Differential MicroRNA Expression in Very Low Birth Weight Infants with and Without Bronchopulmonary Dysplasia and Chronic Pulmonary Hypertension: A Feasibility Study

摘要

Background: Bronchopulmonary dysplasia (BPD) and chronic pulmonary hypertension (cPHTN) are chronic diseases of prematurity that affect up to 40% of very low birth weight infants (VLBW: babies born less than 1500 g and less than 32 weeks gestational age). About 25% of these infants will develop BPD and cPHTN as comorbidities, which increases their mortality rate and respiratory symptoms that can persist into adulthood. Commonalities between cPHTN and BPD are the involvement of lung parenchyma and pulmonary blood vessels and a dysregulated immune system. MicroRNA (miRNA) have emerged as potential biomarkers for diagnosis and prognosis of chronic pulmonary hypertension. Differential miRNA expression has been described in older children and adults with pulmonary hypertension. The pathophysiology of both diseases is multifactorial and requires multiple approaches to evaluate and describe their development. Currently, there are no early biomarkers that reliably identify infants who are at high risk for BPD-cPHTN. We developed a research protocol to detect potential early biomarkers and echocardiographic markers of BPD-cPHTN to identify patients at risk of developing BPD-cPHTN and aid in finding new prevention and treatment targets. The purpose of this study was to assess the feasibility of implementing a protocol to identify predictive and prognostic markers for BPD-cPHTN by evaluating the following specific aims over a 6-month period: 1) recruitment capability and resulting sample characteristics; (2) refinement of data collection procedures and outcome measures; and (3) acceptability and suitability of the study procedures, resources, and ability to manage and implement the study.Methods: This was a mixed methods prospective observational study that took place at the Oklahoma Children's Hospital's: OUHSC neonatal intensive care unit (NICU). VLBWs (<32 wks and <1500 g) were recruited to participate in the study, which included collection of biospecimens and completion of echocardiograms at four time points (events 1- 4). We collected information on the process, the refinement of procedures related to data collection, and acceptability and suitability of the study procedures. Process measures included recruitment capability and resulting participant characteristics, the research nurse's availability, the most common times for parents/legal guardians' availability, the most common times for consent, screening logs with recruitment rates, recruitment capacity, barriers to recruitment, and reasons for non-participation. Data collection procedures and their refinement involved transcribing and entering data into REDCap? from EMRs (Cribnotes? and Meditech?) for demographics, clinical characteristics, and outcome variables.) Acceptability and suitability of the study procedures involved evaluation of adherence to sample collection, storage, and processing instructions, and the tracking of echocardiograph completion times and duration.Results: Sixty-six patients born at < 32 weeks gestational age were born during the study period; Fifty-eight were screened and 40 met inclusion criteria. The consent rate was 34%, with 100% retention of recruited participants. Barriers to parental consent included the stress of a new premature baby, misconceptions regarding clinical research, and parental availability. Obstacles related to approach and consent by research staff included exposure-related quarantine (SARS-COV-19), and work hours. Participant characteristics were varied and comparable to similar studies in neonates.Conclusions: Implementation of the protocol was feasible. Multiple barriers were encountered, processes were augmented and improved to increase recruitment and consent rates. The ultimate goals of this line of research are to understand the molecular and cellular processes that are altered and to detect novel miRNA /biomarkers of BPD-cPHTN in the blood and urine of VLBWs. This understanding may help us to identify patients at risk