Search

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. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by sustained elevations of pulmonary artery pressure. To date, we lack circulating, diagnostic, and prognostic markers that correlate to clinical and functional parameters. In this study, we performed mass spectrometry‐based proteomics analysis to identify circulating biomarkers of PAH. Plasma samples from patients with idiopathic pulmonary arterial hypertension (IPAH, N=9) and matched normal controls (N = 9) were digested with trypsin and analyzed using data‐dependent acquisition on an Orbitrap mass spectrometer. A total of 826 (false discovery rate [FDR] 0.047) and 461 (FDR 0.087) proteins were identified across all plasma samples obtained from IPAH and control subjects, respectively. Of these, 153 proteins showed >2 folds change (p < 0.05) between groups. Circulating levels of carbonic anhydrase 2 (CA2), plasma kallikrein (KLKB1), and the insulin‐like growth factor binding proteins (IGFBP1‐7) were quantified by immunoassay in an independent verification cohort (N=36 PAH and N = 35 controls). CA2 and KLKB1 were significantly different in PAH versus control but were not associated with any functional or hemodynamic measurements. Whereas, IGFBP1 and 2 were associated with higher pulmonary vascular resistance, IGFBP2, 4, and 7 with decreased 6‐min walk distance (6MWD), and IGFBP1, 2, 4, and 7 with worse survival. This plasma proteomic discovery analysis suggests the IGF axis may serve as important new biomarkers for PAH and play an important role in PAH pathogenesis. [ABSTRACT FROM AUTHOR]

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 < 0.0001) compared to controls and discriminated PAH from controls with an AUC of 0.76 (p < 0.0001). A higher IGFBP2 level was associated with a shorter 6-min walk distance (6MWD) in both cohorts after adjustment for age and sex (coefficient - 50.235 and - 57.336 respectively). Cox multivariable analysis demonstrated that higher serum IGFBP2 was a significant independent predictor of mortality in PAHB cohort only (HR, 3.92; 95% CI, 1.37-11.21). IGF1 levels were significantly increased only in the PAHB cohort; however, neither IGF1 nor IGF2 had equivalent levels of associations with clinical variables compared with IGFBP2. Western blotting shown that IGFBP2 protein was significantly increased in the PAH vs control lung tissues. Finally, IGFBP2 mRNA expression and secreted protein levels were significantly higher in PASMC than in PAEC.Conclusions: IGFBP2 protein expression was increased in the PAH lung, and secreted by PASMC. Elevated circulating IGFBP2 was associated with PAH severity and mortality and is a potentially valuable prognostic marker in PAH. [ABSTRACT FROM AUTHOR]