Maternal administration of tadalafil improves fetal ventricular systolic function in a Hey2 knockout mouse model of fetal heart failure

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.