Evaluation of autophagy for patients with dilated cardiomyopathy

• Project/Area Number: 17K16026
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular medicine
• Research Institution: Nippon Medical School
• Principal Investigator: Saito Tsunenori 日本医科大学, 医学部, 助教 (00716631)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 拡張型心筋症 / オートファジー / 電子顕微鏡 / ゲノミクス / 全エクソーム解析 / 次世代シーケンサー / 原因遺伝子 / 循環器内科学 / 心不全 / エキソーム解析 / 心筋生検

Outline of Final Research Achievements

We compared autophagy in cardiomyocytes of dilated cardiomyopathy (DCM) with clinical features and genetic information. Autophagy was a more sensitive prognostic predictor than late gadolinium enhancement in cardiac magnetic resonance, which is a finding reflects myocardial fibrosis. In addition, as a result of whole exome analysis, variants in autophagy-related genes were found in cases without autophagy detected by electron microscopy. It has been demonstrated that autophagy deficiency at the genetic level can cause DCM.

Academic Significance and Societal Importance of the Research Achievements

拡張型心筋症（DCM）の不全心筋におけるオートファジーを臨床像および分子遺伝学的情報と比較した。心筋の線維化を反映する所見であるMRIガドリニウム遅延造影よりもオートファジーの方がより明敏な予後予測指標であり、DCMではまず細胞が障害され、線維化はそれに続発する現象であると考えられた。また全エクソーム解析の結果、電子顕微鏡による観察でオートファジーを認めない症例にオートファジー関連遺伝子の変異を認めた。遺伝子レベルでのオートファジー不全はDCMの原因となりうることが実証された。本研究はオートファジーを標的とした心不全の新規治療法の開発につながりうる。

Research Products

• [Journal Article] Long-term prognostic value of ultrastructural features in dilated cardiomyopathy: comparison with cardiac magnetic resonance. (2020)
  • Author(s): Saito T, Asai K, Tachi M, Sato S, Mozawa K, Adachi A, Sasaki Y, Amano Y, Mizuno K, Kumita SI, Shimizu W.
  • Journal Title: ESC Heart Fail. Volume: 7 Issue: 2 Pages: 682-691
  • DOI: 10.1002/ehf2.12662
  • Peer Reviewed / Open Access
• [Journal Article] Phospholipidosis in cardiomyocytes suffering flecainide intoxication. (2020)
  • Author(s): Saito T, Hayashi M, Shimizu W.
  • Journal Title: Eur Heart J. Volume: 41 Issue: 10 Pages: 1141-1141
  • DOI: 10.1093/eurheartj/ehz833
  • Peer Reviewed
• [Journal Article] Is steroid therapy really banned for lymphocytic myocarditis before excluding viral infection? (2019)
  • Author(s): Saito T, Katayama H, Kodani E.
  • Journal Title: Eur Heart J Volume: 40 Issue: 12 Pages: 2014-2015
  • DOI: 10.1093/eurheartj/ehy738
  • Peer Reviewed
• [Journal Article] Eosinophilic myocarditis associated with anti-mitochondrial M2 antibodies: a mechanism underlying the onset of myocarditis (2018)
  • Author(s): Saito Tsunenori、Kodani Eitaro、Katayama Hironori、Kusama Yoshiki
  • Journal Title: European Heart Journal Volume: 印刷中 Issue: 37 Pages: 3480-3481
  • DOI: 10.1093/eurheartj/ehy246
  • Peer Reviewed / Open Access
• [Journal Article] Myocardial alterations in a patient with mucopolysaccharidosis type IS (2018)
  • Author(s): Izumi Yuki、Saito Tsunenori、Sato Shigeru、Shimizu Wataru
  • Journal Title: European Heart Journal Volume: 印刷中 Issue: 20 Pages: 1863-1863
  • DOI: 10.1093/eurheartj/ehy149
  • Peer Reviewed / Open Access
• [Presentation] Comparison Between Ultrastructural Features and Causative Genes of Dilated Cardiomyopathy Detected by Whole Exome Sequencing. (2019)
  • Author(s): Saito T, Asai K, Sato-saito N, Mozawa K, Oka E, Sato S, Mizuno K, Shimizu W, Gottlieb RA.
  • Organizer: American Heart Association Scientific Sessions 2019
  • Int'l Joint Research
• [Presentation] Dilated cardiomyopathy includes arrhythmogenic cardiomyopathy as a type with severe myocardial degeneration. (2019)
  • Author(s): Mozawa K, Saito T, Oka E, Sato-Saito N, Kodani E, Iwasaki YK, Asai K, Shimizu W.
  • Organizer: American Heart Association Scientific Sessions 2019
  • Int'l Joint Research
• [Presentation] 好酸球性心筋炎における炎症細胞の種類と量についての検討 (2018)
  • Author(s): 齋藤恒徳、小谷英太郎、片山博徳、清水渉
  • Organizer: 第4回日本心筋症研究会
• [Presentation] Ultrastructural assist for searching causative genes of dilated cardiomyopathy using next generation sequencer. (2018)
  • Author(s): Saito T, Asai K, Sato-Saito N, Mozawa K, Oka E, Sato S, Kodani E, Wataru Shimizu.
  • Organizer: 日本人類遺伝学会第63回大会
• [Presentation] 心筋生検の役立て方と電子顕微鏡の活用 (2018)
  • Author(s): 齋藤恒徳
  • Organizer: 第27回日本小児心筋疾患学会学術集会
  • Invited
• [Presentation] 拡張型心筋症の電子顕微鏡所見の臨床的意義とオートファジー発現に関与する因子の探索 (2018)
  • Author(s): 齋藤恒徳
  • Organizer: 第86回日本医科大学医学会総会
  • Invited
• [Presentation] Eosinophilic myocarditis associated with anti-mitochondrial M2 antibodies: a new evidence of the onset of myocarditis (2018)
  • Author(s): Tsunenori Saito
  • Organizer: The American College of Physicians Internal Medicine Meeting 2018
  • Int'l Joint Research
• [Presentation] Clinical utility of myocardial autophagy in patients with dilated cardiomyopathy to predict prognosis and recovery of cardiac function. (2017)
  • Author(s): Tsunenori Saito
  • Organizer: 第81回日本循環器学会学術集会
  • Int'l Joint Research
• [Presentation] 心内膜心筋生検による病理診断の役割と重要性; 拡張型心筋症の心内膜心筋生体標本における電子顕微鏡所見の臨床的有用性 (2017)
  • Author(s): 齋藤恒徳
  • Organizer: 第106回日本病理学会総会
  • Invited
• [Presentation] Comparison between cardiac magnetic resonance and myocardial ultrastructural features in patients with dilated cardiomyopathy to predict recovery of cardiac function. (2017)
  • Author(s): Tsunenori Saito
  • Organizer: 第21回日本心不全学会学術集会
• [Presentation] 好酸球性心筋炎の治療中に抗ミトコンドリアM2抗体陽性筋炎を発症した一例 (2017)
  • Author(s): 齋藤恒徳
  • Organizer: 第39回心筋生検研究会