The issue of plasma asymmetric dimethylarginine reference range – A systematic review and meta-analysis

BACKGROUND: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase, marker and mediator of endothelial dysfunction. Several studies have demonstrated its value in cardiovascular risk stratification and all-cause mortality prediction. The aim was to determine the reference range of plasma ADMA in healthy adults. METHODS AND RESULTS: Taking into account the most widely used ADMA measurement methods, only studies using either high performance liquid chromatography (HPLC) -with fluorescence or mass spectrometric detection-, or enzyme-linked immunosorbent assay (ELISA) to quantify plasma ADMA concentrations were enrolled. 66 studies were included in the quantitative analysis (24 using ELISA and 42 using HPLC) reporting a total number of 5528 non-diabetic, non-hypertensive, non-obese adults without any medication (3178 men and 2350 women, 41.6 ± 16.9 years old). The reference range of ADMA (in μmol/l with 95% confidence interval in parenthesis) was 0.34 (0.29–0.38)– 1.10 (0.85–1.35) with a mean of 0.71 (0.57–0.85) (n = 4093) measured by HPLC and 0.25 (0.18–0.31)– 0.92 (0.76–1.09) with a mean of 0.57 (0.48–0.66) (n = 1435) by ELISA. CONCLUSIONS: Numerous publications suggested that asymmetric dimethylarginine is not only an outstanding tool of disease outcome prediction but also a new potential therapeutic target substance; the reference range provided by this meta-analysis can become of great importance and aid to further investigations. However, developing a standard measurement method would be beneficial to facilitate the clinical usage of ADMA.