadokoro N, Fukushima S, Fujita T, Fukushima N.
  • Journal Title: ASAIO J Volume: 69 Issue: 2 Pages: 151-158
  • DOI: 10.1097/mat.0000000000001739
  • Peer Reviewed / Open Access
• [Journal Article] Induction therapy in the current immunosuppressive Therapy. (2022)
  • Author(s): Takuya Watanabe
  • Journal Title: Intech open. Volume: －
  • Peer Reviewed / Open Access
• [Journal Article] The Predictive Value of Changes in Body Mass Index for the Incidence of Device-Specific Infections in Patients With Implantable Left Ventricular Assist Devices (2021)
  • Author(s): Yasumori Sujino
  • Journal Title: Circulation Journal Volume: 85 Issue: 9 Pages: 1460-1468
  • DOI: 10.1253/circj.CJ-20-1197
  • NAID: 130008077941
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2021-08-25
  • Peer Reviewed / Open Access
• [Journal Article] Reversible left ventricular dysfunction due to severe stenosis of the elephant trunk graft: A case report (2021)
  • Author(s): Eiji Anegawa, Takuya Watanabe
  • Journal Title: J Cardiol Cases Volume: 24 Issue: 4 Pages: 173-176
  • DOI: 10.1016/j.jccase.2021.03.010
  • Peer Reviewed / Open Access
• [Journal Article] Influence of Induction Therapy Using Basiliximab With Delayed Tacrolimus Administration in Heart Transplant Recipients ― Comparison With Standard Tacrolimus-Based Triple Immunosuppression ― (2020)
  • Author(s): Takuya Watanabe
  • Journal Title: Circulation Journal Volume: 84 Issue: 12 Pages: 2212-2223
  • DOI: 10.1253/circj.CJ-20-0164
  • NAID: 130007942481
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2020-11-25
  • Peer Reviewed / Open Access
• [Presentation] Current therapeutic strategies using newly developed mechanical circulatory support devices for patients with acute cardiogenic shock and advanced heart failure (2023)
  • Author(s): Takuya Watanabe,
  • Organizer: The 87th Annual Scientific Meeting of the Japanese Circulation Society JCS 2023
  • Int'l Joint Research
• [Presentation] 急性循環不全に対する機械的循環補助を用いた治療戦略 (2022)
  • Author(s): 渡邉 琢也
  • Organizer: 第60回日本人工臓器学会大会
  • Int'l Joint Research
• [Presentation] 機械的循環補助デバイスを用いた急性心不全治療戦略の現状と課題 (2022)
  • Author(s): 渡邉 琢也
  • Organizer: 第60回日本人工臓器学会大会
  • Int'l Joint Research
• [Presentation] Bridge to bridge（BTB）におけるBiofloat VADの有用性 (2022)
  • Author(s): 渡邉 琢也
  • Organizer: 第28回日本臨床補助人工心臓研究会学術集会
  • Invited
• [Presentation] Destination therapy時代の補助人工心臓を用いた最適なbridge to decision (BTD)治療戦略 (2022)
  • Author(s): 渡邉 琢也
  • Organizer: 第50回人工心臓と補助循環懇話会 学術集会
  • Invited
• [Presentation] Management of Non-cardiac Comorbidities in Patients with Implantable Left Ventricular Assist Device (2022)
  • Author(s): Takuya Watanabe
  • Organizer: Annual meeting, The Japanese Circulation Society
  • Int'l Joint Research
• [Presentation] 心臓移植後の抗体関連拒絶反応とその治療及びドナー特異的抗HLA抗体との関連性の検討 (2021)
  • Author(s): 渡邉 琢也
  • Organizer: 日本移植学会
  • Int'l Joint Research
• [Presentation] DT-LVAD治療の課題と取り組み (2021)
  • Author(s): 渡邉 琢也
  • Organizer: 日本人工臓器学会
  • Int'l Joint Research
• [Presentation] Is exercise rehabilitation indicated for advanced heart failure patients receiving an intravenous inotropic agent (2020)
  • Author(s): Takuya Watanabe
  • Organizer: JCS annual meeting
  • Int'l Joint Research
• [Presentation] Donor-transmitted atherosclerosis and the occurrence of cardiac antibody-mediated rejection influenced on the development of cadiac allograft vasculopathy (2020)
  • Author(s): Takuya Watanabe
  • Organizer: ISHLT annual meeting
  • Int'l Joint Research
• [Presentation] The development of cardiac allograft vasculopathy occurs in early intimal thickening and constrictive remoding in long-term period (2020)
  • Author(s): Satoshi Takeuchi
  • Organizer: ISHLT annual meeting
  • Int'l Joint Research
• [Presentation] External validation of current international short- and long-term prognosis model for survival in heart transplant recipients using marginal donor hearts at single japanese center (2020)
  • Author(s): Nobuichiro Yagi
  • Organizer: TTS annual meeting
  • Int'l Joint Research
• [Presentation] The Era of Destination Therapy is Coming to Japan ー Are We ready for It? (2020)
  • Author(s): Takuya Watanabe
  • Organizer: JCS annual meeting
  • Int'l Joint Research
• [Presentation] The development of cardiac allograft vasculopathy occurs in early intimal thickening and constrictive remodeling in long-term period; Long-term serial intravascular ultrasound study (2020)
  • Author(s): 竹内 智／渡邉 琢也
  • Organizer: International society of heart and lung transplantation; Annual meeting
  • Int'l Joint Research
• [Presentation] Donor-transmitted atherosclerosis and the occurrence of cardiac antibody-mediated rejection influenced on the development of cardiac allograft vasculopathy. (2020)
  • Author(s): 渡邉 琢也
  • Organizer: International society of heart and lung transplantation; Annual meeting
  • Int'l Joint Research
• [Presentation] 国立循環器病研究センターにおける移植心冠動脈病変の現状 (2019)
  • Author(s): 渡邉 琢也
  • Organizer: 日本移植学会
• [Presentation] 心臓移植における抗体関連型拒絶反応を抑制するための国立循環器病研究センターの診断・治療戦略について (2019)
  • Author(s): 渡邉 琢也
  • Organizer: 日本移植学会
• [Presentation] A comparison of novel developed centrifugal-flow and conventional pulsatile-flow extracorporel left ventricular assist devices in patients with cardiogenic shocks as bridge to candidacy for heart transplantation (2019)
  • Author(s): Takuya Watanabe
  • Organizer: International society of mechanical circulatory support conference
  • Int'l Joint Research
• [Book] Induction Therapy in the Current Immunosuppressive Therapy. (2022)
  • Author(s): Takuya Watanabe, Yasumasa Tsukamoto, Hiroki Mochizuki, Masaya Shimojima, Tasuku Hada, Satsuki Fukushima, Tomoyuki Fujita and Osamu Seguchi.
  • Total Pages: 15
  • Publisher: Intechopen.
• [Book] Novel Diagnosis and Therapeutic Approach to Antibody-Mediated Rejection in Heart transplantation. (2020)
  • Author(s): Takuya Watanabe
  • Total Pages: 92
  • Publisher: IntechOpen