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GDF-15 Is a Marker for Survival in Scleroderma-Related Pulmonary Arterial Hypertension

Michael Risbano

C. Meadows

Lixia Zhang

Rubin Tuder

M. Geraci

Todd Bull


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Conference: 2010 International PHA Conference and Scientific Sessions

Release Date: 06.24.2010

Presentation Type: Abstracts

Risbano M, Meadows C, Zhang L, Tuder R, Geraci M, Bull T. 
University of Colorado Denver Health Sciences Center, Denver, CO, USA

BACKGROUNDCurrently few biomarkers are available for pulmonary arterial hypertension (PAH). Systemic sclerosis (SSc) patients, an at-risk population for the development of PAH, would benefit from the identification of such biomarkers. Growth differentiation factor-15 (GDF-15), a circulating cytokine and member of the TGFb superfamily, is elevated in the serum of subjects with pulmonary embolism, acute myocardial infarction and idiopathic pulmonary arterial hypertension (IPAH) measured by immunoradiometric assay. Little is known about GDF-15 in patients with SSc associated PAH (SSc-PAH). We hypothesize that GDF-15 levels would be increased in SSc-PAH as compared to SSc without PAH.

METHODSWhole blood was obtained from stable patients from the University of Colorado Pulmonary Hypertension clinic and Scleroderma clinic. Plasma levels of GDF-15 measured by ELISA were compared between SSc-PAH (n=30) and SSc patients without PAH (n=24). Additionally SSc-PAH levels of GDF-15 were compared to IPAH (n=44) and normal contols (n=13). Subjects were followed for up to 2 years from time of initial blood draw. GDF-15 levels were correlated with clinical parameters. A Receiver operating curve (ROC) was developed to identify the optimal cut-off level of GDF-15. Spearman rank correlation was used to identify correlations with clinical parameters. A Kaplan-Meier curve was generated to analyze the relation of GDF-15 levels to survival. We evaluated lung tissue from SSc-PAH, IPAH and normal controls for expression of GDF-15 via immunofluorescence assay (IFA).

RESULTSPlasma levels of GDF-15 are elevated in SSc-PAH compared to other cohorts. GDF-15 levels directly correlated with right ventricular systolic pressures on Doppler echocardiography (r=0.52, p=0.0005) and NT-proBNP levels (r=0.48, p<0.0003), and inversely correlated with the diffusion of carbon monoxide on pulmonary function testing (r=-0.64, p<0.0001). Analysis of GDF-15 measured in SSc-PAH and SSc without PAH by ROC produced a c-statistic of 0.91 (p<0.0001, 95% confidence interval 0.84-0.99). A GDF-15 value of 125pg/mL was selected to identify patients with PAH (sensitivity 93%, specificity 88%). Kaplan-Meier analysis showed reduced two-year survival in SSc-PAH with elevation of GDF-15 at 125pg/ mL. There is increased expression of GDF-15 in lung tissue of SSC-PAH.

CONCLUSIONGDF-15 is significantly elevated in plasma of SSc-PAH compared to SSc without PAH. GDF- 15 elevation is a strong predictor of mortality in SSc. The correlation of GDF-15 levels with severity of RVSP and NT-proBNP implicates GDF-15 as a promising biomarker for SSc-PAH population. GDF-15 is increased in expression in the lung tissue of SSc-PAH. The role of GDF-15 in the pathogenesis of SSc-PAH merits further investigation.