Asymmetrical Dimethylarginine in Idiopathic Pulmonary Arterial Hypertension

Objective: We explored the potential role of the endogenous NO synthase inhibitor asymmetrical dimethylarginine (ADMA) in patients with idiopathic pulmonary arterial hypertension (IPAH). Method and Results- We correlated plasma ADMA levels and cardiovascular indices from right heart catheterization in 57 patients with IPAH. Predictors of survival in patients with IPAH were studied. Furthermore, the effect of systemic ADMA infusion on pulmonary ventricular resistance and stroke volume was investigated in healthy volunteers using right heart catheterization. Mean plasma ADMA concentrations were significantly higher in patients with IPAH than in control subjects (0.53+/-0.15 versus 0.36+/-0.05 micromol/L; P<0.001). ADMA plasma concentrations correlated significantly with indices of right ventricular function, such as mixed-venous oxygen saturation (r=-0.49; P<0.0001), right atrial pressure (r=0.39; P<0.003), cardiac index (r=-0.35; P<0.008), as well as survival (r=-0.47; P<0.0001). Multiple regression analysis revealed that right atrial pressure (r=0.31; P<0.026) and ADMA (r=0.29; P<0.039) were independent predictors of mortality. Moreover, patients with supra-median plasma ADMA levels had significantly (P<0.021) worse survival than patients with infra-median ADMA values. ADMA infusion in healthy volunteers increased pulmonary vascular resistance (68.9+/-7.6 versus 95.6+/-6.3 dyne x s x cm(-5); P<0.05) and decreased stroke volume (101.1+/-6.7 mL versus 95.6+/-6.3 mL; P<0.05).

Conclusions: Increased ADMA plasma levels are associated with unfavorable pulmonary hemodynamics and worse outcome in patients with IPAH.