elastin and Ductus-Arteriosus--Patent

To investigate whether isolated congenital ductus arteriosus aneurysm (DAA) is caused by loss of function of mutations in the elastin gene (ELN), we screened the elastin gene, which has been proposed as a candidate gene in DAA.. A total of 2249 full-term neonates received echocardiographic screening. Newborns with isolated DAA were divided into two groups: those with large DAA (> or = 10 mm) and small DAA (< 10 mm). ELN gene study was performed randomly for newborns with DAA. There were 186 (8.3%) newborns with DAAs. Among them, 29 had large and 157 had small DAA detected by 2DE. Maximum internal diameter of the DAAs ranged from 6.6 to 14.0 mm (8.3 +/- 1.2 mm). All cases were asymptomatic. Fifteen newborns with large DAA and 14 with small DAA received ELN gene analysis. Among them, 4 infants had single nucleotide variations, including nucleotide 212 C --> T in 2, 278 C --> T in one, and 1232 T --> C in one. We considered the possibility that these might be a neutral single nucleotide polymorphism rather than a mutation.. The incidence of congenital DAA and clinical presentations were consistent with those of our previous report. Based on our findings, the ELN gene can be excluded as a candidate gene in DAA. We consider the presence of DAA may be a normal variant of ductus arteriosus in full-term infants.

Topics: Ductus Arteriosus, Patent; Elastin; Female; Genetic Testing; Heart Aneurysm; Humans; Incidence; Infant; Infant, Newborn; Male; Taiwan; Ultrasonography

The Brown Norway (BN) rat presents several genetically determined arterial phenotypes of interest, i.e., ruptures of the internal elastic lamina (RIEL) in the abdominal aorta (AA), iliac (IAs), and renal arteries, aortic elastin deficit and higher frequency of persistent ductus arteriosus (PDA) than other strains. We investigated the genetic basis of these phenotypes. We established a backcross between BN and the LOU reference strain and performed a genome-wide scan on 104 males and 105 females with 193 microsatellite markers followed by linkage analysis. RIEL in AA and IAs showed highly significant linkage to a locus on chromosome 5 and suggestive linkage to a locus on chromosome 10, which is syntenic to one linked to a syndrome of thoracic aortic aneurysms with PDA in humans. In contrast, renal artery RIEL mapped to a chromosome 3 locus and thoracic aortic elastic content to two loci on chromosome 2. PDA was significantly linked to two different quantitative trait loci (QTL) on chromosomes 8 and 9. This is the first study in rats to identify genetic loci for PDA. We identified 21 candidate genes by functional relevance or integration of our mapping data with global expression analysis. Sequencing these genes identified 47 single nucleotide polymorphisms, but no functionally relevant amino acid changes. By expression analysis, myosin heavy chain 10, nonmuscle, in the chromosome 10 QTL, emerged as a candidate for RIEL in AA and IAs. Furthermore, production of a congenic line for the chromosome 5 QTL proved implication of this locus in RIEL formation.

Topics: Animals; Aorta; Aorta, Abdominal; Aorta, Thoracic; Chromosome Mapping; Chromosomes, Mammalian; Ductus Arteriosus, Patent; Elastin; Female; Gene Expression Profiling; Genetic Linkage; Genotype; Male; Myosins; Oligonucleotide Array Sequence Analysis; Phenotype; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Rats; Rats, Inbred BN; Renal Artery

Persistent ductus arteriosus (PDA) is a common cardiovascular anomaly in children caused by the pathologic persistence of the left sixth pharyngeal arch artery. The inbred Brown-Norway (BN) rat presents with increased vascular fragility due to an aortic elastin deficit resulting from decreased elastin synthesis. The strikingly high prevalence of PDA in BN rats in a pilot study led us to investigate this vascular anomaly in 12 adolescent BN rats. In all BN rats, a PDA was observed macroscopically, whereas a ligamentum arteriosum was found in adult controls. The macroscopic appearance of the PDA was tubular (n = 2), stenotic (n = 8), or diverticular (n = 2). The PDA had the structure of a muscular artery with intimal thickening. In the normal closing ductus of the neonatal controls, the media consisted of layers of smooth muscle cells (SMCs) intermingled with layers of elastin. The intima was thin and poor in elastin. By contrast, the media of PDA in BN rats elastin lamellae were absent and the intima contained many elastic fibers. The abnormal distribution of elastin in the PDA of BN rats suggests that impaired elastin metabolism is related to the persistence of the ductus and implicates a genetically determined factor that may link the PDA with aortic fragility.

Topics: Animals; Ductus Arteriosus; Ductus Arteriosus, Patent; Elastin; Female; Myocytes, Smooth Muscle; Rats; Rats, Inbred BN

The purpose of this study was to determine whether the presence of bowel in the chest during development in the fetal lamb model of congenital diaphragmatic hernia (CDH) results in structural and/or biochemical hypoplasia of the left venticle.. The model was created at 80 days' gestation and delivered at term. The hearts were fixed in 4% formaldehyde solution, components weighed, and right ventricular (RV) and left ventricular (LV) wall thicknesses and both aortic (Ao) and pulmonary artery (PA) root diameters were measured. Fresh specimens were analyzed for protein, DNA, hydroxyproline, and elastin content. All CDH measurements are compared with littermate control tissues.. There were no differences in body weight (kg) between CDH and control littermates (4.25 +/- 0.26 versus 3.71 +/- 0.24, P = NS). CDH lambs have significantly decreased total heart (4.88 +/- .25 versus 6.75 +/- .49, P < .05), left ventricular (1.65 +/- .11 versus 2.15 +/- .19, P < .05), septal (1.29 +/- .11 versus 1.99 +/- .21, P < .05), and combined atrial (0.68 +/- .06 versus 1.14 +/- .15, P < .05) weights (g/kg lamb) without differences in RV weights (1.26 +/- .07 versus 1.57 +/- .17, P = NS). LV and RV wall thickness, and Ao root diameters (cm) were found to be identical in both CDH and control lambs. However, PA root diameters (0.47 +/- .01 versus 0.38 +/- .01, P < .005) and ductus arteriosus diameters were increased in CDH (0.35 +/- .01 versus 0.22 +/- .02, P < .005). Total protein, DNA collagen, and elastin content and DNA/total protein ratios were identical in RV and LV in both CDH and control lambs.. Newborn lambs with left-sided CDH have a significantly lower total heart, LV, septal, and atrial weights without differences of RV weight or ventricular wall thicknesses. Given these findings, the unchanged DNA/protein ratio implies that the left ventricle is hypoplastic in CDH. Ao/PA root ratios suggest that LV hypoplasia in utero may result in increased left atrial pressures, decreased right-to-left shunting through the foramen ovale, and increased PA pressures and flow, resulting in increased PA root and ductus arteriosus diameters. This model simulates the clinical data from human fetuses/neonates with CDH. Further investigations are necessary to determine the functional significance of these findings.

Topics: Animals; Aorta; Blood Pressure; Collagen; Disease Models, Animal; DNA; Ductus Arteriosus, Patent; Elastin; Female; Heart Atria; Heart Defects, Congenital; Heart Septal Defects, Atrial; Heart Septum; Heart Ventricles; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Humans; Hydroxyproline; Organ Size; Pregnancy; Proteins; Pulmonary Artery; Sheep