Common arterial trunk and ventricular non-compaction in Lrp2 knockout mice indicate a crucial role of LRP2 in cardiac development.

Lipoprotein-related receptor protein 2 (LRP2) is important for development of the embryonic neural crest and brain in both mice and humans. Although a role in cardiovascular development can be expected, the hearts ofLrp2knockout (KO) mice have not yet been investigated. We studied the cardiovascular development ofLrp2KO mice between embryonic day 10.5 (E10.5) and E15.5, applying morphometry and immunohistochemistry, using antibodies against Tfap2α (neural crest cells), Nkx2.5 (second heart field), WT1 (epicardium derived cells), tropomyosin (myocardium) and LRP2. TheLrp2KO mice display a range of severe cardiovascular abnormalities, including aortic arch anomalies, common arterial trunk (persistent truncus arteriosus) with coronary artery anomalies, ventricular septal defects, overriding of the tricuspid valve and marked thinning of the ventricular myocardium. Both the neural crest cells and second heart field, which are essential for the lengthening and growth of the right ventricular outflow tract, are abnormally positioned in theLrp2KO. This explains the absence of the aorto-pulmonary septum, which leads to common arterial trunk and ventricular septal defects. Severe blebbing of the epicardial cells covering the ventricles is seen. Epithelial-mesenchymal transition does occur; however, there are fewer WT1-positive epicardium-derived cells in the ventricular wall as compared to normal, coinciding with the myocardial thinning and deep intertrabecular spaces. LRP2 plays a crucial role in cardiovascular development in mice. This corroborates findings of cardiac anomalies in humans withLRP2mutations. Future studies should reveal the underlying signaling mechanisms in which LRP2 is involved during cardiogenesis.

The cardiac phenotype in patients with a CHD7 mutation.

BACKGROUND: Loss-of-function mutations in CHD7 cause Coloboma, Heart Disease, Atresia of Choanae, Retardation of Growth and/or Development, Genital Hypoplasia, and Ear Abnormalities With or Without Deafness (CHARGE) syndrome, a variable combination of multiple congenital malformations including heart defects. Heart defects are reported in 70% to 92% of patients with a CHD7 mutation, but most studies are small and do not provide a detailed classification of the defects. We present the first, detailed, descriptive study on the cardiac phenotype of 299 patients with a CHD7 mutation and discuss the role of CHD7 in cardiac development. METHODS AND RESULTS: We collected information on congenital heart defects in 299 patients with a pathogenic CHD7 mutation, of whom 220 (74%) had a congenital heart defect. Detailed information on the heart defects was available for 202 of these patients. We classified the heart defects based on embryonic cardiac development and compared the distribution to 1007 equally classified nonsyndromic heart defects of patients registered by EUROCAT, a European Registry of Congenital Anomalies. Heart defects are highly variable in patients with CHD7 mutations, but atrioventricular septal defects and conotruncal heart defects are over-represented. Sex did not have an effect on the presence of heart defects, but truncating CHD7 mutations resulted in a heart defect significantly more often than missense or splice-site mutations (χ², P<0.001). CONCLUSIONS: CHD7 plays an important role in cardiac development, given that we found a wide range of heart defects in 74% of a large cohort of patients with a CHD7 mutation. Conotruncal defects and atrioventricular septal defects are over-represented in patients with CHD7 mutations compared with patients with nonsyndromic heart defects.

The role of maternal-fetal cholesterol transport in early fetal life: current insights.

The importance of maternal cholesterol as an exogenous cholesterol source for the growing embryo was first reported in studies of Smith-Lemli-Opitz syndrome. Although most of the fetus's cholesterol is synthesized by the fetus itself, there is now growing evidence that during the first weeks of life, when most organs develop, the fetus largely depends on maternal cholesterol as its cholesterol source. The maternal-fetal cholesterol transport mechanism, by transporters in both the yolk sac and placenta, is becoming better understood. This minireview summarizes current insights on maternal-fetal cholesterol transport based on in vitro and in vivo studies. As the prevalence of maternal diseases, such as diabetes, obesity, and the metabolic syndrome that adversely affect maternal cholesterol levels, is now rapidly reaching epidemic proportions, we urgently need to determine the impact of these maternal conditions on the developing human fetus.

The origin of fetal sterols in second-trimester amniotic fluid: endogenous synthesis or maternal-fetal transport?

OBJECTIVE: Cholesterol is crucial for fetal development. To gain more insight into the origin of the fetal cholesterol pool in early human pregnancy, we determined cholesterol and its precursors in the amniotic fluid of uncomplicated, singleton human pregnancies. STUDY DESIGN: Total sterols were characterized by gas chromatography-mass spectrometry in the second-trimester amniotic fluid of 126 healthy fetuses from week 15 until week 22. RESULTS: The markers of cholesterol biosynthesis, lanosterol, dihydrolanosterol, and lathosterol, were present in low levels until the 19th week of gestation, after which their levels increased strongly. ß-sitosterol, a marker for maternal-fetal cholesterol transport, was detectable in the amniotic fluid. The total cholesterol levels increased slightly between weeks 15 and 22. CONCLUSION: Our results support the hypothesis that during early life the fetus depends on maternal cholesterol supply because endogenous synthesis is relatively low. Therefore, maternal cholesterol can play a crucial role in fetal development.

Combined adverse effects of maternal smoking and high body mass index on heart development in offspring: evidence for interaction?

OBJECTIVE: To study the influence of a possible interaction between maternal smoking and high body mass index (BMI) on the occurrence of specific congenital heart anomalies (CHA) in offspring. DESIGN: Case-control study. SETTING: Data from a population-based birth defects registry in the Netherlands. PATIENTS: Cases were 797 children and fetuses born between 1997 and 2008 with isolated non-syndromic CHA. They were classified into five cardiac subgroups: septal defects (n=349), right ventricular outflow tract obstructive anomalies (n=126), left ventricular outflow tract obstructive anomalies (n=139), conotruncal defects (n=115) and other CHA (n=68). Controls were 322 children and fetuses with chromosomal anomalies without cardiac anomalies. MAIN OUTCOME MEASURES: Investigation of whether an interaction between maternal smoking and high BMI influences the occurrence of CHA in offspring by calculation of the synergy factors and 95% CIs. RESULTS: As opposed to smoking or high BMI alone, the risk for CHA in the offspring of women with high BMI (≥25 kg/m(2)) who also smoked was significantly increased. The adjusted OR was 2.65 (95% CI 1.20 to 5.87) for all CHA, 2.60 (95% CI 1.05 to 6.47) for septal defects and 3.58 (95% CI 1.46 to 8.79) for outflow tract anomalies. The interaction between maternal high BMI and smoking contributed significantly to the occurrence of all offspring-CHA combined, and to the occurrence of all cardiac subgroup anomalies except right ventricular outflow tract obstructive anomalies. CONCLUSIONS: Maternal overweight and smoking may have a synergistic adverse effect on the development of the fetal heart. Overweight women who wish to become pregnant should be strongly encouraged to stop smoking and to lose weight.