Hypoxia inducible factor 2α (HIF2α/EPAS1) is associated with development of pulmonary hypertension in severe congenital diaphragmatic hernia patients.

We show that hypoxia inducible factor 2α (HIF2α) is highly expressed in patients with pulmonary hypertension (PH). HIF2α is expressed in every patient with congenital diaphragmatic hernia, while only half of the controls express HIF2α. Our data suggest that HIF2α is a link between hypoxia and the development of PH.

Premature differentiation of vascular smooth muscle cells in human congenital diaphragmatic hernia.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a rare congenital anomaly characterized by the herniation of abdominal organs into the chest cavity. The high mortality and morbidity of CDH patients are primarily caused by the associated pulmonary hypertension (PH), characterized by the thickening of the vascular media and adventitia. The media consist of heterogeneous populations of vascular smooth muscle cells (VSMC), ranging from synthetic to the characteristic contractile cells. VSMCs are influenced by developmental and environmental cues and may play a role in the development of the structural changes observed in CDH patients. Therefore, we hypothesized that the distribution of the VSMC populations may already be different at the origin of CDH development. METHODOLOGY: We analyzed the protein expression of specific markers associated with synthetic and contractile VSMC phenotypes in human lungs at different developmental stages. Next, we compared lungs of premature and term CDH patients, as well as patients with lung hypoplasia due to renal agenesis or PROM, with age-matched controls. RESULTS: Synthetic and contractile VSMCs are distributed in a temporal and spatial specific pattern along the proximodistal axis of the lung. CDH patients have more abundant contractile VSMCs which are also more distally distributed. This different distribution pattern is already observed from 19 weeks of gestation onwards. CONCLUSION: Our data suggest that the more extensive distribution of contractile VSMCs is associated with an early maturation of the pulmonary vasculature, contrasting the concept that CDH might be the result of delayed maturation of the epithelium.

Reversal of pulmonary vascular remodeling in pulmonary hypertensive rats.

Pulmonary hypertension is responsible for significant mortality and morbidity among newborns and infants. The pathology is characterized by pulmonary vascular remodeling with medial hypertrophy and adventitial thickening, leading to decreased gas exchange. Since it is unknown if these abnormalities are reversible, we analyzed these vascular changes in pulmonary hypertensive rats. Exposure of rats to hypobaric hypoxia for 4 weeks induced clinical signs of pulmonary hypertension, such as increased right ventricular systolic pressure, increased right ventricular weight and considerable pulmonary vascular remodeling. The vascular changes were associated with the expression of Non -Muscle Myosin Heavy Chain B in the pre-acinar vessels and an increased expression of alpha Smooth Muscle Actin, Smooth Muscle Myosin Heavy Chain 2 and Calponin in the intra-acinar vessels. The right ventricular systolic pressure and right ventricular weight gradually decreased after specific periods of recovery in normoxia, although this reversal did not reach baseline levels after six weeks at normoxia. However, the cellular changes in the pulmonary vasculature were completely reversed. Development of pulmonary hypertension is associated with an increase of synthetic perivascular cells in the pre-acinar arteries and an aberrant differentiation of perivascular cells in the smallest intra-acinar arteries. These cellular and structural changes in the pulmonary vasculature are completely reversible after recovery in normoxia.

Vascular abnormalities in human newborns with pulmonary hypertension.

Pulmonary vascular disease embodies all congenital or acquired pathologies that affect the pulmonary vasculature. One of them is pulmonary hypertension of the newborn (PHN), which is clinically characterized by a persistent high pulmonary vascular resistance postnatally and an abnormal vascular response. Morphologically, the vascular walls of the small pulmonary arteries become thickened, leading to increased resistance of these vessels and thus a worsening of gas exchange. PHN occurs as a primary disease or in association with abnormal lung development, for example as in congenital diaphragmatic hernia, and is a critical determinant of morbidity and mortality. Here we review the current knowledge about vascular abnormalities in PHN and discuss the vascular abnormalities in different conditions associated with pulmonary hypertension in human newborns in relation to recent findings from molecular biology.

Sildenafil exposure in neonates with pulmonary hypertension after administration via a nasogastric tube.

OBJECTIVE: To describe the pharmacokinetics and exposure of oral sildenafil (SIL) in neonates (2-5 kg) with pulmonary hypertension (PH). DESIGN: We included 11 neonates (body weight 2-5 kg, postnatal age 2-121 days) who received SIL and extracorporeal membrane oxygenation (ECMO) treatment for PH. SIL capsules were given via a nasogastric tube. Blood samples were collected via a pre-existing arterial line to quantify SIL and metabolite plasma levels (219 samples). Non-linear mixed effects modelling was used to describe SIL and desmethylsildenafil (DMS) pharmacokinetics. RESULTS: A one-compartment model was suitable for SIL and DMS. Interpatient and intrapatient variability for clearance at 100% bioavailability were 87% and 27% (SIL) and 62% and 26% (DMS). Patient weight, postnatal age and post-ECMO time did not explain variability. Concomitant fluconazole use was associated with a 47% reduction in SIL clearance. The exposure expressed as average plasma concentration area under the curve over 24 h (AUC(24 (SIL+DMS))) ranged from 625 to 13 579 ng/h/ml. An oral dose of 4.2 mg/kg/24 h would lead to a median AUC(24 (SIL+DMS)) of 2650 ng/h/ml equivalent to 20 mg three times a day in adults. Interpatient variability was large, with a simulated AUC(24 (SIL+DMS)) range (10th and 90th percentiles) of 1000-8000 ng/h/ml. CONCLUSIONS: SIL pharmacokinetics are highly variable in post-ECMO neonates and infants. In a median patient, the current dose regimen of 0.5-2.0 mg/kg four times a day leads to an exposure comparable to the recommended adult dose of 20 mg four times a day. Careful dose titration, based on efficacy and the occurrence of hypotension, remains necessary. Follow-up research should include appropriate pharmacodynamic endpoints, with a population pharmacokinetic/pharmacodynamic analysis to assign a suitable exposure window or target concentration.