Measurement of asymmetric dimethylarginine in plasma: methodological considerations and clinical relevance

Abstract

Asymmetric dimethylarginine (ADMA) is a potent inhibitor of nitric oxide synthase and is regarded as a novel risk factor for cardiovascular disease. The metabolic pathways of ADMA and homocysteine are strongly intertwined. First, during synthesis of ADMA, two equivalents of homocysteine are formed. Second, homocysteine has been shown to inhibit the ADMA-degrading enzyme dimethylarginine dimethylaminohydrolase. Finally, homocysteine, either directly or by increasing oxidative stress, may promote release of free ADMA by accelerating protein degradation. Currently used techniques for the quantification of ADMA in plasma are mostly based on liquid chromatography with fluorimetric or mass spectrometric detection. Plasma ADMA has a very narrow concentration distribution, with an inter-individual coefficient of variation of approximately 12%, and even slightly elevated ADMA concentrations are associated with increased cardiovascular disease risk. Therefore, to generate useful results in clinical research, high precision of the assay used for the quantification of ADMA assay is a matter of prime importance. Assays with a high coefficient of variation may lead to low statistical power in clinical trials and to a severe underestimation of the strength of associations in epidemiological studies.

Asymmetrical Dimethylarginine in Renal Disease: Limits of Variation or Variation Limits?

“…A variety of techniques have been used for the quantification of ADMA in human plasma samples [82]. Most of these are based on solid-phase extraction of basic plasma components followed by derivatization and liquid chromatography with fluorimetric or mass spectrometric detection [82].…”

“…Most of these are based on solid-phase extraction of basic plasma components followed by derivatization and liquid chromatography with fluorimetric or mass spectrometric detection [82]. Despite the precision of these devices the major limitation lies in the time-consuming, cumbersome and expensive procedure that does not allow high-throughput analysis which is necessary to make this marker readily available for the clinical routine.…”

“…Overall, plasma ADMA has a very narrow concentration distribution, with an interindividual coefficient of variation of approximately 12% [82] which undermines that one cannot be satisfied with the wide range that has been reported in healthy individuals as well as in patients with renal failure. Normal reference values of 0.50–2.20 µ M have been indicated in the literature [52].…”

The biochemistry, measurement and current clinical significance of asymmetric dimethylarginine

“…The author rightly concludes that the effect of imprecision is to miss potentially important findings in clinical studies, and to undermine associations between ADMA and other parameters. 135 …”

Asymmetrical Dimethylarginine Is Increased in Plasma and Decreased in Cerebrospinal Fluid of Patients with Alzheimer’s Disease

“…ADMA plasma levels have been shown to be elevated in various diseases related to endothelial dysfunction like hypertension [7] , coronary heart disease [8] , hypercholesterolemia [9] , and diabetes mellitus [10] . In the healthy general population, a positive correlation of ADMA and homocysteine plasma levels was found [11] . Furthermore, ADMA is an independent cardiovascular risk factor and predicts outcome in patients with end-stage renal disease [12] and coronary heart disease [13] .…”