New Insight into the Cardiac Energy Metabolism in the Pathophysiology of Acute Coronary Syndrome.

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K09531
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Jikei University School of Medicine
• Principal Investigator: Nagoshi Tomohisa 東京慈恵会医科大学, 医学部, 講師 (60408432)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 急性冠症候群 / SGLT / Na利尿ペプチド / インスリン抵抗性 / 虚血再灌流障害 / 共分散構造解析

Outline of Final Research Achievements

Glucose becomes an important preferential substrate for metabolism and ATP generation under specific pathological conditions, such as ischemia-reperfusion injury. Using cardiac catheter database, we found that insulin resistance (IR) is precipitously increased during acute coronary syndrome (ACS) attack, while BNP improves IR and promotes glucose utilization only in ACS subjects, but not in non-ACS. Meanwhile, using ex vivo ischemia-reperfusion model with high fat diet mice hearts, we found that cardiac SGLT1, but not SGLT2, plays a compensatory protective role via enhanced glucose utilization, particularly under IR condition, in which stress-induced GLUT4 upregulation is compromised. A series of our recent clinical and basic studies suggests that the acceleration of the glucose metabolism, along with the restoration of insulin sensitivity, is the ideal metabolic therapy for ACS attack.

Free Research Field

循環器内科学

Academic Significance and Societal Importance of the Research Achievements

IRを主体とした心筋エネルギー代謝障害はACSを含めた重症心不全の病態生理の根幹といえる。虚血急性期病態において、IRを凌駕した心筋糖代謝活性化は心保護的に働く。本研究では、ACS急性期に活性化される神経体液性因子のうち、BNPがカテコラミンと協調して糖利用促進に関わることを示した。心筋糖輸送体に関しては、特に肥満・糖尿病などIR病態下で細胞膜上発現が低下するGLUT4を代償して、SGLT1が虚血心筋への糖供給に重要であることを示した。一方、近年大規模臨床試験で注目された選択的SGLT2阻害薬は、少なくとも短期的な心臓局所への直接作用としては、悪影響を及ぼさないことを確認した。