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Insulin-like growth factor binding protein-2: a new circulating indicator of pulmonary arterial hypertension severity and survival

ABSTRACT: Background Pulmonary arterial hypertension (PAH) is a fatal disease that results from cardio-pulmonary dysfunction with the pathology largely unknown. Insulin-like growth factor binding protein 2 (IGFBP2) is an important member of the insulin-like growth factor family, with evidence suggesting elevation in PAH patients. We investigated the diagnostic and prognostic value of serum IGFBP2 in PAH to determine if it could discriminate PAH from healthy controls and if it was associated with disease severity and survival. Methods Serum IGFBP2 levels, as well as IGF1/2 levels, were measured in two independent PAH cohorts, the Johns Hopkins Pulmonary Hypertension program (JHPH, N?=?127), NHLBI PAHBiobank (PAHB, N?=?203), and a healthy control cohort (N?=?128). The protein levels in lung tissues were determined by western blot. The IGFBP2 mRNA expression levels in pulmonary artery smooth muscle cells (PASMC) and endothelial cells (PAEC) were assessed by RNA-seq, secreted protein levels by ELISA. Association of biomarkers with clinical variables was evaluated using adjusted linear or logistic regression and Kaplan-Meier analysis. Results In both PAH cohorts, serum IGFBP2 levels were significantly elevated (p?

SUBMITTER: Yang J

PROVIDER: S-EPMC7537100 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Insulin-like growth factor binding Protein-4: A novel indicator of pulmonary arterial hypertension severity and survival.

Project description:Proteomic analysis of patients with pulmonary arterial hypertension (PAH) has demonstrated significant abnormalities in the insulin-like growth factor axis (IGF). This study proposed to establish associations between a specific binding protein, insulin-like growth factor binding protein 4 (IGFBP4), and PAH severity as well as survival across varying study cohorts. In all cohorts studied, serum IGFBP4 levels were significantly elevated in PAH compared to controls (p < 0.0001). IGFBP4 concentration was also highest in the connective tissue-associated PAH (CTD-PAH) and idiopathic PAH subtypes (876 and 784 ng/mL, median, respectively). After adjustment for age and sex, IGFBP4 was significantly associated with worse PAH severity as defined by a decreased 6-min walk distance (6MWD), New York heart association functional class (NYHA-FC), REVEAL 2.0 score and higher right atrial pressures. In longitudinal analysis provided by one of the study cohorts, IGFBP4 was prospectively significantly associated with a shorter 6MWD, worse NYHA-FC classification, and decreased survival. Cox multivariable analysis demonstrated higher serum IGFBP4 as an independent predictor of survival in the overall PAHB cohort. Therefore, this study established that higher circulating IGFBP4 levels were significantly associated with worse PAH severity, decreased survival and disease progression. Dysregulation of IGF metabolism/growth axis may play a significant role in PAH cardio-pulmonary pathobiology.

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Circulating nerve growth factor receptor positive cells are associated with severity and prognosis of pulmonary arterial hypertension.

Project description:Pulmonary arterial hypertension (PAH) remains a disease with a poor prognosis, so early detection and treatment are very important. Sensitive and non-invasive markers for PAH are urgently required. This study was performed to identify sensitive markers of the clinical severity and prognosis of PAH. Patients diagnosed with PAH (n = 30) and control participants (n = 15) were enrolled in this observational study. Major EPC and MSC markers (including CD34, CD133, VEGFR2, CD90, PDGFRα, and NGFR) in peripheral blood mononuclear cells (PBMNCs) were assessed by flow cytometry. Associations of these markers with hemodynamic parameters (e.g. mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac index) were assessed. Patients with PAH were followed up for 12 months to assess the incidence of major adverse events, defined as death or lung transplantation. Levels of circulating EPC and MSC markers in PBMNCs were higher in patients with PAH than in control participants. Among the studied markers, nerve growth factor receptor (NGFR) was significantly positively correlated with hemodynamic parameters. During the 12-month follow-up period, major-event-free survival was significantly higher in patients with PAH who had relatively low frequencies of NGFR positive cells than patients who had higher frequencies. These results suggested that the presence of circulating NGFR positive cells among PBMNCs may be a novel biomarker for the severity and prognosis of PAH.

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Proteomics discovery of pulmonary hypertension biomarkers: Insulin-like growth factor binding proteins are associated with disease severity.

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An Overview of Circulating Pulmonary Arterial Hypertension Biomarkers.

Project description:Pulmonary arterial hypertension (PAH), also known as Group 1 Pulmonary Hypertension (PH), is a PH subset characterized by pulmonary vascular remodeling and pulmonary arterial obstruction. PAH has an estimated incidence of 15-50 people per million in the United States and Europe, and is associated with high mortality and morbidity, with patients' survival time after diagnosis being only 2.8 years. According to current guidelines, right heart catheterization is the gold standard for diagnostic and prognostic evaluation of PAH patients. However, this technique is highly invasive, so it is not used in routine clinical practice or patient follow-up. Thereby, it is essential to find new non-invasive strategies for evaluating disease progression. Biomarkers can be an effective solution for determining PAH patient prognosis and response to therapy, and aiding in diagnostic efforts, so long as their detection is non-invasive, easy, and objective. This review aims to clarify and describe some of the potential new candidates as circulating biomarkers of PAH.

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Project description:Microarray analysis of peripheral blood mononuclear (PBMC) cells in pulmonary arterial hypertension. Keywords = mononuclear cells Keywords = gene microarray Keywords = pulmonary arterial hypertension Keywords = Herpesvirus Keywords = biomarker Keywords: other

2003-11-15 | GSE703 | GEO

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