Asymmetric dimethylarginine and all-cause mortality: a systematic review and meta-analysis

Abstract

Asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), impairs the beneficial effect of NO. The predictive value of ADMA for all-cause mortality remains controversial, though it is important in the development of cardiovascular disease (CVD) and progression to dialysis in renal disease. This systematic review and meta-analysis was conducted to investigate the association between circulating ADMA and all-cause mortality. Studies with data pertinent to the association between circulating ADMA and all-cause mortality were reviewed and OR, HR or RR with 95% CI derived from multivariate Cox’s proportional-hazards analysis were extracted. A total of 34 studies reporting 39137 participants were included in final analysis. The results demonstrated that circulating ADMA was independently associated with all-cause mortality (RR = 1.27, 95% CI: 1.20–1.34). The association was still statistically significant in patients with pre-existing renal disease (RR = 1.30, 95% CI: 1.19–1.43) and pre-existing CVD (RR = 1.26, 95% CI: 1.16–1.37). In those without pre-existing renal or CVD, ADMA also predicted all-cause mortality (RR = 1.31, 95% CI: 1.13–1.53). The present study suggests a positive association of circulating ADMA with all-cause mortality. Further studies are needed to investigate the effects of interventions on ADMA, and the value of ADMA as a biomarker.

ADMA and NT pro‐BNP are associated with overall mortality in elderly

“…The statistical correlation between increased ADMA plasma concentration and mortality in older patients is in agreement with the Framingham heart study and a previous study conducted in older patients in Italy . ADMA is an endogenous inhibitor of NO synthase and affects endothelial function, blood pressure and vascular remodelling by reducing NO production . Increased ADMA plasma concentration has been shown to be associated with increased overall mortality in the general population .…”

“…2,6 ADMA is an endogenous inhibitor of NO synthase and affects endothelial function, blood pressure and vascular remodelling by reducing NO production. 19 Increased ADMA plasma concentration has been shown to be associated with increased overall mortality in the general population. 2,20 Furthermore, there is an association between elevated ADMA plasma concentration and increased risk of CV events, 16 and disease progression in patients with diabetes and kidney disease.…”

A functional variant of the dimethylarginine dimethylaminohydrolase-2 gene is associated with myocardial infarction in type 2 diabetic patients

“…There is evidence that elevated levels of ADMA, an endogenous inhibitor of eNOS, are associated with CVD and mortality both in the general population as well as in individuals at high cardiovascular risk [7][8][9][10]. However, studies aimed at evaluating the association of ADMA with CVD in patients with T2DM has led to divergent results [12][13][14][15].…”

“…While GWAS data available for the general population [PhenoScanner database http:// www.pheno scann er.medsc hl.cam.ac.uk/], suggested that the variant rs9267551 C was associated with lower risk of CAD (OR = 0.95, 95% CI 1.028-1.085; p = 3.88 × 10 −8 [24]), to the best of our knowledge, this is the first study showing a role of the rs9267551 polymorphism in the DDAH2 gene on MI in patients with T2DM. Because it has been reported that elevated levels of ADMA are associated with CVD in the general population and that they predicted mortality [7][8][9][10], it is possible that in subjects carrying the C allele less ADMA accumulates in endothelial cells causing vascular protection as a consequence of higher nitric oxide availability.…”

“…NO is synthesized by the endothelial NO synthase (eNOS), whose activity is negatively regulated by the endogenous inhibitor asymmetric dimethylarginine (ADMA), a naturally occurring methylated arginine competing with l-arginine as a substrate for eNOS [5,6]. Although elevated plasma levels of ADMA have been associated with major cardiovascular events and mortality in patients with different cardiovascular risk profile [7][8][9][10][11], the role of ADMA in predicting CVD among patients with diabetes is still subject of debate [12][13][14][15]. ADMA is endogenously generated by several protein arginine methyltransferases (PRMTs), and is metabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH) [16,17], which is encoded by two distinct genes: DDAH1 and DDAH2.…”