Vascular Endothelial Function Is Affected By L-arginine Supplementation: A Meta-analysis Of Randomized Controlled Trials

Background Pevious trials suggest that oral L-arginine administration affects endothelial function.However,most of these studies are small,the conclusions are inconsistent,and the precise effects are therefore under debate.Objective To assess the effect of oral L-arginine supplementation on endothelial function,as measured with the fasting flow-mediated dilation(FMD).Design We conducted a meta-analysis of randomized,placebo-controlled L-arginine supplementation trials evaluating endothelial function.Trials were identified through PubMed,Cochrane Library,Embase,reviews,and reference lists of relevant papers. Weighted mean difference(WMD)was calculated for net changes in FMD by using random-effect models.Previously defined subgroup analyses and meta-regression were performed to explore the influence of study characteristics.Results Thirteen trials were included and evaluated.Since there was only one long-term study,we focused on short-term effects of L-arginine(12 studies,492 participants).In an overall pooled estimate,L-arginine significantly increased FMD (WMD 1.98%,95%confidence interval 0.47 to 3.48;P=0.01).Meta-regression analysis indicated that the baseline FMD was inversely related to effect size (regression coefficient=-0.55,95%confidence interval -1.00 to -0.1;P=0.016). Subgroup analysis also suggested that L-arginine supplementation significantly increased FMD when the baseline FMD levels were lower than 7%(WMD 2.56%, 95%confidence interval 0.87 to 4.25;P=0.003),but had no effect on the FMD when the baseline FMD was higher than 7%(WMD -0.27%,95%confidence interval -1.52 to 0.97;P=0.67).Conclusion Short-term oral L-arginine is effective in improving the fasting vascular endothelial function when the baseline FMD is low. Background Asymmetric dimethylarginine(ADMA),an endogenous inhibitor of nitric oxide synthase(NOS),has been shown to be an independent predictor of cerebrovascular disorders.Dimethylarginine dimethylaminohydrolase-2(DDAH2) promotes the metabolism of ADMA and plays a key role in regulation of the acute inflammatory response.We hypothesized that genetic variation in DDAH2 gene might alter the susceptibility to intracerebral hemorrhage(ICH).Methods The hypothesis was tested in 2 independent case-control studies.We used a haplotype-tagging SNP approach to identify tag single nucleotide polymorphisms (SNPs)in DDAH2.The SNPs were genotyped in 1603 patients with stroke and 1525 control subjects.The study was replicated in another independent case-control study including 322 patients with stroke and 891 control subjects.Results A promoter variant -449C/G(rs805305)in DDAH2 was identified and found to be in complete linkage disequilibrium with the only tag-SNP(rs707916)in the region containing DDAH2.Genotype analyses were conducted for both dominant and additive models.The C allele of the-449 locus showed significantly reduced risk of ICH(dominant model:odds ratio[OR]0.51,95%confidence interval[CI]0.38 to 0.68,P=6.60×10^-6;additive model:OR 0.64,95%CI 0.52 to 0.80,P=5.21×10^-5)than wild-type genotype.No association was observed between the DDAH2 variant and atherothrombotic stroke.The findings were replicated in the second independent population.Conclusions Our results suggest that the DDAH2 common variant may play a protective role in the development of intracerebral hemorrhage,implicating that DDAH2/ADMA pathway acts as a critical regulator of cerebral small vessel disorders. Background Platelet-derived growth factor D(PDGF-D)is the most recently discovered member of the PDGF family and signals mainly through PDGF receptor-β(PDGFR-β). PDGF-D has been observed to stimulate expression of MMP-2 and MMP-9 in vascular SMCs and degradation of vascular basement membrane,which may lead to a loss of vessel wall integrity.We hypothesized that genetic variation in PDGFD gene might alter the susceptibility to intracerebral hemorrhage(ICH).Methods The selection of genetic variants was based on the HapMap CHB sample using the pairwise option of the Haploview version of Tagger program.A minimum r² of 0.8 was chosen as a threshold for all analyses.Only one Tagger SNP(rs3809021,-858A/C) with a minor allele frequency more than 5%was genotyped within the predicted promoter region of PDGFD.The SNPs were genotyped in 1484 patients with stroke and 1528 control subjects.Results Genotype analyses were conducted for both dominant and additive models.The A allele of the -858 locus showed significantly increased risk of ICH(dominant model: odds ratio[OR]1.29,95%confidence interval[CI]1.00 to 1.68,P=0.05;additive model: OR 1.24,95%CI 1.01 to 1.52,P=0.04)than wild-type genotype.Subgroup analyses showed that the A allele of the -858 locus showed significantly increased risk of non-hypertensive ICH(dominant model:OR 2.1,95%CI 1.34 to 3.29,P=0.001;additive model:OR 1.75,95%CI 1.24 to 2.46,P=0.001)than wild-type genotype.No association was observed between the PDGFD variant and hypertensive ICH and atherothrombotic stroke.Conclusions Our results suggest that the PDGFD common variant may play a important role in the development of intracerebral hemorrhage,implicating that PDGFD pathway acts as a critical regulator of cerebral small vessel disorders.