Cause Of Persistent Pulmonary Hypertension Research Articles

Alveolar capillary dysplasia with misalignment of pulmonary veins in a premature newborn: the role of lung ultrasound

BackgroundAlveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a lethal neonatal lung disorder characterized by the decrease of the alveolar units, abnormalities in the air–blood barrier of the lung, and impaired gas exchange. Typically, it affects a full-term newborn; the symptoms usually start within a few hours after birth, resulting in severe respiratory distress and pulmonary hypertension. In most of the cases, this disorder is refractory to conventional pulmonary support.Case presentationWe report a case of a newborn male of 29 weeks gestational age, with birth weight of 850 g and intrauterine growth restriction. Severe respiratory distress appeared a few minutes after birth; non-invasive ventilatory support was provided in the delivery room and, as a consequence of persistent respiratory failure, he was admitted to the neonatal intensive care unit (NICU) where mechanical ventilation was required.Due to the symptoms and pulmonary ultrasound pattern suggestive of respiratory distress syndrome, surfactant treatment was administered. Lung ultrasound (LU) was used for monitoring the responsiveness to surfactant; severe pulmonary hypertension ensued, followed by respiratory failure, refractory shock, and death within 48 h.Owing to the poor response to the established therapy, ACD/MPV was suspected. The diagnosis was confirmed through autopsy. The main goal of this case report is to show the role of LU for monitoring the evolution of this disorder.ConclusionLU could provide essential information to help diagnose and follow-up the underlying cause of persistent pulmonary hypertension of the newborn in an earlier and more effective way than chest X-ray. LU is suitable for routine monitoring of lung disease in the NICU.

Effects of inhaled nitric oxide (iNO) in pulmonary hypertension secondary to arteriovenous malformations: a retrospective cohort study from the European iNO registry

This study aims to assess the effects of inhaled nitric oxide (iNO) on oxygenation in the management of pulmonary hypertension (PH) secondary to arteriovenous malformations (AVMs) in neonates. This is a matched retrospective cohort study from January 1, 2013, to December 31, 2017. The European inhaled nitric oxide registry from 43 neonatal and pediatric ICUs in 13 countries across Europe was used to extract data. The target population was neonates treated with iNO for the management of PH. The cases (PH secondary to AVMs treated with iNO) were matched (1:4 ratio) to controls (PH without AVMs treated with iNO). The main outcome measure was the absolute change of oxygenation index (OI) from baseline to 60 min after starting iNO in cases and controls. The primary outcome of our study was that the mean absolute change in OI from baseline to after 60 min was higher among cases 10.7 (14), than in controls 6 (22.5), and was not statistically different between the groups. The secondary outcome variable — death before discharge — was found to be significantly higher in cases (55%) than in controls (8%). All the other variables for secondary outcome measures remained statistically insignificant. Conclusion: Infants with PH secondary to AVMs treated with iNO did not respond differently compared to those presented with PH without AVMs treated with iNO. Right ventricular dysfunction on echocardiography was higher in cases than controls (cases: 66.7% and controls: 28.6%) but was not statistically significant.What is Known:• Arterioenous malformation (AVM) is a well-known cause of persistent pulmonary hypertension in newborns. Inhaled nitric oxide (iNO) is most commonly used as first-line therapy for pulmonary hypertension in newborns.• Around 40–50% of vein of Galen malformations (VOGMs) are found to have congestive heart failure in the neonatal period.What is New:• Neonates may present with an isolated PH of the newborn as the main feature of the VOGMs. A large proportion of cases with AVMs have been associated with right ventricular cardiac dysfunction. • Results from one of the largest database registries in the world for iNO have been used to answer our research question.

Application of laser scanning cytometry in vascular smooth muscle remodeling.

Pulmonary artery hyperplasia is the result of proliferation of the pulmonary arterial smooth muscles (PASM). Hypoxia-induced PASM proliferation in the fetus and the newborn is the primary cause of persistent pulmonary hypertension of the newborn (PPHN). This study was performed to characterize the utility of the Laser Scanning Cytometry (LSC) method in elucidating arterial cytoskeletal remodeling in an in vitro model of PPHN. The aim was to demonstrate the following: (a) LSC is a valid method for the analysis of nuclear and cytosolic fluorescence and (b) the cumulative effects of mechanical stretch together with hypoxia promote reactive oxygen species (ROS) formation. The molecular events in response to hypoxia and the mechanical overload of the pulmonary circuit were demonstrated in vitro by subjecting hypoxic cultured primary PASM or human airway smooth muscles (hASM) to repetitive stretch-relaxation cycles at rates comparable to dynamic stretch in vivo. The altered cytoskeleton in the form of filamentous to globular actin (F:G actin) ratio was imaged and quantified at the cellular level by LSC as an endpoint. LSC can remove the nuclear G-actin fluorescence from the total G-actin fluorescence. Pulsatile stretch was found to significantly increase the total endogenous ROS and superoxide anion release in normoxic and hypoxic conditions in primary PASM fibers. The effect of stretch was predominant in increasing superoxide anion release, only under hypoxic conditions. These findings, obtained by LSC in vitro are amenable to validation in any in vivo model of interest. The in vitro model is clinically relevant to human pulmonary vascular remodeling.

Secuestro pulmonar una infrecuente causa de hipertension pulmonar persistente en el recién nacido reporte de un caso

Secuestro pulmonar una infrecuente causa de hipertension pulmonar persistente en el recién nacido reporte de un caso

Severe persistent pulmonary hypertension of the newborn and dysmorphic features in neonate with a deletion involving TWIST1 and PHF14: a case report

BackgroundPersistent pulmonary hypertension is a well-known disease of the newborn that in most cases responds well to treatment with nitric oxide and treatment of any underlying causes. Genetic causes of persistent pulmonary hypertension of the newborn are rare. The TWIST1 gene is involved in morphogenetics, and deletions are known to cause Saethre-Chotzen syndrome. Deletions of PHF14 have never been reported in neonates, but animal studies have shown a link between severe defects in lung development and deletions of this gene. There have not, to the best of our knowledge, been any publications of a link between the genes TWIST1 and PHF14 and persistent pulmonary hypertension of the newborn, making this a novel finding.Case presentationWe describe a white male neonate born at term to non-consanguineous white parents; he presented with dysmorphic features and a therapy-refractory persistent pulmonary hypertension. Array-based comparative genomic hybridization revealed the presence of a 14.7 Mb interstitial deletion on chromosome 7, encompassing the genes TWIST1 and PHF14.ConclusionsThe TWIST1 gene can explain our patient’s dysmorphic features. His severe persistent pulmonary hypertension has, however, not been described before in conjunction with the TWIST1 gene, but could be explained by involvement of PHF14, consistent with findings in animal experiments showing lethal respiratory failure with depletion of PHF14. These findings are novel and of importance for the clinical management and diagnostic workup of neonates with severe persistent pulmonary hypertension of the newborn and dysmorphic features.

Retrograde Pulmonary Embolectomy for Acute Pulmonary Embolism: A Simplified Technique

Surgical embolectomy in acute pulmonary embolism is usually reserved for patients with massive pulmonary embolism presenting with cardiogenic shock, or for whom thrombolysis is absolutely contraindicated or has failed. Incomplete removal of thrombotic material lodged in the distal pulmonary arterial bed is considered an important cause of persistent pulmonary hypertension. Retrograde pulmonary embolectomy is an adjunct to conventional pulmonary embolectomy, resulting in more complete embolectomy, specifically of material lodged in the distal pulmonary arterial bed. We describe our simplified technique of retrograde pulmonary embolectomy as a safe adjunct to conventional pulmonary embolectomy.

Alveolar capillary dysplasia as a cause of persistent pulmonary hypertension

Persistent pulmonary hypertension (PPHN) in a term or late preterm has varied etiology. A late preterm neonate operated for esophageal atresia with tracheo-esophageal fistula was complicated by severe pulmonary hypertension and unable to be weaned off from respiratory support. The neonate expired by 15 weeks of life; diagnosis was made on postmortem lung biopsy. Alveolarcapillary dysplasia should be considered in a neonate with idiopathic refractory PPHN, if associated with anomalies.

An unusual cause of refractory persistent pulmonary hypertension of the newborn: anomalous origin of one pulmonary artery

Persistent pulmonary hypertension of the newborn is a source of considerable mortality and morbidity. Anomalous origin of one pulmonary artery, an uncommon congenital cardiac malformation, is a rare cause of persistent pulmonary hypertension. Here, we report the case of a patient with an anomalous origin of one pulmonary artery from the innominate artery who presented with persistent pulmonary hypertension refractory to treatment.

Congenital Diaphragmatic Hernia: Not Quite There Yet

Congenital Diaphragmatic Hernia: Not Quite There Yet

Persistent pulmonary hypertension of non cardiac cause in a neonatal intensive care unit.

Parenchymal lung diseases are the main cause of persistent pulmonary hypertension of the newborn (PPHN). We aimed to assess the non cardiac conditions associated to PPHN in the newborn and the survival rate over the last 15 years, at our center. A retrospective chart review of the neonates admitted for PPHN from 1996 to 2010 was performed. New therapies were introduced in 2003, and the survival rates between two periods (1996–2002 and 2003–2010) were compared. Out of 6750 newborns, 78 (1.1%) had the diagnosis of PPHN of non cardiac cause. The most prevalent causes were associated to pulmonary hypoplasia (30.7%), infection (24.3%), and aspiration syndromes (15.3%). Many other causes were identified in 33.3%. The overall survival rate was 68%. There was a significant difference on survival rates between the two periods (1996–2002 = 63.8% and 2003–2010 = 71.4%, P = 0.04). Our study showed a myriad of non cardiac aetiologies for PPHN of the newborn, most of them related to lung disease or lung hypoplasia. We observed an improvement in survival rate since 2003, which was associated to the use of new therapies.

Misplaced pulmonary arteries in an adult patient with pulmonary hypertension

Misalignment of pulmonary vessels, with or without alveolar capillary dysplasia, is a rare cause of persistent pulmonary hypertension in the newborn. The prognosis is poor, with virtually all patients succumbing to unremitting hypoxaemic respiratory failure and death during the newborn period. We report the CT and histological findings of misplaced pulmonary arteries in a previously healthy young adult patient who presented with pulmonary arterial hypertension. Contiguous high-resolution spiral CT angiography showed small pulmonary arteries coursing within the interlobular septa and enlarged central pulmonary arteries. Surgical lung biopsy demonstrated anomalous muscularised pulmonary arteries in the interlobular septa. This is, to our knowledge, the first report of misplaced pulmonary arteries presenting in an adult patient and may represent a forme fruste of the neonatal vascular anomaly. A possible association with pulmonary arterial hypertension is also suggested in this case.

ABCA3 Deficiency Presenting as Persistent Pulmonary Hypertension of the Newborn

A newborn with persistent pulmonary hypertension (PH) unresponsive to conventional therapies was found to be homozygous for a mutation in the gene encoding adenosine triphosphate binding cassette protein, member A3 (ABCA3). Most causes of PH respond to lung recruitment, inhaled nitric oxide, and hemodynamic support. When PH is prolonged and does not respond to standard therapies, genetic causes of surfactant abnormalities should be considered in the differential diagnosis.

Risk Factors for Persistent Pulmonary Hypertension of the Newborn

Persistent pulmonary hypertension of the newborn, a clinical syndrome that results from the failure of the normal fetal-to-neonatal circulatory transition, is associated with substantial infant mortality and morbidity. We performed a case-control study to determine possible antenatal and perinatal predictors of persistent pulmonary hypertension of the newborn. Between 1998 and 2003, the Slone Epidemiology Center enrolled 377 mothers of infants with persistent pulmonary hypertension of the newborn and 836 mothers of matched control subjects. Within 6 months of delivery, study nurses interviewed participants regarding demographic, medical, and obstetric characteristics. Factors that were independently associated with an elevated risk for persistent pulmonary hypertension of the newborn were infant male gender and black or Asian maternal race compared with white race. High prepregnancy BMI (>27 vs <20) was also associated with persistent pulmonary hypertension of the newborn, as were diabetes and asthma. Compared with infants who were delivered vaginally, the risk for persistent pulmonary hypertension of the newborn was higher for those who were born by cesarean section. Compared with infants who were born within 37 to 41 gestational weeks, the risk was higher for those who were born between 34 and 37 completed weeks and for those born beyond 41 weeks. Compared with infants within the 10th and 90th percentiles of birth weight for gestational age distribution, the risk was higher for infants above the 90th percentile. Our findings suggest an increased risk for persistent pulmonary hypertension of the newborn associated with cesarean delivery; late preterm or postterm birth; being large for gestational age; and maternal black or Asian race, overweight, diabetes, and asthma. It remains unclear whether some of these factors are direct causes of persistent pulmonary hypertension of the newborn or simply share common causes with it; however, clinicians should be alert to the increased need for monitoring and intervention among pregnancies with these risk factors.

Alveolar capillary dysplasia: a logical approach to a fatal disease

Purpose The aim of the study was to review the authors' experience with alveolar capillary dysplasia (ACD), a cause of persistent pulmonary hypertension of the neonate (PPHN) caused by decreased alveolar units, dilated anomalous pulmonary veins, thick-walled arterioles, and thickened interalveolar septa. Methods The records of all neonates with ACD were reviewed from Children's Hospital, Columbus, Ohio, and Sophia's Children's Hospital, Rotterdam, The Netherlands. The clinical characteristics and pathological findings are discussed. Results Eight neonates were diagnosed with ACD from 1994 to 2002. Twenty-five percent (2/8) experienced respiratory distress immediately after birth, whereas 75% (6/8) had normal Apgar scores but deteriorated 1.5 hours to 30 days after birth. All infants required conventional ventilation initially; 50% (4/8) were placed on high-frequency oscillating ventilation and 87% (7/8) on extracorporeal membrane oxygenation. A premorbid diagnosis was established in 3 patients by open lung biopsy. The diagnosis of ACD was confirmed at autopsy in all patients. Conclusions ACD is a fatal disease that should be suspected in all neonates with respiratory failure and PPHN who fail conventional therapy. Prompt diagnosis helps to avoid prolongation of costly treatment modalities in a uniformly fatal disease. An algorithm is proposed in which neonates with PPHN who fail treatment with extracorporeal membrane oxygenation are managed by open lung biopsy.

Alveolar Capillary Dysplasia with Congenital Misalignment of Pulmonary Vessels

Alveolar capillary dysplasia with misalignment of pulmonary vessels is an uncommon congenital cause of persistent pulmonary hypertension of the newborn. It is universally fatal, and diagnosis is entirely dependent upon surgical lung biopsy. We present a case of alveolar capillary dysplasia with misalignment of pulmonary vessels occurring in a full-term neonate, emphasizing that early involvement of the thoracic surgeon for a histological diagnosis allows expensive and ineffective treatments to be avoided.

Dysplasie alvéolo-capillaire avec défaut d’alignement des vaisseaux pulmonaires: Revue de la littérature à propos d’un nouveau cas

Alveolar capillary dysplasia (ACD), with or without pulmonary vein misalignment is a uniformly fatal cause of persistent pulmonary hypertension and respiratory failure, first described in 1981. We report the case of ACD in a full term newborn with post mortem pathologic confirmation. Sixty five cases have been reported in the literature, most are sporadic, but a few cases of familial ACD suggest an autosomal recessive inheritance. In 55% of the reported cases of ACD other cardiovascular, digestive or urogenital anomalies were associated. ACD is presumed to be a primary capillary disorder. It affects full-term neonates who exhibit respiratory distress during the early post natal period due to pulmonary hypertension and die within 3 weeks of birth. Histologic findings include a decrease in the number of alveolar capillaries, which are placed centrally within the intralobular septa, ectatic veins accompany the bronchovascular bundles instead of being in their normal position in the interlobular septum, and muscularized pulmonary arteries extend to the distal level. Prognosis is very poor, intravenous prostacyclin with inhaled nitric oxide have been reported in the cases with the best survival.

Chronic in ovo hypoxia decreases pulmonary arterial contractile reactivity and induces biventricular cardiac enlargement in the chicken embryo.

Although chronic prenatal hypoxia is considered a major cause of persistent pulmonary hypertension of the newborn, experimental studies have failed to consistently find pulmonary hypertensive changes after chronic intrauterine hypoxia. We hypothesized that chronic prenatal hypoxia induces changes in the pulmonary vasculature of the chicken embryo. We analyzed pulmonary arterial reactivity and structure and heart morphology of chicken embryos maintained from days 6 to 19 of the 21-day incubation period under normoxic (21% O(2)) or hypoxic (15% O(2)) conditions. Hypoxia increased mortality (0.46 vs. 0.14; P < 0.01) and reduced the body mass of the surviving 19-day embryos (22.4 +/- 0.5 vs. 26.6 +/- 0.7 g; P < 0.01). A decrease in the response of the pulmonary artery to KCl was observed in the 19-day hypoxic embryos. The contractile responses to endothelin-1, the thromboxane A(2) mimetic U-46619, norepinephrine, and electrical-field stimulation were also reduced in a proportion similar to that observed for KCl-induced contractions. In contrast, no hypoxia-induced decrease of response to vasoconstrictors was observed in externally pipped 21-day embryos (incubated under normoxia for the last 2 days). Relaxations induced by ACh, sodium nitroprusside, or forskolin were unaffected by chronic hypoxia in the pulmonary artery, but femoral artery segments of 19-day hypoxic embryos were significantly less sensitive to ACh than arteries of control embryos [pD(2) (= -log EC(50)): 6.51 +/- 0.1 vs. 7.05 +/- 0.1, P < 0.01]. Pulmonary vessel density, percent wall area, and periarterial sympathetic nerve density were not different between control and hypoxic embryos. In contrast, hypoxic hearts showed an increase in right and left ventricular wall area and thickness. We conclude that, in the chicken embryo, chronic moderate hypoxia during incubation transiently reduced pulmonary arterial contractile reactivity, impaired endothelium-dependent relaxation of femoral but not pulmonary arteries, and induced biventricular cardiac hypertrophy.

Familial persistent pulmonary hypertension of the newborn resulting from misalignment of the pulmonary vessels (congenital alveolar capillary dysplasia).

Misalignment of the pulmonary veins with congenital alveolar capillary dysplasia, although rare, has been reported as a cause of persistent pulmonary hypertension of the newborn. Reported cases have been mainly...

ASSOCIATION OF ENDOTHELIAL NITRIC OXIDE SYNTHASE AND CAVEOLIN IS REGULATED BY AGONIST-STIMULATED TYROSINE PHOSPHORYLATION. † 1090

An impairment in production of nitric oxide (NO) by the endothelial nitric oxide synthase (eNOS) appears to be an underlying cause of persistent pulmonary hypertension of the newborn (PPHN). A detailed understanding of eNOS regulation may therefore provide insights into the molecular defects associated with PPHN and other diseases characterized by abnormalities in eNOS activity or expression. In the present study, we have examined the role of tyrosine phosphorylation in agonist-activation and regulation of eNOS in cultured endothelial cells. Treatment of bovine aortic endothelial cells(BAEC) or bovine lung microvascular endothelial cells (BLMVEC) with bradykinin(10 μM), histamine (10 μM), or ATP (1 mM) produces a transient increase in detergent insolubilities of both eNOS and the plasmalemmal caveolae marker protein, caveolin. Agonist-stimulated changes in detergent solubilities are blocked by the tyrosine kinase inhibitor, geldanamycin and are mimicked by the tyrosine phosphatase inhibitors, phenylarsine oxide and sodium orthovanadate. Increases in detergent insolubilities of eNOS and caveolin are temporally correlated with increases in the amount of eNOS associated with caveolin. Bradykinin and phenylarsine oxide increase the association by 82% and 380%, respectively. Conversely, geldanamycin decreases association by 86%. Taken together, these results suggest that agonist-activation of eNOS in endothelial cells involves tyrosine phosphorylation-dependent formation of a detergent-insoluble complex of eNOS and caveolin. Complex formation of eNOS and caveolin in plasma membrane caveolae may have a role in regulation of eNOS activity or Ca2+-sensitivity or in increasing the efficiency of extracellular NO release.

Nitric oxide inhalation therapy for an infant with persistent pulmonary hypertension caused by misalignment of pulmonary veins with alveolar capillary dysplasia

Misalignment of pulmonary veins with alveolar capillary dysplasia (MPV) has been reported to be a rare cause of persistent pulmonary hypertension of the newborn (PPHN) and to be fatal despite extracorporeal membrane oxygenation (ECMO). A full-term female neonate with PPHN was brought to the hospital for ECMO therapy at 2 days of age. On the 14th day of life, she was extubated early after the second run of ECMO, and underwent nitric oxide (NO) inhalation therapy in the incubator. She died of catheter-related sepsis on the 61st day of life. After autopsy findings revealed MPV, the longest survival with this disease was documented. NO inhalation therapy in the incubator may provide time for lung transplantation.