Abstract 20431: Portopulmonary Hypertension is Marked by Severely Diminished Circulating Bone Morphogenetic Protein 9
Abstract Background: Defects in bone morphogenetic protein (BMP) signaling contribute to the pathogenesis of pulmonary arterial hypertension (PAH). BMP9 is a circulating vascular endothelial quiescence factor with protective effects in PAH. We hypothesized that diminished BMP9 signaling may contribute to PAH.
Methods and Results: Circulating levels of BMP9 and its circulating antagonist soluble Endoglin (sEng) were measured in 215 patients with WHO Group 1 PAH, Group 2 or Group 3 pulmonary hypertension, and 63 healthy individuals using a sensitive immunoassay. BMP9 was minimally decreased among patients with Group 1 PAH as a whole (187 ± 9 pg/mL vs. 218 ± 10 pg/mL in healthy controls, mean ± SEM, n=174, p=0.0026), but was profoundly decreased among patients with portopulmonary hypertension (PoPH, 76 ± 9 pg/mL, n=37, p<0.0001), segregating PoPH from all other etiologies of PAH (ROC-AUC=0.91 ± 0.03, p<0.0001). BMP9 levels were significantly lower in PoPH vs. patients with liver disease without PAH (218 ± 19 pg/mL, n=43, p<0.0001 vs. PoPH) even after accounting for severity of liver disease, and predicted transplant-free survival in PAH. Among individuals with mild hepatic dysfunction (MELD score ≤ 10), a BMP9 level <160 pg/mL was 92% sensitive and 91% specific for the presence of PoPH. Circulating sEng correlated negatively with BMP9 (r=-0.32, p=0.0005) and was most elevated in PoPH. Further supporting specificity for PoPH, BMP9 levels correlated inversely with the development of pulmonary hypertension in cirrhotic mice, but were preserved in other rodent models of pulmonary hypertension examined.
Conclusion: Diminished plasma BMP9 is a sensitive and specific marker of PoPH. Given the need for early recognition of PAH in liver disease, decreased BMP9 levels may be a useful screening tool for PoPH in high-risk populations. In light of its role in maintaining pulmonary vascular endothelial homeostasis, we propose that loss of BMP9 may be a penetrance factor for the development of PAH in liver disease.
Author Disclosures: I. Nikolic: None. L. Yung: None. S.D. Paskin-Flerlage: None. R. Malhotra: None. A.D. Faugno: None. C.S. Lai: None. P.D. Upton: None. P. ten Dijke: None. N.W. Morrell: None. R.T. Zamanian: None. R. Chung: None. C. Elliott: None. R.W. Channick: None. K.E. Roberts: None. P.B. Yu: None.
- © 2016 by American Heart Association, Inc.