Visceral heterotaxy syndrome causes abnormal arrangement of thoracoabdominal organs and severe complex cardiac anomalies by abnormal laterality. The purpose of the present study is to analyze the incidence and pattern of heterotaxy syndrome in etretinate and all-tran retinoic acid treated pregnant DDY mice. Pregnant DDY mice were intragastrically given a single dose of 15 mg/kg of etretinate at day 6, 7 of gestation, 30 mg/kg of etretinate at day 7 of gestation and 20 mg/kg of all-trans retinoic acid at day 7 of gestation. The incidence of visceral heterotaxy was highest in the etretinate 15 mg/kg treated group on day 7 of gestation (38.5%). The major cardiovascular anomalies in heterotaxy syndrome were common atrium, common atrioventricular valve, atrioventricular septal defect, transposition of great arteries, pulmonary atresia, pulmonary artery hypoplasia and aortic arch anomalies. Atrial situs of heterotaxy syndrome were right isomerism, solitus-like, inversus-like and left atrial aplasia, but right isomerism was observed most frequently. The results suggest that retinoic acid exerts a significant effect on the determination of atrial situs during the development of mouse embryo.
*Abnormalities, Drug-Induced ; Animal ; Blood Vessels/abnormalities ; Female ; Heart Defects, Congenital/chemically induced ; Mice ; Pregnancy ; Syndrome ; Tretinoin/*toxicity

To determine the ventricular looping pattern in relation to cardiac laterality, we studied rat embryos treated with retinoic acid (RA). A total of 243 Wistar rat embryos from an in vivo treated group (a single dose of 20-40 mg/kg all-trans RA administered to pregnant rats on day 6.5 to 9.5) and 29 control embryos were examined on day 13 of gestation. Twenty-nine embryos from the in-vitro treated group (treated by all-trans RA at 2 x 10(-7) M for 6 hr on day 9.0 or 9.5 during the entire embryo culture for 72 hr) and seven control embryos were examined on day 12 of gestation. Abnormalities in cardiac laterality and ventricular looping were found in the in-vivo groups treated on day 8.5 and 8.75 and in the in-vitro group on day 9.0. Among 25 animals with abnormal laterality, right isomerism was the most common feature (22 cases), while the type of ventricular looping varied. Cases with normal laterality had a low incidence of abnormal looping (1.4%). In rat embryos treated with all-trans RA, normal cardiac looping was expected when cardiac laterality was normal. But in cases with abnormal laterality, the type of abnormal ventricular looping was unexpected.
Animal ; Cell Division ; Female ; Heart/drug effects* ; Heart Defects, Congenital/pathology ; Heart Defects, Congenital/chemically induced* ; Heart Ventricle/pathology ; Heart Ventricle/abnormalities* ; Incidence ; Male ; Pregnancy ; Rats ; Rats, Wistar ; Tretinoin/pharmacology*

OBJECTIVETo investigate the genetic abnormalities of fetuses with congenital heart diseases (CHD), and to provide guidance for the management of pregnancy and genetic counseling.

METHODSEighty-one fetuses with CHD detected by fetal echocardiography were analyzed by karyotyping after amniocentesis, cordocentesis or chorionic sampling. Then 22q11.2 deletion/duplication was detected by a competitive fluorescent multiplex short tandem repeat assay in 47 CHD fetuses without chromosomal abnormalities. With fluorescence in situ hybridization (FISH) using LSI dual color DNA probe, the deletion/duplication status was confirmed.

RESULTSThirty-four of 81 CHD fetuses had chromosomal anomalies, and 1 of the 47 CHD fetuses without chromosomal anomalies had duplication at chromosome 22q11. The incidence of aneuploidy associated CHD was 43.2%. The rate of chromosomal anomalies is higher in the cases associated with extra-cardiac anomalies than in that with isolated CHD (64.5% versus 28.0%). In the 35 fetuses with chromosomal abnormalities, 19 (54.3%) were trisomy 18.

CONCLUSIONChromosomal abnormalities occurred in 43.2% of CHD cases and trisomy 18 is the most common aneuploidy. The likelihood of chromosomal anomaly increases when there is extracardiac involvement. Testing for the 22q11.2 microdeletion/duplication is recommended in all CHD fetuses without chromosomal anomalies. It is important for the further management of pregnancy and genetic counseling.

Adult ; Amniocentesis ; methods ; Chromosome Aberrations ; chemically induced ; classification ; Female ; Fetal Development ; genetics ; Gestational Age ; Heart Defects, Congenital ; diagnostic imaging ; genetics ; Humans ; Karyotyping ; Pregnancy ; Trisomy ; physiopathology ; Ultrasonography, Prenatal

BACKGROUND: Many studies have investigated heavy metal exposure could increase the occurrence of congenital heart defects (CHDs). However, there are limited data regarding the relationship between cobalt exposure and CHD occurrence in offspring. The aim of this study was to analyze the association between cobalt exposure in mothers and the risk of CHDs in offspring. MATERIALS AND METHODS: In order to explore the association between cobalt exposure and occurrence of congenital heart defect (CHD), a case-control study with 490 controls and 399 cases with CHDs in China were developed. The concentrations of cobalt in hair of pregnant woman and fetal placental tissue were measured and processed by a logistic regression analysis to explore the relationship between cobalt exposure and risk of CHDs. RESULTS: The median concentration of hair cobalt in the control and case group was 0.023 ng/mg and 0.033 ng/mg (aOR, 1.837; 95% CI, 1.468-2.299; P < 0.001), respectively. And the median (5-95% range) fetal placental cobalt concentrations were 19.350 ng/g and 42.500 ng/g (aOR, 2.924; 95% CI, 2.211-3.868; P < 0.001) in the control and case groups, respectively. Significant differences in the middle level of cobalt in hair were found in the different CHD subtypes, including septal defects, conotruncal defects, right ventricular outflow tract obstruction, and left ventricular outflow tract obstruction (P < 0.001). Dramatically, different cobalt concentrations in fetal placental tissue were found in all subtypes of cases with CHDs (P < 0.01). CONCLUSIONS The finding suggested that the occurrence of CHDs may be associated with cobalt exposure.
Adolescent ; Adult ; Case-Control Studies ; China ; Cobalt ; adverse effects ; Female ; Hair ; chemistry ; Heart Defects, Congenital ; chemically induced ; Humans ; Maternal Exposure ; adverse effects ; Placenta ; chemistry ; Pregnancy ; Prenatal Exposure Delayed Effects ; chemically induced ; Risk Factors ; Young Adult

OBJECTIVE: To investigate the relationship between homocysteine (HCY) and congenital heart defects, and to observe the toxic effect of different doses of HCY on embryonic heart development in mammalian. METHODS: A total of 30 SD pregnant rats were randomly divided into 3 groups: a high dose group [200 mg/(kg.d)], a low dose group [(100 mg/(kg.d)] and a control group (equal volume of physiologic saline, n=10 in each group). The HCY or vehicle was given intraperitoneally from 7 to 20 days after uterineincision delivery. The contents of HCY in serum were analyzed by high performance liquid chromatogram electrochem before the pregnancy and 20 days after the pregnancy. The structure changes of the newborn rats heart were observed by stereoscope. The ultrastructure changes of cadiomyocyte were observed through transmission electron microscope. RESULTS: Comparing with the control, serum HCY in rats 20 days after pregnancy was significantly increased in the high or low dose group [(30.47 ± 1.12), (20.90 ± 1.08)vs(10.98 ± 0.77)μmol/L, P<0.01)], indicating that the hyperhomocysteinemia animal model was successfully established. The incidence rate of congenital heart defects in neonatal was significantly increased in the high or low dose group(14.13%, 9.57% vs 0.76%, P<0.01). The number of apoptotic cells were significantly increased in the high dose group. CONCLUSION Hyperhomocysteinemia may exert toxic effect on embryonic heart development in pregnancy rats, which led to congenital heart defects in the newborn rats. Hyperhomocysteinemia induced cardiomyocyte apoptosis may, at least partially, contribute to the heart defects.
Animals ; Apoptosis ; drug effects ; Female ; Fetal Diseases ; chemically induced ; Heart Defects, Congenital ; chemically induced ; pathology ; Hyperhomocysteinemia ; complications ; Myocytes, Cardiac ; pathology ; Pregnancy ; Pregnancy Complications ; Random Allocation ; Rats ; Rats, Sprague-Dawley

Background: Valproic acid (VPA) exposure during pregnancy has been proven to contribute to congenital heart disease (CHD). Our previous findings implied that disruption of planar cell polarity (PCP) signaling pathway in cardiomyocytes might be a factor for the cardiac teratogenesis of VPA. In addition, the teratogenic ability of VPA is positively correlated to its histone deacetylase (HDAC) inhibition activity. This study aimed to investigate the effect of the VPA on cardiac morphogenesis, HDAC1/2/3, and PCP key genes (Vangl2/Scrib/Rac1), subsequently screening out the specific HDACs regulating PCP pathway. Methods: VPA was administered to pregnant C57BL mice at 700 mg/kg intraperitoneally on embryonic day 10.5. Dams were sacrificed on E15.5, and death/absorption rates of embryos were evaluated. Embryonic hearts were observed by hematoxylin-eosin staining to identify cardiac abnormalities. H9C2 cells (undifferentiated rat cardiomyoblasts) were transfected with Hdac1/2/3 specific small interfering RNA (siRNA). Based on the results of siRNA transfection, cells were transfected with Hdac3 expression plasmid and subsequently mock-treated or treated with 8.0 mmol/L VPA. Hdac1/2/3 as well as Vangl2/Scrib/Rac1 mRNA and protein levels were determined by real-time quantitative polymerase chain reaction and Western blotting, respectively. Total HDAC activity was detected by colorimetric assay. Results: VPA could induce CHD (P < 0.001) and inhibit mRNA or protein expression of Hdac1/2/3 as well as Vangl2/Scrib in fetal hearts, in association with total Hdac activity repression (all P < 0.05). In vitro, Hdac3 inhibition could significantly decrease Vangl2/Scrib expression (P < 0.01), while knockdown of Hdac1/2 had no influence (P > 0.05); VPA exposure dramatically decreased the expression of Vanlg2/Scrib together with Hdac activity (P < 0.01), while overexpression of Hdac3 could rescue the VPA-induced inhibition (P > 0.05). Conclusion VPA could inhibit Hdac1/2/3, Vangl2/Scrib, or total Hdac activity both in vitro and in vivo and Hdac3 might participate in the process of VPA-induced cardiac developmental anomalies.
Animals ; Cell Polarity ; Enzyme Inhibitors ; adverse effects ; Female ; Fetal Heart ; embryology ; Heart Defects, Congenital ; chemically induced ; physiopathology ; Histone Deacetylase Inhibitors ; Histone Deacetylases ; drug effects ; physiology ; Mice ; Mice, Inbred C57BL ; Nerve Tissue Proteins ; Pregnancy ; Rats ; Transfection ; Valproic Acid ; adverse effects

OBJECTIVETo study the effect of methotrexate (MTX), a folic acid antagonist which can lead to folic acid deficient, on the cardiac development and on the expressions of BMP2b and HAS2 in zebrafish.

METHODSThe zebrafish embryos at 6-48 hrs post fertilization (hpf) were treated with various concentrations of MTX (0.5 x 10(-3), 1.0 x 10(-3) and 2.0 x 10(-3) M). At 48 hpf, the percentage of cardiac malformation and heart rate were recorded. The zebrafish embryos at 6-10 hpf treated with 1.5 x 10(-3) M MTX were used as the MTX treatment group. At 24 and 48 hpf the cardiac morphology was observed under a microscope. The expressions of BMP2b and HAS2 in zebrafish were detected by in situ antisense RNA hybridization and real-time PCR.

RESULTS6-12 hpf, the early embryonic developmental stage, was a sensitive period that MTX affected cardiac formation of zebrafish. The retardant cardiac development and the evidently abnormal cardiac morphology was found in the MTX treatment group. The results of in situ antisense RNA hybridization showed that the expressions of BMP2b and HAS2 in the zebrafish heart were reduced in the MTX treatment group at 36 and 48 hpf. The real-time PCR results demonstrated that the BMP2b expression decreased at 12, 24, 36 and 48 hpf, and that the HAS2 expression decreased at 24, 36 and 48 hpf in the treatment group compared with the control group without MTX treatment.

CONCLUSIONSThe inhibition of folic acid function may affect cardiac development of early embryos, resulting in a retardant development and a morphological abnormality of the heart in zebrafish, possibly by down-regulating the expressions of BMP2b and HAS2.

Abnormalities, Drug-Induced ; etiology ; Animals ; Bone Morphogenetic Protein 2 ; Bone Morphogenetic Proteins ; genetics ; Down-Regulation ; Folic Acid Antagonists ; toxicity ; Gene Expression Regulation ; drug effects ; Glucuronosyltransferase ; genetics ; Heart Defects, Congenital ; chemically induced ; Hyaluronan Synthases ; Methotrexate ; toxicity ; Polymerase Chain Reaction ; Zebrafish ; Zebrafish Proteins ; genetics

PURPOSE: To investigate and compare the effects of propofol and midazolam on inflammation and oxidase stress in children with congenital heart disease undergoing cardiac surgery. MATERIALS AND METHODS: Thirty-two ASA class I-II children with congenital heart disease undergoing cardiac surgery were randomly divided into two groups: propofol combined with low dose fentanyl (PF group, n = 16) and midazolam combined with low dose fentanyl (MF group, n = 16). Tracheal extubation time and length of Intensive Care Unit (ICU) stay were recorded. Blood samples were taken before operation (T0), at 2 h after release of the aorta cross-clamp (T3) and at 24 h after operation (T4) to measure interleukin 6 (IL-6), IL-8, superoxide dismutase (SOD) and malondialdehyde (MDA) levels. Myocardium samples were collected at 10-20 min after aorta cross-clamp (T1) and at 10-20 min after the release of the aorta cross-clamp (T2) to detect heme oxygenase-1 (HO-1) expression. RESULTS: Tracheal extubation time and length of ICU stay in PF group were significantly shorter than those of the MF group (p < 0.05, respectively). After cardiopulmonary bypass, IL-6, IL-8 and MDA levels were significantly increased, and the SOD level was significantly reduced in both two groups, but PF group exhibited lower IL-6, IL-8 and MDA levels and higher SOD levels than the MF group (p < 0.05, respectively). The HO-1 expression in the PF group was significantly higher than that in MF group at the corresponding time points (p < 0.05, respectively). CONCLUSION: Propofol is superior to midazolam in reducing inflammation and oxidase stress and in improving post-operation recovery in children with congenital heart disease undergoing cardiac surgery.
Anesthesia, Intravenous/*adverse effects ; Anesthetics, Intravenous/*adverse effects ; Cardiac Surgical Procedures/*adverse effects ; Child ; Female ; Heart Defects, Congenital/*surgery ; Heme Oxygenase-1/blood ; Humans ; Inflammation/*chemically induced ; Interleukin-6/blood ; Interleukin-8/blood ; Male ; Malondialdehyde/blood ; Midazolam/*adverse effects ; Oxidative Stress/*drug effects ; Propofol/*adverse effects ; Superoxide Dismutase/blood

Acute kidney injury (AKI) is closely associated with the mortality of hospitalized patients and long-term development of chronic kidney disease, especially in children. The purpose of our study was to assess the evidence of contrast-induced AKI after cardiac catheterization in children with heart disease and evaluate the clinical usefulness of candidate biomarkers in AKI. A total of 26 children undergoing cardiac catheterization due to various heart diseases were selected and urine and blood samples were taken at 0 hr, 6 hr, 24 hr, and 48 hr after cardiac catheterization. Until 48 hr after cardiac catheterization, there was no significant increase in serum creatinine level in all patients. Unlike urine kidney injury molecule-1, IL-18 and neutrophil gelatinase-associated lipocalin, urine liver-type fatty acid-binding protein (L-FABP) level showed biphasic pattern and the significant difference in the levels of urine L-FABP between 24 and 48 hr. We suggest that urine L-FABP can be one of the useful biomarkers to detect subclinical AKI developed by the contrast before cardiac surgery.
Acute Kidney Injury/blood/*chemically induced/*urine ; Biological Markers/urine ; Cardiac Catheterization/*adverse effects ; Child ; Contrast Media/adverse effects/diagnostic use ; Fatty Acid-Binding Proteins/*urine ; Female ; Heart Defects, Congenital/complications/*radiography ; Humans ; Iohexol/adverse effects/*analogs & derivatives/diagnostic use ; Male ; Radiography, Interventional/adverse effects ; Reproducibility of Results ; Sensitivity and Specificity