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Circulating Angiogenic Modulatory Factors Predict Functional Class and Survival in Pulmonary Arterial Hypertension

R. Malhotra

S. Paskin-Flerlage

Roham Zamanian


P. Zimmerman

Joanne Schmidt

D. Deng

M. Southwood

R. Spencer

C. Lai

W. Parker

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Conference: 2012 International PHA Conference and Scientific Sessions

Release Date: 06.22.2012

Presentation Type: Abstracts

Malhotra R,1* Paskin-Flerlage S,2* Zamanian R,3* Zimmerman P,4 Schmidt J,4 Deng D,2 Southwood M,5Spencer R,Lai C,Parker W,Morrell N,5 Elliott CG,4# Yu P.2#

1. Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114

2. Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115

3. Stanford University Medical Center, Division of Pulmonary and Critical Care Medicine, 300 Pasteur Drive, Stanford, CA 94305

4. University of Utah, Department of Internal Medicine, Intermountain Medical Center, Murray, UT 84157

5. University of Cambridge School of Clinical Medicine, Department of Medicine, Addenbrooke's Hospital, Cambridge, UK CB2 0QQ

6. Duke University Medical Center, Department of Surgery, Durham, NC 27710

* Authors contributed equally to this manuscript

# Authors contributed equally to this manuscript

BACKGROUND: Pulmonary arterial hypertension (PAH) is a condition of progressive pulmonary vascular obstruction in which diagnosis is frequently delayed. We hypothesized that circulating levels of angiogenic modulatory factors might reflect vascular remodelling activity and serve as biomarkers of early PAH.

METHODSLevels of soluble endoglin (sEng), soluble VEGF receptor 1 (sVEGFR1), N-terminal brain natriuretic peptide (NT-proBNP), C-reactive protein (CRP) and other putative biomarkers were measured in peripheral venous blood from 97 patients with PAH, 16 first-degree relatives of patients with idiopathic or familial PAH, and 56 controls. Biomarker levels were correlated with the presence of disease, functional class, invasive hemodynamics, six-minute walk distance (6MWD), and transplant-free survival. Endoglin expression was analyzed in lung tissues from 6 individuals with idiopathic or familial PAH vs. 4 individuals without PAH.

RESULTS: Levels of sEng, sVEGFR1, CRP and NT-proBNP were elevated in group I PAH of diverse etiologies, with sEng performing better than NT-proBNP in detecting the presence of PAH (receiver operator characteristic (ROC) area under curve (AUC) of 0.82±0.03 vs. 0.71±0.05, p=0.016). While sEng, sVEGFR1, and NT-proBNP correlated with NYHA class, sEng levels were also more sensitive in detecting NYHA class I - II disease (ROC AUC of 0.87±0.05 vs. 0.67±0.08 for NT-proBNP, p=0.028). sEng, sVEGFR1, CRP, and NT-proBNP predicted transplant-free survival (median follow-up time 3.2 yrs) by univariate Cox regression, as did cardiac index, pulmonary vascular resistance, NYHA class, and 6MWD. sEng and CRP were independent predictors of survival in multivariate analysis. Endoglin expression was markedly enhanced in the microvascular endothelium and endovascular lesions of PAH vs. control lung tissues.

CONCLUSIONSAngiogenic modulatory proteins sEng and sVEGFR1 are sensitive markers of early group I PAH disease, and may reflect underlying vascular remodelling activity.