Increased Expression of Growth Differentiation Factor-15 in Systemic Sclerosis-Associated Pulmonary Arterial Hypertension

Background Growth differentiation factor (GDF)-15 is a secreted member of the transforming growth factor-β cytokine superfamily. GDF-15 levels are elevated in the serum of patients with cardiovascular diseases. We hypothesized that GDF-15 levels would also be increased in the plasma and lung tissue of patients with systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH). Methods GDF-15 levels were measured in plasma in subjects with SSc-PAH (n = 30) and compared with subjects with systemic sclerosis (SSc) without pulmonary arterial hypertension (PAH) (n = 24). Patients with idiopathic PAH (IPAH) (n = 44) and normal individuals (n = 13) served as control subjects. Immunohistochemistry and immunofluorescence assay identified GDF-15 protein in lung tissue from patients with SSc-PAH and IPAH. Results Patients with SSc-PAH had significantly higher mean circulating levels of GDF-15 in plasma compared with patients with SSc without PAH (422.3 ± 369.5 pg/mL vs 108.1 ± 192.8 pg/mL, P = .004). GDF-15 levels correlated positively with estimated right ventricular systolic pressure on echocardiogram and plasma levels of the amino terminal propeptide form of brain natriuretic peptide. There was an inverse correlation between circulating GDF-15 and diffusing capacity of the lung for carbon monoxide (D lco ) and a positive correlation with the FVC to D lco ratio on pulmonary function test. GDF-15 levels > 125 pg/mL were associated with reduced survival. GDF-15 protein expression was increased in lung tissue from patients with SSc-PAH. Conclusions GDF-15 may be a useful biomarker in PAH associated with SSc. Its presence in lung tissue may suggest a role in the pathology of the disease.