Homoarginine predicts mortality in treatment-naive patients with pulmonary arterial hypertension

BackgroundPulmonary arterial hypertension (PAH) is a rare progressive disease with a 3-year mortality rate of approx. 45% in incident patients. The prostacyclin, endothelin-1 (ET-1), and nitric oxide (NO) pathways are validated therapeutic targets, however the underlying pathomechanisms are not yet fully understood. In the present study, we investigated metabolites of the NO pathway (e.g. l-arginine, asymmetric dimethylarginine (ADMA), and homoarginine), which are potentially involved in the pathophysiology of PAH.MethodsNewly diagnosed, treatment-naïve incident PAH patients were recruited from six centers and followed for three years. In longitudinal analyses we investigated the prognostic potential of these markers. Cross-sectional analysis was later used to study associations between prognostic relevant markers and clinical phenotypes of PAH.ResultsAmong 108 enrolled patients (53 ± 17 years, mean ± SD), 76 had idiopathic (i)PAH. Kaplan-Meier survival analysis and adjusted Cox proportional hazard models identified homoarginine as an independent predictor of mortality (HR:0.51, CI:0.28-0.94 for PAH and HR:0.41 CI:0.19-0.88 for iPAH), but not l-arginine or ADMA. Homoarginine was lower in 27 patients who died during the follow-up, i.e. 1.26 ± 0.48 vs. 1.64 ± 0.69 μmol/L, P < 0.01. In Pearson's correlation analysis homoarginine correlated with 6-minute walking distance (r = 0.31), cardiac output (r = 0.23), right atrial pressure (r = − 0.21), big ET-1 (r = − 0.31), and NT-proBNP (r = − 0.21; P < 0.05 for all).ConclusionHomoarginine was found an independent predictor for mortality in newly diagnosed PAH and iPAH patients. Further experimental studies are necessary to elucidate the involvement of homoarginine in the pathophysiology of PAH and its potential role as a therapeutic option for these patients.