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

Abstract

BackgroundAsymmetric 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 resultsTaking 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.ConclusionsNumerous 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.

Asymmetric dimethylarginine levels are associated with augmentation index across naïve untreated patients with different hypertension phenotypes

“…A recent metaanalysis aiming to establish ADMA reference values has found small differences between different methods. 29 Finally, our study population consisted of never-treated hypertensive patients with a recent diagnosis of EH and no comorbidities, suggesting that our findings are relevant only to the very early stages of EH.…”

Mono- Or Combined Antihypertensive Therapy in Women With Arterial Hypertension and Moderate Risk of Cardiovascular Diseases: What’s Better?

“…Кроме того, вазоактивные агенты, воспале-ние, механические и метаболические факторы способ-ствуют образованию активных форм кислорода, что сопровождается снижением биодоступности оксида азота и в итоге усиливает реактивность клеток гладких мышц сосудов [16]. В этих условиях происходит повы-шение концентрации АДМА, который реализует свой Комбинированная терапия Монотерапия провоспалительный и профиброгенный потенциал путем накопления коллагена в клубочках и афферент-ных артериолах, увеличивая экспрессию эндостатина, способного взаимодействовать с экспрессируемыми почечными эндотелиоцитами [17]. Наряду с этим, АДМА, накапливающийся в сыворотке крови больных АГ, по мере ухудшения функции почек усиливает свой эндоте-лийтоксический потенциал, вызывая разобщение e-NOS, подавление выработки оксида азота и повышение син-теза супероксида [18,19].…”

Cardiovascular biomarkers in clinical studies of type 2 diabetes

“…Asymmetric dimethylarginine is a naturally occurring substance produced as a byproduct of the proteolysis of post‐translational methylated proteins. Its major function is the competitive inhibition of nitric oxide synthase (NOS), which is responsible for generating nitric oxide from L‐Arginine . In addition to nitric oxide, NOS can generate reactive oxygen species.…”

“…Hence, increased ADMA levels can reduce nitric oxide bioavailability and further increase oxidative stress, thus impairing both insulin sensitivity and vascular function. When compared with healthy controls, the concentration of ADMA has been shown to be elevated in patients with hypertension, CHD, CHF, stroke, obesity, diabetes, kidney injury and even inflammatory bowel disease . A recent meta‐analysis including nearly 20 000 participants from the general population or with pre‐existing CVD or kidney disease, confirmed ADMA as a predictor of new CV events, with a risk ratio of 1.42 for an adverse CV outcome for patients in the top tertile of ADMA values compared with patients in the bottom tertile .…”

“…Currently, high‐performance liquid chromatography with fluorescence or mass spectrometric detection, and ELISA are the most frequently used analytical methods to determine plasma ADMA concentrations . A recent meta‐analysis found that the ELISA method provides lower ADMA concentrations compared with the high‐performance liquid chromatography method and that body mass index can affect ADMA levels, as shown in Table . ADMA can be measured in both heparin plasma and EDTA plasma but not in serum because of high levels of arginine …”