Conference: 2018 PHA International PH Conference & Scientific Sessions
Release Date: 06.28.2018
Presentation Type: Abstracts
File Download: Conference 2018_1031
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Abstract presented at the 2018 International PH Conference and Scientific Sessions in Orlando, Fla., June 28-July 1, 2018.
Upton PD, Goumans MJ, Zamanian RT, Elliott G, Morrell NW, Chung RT, Channick RW, Roberts KE, Yu PB
Bone Morphogenetic Protein 9 (BMP9) is a circulating endothelial quiescence factor with protective effects in pulmonary arterial hypertension (PAH). Loss-of-function mutations in BMP9 receptors and downstream effectors have been reported in heritable PAH. We sought to determine how an acquired deficiency of BMP9 signaling might contribute to PAH.
Plasma levels of BMP9 and antagonist soluble Endoglin (sEng) were measured in Group 1 PAH, Group 2 and 3 pulmonary hypertension (PH), and in patients with severe liver disease without PAH. Mice with CCl4-induced cirrhosis and portal hypertension were assessed for PH and levels of circulating BMP9. The impact of administering the BMP9 ligand trap ALK1-Fc was assessed in wild-type mice.
BMP9 levels were markedly lower in portopulmonary hypertension (PoPH) as compared to controls in a derivation cohort (46 pg/mL [IQR 21-71 pg/mL] vs. 210 pg/mL [IQR 190-246 pg/mL], p<0.0001), and confirmed in a distinct validation cohort. Across both cohorts diminished BMP9 was present in PoPH but not other etiologies of Group 1 PAH (ROC-AUC=0.91±0.03, p<0.0001), but was an independent predictor of transplant-free survival (Cox HR 0.74 per 50 pg/mL increase, 95% CI 0.56-0.97. p=0.03) in Group 1 PAH regardless of PoPH status. Diminished BMP9 distinguished PoPH from patients with liver disease without PAH (223 pg/ml [IQR 153-282 pg/mL], p<0.0001 vs. PoPH), particularly among individuals with mild hepatic dysfunction (MELD score ≤ 10), and was more sensitive for the presence of PoPH among patients with liver disease than echocardiographic RVSP, with equivalent specificity. BMP9 levels were decreased in mice with PH associated with CCl4-induced portal hypertension and cirrhosis, but were normal in other rodent models of PH including monocrotaline-treated rats, and SUGEN-hypoxia-treated rats and mice. Administration of potent BMP9 ligand trap ALK1-Fc severely exacerbated PH and pulmonary vascular remodeling in mice treated with hypoxia vs. hypoxia alone (50±8 mmHg vs. 34±1 mmHg, p=0.04).
BMP9 is a sensitive and specific biomarker of PoPH, predicting transplant-free survival and the presence of PAH in end-stage liver disease. In rodent models, acquired deficiency of BMP9 signaling can predispose to or exacerbate PH, thereby providing a new mechanistic link between PoPH and heritable PAH. These findings raise concerns about the effects of anti-angiogenic therapies targeting BMP9/ALK1 signaling, while describing a novel experimental model of severe PH and remodeling due to acquired loss of BMP signaling.
Circulating BMP9 is profoundly decreased in portopulmonary hypertension
Figure 1: Circulating BPM9 is profoundly decreased in PoPH