Patent ductus arteriosus in mice with smooth muscle-specific Jag1 deletion

The ductus arteriosus is an arterial vessel that shunts blood flow away from the lungs during fetal life, but normally occludes after birth to establish the adult circulation pattern. Failure of the ductus arteriosus to close after birth is termed patent ductus arteriosus and is one of the most common congenital heart defects. Mice with smooth muscle cell-specific deletion of Jag1, which encodes a Notch ligand, die postnatally from patent ductus arteriosus. These mice exhibit defects in contractile smooth muscle cell differentiation in the vascular wall of the ductus arteriosus and adjacent descending aorta. These defects arise through an inability to propagate the JAG1-Notch signal via lateral induction throughout the width of the vascular wall. Both heterotypic endothelial smooth muscle cell interactions and homotypic vascular smooth muscle cell interactions are required for normal patterning and differentiation of the ductus arteriosus and adjacent descending aorta. This new model for a common congenital heart defect provides novel insights into the genetic programs that underlie ductus arteriosus development and closure.     

Altered plasma proteins released from platelets and endothelial cells are associated with human patent ductus arteriosus

Patent ductus arteriosus is the third most common congenital heart disease and resulted from the persistence of ductal patency after birth. Ductus arteriosus closure involves functional and structural remodeling, controlled by many factors. The changes in plasma protein levels associated with PDA closure are not known. Here we for the first time demonstrate six key differential plasma proteins in human patent ductus arteriosus patients using proteomic technology and present a model to illustrate the constriction and closure of ductus arteriosus. Differentially expressed proteins were analyzed by using isobaric tags for relative and absolute quantification and validated by enzyme-linked immunosorbent assay in new samples. The proteomic data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the data set identifier PXD008568. We found 74 upregulated and 98 downregulated proteins in the plasma of patients with PDA. Five decreased proteins (platelet factor 4, fibrinogen, von Willebrand factor, collagen, and mannose binding lectin-associated serine protease-2) and one increased protein (fibronectin) may increase the risk of patent ductus arteriosus. Those proteins are closely related to platelet activation and coagulation cascades, complement mannan-binding-lectin, and other systemic signaling pathways. Our findings for the first time indicate that the differential proteins involved in different pathways may play key roles in the nonclosure of the ductus arteriosus in humans and may be developed as biomarkers for diagnosis. All those findings may be served as the basis of understanding the etiology and pathogenesis of patent ductus arteriosus.     

SURGICAL TREATMENT OF PATENT DUCTUS ARTERIOSUS

Since it would appear that diagnosis of patent ductus arteriosus can be made accurately in a high percentage of cases, and as the surgical treatment of this lesion is highly successful with a low mortality and morbidity rate, operation is advisable for all patients with this lesion except those who are 35 years of age or older and who have no progressive cardiac hypertrophy and no incapacitation due to the fistula. The optimum age for operation is three years. The vast majority of the patients have a ductus that can be divided, and division has advantages over ligation.In cases in which patent ductus arteriosus is complicated by subacute bacterial endocarditis, operation should be done following intensive penicillin therapy.     

Surgical removal of duct occluder device under mild hypothermia without cardiopulmonary bypass

Because the use of percutaneous intervention is increasing for the closure of the patent ductus arteriosus, the procedure-related complications are also on rise, with migration of the device being most common. The routine practice is to remove the migrated duct occluder device under cardiopulmonary bypass. Amplatzer duct occluder used in a 4-month-old infant dislodged into the descending thoracic aorta. It was removed by the posterolateral thoracotomy under mild hypothermia through juxtaductal aortotomy between the aortic cross-clamps. The use of cardiopulmonary bypass is thus avoided.     

Mathematical model of flow through the patent ductus arteriosus

The ductus arteriosus is one of several shunts in the cardiovascular system. It is a small vessel connecting the aortic arch and pulmonary artery that allows blood to bypass the pulmonary circulation. It is open during foetal development because the foetal lungs cannot function and oxygenation of the blood occurs by exchange with the maternal blood in the placenta. Normally it closes a few days after birth; however, in a small number of people closure does not occur, leading to a condition known as patent ductus arteriosus. In this paper our aim is to investigate the resulting cardiovascular effects. We develop a mathematical model of the haemodynamics in three different idealised geometries by assuming that the entry flow is irrotational and remains so in the core until at least the shunt position. We argue that separation or diffusion of vorticity into the core flow is delayed due to the high frequency associated with the pulsatile component of the flow profile. The analysis uses complex potential theory, Schwarz–Christoffel transformations, conformal mappings and Fourier series. The main results are based on the assumption that the flow in patients with patent ductus arteriosus is similar to the flow in healthy adults, and we apply this assumption using boundary conditions that are representative of physiological values in healthy adults. The model suggests that the pressures in the aorta and pulmonary artery are likely to equalise, that the shear stress increases near the edges of the shunt and that backflow of large volumes may occur from the pulmonary artery into the aorta or towards the ventricles due to the presence of the patent shunt. Our results strongly suggest that an abnormal compensatory physiology develops in patients with patent ductus arteriosus.     

Prostaglandin E2 in the lung lavage fluid of premature newborns before and after surgical or medical closure of a patent ductus arteriosus

To analyze the role of prostaglandin E2 in maintaining ductal patency in premature newborns, we measured the PGE2 concentration in the lung lavage fluid of nine patients within 24 h before and 4-8 h after surgical ligation of a patent ductus arteriosus and in two patients before and after closure of the ductus following intravenous indomethacin. The concentration of PGE2 ranged from 240 to 3770 pg/ml (mean 1666 +/- 1256 pg/ml) before operative intervention and show a significant decrease to 0-300 pg/ml (mean 93 +/- 106 pg/ml, P less than 0.001, Student's two-tailed t-test) within a few hours after ligation of the ductus arteriosus. The same significant decrease could be seen in two patients with successful indomethacin therapy (0.25 mg/kg in three doses/day) with concomitant ductus closure. In contrast, when indomethacin was given in a reduced dose (0.1 mg/kg in three doses/day), only a slight effect on PGE2 synthesis could be seen without closure of ductus arteriosus. We suggest that the fall of PGE2 levels in lung lavage fluid reflects the local synthesis in the ductus arteriosus itself and is responsible for the decrease induced by surgical ligation or pharmacological inhibition by indomethacin.     

Effect of the administration of prostaglandins (PGE2) in the early postnatal period on closure of the ductus arteriosus in the laboratory rat

Maintenance of a patent ductus arteriosus by means of prostaglandins enables the surgical correction of a congenital heart defect in infants to be postponed until a phase of development when the operation hazards are smaller. We investigated the pathophysiological consequences of this therapeutic measure in an experimental model in which E2 prostaglandin was administered to newborn laboratory rats. It was found that, physiologically, the ductus arteriosus (DA) closed progressively within 180 min after birth. The repeated administration of PGE2 (subcutaneously, 15 micrograms.kg-1 every 30 min from the 5th min after birth) blocked closure of the DA, which was still fully patent 300 min after birth. Histological tests showed no significant differences in the structure of the tunica media of the physiologically patent and the PGE2-treated DA. The results show that PGE2 also inhibit physiological closure of the DA in newborn rats. Long-term study of this pathophysiological process is at present impeded by the need for the continuous administration of prostaglandins.     

Percutaneous closure of an adult patent ductus arteriosus

A 23-year-old asymptomatic male was referred to our outpatient clinic because of an incidentally discovered grade III continuous machinery murmur at the third intercostal space on the left sternal edge. The echocardiography showed the presence of a patent ductus arteriosus (PDA).     

Retrograde brachial aortography; its use in the diagnosis of patent ductus arteriosus and coarctation of the aorta in infancy

Patent ductus arteriosus and coarctation of the aorta are among the commonest causes of congestive heart failure early in life. When medical therapy fails to control heart failure in these cases, surgical division of the ductus or excision of the coarcted segment can be performed. But the recognition of these anomalies in infancy is more difficult than in childhood or adult life. Retrograde thoracic aortography is a technique which permits positive identification. In the presence of patent ductus arteriosus, opacification of the pulmonary arteries from the descending aorta will be clearly shown; if coarctation is present, its position, severity, and the length of the involved segment can usually be demonstrated. Properly employed, retrograde brachial aortography is a relatively safe and effective diagnostic procedure.     

Natural History of Isolated Patent Ductus Arteriosus and the Effect of Surgical Correction: Twenty Years' Experience at The Hospital for Sick Children,Toronto

Seven hundred and forty-four cases of patent ductus arteriosus were diagnosed at The Hospital for Sick Children, Toronto, in the 20-year period from 1947 to 1966. Of these 705 have been treated surgically. It is concluded that operation is best performed between 6 and 12 months of age. Isolated ductus arteriosus is rarely a cause of congestive heart failure, and is more likely to be so in the presence of the rubella syndrome. Failure associated with the anomaly in the neonatal period can usually be successfully managed by medical treatment. Spontaneous closure after one month of age is not to be expected. Surgical treatment at the appropriate time prevents the subsequent development of Eisenmenger''s complex.     

Age-dependent changes in the response of the lamb ductus arteriosus to oxygen and ibuprofen.

Circular strips of ductus arteriosus from lambs of gestational age between 90 and 144 days (term 147 days) were studied in vitro at low (8--16 torr (1 torr = 133.322 Pa)) and high (426--622 torr) PO2. Potassium- and oxygen-induced contractions increased with the gestational age and attained a maximum at term. At low PO2, ibuprofen, a blocker of prostaglandin synthesis, produced a dose-dependent contraction of the ductus at all ages and enhanced the potassium-induced contraction of the immature ductus (90--124 days). Both effects were relatively greater in the 103- to 107-day gestational group. At that age, ibuprofen also potentiated the oxygen-induced contraction. These findings, while confirming that a prostaglandin is involved in ductus patency, indicate that the prostaglandin-relaxing mechanism becomes functional at an early stage of gestation and reaches maximal activity before term. The existence of an active, prostaglandin-mediated relaxation in the preterm ductus may account, in part, for the reduced responsiveness of the vessel to oxygen. It is confirmed that ibuprofen and other nonsteroidal antiinflammatory drugs are well suited for the management of the premature infant with patent ductus arteriosus.     

Hypotriploidy 68,XX: a new case report and review of earlier cases

We report a prematurely born patient with a 68,XX karyotype. She presented with syndactyly of 2nd and 3rd toes, minor facial features, microcephaly, slender hands, bicuspid aortic valve, patent ductus arteriosus and hypotonia. Comparison with other reported cases is given.     

Rubella Syndrome—Cardiovascular Manifestations and Surgical Therapy in Infants

Of nine patients under five months of age with cardiovascular manifestations of the rubella syndrome, six had patent ductus arteriosus. Three of these six also had pulmonary artery stenosis. One infant had bilateral isolated pulmonary artery stenosis. The significant clinical findings leading to the diagnosis of pulmonary artery stenosis were axillary murmurs in the presence of right ventricular hypertrophy. Demonstration of a gradient across the stenosis at the time of catheterization, together with cineangiography, established the diagnosis. In two cases ventricular septal defect was the only cardiac anomaly.Six babies under five months of age had interruption of a patent ductus arteriosus because of uncontrollable congestive heart failure or failure to thrive. Although growth failure was not necessarily due to heart disease, all were developing satisfactorily following operation.Diagnosis and therapy of the cardiac complications of the rubella syndrome is possible in the first few months of life. Early recognition of cardiac defects in the young infant with the rubella syndrome permits aggressive medical management and in selected instances surgical therapy.     

Postnatal constriction, ATP depletion, and cell death in the mature and immature ductus arteriosus

After birth, constriction of the full-term ductus arteriosus induces oxygen, glucose and ATP depletion, cell death, and anatomic remodeling of the ductus wall. The immature ductus frequently fails to develop the same degree of constriction or anatomic remodeling after birth. In addition, the immature ductus loses its ability to respond to vasoconstrictive agents, like oxygen or indomethacin, with increasing postnatal age. We examined the effects of premature delivery and postnatal constriction on the immature baboon ductus arteriosus. By 6 days after birth, surrogate markers of hypoxia (HIF1alpha/VEGF mRNA) and cell death [dUTP nick-end labeling (TUNEL)-staining] increased, while glucose and ATP concentrations (bioluminescence imaging) decreased in the immature ductus. TUNEL-staining was significantly related to the degree of glucose and ATP depletion. Glucose and ATP depletion were directly related to the degree of ductus constriction; while TUNEL-staining was logarithmically related to the degree of ductus constriction. Extensive cell death (>15% TUNEL-positive cells) occurred only when there was no Doppler flow through the ductus lumen. In contrast, HIF1alpha/VEGF expression and ATP concentrations were significantly altered even when the immature ductus remained open after birth. Decreased ATP concentrations produced decreased oxygen-induced contractile responses in the immature ductus. We hypothesize that ATP depletion in the persistently patent immature newborn ductus is insufficient to induce cell death and remodeling but sufficient to decrease its ability to constrict after birth. This may explain its decreasing contractile response to oxygen, indomethacin, and other contractile agents with increasing postnatal age.     

Morbidity and survival in neonates ventilated for the respiratory distress syndrome.

In a retrospective analysis the records of all (210) infants ventilated to treat the respiratory distress syndrome over three years were reviewed. A mortality of 19% was found. Intraventricular haemorrhage was associated than a significant increase in mortality in infants of less with 30 weeks'' gestation (p less than 0.001) and was the commonest cause of death. Pneumothoraces developed in one third of babies regardless of gestational age but were significantly associated with an increase in mortality only in infants of 27-29 weeks'' gestation. Patent ductus arteriosus was present in 31 infants and was commoner in babies of very low birth weight. The presence of a patent ductus arteriosus was not associated with decreased survival but was significantly related to an increased need for prolonged respiratory support (p less than 0.001). Thirty six infants developed chronic lung disease, three of whom died. Comparison with data from earlier studies indicated a steady improvement over the past decade in outcome for infants ventilated for the respiratory distress syndrome.     

Patent ductus arteriosus and microdeletion 22q11 in a patient with Klinefelter syndrome

We describe an uncommon association of deletion 22q11 in a patient with Klinefelter syndrome. Even though congenital heart defects (CHD) are not associated with Klinefelter syndrome, further investigation of this patient with patent ductus arteriosus showed a microdeletion of chromosome 22q11.2. While this finding may be coincidental, it is important to further evaluate patients when the clinical features are suggestive of a secondary abnormality.