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Meta-Analysis
. 2016 Nov 3;11(11):e0165811.
doi: 10.1371/journal.pone.0165811. eCollection 2016.

Asymmetric and Symmetric Dimethylarginine as Risk Markers for Total Mortality and Cardiovascular Outcomes: A Systematic Review and Meta-Analysis of Prospective Studies

Sabrina Schlesinger  1 , Svenja R Sonntag  1 , Wolfgang Lieb  1 , Renke Maas  2
Affiliations
Meta-Analysis

Asymmetric and Symmetric Dimethylarginine as Risk Markers for Total Mortality and Cardiovascular Outcomes: A Systematic Review and Meta-Analysis of Prospective Studies

Sabrina Schlesinger et al. PLoS One. .

Abstract

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.

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Conflict of interest statement

The author RM was named as a co-inventor on the patent "Method for determination of arginine, methylated arginines and derivatives thereof." EP1666884 A1/B1, US 2006094122, DE602004020360 D1. The patent was owned and later transferred to a third party by his previous employer. The author does not work for the previous or current owner of the patent and receives no royalties or consulting fees from it and does not pursue any activity in relation to the patent.

Figures

Fig 1
Fig 1. ADMA and all-cause mortality: a) high versus low analysis, and b) non-linear dose-response analysis (based on 7 studies, p for non-linearity = 0.035).
Black square: point estimate for individual study; horizontal line: 95% CI for observed effect in each study; diamond: pooled estimate and 95% CI for meta-analysis. Random-effects estimate (DerSimonian and Laird method).
Fig 2
Fig 2. ADMA and CVD: a) high versus low analysis, and b) non-linear dose-response analysis (based on 10 studies, p for non-linearity = 0.370).
Black square: point estimate for individual study; horizontal line: 95% CI for observed effect in each study; diamond: pooled estimate and 95% CI for meta-analysis. Random-effects estimate (DerSimonian and Laird method).
Fig 3
Fig 3. SDMA and all-cause mortality: a) high versus low analysis, and b) non-linear dose-response analysis (based on 4 studies, p for non-linearity = 0.010).
Black square: point estimate for individual study; horizontal line: 95% CI for observed effect in each study; diamond: pooled estimate and 95% CI for meta-analysis. Random-effects estimate (DerSimonian and Laird method).
Fig 4
Fig 4. SDMA and CVD: a) high versus low analysis, and b) non-linear dose-response analysis (based on 5 studies, p for non-linearity = 0.059).
Black square: point estimate for individual study; horizontal line: 95% CI for observed effect in each study; diamond: pooled estimate and 95% CI for meta-analysis. Random-effects estimate (DerSimonian and Laird method).
See this image and copyright information in PMC

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