Asymmetric and Symmetric Dimethylarginine as Risk Markers for Total Mortality and Cardiovascular Outcomes: A Systematic Review and Meta-Analysis of Prospective Studies.
BACKGROUND
A growing number of studies linked elevated concentrations of circulating asymmetric (ADMA) and symmetric (SDMA) dimethylarginine to mortality and cardiovascular disease (CVD) events. To summarize the evidence, we conducted a systematic review and quantified associations of ADMA and SDMA with the risks of all-cause mortality and incident CVD in meta-analyses accounting for different populations and methodological approaches of the studies.


METHODS
Relevant studies were identified in PubMed until February 2015. We used random effect models to obtain summary relative risks (RR) and 95% confidence intervals (95%CIs), comparing top versus bottom tertiles. Dose-response relations were assessed by restricted cubic spline regression models and potential non-linearity was evaluated using a likelihood ratio test. Heterogeneity between subgroups was assessed by meta-regression analysis.


RESULTS
For ADMA, 34 studies (total n = 32,428) investigating associations with all-cause mortality (events = 5,035) and 30 studies (total n = 30,624) investigating the association with incident CVD (events = 3,396) were included. The summary RRs (95%CI) for all-cause mortality were 1.52 (1.37-1.68) and for CVD 1.33 (1.22-1.45), comparing high versus low ADMA concentrations. Slight differences were observed across study populations and methodological approaches, with the strongest association of ADMA being reported with all-cause mortality in critically ill patients. For SDMA, 17 studies (total n = 18,163) were included for all-cause mortality (events = 2,903), and 13 studies (total n = 16,807) for CVD (events = 1,534). High vs. low levels of SDMA, were associated with increased risk of all-cause mortality [summary RR (95%CI): 1.31 (1.18-1.46)] and CVD [summary RR (95%CI): 1.36 (1.10-1.68) Strongest associations were observed in general population samples.


CONCLUSIONS
The dimethylarginines ADMA and SDMA are independent risk markers for all-cause mortality and CVD across different populations and methodological approaches.
Institute of Epidemiology, Christian-Albrechts University of Kiel, Kiel, Germany.
Sabrina
S
Schlesinger
Institute of Epidemiology, Christian-Albrechts University of Kiel, Kiel, Germany.
Svenja R
SR
Sonntag
Institute of Epidemiology, Christian-Albrechts University of Kiel, Kiel, Germany.
Wolfgang
W
Lieb
Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Renke
R
Maas
D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry; D015415:Biomarkers / Q000097:blood / Q000737:chemistry; D002318:Cardiovascular Diseases / Q000097:blood* / Q000401:mortality*; D006801:Humans; D011446:Prospective Studies; D012307:Risk Factors
D015415:Biomarkers; C024917:symmetric dimethylarginine; D001120:Arginine