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

Abstract

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.

High Plasma Dimethylarginine Levels are Associated with Adverse Clinical Outcome After Stroke

“…In another study, treatment with statins resulted in a significant reduction of markers of oxidative stress 13) . The structural isomer of ADMA, SDMA, has no effect on nitric oxide synthesis but is also related to cardiovascular events 14) . SDMA has also been shown to be an independent predictor of overall mortality after acute stroke 15) .…”

Asymmetric and symmetric dimethylarginine as risk markers for total mortality and cardiovascular outcomes: A systematic review and meta-analysis of prospective studies

“…Other studies did not find a relevant increment in the C-statistic once ADMA or SDMA were added to the statistical prediction models in different clinical settings. [11,15,18,23,69] This concept also warrants further investigation. It needs to be established, however, whether inclusion of ADMA or SDMA improves risk prediction models (e. g. discrimination, reclassification) [81] beyond classic risk factors or that the increased risk for CVD and mortality associated with higher ADMA or SDMA can be specifically treated.…”

“…[9][10][11] However some conflicting results were observed; for example in the Framingham Offspring Study, ADMA was positively related to all-cause mortality, but not to incident CVD. [12] With respect to SDMA, initial studies did not find an association with adverse outcomes, [7,13,14] but some more recent studies reported positive associations with all-cause mortality or CVD.…”

“…[12] With respect to SDMA, initial studies did not find an association with adverse outcomes, [7,13,14] but some more recent studies reported positive associations with all-cause mortality or CVD. [11,15,16] Overall, prior studies on ADMA/SDMA and CVD or all-cause mortality were derived from many different study populations (general population, [15,17,18] patients with CVD, [9,11,19,20] renal diseases, [7,13,[21][22][23][24] diabetes, [25,26] or critically ill patients from intensive care unit,[27-29] respectively), differed in their methodological approaches (e.g. using types of samples (plasma vs. serum) or methods to determine the biomarker levels (HPLC vs. tandem mass spectroscopy vs. ELISA), or considered different confounders in their analysis.…”

Asymmetric and symmetric dimethylarginine in patients presenting with risk factors for coronary heart disease

“…The pattern of risk linked to SDMA is different from that linked to ADMA, suggesting different pathophysiological roles of these 2 methylarginine metabolites [10]. Because SDMA does not inhibit NOS, this structural isomer was thought to be inert [11].…”