Insulin-like growth factors (IGFs), and their binding proteins (IGFBPs), play a significant role in cardiovascular function and may influence the pathobiology of PAH. We determined the diagnostic and prognostic value of IGF1 and IGFBP2 in pediatric PAH.
Serum was analyzed by ELISA for IGF1 and IGFBP2 in pediatric PAH subjects from the NHLBI PAH Biobank (PAHB, n = 175) and a cohort of asthmatic subjects (n = 46, age 0-21 years) as a chronic pediatric pulmonary disease control. Biomarkers were analyzed with demographic and clinical variables for PAH severity.
Serum IGF1 was significantly lower in PAH compared to controls, while IGFBP2 was elevated in PAH subjects compared to controls. In the PAHB, IGF1 was negatively associated with mPAP and PVR, while IGFBP2 was positively associated with PVR and negatively associated with cardiac output and 6-min walk distance. Higher IGFBP2 levels were associated with use of prostacyclin therapy. IGFBP2 was associated with death, transplant, or palliative shunt with a Cox proportional hazard ratio of 8.8 (p < 0.001) but not IGF1 (p = 0.13).
Circulating IGFBP2 is a novel marker for pediatric PAH, which is associated with worse functional status, and survival. IGF axis dysregulation may be an important mechanistic target in pediatric pulmonary arterial hypertension.
Pediatric pulmonary hypertension is a severe disease, with poorly understood pathobiology.There are few studies looking at the pathobiology of pulmonary hypertension only in children.The IGF axis is dysregulated in pediatric pulmonary arterial hypertension.IGF axis dysregulation, with increased IGFBP2, is associated with worse clinical outcomes in pediatric pulmonary artery hypertension.IGF axis dysregulation gives new insight into the disease process and may be a mechanistic or therapeutic target.Fig. 1IGF1 AND IGFBP2 CONCENTRATION (NG/ML) IN PAH BIOBANK VERSUS CONTROLS.: a IGF1 concentration (ng/mL) in PAH Biobank versus asthmatic subjects. b IGFBP2 concentration (ng/mL) in PAH Biobank versus asthmatic subjects.Fig. 2ROC CURVE OF IGF1 AND IGFBP2 IN PAH BIOBANK VERSUS CONTROLS.: a ROC curve of IGF1 in PAH Biobank subjects versus controls. AUC 0.82. Cut point for IGF1 of 177 ng/mL gives a sensitivity of 73.9% and a specificity of 78.3%. b ROC curve of IGFBP2 in PAH Biobank subjects versus controls. AUC 0.80. Cut point for IGFBP2 of 185 ng/mL gives a sensitivity of 72.2% and a specificity of 80.4%.Fig. 3IGFBP2 CONCENTRATIONS IN PAH SUBJECTS BY MEDICATION COMBINATION.: a IGFBP2 concentration in PAH subjects on a PDE5 inhibitor, a PDE5 inhibitor and an ERA, a PDE5 inhibitor and IV/SQ PCA, or a combination of PDE5 inhibitor, ERA, and IV/SQ PCA. b IGFBP2 concentrations in PAH subjects on an IV/SQ PCA and any other therapy versus subject not on IV/SQ PCA and any other therapy.Fig. 4Kaplan-Meier curve showing time to death, transplant, or palliative shunt (Pott’s shunt or atrial septostomy) dichotomized by the median IGFBP2 level.

References

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