Received on February 2, 2009
Accepted on May 29, 2009

Lipids, Lipoproteins, and Cardiovascular Risk Factors

Asymmetric Dimethylarginine Reference Intervals Determined with Liquid Chromatography–Tandem Mass Spectrometry: Results from the Framingham Offspring Cohort

¹ Clinical Pharmacology Unit, Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
² Department of Biostatistics, Boston University School of Public Health, Boston, MA
³ Clinical Pharmacology Unit, Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, and Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen, Erlangen, Germany
⁴ Department of Biostatistics, Boston University School of Public Health, Boston, MA, and Framingham Heart Study, Framingham, MA
⁵ Institute of Pharmacy, University of Hamburg, Hamburg, Germany
⁶ Framingham Heart Study, Framingham, MA, and Preventive Medicine and Cardiology Sections, Department of Medicine, Boston University School of Medicine, Boston, MA

^* To whom correspondence should be addressed. E-mail: schwedhelm{at}uke.uni-hamburg.de.

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) µmol/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 µmol/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.