BPD-associated Pulmonary Hypertension Research Articles

Biomarker screening for pulmonary hypertension in VLBW infants at risk for bronchopulmonary dysplasia.

Very low birth weight (VLBW) infants demonstrate altered alveolar and pulmonary vascular development and carry an increased risk of developing bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH). Risk stratification for BPD-associated PH (BPD-PH) in at-risk infants may help tailor management, improve outcomes, and optimize resource utilization. VLBW infants were screened for PH with blood gas measurements, serum NT-proBNP and bicarbonate (HCO3) levels, and echocardiograms if they remained on respiratory support at 34 weeks corrected gestational age. We then tested 11 models using different cutoffs for NT-proBNP and HCO3 to predict infants at low risk of BPD-PH. We identified PH in 34 of 192 (17.6%) VLBW infants. The median NT-proBNP in VLBWs with PH was 2769 pg/mL versus 917 pg/mL in those without PH (p < 0.0001). A model with NT-proBNP < 950 pg/mL and HCO3 < 32 mmol/L had a sensitivity of 100%, specificity of 34.2%, and negative predictive value of 100%. Using this model, 54 of 192 (28%) of the patients in this study would have been categorized as low risk for PH and could have avoided a screening echocardiogram. NT-proBNP and HCO3 together may serve as sensitive and cost-effective screening tools for BPD-PH in VLBW infants. NT-proBNP and HCO3 concentrations obtained together may help identify very low birth weight infants at risk for bronchopulmonary dysplasia who should undergo screening for pulmonary hypertension with echocardiography. This large dataset demonstrates that NT-proBNP and HCO3 levels together are more sensitive than NT-proBNP alone in identifying VLBW infants to undergo echocardiography. The combination of NT-proBNP and HCO3 levels may identify VLBW infants at low risk for pulmonary hypertension and thus those who may be able to avoid screening echocardiography.

Cardiovascular Sequelae of Bronchopulmonary Dysplasia in Preterm Neonates Born before 32 Weeks of Gestational Age: Impact of Associated Pulmonary and Systemic Hypertension.

Bronchopulmonary dysplasia (BPD) remains the most common respiratory disorder of prematurity for infants born before 32 weeks of gestational age (GA). Early and prolonged exposure to chronic hypoxia and inflammation induces pulmonary hypertension (PH) with the characteristic features of a reduced number and increased muscularisation of the pulmonary arteries resulting in an increase in the pulmonary vascular resistance (PVR) and a fall in their compliance. BPD and BPD-associated pulmonary hypertension (BPD-PH) together with systemic hypertension (sHTN) are chronic cardiopulmonary disorders which result in an increased mortality and long-term problems for these infants. Previous studies have predominantly focused on the pulmonary circulation (right ventricle and its function) and developing management strategies accordingly for BPD-PH. However, recent work has drawn attention to the importance of the left-sided cardiac function and its impact on BPD in a subset of infants arising from a unique pathophysiology termed postcapillary PH. BPD infants may have a mechanistic link arising from chronic inflammation, cytokines, oxidative stress, catecholamines, and renin-angiotensin system activation along with systemic arterial stiffness, all of which contribute to the development of BPD-sHTN. The focus for the treatment of BPD-PH has been improvement of the right heart function through pulmonary vasodilators. BPD-sHTN and a subset of postcapillary PH may benefit from afterload reducing agents such as angiotensin converting enzyme inhibitors. Preterm infants with BPD-PH are at risk of later cardiac and respiratory morbidities as young adults. This paper reviews the current knowledge of the pathophysiology, diagnosis, and treatment of BPD-PH and BPD-sHTN. Current knowledge gaps and emerging new therapies will also be discussed.

Patent Ductus Arteriosus and Bronchopulmonary Dysplasia–Associated Pulmonary Hypertension

Bronchopulmonary dysplasia (BPD) is often associated with pulmonary vascular disease and secondary pulmonary hypertension (PH). The pathogenesis of BPD-associated PH (BPD-PH) is complex and involves prenatal and postnatal factors that disrupt pulmonary vascular development, and patent ductus arteriosus (PDA) is a factor potentially associated with risk of BPD-PH that has been identified in very recent studies. To explore the association of PDA with BPD-PH using a bayesian model-averaged (BMA) meta-analysis of studies. PubMed and Embase were searched up to April 2023. Key search terms included BPD and PH. Studies examining infants with gestational age 32 weeks or less and reporting data on PDA and risk of BPD-PH. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and the Meta-Analysis of Observational Studies in Epidemiology reporting guidelines. Two independent reviewers extracted data, with a third reviewer checking for accuracy and completeness. Data pooling and effect size calculations were performed by BMA. The primary outcome was BPD-PH. BMA was used to calculate Bayes factors (BFs). The BF10 is the ratio of the probability of the data under the alternative hypothesis (H1, association of PDA with BPD-HP) over the probability of the data under the null hypothesis (H0). A total of 32 studies (8513 infants) were included. BMA showed that the evidence in favor of H1 was weak for any PDA (BF10 = 2.90; 10 studies), moderate for hemodynamically significant PDA (BF10 = 3.77; 3 studies), and extreme for surgically ligated or catheter-occluded PDA (BF10 = 294.9; 16 studies). In contrast, the evidence in favor of H0 was weak for medically treated PDA (BF10 = 0.55; 6 studies). In addition, BMA found strong evidence in favor of H1 when prolonged exposure to PDA was analyzed as a dichotomous variable (BF10 = 11.80; 6 studies) and extreme evidence (BF10 = 113.60; 3 studies) when PDA exposure time was analyzed as a continuous variable. In this bayesian meta-analysis, the data suggest that prolonged exposure to PDA might be associated with increased risk of pulmonary vascular disease in extremely preterm infants. This highlights the need to monitor for PH in high-risk preterm infants with prolonged exposure to PDA and to incorporate PH risk into clinical decisions regarding PDA management.

CLINICAL CASE OF CARDIORESPIRATORY MONITORING TO CONTROL SUPPLEMENTAL OXYGEN THERAPY IN PREMATURE INFANT

One of the most common respiratory pathologies in infants born prematurely is bronchopulmonary dysplasia (BPD). Pulmonary hypertension is considered a formidable and difficult to diagnose complication of BPD. Maintaining the proper level of oxygen saturation is an integral part of nursing such patients. To diagnose respiratory pauses and episodes of desaturation during sleep, children undergo cardiorespiratory monitoring (KRM) aimed at recording episodes of apnea and hypopnea. The article discusses a clinical case of cardiorespiratory monitoring during sleep in a hospital and outpatient setting to monitor additional oxygen therapy in a premature baby suffering from bronchopulmonary dysplasia and BPD-associated pulmonary hypertension.

Current diagnosis and treatment practice for pulmonary hypertension in bronchopulmonary dysplasia-A survey study in Germany (PUsH BPD).

Pulmonary hypertension (PH) is the most severe complication in preterm infants with bronchopulmonary dysplasia (BPD) and associated with significant mortality. Diagnostic and treatment strategies, however, still lack standardization. By the use of a survey study (PH in BPD), we assessed clinical practice (diagnosis, treatment, follow-up) in preterm infants with early postnatal persistent pulmonary hypertension of the newborn(PPHN) as well as at risk for or with established BPD-associated PH between 06/2018 and 10/2020 in two-thirds of all German perinatal centers with >70 very low birthweight infants/year including their cardiology departments and outpatient units. Data wereanalyzed descriptively by measures of locations and distributional shares. In routine postnatal care, clinical presentation and echocardiography were reported as the main diagnostic modalities to screen for PPHN in preterm infants, whereas biomarkers brain natriuretic peptide/N-terminal pro b-type natriuretic peptide were infrequently used. For PPHN treatment, inhaled nitric oxidewas used in varying frequency. The majority of participants agreed to prescribe diuretics and steroids (systemic/inhaled) for infants at risk for or with established BPD-associated PH and strongly agreed on recommending respiratory syncytial virus immunization and the use of home monitoring upon discharge. Reported oxygen saturation targets, however, varied in these patients in in- and outpatient care. The survey reveals shared practices in diagnostic and therapeutic strategies for preterms with PPHN and BPD-associated PH in Germany. Future studies are needed to agree on detailed echo parameters and biomarkers to diagnose and monitor disease next to a much-needed agreement on the use of pulmonary vasodilators, steroids, and diuretics as well as target oxygen saturation levels.

Efficacy of Sildenafil in Infants with Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension.

Background: Pulmonary hypertension (PH) is a common comorbidity in infants with bronchopulmonary dysplasia (BPD). Sildenafil is a widely recognized therapy for PH, but its efficacy in infants with BPD is questionable. We propose to assess the efficacy of sildenafil in BPD-associated PH as evaluated based on transthoracic echocardiography (TTE) changes and clinical measures. Methods: Data were retrospectively and prospectively collected. Inclusion criteria were gestational age (GA) < 32 weeks, birth weight (BW) < 1500 g with severe BPD, diagnosis of PH via TTE on sildenafil treatment. PH was evaluated via TTE, which was performed monthly after 36 weeks post-menstrual age (PMA) as a standard of care, and re-reviewed by a single pediatric cardiologist, who was blind to the initial reading. Results: In total, 19 patients were enrolled in the study, having a median GA of 24 3/7 weeks (IQR 23 5/7-25 5/7) and a median BW of 598 g (IQR 572-735). Sildenafil treatment was started at a median PMA of 40.4 weeks. The median respiratory severity score (RSS) at 28 d was 6.5, RSS and FiO2 showed improvement about 12 weeks after starting sildenafil treatment. Conclusions: Improvement in PH was noted via TTE, and patients had improvement in their RSS and FiO2 after prolonged therapy. However, TTE improvements did not correlate with clinical improvements.

Pulmonary hypertension in preterm infants with moderate-to-severe bronchopulmonary dysplasia (BPD).

To describe clinical characteristics of pulmonary hypertension (PH) associated with moderate to severe BPD (MSBPD) in premature infants born ≤32 weeks gestation. This was a single centre retrospective cohort study, with reanalysis of echocardiographic studies for PH of infants born ≤32 weeks gestation with MSBPD admitted to a tertiary surgical neonatal service. In total, 268 babies with MSBPD were included in the study. Incidence of BPD-associated PH (BPD-PH) was 12.6% (34), of which 41% infants were observed to have severe PH. On multivariate analysis, need for positive pressure respiratory support at 36 weeks post menstrual age (PMA) was independently associated with PH (p = 0.001; 95% CI 2-13.5) Presence of PH and severity of PH were associated with increased mortality. Of babies with MSBPD-PH, 32% died before discharge from the neonatal unit. Babies with MSBPD and PH are more likely to die before discharge from the neonatal unit. Need for positive pressure respiratory support at 36 weeks PMA is independently associated with PH. Babies with MSBPD with less than severe PH are also associated with increased mortality when compared to babies with MSBPD with no PH.

Patent Ductus Arteriosus and Development of Bronchopulmonary Dysplasia-associated Pulmonary Hypertension.

Rationale: Extremely preterm infants with evolving bronchopulmonary dysplasia (BPD) are at risk for development of BPD-associated pulmonary hypertension (BPD-PH). A patent ductus arteriosus (PDA) shunt may be a modifiable risk factor for BPD-PH development. Objective: To determine whether the presence and duration of ductus arteriosus patency differs between extremely preterm infants with and without BPD-PH. Methods: We conducted a retrospective case-control study among preterm infants of gestational age 22 weeks, 0 days, to 28 weeks, 6 days, who remained on respiratory support on postnatal day 28 at the University of Alabama at Birmingham from 2017 to 2020. Infants who were diagnosed with PH (cases) by echocardiography were compared with infants without PH (control subjects). Data from echocardiograms performed during the hospitalization after postnatal day 28 were included. Logistic regression adjusted for covariates that differed significantly between groups. A probit analysis related the duration of ductal patency to the development of BPD-PH. Measurements and Main Results: A total of 138 infants developed BPD alone, and 82 infants developed BPD-PH. After adjustment for differing covariates between groups, both PDA (adjusted odds ratio, 4.29; 95% confidence interval, 1.89-9.77) and moderate to large PDA (adjusted odds ratio, 4.15; 95% confidence interval, 1.78-9.64) remained significantly related to BPD-PH at discharge. By probit analysis, each additional month of PDA and hemodynamically significant PDA exposure was associated with an increased probability for the composite outcome of BPD-PH at discharge or death with coefficients of 0.40 (P < 0.001) and 0.45 (P < 0.001), respectively. Conclusions: In extremely preterm infants on respiratory support on postnatal day 28, both the presence of and a longer duration of ductus arteriosus patency were associated with the development of BPD-PH.

27 Neurodevelopmental Outcomes of Preterm Infants Born &amp;lt;29 weeks with Bronchopulmonary Dysplasia Associated Pulmonary Hypertension: A Multicenter Study

Abstract Background More than 1 in 4 preterm infants with bronchopulmonary dysplasia (BPD) develop BPD-associated pulmonary hypertension (BPD-PH) that is associated with significant morbidity. Data regarding neurodevelopmental outcomes with BPD-PH in preterm infants are lacking. Objectives To determine neurodevelopmental outcomes of preterm infants born &amp;lt; 29 weeks gestational age (GA) with BPD associated pulmonary hypertension at 18 to 24 months corrected gestational age (CGA). Design/Methods In this retrospective cohort study, preterm infants born &amp;lt; 29 weeks GA between January 2016 and December 2019 at level 3 Neonatal Intensive Care Units at Foothills Hospital in Calgary and the University of Texas Medical Branch (UTMB) in Galveston, who were evaluated at 18-24 months CGA in the neonatal follow-up clinics were included. We compared demographic factors, neurodevelopmental status including Bayley-III scores and sensory impairments between the two groups based on the presence of PH at 36 weeks CGA: Group I: BPD with PH and Group II: BPD without PH, using univariate and multivariable regression models. The primary outcome was a composite of death or neurodevelopmental impairments (NDI). NDI was defined as any cerebral palsy (GMFCS≥1), Bayley-III score &amp;lt; 85 on one or more of the cognitive, motor, or language composite scores, sensorineural or mixed hearing impairment or unilateral or bilateral visual impairment. Results Of 372 eligible infants, 118 (Group I [BPD-PH] =7, Group II [BPD with no PH] =111) were lost to follow up. Of the remaining 254 infants, 52 in Group I and 202 in Group II were followed at 18-24 months CGA. Group I and Group II had median (IQR) birth weight of 710g (323) and 815g (314) [p=0.004] and median gestational ages (IQR) were 25 weeks (2) and 26 weeks (2) [p=0.020], respectively . Rates of associated impairments are shown in Figure 1. Infants in BPD-PH group (Group I) were more likely to have mortality or NDI (adjusted Odds Ratio [aOR] 3.82; 95% CI: 1.17-12.41) (Table 1). Conclusion BPD-PH in preterm infants born &amp;lt; 29 weeks GA is associated with increased odds of the composite outcome of death or neurodevelopmental impairment and language delay at 18-24 months CGA.

Episodes of apnea and periodic breathing in premature infants with BPD-associated pulmonary hypertension

Premature infants with bronchopulmonary dysplasia-associated pulmonary hypertension have a longer persistence of apnea of prematurity and periodic breathing. We hypothesized that apnea of prematurity and periodic breathing may be associated with the persistence of pulmonary hypertension in infants with bronchopulmonary dysplasia.The aim of the study was to determine the characteristics of apnea episodes and periodic breathing in premature infants with bronchopulmonary dysplasia-associated pulmonary hypertension.Characteristics of children and research methods. Cardiorespiratory monitoring was conducted on 27 premature infants born at 22 0/7 — 29 0/7 weeks of gestation with a body weight of &lt;1000 grams. All infants had bronchopulmonary dysplasia, and 14 infants with severe bronchopulmonary dysplasia were diagnosed pulmonary hypertension (main cohort).Results. The group of infants with bronchopulmonary dysplasia + pulmonary hypertension had lower average SpO2, higher desaturation index and apnea/hypopnea index as compared to infants without pulmonary hypertension. Four infants from the main cohort had obstructive apnea index of ˃1 events/hour and had high values of 1,1; 2,5; 5,8, and 8,6/hour. In the comparison group, only one infant had a high obstructive apnea index (1,1/hour). Eleven infants(78%) with pulmonary hypertension had episodes of periodic breathing, at the same time only six infants (46%) in the group without pulmonary hypertension had such episodes. Periodic breathing episodes with a drop of SpO2 &lt;90% were registered in 82% of cases in the main cohort and in 67% of cases in infants of the comparison group.Conclusion. Premature infants with bronchopulmonary dysplasia and pulmonary hypertension had more significant decrease in mean SpO2, increased desaturation index and apnea/hypopnea index and tend to have obstructive apnea index &gt;1/hour and longer periodic breathing than infants without pulmonary hypertension.

Type 2 immune polarization is associated with cardiopulmonary disease in preterm infants.

Postnatal maturation of the immune system is poorly understood, as is its impact on illnesses afflicting term or preterm infants, such as bronchopulmonary dysplasia (BPD) and BPD-associated pulmonary hypertension. These are both cardiopulmonary inflammatory diseases that cause substantial mortality and morbidity with high treatment costs. Here, we characterized blood samples collected from 51 preterm infants longitudinally at five time points, 20 healthy term infants at birth and age 3 to 16 weeks, and 5 healthy adults. We observed strong associations between type 2 immune polarization in circulating CD3+CD4+ T cells and cardiopulmonary illness, with odds ratios up to 24. Maternal magnesium sulfate therapy, delayed hepatitis B vaccination, and increasing fetal, but not maternal, chorioamnionitis severity were associated with attenuated type 2 polarization. Blocking type 2 mediators such as interleukin-4 (IL-4), IL-5, IL-13, or signal transducer and activator of transcription 6 (STAT6) in murine neonatal cardiopulmonary disease in vivo prevented changes in cell type composition, increases in IL-1β and IL-13, and losses of pulmonary capillaries, but not gains in larger vessels. Thereby, type 2 blockade ameliorated lung inflammation, protected alveolar and vascular integrity, and confirmed the pathological impact of type 2 cytokines and STAT6. In-depth flow cytometry and single-cell transcriptomics of mouse lungs further revealed complex associations between immune polarization and cardiopulmonary disease. Thus, this work advances knowledge on developmental immunology and its impact on early life disease and identifies multiple therapeutic approaches that may relieve inflammation-driven suffering in the youngest patients.

9 The Burden of Bronchopulmonary Dysplasia and Pulmonary Vascular Disease in Premature Infants

Abstract Primary Subject area Neonatal-Perinatal Medicine Background Extremely premature infants are at a high risk of bronchopulmonary dysplasia (BPD) and BPD-associated pulmonary hypertension (PH). Prolonged patency of the ductus arteriosus (PDA) may worsen PH; however, due to the lack of evidence supporting improvement in outcomes after strategies to promote ductal closure, our center has adopted a strict non-intervention policy since 2013. Objectives Assess PH prevalence and severity, as well as the impact of BPD on echocardiographic parameters of cardiac performance. Design/Methods Retrospective cohort of infants &amp;lt;29 weeks gestational age at birth, admitted between 2015 and 2019, and without genetic/congenital anomalies. Measurements from the echocardiography acquired closest to 36 weeks were done by masked experts. Severe BPD was defined as positive pressure support at 36 weeks. PH was defined as an estimated systolic pulmonary pressure (SPAP) ≥40 mmHg or an abnormal septal curvature by eccentricity index (EI) (&amp;gt;1.3). Results Out of 387 infants, 222 were included, of which 27 (12%) were categorized as severe BPD and 78 (35%) had PH. Severe BPD was associated with lower birth weight (704±214 vs 842±229g, p&amp;lt;0.01), longer hospitalization (median 138 [IQR 108-167] vs 103 [IQR 86-125] days, p&amp;lt;0.01) and longer mechanical ventilation duration (median 82 [IQR 33-107] vs 17 [IQR 2-32] days, p&amp;lt;0.01), with no difference in gestational age at birth. Severe BPD was associated with PH (70% vs 43%, p&amp;lt;0.01). The combined outcome of death (after the 36 weeks echocardiography) or severe BPD was associated with PH (68% vs 30%, p&amp;lt;0.01), smaller left ventricle length in diastole (2.8±0.5 vs 3.0±0.5 cm, p=0.03), decrease in the tricuspid annular plane systolic excursion (0.7±0.2 vs 0.9±0.2 cm, p&amp;lt;0.01), abnormal EI (1.31±0.25 vs 1.17±0.18, p&amp;lt;0.01) and smaller right ventricle fraction area change (41.3±5.8 vs 47.8±7.6%, p&amp;lt;0.01), without a significant increase on SPAP (35±21 vs 35±14, p=0.15). Other echocardiographic markers were similar. Conclusion In the context of a PDA non-intervention policy, a third of our population was affected by PH at 36 weeks. Furthermore, those with severe BPD or death had signs of RV dysfunction (despite similar SPAP estimate), indicating that the effect of BPD on pulmonary vascular remodelling and cardiac function may be underestimated.

Risk factors and clinical characteristics for bronchopulmonary dysplasia associated pulmonary hypertension in very-low-birth-weight infants

BackgroundPulmonary hypertension (PH) is a common complication of bronchopulmonary dysplasia (BPD) in very-low-birth-weight infants (VLBWIs). Although recent studies have increased awareness that PH contributes significantly to the high morbidity and mortality of BPD, the risk factors and clinical characteristics for PH in VLBWIs are little known.ObjectivesTo investigate the risk factors and clinical characteristics for BPD-associated pulmonary hypertension (BPD-PH) in VLBWIs.MethodsA retrospective case–control observational study of VLBWIs with BPD admitted to a neonatal intensive care unit (NICU) over 4 years. According to echocardiograms confirming elevated pulmonary artery pressure after 28 days after birth, we divided BPD infants into PH group (n = 18) and non-PH group (n = 65). We compared pre- and postnatal characteristics between VLBWIs with or without PH. Multivariable logistic regression analysis was conducted with backward selection.ResultsA total of 83 infants with BPD were divided into PH group (n = 18) or non-PH group (n = 65). The average birth weight of the infants with BPD was 1078.1 g. Compared with those infants of the non-PH group, the birth weight of BPD-PH infants was significantly lower (968.1 ± 187.7 vs. 1108.5 ± 185.8, P = 0.006). Infants in the PH group had a higher incidence of patent ductus arteriosus (PDA) and underwent longer durations of oxygen therapy and mechanical ventilation compared to those in the non-PH group. In all subjects, birth weight (OR 0.995; 95% CI 0.991–0.999; P = 0.025) and PDA (OR 13.355; 95% CI 2.950–60.469; P = 0.001) were found to be specific risk factors for BPD-PH in this cohort.ConclusionsThe study shows PDA and birth weight are specific risk factors for BPD-PH in VLBWIs.

Chitin-Derived AVR-48 Prevents Experimental Bronchopulmonary Dysplasia (BPD) and BPD-Associated Pulmonary Hypertension in Newborn Mice.

Bronchopulmonary dysplasia (BPD) is the most common complication of prematurity and a key contributor to the large health care burden associated with prematurity, longer hospital stays, higher hospital costs, and frequent re-hospitalizations of affected patients through the first year of life and increased resource utilization throughout childhood. This disease is associated with abnormal pulmonary function that may lead to BPD-associated pulmonary hypertension (PH), a major contributor to neonatal mortality and morbidity. In the absence of any definitive treatment options, this life-threatening disease is associated with high resource utilization during and after neonatal intensive care unit (NICU) stay. The goal of this study was to test the safety and efficacy of a small molecule derivative of chitin, AVR-48, as prophylactic therapy for preventing experimental BPD in a mouse model. Two doses of AVR-48 were delivered either intranasally (0.11 mg/kg), intraperitoneally (10 mg/kg), or intravenously (IV) (10 mg/kg) to newborn mouse pups on postnatal day (P)2 and P4. The outcomes were assessed by measuring total inflammatory cells in the broncho-alveolar lavage fluid (BALF), chord length, septal thickness, and radial alveolar counts of the alveoli, Fulton’s Index (for PH), cell proliferation and cell death by immunostaining, and markers of inflammation by Western blotting and ELISA. The bioavailability and safety of the drug were assessed by pharmacokinetic and toxicity studies in both neonatal mice and rat pups (P3-P5). Following AVR-48 treatment, alveolar simplification was improved, as evident from chord length, septal thickness, and radial alveolar counts; total inflammatory cells were decreased in the BALF; Fulton’s Index was decreased and lung inflammation and cell death were decreased, while angiogenesis and cell proliferation were increased. AVR-48 was found to be safe and the no-observed-adverse-effect level (NOAEL) in rat pups was determined to be 100 mg/kg when delivered via IV dosing with a 20-fold safety margin. With no reported toxicity and with a shorter half-life, AVR-48 is able to reverse the worsening cardiopulmonary phenotype of experimental BPD and BPD-PH, compared to controls, thus positioning it as a future drug candidate.

Early pulmonary hypertension is a risk factor for bronchopulmonary dysplasia-associated late pulmonary hypertension in extremely preterm infants

This study evaluated whether early pulmonary hypertension (PH) in extremely preterm infants (EPIs) at 22–27 weeks of gestation detected clinically with echocardiography at 4–7 postnatal days (PND) is a risk factor for death before 36 weeks post-menstrual age (PMA) or late PH in moderate or severe (m/s) bronchopulmonary dysplasia (BPD) (BPD-PH). We analyzed risk factors for death before 36 weeks PMA or BPD-PH. Among 247 EPIs enrolled, 74 (30.0%) had early PH. Twenty-one (28.4%) infants with early PH and 18 (10.4%) without early PH died before 36 weeks PMA; 14 (18.9%) infants with early PH and 9 (5.2%) without early PH had BPD-PH at 36–38 weeks PMA. Multivariate analysis revealed that early PH (adjusted odds ratio, 6.55; 95% confidence interval, 3.10–13.82, P < 0.05), clinical chorioamnionitis (2.50; 1.18–5.31), intraventricular hemorrhage (grade 3–4) (3.43; 1.26–9.37), and late sepsis (6.76; 3.20–14.28) independently increased the risk of development of death before 36 weeks PMA or BPD-PH. Subgroup analysis among m/s BPD patients revealed that early PH (4.50; 1.61–12.58) and prolonged invasive ventilator care (> 28 days) (4.91; 1.02–23.68) increased the risk for late PH independently. In conclusion, EPIs with early PH at 4–7 PND should be monitored for BPD-associated late PH development.

Evidence for the Management of Bronchopulmonary Dysplasia in Very Preterm Infants.

Background: Very preterm birth often results in the development of bronchopulmonary dysplasia (BPD) with an inverse correlation of gestational age and birthweight. This very preterm population is especially exposed to interventions, which affect the development of BPD. Objective: The goal of our review is to summarize the evidence on these daily procedures and provide evidence-based recommendations for the management of BPD. Methods: We conducted a systematic literature research using MEDLINE/PubMed on antenatal corticosteroids, surfactant-replacement therapy, caffeine, ventilation strategies, postnatal corticosteroids, inhaled nitric oxide, inhaled bronchodilators, macrolides, patent ductus arteriosus, fluid management, vitamin A, treatment of pulmonary hypertension and stem cell therapy. Results: Evidence provided by meta-analyses, systematic reviews, randomized controlled trials (RCTs) and large observational studies are summarized as a narrative review. Discussion: There is strong evidence for the use of antenatal corticosteroids, surfactant-replacement therapy, especially in combination with noninvasive ventilation strategies, caffeine and lung-protective ventilation strategies. A more differentiated approach has to be applied to corticosteroid treatment, the management of patent ductus arteriosus (PDA), fluid-intake and vitamin A supplementation, as well as the treatment of BPD-associated pulmonary hypertension. There is no evidence for the routine use of inhaled bronchodilators and prophylactic inhaled nitric oxide. Stem cell therapy is promising, but should be used in RCTs only.

Bronchopulmonary Dysplasia and Pulmonary Hypertension. The Role of Smooth Muscle adh5.

Bronchopulmonary dysplasia (BPD) is characterized by alveolar simplification, airway hyperreactivity, and pulmonary hypertension. In our BPD model, we have investigated the metabolism of the bronchodilator and pulmonary vasodilator GSNO (S-nitrosoglutathione). We have shown the GSNO catabolic enzyme encoded by adh5 (alcohol dehydrogenase-5), GSNO reductase, is epigenetically upregulated in hyperoxia. Here, we investigated the distribution of GSNO reductase expression in human BPD and created an animal model that recapitulates the human data. Blinded comparisons of GSNO reductase protein expression were performed in human lung tissues from infants and children with and without BPD. BPD phenotypes were evaluated in global (adh5-/-) and conditional smooth muscle (smooth muscle/adh5-/-) adh5 knockout mice. GSNO reductase was prominently expressed in the airways and vessels of human BPD subjects. Compared with controls, expression was greater in BPD smooth muscle, particularly in vascular smooth muscle (2.4-fold; P = 0.003). The BPD mouse model of neonatal hyperoxia caused significant alveolar simplification, airway hyperreactivity, and right ventricular and vessel hypertrophy. Global adh5-/- mice were protected from all three aspects of BPD, whereas smooth muscle/adh5-/- mice were only protected from pulmonary hypertensive changes. These data suggest adh5 is required for the development of BPD. Expression in the pulmonary vasculature is relevant to the pathophysiology of BPD-associated pulmonary hypertension. GSNO-mimetic agents or GSNO reductase inhibitors, both of which are currently in clinical trials for other conditions, could be considered for further study in BPD.

Early diagnosis and targeted approaches to pulmonary vascular disease in bronchopulmonary dysplasia.

Pulmonary hypertension has emerged as a life-threatening disease in preterm infants suffering from bronchopulmonary dysplasia (BPD). Its development is closely linked to respiratory disease, as vasculogenesis and alveologenesis are closely interconnected. Once clinically significant, BPD-associated pulmonary hypertension (BPD-PH) can be challenging to manage, due to poor reversibility and multiple comorbidities frequently associated. The pulmonary vascular disease process underlying BPD-PH is the result of multiple innate and acquired factors, and emerging evidence suggests that it progressively develops since birth and, in certain instances, may begin as early as fetal life. Therefore, early recognition and intervention are of great importance in order to improve long-term outcomes. Based on the most recent knowledge of BPD-PH pathophysiology, we review state-of-the-art screening and diagnostic imaging techniques currently available, their utility for clinicians, and their applicability and limitations in this specific population. We also discuss some biochemical markers studied in humans as a possible complement to imaging for the detection of pulmonary vascular disease at its early stages and the monitoring of its progression. In the second part, we review pharmacological agents currently available for BPD-PH treatment or under preclinical investigation, and discuss their applicability, as well as possible approaches for early-stage interventions in fetuses and neonates. IMPACT: BPD-associated PH is a complex disease involving genetic and epigenetic factors, as well as environmental exposures starting from fetal life. The value of combining multiple imaging and biochemical biomarkers is emerging, but requires larger, multicenter studies for validation and diffusion. Since "single-bullet" approaches have proven elusive so far, combined pharmacological regimen and cell-based therapies may represent important avenues for research leading to future cure and prevention.

Нарушения дыхания во сне и БЛД-ассоциированная легочная гипертензия у недоношенных детей

This article presents current data on the features of sleep-related breathing disorders in preterm infants with bronchopulmonary dysplasia (BPD) and pulmonary hypertension. The data on BPD-associated pulmonary hypertension, morphological changes in lung tissue, possible complications and clinical outcomes in this pathology were summarized. The basic data on intermittent hypoxic episodes, apnea and periodic breathing and their influence on the development and maintenance of pulmonary hypertension were reviewed. The methods were described that allow to accurately differentiate the character of sleep-related breathing disorders for the purpose of timely diagnosis and correction of therapy. The feasibility of using polysomnography and cardiorespiratory sleep monitoring as diagnostic methods for this category of patients was substantiated. Key words: BPD-associated pulmonary hypertension, breathing disorder, preterm infants

Endothelial to mesenchymal transition during neonatal hyperoxia-induced pulmonary hypertension.

Bronchopulmonary dysplasia (BPD), a chronic lung disease in premature infants, results from mechanical ventilation and hyperoxia, amongst other factors. Although most BPD survivors can be weaned from supplemental oxygen, many show evidence of cardiovascular sequelae in adulthood, including pulmonary hypertension and pulmonary vascular remodeling. Endothelial-mesenchymal transition (EndoMT) plays an important role in mediating vascular remodeling in idiopathic pulmonary arterial hypertension. Whether hyperoxic exposure, a known mediator of BPD in rodent models, causes EndoMT resulting in vascular remodeling and pulmonary hypertension remains unclear. We hypothesized that neonatal hyperoxic exposure causes EndoMT, leading to the development of pulmonary hypertension in adulthood. To test this hypothesis, newborn mice were exposed to hyperoxia and then allowed to recover in room air until adulthood. Neonatal hyperoxic exposure gradually caused pulmonary vascular and right ventricle remodeling as well as pulmonary hypertension. Male mice were more susceptible to developing pulmonary hypertension compared to female mice, when exposed to hyperoxia as newborns. Hyperoxic exposure induced EndoMT in mouse lungs as well as in cultured lung microvascular endothelial cells (LMVECs) isolated from neonatal mice and human fetal donors. This was augmented in cultured LMVECs from male donors compared to those from female donors. Using primary mouse LMVECs, hyperoxic exposure increased phosphorylation of both Smad2 and Smad3, but reduced Smad7 protein levels. Treatment with a selective TGF-β inhibitor SB431542 blocked hyperoxia-induced EndoMT in vitro. Altogether, we show that neonatal hyperoxic exposure caused vascular remodeling and pulmonary hypertension in adulthood. This was associated with increased EndoMT. These novel observations provide mechanisms underlying hyperoxia-induced vascular remodeling and potential approaches to prevent BPD-associated pulmonary hypertension by targeting EndoMT. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.