Elevated levels of circulating insulin-like growth factor binding protein 2 (IGFBP2) were found to be associated with pulmonary arterial hypertension (PAH) severity and mortality and may represent a prognostic marker for this condition, according to a study published in BMC Medicine.

In this study, participants with PAH were recruited from 2 independent PAH cohorts, the single-center Johns Hopkins Pulmonary Hypertension program (JHPH; n=127; median age 62; 84% women) and the multicenter NHLBI PAHBiobank (PAHB; n=203; median age 56; 78% women). In addition, 128 healthy individuals were enrolled in the control cohort (median age 43; 75% women).

Serum levels of IGFBP2 were found to be elevated in participants with vs without PAH (P <.0001; area under the curve for discriminating PAH from controls, 0.76; P <.0001). Higher IGFBP2 levels were associated with a shorter 6-min walk distance in both PAH and control cohorts after adjusting for age and sex (coefficient, −50.235 and −57.336, respectively).


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Higher serum levels of IGFBP2 were found to be a significant independent predictor of mortality in the PAHB cohort only in a multivariable analysis (hazard ratio, 3.92; 95% CI, 1.37-11.21). Levels of insulin-like growth factor 1 (IGF1) were significantly increased only in the PAHB cohort, but neither IGF1 nor IGF2 had equivalent levels of associations with clinical variables compared with IGFBP2. Levels of IGFBP2 protein were found to be increased in the lungs of patients with vs without PAH. In addition, IGFBP2 mRNA expression and secreted protein levels were significantly higher in pulmonary artery smooth muscle cells (PASMC) compared with pulmonary artery endothelial cells (PAEC).

“We found IGFBP2 serum levels to be significantly increased in PAH patients and associated with increased risk for death,” noted the study authors. “We also found that IGFBP2 was increased in the IPAH lung and is highly expressed and released by PASMC. Although the function of IGFBP2 in angiogenesis and cardiac development remains elusive, this study suggests that IGFBP2 contributes to vascular function in PAH; IGFBP2 may be a key factor for PAH development and may give insight into new treatments.”

Study limitations include the fact that the PAHB cohort was from a multi-center registry, with missing or incomplete covariates, and that serum was not collected at the time of assessment of other clinical variables.

“IGFBP2 is a potential new circulating PAH biomarker associated with disease severity and survival and provides valuable clinical prognostic information,” concluded the investigators. “The increased expression of IGFBP2 in PAH lung and PASMC suggests that IGFBP2 could have a direct role in pulmonary pathobiology of PAH. Further improved understanding of this new pathway is needed to support the possible utility development for PAH clinical care.”

Disclosures: One of the study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of disclosures.

Reference

Yang J, Griffiths M, Nies MK, et al. Insulin-like growth factor binding protein-2: A new circulating indicator of pulmonary arterial hypertension severity and survival [published online October 6, 2020]. BMC Med. doi: 10.1186/s12916-020-01734-3