2019 Fiscal Year Final Research Report

New approach in rodent model using high-frequency ultrasound imaging systems and development of novel therapies for fetal heart failure

Research Project

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Project/Area Number	17K16316
Research Category	Grant-in-Aid for Young Scientists (B)
Allocation Type	Multi-year Fund
Research Field	Embryonic/Neonatal medicine
Research Institution	National Center for Child Health and Development (2019) Mie University (2017-2018)
Principal Investigator	Miyoshi Takekazu 国立研究開発法人国立成育医療研究センター, 臨床研究センター, 上級専門職 (70626697)
Project Period (FY)	2017-04-01 – 2020-03-31
Keywords	胎児心不全 / 胎児心疾患 / 胎児治療 / 小動物用超音波高解像度イメージングシステム / PDE5阻害剤 / マウス
Outline of Final Research Achievements	We first used an ultra-high-frequency ultrasound imaging systemin utero and demonstrated that Hey2 knockout embryos had worsening right ventricular hypoplasia and marked left ventricular (LV) dilatation as gestation progressed. In both ventricles, fractional shortening was significantly lower in Hey2 knockout embryos than in wild-type embryos, indicating that the embryos can be used as a murine model of fetal heart failure. Subsequently, we evaluated the effect of tadalafil treatment (0.04 or 0.08 mg/ml; T0.04 or T0.08 groups, respectively) on fetoplacental circulation in Hey2 knockout embryos. LV fractional shortening was significantly higher in the T0.04 group than in control, whereas LV dilation, mitral E/A ratio, and umbilical artery resistance index were not significantly different among all groups. Therefore, our findings suggest that tadalafil is a potential agent to treat impaired fetal ventricular systolic function.
Free Research Field	胎児循環器学
Academic Significance and Societal Importance of the Research Achievements	小動物用超音波高解像度イメージングシステムを応用し、従来困難であったマウス胎仔心臓の機能的評価をリアルタイムに行なうことで、Hey2ホモ接合型欠損マウスが胎児心不全モデルマウスになりうることを初めて示した。本実験系は、様々な遺伝子改変マウスの胎仔心機能や循環動態の観察などに広く応用できると考えられる。さらに、本実験系を用いて、PDE5阻害剤が胎児心不全に対する新規治療法となりうることを初めて示した。胎仔心臓に対するPDE5阻害剤の作用機序や最適な投与量については更なる検討が必要であるが、胎児水腫への進行を抑制し、在胎期間を延長させることで、胎児心疾患の予後改善に寄与すると考えている。