BACKGROUND There is no established transplacental treatment for heart failure (HF) in utero, and no animal models or experimental systems of fetal HF have been established. This study aimed to investigate the effect of maternal tadalafil administration on fetal cardiovascular function and uteroplacental circulation in a murine model of fetal HF. METHODS AND RESULTS We first used an ultra-high-frequency ultrasound imaging system in utero and demonstrated that Hey2-/- embryos had worsening right ventricular hypoplasia and marked left ventricular (LV) dilatation as gestation progressed. In both ventricles, fractional shortening (FS) and the E/A ratio were significantly lower in Hey2-/- embryos than in wild-type embryos, indicating that the embryos can be used as a murine model of fetal HF. 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-/- embryos. LV FS was significantly higher in the T0.04 group than in control (P < 0.01), whereas LV dilation, mitral E/A ratio, and umbilical artery resistance index were not significantly different among all groups. The thinness of the LV compacted layer did not differ between the T0.04 and vehicle-treated Hey2-/- embryos. CONCLUSIONS A phenotype comprising marked dilatation and reduced FS of the left ventricles was identified in Hey2-/- embryos, suggesting these embryos as a murine model of fetal HF. In addition, maternal administration of tadalafil improved LV systolic function without altering LV morphological abnormalities in Hey2-/- embryos. Our findings suggest that tadalafil is a potential agent to treat impaired fetal ventricular systolic function.

中文翻译：

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在胎儿心力衰竭的Hey2基因敲除小鼠模型中，母亲使用他达拉非可改善胎儿心室收缩功能。

背景技术在子宫内尚未建立经胎盘治疗心力衰竭（HF），并且尚未建立胎儿HF的动物模型或实验系统。这项研究旨在调查母体他达拉非对胎儿心衰小鼠模型中胎儿心血管功能和子宫胎盘循环的影响。方法和结果我们首先在子宫内使用超高频超声成像系统，证明Hey2-/-胚胎随着妊娠的进行而恶化，右室发育不全，左室（LV）扩张明显。在两个心室中，Hey2-/-胚胎的分数缩短（FS）和E / A比均显着低于野生型胚胎，表明该胚胎可用作胎儿HF的鼠模型。随后，我们评估了他达拉非治疗（分别为0.04或0.08 mg / ml； T0.04或T0.08组）对Hey2-/-胚胎胎盘循环的影响。T0.04组的LV FS显着高于对照组（P <0.01），而所有组的LV扩张，二尖瓣E / A比和脐动脉阻力指数均无显着差异。LV压实层的厚度在T0.04和媒介物处理的Hey2-/-胚胎之间没有差异。结论在Hey2-/-胚胎中鉴定出包含明显扩张和左心室FS降低的表型，表明这些胚胎是胎儿HF的鼠模型。此外，他达拉非的母体给药改善了左心室收缩功能，而没有改变Hey2-/-胚胎中的左心室形态异常。