Early angiogenic proteins associated with high risk for bronchopulmonary dysplasia and pulmonary hypertension in preterm infants

Early pulmonary vascular disease in preterm infants is associated with the subsequent development of bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH); however, mechanisms that contribute to or identify infants with increased susceptibility for BPD and/or PH are incompletely understood. Therefore, we tested if changes in circulating angiogenic peptides during the first week of life are associated with the later development of BPD and/or PH. We further sought to determine alternate peptides and related signaling pathways with the risk for BPD or PH. We prospectively enrolled infants with gestational age <34 wk and collected blood samples during their first week of life. BPD and PH were assessed at 36 wk postmenstrual age. Samples were assayed for each of the 1,121 peptides included in the SOMAscan scan technology, with subsequent pathway analysis. Of 102 infants in the study, 82 had BPD, and 13 had PH. Multiple angiogenic proteins (PF-4, VEGF121, ANG-1, bone morphogenetic protein 10 [BMP10], hepatocyte growth factor (HGF), ANG-2) were associated with the subsequent diagnosis of BPD; and FGF-19, PF-4, connective tissue activating peptide (CTAP)-III, and PDGF-AA levels were associated with BPD severity. Early increases in BMP10 was strongly associated with the late risk for BPD and PH. We found that early alterations of circulating angiogenic peptides and others were associated with the subsequent development of BPD. We further identified peptides that were associated with BPD severity and BPD-associated PH, including BMP10. We speculate that proteomic biomarkers during the first week of life may identify infants at risk for BPD and/or PH to enhance care and research.

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Left Ventricle Phenotyping Utilizing Tissue Doppler Imaging in Premature Infants with Varying Severity of Bronchopulmonary Dysplasia

Journal of Clinical Medicine ◽

10.3390/jcm10102211 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2211

Author(s):

Eunice Torres ◽

Philip T. Levy ◽

Afif El-Khuffash ◽

Hongjie Gu ◽

Aaron Hamvas ◽

...

Keyword(s):

Left Ventricle ◽

Preterm Infants ◽

Bronchopulmonary Dysplasia ◽

Tissue Doppler Imaging ◽

Myocardial Dysfunction ◽

Tissue Doppler ◽

Doppler Imaging ◽

Pulmonary Vascular Disease ◽

Lv Function ◽

Postmenstrual Age

Bronchopulmonary dysplasia (BPD) is characterized by alveolar-capillary simplification and is associated with pulmonary hypertension (PH) in preterm infants. The contribution of left ventricle (LV) disease towards this severe BPD-PH phenotype is not well established. We aimed to describe the longitudinal trajectory of the LV function as measured by tissue Doppler imaging (TDI) and its association with BPD-PH. We retrospectively assessed prospectively acquired clinical and echocardiographic data from 77 preterm infants born between 2011 and 2013. We characterized the LV function by measuring systolic and diastolic myocardial velocities (s’, e’, a’), isovolumetric relaxation time (IVRT), and myocardial performance index with TDI at three time periods from 32 and 36 weeks, postmenstrual age through one year of age. We also measured post systolic motion (PSM), a marker of myocardial dysfunction that results from asynchronous movement of the ventricular walls, and not previously described in preterm infants. Patients were stratified into groups according to BPD severity and the presence of PH and compared over time. Conventional TDI measures of the LV function were similar between groups, but the septal PSM was significantly prolonged over the first year of age in patients with BPD-PH. PSM provides a novel objective way to assess the hemodynamic impact of lung and pulmonary vascular disease severity on LV function in preterm infants with BPD and PH.

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Pulmonary hypertension in extremely preterm infants: a call to standardize echocardiographic screening and follow-up policy

European Journal of Pediatrics ◽

10.1007/s00431-021-03931-5 ◽

2021 ◽

Author(s):

Sanne Arjaans ◽

Elvira. A. H. Zwart ◽

Marc Roofthooft ◽

Elisabeth M. W. Kooi ◽

Arend F. Bos ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Preterm Infants ◽

Bronchopulmonary Dysplasia ◽

Early Onset ◽

Late Onset ◽

Treatment Strategies ◽

Subsequent Development ◽

Extremely Preterm ◽

Extremely Preterm Infants

AbstractPulmonary hypertension (PH) is a frequent complication in extremely preterm born infants that seriously affects outcome. We aimed to describe the prevalence of PH in extremely preterm infants and the policy on screening and follow-up in the ten Dutch intensive care units (NICUs). We performed a retrospective cohort study at the University Medical Centre Groningen on infants with gestational age < 30 weeks and/or birthweight < 1000 g, born between 2012 and 2013. Additionally, we carried out a survey among the Dutch NICUs covering questions on the awareness of PH, the perceived prevalence, and policy regarding screening and following PH in extremely preterm infants. Prevalence of early-onset PH in our study was 26% and 5% for late-onset PH. PH was associated with poor survival and early-onset PH was associated with subsequent development of bronchopulmonary dysplasia (BPD). All the NICUs completed the questionnaire and we found that no standardized policy existed regarding screening and following PH in extremely preterm infants.Conclusion: Despite the frequent occurrence of PH and its clinically important consequences, (inter-)national standardized guidelines regarding screening and following of PH in extremely preterm infants are lacking. Standardizing screening and follow-up will enable early identification of infants with late-onset PH and allow for earlier treatment. Additionally, greater clarity is required regarding the prevalence of early PH as are new preventive treatment strategies to combat BPD. What is known? • Pulmonary hypertension (PH) substantially impairs the survival of extremely preterm infants. • PH is associated with bronchopulmonary dysplasia (BPD): Early-onset PH predicts the development of BPD. Late-onset PH is prevalent in infants with severe BPD. What is new? • Pulmonary hypertension (PH) is prevalent in preterm infants. Its consequences for morbidity and mortality justify a standardized policy aimed at early detection to improve prevention and treatment. • No structured policy exists in the Netherlands regarding screening/follow-up for PH in extremely preterm infants.

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Incidence, risk factors, and outcomes of pulmonary hypertension in preterm infants with bronchopulmonary dysplasia

Paediatrics & Child Health ◽

10.1093/pch/pxz024 ◽

2019 ◽

Vol 25 (4) ◽

pp. 222-227 ◽

Cited By ~ 1

Author(s):

Katelyn MacKenzie ◽

Kathy Cunningham ◽

Sumesh Thomas ◽

Tapas Mondal ◽

Salhab el Helou ◽

...

Keyword(s):

Risk Factors ◽

Pulmonary Hypertension ◽

Preterm Infants ◽

Bronchopulmonary Dysplasia ◽

Significant Risk ◽

Control Groups ◽

Short Term ◽

Postmenstrual Age ◽

Incidence Risk ◽

Echocardiographic Assessment

Abstract Objectives To determine the incidence and risk factors for pulmonary hypertension (PH) in preterm infants with moderate to severe bronchopulmonary dysplasia (BPD) and to compare short-term outcomes. Methods Preterm infants <32 weeks gestation born August 2013 through July 2015 with moderate to severe BPD at 36 weeks postmenstrual age were categorized into BPD-PH (exposure) and BPD-noPH (control) groups. Results Of 92 infants with BPD, 87 had echocardiographic assessment, of whom 24 (28%) had PH. On multiple logistic regression after adjustment for gestational age and sex, no significant risk factors for PH were identified based on data from this cohort. There were no differences in resource utilization or clinical outcomes including survival to discharge. Conclusion Approximately one out of four patients with moderate to severe BPD were identified as having PH. No significant risk factors for PH were identified. No differences in outcomes were identified for those with and without PH.

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Lung Ultrasound in Bronchopulmonary Dysplasia: Patterns and Predictors in Very Preterm Infants

Neonatology ◽

10.1159/000517585 ◽

2021 ◽

pp. 1-9

Author(s):

Victoria Aldecoa-Bilbao ◽

Mar Velilla ◽

Marta Teresa-Palacio ◽

Carla Balcells Esponera ◽

Ana Herranz Barbero ◽

...

Keyword(s):

Preterm Infants ◽

Bronchopulmonary Dysplasia ◽

Lung Ultrasound ◽

Respiratory Support ◽

Very Preterm Infants ◽

Very Preterm ◽

Pleural Line ◽

Respiratory Management ◽

Postmenstrual Age ◽

Severity Of The Disease

Introduction: Lung ultrasound (LUS) is useful for respiratory management in very preterm infants (VPI), but little is known about the echographic patterns in bronchopulmonary dysplasia (BPD), the relation between the image findings, and the severity of the disease and its long-term outcomes. We aimed to describe LUS patterns in BPD and analyze the accuracy of LUS to predict the need for respiratory support at 36 weeks postmenstrual age (PMA) in VPI. Methods: Preterm infants ≤30.6 weeks of gestational age were recruited. LUS was performed at admission, at 7th, and 28th day of life (DOL) with a standardized protocol (6 zones: anterior, lateral, and posterior fields). Clinical data, respiratory outcomes, and image findings were recorded. Results: Eighty-nine patients were studied. Infants with BPD had significantly higher LUS score at admission, at 7th, and 28th DOL. Patients with BPD exhibited more consolidations and pleural line abnormalities at 7th and 28th DOL than those without BPD (p < 0.001), regardless of the definition used for BPD. LUS at 7th DOL predicted NICHD 2001-BPD with R2 = 0.522; AUC = 0.87 (0.79–0.94), p < 0.001, and Jensen 2019-BPD with R2 = 0.315 (AUC = 0.80 [0.70–0.90], p < 0.001). A model including mechanical ventilation >5 days, oxygen therapy for 7 days and LUS score at 7th DOL accurately predicted the need for respiratory support at 36 weeks PMA (R2 = 0.655, p < 0.001) with an AUC = 0.90 (0.84–0.97), p < 0.001. Conclusion: LUS score, pleural line abnormalities, and consolidations can be useful to diagnose BPD in VPI and to predict its severity after the first week of life.

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258 Fetal Haemoglobin Levels in Preterm Infants at 36 Weeks Postmenstrual Age: Effect of Bronchopulmonary Dysplasia, Sepsis and Transfusions

Archives of Disease in Childhood ◽

10.1136/archdischild-2012-302724.0258 ◽

2012 ◽

Vol 97 (Suppl 2) ◽

pp. A75-A75

Author(s):

B. Perrone ◽

P. Marchionni ◽

A. Bartoli ◽

C. Gidiucci ◽

M. Pasqualini ◽

...

Keyword(s):

Preterm Infants ◽

Bronchopulmonary Dysplasia ◽

Age Effect ◽

Fetal Haemoglobin ◽

Postmenstrual Age

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Endothelial Extracellular Signal-Regulated Kinase 2 (ERK2)-Deficient Mice Display Increased Susceptibility to Hyperoxia-Induced Experimental Bronchopulmonary Dysplasia and Pulmonary Hypertension

10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a6039 ◽

2019 ◽

Author(s):

B. Shivanna ◽

A. Shrestha ◽

C. Reynolds ◽

R. Menon

Keyword(s):

Pulmonary Hypertension ◽

Bronchopulmonary Dysplasia ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal ◽

Deficient Mice ◽

Increased Susceptibility

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Targeting Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension (BPD-PH): Potential Role of the FGF Signaling Pathway in the Development of the Pulmonary Vascular System

Cells ◽

10.3390/cells9081875 ◽

2020 ◽

Vol 9 (8) ◽

pp. 1875

Author(s):

Cho-Ming Chao ◽

Lei Chong ◽

Xuran Chu ◽

Amit Shrestha ◽

Judith Behnke ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Signaling Pathway ◽

Preterm Infants ◽

Bronchopulmonary Dysplasia ◽

Potential Role ◽

Vascular System ◽

Point Of View ◽

Pulmonary Vasculature ◽

Curative Therapy

More than 50 years after the first description of Bronchopulmonary dysplasia (BPD) by Northway, this chronic lung disease affecting many preterm infants is still poorly understood. Additonally, approximately 40% of preterm infants suffering from severe BPD also suffer from Bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH), leading to a significant increase in total morbidity and mortality. Until today, there is no curative therapy for both BPD and BPD-PH available. It has become increasingly evident that growth factors are playing a central role in normal and pathologic development of the pulmonary vasculature. Thus, this review aims to summarize the recent evidence in our understanding of BPD-PH from a basic scientific point of view, focusing on the potential role of Fibroblast Growth Factor (FGF)/FGF10 signaling pathway contributing to disease development, progression and resolution.

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