Role of Rho kinase in cardiac remodeling and cardiomyopathy induced by coronary microvascular dysfunction

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K08531
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Tohoku University
• Principal Investigator: Tatebe Shunsuke 東北大学, 大学病院, 非常勤講師 (90456062)
• Co-Investigator(Kenkyū-buntansha): 佐藤 公雄 東北大学, 高度教養教育・学生支援機構, 准教授 (80436120) ; 大田 英揮 東北大学, 医学系研究科, 准教授 (40586905) ; 小山 涼子 (齋藤涼子) 東北大学, 大学病院, 特任准教授 (30733349) ; 森田 佳明 東北大学, 大学病院, 助教 (80628074)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: 冠微小循環障害 / 心筋線維化 / 末梢血Rhoキナーゼ活性 / 心臓MRI / 細胞外分画容積 / 心筋生検 / 微小循環抵抗指数

Outline of Final Research Achievements

This study has been conducted to evaluate the hypothesis that microvascular dysfunction associated with cardiomyopathy promotes myocardial remodeling via increased Rho/Rho kinase pathway activity by evaluating Rho kinase activity in circulating neutrophils, invasive tests for coronary microvascular dysfunction (CMD) including the index of microvascular resistance (IMR) and acetylcholine (ACh) provocation test, cardiac magnetic resonance derived extracellular volume, and myocardial biopsy. Patients with an elevated IMR with positive Ach provocation test had a poor prognosis, and IMR was significantly decreased by intracoronary administration of the Rho kinase inhibitor fasudil, indicating that the Rho kinase pathway is involved in CMD. Furthermore, BNP levels, a biomarker of myocardial remodeling in patients with positive Ach test, were found to be a predictor of reduced coronary microvascular diastolic function.

Free Research Field

循環器内科学

Academic Significance and Societal Importance of the Research Achievements

本研究による冠微小循環障害におけるRhoキナーゼ経路の関与の解明は、同経路の阻害が新たな治療標的となる可能性を示した。また化学療法関連心筋症等、種々の心疾患において、心臓MRIや病理学的なパラメータを、新たな診断あるいは予後バイオマーカーとして同定した。本研究の成果を、更に大規模臨床研究へ発展させることで、当該疾患の診療ガイドライン策定にも資する新たな臨床エビデンスを構築可能なものと考える。