Asymmetric Dimethyl-l-Arginine is a Biomarker for Disease Stage and Follow-Up of Pulmonary Hypertension Associated with Congenital Heart Disease

Abstract

This study investigated the clinical value of plasma asymmetrical dimethyl-L-arginine (ADMA) level in the diagnosis, staging, and treatment response in congenital heart disease (CHD) patients with pulmonary arterial hypertension (PAH). This was a single-center prospective observational study in 80 CHD patients. Plasma ADMA levels were measured by enzyme-linked immunosorbent assay. Plasma ADMA levels were significantly increased in CHD patients with PAH compared with CHD patients without PAH (P < 0.01) and healthy controls (P < 0.001). In CHD patients with severe PAH, plasma ADMA levels were significantly higher in patients with Eisenmenger's syndrome (ES) than in patients exhibiting low pulmonary vascular resistance (P < 0.001). The plasma ADMA levels significantly correlated with pulmonary arterial pressure (P < 0.001) and pulmonary vascular resistance (P < 0.001) in patients with CHD. Severe PAH was identified by plasma ADMA with a cutoff value of 0.485 μmol/L (P < 0.001) with a specificity of 82.8 % and a sensitivity of 90 %. ES was identified by plasma ADMA with a cutoff value of 0.85 μmol/L (P < 0.05) with a specificity of 85.2 % and a sensitivity of 64.3 %. ADMA levels were significantly decreased after sildenafil therapy for 6 months compared with before therapy levels (0.91 ± 0.22 vs. 0.57 ± 0.30, P < 0.01). Our study suggests that plasma ADMA level may be used as a biomarker for identifying PAH in patients with CHD, assessing pulmonary vascular remodeling, and evaluating the treatment response of CHD patients with PAH to sildenafil.

Role of plasma asymmetric dimethyl-L-arginine levels in detection of pulmonary hypertension in children with CHD

“…This comes in agreement with results of other investigators. 7,9 Moreover, there was a significant positive correlation between asymmetric dimethyl-L-arginine levels and right ventricular diameter. This is in agreement with the study by Sanli et al 8 As higher asymmetric dimethyl-L-arginine levels were found with higher pulmonary pressure, and pulmonary vascular resistance that were reflected on increased the right ventricular diameter.…”

“…This agreed with the results of previous studies. [7][8][9][10][11] We have found that plasma asymmetric dimethyl-L-arginine levels were significantly reduced after treatment with sildenafil for 6 months. The reduced asymmetric dimethyl-L-arginine levels were accompanied by significant reduction in pulmonary pressure.…”

“…This was in accordance with the results of other investigators. 7,9 The pulmonary vasodilating effect of nitric oxide is mediated through cyclic guanosine monophosphate, which is degraded by phosphodiesterases, especially phosphodiesterase type 5; these phosphodiesterases are inhibited by sildenafil, which promotes nitric oxide-mediated vasodilatation that leads to decreased pulmonary pressure and consequently decreased level of asymmetric dimethyl-L-arginine. 13 Moreover, our study showed that asymmetric dimethyl-L-arginine levels were significantly higher in children with pulmonary hypertensionassociated CHD with poor prognosis and weak response to sildenafil treatment compared with those with better prognosis who responded well to sildenafil treatment.…”

“…This comes in agreement with the results of other investigators. 7,9,14 Hence, plasma asymmetric dimethyl-L-arginine levels can be used to predict response to treatment with sildenafil in children with pulmonary hypertension-associated CHD.…”

Can ADMA play a role in determining pulmonary hypertension related to chronic obstructive pulmonary disease?

“…Fang et al reported that plasma ADMA levels are markedly related with pulmonary arterial pressure, right ventricular pressure, pulmonary vascular resistance, and mixed venous oxygen saturation. Thus, plasma ADMA level is effective in follow‐up evaluation in CHD patients with PH . Endothelial damage is correlated with an imbalance between endothelium‐derived vasoactive mediators which favour a vasoconstrictive and proliferative phenotype that presents the basis for the development of pulmonary vascular remodelling and the eventual progression to PH when additional elements, such as hypoxia and emphysema, concur…”