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

Circulation, vol. 144

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.

Authors 10

1. Aida Llucià Valldeperas

   Amsterdam University Medical Centers · University of Amsterdam

   Affiliation as printed

   Pulmonary Medicine, Amsterdam Univ Med Cntr, Amsterdam

2. Jessie van Wezenbeek

   Amsterdam University Medical Centers · University of Amsterdam

   Affiliation as printed

   Pulmonary Medicine, Amsterdam Univ Med Cntr, Amsterdam

   Jessie Van Wezenbeek Pulmonary Medicine, Amsterdam Univ Med Cntr, Amsterdam

3. Joanne A. Groeneveldt

   Amsterdam University Medical Centers · University of Amsterdam

   Affiliation as printed

   Pulmonary Medicine, Amsterdam Univ Med Cntr, Amsterdam

   Joanne A Groeneveldt Pulmonary Medicine, Amsterdam Univ Med Cntr, Amsterdam

4. Gonzalo Sánchez‐Duffhues Aachen Cell and Chemical Biology Gonzalo Sanchez-Duffhues Cell and Chemical Biology

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Cell and Chemical Biology, Leiden UMC, Leiden

   Gonzalo Sanchez-Duffhues Cell and Chemical Biology, Leiden UMC, Leiden

5. Rowan Smal

   Amsterdam University Medical Centers · University of Amsterdam

   Affiliation as printed

   Pulmonary Medicine, Amsterdam Univ Med Cntr, Amsterdam

   Rowan Smal Pulmonary Medicine, Amsterdam Univ Med Cntr, Amsterdam

6. Xiaoke Pan

   Amsterdam University Medical Centers · University of Amsterdam

   Affiliation as printed

   Pulmonary Medicine, Amsterdam Univ Med Cntr, Amsterdam

   Xiaoke Pan Pulmonary Medicine, Amsterdam Univ Med Cntr, Amsterdam

7. Anton Vonk Noordegraaf

   Amsterdam University Medical Centers · University of Amsterdam

   Affiliation as printed

   Pulmonary Medicine, Amsterdam Univ Med Cntr, Amsterdam

   anton vonk noordegraaf Pulmonary Medicine, Amsterdam Univ Med Cntr, Amsterdam

8. Harm Jan Bogaard

   Amsterdam University Medical Centers · University of Amsterdam

   Affiliation as printed

   Pulmonary Medicine, Amsterdam Univ Med Cntr, Amsterdam, Netherlands

   Harm J Bogaard Pulmonary Medicine, Amsterdam Univ Med Cntr, Amsterdam, Netherlands

9. Marie‐José Goumans Aachen Marie Jose Goumans LUMC

   Leiden University Medical Center

   Affiliation as printed

   LUMC, Leiden

   Marie Jose Goumans LUMC, Leiden

10. Frances S. de Man

    Amsterdam University Medical Centers

    Affiliation as printed

    Amsterdam Univ Med Cntr, Amsterdam

    Frances S De Man Amsterdam Univ Med Cntr, Amsterdam