Abstract 10462: Increased Bone Morphogenetic Protein 10 Activity is Associated with Increased Right Atrial Wall Stress and Disease Severity in Pulmonary Hypertension

Abstract

Background: Pulmonary Hypertension (PH) is characterized by increased right atrial (RA) stretch and pressure. The major predisposing risk factor for PH involves mutations in bone morphogenetic protein (BMP) receptor 2 (BMPR2), for which BMP9 and BMP10 are ligands. In adults, BMP10 is produced by RA cardiomyocytes, however, the mechanism to BMP10 release is unknown. We hypothesize that RA wall stress may be a trigger for BMP10 secretion. Methods: We determined BMP10 and BMP9 levels in plasma samples from PH-patients (22 idiopathic pulmonary arterial hypertension (iPAH), 14 hereditary PAH (hPAH) and 11 chronic thromboembolic PH (CTEPH)) and 16 controls by ELISA. To study BMP10 and BMP9 activity, we exposed endothelial cells to 10% serum and analyzed BMP-activity as read out of the BRE-luciferase reporter assay. Serum was incubated with trap antibodies: anti-BMP9 to inhibit BMP9 ligand, and ALK1-Fc to inhibit both BMP9 and BMP10 ligands. BMP9 and BMP10 activity were deducted from the difference vs baseline and BMP9-activity, respectively. Results: Circulating BMP10 levels were higher in PH-patients: 16.5 [9.5-69.7] pg/mL in iPAH, 17.1 [1.4-113.4] pg/mL in hPAH and 37.8 [10.7-87.1] pg/mL in CTEPH, vs 6.1 [0-8.7] pg/mL in controls (A). No differences were observed in BMP9 levels (B). BMP10 and BMP9 activity appeared lower in iPAH, only a trend was seen in BMP9-activity in iPAH vs hPAH (C,D). Next, we divided the PH cohort on median BMP10-activity. Higher active BMP10 in PH was associated with an increase in RA volume and pressure, and reduced RA compliance (E). Further, higher BMP10-activity in PH-patients was associated with worse disease status, shown by worse right ventricular function, lower stroke volume and increased NTproBNP (F). Conclusions: BMP10 circulating levels were increased in PH, whereas no difference in circulating BMP10-activity was observed. High BMP10-activity was associated with increased RA wall stress and disease severity in PH-patients.