Reference values for plasma concentrations of asymmetrical dimethylarginine (ADMA) and other arginine metabolites in men after validation of a chromatographic method

Meinitzer, Andreas; Puchinger, Markus; Winklhofer‐Roob, Brigitte M.; Rock, Edmond; Ribalta, Josep; Roob, Johannes M.; Sundl, Isabella; Halwachs‐Baumann, Gabriele; März, Winfried

doi:10.1016/j.cca.2007.07.006

Cited by 75 publications

(55 citation statements)

References 37 publications

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Section: Discussionmentioning

confidence: 69%

“…16 The present finding that homoarginine levels are related to mortality and cardiovascular risk cautions against the use of homoarginine as an internal standard. 16 The present study has potential limitations. Despite the adjustments that were made in the associations of homoarginine with adverse outcomes, residual confounding (eg, by impaired renal function) cannot be completely ruled out; however, because the known important confounders were considered, the effect of potential residual confounding is likely to be small.…”

Section: Discussionmentioning

confidence: 69%

“…In both studies, homoarginine was uniformly measured in serum stored at Ϫ80°C by use of a reversephase high-performance liquid chromatography method. 16,17 Intraday coefficients of variation (CVs) at different concentrations (mean levels) were 4.7% (1.21 mol/L) and 2.2% (3.53 mol/L), and between-day CVs were 7.9% (1.25 mol/L) and 6.8% (3.66 mol/ L), respectively. C-reactive protein was measured with highsensitivity immunonephelometry (Dade Behring, Marburg, Germany), with an intra-assay and interassay CV of 2.3% to 4.4% and 2.6% to 5.7%, respectively.…”

Section: Data Collectionmentioning

confidence: 99%

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Homoarginine, Cardiovascular Risk, and Mortality

et al. 2010

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Background-Homoarginine is an amino acid derivative that may increase nitric oxide availability and enhance endothelial function. The effect of the level of homoarginine on cardiovascular outcome and mortality is unknown. Methods and Results-We assessed cardiovascular and all-cause mortality according to homoarginine levels in a cohort of 3305 subjects referred for coronary angiography from the LUdwigshafen RIsk and Cardiovascular Health (LURIC) Study. After investigating the relation of homoarginine with kidney function and markers of endothelial dysfunction, we explored its effects on adverse outcomes in a second high-risk cohort of 1244 patients with type 2 diabetes mellitus receiving maintenance hemodialysis (4D study [Die Deutsche Diabetes Dialyse Studie]). In the LURIC study, mean serum homoarginine levels were 2.6Ϯ1.1 mol/L. During a median follow-up of 7.7 years, 766 patients died. After adjustments for age and sex, patients in the lowest quartile (Ͻ1.85 mol/L) had a Ͼ4-fold higher rate of dying of cardiovascular disease (hazard ratio 4.1, 95% confidence interval 3.0 to 5.7) than patients in the highest quartile (Ͼ3.1 mol/L). Lower homoarginine levels were associated with lower estimated glomerular filtration rate and higher levels of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1. Hemodialysed patients had lower mean homoarginine levels of 1.2Ϯ0.5 mol/L and experienced a 5-fold increased mortality rate compared with LURIC patients (608 deaths during a median follow-up of 4 years). Homoarginine consistently affected mortality, which was 2-fold higher in 4D study patients in the lowest quartile (Ͻ0.87 mol/L) than in patients in the highest quartile (Ͼ1.4 mol/L). Conclusions-Homoarginine levels are independently associated with cardiovascular and all-cause mortality in patients referred for coronary angiography and in patients undergoing hemodialysis. Future studies are needed to elucidate the underlying pathomechanisms. (Circulation. 2010;122:967-975.)

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 69%

Section: Data Collectionmentioning

confidence: 99%

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Homoarginine, Cardiovascular Risk, and Mortality

et al. 2010

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“…Due to our longer duration of ANG II treatment (4 vs. 2 wk), we may have missed a transient increase of ADMA after 2 wk. A further explanation for the discrepant findings may result from different detection methods for ADMA (HPLC vs. ELISA/LC-MS), the variation of which in the literature is substantial, especially for HPLC methods (24). We took several steps to exclude other possible explanations.…”

Section: Discussionmentioning

confidence: 99%

Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice

Jacobi¹,

Maas²,

Cordasic³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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RH, Hilgers KF. Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice. Am J Physiol Heart Circ Physiol 294: H1058-H1066, 2008. First published December 21, 2007 doi:10.1152/ajpheart.01103.2007.-The aim of the present study was to investigate the role of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) and its degrading enzyme dimethylarginine dimethylaminohydrolase (DDAH) in angiotensin II (ANG II)-induced hypertension and target organ damage in mice. Mice transgenic for the human DDAH1 gene (TG) and wild-type (WT) mice (each, n ϭ 28) were treated with 1.0 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ANG II, 3.0 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ANG II, or phosphate-buffered saline over 4 wk via osmotic minipumps. Blood pressure, as measured by tail cuff, was elevated to the same degree in TG and WT mice. Plasma levels of ADMA were lower in TG than WT mice and were not affected after 4 wk by either dose of ANG II in both TG and WT animals. Oxidative stress within the wall of the aorta, measured by fluorescence microscopy using the dye dihydroethidium, was significantly reduced in TG mice. ANG II-induced glomerulosclerosis was similar between WT and TG mice, whereas renal interstitial fibrosis was significantly reduced in TG compared with WT animals. Renal mRNA expression of protein arginine methyltransferase (PRMT)1 and DDAH2 increased during the infusion of ANG II, whereas PRMT3 and endogenous mouse DDAH1 expression remained unaltered. Chronic infusion of ANG II in mice has no effect on the plasma levels of ADMA after 4 wk. However, an overexpression of DDAH1 alleviates ANG II-induced renal interstitial fibrosis and vascular oxidative stress, suggesting a blood pressure-independent effect of ADMA on ANG II-induced target organ damage. dimethylarginine dimethylaminohydrolase; hypertension; transgenic ASYMMETRIC DIMETHYLARGININE (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is increasingly recognized as a potential risk factor and prognostic biomarker in cardiovascular disease (38). Thus far, elevated ADMA levels have been associated with all established cardiovascular risk factors (38). Furthermore, recent data from genetic mouse models indicate a causal role for ADMA in the pathophysiology of vascular disease (7,19). ADMA derives from the posttranslational methylation of L-arginine residues within proteins catalyzed by enzymes called protein arginine methyltransferases (PRMTs). Upon proteolysis, methylarginines are released into the circulation. Although ϳ15% of ADMA are excreted via the urine, the major elimination occurs through enzymatic degradation (ϳ85%) (1). The enzyme dimethylarginine dimethylaminohydrolase (DDAH), of which two isoforms with distinct tissue distribution have been described, catalyzes the hydrolysis of ADMA to L-citrulline and dimethylamine (38).Thus far, clinical studies have mostly addressed the prognostic value of ADMA in cardiovascular or kidney disease as well as the impact of pharmacological interventions aimed at lowering ADMA levels ...

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“…Standard laboratory methods have been outlined in detail (17 ). We measured ADMA and SDMA in frozen serum (Ϫ80°C) with the reversedphase HPLC method (19 ), with slight modifications (20 ). Within-day CVs for SDMA were 4.6% (0.60 mol/L) and 1.9% (1.0 mol/L), and between-day CVs were 9.8% (0.60 mol/L) and 6.1% (1.0 mol/L).…”

Section: Laboratory Proceduresmentioning

confidence: 99%

Symmetrical and Asymmetrical Dimethylarginine as Predictors for Mortality in Patients Referred for Coronary Angiography: The Ludwigshafen Risk and Cardiovascular Health Study

et al. 2011

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BACKGROUND Asymmetrical dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, has been linked to cardiovascular risk. The clinical role of its structural isomer symmetrical dimethylarginine (SDMA) remains largely unclear. METHODS We measured SDMA and ADMA in 3229 patients undergoing coronary angiography at baseline (1997–2000) and recorded total and cardiovascular mortality during a median follow-up time of 7.7 years. We investigated associations of SDMA with cardiovascular risk factors and mortality and compared its role as a cardiovascular risk factor with ADMA, which predicted mortality in previous analyses of our study. RESULTS In linear regression analyses including common cardiovascular risk factors as covariates, SDMA and ADMA were significantly associated with cystatin C, N-terminal pro-B–type natriuretic peptide, New York Heart Association classification, and homocysteine. The regression coefficients were higher for SDMA than for ADMA. In Cox proportional-hazards models adjusted for cardiovascular risk factors, the hazard ratios (HRs) (with 95% CI) in the second, third, and fourth SDMA quartile compared to the lowest quartile were 0.77 (0.60–0.99), 0.99 (0.78–1.25), and 1.51 (1.20–1.91) for total mortality and 0.92 (0.68–1.25), 0.93 (0.68–1.26), and 1.54 (1.14–2.01) for cardiovascular mortality. The same calculations for ADMA quartiles revealed HRs of 1.05 (0.83–1.32), 1.19 (0.95–1.50), and 1.61 (1.30–1.99) for total mortality and HR of 1.00 (0.74–1.34), 1.26 (0.95–1.68), and 1.54 (1.18–2.02) for cardiovascular mortality. CONCLUSIONS Serum concentrations of SDMA are independently associated with increased cardiovascular and all-cause mortality in patients undergoing coronary angiography. The pattern of risk linked to SDMA is different from that linked to ADMA, suggesting different pathophysiological roles of these 2 methylarginine metabolites.

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Reference values for plasma concentrations of asymmetrical dimethylarginine (ADMA) and other arginine metabolites in men after validation of a chromatographic method

Cited by 75 publications

References 37 publications

Homoarginine, Cardiovascular Risk, and Mortality

Homoarginine, Cardiovascular Risk, and Mortality

Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice

Symmetrical and Asymmetrical Dimethylarginine as Predictors for Mortality in Patients Referred for Coronary Angiography: The Ludwigshafen Risk and Cardiovascular Health Study

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