Circulating angiopoietins in idiopathic pulmonary arterial hypertension.
OBJECTIVE
To determine the diagnostic utility of circulating angiopoietin-1 (Ang-1) and its antagonist angiopoietin-2 (Ang-2) as potential biomarkers of disease severity or response to treatment in idiopathic pulmonary arterial hypertension (IPAH). Imbalances in angiogenic factors including vascular endothelial cell growth factor (VEGF) and the angiopoetin-Tie2 receptor system have been implicated in the pathogenesis of IPAH.


RESULTS
Plasma Ang-1, Ang-2, soluble Tie2 (sTie2), and VEGF were determined by in-house immunoassays in two cohorts of IPAH patients: a retrospective cohort (n = 81) and a prospective cohort (n = 25). Ten patients with normal pulmonary artery pressures and 14 apparently healthy subjects served as controls. Plasma levels of all angiogenic factors were elevated in IPAH patients compared with controls (all P < 0.005). Angiopoietin-2, but not Ang-1, sTie2, and VEGF correlated with cardiac index (r = -0.53, P < 0.001), pulmonary vascular resistance (PVR) (r= 0.60, P < 0.001), and mixed venous oxygen saturation (SvO(2)) (r= -0.63, P < 0.001). In multivariate analysis, elevated Ang-2 was an independent risk factor of mortality (P = 0.004). The patients in the prospective cohort were studied longitudinally at baseline and 3 months after initiation of therapy. Changes in Ang-2 after initiation of therapy correlated with changes in mean right atrial pressure (r = 0.6, P = 0.008), PVR (r = 0.51, P = 0.04), and inversely related to changes in SvO(2) (r = -0.75, P < 0.001). Histological studies showed that the expression of Ang-2 mRNA and protein was up-regulated in plexiform lesions from IPAH lung tissue samples.


CONCLUSIONS
Ang-2 may be involved in the pathogenesis of IPAH, and plasma Ang-2 might serve as a promising new biomarker of disease severity and response to treatment in patients with IPAH.
Kümpers
Philipp
P
Division of General Internal Medicine, Nephrology, and Rheumatology, Department of Medicine D, University Hospital Münster, Albert-Schweitzer-Strasse 33, 48149 Münster, Germany. pkuempers@gmx.de
Nickel
Nils
N
Lukasz
Alexander
A
Golpon
Heiko
H
Westerkamp
Volker
V
Olsson
Karen M
KM
Jonigk
Danny
D
Maegel
Lavinia
L
Bockmeyer
Clemens L
CL
David
Sascha
S
Hoeper
Marius M
MM
D000328:Adult; D042683:Angiopoietin-1 / Q000097:blood*; D042702:Angiopoietin-2 / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood / Q000175:diagnosis / Q000628:therapy; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood; D010446:Peptide Fragments / Q000097:blood; D011446:Prospective Studies; D012189:Retrospective Studies; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
D042683:Angiopoietin-1; D042702:Angiopoietin-2; D015415:Biomarkers; D010446:Peptide Fragments; D042461:Vascular Endothelial Growth Factor A; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain