Sex-specific differences in the mechanisms for enhanced thromboxane A2-mediated vasoconstriction in adult offspring exposed to prenatal hypoxia.

BACKGROUND: Prenatal hypoxia, a common pregnancy complication, leads to impaired cardiovascular outcomes in the adult offspring. It results in impaired vasodilation in coronary and mesenteric arteries of the adult offspring, due to reduced nitric oxide (NO). Thromboxane A2 (TxA2) is a potent vasoconstrictor increased in cardiovascular diseases, but its role in the impact of prenatal hypoxia is unknown. To prevent the risk of cardiovascular disease by prenatal hypoxia, we have tested a maternal treatment using a nanoparticle-encapsulated mitochondrial antioxidant (nMitoQ). We hypothesized that prenatal hypoxia enhances vascular TxA2 responses in the adult offspring, due to decreased NO modulation, and that this might be prevented by maternal nMitoQ treatment. METHODS: Pregnant Sprague-Dawley rats received a single intravenous injection (100 µL) of vehicle (saline) or nMitoQ (125 µmol/L) on gestational day (GD)15 and were exposed to normoxia (21% O2) or hypoxia (11% O2) from GD15 to GD21 (term = 22 days). Coronary and mesenteric arteries were isolated from the 4-month-old female and male offspring, and vasoconstriction responses to U46619 (TxA2 analog) were evaluated using wire myography. In mesenteric arteries, L-NAME (pan-NO synthase (NOS) inhibitor) was used to assess NO modulation. Mesenteric artery endothelial (e)NOS, and TxA2 receptor expression, superoxide, and 3-nitrotyrosine levels were assessed by immunofluorescence. RESULTS: Prenatal hypoxia resulted in increased U46619 responsiveness in coronary and mesenteric arteries of the female offspring, and to a lesser extent in the male offspring, which was prevented by nMitoQ. In females, there was a reduced impact of L-NAME in mesenteric arteries of the prenatal hypoxia saline-treated females, and reduced 3-nitrotyrosine levels. In males, L-NAME increased U46619 responses in mesenteric artery to a similar extent, but TxA2 receptor expression was increased by prenatal hypoxia. There were no changes in eNOS or superoxide levels. CONCLUSIONS: Prenatal hypoxia increased TxA2 vasoconstrictor capacity in the adult offspring in a sex-specific manner, via reduced NO modulation in females and increased TP expression in males. Maternal placental antioxidant treatment prevented the impact of prenatal hypoxia. These findings increase our understanding of how complicated pregnancies can lead to a sex difference in the programming of cardiovascular disease in the adult offspring.

Prenatal hypoxia, when the fetus does not receive enough oxygen, is a common problem during pregnancy that impacts the developing fetus. It is associated with an increased risk of cardiovascular disease in the offspring in adulthood. While the mechanisms are not fully understood, the blood vessel function in the offspring may be impacted by prenatal hypoxia. We hypothesize that prenatal hypoxia increases the constriction of the blood vessels in the offspring. The placenta, an essential organ for fetal development, supplies oxygen and nutrients to the fetus. In prenatal hypoxia pregnancies, the placenta does not work properly. We have been studying a placental treatment (called nMitoQ) to improve placenta function and thereby the blood vessel function of the offspring. We used a rat model of prenatal hypoxia, where pregnant rats (dams) were placed in a low oxygen environment (hypoxia) during the last trimester of pregnancy. Control rats were kept in normal oxygen conditions. The dams were treated with nMitoQ, or with saline (control). Next, we studied the blood vessels of the offspring in adulthood. We found that prenatal hypoxia increases the constriction of the blood vessels, which was prevented by treating the dams with nMitoQ. Interestingly, this impact was more severe in females compared to males, and the mechanisms were different between the sexes. This study helps in the understanding of how complicated pregnancies can impair cardiovascular health in the offspring, and in a potential development of targeted and sex-specific therapies for those offspring at high risk for future cardiovascular disease.

A Comparison of Force-Plate Based Center of Mass Estimation Algorithms.

Estimating horizontal center of mass (CoM) is an important process that is used in the control of self-paced treadmills, as well as in clinical and scientific biomechanical analysis. Many laboratories use motion-capture to estimate CoM, while others use force-plate based estimates, either because they cannot access motion-capture or they do not want to be taxed with post-processing optoelectronic data. Three force-plate derived center of mass estimation algorithms were compared against a benchmark motion-capture technique. Two of them have recently been reported in the literature, and both rely on numerical integration of 2nd-order differential equations. We propose a third technique that uses an algebraic equation to directly relate center of pressure to center of mass without numerical drift. Twenty-four healthy adults participated in a five-minute steady-state walking test to compare these algorithms. The sample-by-sample standard deviation of the three force-plate based algorithms from the motion-capture benchmark algorithm was evaluated. The algebraic technique provided less error than either of the two more common integration techniques (p<0.05). The results of this study support the viability of using only ground reaction forces for self-paced treadmills and also show that a simple algebraic model is preferred to integration approaches. The use of an algebraic estimation simplifies control implementation for self-paced treadmill applications and eliminates the need for event-based drift recalibration.

Accuracy of Fetal Echocardiography in Defining Anatomic Details: A Single-Institution Experience over a 12-Year Period.

BACKGROUND: Fetal echocardiography has evolved over four decades, now permitting the prenatal diagnoses of most major congenital heart disease (CHD). To identify areas for targeted improvement, the authors explored the diagnostic accuracy of fetal echocardiography in defining major fetal CHD. METHODS: All fetuses with major fetal CHD (11 subtypes) at a single institution between 2007 and 2018 were identified (n = 827). Fetal echocardiography reports were compared with postnatal imaging and surgical or autopsy reports, and findings were categorized as follows: category 1, no errors; category 2, minor errors without impact on care, considered "accurate"; category 3, errors with minor impact on surgical approach; and category 4, errors with major impact on neonatal care or outcomes, considered "inaccurate." In addition, the contributions of era, gestational age at first fetal echocardiography, serial fetal echocardiography, maternal weight, and reviewer level of training were examined. RESULTS: Of 589 fetuses with autopsy or postnatal confirmation, accurate diagnoses were made in 530 (90%). The highest rates of accuracy were observed in univentricular hearts (97.6%; 95% CI, 87.4%-99.6%), tetralogy of Fallot (97.2%; 95% CI, 90.0%-99.2%), and transposition of the great arteries (96.1%; 95% CI, 89.2%-98.6%), and the lowest were observed in double-outlet right ventricle (81.1%; 95% CI, 70.4%-88.6%), truncus arteriosus (72.7%; 95% CI, 51.8%-86.8%), and heterotaxy (71.1%; 95% CI, 56.6%-82.2%). Greater accuracy was associated with later diagnostic era (2012-2018, P = .026), first fetal echocardiography at ≤25 weeks (P = .028), and formal fetal cardiology training of the reviewer (P = .001). Maternal pre-pregnancy weight did not affect accuracy. CONCLUSIONS: The diagnostic accuracy of fetal echocardiography for major CHD is high, particularly in the hands of fetal cardiology-trained practitioners. There are lesion-specific as well as general modifiable and nonmodifiable factors that affect diagnostic accuracy.

Extra-cardiac diagnoses and postnatal outcomes of fetal tetralogy of fallot.

OBJECTIVE: Past studies of fetal tetralogy of fallot (ToF) have reported extra-cardiac anomalies (ECAs) in 17%-45%, genetic syndromes in as low as 20% and poor postnatal outcomes. This study sought to examine these factors in a contemporary cohort. METHODS: A retrospective review examining 83 fetuses with ToF diagnosed 2012-2019. Referral indication, ToF subtype, additional cardiac, extra-cardiac and genetic diagnoses, pregnancy outcomes and survival were documented. RESULTS: The mean gestational age at diagnosis was 23 ± 4 weeks. Of 94% (78/83) with genetic testing (GT), 30% (23/78, 95%CI 21%-40%) had genetic anomalies (GA), including Trisomy 21 (39%, 9/23), 22q11 deletion (35%, 8/23), Trisomy 13 or 18 (17%, 4/23) and 9% (2/23) others. A further 4% (3/78) had VACTERL association. Forty-one percent (34/83, 95%CI 31%-52%) had ≥1 major ECA of whom 41% (14/34) also had a genetic anomaly. OUTCOMES: 22% (18/83) pregnancy termination, 5% (4/83) intrauterine death and 72% (60/83) live birth. Of live births, 3% (2/60) experienced neonatal death, 7% late death (4/60) and 90% (54/60) were alive at last follow-up (mean age 3.5 ± 2.4 years). CONCLUSION: In a cohort of fetuses with ToF and high rates of GT, compared to previous reports, GA were more common and there were similar rates of ECAs.