Cardiac Ventricular Septal Defect Research Articles

ING4 and ING5 are essential for histone H3 lysine 14 acetylation and epicardial cell lineage development.

Inhibitor of growth 4 and 5 (ING4, ING5) are structurally similar chromatin-binding proteins in the KAT6A, KAT6B and KAT7 histone acetyltransferase protein complexes. Heterozygous mutations in the KAT6A or KAT6B gene cause human disorders with cardiac defects, but the contribution of their chromatin-adaptor proteins to development is unknown. We found that Ing5-/- mice had isolated cardiac ventricular septal defects. Ing4-/-Ing5-/- embryos failed to undergo chorioallantoic fusion and arrested in development at embryonic day 8.5, displaying loss of histone H3 lysine 14 acetylation, reduction in H3 lysine 23 acetylation levels and reduced developmental gene expression. Embryonic day 12.5 Ing4+/-Ing5-/- hearts showed a paucity of epicardial cells and epicardium-derived cells, failure of myocardium compaction, and coronary vasculature defects, accompanied by reduced expression of epicardium genes. Cell adhesion gene expression and proepicardium outgrowth were defective in the ING4- and ING5-deficient state. Our findings suggest that ING4 and ING5 are essential for heart development and promote epicardium and epicardium-derived cell fates and imply mutation of the human ING5 gene as a possible cause of isolated ventricular septal defects.

Hypothesis: human trophectoderm biopsy downregulates the expression of the placental growth factor gene.

Preeclampsia (PE) and intrauterine growth retardation (IUGR) are the results of defective placentation associated with the downregulation of different genes in the human trophoblast including the Placental Growth Factor (PGF). TrophEctoderm (TE) biopsy is increasingly performed for Pre-implantation Genetic Testing of Aneuploidies and it involves the traumatical removal of an unpredictable number of mural TE cells from the human blastocyst. We observed strikingly similar obstetrical and neonatal complications in pregnancies where the placenta bears PGF downmodulation or a TE biopsy has been done. In both groups, the risk of PE, IUGR, congenital cardiac ventricular septal defects, caesarean section, sex ratio in favour of males and preterm birth is significantly increased compared to controls. Given the high degree of correlation, the observation may not be a casual one. We postulate herein that the TE biopsy may induce persistent dysregulation of different genes in the placenta including PGF. The mechanism proposed is the disruption of tight junctions caused by the TE biopsy.

Schizencephaly accompanied by occipital encephalocele and deletion of chromosome 22q13.32: a case report

Background: Schizencephaly is a neuronal migration anomaly characterized by presence of a cleft between ependymal layer of the ventricle and pia mater of the cerebral cortex. It may be associated with additional cerebral abnormalities, including polymicrogyria, pachygyria, gray matter heterotopy, ventriculomegaly and corpus callosum agenesis. Case Report: We present a female fetus with schizencephaly accompanied by occipital encephalocele, polymicrogyria, agenesis of the corpus callosum, dysmorphic facies and cardiac muscular ventricular septal defect. Array comparative genomic hybridization (array-cGH) analysis revealed a deletion of chromosome 22q13.32 including FAM19A5 gene that is a member of TAFA family. Conclusions: Schizencephaly may be accompanied by unexpected structural and genetic anomalies as in our case with occipital encephalocele, dysmorphic facies, cardiac ventricular septal defect and chromosome 22q13.32 deletion.

Developmental and reproductive toxicity studies on artemisone

In order to justify clinical studies in women of child-bearing age with artemisone, a new artimisinin derivative, studies to assess fertility and early embryonic development in rats, developmental toxicity in rats and rabbits, and peri-post natal development in rats were performed. In the study on fertility and early embryonic development (dose levels 0-5-20-80 mg/kg bw/day), doses inducing clinical and organ toxicity were used. Only in severe toxicity conditions, a reduction of the number of estruses, a prolonged time to insemination, decreased numbers of corpora lutea, implantation sites, and viable fetuses were found. Two developmental toxicity studies were performed in rats (dose levels 0-1-2 mg/kg bw/day) and rabbits (dose levels 0-2.5-5.0-7.5 mg/kg bw/day). It was shown that rats were about 5 times more sensitive than rabbits. In rats, artemisone induced total litter loss (late resorptions) at 2 mg/kg body weight and above with an increased incidence of a common vascular variation and retarded ossification at this dose. In rabbits, maternal toxicity, abortion and a slightly increased incidence of cardiac ventricular septal defects was observed at 7.5 mg/kg body weight. In a pre- and postnatal developmental toxicity study in rats (dose levels 0-1-2-4 mg/kg bw/day), 4 mg/kg body weight artemisone induced clinical symptoms and affected postnatal survival, body weight gain in the F1 pups, and motor activity. In summary, artemisone was shown to be embryo- and fetotoxic and induced cardiac ventricular septal defects and retarded ossification in dosages where total litter loss and abortions were observed. However, no effect on reproductive and developmental parameters below severe toxic dosages could be observed.

Vascular Branching Morphogenesis of the Placenta Requires Expression of Ott1(Rbm15) in the Trophoblast Compartment.

OTT1(RBM15) is a transcriptional activator/repressor known to be a fusion partner in t(1;22) infant acute megakaryocytic leukemia. Conditional deletion of Ott1 in adult mice resulted in expansions of the megakaryocytic, myeloid and pluripotent Lin−Sca-1+c-Kit+ populations and a block in pre B lymphoid development, suggesting a global regulatory role in hematopoiesis. Germline deletion of Ott1 is homozygous lethal after E9.5, producing developmentally delayed embryos with open notochords. Further investigation into the cause of embryonic death revealed a placental defect characterized by arrested vascular branching morphogenesis of the invading fetal vessels, leading to embryonic demise through inadequate oxygenation. Histopathology and in situ hybridization of Ott1-deficient placentas identified a dramatic reduction in the spongiotrophoblast and syncytiotrophoblast layers. Expression of Vegf, a critical element of placental vasculogenesis, was still observed, thus excluding the requirement for Ott1 in its induction. By using Sox2-cre with a conditional allele of Ott1, complete excision of Ott1 was achieved within the embryo yet the placental trophoblast compartment was left undeleted. These embryos were now able to form normal placentas with intact vascular branching morphogenesis and survive to term. This result demonstrates that Ott1-mediated vascular branching morphogenesis is regulated by the trophoblast compartment rather than the invading fetal vasculature. Additionally, the Sox2-cre-deleted pups manifested cardiac ventricular septal defects and hyposplenia and succumbed during the perinatal period. Hox, Notch and hypoxia-related pathways are important for both cardiac and splenic development, however downstream target gene expression was not perturbed. In summary, Ott1-dependent pathways, in addition to their implicit involvement in a congenital leukemia, are essential for vascular branching morphogenesis in the placenta and organogenesis of the mesoderm-derived heart, spleen and blood. Mutation of OTT1 or alterations in its regulation may therefore underlie human disorders such as placental insufficiency, asplenia or congenital cardiac malformations.

The Gα13-Rho Signaling Axis Is Required for SDF-1-induced Migration through CXCR4

The CXC chemokine stromal cell-derived factor-1alpha (SDF-1) binds to CXCR4, a seven-transmembrane G protein-coupled receptor that plays a critical role in many physiological processes that involve cell migration and cell fate decisions, ranging from stem cell homing, angiogenesis, and neuronal development to immune cell trafficking. CXCR4 is also implicated in various pathological conditions, including metastatic spread and human immunodeficiency virus infection. Although SDF-1-induced cell migration in CXCR4-expressing cells is sensitive to pertussis toxin treatment, hence involving heterotrimeric G proteins of the G(i) family, whether other G proteins participate in the chemotactic response to SDF-1 is still unknown. In this study, we took advantage of the potent chemotactic activity of SDF-1 in Jurkat T-cells to examine the nature of the heterotrimeric G protein subunits contributing to CXCR4-mediated cell migration. We observed that whereas G(i) and Gbetagamma subunits are involved in SDF-1-induced Rac activation and cell migration, CXCR4 can also stimulate Rho potently leading to the phosphorylation of myosin light chain through the Rho effector, Rho kinase, but independently of G(i). Furthermore, we found that Galpha(13) mediates the activation of Rho by CXCR4 and that the functional activity of both Galpha(13) and Rho is required for directional cell migration in response to SDF-1. Collectively, our data indicate that signaling by CXCR4 to Rho through Galpha(13) contributes to cell migration when stimulated by SDF-1, thus identifying the Galpha(13)-Rho signaling axis as a potential pharmacological target in many human diseases that involve the aberrant function of CXCR4.

Percutaneous closure of a residual ventricular septal defect in a challenging patient

Percutaneous transcatheter closure of congenital or acquired cardiac ventricular septal defects has emerged as a valid alternative to surgical closure in selected cases. It avoids the considerable morbidity and mortality related to open heart surgical procedures. The choice of the device is determined by the particular VSD morphology and thanks to considerable material and technical improvements procedural success rates of over 90% are nowadays achievable. We discuss the case of a young woman who required VSD closure, and in whom re-open-heart surgery was avoided by a successful percutaneous closure using an Amplatzer Patent Ductus Arteriosus Occluder.

Familial lethal skeletal dysplasia with cloverleaf skull and multiple anomalies of brain, eye, face and heart: a new autosomal recessive multiple congenital anomalies syndrome.

We report on a 'new' lethal familial short-limb bone dysplasia associated with multiple anomalies in three sibs born to Arabic-Muslim consanguineous healthy parents. Clinical abnormalities included short limbs and short hands, cloverleaf skull, frontal bossing, wide anterior fontanel, hypertelorism, bilateral microphthalmia, cataract, low-set ears, narrow chest, ambiguous genitalia, cardiac ventricular septal defect (VSD) and agenesis of the corpus callosum. Radiological abnormalities included cloverleaf skull, hypoplastic clavicles and scapulae, thin, wavy cupped ribs, flat vertebral bodies with coronal clefting and several unossified vertebral pedicles and hypo-ossification of the pubic bone. The main changes noted in the long bones consisted of short-bowed long bones with abnormal metaphyses and unossified epiphyses. Chondro-osseous morphology documented degenerating chondrocytes with disorganization of the hypertrophied cartilage and short disorganized columns of hypertrophied areas. An autosomal recessive mode of inheritance seems most likely.

Ambient air pollution and risk of birth defects in Southern California.

The authors evaluated the effect of air pollution on the occurrence of birth defects ascertained by the California Birth Defects Monitoring Program in neonates and fetuses delivered in southern California in 1987-1993. By using measurements from ambient monitoring stations of carbon monoxide (CO), nitrogen dioxide, ozone, and particulate matter <10 microm in aerodynamic diameter, they calculated average monthly exposure estimates for each pregnancy. Conventional, polytomous, and hierarchical logistic regression was used to estimate odds ratios for subgroups of cardiac and orofacial defects. Odds ratios for cardiac ventricular septal defects increased in a dose-response fashion with increasing second-month CO exposure (odds ratio (OR)(2nd quartile) CO = 1.62, 95% confidence interval (CI): 1.05, 2.48; OR(3rd quartile) CO = 2.09, 95% CI: 1.19, 3.67; OR(4th quartile) CO = 2.95, 95% CI: 1.44, 6.05). Similarly, risks for aortic artery and valve defects, pulmonary artery and valve anomalies, and conotruncal defects increased with second-month ozone exposure. The study was inconclusive for other air pollutants. The authors' results are supported by the specificity of the timing of the effect and some evidence from animal data; however, this is the first known study to link ambient air pollution during a vulnerable window of development to human malformations. Confirmation by further studies is needed.

Truncus arteriosus and other lethal internal anomalies in Goltz syndrome

An infant girl of 36 weeks gestational age was found to have cardiovascular and other lethal internal anomalies in addition to characteristic external abnormalities of focal dermal hypoplasia (Goltz syndrome). The internal anomalies included truncus arteriosus type II with truncal origin of hypoplastic pulmonary arteries, cardiac ventricular septal defect, severe hypoplasia of lungs and pulmonary veins, massive diaphragmatic hernia, and absence of the right kidney. Such a combination of severe anomalies has not been reported previously in Goltz syndrome.

Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1.

The chemokines are a large family of small, structurally related cytokines. The physiological importance of most members of this family has yet to be elucidated, although some are inducible inflammatory mediators that determine leukocyte chemotaxis. Pre-B-cell growth-stimulating factor/stromal cell-derived factor-1 (PBSF/SDF-1) is a member of the CXC group of chemokines PBSF/SDF-1 stimulates proliferation of B-cell progenitors in vitro and is constitutively expressed in bone-marrow-derived stromal cells. Here we investigate the physiological roles of PBSF/SDF-1 by generating mutant mice with a targeted disruption of the gene encoding PBSF/SDF-1. We found that mice lacking PBSF/SDF-1 died perinatally and that although the numbers of B-cell progenitors in mutant embryos were severely reduced in fetal liver and bone marrow, myeloid progenitors were reduced only in the bone marrow but not in the fetal liver, indicating that PBSF/SDF-1 is responsible for B-cell lymphopoiesis and bone-marrow myelopoiesis. In addition, the mutants had a cardiac ventricular septal defect. Hence, we have shown that the chemokine PBSF/SDF-1 has several essential functions in development.

Effects of prenatal nitrofen exposure on cardiac structure and function in the rat

The herbicide nitrofen was administered to pregnant Fischer-344 and Sprague-Dawley rats on Days 10–13 of gestation (po, 20 or 40 mg/kg daily) and its effects on cardiac structure and function were investigated in the offspring. In the 21-day fetuses, nitrofen did not influence intrauterine growth or basal heart rate. In contrast, the herbicide produced a marked depression of heart rate and abnormal electrocardiographic (ECG) profiles in the newborn rats, in conjunction with labored respiratory movements and a profound increase in postnatal mortality. A few animals displayed cardiac ventricular septal defects and diaphragmatic hernias but these malformations did not appear to be associated with the ECG changes. The chronotropic deficiencies seen in the nitrofen-treated pups were reversible by acute hyperoxia (40% oxygen). These results suggest that the teratogenic effects of nitrofen on cardiac physiology and on postnatal mortality cannot be accounted for solely by specific gross anatomical damages to the rat heart and diaphragm; rather, other more subtle morphological and physiological factors which contribute to improper systemic delivery and cellular utilization of oxygen may be involved.