RESUMEN
Iron deficiency (ID) is common during gestation and in early infancy and has been shown to adversely affect cardiac development and function, which could lead to lasting cardiovascular consequences. Ketone supplementation has been shown to confer cardioprotective effects in numerous disease models. Here we tested the hypothesis that maternal ketone supplementation during gestation would mitigate cardiac dysfunction in ID neonates. Female Sprague Dawley rats were fed an iron-restricted or iron-replete diet before and throughout pregnancy. Throughout gestation, iron-restricted dams were given either a daily subcutaneous injection of ketone solution (containing ß-hydroxybutyrate [ßOHB]) or saline (vehicle). Neonatal offspring cardiac function was assessed by echocardiography at postnatal days (PD)3 and 13. Hearts and livers were collected post-mortem for assessments of mitochondrial function and gene expression profiles of markers oxidative stress and inflammation. Maternal iron restriction caused neonatal anemia and asymmetric growth restriction at all time points assessed, and maternal ßOHB treatment had no effect on these outcomes. Echocardiography revealed reduced ejection fraction despite enlarged hearts (relative to body weight) in ID offspring, resulting in impaired oxygen delivery, which was attenuated by maternal ßOHB supplementation. Further, maternal ketone supplementation affected biochemical markers of mitochondrial function, oxidative stress and inflammation in hearts of neonates, implicating these pathways in the protective effects conferred by ßOHB. In summary, ßOHB supplementation confers protection against cardiac dysfunction in ID neonates, and could have implications for the treatment of anemic babies.
RESUMEN
We aimed to evaluate fetal and placental oxygen saturation (sO2) in anemic and non-anemic pregnant rats throughout gestation using photoacoustic imaging (PAI). Female Sprague-Dawley rats were fed an iron-restricted or iron-replete diet before and during pregnancy. On gestational days 13, 18, and 21, PAI was coupled with high resolution ultrasound to measure oxygenation of the fetus, whole placenta, mesometrial triangle, as well as the maternal and fetal faces of the placenta. PAI was performed in 3D, which allowed sO2 to be measured within an entire region, as well as in 2D, which enabled sO2 measurements in response to a hypoxic event in real time. Both 3D and 2D PAI were performed at varying levels of FiO2 (fraction of inspired oxygen). Iron restriction caused anemia in dams and fetuses, a reduction in fetal body weight, and an increase in placental weight, but overall had minimal effects on sO2. Reductions in FiO2 caused corresponding reductions in sO2 which correlated to the severity of the hypoxic challenge. Regional differences in sO2 were evident within the placenta and between the placenta and fetus. In conclusion, PAI enables non-invasive measurement of sO2 both rapidly and with a high degree of sensitivity. The lack of overt changes in sO2 levels between control and anemic fetuses may suggest reduced oxygen extraction and utilization in the latter group, which could be attributed to compensatory changes in growth and developmental trajectories.