Pediatric Pulmonary Hypertension: Insulin Like Growth Factor Binding Protein 2 is a novel marker associated with disease severity and survival

BACKGROUND: 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. METHODS: 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) as a chronic pediatric pulmonary disease control. Biomarkers were analyzed with demographic, and clinical variables for PAH severity. RESULTS: 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 minute-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). CONCLUSION: 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.