Trends in Ductus Arteriosus Stent Versus Blalock-Taussig-Thomas Shunt Use and Comparison of Cost, Length of Stay, and Short-Term Outcomes in Neonates With Ductal-Dependent Pulmonary Blood Flow: An Observational Study Using the Pediatric Health Information Systems Database.

BACKGROUND: The modified Blalock-Taussig-Thomas shunt is the gold standard palliation for securing pulmonary blood flow in infants with ductal-dependent pulmonary blood flow. Recently, the ductus arteriosus stent (DAS) has become a viable alternative. METHODS AND RESULTS: This was a retrospective multicenter study of neonates ≤30 days undergoing DAS or Blalock-Taussig-Thomas shunt placement between January 1, 2017 and December 31, 2020 at hospitals reporting to the Pediatric Health Information Systems database. We performed generalized linear mixed-effects modeling to evaluate trends in intervention and intercenter variation, propensity score adjustment and inverse probability weighting with linear mixed-effects modeling to analyze length of stay and cost of hospitalization, and generalized linear mixed modeling to analyze differences in 30-day outcomes. There were 1874 subjects (58% male, 61% White) from 45 centers (29% DAS). Odds of DAS increased with time (odds ratio [OR] 1.23, annually, P<0.01 [95% CI, 1.10-1.38]) with significant intercenter variation (median OR, 3.81 [95% CI, 2.74-5.91]). DAS was associated with shorter hospital length of stay (ratio of geometric means, 0.76 [95% CI, 0.63-0.91]), shorter intensive care unit length of stay (ratio of geometric means, 0.77 [95% CI, 0.61-0.97]), and less expensive hospitalization (ratio of geometric means, 0.70 [95% CI, 0.56-0.87]). Intervention was not significantly associated with odds of 30-day transplant-free survival (OR,1.18 [95% CI, 0.70-1.99]) or freedom from catheter reintervention (OR, 1.02 [95% CI, 0.65-1.58]), but DAS was associated with 30-day freedom from composite adverse outcome (OR, 1.51 [95% CI, 1.11-2.05]). CONCLUSIONS: Use of DAS is increasing, but there is variability across centers. Though odds of transplant-free survival and reintervention were not significantly different after DAS, and DAS was associated with shorter length of stay and lower in-hospital costs.

Effect of phototherapy on the ductus arteriosus diameter in extremely premature infants: A randomised controlled trial.

Patent ductus arteriosus (PDA) is a common complication among preterm infants (especially birth weight < 1000 g) and is closely associated with mortality and morbidity. Phototherapy (PT) is frequently used in the treatment of jaundice in premature infants in the first week of life. The relationship between PT and PDA has been investigated in a small number of studies but has not been fully elucidated because the studies had varying results. AIM: To examine the effect of PT on parameter (DA diameter, left atrial/aortic root ratio) in premature infants. METHODS: The study was planned as a prospective, randomised, double-blind study. A total of 83 infants <1000 g and < 30 weeks of gestation were included, and they were divided into two groups: the non-shielded and shielded groups. The babies included in the study were evaluated with a Doppler echocardiogram before and after PT. RESULTS: The hemodynamically significant PDA (hs-PDA) and left atrial/aortic root ratio significantly decreased in the shielded group, and the need for treatment due to PDA was significantly lower. The PT times of both groups were similar. CONCLUSION: Shielding application decreases the rate and severity of hs-PDA in extremely premature babies receiving PT.

Congenital heart disease: addressing the need for novel lower-risk percutaneous interventional strategies.

INTRODUCTION: With the advent of improved neonatal care, increasingly vulnerable higher-risk patients with complex congenital heart anomalies are presenting for intervention. This group of patients will always have a higher risk of an adverse event during a procedure but by recognizing this risk and with the introduction of risk scoring systems and thus the development of novel lower risk procedures, the rate of adverse events can be reduced. AREA COVERED: This article reviews risk scoring systems for congenital catheterization and demonstrates how they can be used to reduce the rate of adverse events. Then, novel low risk strategies are discussed for low-weight infants e.g. patent ductus arteriosus (PDA) stent insertion; premature infants e.g. PDA device closure; and transcatheter pulmonary valve replacement. Finally, how risk is assessed and managed within the inherent bias of an institution is discussed. EXPERT OPINION: There has been a remarkable improvement in the rate of adverse events in congenital cardiac interventions, but now, as the benchmark of mortality rate is switched to morbidity and quality of life, continued innovation into lower risk strategies and understanding the inherent bias when assessing risk will be key to continuing this improvement.

Blalock-Taussig Shunt versus Ductal Stenting as Palliation for Duct-Dependent Pulmonary Circulation.

Objectives: There is limited data published from outside North America and Europe comparing the outcomes of a modified Blalock-Taussig shunt (MBTS) and ductal stenting as the first palliative procedure for infants with duct-dependent pulmonary circulation. This study reports the National Heart Center's, in Muscat, Oman, experience in comparing the outcomes of these 2 interventions. Methods: This retrospective study included all infants with duct-dependent pulmonary circulation who received either a MBTS or ductal stenting from 2016-2019. The primary outcomes were death or re-interventions. Secondary outcomes included death, subsequent re-interventions, survival to subsequent surgical intervention, survival to hospital discharge, post-procedural mechanical ventilation and duration of intensive care unit stay. Results: A total of 71 patients were included in the study, 33 (46%) of whom received ductal stenting. The prevalence of the primary outcome (death or re-intervention) in the patent ductus arteriosus (PDA) stent group was 54.5% versus 31.6% in the MBTS group but this was not statistically significant (P = 0.06). There was no difference between the 2 groups in terms of time to next surgical intervention (P = 0.233). The PDA stent group had shorter post-procedural, mechanical ventilation and intensive care unit stay durations (P <0.05). Syndromic patients were at higher risk of mortality compared to non-syndromic patients. Conclusion: MBTS and ductal stenting are both acceptable modalities as a palliative intervention for infants with duct-dependant pulmonary circulation. Syndromic patients are at higher risk of mortality. This can be considered an important factor for patient selection.

Early Amino Acids in Extremely Preterm Infants and Neurodisability at 2 Years.

BACKGROUND: Whether higher parenteral amino acid intake improves outcomes in infants with extremely low birth weight is unclear. METHODS: In this multicenter, parallel-group, double-blind, randomized, placebo-controlled trial, we assigned infants with birth weights of less than 1000 g at 8 neonatal intensive care units to receive amino acids at a dose of 1 g per day (intervention group) or placebo in addition to usual nutrition for the first 5 days after birth. The primary outcome was survival free from neurodisability as assessed with the Bayley Scales of Infant and Toddler Development and neurologic examination at 2 years, corrected for gestational age at birth. Secondary outcomes were the components of the primary outcome as well as the presence or absence of neonatal disorders, the rate of growth, and nutritional intake. RESULTS: We enrolled 434 infants (217 per group) in this trial. Survival free from neurodisability was observed in 97 of 203 children (47.8%) in the intervention group and in 102 of 205 (49.8%) in the placebo group (adjusted relative risk, 0.95; 95% confidence interval [CI], 0.79 to 1.14; P = 0.56). Death before the age of 2 years occurred in 39 of 217 children (18.0%) in the intervention group and 42 of 217 (19.4%) in the placebo group (adjusted relative risk, 0.93; 95% CI, 0.63 to 1.36); neurodisability occurred in 67 of 164 children (40.9%) in the intervention group and 61 of 163 (37.4%) in the placebo group (adjusted relative risk, 1.16; 95% CI, 0.90 to 1.50). Neurodisability was moderate to severe in 27 children (16.5%) in the intervention group and 14 (8.6%) in the placebo group (adjusted relative risk, 1.95; 95% CI, 1.09 to 3.48). More children in the intervention group than in the placebo group had patent ductus arteriosus (adjusted relative risk, 1.65; 95% CI, 1.11 to 2.46). In a post hoc analysis, refeeding syndrome occurred in 42 of 172 children in the intervention group and 26 of 166 in the placebo group (adjusted relative risk, 1.64; 95% CI, 1.09 to 2.47). Eight serious adverse events occurred. CONCLUSIONS: In infants with extremely low birth weight, extra parenteral amino acids at a dose of 1 g per day for 5 days after birth did not increase the number who survived free from neurodisability at 2 years. (Funded by the New Zealand Health Research Council and others; ProVIDe Australian New Zealand Clinical Trials Registry number, ACTRN12612001084875.).

Interventions to prevent hypothermia in extremely preterm low-weight infants undergoing cardiac catheterisation.

BACKGROUND: In January 2019, a new device called the Amplatzer Piccolo Occluder was approved by the US Food and Drug Administration for percutaneous closure of patent ductus arteriosus in infants weighing more than 700 g and of postnatal age more than 3 days. Premature low-weight infants are predisposed to hypothermia when transported outside of the thermo-neutral environment. At our institution, 90% of extremely preterm low-weight infants developed transient moderate hypothermia in the cardiac catheterisation suite. METHODS: We conducted a study testing multiple hypotheses aimed at preventing hypothermia in the cardiac catheterisation suite. Interventions included increasing ambient room temperature, reducing exposure to cold environment and reducing overall time spent in the remote location. The primary outcome was the proportion of patients who developed transient hypothermia at the start of the procedure in the cardiac catheterisation suite. The secondary measures included mean core body temperature at four different instances, as well as anaesthesia time, procedure time and radiation exposure. RESULTS: During the study period, 10 patients were enrolled in each group. The postintervention group saw a reduction in transient hypothermia from 90% to 40% (absolute risk reduction 50%, p=0.02). Data analysis showed an improvement in mean core body temperature (35.4°C vs 36.4°C, p<0.01) as well as a smaller percentage drop in temperature (4% vs 1.3%, p<0.01) between the two groups, both of which were statistically significant. The anaesthesia time, procedure time and radiation exposure reduced between the two groups. CONCLUSION: The application of the interventions reduced hypothermia in this high-risk population. The implementation of a protocol with collaboration of a multidisciplinary team is indispensable in providing optimal care to extremely preterm infants.

Horn-shaped" deformity of the Occlutech®-PDA device: case report / [Deformidad en "forma de claxon" del dispositivo Occlutech-PDA.]

Background: The phenomenon of deformation of devices for closure of intracardiac defects in catheterization has been reported, but not of devices for closure of patent ductus arteriosus. Objective: to report a case of deformation of a relatively new type of device for closure of patent ductus arteriosus. Methods: report an adult with hypertensive patent ductus arteriosus and a positive balloon occlusion test will be presented, in whom the occlusion was attempted with an Occlutech®-PDA device. Results: Upon delivery, the device took the shape of a "horn" instead of a "champagne cork" (usual appearance), so it was extracted prior to it is release and the procedure was carried out with another device. Conclusion: To our knowledge, no deformation during the delivery transcatheter of the Occlutech®-PDA device has been published. Adverse events related to new technologies, as in our case, should be reported as soon as possible, since it can help manufacturers to improve their quality and provide greater safety to patients.

Introducción: Existen comunicados sobre el fenómeno de la deformación de dispositivos oclusores de defectos intracardíacos durante el cateterismo, pero no acerca de los dispositivos oclusores para el conducto arterioso persistente. Objetivo: comunicar un caso de deformación de un relativamente nuevo tipo de dispositivo oclusor de conducto arterioso persistente. Método: se presenta un paciente adulto con conducto arterioso persistente hipertensivo y prueba de oclusión con balón positiva, en quien se intentó ocluirle con un dispositivo Occlutech®-PDA. Resultado: al momento de la entrega, el dispositivo adoptó la "forma de claxon" en lugar de "corcho de champagne" (apariencia habitual), motivo por el que fue retirado previo a su liberación y el procedimiento fue llevado a cabo con otro dispositivo. Conclusión: hasta donde conocemos, no hay comunicados acerca de deformación del dispositivo Occlutech®-PDA durante su implante mediante cateterismo. Los eventos adversos relacionados a nuevas tecnologías, como el presentado en este caso, deben ser comunicados tan pronto como sea posible, ya que esto puede ayudar a los fabricantes a mejorar su calidad y proveer mayor seguridad a los pacientes.

Mouse models of patent ductus arteriosus (PDA) and their relevance for human PDA.

The ductus arteriosus (DA) is a unique fetal vascular shunt, which allows blood to bypass the developing lungs in utero. After birth, changes in complex signaling pathways lead to constriction and permanent closure of the DA. The persistent patency of the DA (PDA) is a common disorder in preterm infants, yet the underlying causes of PDA are not fully defined. Although limits on the availability of human DA tissues prevent comprehensive studies on the mechanisms of DA function, mouse models have been developed that reveal critical pathways in DA regulation. Over 20 different transgenic models of PDA in mice have been described, with implications for human DA biology. Similarly, we enumerate 224 human single-gene syndromes that are associated with PDA, including a small subset that consistently feature PDA as a prominent phenotype. Comparison and functional analyses of these genes provide insight into DA development and identify key regulatory pathways that may serve as potential therapeutic targets for the management of PDA.

Cardiovascular changes during phototherapy in newborns.

Phototherapy is the most effective non-invasive method of neonatal hyperbilirubinemia treatment. Application of this method can be associated with side effects including changes in the cardiovascular system. During phototherapy, the primary effects in the cardiovascular system include cutaneous vasodilation leading to skin hyperperfusion and subsequent redistribution of blood. The increased blood flow through the skin is associated with increased transepidermal water loss. Further effects include an increase in cerebral blood flow. Redistribution of blood to the cutaneous bed is compensated by hypoperfusion in the splanchnic area (mostly postprandial) and a significant reduction of the renal blood flow. Regarding closure/reopening of the ductus arteriosus, the results suggest that that phototherapy does not affect ductal patency. During phototherapy the cardiac output can be slightly reduced due to a decreased stroke volume, especially in preterm newborns. Systemic blood pressure is decreased and heart rate is elevated in both preterm and term newborns during phototherapy. The heart rate variability is slightly reduced. Symbolic dynamics analysis of the short-term HRV showed that during phototherapy the activity of the ANS regulating the heart rate is shifted towards the dominancy of the sympathetic activity. The responses in the cardiovascular system of premature/mature newborns without other pathology confirm a well physiologically functioning control of this system, even under specific conditions of phototherapy.

Artificial intelligence model comparison for risk factor analysis of patent ductus arteriosus in nationwide very low birth weight infants cohort.

Despite the many comorbidities and high mortality rate in preterm infants with patent ductus arteriosus (PDA), therapeutic strategies vary depending on the clinical setting, and most studies of the related risk factors are based on small sample populations. We aimed to compare the performance of artificial intelligence (AI) analysis with that of conventional analysis to identify risk factors associated with symptomatic PDA (sPDA) in very low birth weight infants. This nationwide cohort study included 8369 very low birth weight (VLBW) infants. The participants were divided into an sPDA group and an asymptomatic PDA or spontaneously close PDA (nPDA) group. The sPDA group was further divided into treated and untreated subgroups. A total of 47 perinatal risk factors were collected and analyzed. Multiple logistic regression was used as a standard analytic tool, and five AI algorithms were used to identify the factors associated with sPDA. Combining a large database of risk factors from nationwide registries and AI techniques achieved higher accuracy and better performance of the PDA prediction tasks, and the ensemble methods showed the best performances.

Cardiac anomalies associated with Escobar syndrome: A case report and a review of the literature.

RATIONALE: Escobar syndrome (ES) is an autosomal recessive disorder. It is highly characterized by facial abnormalities, congenital diaphragmatic muscle weakness, myasthenic-like features, and skin pterygiums on multiple body legions. ES is a rare condition associated with many external and internal abnormalities. The internal malformations described in ES affect many organs including the heart, lungs, esophagus, liver, spleen, and intestine. The purpose of this paper is to explore the cardiac manifestations associated with ES. PATIENT CONCERNS: A 3.5-year-old girl, who was born for double first cousins, was admitted to the hospital for neuromuscular evaluation of multiple congenital contractures. DIAGNOSIS: The girl was diagnosed with ES and isolated dextrocardia which is a rare cardiac manifestation. However, to the best of our knowledge, no similar cases have been reported to date, and this case is thus believed to be very rare. INTERVENTIONS: The patient underwent an operative intervention to correct the bilateral fixed flexion deformity at her knees which was related to the posterior bilateral fibrotic bands/pterygia. OUTCOMES: Post-operatively, complete knee extension was obtained, the patient was fitted with a cast and extension night splint. She was discharged alive and had no complications. The patient was followed regularly in the orthopedic clinic and had periodic physiotherapy sessions. CONCLUSIONS: ES and isolated dextrocardia concurrence in the presented case resulted from different pathogenic mechanisms. Our findings suggest that ES might be caused by dysfunction in the acetylcholine receptor throughout fetal life, which may have affected muscle strength and movement. Other cardiac conditions include hypoplastic left-sided heart, Hypertrophic cardiomyopathy, patent ductus arteriosus, and heterotaxia.

The molecular mechanisms of oxygen-sensing in human ductus arteriosus smooth muscle cells: A comprehensive transcriptome profile reveals a central role for mitochondria.

The ductus arteriosus (DA) connects the fetal pulmonary artery and aorta, diverting placentally oxygenated blood from the developing lungs to the systemic circulation. The DA constricts in response to increases in oxygen (O2) with the first breaths, resulting in functional DA closure, with anatomic closure occurring within the first days of life. Failure of DA closure results in persistent patent ductus arteriosus (PDA), a common complication of extreme preterm birth. The DA's response to O2, though modulated by the endothelium, is intrinsic to the DA smooth muscle cells (DASMC). DA constriction is mediated by mitochondrial-derived reactive oxygen species, which increase in proportion to arterial partial pressure of oxygen (PaO2). The resulting redox changes inhibit voltage-gated potassium channels (Kv) leading to cell depolarization, calcium influx and DASMC constriction. To date, there has not been an unbiased assessment of the human DA O2-sensors using transcriptomics, nor are there known molecular mechanisms which characterize DA closure. DASMCs were isolated from DAs obtained from 10 term infants at the time of congenital heart surgery. Cells were purified by flow cytometry, negatively sorting using CD90 and CD31 to eliminate fibroblasts or endothelial cells, respectively. The purity of the DASMC population was confirmed by positive staining for α-smooth muscle actin, smoothelin B and caldesmon. Cells were grown for 96 h in hypoxia (2.5% O2) or normoxia (19% O2) and confocal imaging with Cal-520 was used to determine oxygen responsiveness. An oxygen-induced increase in intracellular calcium of 18.1% ± 4.4% and SMC constriction (-27% ± 1.5% shortening) occurred in all cell lines within five minutes. RNA sequencing of the cells grown in hypoxia and normoxia revealed significant regulation of 1344 genes (corrected p < 0.05). We examined these genes using Gene Ontology (GO). This unbiased assessment of altered gene expression indicated significant enrichment of the following GOterms: mitochondria, cellular respiration and transcription. The top regulated biologic process was generation of precursor metabolites and energy. The top regulated cellular component was mitochondrial matrix. The top regulated molecular function was transcription coactivator activity. Multiple members of the NADH-ubiquinone oxidoreductase (NDUF) family are upregulated in human DASMC (hDASMC) following normoxia. Several of our differentially regulated transcripts are encoded by genes that have been associated with genetic syndromes that have an increased incidence of PDA (Crebb binding protein and Histone Acetyltransferase P300). This first examination of the effects of O2 on human DA transcriptomics supports a putative role for mitochondria as oxygen sensors.

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.

Association between intrauterine growth restriction and patent ductus arteriosus: Use of a dichorionic twin pregnancy model.

OBJECTIVE: To evaluate the association between intrauterine growth restriction (IUGR) and the incidence of fetuses with patent ductus arteriosus (PDA) and Hemodynamically significant PDA (Hs-PDA) in dichorionic twins (DC) with selective IUGR. MATERIALS AND METHODS: This is an observational cohort study and retrospective case assessment, involved twins born at Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan between 2013 and 2018. DC twins with selective IUGR (sIUGR) were defined as the presence of a birth weight discordance of >25% and a smaller twin with a birth weight below the tenth percentile. PDA was diagnosed using echocardiography between postnatal day 3 and 7. Hs-PDA was defined as PDA plus increased pulmonary circulation, poor systemic perfusion, cardiomegaly, pulmonary edema, or hypotension requiring pharmacotherapeutic intervention. RESULT: A total of 1187 twins were delivered during the study period, and 53 DC twins with selective IUGR were included in this study. DC twins with PDA have higher rate of preterm birth, lower gestational age of delivery, and lower mean birth weight of both twins compared with DC twins without PDA. In a comparison of the sIUGR twin with the appropriate for gestational age co-twin, both the incidences of PDA (28.30% vs. 7.55%, respectively; P = 0.003) and Hs-PDA (24.53% vs. 5.66%, respectively; P = 0.002) were higher in sIUGR fetuses than in the appropriate for gestational age co-twins. Small gestational age of delivery was the only variable to predict PDA and Hs-PDA [p = 0.002, Odds ratio = 0.57 (0.39-0.82), p = 0.009, Odds ratio = 0.71 (0.55-0.92), respectively]. CONCLUSION: An analysis of dichorionic twins with sIUGR indicated that IUGR increased the risk of PDA and hemodynamically significant PDA.

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.

Trans-Catheter Closure of Patent Ductus Arteriosus, which device should we use?

Despite the operational experience in the percutaneous closure of Patent ductus arteriosus (PDA), complications can arise during the procedure. To overcome these complications the choice of the device must be adapted to each patient. AIM: To report the experience of the cardiology department in the transcatheter device closure of PDA and to determine the influencing factors of choice of the device. METHODS: Our study included patients with patent ductus arteriosus that are admitted for transcatheter closure, between September 2003 and June 2016. RESULT: One hundred and fifty-three patients were included in our study. Transcatheter closure was not done in 9 cases. The transcatheter closure was successful in 140 patients. The complications were observed in 11 patients that includes device embolization in 3 cases, aortic protrusion in four cases pulmonary protrusion in three cases and inguinal hematoma in one another. Three predictive factors of complications were: age < 2 years, tubular PDA type C and ratio duct diameter/weight > 0.95. A mild residual shunt was observed at the end of the procedure in 22.85 % of the patients. The risk of residual shunt was significantly increased when the age < 2 years, the large PDA, the presence of pulmonary hypertension and the tubular C PDA. CONCLUSION: The choice of the device depends essentially on age, the weight and the duct anatomy.

Proteomics analysis of plasma protein changes in patent ductus arteriosus patients.

OBJECTIVE: Patent ductus arteriosus (PDA) is a congenital heart defect with an unclear etiology that occurs commonly among newborns. Adequately understanding the molecular pathogenesis of PDA can contribute to improved treatment and prevention. Plasma proteins may provide evidence to explore the molecular mechanisms of abnormal cardiac development. METHODS: Isobaric tags for relative and absolute quantitation (iTRAQ) proteomics technology was used to measure different plasma proteins in PDA patients (n = 4) and controls (n = 4). The candidate protein was validated by ELISA and Western blot (WB) assays in a larger sample. Validation of the location and expression of this protein was performed in mouse heart sections. RESULTS: There were three downregulated proteins and eight upregulated proteins identified in the iTRAQ proteomics data. Among these, protein disulfide-isomerase A6 (PDIA6) was further analyzed for validation. The plasma PDIA6 concentrations (3.2 ± 0.7 ng/ml) in PDA patients were significantly lower than those in normal controls (5.8 ± 1.2 ng/ml). In addition, a WB assay also supported these results. PDIA6 was widely expressed in mouse heart outflow tract on embryonic day 14.5. CONCLUSION: Plasma proteomics profiles suggested novel candidate molecular markers for PDA. The findings may allow development of a new strategy to investigate the mechanism and etiology of PDA.

Early neurobehavior at 30 weeks postmenstrual age is related to outcome at term equivalent age.

AIMS: To determine 1) the relationship between infant medical factors and early neurobehavior, and 2) the relationship between early neurobehavior at 30 weeks postmenstrual age (PMA) and neurobehavior at term equivalent age. STUDY DESIGN: In this prospective longitudinal study, 88 very preterm infants born ≤30 weeks estimated gestational age (EGA) had neurobehavioral assessments at 30 weeks PMA using the Premie-Neuro and at term equivalent age using the NICU Network Neurobehavioral Scale (NNNS) and Hammersmith Neonatal Neurological Evaluation (HNNE). RESULTS: Lower Premie-Neuro scores at 30 weeks PMA were related to being more immature at birth (p = 0.01; ß = 3.87); the presence of patent ductus arteriosus (PDA; p < 0.01; ß = -16.50) and cerebral injury (p < 0.01; ß = -20.46); and prolonged exposure to oxygen therapy (p < 0.01; ß = -0.01), endotracheal intubation (p < 0.01; ß = -0.23), and total parenteral nutrition (p < 0.01; ß = -0.35). After controlling for EGA, PDA, and number of days of endotracheal intubation, lower Premie-Neuro scores at 30 weeks PMA were independently related to lower total HNNE scores at term (p < 0.01; ß = 0.12) and worse outcome on the NNNS with poorer quality of movement (p < 0.01; ß = 0.02) and more stress (p < 0.01; ß = -0.004), asymmetry (p = 0.01; ß = -0.04), excitability (p < 0.01; ß = -0.05) and suboptimal reflexes (p < 0.01; ß = -0.06). CONCLUSION: Medical factors were associated with early neurobehavioral performance at 30 weeks PMA. Early neurobehavior at 30 weeks PMA was a good marker of adverse neurobehavior at NICU discharge.

Do Calcium and Potassium Levels Influence Ductal Patency in Preterm Infants?

OBJECTIVE: We investigated the relationship of serum potassium (K+) and ionized calcium (iCa2+) levels with the persistence of ductus arteriosus. STUDY DESIGN: This retrospective cohort study included infants with birth weight < 1,500 g and gestational age < 32 weeks. Serum K+ and iCa2+ levels at the 1st and 48th hour of life were measured from samples. The difference between the two levels was calculated for both serum K+ (ΔK+) and iCa2+ (ΔCa2+). These values were compared between hemodynamically significant patent ductus arteriosus (hsPDA) and non-hsPDA. RESULTS: Of 1,322 hospitalized preterm nonates, 1,196 were included in the study. Mean serum K+ levels at the 1st and 48th hour were higher and iCa2+ levels at the 1st and 48th hour were lower in hsPDA and non-hsPDA, respectively (p < 0.001). Ionized ΔCa2+ (-0.06 ± 0.13 vs. -0.02 ± 0.12 mmol/L) was higher in hsPDA (p < 0.001). CONCLUSION: We demonstrated that serum K+ and iCa2+ level might play a role in ductal constriction.