Procedure-related pulmonary hypertension in patients with hepatocellular carcinoma undergoing percutaneous ethanol injection--role of ethanol, hemolysis, asymmetric dimethylarginine, and the nitric oxide system.

OBJECTIVE: Local percutaneous tumor ablation with ethanol injection (PEI) under general anesthesia is an established therapy for patients with nonresectable hepatocellular carcinoma (HCC). There are reports of sudden hypotension immediately after PEI therapy, which was attributed to an acute increase in pulmonary vascular resistance. The aim of our study was to objectively confirm pulmonary hypertension by right heart catheterization and to evaluate biochemical markers with relevance to the pulmonary circulation. DESIGN: Cross-sectional clinical study. SETTING: Interventional Gastroenterology in a tertiary care center. PATIENTS: We studied 40 patients with HCC who underwent percutaneous ethanol injection under general anesthesia for the treatment of nonresectable HCC. RESULTS: In patients with HCC, PEI leads to a significant increase in pulmonary arterial pressure. Concomitantly, free hemoglobin and blood ethanol level significantly increased, whereas the l-arginine/asymmetric dimethylarginine ratio, a parameter of nitric oxide (NO) production capacity, and nitrite, a marker of NO synthesis, significantly decreased. CONCLUSION: Procedure-related pulmonary hypertension in patients undergoing PEI is multifactorial. Plasma concentrations of the NO precursor l-arginine are reduced by arginase released from lysed erythrocytes, a condition further exacerbated by the increased concentrations of symmetric dimethylarginine, which may compete with the cellular uptake of l-arginine. The result would be reduced synthesis of NO, the concentration of which would be further decreased extracellularly through free hemoglobin. Predictably, the result would be severe endothelial dysfunction and pulmonary hypertension in patients undergoing PEI. These mechanisms might also be relevant in other states of (sudden) hemolysis.

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.