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Published ahead of print on June 19, 2008, doi:10.1164/rccm.200802-235OC

Am. J. Respir. Crit. Care Med., Volume 178, Number 5, September 2008, 534-541

A more recent version of this article appeared on September 1, 2008
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Submitted on February 8, 2008
Accepted on June 19, 2008

Growth Differentiation Factor-15 in Idiopathic Pulmonary Arterial Hypertension

Nils Nickel1, Tibor Kempf2, Heike Tapken2, Jorn Tongers2, Florian Laenger3, Ulrich Lehmann3, Heiko Golpon1, Karen Olsson1, Martin R Wilkins4, J. Simon R Gibbs5, Marius M Hoeper1, and Kai C Wollert2*

1 Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany, 2 Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany, 3 Department of Pathology, Hannover Medical School, Hannover, Germany, 4 Department of Experimental Medicine and Toxicology, Imperial College London, London, United Kingdom, 5 National Heart and Lung Institute, Hammersmith Campus, Imperial College London, London, United Kingdom

* To whom correspondence should be addressed. E-mail: wollert.kai{at}mh-hannover.de.

Rationale. Growth-differentiation factor-15 (GDF-15) is a stress-responsive, transforming growth factor-{beta}-related cytokine. Circulating levels of GDF-15 provide independent prognostic information in patients with acute pulmonary embolism and chronic left-sided heart failure. Objectives. To assess the prognostic value of GDF-15 in idiopathic pulmonary arterial hypertension. Methods. GDF-15 levels were determined in 76 treatment-naive patients at the time of baseline right heart catheterization. Patients were followed for a median (range) of 48 (0-101) months (first cohort). Twenty-two additional patients were studied at baseline and 3-6 months after initiation of therapy (second cohort). Measurements and Main Results. Fifty-five % of the patients in the first cohort presented with GDF-15 levels above 1,200 ng/L, the previously defined upper reference limit. The risk of death or transplantation at 3 years was 15% and 44% in patients with GDF-15 levels below or above 1,200 ng/L, respectively (P=0.006). Elevated levels of GDF-15 were associated with increased mean right atrial and pulmonary capillary wedge pressures, a lower mixed venous oxygen saturation (SvO2), and higher levels of uric acid and N-terminal pro-brain natriuretic peptide (NT-proBNP). After adjustment for hemodynamic and biochemical variables, GDF-15 remained an independent predictor of adverse outcomes (P=0.002). GDF-15 provided prognostic information in clinically relevant patient subgroups, and added prognostic information to hemodynamic variables and NT-proBNP. Changes in GDF-15 over time in the second cohort were related to changes in NT-proBNP (P=0.031) and inversely related to changes in SvO2 (P<0.001). Conclusions. GDF-15 is a promising new biomarker in idiopathic pulmonary arterial hypertension.
Key words: idiopathic pulmonary artery hypertension, biomarker, risk stratification




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