冠動脈ステント留置後の冠動脈内皮機能に対する脂質低下療法の効果
キーワード：冠動脈インターベンション、酸化コレステロール、スタチン、エゼチミブ、PCSK9阻害薬
2018.04～2024.03.

循環器疾患リアルワールドデータベースの構築
キーワード：電子カルテ、心臓カテーテル検査、冠動脈インターベンション、SS-MIX、データベース
2017.04～2022.03.

細胞外微粒子の心血管病態における役割の解明と新規治療法の開発
キーワード：エクソソーム、動脈硬化、心筋梗塞
2017.10～2023.03.

動脈硬化性心血管病の病態形成における酸化脂質の役割
キーワード：動脈硬化、酸化コレステロール、血管内皮機能、マクロファージ
2011.04～2025.03.

炎症性単球／マクロファージの心血管病における役割の解明と新規治療法の開発
キーワード：炎症　単球　マクロファージ　動脈硬化　急性冠症候群
2012.04～2019.03.

単球選択性ナノ粒子による新規動脈硬化プラーク破綻予防治療の開発
キーワード：動脈硬化　マクロファージ　ナノ粒子
2008.04～2011.03.

心血管の炎症における酸化ステロールの分子生物学的役割と治療標的の解明
2021.04～2024.03, 代表者：的場　哲哉, 九州大学, 科学研究費助成事業.

循環器救急疾患に対する救急医療現場の連携推進のための課題抽出と専門医間の連携構築を目指したガイドブックの作成（２２ＦＡ１６０１）
2022.04～2024.03, 代表者：野口 暉夫, 国立研究開発法人国立循環器病研究センター, 厚生労働科学研究費補助金
"【1年目】
１．救急医療従事者から見た連携遅延の実態調査行うために、以下5項目の全国アンケート調査を行い改善点の提言を行う。また、総務省消防庁による全国救急搬送データと急性期医療機関情報の連結に関する検討も行う
①全国消防本部・日本救急救命学会：プレホスピタル12誘導心電図、病院前主幹動脈閉塞脳卒中スケールの使用率調査
②救急医学会：患者受け入れ根拠のQIの抽出、専門医への連携方法の調査
③日本循環器学会：12誘導心電図伝送の有無と伝送手段の調査
④日本胸部外科学会：大動脈解離のQI使用の有無と画像伝送の有無　
⑤日本脳卒中学会：病院前主幹動脈閉塞脳卒中スケールの実施状況と画像伝送の有無
２．病院前システム遅延の原因抽出：大阪府MC協議会を介した調査と、大阪府、広島県、岐阜県、茨城県、福岡県の公開データ、J-ASPECT 研究データを用いて、主幹動脈閉塞脳卒中スケール使用の有無による脳卒中患者のプロセス指標、アウトカム指標の比較を以下の項目で行う
①プレホスピタル12誘導心電図の使用率の調査
②急性解離診療のQIを用いた専門病院選定率の調査
③各府県データ、J-ASPECT 研究を用いて、主幹動脈閉塞脳卒中スケールを導入している医療圏における病院前プロセス指標、急性期再開通療法の実施割合、院内プロセス指標と院内死亡、機能的自立の割合を非導入の医療圏と比較する
３．初期対応診療医・救急医と専門医の連携の現状把握のために文献のシステマティックレビューを行う
①専門医以外の医療従事者の12誘導心電図判読能力
②循環器専門医の勤務日と非勤務日に搬送されたST上昇型急性心筋梗塞の診療QI達成率
③大動脈解離の診療のQI充足率
④脳卒中センター以外の脳卒中応需施設の構造指標と脳卒中患者転送状況に関する現状把握と課題の抽出を行う
【2年目】
･循環器救急疾患に対する救急医療現場と専門医による治療の連携推進のためのガイドブックを作成する
･ガイドブックを日本循環器学会、日本救急医学会、日本臨床救急医学会、日本集中治療医学会、日本救急救命学会、日本脳卒中学会のホームページで公開し、メディカルコントロール協議会に周知する
･日本蘇生協議会蘇生ガイドライン2025や、救急蘇生法の指針2025にガイドブックの内容を反映させ、最終的には各地域のMC協議会のプロトコルに記載されるように提案する".

リアルワールド電子カルテ情報を用いた循環器病の再発・重症化・合併症のリスク因子の分析と介入の費用対効果
2022.04～2024.03, 代表者：永井 良三, 自治医科大学, 厚生労働科学研究費補助金
"1．重症虚血性心疾患の多目的データプラットフォームの構築（CLIDAS）
CLIDASの主要システムの骨格は、7施設においてほぼ完成した。すなわち全データに対して臨床項目による問い合わせ(クエリー)を行い、該当情報を抽出して分析するアプリケーション(CLIDAS-DMS)を、上記7施設に実装した。令和4年度はCLIDASのデータを用いて、虚血性疾患の2次予防（再発・重症化・合併症防止）において、年齢、性、体重、高血圧、脂質異常症、喫煙などの基礎データや、心機能・冠動脈治療部位・血管径・使用デバイスとイベント発生率との関連を明らかにする。
研究体制は、研究代表者と自治医科大学のスタッフ（興梠、藤田、甲谷）が全体を統括する。臨床クエスチョンの設定は全研究者で行い、データの収集とクレンジング、解析は、2名の女性研究を含む各施設の若手研究者が担当する。またプレシジョン社（代表：佐藤寿彦）に委託してシステムの改善を進める。
2.自治体のレセプトデータを用いた薬物療法と血管内治療の費用対効果分析
薬剤（スタチン、心不全薬（β遮断薬、レニン-アンジオテンシン系阻害薬、トルバプタン、イバブラジン、SGLT2阻害薬）等）や血管内治療デバイス使用症例の重症化、再発作、合併症（心不全と脳卒中）の予防効果（千人年あたり）を明らかにしたのち、これまで蓄積してきた熊本県と栃木県の合計約200万人の時系列レセプトデータを用いて、イベント発症防止の費用対効果を分析する。具体的にはCLIDASを用いて効果の推定を行い、この効果検証と同様の背景を持った対象者に対して退院後アウトカム発生までの医療費を集計することで費用を推定する。この際、治療内容だけでなく、検査値・処方内容を含めた背景因子による層別化分析も行う。この部分の研究は、内閣府ImPACT研究の成果を活用し、7年にわたってデータを維持してきた自治医科大学データサイエンスセンターの笹渕が担当する。
".

クリニカルパスデータの標準化・利活用に係る研究
2018.10～2021.03, 代表者：副島 秀久, 社会福祉法人恩賜財団済生会熊本病院, 医療研究開発推進事業費補助金（日本）
本事業は、日本クリニカルパス学会と日本医療情報学会の合同委員会が主催し、コンセプトは既に広く普及しているもののシステムや運用が標準化されていないクリニカルパス（以下パス）の医療施設・ベンダー間の標準化や相互運用性を進め、複数医療施設に集積したパスデータの統合解析を次世代医療基盤法上で可能とすることを目的とする。まず、収集するデータの解析を志向し、またパス移植性など相互運用性も考慮したパス標準データリポジトリ（以下リポジトリ）規格を定める。リポジトリ規格には、アウトカム・アセスメント（観察項目）・タスクの三層データ構造によるアウトカムユニットを医療工程の最小単位として用い、そのマスターにはHELICS標準化の最終段階である標準アウトカムマスター（以下BOM）の使用を前提とする。次に、実証ターゲットをパスシステムのトップ4ベンダーおよび導入4医療施設とする。リポジトリ規格のデータ構造へデータ出力する標準アウトカム志向型パスシステム（以下標準パスシステム）を各医療施設に導入し、リポジトリおよびその間のインタフェイス（以下IF）を構築する。さらに、複数医療施設から出力されるパスデータの解析基盤を構築する。8種以上の実証用標準的パスを実証医療施設や研究分担者、協力臨床学会等の専門医により策定し、標準パスシステムへ格納し、倫理審査や各医療施設のオーソライズを経て、実入院患者を用いた標準パスシステム実証研究を約1年間行う。蓄積したパスデータをベンチマーク、統合解析するとともに、認定機関により匿名加工情報化しても同様の解析ができることを確認する。実証研究を経て抽出された課題への対策を検討し、標準パスシステム、IF、リポジトリ規格、解析基盤の改修を行う。8種以上の実証用標準的パスも、解析を経て改訂し学会主導の標準パスとする。タスクを含むBOMの改訂、リポジトリ規格のJAHIS標準化を行い、後者はHELICS標準へも申請する。本事業によりベンダー間でパスシステムの標準化が進み、その出力形式やパス移植などの相互運用性が確保されることから、多くの他のパス内容も標準化されるのみならず、パス解析基盤が次世代医療基盤上に構築され、パス活動が活性化と医療の質や効率が劇的に向上することが期待される。アウトカムユニットを中心とした工程管理は次世代電子カルテの技術要素として期待される。.

分化再生と生体恒常性を制御するエクソソームの新しい細胞同調機能の解明とナノ粒子による生体機能制御への応用
2017.10～2023.03, 代表者：山下　潤, 京都大学 iPS細胞研究所, 国立研究開発法人　科学技術振興機構（日本）
分化再生と生体恒常性を制御するエクソソームの新しい細胞同調機能の解明とナノ粒子による生体機能制御への応用.

主要原著論文

1.	Tetsuya Matoba, Kazuo Sakamoto, Michikazu Nakai, Kenzo Ichimura, Masahiro Mohri, Yasuyuki Tsujita, Masao Yamasaki, Yasushi Ueki, Nobuhiro Tanaka, Yohei Hokama, Motoki Fukutomi, Katsutaka Hashiba, Rei Fukuhara, Satoru Suwa, Hirohide Matsuura, Hayato Hosoda, Takahiro Nakashima, Yoshio Tahara, Yoko Sumita, Kunihiro Nishimura, Yoshihiro Miyamoto, Naohiro Yonemoto, Tsukasa Yagi, Eizo Tachibana, Ken Nagao, Takanori Ikeda, Naoki Sato, Hiroyuki Tsutsui, Institutional Characteristics and Prognosis of Acute Myocardial Infarction With Cardiogenic Shock in Japan - Analysis From the JROAD/JROAD-DPC Database., Circulation journal : official journal of the Japanese Circulation Society, 10.1253/circj.CJ-20-0655, 85, 10, 1797-1805, 2021.03, BACKGROUND: The high mortality of acute myocardial infarction (AMI) with cardiogenic shock (i.e., Killip class IV AMI) remains a challenge in emergency cardiovascular care. This study aimed to examine institutional factors, including the number of JCS board-certified members, that are independently associated with the prognosis of Killip class IV AMI patients.Methods and Results:In the Japanese registry of all cardiac and vascular diseases-diagnosis procedure combination (JROAD-DPC) database (years 2012-2016), the 30-day mortality of Killip class IV AMI patients (n=21,823) was 42.3%. Multivariate analysis identified age, female sex, admission by ambulance, deep coma, and cardiac arrest as patient factors that were independently associated with higher 30-day mortality, and the numbers of JCS board-certified members and of intra-aortic balloon pumping (IABP) cases per year as institutional factors that were independently associated with lower mortality in Killip class IV patients, although IABP was associated with higher mortality in Killip classes I-III patients. Among hospitals with the highest quartile (≥9 JCS board-certified members), the 30-day mortality of Killip class IV patients was 37.4%. CONCLUSIONS: A higher numbers of JCS board-certified members was associated with better survival of Killip class IV AMI patients. This finding may provide a clue to optimizing local emergency medical services for better management of AMI patients in Japan..
2.	Satoshi Yasuda, Koichi Kaikita, Masaharu Akao, Junya Ako, Tetsuya Matoba, Masato Nakamura, Katsumi Miyauchi, Nobuhisa Hagiwara, Kazuo Kimura, Atsushi Hirayama, Kunihiko Matsui, Hisao Ogawa, Antithrombotic Therapy for Atrial Fibrillation with Stable Coronary Disease., The New England journal of medicine, 10.1056/NEJMoa1904143, 381, 12, 1103-1113, 2019.09, [URL], BACKGROUND: There are limited data from randomized trials evaluating the use of antithrombotic therapy in patients with atrial fibrillation and stable coronary artery disease. METHODS: In a multicenter, open-label trial conducted in Japan, we randomly assigned 2236 patients with atrial fibrillation who had undergone percutaneous coronary intervention (PCI) or coronary-artery bypass grafting (CABG) more than 1 year earlier or who had angiographically confirmed coronary artery disease not requiring revascularization to receive monotherapy with rivaroxaban (a non-vitamin K antagonist oral anticoagulant) or combination therapy with rivaroxaban plus a single antiplatelet agent. The primary efficacy end point was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death from any cause; this end point was analyzed for noninferiority with a noninferiority margin of 1.46. The primary safety end point was major bleeding, according to the criteria of the International Society on Thrombosis and Hemostasis; this end point was analyzed for superiority. RESULTS: The trial was stopped early because of increased mortality in the combination-therapy group. Rivaroxaban monotherapy was noninferior to combination therapy for the primary efficacy end point, with event rates of 4.14% and 5.75% per patient-year, respectively (hazard ratio, 0.72; 95% confidence interval [CI], 0.55 to 0.95; P
3.	Masaki Fujiwara, Tetsuya Matoba, Jun-Ichiro Koga, Arihide Okahara, Daiki Funamoto, Kaku Nakano, Hiroyuki Tsutsui, Kensuke Egashira, Nanoparticle incorporating Toll-like receptor 4 inhibitor attenuates myocardial ischaemia-reperfusion injury by inhibiting monocyte-mediated inflammation in mice., Cardiovascular research, 10.1093/cvr/cvz066, 115, 7, 1244-1255, 2019.06, [URL], AIMS: Myocardial ischaemia-reperfusion (IR) injury hampers the therapeutic effect of revascularization in patients with acute myocardial infarction (AMI). Innate immunity for damage-associated protein patterns promotes the process of IR injury; however, the blockade of Toll-like receptor 4 (TLR4) in myocardial IR injury has not been translated into clinical practice. Therefore, we aimed to examine whether the nanoparticle-mediated administration of TAK-242, a chemical inhibitor of TLR4, attenuates myocardial IR injury in a clinically feasible protocol in a mouse model. METHODS AND RESULTS: We have prepared poly-(lactic-co-glycolic acid) nanoparticles containing TAK-242 (TAK-242-NP). TAK-242-NP significantly enhanced the drug delivery to monocytes/macrophages in the spleen, blood, and the heart in mice. Intravenous administration of TAK-242-NP (containing 1.0 or 3.0 mg/kg TAK-242) at the time of reperfusion decreased the infarct size, but the TAK-242 solution did not even when administered at a dosage of 10.0 mg/kg. TAK-242-NP inhibited the recruitment of Ly-6Chigh monocytes to the heart, which was accompanied by decreased circulating HMGB1, and NF-κB activation and cytokine expressions in the heart. TAK-242-NP did not decrease the infarct size further in TLR4-deficient mice, confirming the TLR4-specific mechanism in the effects of TAK-242-NP. Furthermore, TAK-242-NP did not decrease the infarct size further in CCR2-deficient mice, suggesting that monocyte/macrophage-mediated inflammation is the primary therapeutic target of TAK-242-NP. CONCLUSION: The nanoparticle-mediated delivery of TAK-242-NP represent a novel and clinical feasible strategy in patients undergone coronary revascularization for AMI by regulating TLR4-dependent monocytes/macrophages-mediated inflammation..
4.	Tetsuya Matoba, Takahide Kohro, Hideo Fujita, Masaharu Nakayama, Arihiro Kiyosue, Yoshihiro Miyamoto, Kunihiro Nishimura, Hideki Hashimoto, Yasuaki Antoku, Naoki Nakashima, Kazuhiko Ohe, Hisao Ogawa, Hiroyuki Tsutsui, Ryozo Nagai, Architecture of the Japan Ischemic Heart Disease Multimodal Prospective Data Acquisition for Precision Treatment (J-IMPACT) System., International heart journal, 10.1536/ihj.18-113, 60, 2, 264-270, 2019.03, [URL], The utilization of electronic medical records and multimodal medical data is an ideal approach to build a real-time and precision registry type study with a smaller effort and cost, which may fill a gap between evidence-based medicine and the real-world clinical practice. The Japan Ischemic heart disease Multimodal Prospective data Acquisition for preCision Treatment (J-IMPACT) project aimed to build an clinical data registry system that electronically collects not only medical records, but also multimodal data, including coronary angiography and percutaneous coronary intervention (PCI) report, in standardized data formats for clinical studies.The J-IMPACT system comprises the standardized structured medical information exchange (SS-MIX), coronary angiography and intervention reporting system (CAIRS), and multi-purpose clinical data repository system (MCDRS) interconnected within the institutional network. In order to prove the concept, we acquired multimodal medical data of 6 consecutive cases that underwent PCI through the J-IMPACT system in a single center. Data items regarding patient background, laboratory data, prescriptions, and PCI/cardiac catheterization report were correctly acquired through the J-IMPACT system, and the accuracy of the multimodal data of the 4 categories was 100% in all 6 cases.The application of J-IMPACT system to clinical studies not only fills the gaps between randomized clinical trials and real-world medicine, but may also provide real-time big data that reinforces precision treatment for each patient..
5.	Masaki Tokutome, Tetsuya Matoba, Yasuhiro Nakano, Arihide Okahara, Masaki Fujiwara, Jun-Ichiro Koga, Kaku Nakano, Hiroyuki Tsutsui, Kensuke Egashira, Peroxisome proliferator-activated receptor-gamma targeting nanomedicine promotes cardiac healing after acute myocardial infarction by skewing monocyte/macrophage polarization in preclinical animal models., Cardiovascular research, 10.1093/cvr/cvy200, 115, 2, 419-431, 2019.02, [URL], Aims: Monocyte-mediated inflammation is a major mechanism underlying myocardial ischaemia-reperfusion (IR) injury and the healing process after acute myocardial infarction (AMI). However, no definitive anti-inflammatory therapies have been developed for clinical use. Pioglitazone, a peroxisome proliferator-activated receptor-gamma (PPARγ) agonist, has unique anti-inflammatory effects on monocytes/macrophages. Here, we tested the hypothesis that nanoparticle (NP)-mediated targeting of pioglitazone to monocytes/macrophages ameliorates IR injury and cardiac remodelling in preclinical animal models. Methods and results: We formulated poly (lactic acid/glycolic acid) NPs containing pioglitazone (pioglitazone-NPs). In a mouse IR model, these NPs were delivered predominantly to circulating monocytes and macrophages in the IR heart. Intravenous treatment with pioglitazone-NPs at the time of reperfusion attenuated IR injury. This effect was abrogated by pre-treatment with the PPARγ antagonist GW9662. In contrast, treatment with a pioglitazone solution had no therapeutic effects on IR injury. Pioglitazone-NPs inhibited Ly6Chigh inflammatory monocyte recruitment as well as inflammatory gene expression in the IR hearts. In a mouse myocardial infarction model, intravenous treatment with pioglitazone-NPs for three consecutive days, starting 6 h after left anterior descending artery ligation, attenuated cardiac remodelling by reducing macrophage recruitment and polarizing macrophages towards the pro-healing M2 phenotype. Furthermore, pioglitazone-NPs significantly decreased mortality after MI. Finally, in a conscious porcine model of myocardial IR, pioglitazone-NPs induced cardioprotection from reperfused infarction, thus providing pre-clinical proof of concept. Conclusion: NP-mediated targeting of pioglitazone to inflammatory monocytes protected the heart from IR injury and cardiac remodelling by antagonizing monocyte/macrophage-mediated acute inflammation and promoting cardiac healing after AMI..
6.	Katsuya Honda, Tetsuya Matoba, Yoshibumi Antoku, Jun-Ichiro Koga, Ikuyo Ichi, Kaku Nakano, Hiroyuki Tsutsui, Kensuke Egashira, Lipid-Lowering Therapy With Ezetimibe Decreases Spontaneous Atherothrombotic Occlusions in a Rabbit Model of Plaque Erosion: A Role of Serum Oxysterols., Arteriosclerosis, thrombosis, and vascular biology, 10.1161/ATVBAHA.117.310244, 38, 4, 757-771, 2018.04, OBJECTIVE: Plaque erosion is increasing its importance as one of the mechanisms of acute coronary syndromes in this statin era. However, the clinical efficacy of currently used lipid-lowering agents in the prevention of thrombotic complications associated with plaque erosion has not been clarified. Therefore, we examined the therapeutic effects of ezetimibe or rosuvastatin monotherapy on spontaneous atherothrombotic occlusion. APPROACH AND RESULTS: Femoral arteries of Japanese white rabbits, fed a high-cholesterol diet, were injured by balloon catheter, and then angiotensin II was continuously administrated. In 94% of these arteries, spontaneous thrombotic occlusions were observed after 5 weeks (median) of balloon injury. Histochemical analyses indicated that the injured arteries had similar pathological features to human plaque erosions; (1) spontaneous thrombotic occlusion, (2) lack of endothelial cells, and (3) tissue factor expression in vascular smooth muscle cells. Ezetimibe (1.0 mg/kg per day), but not rosuvastatin (0.6 mg/kg per day), significantly decreased thrombotic occlusion of arteries accompanied with accelerated re-endothelialization and the decreases of serum oxysterols despite the comparable on-treatment serum cholesterol levels. The 7-ketocholesterol inhibited the migration of human umbilical vein endothelial cells. Both 7-ketocholesterol and 27-hydroxycholesterol increased tissue factor expression in cultured rat vascular smooth muscle cells. Tissue factor expression was also induced by serum from vehicle- or rosuvastatin-treated rabbits, but the induction was attenuated with serum from ezetimibe-treated rabbits. CONCLUSIONS: We have established a novel rabbit model of spontaneous atherothromobotic occlusion without plaque rupture that is feasible to test the therapeutic effects of various pharmacotherapies. Ezetimibe may decrease atherothrombotic complications after superficial plaque erosion by reducing serum oxysterols..
7.	Susumu Takase, Tetsuya Matoba, Soichi Nakashiro, Yasushi Mukai, Shujiro Inoue, Keiji Oi, Taiki Higo, Shunsuke Katsuki, Masao Takemoto, Nobuhiro Suematsu, Kenichi Eshima, Kenji Miyata, Mitsutaka Yamamoto, Makoto Usui, Kenji Sadamatsu, Shinji Satoh, Toshiaki Kadokami, Kiyoshi Hironaga, Ikuyo Ichi, Koji Todaka, Junji Kishimoto, Kensuke Egashira, Kenji Sunagawa, Ezetimibe in Combination With Statins Ameliorates Endothelial Dysfunction in Coronary Arteries After Stenting: The CuVIC Trial (Effect of Cholesterol Absorption Inhibitor Usage on Target Vessel Dysfunction After Coronary Stenting), a Multicenter Randomized Controlled Trial., Arteriosclerosis, thrombosis, and vascular biology, 10.1161/ATVBAHA.116.308388, 37, 2, 350-358, 2017.02, [URL], OBJECTIVES: We sought to investigate whether treatment with ezetimibe in combination with statins improves coronary endothelial function in target vessels in coronary artery disease patients after coronary stenting. APPROACH AND RESULTS: We conducted a multicenter, prospective, randomized, open-label, blinded-end point trial among 11 cardiovascular treatment centers. From 2011 to 2013, 260 coronary artery disease patients who underwent coronary stenting were randomly allocated to 2 arms (statin monotherapy, S versus ezetimibe [10 mg/d]+statin combinational therapy, E+S). We defined target vessel dysfunction as the primary composite outcome, which comprised target vessel failure during treatment and at the 6- to 8-month follow-up coronary angiography and coronary endothelial dysfunction determined via intracoronary acetylcholine testing performed in cases without target vessel failure at the follow-up coronary angiography. Coadministration of ezetimibe with statins further lowered low-density lipoprotein cholesterol levels (83±23 mg/dL in S versus 67±23 mg/dL in E+S; P
8.	Shunsuke Katsuki, Tetsuya Matoba, Kenji Sunagawa, Kensuke Egashira, Nanoparticle-Mediated Delivery of Pitavastatin Inhibits Atherosclerotic Plaque Destabilization/Rupture in Mice by Regulating the Recruitment of Inflammatory Monocytes, CIRCULATION, 10.1161/CIRCULATIONAHA.113.002870, 129, 8, 896-906, 2014.02, Preventing atherosclerotic plaque destabilization and rupture is the most reasonable therapeutic strategy for acute myocardial infarction. Therefore, we tested the hypotheses that (1) inflammatory monocytes play a causative role in plaque destabilization and rupture and (2) the nanoparticle-mediated delivery of pitavastatin into circulating inflammatory monocytes inhibits plaque destabilization and rupture. We used a model of plaque destabilization and rupture in the brachiocephalic arteries of apolipoprotein E-deficient (ApoE(-/-)) mice fed a high-fat diet and infused with angiotensin II. The adoptive transfer of CCR2(+/+)Ly-6C(high) inflammatory macrophages, but not CCR2(-/-) leukocytes, accelerated plaque destabilization associated with increased serum monocyte chemoattractant protein-1 (MCP-1), monocyte-colony stimulating factor, and matrix metalloproteinase-9. We prepared poly(lactic-co-glycolic) acid nanoparticles that were incorporated by Ly-6G(-)CD11b(+) monocytes and delivered into atherosclerotic plaques after intravenous administration. Intravenous treatment with pitavastatin-incorporated nanoparticles, but not with control nanoparticles or pitavastatin alone, inhibited plaque destabilization and rupture associated with decreased monocyte infiltration and gelatinase activity in the plaque. Pitavastatin-incorporated nanoparticles inhibited MCP-1-induced monocyte chemotaxis and the secretion of MCP-1 and matrix metalloproteinase-9 from cultured macrophages. Furthermore, the nanoparticle-mediated anti-MCP-1 gene therapy reduced the incidence of plaque destabilization and rupture. The recruitment of inflammatory monocytes is critical in the pathogenesis of plaque destabilization and rupture, and nanoparticle-mediated pitavastatin delivery is a promising therapeutic strategy to inhibit plaque destabilization and rupture by regulating MCP-1/CCR2-dependent monocyte recruitment in this model..
9.	Tetsuya Matoba, Kensuke Egashira, Anti-inflammatory gene therapy for cardiovascular disease., Curr Gene Ther, 11, 6, 442-446, 2011.12, [URL], Inflammation in the vascular wall is an essential hallmark during the development of atherosclerosis, for which major leukocytes infiltrated in the lesions are monocytes/macrophages. Therefore, monocyte chemoattractant protein-1 (MCP-1) and its primary receptor CC chemokine receptor 2 (CCR2) are feasible molecular targets for gene therapy to inhibit monocyte/macrophage-mediated inflammation in atherogenesis. A mutant MCP-1 that lacks N-terminal 7 amino acids (7ND) has been shown to heterodimerize with native MCP-1, bind to CCR2 and block MCP-1-mediated monocyte chemotaxis by a dominant-negative manner. Gene therapy using intramuscular transfection with plasmid DNA encoding 7ND showed inhibitory effects on atherosclerosis in hypercholesterolemic mice, and neointima formation after vascular injury in animal models. Bare metal stents for coronary intervention were coated with multiple thin layers of biocompatible polymer with 7ND plasmid. The 7ND gene-eluting stent inhibited macrophage infiltration surrounding stent struts and in-stent neointima formation in rabbit femoral arteries and cynomolgus monkey iliac arteries. Finally, the authors describe new application of 7ND plasmid encapsulated in polymer nanoparticle (NP) that functions as gene delivery system with unique in vivo kinetics. NP-mediated 7ND gene delivery inhibited MCP-1-induced chemotaxis of mouse peritoneal macrophage ex vivo, which may be applicable for the treatment of atherosclerotic cardiovascular disease. In conclusion, anti-inflammatory gene therapy targeting MCP-1/CCR2 signal, with a novel NP-mediated gene delivery system, is a potent therapeutic strategy for the treatment of cardiovascular diseases..

主要総説, 論評, 解説, 書評, 報告書等

主要学会発表等

1.	Tetsuya Matoba 1, H. Fujita 2, T. Kohro 3, T. Kabutoya 4, Y. Ohba 4, Y. Imai 4, K. Kario 4, A. Kiyosue 5, Y. Mizuno 5, M. Nakayama 6, K. Nochioka 6, Y. Miyamoto 7, Y. Iwanaga 7, Y. Nakao 7, T. Iwai 7, K. Tsujita 8, T. Nakamura 9, H. Sato 10, Y. Nakano 1, H. Tsutsui 1, R. Nagai 11 (1) Kyushu University, Cardiovascular Medicine, Fukuoka, Japan; (2) Jichi Medical University Saitama Medical Center, Cardiology, Saitama, Japan; (3) Jichi Medical University, Medical Informatics, Tochigi, Japan; (4) Jichi Medical University, Cardiology, Tochigi, Japan; (5) University of Tokyo Hospital, Cardiology, Tokyo, Japan; (6) Tohoku University Graduate School of Medicine, Medical Informatics, Sendai, Japan; (7) National Cerebral and Cardiovascular Center Hospital, Cerebral and Cardiovascular Disease Information, Osaka, Japan; (8) Kumamoto University Hospital, Cardiovascular Center, Kumamoto, Japan; (9) Kumamoto University Hospital, Medical Informatics, Kumamoto, Japan; (10) Precision, Tokyo, Japan; (11) Jichi Medical University, Tochigi, Japan, Clinical Deep Data Accumulation System (CLIDAS) reveals Real-World Medical Therapy and Prognosis of Japanese patients after Percutaneous Coronary Intervention, 日本循環器学会学術集会, 2022.03.
2.	Tetsuya Matoba1, Isashi Baba1, Tomohiro Minakawa2, Yu Sakurai3, Hidetaka Akita3, Jun K. Yamashita2, Hiroyuki Tsutsui1 1 Department of Cardiovascular Medicine, Kyushu University. 2 Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University. 3 Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Science, Chiba University., Efficacy of microRNA Delivery by Lipid and Polymeric Nanoparticles, Pacifichem 2021, 2021.12.
3.	的場哲哉1, 藤田英雄2, 興梠貴英2, 甲谷友幸2, 清末有宏3, 水野由子3, 中山雅晴4, 後岡広太郎4, 宮本恵宏5, 岩永善高5, 中村太志6, 辻田賢一6, 佐藤寿彦7, 筒井裕之1, 永井良三2 1九州大学, 2自治医科大学, 3東京大学, 4東北大学, 5国立循環器病研究センター, 6熊本大学, 7 プレシジョン, for the CLIDAS Research Group, JAS 2017ガイドラインが定義する高リスク二次予防患者の予後と脂質管理―リアルワールドデータベースCLIDASの解析から―, 日本動脈硬化学会, 2021.10.
4.	Tetsuya Matoba, Kazuo Sakamoto, Hiroyuki Tsutsui., Management of Cardiogenic shock in Acute Myocardial Infarction, The 19th International Symposium on Atherosclerosis (ISA 2021), 2021.10, The in-hospital mortality rate of acute myocardial infarction (AMI) has been decreased to 4-5% owing to the spread of coronary care unit (CCU) and the generalization of emergency coronary reperfusion therapy. However, a recent report from the Japanese circulation society (JCS) cardiovascular shock registry (2012-2015), a prospective, observational, multicenter, cohort study that accumulated 979 cardiovascular shock patients among 82 JCS certified teaching hospitals, revealed that the 30-day mortality of acute coronary syndrome (ACS) with cardiogenic shock was as high as 34%, which remains as a challenge in emergency cardiovascular medicine. Management of cardiogenic shock in AMI includes early coronary reperfusion with primary percutaneous coronary intervention (PCI) and mechanical circulatory support; intra-aortic balloon pump, veno-arterial extracorporeal membrane oxygenation, and percutaneous left ventricular assist device (pLVAD or Impella) that had shown the clinical benefit for cardiogenic shock. Since a comprehensive management of cardiogenic shock state as well as early reperfusion therapy is vitally important for the treatment of AMI with cardiogenic shock (Killip class IV), functionally sufficient medical facilities and experienced medical staff are indispensable in order to increase the chance of survival of the patients with Killip class IV AMI. Our recent analysis in the Japanese registry of all cardiac and vascular diseases-diagnosis procedure combination (JROAD-DPC) database (year 2012-2016), 30-day mortality of Killip class IV AMI patients (n=21823) was 42.3%. A multivariate analysis identified age, female gender, admission by ambulance, deep coma, and cardiac arrest as personal factors that were independently associated with higher 30-day mortality, and the number of JCS board certified members as institutional factors that were independently associated with lower mortality in Killip class IV patients. Current guidelines state that patients with suspected STEMI should be transported to a PCI capable center. To further seek better survival of AMI patients with cardiogenic shock, establishing cardiac shock center in the local community may be effective, in which JCS board certified members manage critically ill patients in cooperation with interventional cardiologists, emergency physicians, and intensive care physicians..
5.	26. 的場哲哉, 古賀 純一郎, 香月 俊輔, 内川 智貴, 馬場 功士, 江頭 健輔, 筒井 裕之, 酸化ステロールの炎症と老化における役割, 第52回日本動脈硬化学会総会, 2020.07.
6.	的場哲哉1, 興梠貴英2, 藤田英雄2, 中山雅晴3, 清末有宏4, 橋本英樹4, 大江和彦4, 宮本恵宏5, 西村邦宏5, 小川久雄5, 安徳恭彰1, 中島直樹1, 筒井裕之1, 永井良三2 1九州大学, 2自治医科大学, 3東北大学, 4東京大学, 5国立循環器病研究センター;日本循環器学会IT/Database委員会, 心臓カテーテルを中心とした多モダリティ循環器診療情報を収集するJ-IMPACTシステム, 第38回医療情報学連合大会（第19回日本医療情報学会学術大会）, 2019.06, 循環器疾患は心筋梗塞、脳卒中を代表とした血管病により日本人の生活の質を損ねる重大な疾患領域である。特徴的に発展した心臓カテーテル検査・心臓カテーテルインターベンション治療の診療情報、また、大規模臨床試験のエビデンスに基づく薬物療法などの診療情報などは、構造化データとして個別患者のリスク予測や治療プロセスの再評価に利用されるべきであるが、多モダリティの診療情報を電子的に収集するシステムは存在しなかった。我々は日本循環器学会およびImPACT事業の支援を受け、電子カルテにおける患者基本情報、処方、検体検査データをSS-MIX2標準ストレージから、また、生理検査や心臓カテーテル検査・心臓カテーテルインターベンション治療レポートの情報をSS-MIX2拡張ストレージから収集するJapan Ischemic Heart Disease Multimodal Prospective Data Acquisition for Precision Treatment (J-IMPACT)システムを開発してきた。本発表ではJ-IMPACTシステムの現状と課題を議論したい。.
7.	Tetsuya Matoba, Gentaro Ikeda, Jun-ichiro Koga, Hiroyuki Tsutsui, Kensuke Egashira, Targeting Cyclophilin D and Inflammation with Nano-medicines in Myocardial Ischemia-Reperfusion Injury, 3rd Annual 2019 International Hawaii Cardiovascular Symposium, 2019.02, Aims: The opening of mitochondrial permeability transition pore (mPTP) and inflammation may cooperatively progress myocardial ischemia-reperfusion (IR) injury; however, clinical trials of cardioprotection with cyclosporine A (CsA) or anti-inflammatory agents ended with neutral results. In this pre-clinical study, we examined the ischemic time-dependent contribution of the 2 mechanisms, and tested the therapeutic effects of nanoparticle-mediated medicine that targets mPTP opening and inflammation in the mouse model of myocardial IR injury. Methods and Results: We employed mice lacking cyclophilin D (CypD, a key molecule for mPTP opening) and CCR2 (a receptor for monocyte chemoattractant protein-1) and found that CypD contributed to progression of myocardial IR injury caused by shorter durations of ischemia (30-45 minutes), whereas CCR2 contributed to IR injury caused by longer durations of ischemia (60-90 minutes). Double deficiency of CypD and CCR2 showed larger cardioprotection over single deficiency regardless of the durations of ischemia. CypD deficiency induced production of interleukin-1β proteins and recruitment of Ly6Chigh inflammatory monocytes in the IR-injured myocardium despite the reduction in the infarction, whereas CCR2-deficiency markedly inhibited these inflammations. Anti-interleukin-1β treatment reduced the recruitment of monocytes to the myocardium, resulted in smaller infarct size in CypD-deficient mice. Then we engineered poly (lactic-co-glycolic acid) nanoparticle containing CsA (CsA-NP) that inhibits mPTP opening and pitavastatin (Pitava-NP) that reduces monocyte-mediated inflammation. Simultaneous treatment with CsA-NP and Pitava-NP at the time of reperfusion presented a remarkable reduction in infarct size after IR injury with 30 or 60 minutes of ischemia. Conclusions: The mechanism of myocardial IR injury differs depending on the durations of ischemia. Simultaneous targeting to mitochondrial injury and inflammation with nano-medicines is a promising strategy that provides a solution for myocardial IR injury..
8.	Tetsuya Matoba, Kazuo Sakamoto, Masahiro Mohri, Yasuyuki Tsujita, Masao Yamasaki, Yasushi Ueki, Nobuhiro Tanaka, Yohei Hokama, Motoki Fukutomi, Katsutaka Hashiba, Rei Fukuhara, Yasushi Ueki, Satoru Suwa, Hirohide Matsuura, Eizo Tachibana, Takahiro Nakashima, Hayato Hosoda, Yoshio Tahara, Michikazu Nakai, Kunihiro Nishimura, Naohiro Yonemoto, Ken Nagao, The Impact of Institutional Characteristics on the Prognosis of Acute Myocardial Infarction with Cardiogenic Shock: Analysis from the JROAD/JROAD-DPC, 日本循環器学会学術集会, 2018.06.
9.	Tetsuya Matoba, Kaku Nakano, Kenji Sunagawa, Kensuke Egashira, Nanoparticle-Mediated Monocyte-Selective Drug Delivery System for Treatment of Atherosclerotic Cardiovascular Disease, Cardiovascular System Dynamics Society 2010, 2010.09.

所属学会名

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海外渡航状況, 海外での教育研究歴