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Growth Differentiation Factor-15 in Idiopathic Pulmonary Arterial Hypertension

Nils Nickel^1,*, Tibor Kempf^2,*, Heike Tapken², Jörn Tongers², Florian Laenger³, Ulrich Lehmann³, Heiko Golpon¹, Karen Olsson¹, Martin R. Wilkins⁴, J. Simon R. Gibbs⁵, Marius M. Hoeper^1, and Kai C. Wollert^2,

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

Correspondence and requests for reprints should be addressed to Kai C. Wollert, M.D., Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. E-mail: wollert.kai{at}mh-hannover.de

Rationale: Growth-differentiation factor (GDF)-15 is a stress-responsive, transforming growth factor-β–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 monitored for a median (range) of 48 (0–101) months (first cohort). Twenty-two additional patients were studied at baseline and 3 to 6 months after initiation of therapy (second cohort).

Measurements and Main Results: Fifty-five percent 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 (Sv_O2), 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 Sv_O2 (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

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Growth differentiation factor (GDF)-15 is a stress-responsive member of the transforming growth factor-β cytokine superfamily, and an emerging biomarker in patients with cardiovascular disease. Its clinical significance in idiopathic pulmonary arterial hypertension (IPAH) is uncertain. What This Study Adds to the Field Circulating GDF-15 levels are elevated and independently related to the risk of death or transplantation in patients with IPAH. The information provided by GDF-15 is additive to that of established hemodynamic and biochemical markers, including N-terminal pro-brain natriuretic peptide.