Incidence of congenital heart disease in fetuses diagnosed with single isolated umbilical artery. Systematic review and meta-analysis.

OBJECTIVE: To estimate the proportion of heart disease in fetuses with a prenatal diagnosis of a single isolated umbilical artery. METHODS: We performed a search strategy in MEDLINE (OVID), EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to the present. We assessed the risk of bias and performed a meta-analysis. We completed the subgroup analysis according to the region. RESULTS: We found 1384 studies by the search strategy. After carefully reviewing the full-text, 15 studies were included. A total of 2008 fetuses with a single isolated umbilical artery were included, and 177 had cardiac malformations. There was an overall incidence of 9% 95%CI (0.05-0.14) I2 90%. The incidence by country of origin was between 5% and 19%. The most common heart disease reported was a ventricular septal defect. Seven studies were found describing 25 cases. We described other malformations, such as tetralogy of Fallot, coarctation of the aorta, and hypoplastic left ventricle, among others. CONCLUSION: The incidence of congenital heart disease in fetuses with a single isolated umbilical artery was high. In addition, half of these correspond to significant heart disease. Based on the above, we suggest that fetuses with a single isolated umbilical artery should have a complete anatomic evaluation emphasizing cardiac evaluation.

Growth patterns and cardiovascular abnormalities in SGA fetuses: 2. Normal growth and progressive growth restriction.

OBJECTIVES: To characterize growth processes and their associated cardiovascular abnormalities in SGA fetuses with normal growth and progressive growth restriction patterns as defined by Individualized Growth Assessment (IGA). METHODS: A SGA cohort (EFW and BW < 10th percentile) was derived from the PORTO study that included 47 fetuses with normal growth outcome (SGA Normal) and 34 fetuses with progressive growth restriction (SGA Growth Restricted, Pattern 1). Composite fetal size parameters were used to quantify growth pathology at individual third trimester time points (individual composite Prenatal Growth Assessment Score {icPGAS}) and calculated cumulatively during the third trimester (Fetal Growth Pathology Score 1{FGPS1}). Paired Doppler evaluations of the umbilical artery (UA), middle cerebral artery (MCA), ductus venosus (DV) and myocardial performance index (MPI) were used to detect cardiovascular anomalies. Outcome variables were birth age and birth weight. RESULTS: Ranking fetuses with respect to the severity of the 3rd trimester growth pathology (-FGPS1) revealed three subgroups in each of these two groups. In SGA Normal, no (51%), minimal (19%) or minor (30%) growth abnormalities were present. Although vascular flow abnormalities occurred without growth abnormalities (UA: 38%; MCA: 35%), they increased with minor growth disturbances (UA: 64%; MCA: 50%). All fetuses delivered at term and in only 7 cases (minor growth abnormalities subgroup) were the neonates abnormally small based on IGA criteria. In SGA Growth Restricted, Pattern 1, the progression of growth restriction was slow (47%), moderate (21%) and rapid (32%). Corresponding median -FGPS1 values were -1.34%, -2.67% and -4.88%, respectively. The median age of onset was 33.6, 29.7 and 29.7 weeks in these three subgroups. UA abnormalities occurred infrequently in the first two subgroups but were found in all cases of rapidly progressing pathology. Similar results were found for the MCA and DV + MPI Doppler parameters (rapid progression: MCA = 50%; DV + MPI = 50%). Premature delivery occurred less frequently with slow progression but was nearly 100% in the moderately and rapidly progressive subgroups. CONCLUSIONS: Negative FGPS1 growth restriction patterns can be used to classify SGA fetuses. Subgroups, based on ranked -FGPS1 values in both SGA Normal and SGA Growth Restricted Pattern 1 groups had marked differences in cardiovascular abnormalities and neonatal outcomes. The characteristics of these two groups are consistent with small, normally growing fetuses and fetuses with "early" growth restriction, respectively.

Growth patterns and cardiovascular abnormalities in SGA fetuses: 3. Late, adaptive and recovering growth restriction.

OBJECTIVE: To characterize abnormal growth processes and their associated cardiovascular abnormalities in SGA fetuses using Individualized Growth Assessment (IGA). METHODS: This longitudinal investigation utilized a SGA cohort [EFW and BW <10th percentile] derived from the PORTO study. Fetuses categorized by their Fetal Growth Pathology Score [FGPS1] patterns [Pattern 2 {n = 12}, Pattern 3 {n = 11}, Pattern 5 {n = 13}] were evaluated. Growth pathology was measured using the -FGPS1 and the individual composite Prenatal Growth Assessment Score {-icPGAS]. Paired cardiovascular assessments utilized measurements of the Pulsatility Index [umbilical artery {UA}, middle cerebral artery {MCA}, ductus venosus {DV}] and the myocardial performance index [MPI; heart]. Outcome variables were birth age [preterm or, term] and birth weight [small or normal (IGA criteria)]. RESULTS: Pattern 2 was usually characterized by a single, growth abnormality (67% of cases) of variable magnitude that occurred within two weeks of delivery {median onset age: 37.6 weeks}. The incidence of UA abnormalities was low (25%) while those of MCA and DV/MPI were high {60%, 42%}. Most neonates were of normal size (67%) and delivered at term (67%).Pattern 3 had an initial progressive growth restriction phase, followed by constant but abnormally low growth. Growth pathology had an early onset (median age: 31.6 weeks), was moderate but persistently abnormal. The incidences of cardiovascular abnormalities were moderate [30-50%]. Most neonates were abnormally small (80%) but delivered at term (90%).Pattern 5 had an initial progressive phase with an early onset [onset age {median}: 31.6 weeks]. However, this process was arrested and returned toward normal. Growth pathology magnitudes were minor as were the incidences of cardiovascular abnormalities. Neonatal size was usually normal and all fetuses delivered at term. CONCLUSIONS: Characteristics of SGA Growth Restricted, Patterns 2, 3 and 5 are clearly different from those found in SGA Normal or SGA Growth Restricted Pattern 1 groups. They also differed from one another, indicating that growth restriction can manifest itself in several different ways. Pattern 2 is similar to "late" growth restriction reported previously. Patterns 3 and 5 are novel and have been designated as "adaptive" and "recovering" types of growth restriction.

Downregulation of large-conductance Ca2+-activated K+ channels in human umbilical arterial smooth muscle cells in gestational diabetes mellitus.

AIMS: We investigated the changes in large-conductance Ca2+-activated K+ (BKCa) channels from human umbilical arterial smooth muscle cells experiencing gestational diabetes mellitus (GDM). MAIN METHODS: Whole-cell patch-clamp technique, arterial tone measurement, RT-PCR, Quantitative real-time PCR, western blot were performed in human umbilical arterial smooth muscle cells. KEY FINDINGS: Whole-cell BKCa current density was decreased in the GDM group compared with the normal group. The vasorelaxant effects of the synthetic BKCa channel activator NS-1619 (10 µM) were impaired in the GDM group compared with the normal group. Reverse-transcription polymerase chain reaction (RT-PCR), real-time RT-PCR, and western blot analyses suggested that the mRNA, total RNA, and protein expression levels of the BKCa channel were decreased in the GDM group relative to the normal group. In addition, the expression levels of protein kinase A and protein kinase G, which regulate BKCa channel activity, remained unchanged between the groups. Applying the BKCa channel inhibitor paxilline (10 µM) induced vasoconstriction and membrane depolarization of isolated umbilical arteries in the normal group but showed less of an effect on umbilical arteries in the GDM group. SIGNIFICANCE: Our results demonstrate for the first time impaired BKCa current and BKCa channel-induced vasorelaxation activities that were not caused by impaired BKCa channel-regulated protein kinases, but by decreased expression of the BKCa channels, in the umbilical arteries of GDM patients.

Necrotizing Funisitis as an Intrauterine manifestation of Cryopyrin-Associated Periodic Syndrome: a case report and review of the literature.

BACKGROUND: Cryopyrin-associated periodic syndrome (CAPS) is a life-long, autoinflammatory disease associated with a gain-of-function mutation in the nucleotide-binding domain, leucine-rich repeat family, pyrin domain containing 3 (NLRP3) gene, which result in uncontrolled production of IL-1ß and chronic inflammation. Chronic infantile neurologic cutaneous and articular (CINCA) syndrome/neonatal-Onset multisystem inflammatory disease (NOMID) is the most severe form of CAPS. Although the first symptoms may be presented at birth, there are few reports on the involvement of the placenta and umbilical cord in the disease. Therefore, we present herein a preterm case of CINCA/NOMID syndrome and confirms intrauterine-onset inflammation with conclusive evidence by using fetal and placental histopathological examination. CASE PRESENTATION: The female patient was born at 33weeks of gestation by emergency caesarean section and weighted at 1,514 g. The most common manifestations of CINCA/NOMID syndrome including recurrent fever, urticarial rash, and ventriculomegaly due to aseptic meningitis were presented. She also exhibited atypical symptoms such as severe hepatosplenomegaly with cholestasis. The genetic analysis of NLRP3 revealed a heterozygous c.1698 C > G (p.Phe566Leu) mutation, and she was diagnosed with CINCA/NOMID syndrome. Further, a histopathological examination revealed necrotizing funisitis, mainly inflammation of the umbilical artery, along with focal neutrophilic and lymphocytic villitis. CONCLUSIONS: The necrotizing funisitis, which only involved the artery, was an unusual observation for chorioamnionitis. These evidences suggest that foetal inflammation, probably due to overproduction of IL-1ß, caused tissue damage in utero, and the first symptom of a newborn with CINCA/NOMID.

Fetal Urinoma Due to Circulatory Disorders in an Umbilical Artery: Case Report.

Fetal urinoma is defined as an encapsulated accumulation of extravasated urine within the perirenal space or retroperitoneum. It is an uncommon finding in prenatal practice, and the vast majority of known cases are strongly associated with the existence of a urinary obstruction, such as posterior urethral valves, ureteropelvic junction obstruction, or ureterocele. We report a unique case of prenatally detected fetal bladder urinoma that occurred in the absence of an apparent obstructive uropathy, but was associated with extensive ischemic necrosis and calcifications of adjacent bladder wall, coexistent with signs of vascular supply decompensation.

10 cases of umbilical cord thrombosis in the third trimester.

BACKGROUND: Thrombosis of umbilical vessels is a rare occurrence that is difficult to detect during routine antenatal examinations but can lead to poor perinatal outcomes. OBJECTIVE: The aim of this study is to examine the association between meaningful clinical manifestations and features associated with thrombosis of umbilical vessels, and to evaluate optimal management options. METHODS: A retrospective study of umbilical cord thrombi cases enrolled between 2015-2019 was carried out. Data were analyzed from the medical archives where the diagnosis of all cases was established by histopathology. RESULTS: Gross examination reported additional cord abnormalities (7/10), including the irregular length of the umbilical cord, narrowed cord with hyper-coiling, swollen cord with deficiency of Wharton's jelly, placenta velamentous and umbilical infarction. Pathological examination accounted for 10 cases of umbilical cord thrombosis including umbilical artery embolism (3/10), umbilical vein thrombi (5/10) and funisitis (2/10). Clinical findings depicted that the chief complaint was decreased fetal movement companied by nonreactive NST tests (5/10). With the exception of two stillbirths, the remaining pregnancies (8/10) were terminated by cesarean section. All neonates are alive, including one VLBW and three LBW cases. CONCLUSION: We have observed that umbilical structural dysplasia, maternal coagulation disorder, vascular endothelial injury and elevated blood glucose may lead to the formation of thrombosis. Focus on specific signs during a prenatal ultrasound, EFM monitoring and counting fetal movements can help in early identification of umbilical cord thrombi. Our results support the more effective approach of emergency cesarean section during the third trimester.

ABCG1 Attenuates Oxidative Stress Induced by H2O2 through the Inhibition of NADPH Oxidase and the Upregulation of Nrf2-Mediated Antioxidant Defense in Endothelial Cells.

Summary. Oxidative stress is an important factor that is related to endothelial dysfunction. ATP-binding cassette transporter G1 (ABCG1), a regulator of intracellular cholesterol efflux, has been found to prevent endothelial activation in vessel walls. To explore the role of ABCG1 in oxidative stress production in endothelial cells, HUAECs were exposed to H2O2 and transfected with the specific ABCG1 siRNA or ABCG1 overexpression plasmid. The results showed that overexpression of ABCG1 by ABCG1 plasmid or liver X receptor (LXR) agonist T0901317 treatment inhibited ROS production and MDA content induced by H2O2 in HUAECs. Furthermore, ABCG1 upregulation blunted the activity of prooxidant NADPH oxidase and the expression of Nox4, one of the NADPH oxidase subunits. Moreover, the increased migration of Nrf2 from the cytoplasm to the nucleus and antioxidant HO-1 expression were detected in HUAECs with upregulation of ABCG1. Conversely, ABCG1 downregulation by ABCG1 siRNA increased NADPH oxidase activity and Nox4 expression and abrogated the increase at Nrf2 nuclear protein levels. In addition, intracellular cholesterol load interfered with the balance between NADPH oxidase activity and HO-1 expression. It was suggested that ABCG1 attenuated oxidative stress induced by H2O2 in endothelial cells, which might be involved in the balance between decreased NADPH oxidase activity and increased Nrf2/OH-1 antioxidant defense signaling via its regulation for intracellular cholesterol accumulation.

Intermittent absent and reversed umbilical artery flows in appropriately grown monochorionic diamniotic twins in relation to proximate cord insertion: A harmful combination?

OBJECTIVE: To compare the prevalence of intermittent absent or reversed end-diastolic flow (iAREDF) in the umbilical artery in appropriately grown monochorionic diamniotic (MCDA) pregnancies with and without proximate cord insertion (PCI), and to evaluate pregnancy outcome. METHODS: The prevalence of iAREDF in MCDA pregnancies with PCI (n = 11) was compared with a control group without PCI (n = 33). PCI was defined as a distance between the cord insertions below the fifth percentile. Placental sharing, number, and diameter of anastomoses were assessed by placental examination. Pregnancy outcome was evaluated. RESULTS: iAREDF was present in 7/11 PCI pregnancies, compared with 0/33 in the control group (P ≤ .01). All PCI pregnancies and 94% of controls had arterioarterial (AA)-anastomoses (P = .56), the diameter was larger in the PCI group, respectively 3.3 vs 2.1 mm (P = .03). Three cases with iAREDF had adverse outcome, two resulted in fetal death of which one with brain damage in the co-twin, another underwent early premature emergency section for fetal distress. CONCLUSION: iAREDF occurs in a large proportion of MCDA pregnancies with PCI and is related to the diameter of the AA anastomosis. We hypothesize that iAREDF in appropriately grown MCDA twin pregnancies reflects an unstable hemodynamic balance with an increased risk for fetal deterioration. Whether outcome in these pregnancies can be improved by altered management requires further investigation.

Morphology, intrafetal vascular pattern, and umbilical artery Doppler indices of acardiac twins.

BACKGROUND: Twin reversed arterial perfusion (TRAP) sequence consists of acardiac twin (A) paradoxically perfused by pump twin (P) through an umbilical artery (UA). We proposed characterization of acardiac twins with intrafetal vascular pattern (IVP), and assessed its correlation with morphology and UA Doppler indices. METHODS: We prospectively evaluated 21 cases of TRAP sequence. Morphology (acardia vs hemicardia) and IVP (simple vs complex) of acardiac twins were characterized with ultrasound and color Doppler. Twins weight ratio (A/P Wt) and UA Doppler indices of acardiac and pump twins including (1) difference of systolic/diastolic ratio (UA ∆S/D), (2) difference of resistance index (UA ∆RI), and (3) ratio of pulsatility index (UA PI A/P) were calculated. RESULTS: The median (min, max) gestational age at diagnosis was 18 (11, 27) weeks. Acardia (n = 14) were associated with simple IVP (n = 16) (P < .05). After exclusion of acardia with complex IVP (n = 1), the A/P Wt, UA ∆S/D, UA ∆RI, and UA PI A/P of acardia with simple IVP (n = 13), hemicardia with simple IVP (n = 3), and hemicardia with complex IVP (n = 4) were not significantly different (P > .05). CONCLUSIONS: Most of acardiac twins were acardia with simple IVP. Morphology and IVP of acardiac twins were not associated with UA Doppler indices.

Antibody against Na/K-ATPase Inhibitor Lowers Blood Pressure and Increases Vascular Fli1 in Experimental Preeclampsia.

BACKGROUND: Previous studies implicated cardiotonic steroids, including Na/K-ATPase inhibitor marinobufagenin (MBG), in the pathogenesis of preeclampsia (PE). We demonstrated that MBG induces fibrosis via mechanism involving inhibition of Fli1, a nuclear transcription factor and a negative regulator of collagen-1 synthesis. We hypothesized that PE blockade of increased MBG with antibody would lessen the fibrosis of umbilical arteries and lower the blood pressure in rats with PE. METHODS: We tested 36 pregnant Sprague-Dawley rats in which 12 were made hypertensive by 1.8% Na supplementation (days 6-19 of gestation), 12 pregnant rats served controls. At day 19, PE rats received one intraperitoneal injection of polyclonal anti-MBG-4 antibody (0.5 ug/ml) for 4 hours. RESULTS: PE was associated with higher blood pressure (117 ± 2 vs. 107 ± 2 mm Hg; P < 0.01), plasma MBG levels (1.54 ± 0.34 vs. 0.49 ± 0.11 nmol/L; P < 0.01), protein excretion (26 vs. 12 mg/24 hours), sFlt-1 (3-fold), decrease in Fli1 (7-fold) and increase in collagen-1 in aorta (4-fold) vs. control rats (all P < 0.01). In 12 rats treated with polyclonal anti-MBG-4 antibody blood pressure dropped (93 ± 3 mm Hg) and Fli1 was decreased much less (2-fold; P < 0.01 vs. nontreated rats). CONCLUSIONS: These results demonstrate that in experimental PE elevated MBG level is implicated in umbilical fibrosis via suppression of Fli1.

Is umbilical vein varix associated with changes in cerebroplacental ratio?

Objective: We aimed to review a single-center experience in follow-up and management of fetuses with umbilical vein varix (UVV) and to assess the effect of UVV on fetal Doppler parameters.Methods: We reviewed retrospectively maternal antenatal records, delivery records, and newborn records to identify cases of UVV. Further, we retrospectively compared 25 fetuses with isolated UVV and available cerebroplacental ratio (CPR) analysis with 75 matched controls.Results: We identified 67 cases of UVV. The median gestational age (GA) at diagnosis was 34 weeks (range: 26-41 weeks). The average diameter of UVV at diagnosis was 10.1 mm (range: 9-14 mm). The median GA at delivery was 36 + 6 (range: 33-41 weeks), with an average birth weight of 2918 g (range: 1278-4140 g). There was a single case of intrauterine death at 35 weeks. CPR was 2.13 ± 0.62 in isolated UVV group compared with 1.84 ± 0.61 in the control group (p < .05). Other Doppler parameters did not differ between fetuses with UVV compared with controls.Conclusions: CPR was significantly increased in the UVV group compared with control fetuses. This finding suggests that UVV is not associated with chronic fetal oxygen deprivation; it, therefore, may contribute to our understanding of the pathophysiology explaining abnormal pregnancy outcome in cases with UVV.

Umbilical artery thrombosis: Two case reports.

RATIONALE: The umbilical cord is the way to exchange gas, supply nutrients, excrete metabolized. Thrombosis of the umbilical cord leads to fetal hypoxia, which jeopardizes fetal health and can cause fetal death. Umbilical vessel thrombosis, which is rarely reported, is difficult to detect prenatally. PATIENT CONCERNS: Both pregnant women had an unremarkable pregnancy course until a routine ultrasound scan in the third trimester showed a single umbilical artery. However, one umbilical vein and 2 umbilical arteries were seen during an ultrasound examination at 32 weeks. Case 2 had a better pregnancy outcome because of the timely discovery of this complication. DIAGNOSIS: Both cases were diagnosed as umbilical artery thrombosis. INTERVENTIONS: The first patient received no interventions until they reported decreased fetal movements and gradually disappear. The second patient underwent an emergency cesarean section. OUTCOMES: In Case 1, an emergency ultrasound examination showed intrauterine fetal death, and the patient vaginally delivered a stillborn child weighing 3300 g in a day. In Case 2, a female neonate weighing 2860 g was delivered by cesarean section, and exhibited Apgar scores of 10 and 10 at 1 and 5 minutes. CONCLUSION: In the late-term abortions, obstetricians should be vigilant if ultrasound imaging shows suspected umbilical vascular thrombosis or shows 1 umbilical artery when there had previously been 2. The fetus should be closely monitored and interventions implemented as early as possible to improve the prenatal detection rate of umbilical vessel thrombosis and avoid adverse pregnancy outcomes.

Identification of atheroprone shear stress responsive regulatory elements in endothelial cells.

AIMS: Oscillatory shear stress (OSS) is an atheroprone haemodynamic force that occurs in areas of vessel irregularities and is implicated in the pathogenesis of atherosclerosis. Changes in signalling and transcriptional programme in response to OSS have been vigorously studied; however, the underlying changes in the chromatin landscape controlling transcription remain to be elucidated. Here, we investigated the changes in the regulatory element (RE) landscape of endothelial cells under atheroprone OSS conditions in an in vitro model. METHODS AND RESULTS: Analyses of H3K27ac chromatin immunoprecipitation-Seq enrichment and RNA-Seq in primary human umbilical vein endothelial cells 6 h after onset of OSS identified 2806 differential responsive REs and 33 differentially expressed genes compared with control cells kept under static conditions. Furthermore, gene ontology analyses of putative RE-associated genes uncovered enrichment of WNT/HIPPO pathway and cytoskeleton reorganization signatures. Transcription factor (TF) binding motif analysis within RE sequences identified over-representation of ETS, Zinc finger, and activator protein 1 TF families that regulate cell cycle, proliferation, and apoptosis, implicating them in the development of atherosclerosis. Importantly, we confirmed the activation of EGR1 as well as the YAP/TAZ complex early (6 h) after onset of OSS in both cultured human vein and artery endothelial cells and, by undertaking luciferase assays, functionally verified their role in RE activation in response to OSS. CONCLUSIONS: Based on the identification and verification of specific responsive REs early upon OSS exposure, we propose an expanded mechanism of how OSS might contribute to the development of atherosclerosis.

Reference charts for umbilical Doppler pulsatility index in fetuses with isolated two-vessel cord.

PURPOSE: To determine reference values for umbilical Doppler pulsatility index in fetuses with isolated two-vessel cord and to compare these values with standard umbilical Doppler pulsatility index curves from 23 to 40 gestational weeks. METHODS: A retrospective longitudinal cohort study was conducted between January 2014 and December 2017 in a tertiary referral hospital and included 62 pregnant women with isolated single umbilical artery (two-vessel cord) and 174 measurements. Only uncomplicated term pregnancies were included. A reference curve for umbilical Doppler pulsatility index was built up and compared with a standard curve commonly used for fetuses with three-vessel cord. RESULTS: Umbilical Doppler pulsatility index values were much lower than expected in cases with two-vessel cord compared to 3-vessel cord: mean of the regression equations was 1.02 ± 0.23 vs. 0.86 ± 0.19, respectively (p value < 0.001). This difference was quite constant across the gestational weeks considered, showing that the slopes of the two regressions were very similar. CONCLUSION: Reference curves for umbilical Doppler pulsatility index in two-vessel cord pregnancies were determined. Pulsatility index values were significantly different compared with those commonly used for three-vessel cord. Using lower reference values for umbilical pulsatility index in cases with two-vessel cord may allow a better identification of fetuses affected with intrauterine growth restriction, thus improving fetal surveillance.

Antibody to Marinobufagenin Reverses Placenta-Induced Fibrosis of Umbilical Arteries in Preeclampsia.

BACKGROUND: Previous studies implicated cardiotonic steroids, including Na/K-ATPase inhibitor marinobufagenin (MBG), in the pathogenesis of preeclampsia (PE). Immunoneutralization of heightened MBG by Digibind, a digoxin antibody, reduces blood pressure (BP) in patients with PE, and anti-MBG monoclonal antibody lessens BP in a rat model of PE. Recently, we demonstrated that MBG induces fibrosis in cardiovascular tissues via a mechanism involving inhibition of Fli-1, a nuclear transcription factor and a negative regulator of collagen-1 synthesis. OBJECTIVES AND METHODS: We hypothesized that in PE, elevated placental MBG levels are associated with development of fibrosis in umbilical arteries. Eleven patients with PE (mean BP 124 ± 4 mmHg; age 29 ± 2 years; 39 weeks gest. age) and 10 gestational age-matched normal pregnant subjects (mean BP 92 ± 2 mmHg; controls) were enrolled in the clinical study. RESULTS: PE was associated with a higher placental (0.04 ± 0.01 vs. 0.49 ± 0.11 pmol/g; p < 0.01) and plasma MBG (0.5 ± 0.1 vs. 1.6 ± 0.5 nmol/L; p < 0.01), lower Na/K-ATPase activity in erythrocytes (2.7 ± 0.2 vs. 1.5 ± 0.2 µmol Pi/mL/hr; p < 0.01), 9-fold decrease of Fli-1 level and 2.5-fold increase of collagen-1 in placentae (p < 0.01) vs. control. Incubation of umbilical arteries from control patients with 1 nmol/L MBG was associated with four-fold decrease in Fli-1 level and two-fold increase in collagen-1 level vs. those incubated with placebo (p < 0.01), i.e., physiological concentration of MBG mimicked effect of PE in vitro. Collagen-1 abundance in umbilical arteries from PE patients was 4-fold higher than in control arteries, and this PE-associated fibrosis was reversed by monoclonal anti-MBG antibody ex vivo. CONCLUSION: These results demonstrate that elevated placental MBG level is implicated in the development of fibrosis of the placenta and umbilical arteries in PE.

An Ex Vivo Vessel Injury Model to Study Remodeling.

OBJECTIVE: Invasive coronary interventions can fail due to intimal hyperplasia and restenosis. Endothelial cell (EC) seeding to the vessel lumen, accelerating re-endothelialization, or local release of mTOR pathway inhibitors have helped reduce intimal hyperplasia after vessel injury. While animal models are powerful tools, they are complex and expensive, and not always reflective of human physiology. Therefore, we developed an in vitro 3D vascular model validating previous in vivo animal models and utilizing isolated human arteries to study vascular remodeling after injury. APPROACH: We utilized a bioreactor that enables the control of intramural pressure and shear stress in vessel conduits to investigate the vascular response in both rat and human arteries to intraluminal injury. RESULTS: Culturing rat aorta segments in vitro, we show that vigorous removal of luminal ECs results in vessel injury, causing medial proliferation by Day-4 and neointima formation, with the observation of SCA1+ cells (stem cell antigen-1) in the intima by Day-7, in the absence of flow. Conversely, when endothelial-denuded rat aortae and human umbilical arteries were subjected to arterial shear stress, pre-seeding with human umbilical ECs decreased the number and proliferation of smooth muscle cell (SMC) significantly in the media of both rat and human vessels. CONCLUSION: Our bioreactor system provides a novel platform for correlating ex vivo findings with vascular outcomes in vivo. The present in vitro human arterial injury model can be helpful in the study of EC-SMC interactions and vascular remodeling, by allowing for the separation of mechanical, cellular, and soluble factors.

Catheter-Related Arterial Thrombosis in Neonates and Children: A Systematic Review.

Catheter-related arterial thrombosis (CAT) is increasingly recognized in children. Available data are scarce and based on expert opinions. This systematic review aimed to identify knowledge on paediatric CAT. Among 3,484 publications, 22 met inclusion criteria. Fourteen reported on CAT due to umbilical arterial catheter (UAC), two to extremity indwelling catheter (EIC), one to both and five to cardiac catheter (CC). The overall cumulative incidence of CAT was 21% (95% confidence interval [CI], 13-31) with a relative incidence of 20% (95% CI, 10-33) for UAC and 11% (95% CI, 3-21) for CC-related CAT. The incidence of EIC-related CAT ranged from 3.4 to 63%. Clinical presentation of CAT included symptoms of acute limb ischaemia (79%, 95% CI, 54-97), arterial hypertension (55%, 95% CI, 23-86) and congestive heart failure (28%, 95% CI, 7-53). Underlying conditions of UAC-related CAT included prematurity (70%, 95% CI, 31-98), respiratory distress syndrome (56%, 95% CI, 46-65), asphyxia (41%, 95% CI, 15-69), infection (32%, 95% CI, 13-55), persistent ductus arteriosus (28%, 95% CI, 13-45), meconium aspiration (16%, 95% CI, 8-25) and congenital heart disease (9%, 95% CI, 2-19). Congenital heart disease was the likely condition in EIC- and CC-related CAT. Antithrombotic treatment included thrombolysis (71%, 95% CI, 47-91), heparin (70%, 95% CI, 41-94) and thrombectomy (46%, 95% CI, 10-95) alone or in combination. Complete resolution rate of CAT was 82% (95% CI, 65-96). Long-term complications included arterial hypertension (26%, 95% CI, 0-66) and limb amputation (12%, 95% CI, 1-31). The overall all-cause mortality rate was 7% (95% CI, 2-14). In conclusion, CAT occurs at an increased incidence in neonates and children and is potentially associated with poor outcome. However, limited data are available on paediatric CAT. This systematic review identifies the rationale for further studies on CAT in paediatric patients.