Aortic dissection in a young male with persistent ductus arteriosus and a novel variant in MYLK.

Pathogenic variants in several genes involved in the function or regulation of smooth muscle cells (SMC) are known to predispose to congenital heart disease and thoracic aortic aneurysm and dissection (TAAD). Variants in MYLK are primarily known to predispose to TAAD, but a growing body of evidence points toward MYLK also playing an essential role in the regulation of SMC contraction outside the aorta. In this case report, we present a patient with co-occurrence of persistent ductus arteriosus (PDA) and thoracic aortic dissection. Genetic analyses revealed a novel splice acceptor variant (c.3986-1G > A) in MYLK, which segregated with disease in the family. RNA-analyses on fibroblasts showed that the variant induced skipping of exon 24, which resulted in an in-frame deletion of 101 amino acids. These findings suggest that MYLK-associated disease could include a broader phenotypic spectrum than isolated TAAD, including PDA and obstructive pulmonary disease. Genetic analyses could be considered in families with TAAD and PDA or obstructive pulmonary disease.

A histological study of the adult ligamentum arteriosum: Novel findings with application to a patent ductus arteriosus.

The ligamentum arteriosum (LA) is the vestigial fibrous remnant of the ductus arteriosus (DA), a fetal vessel arising from the left dorsal segment of the sixth aortic arch that connects the left pulmonary artery to the aortic arch. Incomplete obliteration of the DA results in a patent ductus arteriosus (PDA), causing the shunting of oxygen-rich blood to recirculate to the lungs, which can lead to pulmonary hypertension. The current study aims to further elucidate the structural characteristics of the LA via histological analysis with data gathered from adult cadaveric specimens. The LA was harvested and histologically observed with Hematoxylin and Eosin, van Gieson, and Masson's trichrome staining. Fibrous and muscle tissues were observed in all 25 specimens. The LA was categorized into three types based on the morphological features of the LA. Type I (vessel-like structure), type II (fibrotic tissue with duct-like structure), and type III (no duct-like structure) were found in 4.0%, 80.0%, and 16.0%, respectively. Finally, the remnant of a valve in the LA was also observed at the junction between the AA and LA. We suggest that this valve be called the "pulmonary-aortic valve." In the majority of the adult LAs, a duct-like structure was still present. These data could better elucidate our understanding of the pathology and etiology of a PDA.

Vav2 promotes ductus arteriosus anatomic closure via the remodeling of smooth muscle cells by Rac1 activation.

The ductus arteriosus (DA), bridging the aorta and pulmonary artery, immediately starts closing after birth. Remodeling of DA leads to anatomic obstruction to prevent repatency. Several histological changes, especially extracellular matrices (ECMs) deposition and smooth muscle cells (SMCs) migration bring to anatomic closure. The genetic etiology and mechanism of DA closure remain elusive. We have previously reported a novel copy number variant containing Vav2 in patent ductus arteriosus (PDA) patients, but its specific role in DA closure remains unknown. The present study revealed that the expression of Vav2 was reduced in human patent DA, and it was less enrichment in the adjacent aorta. Matrigel experiments demonstrated that Vav2 could promote SMC migration from PDA patient explants. Smooth muscle cells with Vav2 overexpression also presented an increased capacity in migration and downregulated contractile-related proteins. Meanwhile, SMCs with Vav2 overexpression exhibited higher expression of collagen III and lessened protein abundance of lysyl oxidase, and both changes are beneficial to DA remodeling. Overexpression of Vav2 resulted in increased activity of Rac1, Cdc42, and RhoA in SMCs. Further investigation noteworthily found that the above alterations caused by Vav2 overexpression were particularly reversed by Rac1 inhibitor. A heterozygous, rare Vav2 variant was identified in PDA patients. Compared with the wild type, this variant attenuated Vav2 protein expression and weakened the activation of downstream Rac1, further impairing its functions in SMCs. In conclusion, Vav2 functions as an activator for Rac1 in SMCs to promote SMCs migration, dedifferentiation, and ECMs production. Deleterious variant potentially induces Vav2 loss of function, further providing possible molecular mechanisms about Vav2 in PDA pathogenesis. These findings enriched the current genetic etiology of PDA, which may provide a novel target for prenatal diagnosis and treatment. KEY MESSAGES: Although we have proposed the potential association between Vav2 and PDA incidence through whole exome sequencing, the molecular mechanisms underlying Vav2 in PDA have never been reported. This work, for the first time, demonstrated that Vav2 was exclusively expressed in closed DAs. Moreover, we found that Vav2 participated in the process of anatomic closure by mediating SMCs migration, dedifferentiation, and ECMs deposition through Rac1 activation. Our findings first identified a deleterious Vav2 c.701C>T variant that affected its function in SMCs by impairing Rac1 activation, which may lead to PDA defect. Vav2 may become an early diagnosis and an effective intervention target for PDA clinical therapy.

Anatomy of the Ductus Arteriosus in Fetal Autopsies: Correlations With Placental Pathology and Cause of Death.

BACKGROUND: Differences in the shape of the ductus arteriosus (DA), an important vascular shunt between the pulmonary artery and aorta, may reflect fetoplacental blood flow. Our aim was to examine tapering of the DA in a fetal autopsy population and correlate it with placental pathology and cause of death (COD). METHODS: This autopsy case control study of stillborn fetuses selected cases (tapered DA) and consecutive age-matched controls (no DA tapering) between January 2017 and January 2022. We abstracted demographic and clinical data from pathology reports. Autopsy data included COD and histologic evidence of fetal hypoxia. Placental pathology included umbilical cord abnormalities, acute and chronic inflammation, fetal vascular malperfusion (FVM), and maternal vascular malperfusion (MVM). RESULTS: We identified 50 cases and 50 controls. Gestational age ranged from 18 to 38 weeks. Maternal and fetal demographic characteristics did not differ significantly between cases and controls. COD related to an umbilical cord accident/FVM was significantly more prevalent in cases vs controls (46% vs 26%, P = .037), and FVM in the placenta, regardless of COD, trended higher in cases than controls. CONCLUSION: Tapering of the DA is present in stillborn fetuses and associated with COD related to fetal vascular blood flow obstruction.

Ligamentum arteriosum: Muscular and contractile.

Ductus arteriosus is a muscular artery in fetal circulation, spanning from the bifurcation of the pulmonary trunk to the aortic arch, shunting blood directly from pulmonary circulation into systemic circulation thus by-passing the fluid-filled lungs. Postnatally, it changes name to the ligamentum arteriosum (LA), when a cascade of anatomical and physiological processes leads to its closure. Though the LA has generally been considered as a fibrosed remnant of the ductus arteriosus, anecdotal and contradictory reports still describe the LA as a small muscular artery. We hypothesized the likelihood of contractile muscular elements retainment in this so-called ligament. To investigate this, mediastinum of wild-type mouse, pig, and human LA were subjected to routine and special histological staining, single-immunolabeling, electron microscopy (mouse and pig only), and tension recording of explanted pig LA in organ bath experiments. Contrary to a canonical ligament, the LA was mainly made up of α-smooth muscle actin-positive cells in all three species, confirmed by routine and special histological staining as well as transmission electron microscopy. Myocytes within the LA contracted in response to exogenous noradrenalin (NA). NA-induced precontracted LA relaxed upon administration of the α1-adrenergic blockers (prazosin and tamsulosin). Though the LA does not function in its original capacity as fetal shunt, it is clearly not a passive structure, and may be described as muscular and contractile. The contractile abilities of LA myocytes may act on the two great vessels to which it is attached causing a change in their distensibility.

The ductus arteriosus: a review of embryology to intervention.

This article reviews the physiology of the ductus arteriosus, the pathophysiology of the patent ductus arteriosus (PDA), and the role advanced imaging such as computed tomography (CT) and magnetic resonance imaging (MRI) can play in guiding diagnosis and percutaneous or surgical intervention. A PDA can have variable clinical and radiologic presentations and can be important to characterize in patients with vascular rings, aortic maldevelopment and congenital heart disease. An understanding of the PDA and the application of CT and MRI can allow the radiologist to provide key information to physicians who plan to close a PDA or maintain PDA patency in the setting of ductal-dependent congenital heart disease.

Maternal ingestion of cocoa causes constriction of fetal ductus arteriosus in rats.

Maternal consumption of polyphenol-rich foods has been associated with fetal ductus arteriosus constriction (DAC), but safety of chocolate exposure in fetal life has not been studied. This experimental study tested the hypothesis that maternal cocoa consumption in late pregnancy causes fetal DAC, with possible associated antioxidant effects. Pregnant Wistar rats, at the 21st gestational day, received by orogastric tube cocoa (720 mg/Kg) for 12 h, indomethacin (10 mg/Kg), for 8 h, or only water, before cesaren section. Immediately after withdrawal, every thorax was obtained and tissues were fixed and stained for histological analysis. The ratio of the narrowest part of the pulmonary artery to the fetal ductus inner diameter and increased ductal inner wall thickness characterized ductal constriction. Substances reactive to thiobarbituric acid were quantified. Statistical analysis used ANOVA and Tukey test. Cocoa (n = 33) and indomethacin (n = 7) reduced fetal internal ductus diameter when compared to control (water, n = 25) (p < 0.001) and cocoa alone increased ductus wall thickness (p < 0.001), but no change was noted in enzymes activity. This pharmacological study shows supporting evidences that there is a cause and effect relationship between maternal consumption of cocoa and fetal ductus arteriosus constriction. Habitual widespread use of chocolate during gestation could account for undetected ductus constriction and its potentially severe consequences, such as perinatal pulmonary hypertension, cardiac failure and even death. For this reason, dietary guidance in late pregnancy to avoid high chocolate intake, to prevent fetal ductal constriction, may represent the main translational aspect of this study.

Molecular Mechanisms Underlying Remodeling of Ductus Arteriosus: Looking beyond the Prostaglandin Pathway.

The ductus arteriosus (DA) is a physiologic vessel crucial for fetal circulation. As a major regulating factor, the prostaglandin pathway has long been the target for DA patency maintenance or closure. However, the adverse effect of prostaglandins and their inhibitors has been a major unsolved clinical problem. Furthermore, a significant portion of patients with patent DA fail to respond to cyclooxygenase inhibitors that target the prostaglandin pathway. These unresponsive medical patients ultimately require surgical intervention and highlight the importance of exploring pathways independent from this well-recognized prostaglandin pathway. The clinical limitations of prostaglandin-targeting therapeutics prompted us to investigate molecules beyond the prostaglandin pathway. Thus, this article introduces molecules independent from the prostaglandin pathway based on their correlating mechanisms contributing to vascular remodeling. These molecules may serve as potential targets for future DA patency clinical management.

The effects of ductal size on the severity of pulmonary hypertension in children with patent ductus arteriosus (PDA): a multi-center study.

INTRODUCTION: Patent ductus arteriosus (PDA) is a common acyanotic heart disease that presents with variable symptoms. OBJECTIVES: This study is therefore aimed at determining the relationship between gender, age, and size of PDA and pulmonary hypertension. This study also seeks to determine the prevalence of elevated pulmonary artery systolic pressure in children with PDA. PATIENTS AND METHODS: A descriptive study of children with patent ductus arteriosus was carried out from 2016 to 2020 in three institutions. The data were analysed with the IBM SPSS statistics for windows, version 20 (IBM Corp, Chicago) RESULT: The mean ductal size was 3.78 (2.39) mm, with a minimum of 1.0 mm and a maximum size of 10.0 mm. The mean ductal size for males, 4.02 (2.53) mm was comparable with that of the females, 3.61 (2.28) mm (Student T-test = 0.8, 0.4). The mean pulmonary artery systolic pressure (PASP) of the patients was 43.36 (24.46) mmHg. Also the mean PASP was comparable among the males and the females, 48.37 (26.69) mmHg versus 39.63 (22.16) mmHg (Student T-test = 1.81, p = 0.07). There was no correlation between age and PASP (correlation coefficient = 0.009, p = 0.92). Sixty point two percent (60.2%) (62/103) of children with PDA had pulmonary hypertension. The proportion of males with pulmonary hypertension, 48.39% (30/62) was comparable with that of the females, 51.61% (32/62) (Chi2 = 2.05, p = 0.15) and females are 1.8 times more likely to have pulmonary hypertension as males (odds ratio 1.81, 95% CI 0.8-4.1). There was a positive correlation between ductal size and PASP (Pearson correlation coefficient = 0.26, p value = 0.007). Those with moderate and large sized duct tend to have moderate and severe pulmonary hypertension respectively and this is statistically significant. Chi2 = 17.85, p = 0.007 CONCLUSION: The prevalence of pulmonary hypertension in children with PDA is 60.2%. Moderate and large size duct presents with moderate and severe pulmonary hypertension respectively. Females are 1.8 times more likely to have pulmonary hypertension than the males.

Improvement in fetal pulmonary hypertension and maturity after reversal of ductal constriction: prospective cohort study.

OBJECTIVES: To test the hypotheses that estimated mean pulmonary arterial pressure (MPAP) decreases and pulmonary vascular maturation, assessed by the ratio of pulmonary arterial flow acceleration time to ejection time (AT/ET ratio), increases after reversal of fetal ductus arteriosus constriction by reducing maternal intake of the causal agent (prostaglandin inhibitors, such as polyphenol-rich foods or non-steroidal anti-inflammatory drugs), and that these effects are independent of gestational age, which are inferences not yet demonstrated in the clinical setting. METHODS: This was a prospective cohort study comparing Doppler echocardiographic ductal flow dynamics, MPAP and pulmonary arterial flow AT/ET ratio in third-trimester fetuses (≥ 28 weeks' gestation) with ductus arteriosus constriction, at the time of diagnosis and after 2 weeks of reduced maternal intake of prostaglandin inhibitors either by suspending the use of pharmacological agents with potential for prostaglandin inhibition or by restricting the consumption of polyphenol-rich foods. MPAP was estimated using the Dabestani equation (MPAP = 90 - (0.62 × AT)), and pulmonary vascular maturity was assessed using the AT/ET ratio, according to reported validation studies. Student's t-test was used for comparison of variables at diagnosis with those after reversal of ductal constriction. Change in MPAP and pulmonary AT/ET ratio between the two assessments was compared with the expected change in the same gestational period in normal fetuses based on reference curves of MPAP and pulmonary AT/ET ratio constructed in normal fetuses from healthy pregnant women at 19-37 weeks' gestation, encompassing the same gestational age range as the study group (28-37 weeks). RESULTS: Seventy pregnancies with fetal ductus arteriosus constriction were included in the study. After 2 weeks of reduced maternal intake of prostaglandin inhibitors, normalization of mean systolic (change from 1.86 ± 0.34 m/s at diagnosis to 1.38 ± 0.41 m/s; P < 0.001) and diastolic (change from 0.41 ± 0.11 m/s to 0.21 ± 0.065 m/s; P < 0.001) ductal velocities and of mean pulsatility index (change from 1.99 ± 0.20 to 2.55 ± 0.42; P < 0.001) was demonstrated. MPAP decreased between the assessments (change from 66.7 ± 6.90 mmHg at diagnosis to 54.5 ± 6.70 mmHg after 2 weeks; P < 0.001) and mean pulmonary AT/ET ratio increased (change from 0.20 ± 0.06 to 0.33 ± 0.07; P < 0.001). Change in MPAP between diagnosis and after 2 weeks of reduced maternal intake of prostaglandin inhibitors was -12.2 ± 0.30 mmHg, which was 5.3-times higher than that in 305 normal fetuses over 2 weeks during the same gestational period (-2.3 ± 0.19 mmHg) (P < 0.001), and change in pulmonary AT/ET ratio between the two assessments was 0.13 ± 0.08, which was 8.7-times higher than that in normal fetuses in the same gestational period (0.015 ± 0.08) (P < 0.001). CONCLUSIONS: Resolution of fetal ductal constriction is followed by a fall in MPAP and by an increase in pulmonary vascular maturity, to a significantly greater degree than is observed in normal fetuses in the same gestational-age period. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Evaluation of Ductal Tissue in Coarctation of the Aorta Using X-Ray Phase-Contrast Tomography.

We assessed the histological accuracy of X-ray phase-contrast tomography (XPCT) and investigated three-dimensional (3D) ductal tissue distribution in coarctation of the aorta (CoA) specimens. We used nine CoA samples, including the aortic isthmus, ductus arteriosus (DA), and their confluences. 3D images were obtained using XPCT. After scanning, the samples were histologically evaluated using elastica van Gieson (EVG) staining and transcription factor AP-2 beta (TFAP2B) immunostaining. XPCT sectional images clearly depicted ductal tissue distribution as low-density areas. In comparison with EVG staining, the mass density of the aortic wall positively correlated with elastic fiber formation (R = 0.69, P < 0.001). TFAP2B expression was consistent with low-density area including intimal thickness on XPCT images. On 3D imaging, the distances from the DA insertion to the distal terminal of the ductal media and to the intima on the ductal side were 1.63 ± 0.22 mm and 2.70 ± 0.55 mm, respectively. In the short-axis view, the posterior extension of the ductal tissue into the aortic lumen was 79 ± 18% of the diameter of the descending aorta. In three specimens, the aortic wall was entirely occupied by ductal tissue. The ductal intima spread more distally and laterally than the ductal media. The contrast resolution of XPCT images was comparable to that of histological assessment. Based on the 3D images, we conclude that complete resection of intimal thickness, including the opposite side of the DA insertion, is required to eliminate residual ductal tissue and to prevent postoperative re-coarctation.

Utility of modified vascular corrosion casting technique in the diagnosis of fetal ductus arteriosus abnormalities.

The anatomy of ductus arteriosus (DA) can be varied in different congenital heart defects (CHDs), and it is difficult to fully discover the DA and other associated cardiac anomalies by prenatal ultrasound. This study was aimed to use the modified vascular corrosion casting technique to prepare fetal cardiovascular casts with DA anomalies, assess the casting effectiveness in evaluating the great vessels of the fetal heart and investigate the utility of cardiovascular casting for the demonstration of fetal DA abnormalities. This retrospective study enrolled fourteen fetuses (23 to 28+2 gestational weeks) with severe CHDs diagnosed by prenatal echocardiography and casting technique from January 2013 to July 2019. The sonographic features of DAs were carefully observed and other associated cardiovascular anomalies were also evaluated during the screening. The architectures of DAs and the whole cardiovascular system were observed and analyzed, and then the cast findings were compared with prenatal ultrasonic results. In fourteen cases, 18 ductal abnormities were indicated by prenatal echocardiography in fourteen cases, while 25 were revealed by casting. Cast findings included 4 cases of ductal stenosis, 1 case of ductal dilation, 6 cases of ductal circuity, 3 cases of right-sided ductus, 5 cases of anomalous ductal connection, 1 case of bilateral ductus and 5 cases of absent ductus. Cast findings consisted with ultrasound in 10 ductal abnormalities, revealed additional 15 ductal abnormalities miss-diagnosed by sonography, and corrected 6 abnormalities misdiagnosed prenatally. Meanwhile, 3 ductal abnormalities (reversed flow) could not be demonstrated by casts but only by ultrasound. Cast models can visually display the anatomical characteristics of ductus arteriosus, and could be successfully used in the demonstration of ductus abnormalities in fetuses with severe CHDs. Comparing with ultrasound, casting technique has its own superiority in exhibiting ductus abnormalities, especially in certain types such as course, origin and absence abnormalities of ductus.

Pulmonary ductal coarctation and left pulmonary artery interruption; pathology and role of neural crest and second heart field during development.

OBJECTIVES: In congenital heart malformations with pulmonary stenosis to atresia an abnormal lateral ductus arteriosus to left pulmonary artery connection can lead to a localised narrowing (pulmonary ductal coarctation) or even interruption We investigated embryonic remodelling and pathogenesis of this area. MATERIAL AND METHODS: Normal development was studied in WntCre reporter mice (E10.0-12.5) for neural crest cells and Nkx2.5 immunostaining for second heart field cells. Data were compared to stage matched human embryos and a VEGF120/120 mutant mouse strain developing pulmonary atresia. RESULTS: Normal mouse and human embryos showed that the mid-pharyngeal endothelial plexus, connected side-ways to the 6th pharyngeal arch artery. The ventral segment formed the proximal pulmonary artery. The dorsal segment (future DA) was solely surrounded by neural crest cells. The ventral segment had a dual outer lining with neural crest and second heart field cells, while the distal pulmonary artery was covered by none of these cells. The asymmetric contribution of second heart field to the future pulmonary trunk on the left side of the aortic sac (so-called pulmonary push) was evident. The ventral segment became incorporated into the pulmonary trunk leading to a separate connection of the left and right pulmonary arteries. The VEGF120/120 embryos showed a stunted pulmonary push and a variety of vascular anomalies. SUMMARY: Side-way connection of the DA to the left pulmonary artery is a congenital anomaly. The primary problem is a stunted development of the pulmonary push leading to pulmonary stenosis/atresia and a subsequent lack of proper incorporation of the ventral segment into the aortic sac. Clinically, the aberrant smooth muscle tissue of the ductus arteriosus should be addressed to prohibit development of severe pulmonary ductal coarctation or even interruption of the left pulmonary artery.

Sudden Death Caused by Rupture of Spontaneous Ductus Arteriosus Aneurysm in an Adult.

A 55-year-old man complained of sudden onset of severe neck pain. This was followed by prompt loss of consciousness and death. Autopsy revealed rupture of a saccular aneurysm, which was considered to have resulted from enlargement of the remaining ductal tissue, and was located on the medial aspect of the uppermost portion of the descending aorta. Dense blood extravasation was noted in the posterior mediastinum and extending to the strap muscles of the neck and larynx. Histological examination of the rupture site revealed disappearance of the medial elastic fibers and thickened intima covered with dense fibrous tissue. Spontaneous ductus arteriosus aneurysm in adults is a rare finding, but widespread use of imaging technologies has revealed that it develops more frequently than previously recognized. Fatal complications may occur even when the aneurysm is relatively small. Therefore, pathologists should be aware of this aneurysm as a potential cause of sudden death.

Antenatal Administration of Betamethasone Contributes to Intimal Thickening of the Rat Ductus Arteriosus.

BACKGROUND: Antenatal betamethasone (BMZ) is a standard therapy for reducing respiratory distress syndrome in preterm infants. Recently, some reports have indicated that BMZ promotes ductus arteriosus (DA) closure. DA closure requires morphological remodeling; that is, intimal thickening (IT) formation; however, the role of BMZ in IT formation has not yet been reported. Methods and Results: First, DNA microarray analysis using smooth muscle cells (SMCs) of rat preterm DA on gestational day 20 (pDASMCs) stimulated with BMZ was performed. Among 58,717 probe sets, ADP-ribosyltransferase 3 (Art3) was markedly increased by BMZ stimulation. Quantitative reverse transcription polymerase chain reaction (RT-PCR) confirmed the BMZ-induced increase of Art3 in pDASMCs, but not in aortic SMCs. Immunocytochemistry showed that BMZ stimulation increased lamellipodia formation. BMZ significantly increased total paxillin protein expression and the ratio of phosphorylated to total paxillin. A scratch assay demonstrated that BMZ stimulation promoted pDASMC migration, which was attenuated byArt3-targeted siRNAs transfection. pDASMC proliferation was not promoted by BMZ, which was analyzed by a 5'-bromo-2'-deoxyuridine (BrdU) assay. Whether BMZ increased IT formation in vivo was examined. BMZ or saline was administered intravenously to maternal rats on gestational days 18 and 19, and DA tissues were obtained on gestational day 20. The ratio of IT to tunica media was significantly higher in the BMZ-treated group. CONCLUSIONS: These data suggest that antenatal BMZ administration promotes DA IT through Art3-mediated DASMC migration.

Maternal paracetamol intake and fetal ductus arteriosus constriction or closure: a case series analysis.

Recent case reports describe an association between maternal paracetamol intake and fetal ductus arteriosus constriction or closure. To put these cases into perspective and explore causality, a structured literature search was conducted. The World Health Organization Uppsala Monitoring Centre (WHO-UMC) causality tool was applied to the cases retrieved. The search resulted in 12 papers with 25 case descriptions, of which one case was classified as unlikely, nine as possible, 11 as probable and four as certain. Consequently, we concluded that a causal relationship between maternal paracetamol intake and fetal ductus arteriosus constriction or closure is likely. These findings suggest that pharmacovigilance studies on paracetamol safety during pregnancy are warranted to quantify the event and put the current findings into clinical perspective. Although analgesia during pregnancy and during the peripartum period is of obvious relevance, alternative analgesics such as opioids or other nonsteroidal anti-inflammatory drugs also have side effects.

High incidence of ductal closure or narrowing at birth in patients with right ventricular outflow tract obstruction with normal orientation of the ductus arteriosus.

BACKGROUND: Ductal patency is mandatory to manage patients with ductal-dependent pulmonary circulation. The aim of this study is to elucidate the morphological and haemodynamic features of ductus arteriosus with right ventricular outflow tract obstruction, and investigate the appropriate perinatal management.Patients and methodsPatients with prenatal diagnosis of right ventricular outflow tract obstruction at our institution between 2010 and 2015 were included in the study. Reverse orientation of the ductus arteriosus is defined as an inferior angle of 90°. We retrospectively reviewed the shape and flow pattern of ductus arteriosus and the clinical characteristics of the cases. RESULTS: A total of 39 patients were enrolled. The shape was divided into normal orientation (n=15) and reverse orientation (n=24) of the ductus arteriosus. There was no significant difference in the type of oxygen saturation at birth and age at shunt operation between both the groups. However, the median narrowest diameter of ductus arteriosus in the normal orientation group was significantly smaller than that in the reverse orientation group (2.0 [1.0-5.4] versus 3.0 [1.3-4.4] mm, p<0.05). In two patients of the normal orientation group, ductus arteriosus had closed at birth, and one of whom died because of severe cyanosis. CONCLUSIONS: Normal orientation pattern might have high incidence of an early narrowing or closure of ductus arteriosus at birth. The critical patients need careful evaluation by repeated foetal echocardiography and further maternal interventions.

Prostaglandin E2 Receptor EP4 Inhibition Contracts Rat Ductus Arteriosus.

BACKGROUND: Patent ductus arteriosus (PDA) is common in premature infants. Cyclooxygenase inhibitors such as indomethacin, which inhibit prostaglandin E2(PGE2) synthesis, are currently the sole treatments for patients with PDA. Their efficacy are, however, frequently limited, and adverse effects are problematic. Because the PGE2-specific receptor EP4 selectively expresses in rat ductus arteriosus (DA), it is hypothesized that EP4 inhibition would promote DA closure with fewer side-effects.Methods and Results:A new chemical compound EP4 antagonist, RQ-15986 (renamed from CJ-042794), was used. Whether RQ-15986 selectively contracted the DA was examined by measuring the isometric tension of rat DA ex vivo at embryonic day 19 (e19) and e21. RQ-15986 at a dose of 10-6mol/L increased the isometric tension of the DA up to 44.8±6.2% and 69.1±12.9% to the maximal KCl-induced tension at e19 and e21 respectively. The effect of RQ-15986 on rat DA in vivo was also tested by using a rapid whole-body freezing method. RQ-15986 inhibited PGE1-induced DA dilatation in neonatal rats. Furthermore, RQ-15986 contracted the DA in a dose-dependent manner, and the constriction was greater at e21 than at e19. Moreover, RQ-15986 did not contract the aorta or the marginal artery of the colon. CONCLUSIONS: EP4 inhibition contracts rat DA with fewer side-effects. EP4 inhibition is a promising alternative strategy to treat patients with PDA.

In-utero idiopathic ductal constriction: a prenatal manifestation of Alagille and Williams syndrome arteriopathy.

OBJECTIVE: Williams and Alagille syndromes are genetic disorders associated with pathologic arterial narrowing. We hypothesized that fetal idiopathic ductus arteriosus (DA) constriction may represent a prenatal manifestation of the arteriopathy associated with these syndromes. METHODS: Multi-institutional case series review of the pre- and postnatal medical records, echocardiograms, and genetic test results of fetuses presenting with idiopathic DA constriction. RESULTS: We identified four cases of idiopathic fetal DA constriction at 21-36 weeks of gestation. All had right ventricular hypertension, dilation, hypertrophy, and dysfunction and either DA constriction or absence. All demonstrated progressive peripheral pulmonary artery stenosis after birth. Three met clinical diagnostic criteria for Alagille syndrome; two tested had confirmatory JAG1 mutations. One also developed supravalvar aortic stenosis after birth and was positive for 7q11.23 deletion (Williams syndrome). CONCLUSION: This is the first case series to suggest that idiopathic fetal DA constriction may be a prenatal manifestation of genetic arteriopathy.

Transcriptional profiling of the ductus arteriosus: Comparison of rodent microarrays and human RNA sequencing.

DA closure is crucial for the transition from fetal to neonatal life. This closure is supported by changes to the DA's signaling and structural properties that distinguish it from neighboring vessels. Examining transcriptional differences between these vessels is key to identifying genes or pathways responsible for DA closure. Several microarray studies have explored the DA transcriptome in animal models but varied experimental designs have led to conflicting results. Thorough transcriptomic analysis of the human DA has yet to be performed. A clear picture of the DA transcriptome is key to guiding future research endeavors, both to allow more targeted treatments in the clinical setting, and to understand the basic biology of DA function. In this review, we use a cross-species cross-platform analysis to consider all available published rodent microarray data and novel human RNAseq data in order to provide high priority candidate genes for consideration in future DA studies.