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. 2009 Aug;55(8):1539-45.
doi: 10.1373/clinchem.2009.124263. Epub 2009 Jun 18.

Asymmetric dimethylarginine reference intervals determined with liquid chromatography-tandem mass spectrometry: results from the Framingham offspring cohort

Edzard Schwedhelm  1 , Vanessa Xanthakis, Renke Maas, Lisa M Sullivan, Friedrich Schulze, Ulrich Riederer, Ralf A Benndorf, Rainer H Böger, Ramachandran S Vasan
Affiliations

Asymmetric dimethylarginine reference intervals determined with liquid chromatography-tandem mass spectrometry: results from the Framingham offspring cohort

Edzard Schwedhelm et al. Clin Chem. 2009 Aug.

Abstract

Background: Accumulating evidence links higher circulating asymmetric dimethylarginine (ADMA) to greater risk of cardiovascular disease (CVD). Relatively small differences in ADMA concentrations between healthy individuals and those with disease underscore the need to formulate reference intervals that may aid risk stratification of individuals.

Methods: We formulated reference intervals for plasma ADMA concentrations using a community-based reference sample from the Framingham Offspring Study consisting of 1126 nonsmoking individuals [mean (SD) age 56 (9) years; 60% women] who were free of clinical CVD, hypertension, diabetes, and obesity and who attended a routine examination at which ADMA was assayed. ADMA concentrations were determined using a validated tandem mass spectrometry-liquid chromatography assay.

Results: In the study sample, the mean ADMA concentration was 0.52 (0.11) micromol/L, and the reference limits were 0.311 and 0.732 (2.5th and 97.5th percentile). The sex-specific reference limits were 0.310 and 0.745 in men and 0.313 and 0.721 micromol/L in women. In multivariable regression analysis, ADMA plasma concentrations were positively correlated with age and total plasma homocysteine (both P < 0.001).

Conclusions: Reference limits calculated for circulating ADMA in our large community-based healthy reference sample confirm the previous observation of a relatively narrow distribution of concentrations. This suggests a tight physiological control of ADMA plasma concentrations, presumably by dimethylarginine dimethylaminohydrolase (DDAH) metabolism of ADMA.

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Conflict of interest statement

Authors’ Disclosures of Potential Conflicts of Interest: Upon manuscript submission, all authors completed the Disclosures of Potential Conflict of Interest form. Potential conflicts of interest:

Figures

Fig. 1
Fig. 1. Study design of The Framingham Heart Study, 6th examination cycle (1995–1998), offspring cohort
Nonhealthy participants were excluded from the reference population by a stepwise exclusion procedure. *Not eligible for the following reasons: serum creatinine concentration >176 mmol/L (n = 15), missing ADMA (n = 79), and missing covariate data (n = 118).
Fig. 2
Fig. 2. Histogram of plasma ADMA with reference interval
ADMA was determined from EDTA plasma samples using LC-MS/MS and stable isotope dilution with [2H6]ADMA.
Fig. 3
Fig. 3. Association between age and ADMA in men and women
Data represent mean (SE). The unadjusted relationship between age and ADMA was significant for both men and women (Pearson r = 0.15 and r = 0.14 in men and women, respectively; P < 0.002 for both).
Fig. 4
Fig. 4. Association between quartiles (Q) of plasma ADMA and total homocysteine
Data represent mean (SE). The unadjusted relationship between ADMA and homocysteine was significant for pooled sex (Pearson r = 0.12, P < 0.001).
See this image and copyright information in PMC

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