The Role of Asymmetric Dimethylarginine (ADMA) in Endothelial Dysfunction and Cardiovascular Disease

Endothelium plays a crucial role in the maintenance of vascular tone and structure. Endothelial dysfunction is known to precede overt coronary artery disease. A number of cardiovascular risk factors, as well as metabolic diseases and systemic or local inflammation cause endothelial dysfunction. Nitric oxide (NO) is one of the major endothelium derived vaso-active substances whose role is of prime importance in maintaining endothelial homeostasis. Low levels of NO are associated with impaired endothelial function. Asymmetric dimethylarginine (ADMA), an analogue of L-arginine, is a naturally occurring product of metabolism found in human circulation. Elevated levels of ADMA inhibit NO synthesis and therefore impair endothelial function and thus promote atherosclerosis. ADMA levels are increased in people with hypercholesterolemia, atherosclerosis, hypertension, chronic heart failure, diabetes mellitus and chronic renal failure. A number of studies have reported ADMA as a novel risk marker of cardiovascular disease. Increased levels of ADMA have been shown to be the strongest risk predictor, beyond traditional risk factors, of cardiovascular events and all-cause and cardiovascular mortality in people with coronary artery disease. Interventions such as treatment with L-arginine have been shown to improve endothelium-mediated vasodilatation in people with high ADMA levels. However the clinical utility of modifying circulating ADMA levels remains uncertain

Asymmetric Dimethylarginine, L-Arginine, and Endothelial Dysfunction in Essential Hypertension

ObjectivesWe investigated the relationship between ADMA plasma levels and endothelium-dependent vasodilation in 36 never-treated essential hypertensives and in 8 normotensive healthy subjects.BackgroundIt has been demonstrated that endothelium-dependent vasodilatation is impaired in essential hypertension. The potential contribution of asymmetric dimethylarginine (ADMA) to endothelial dysfunction of hypertensive humans has received poor attention.MethodsEndothelial function was measured during intra-arterial infusion of acetylcholine (ACh), alone and during co-infusion of L-arginine, and sodium nitroprusside at increasing doses. Concentrations of ADMA and L-arginine in plasma were measured by high-performance liquid chromatography.ResultsHypertensive subjects had significantly higher ADMA and L-arginine plasma concentrations than normotensive healthy controls; ACh-stimulated forearm blood flow (FBF) was significantly reduced in hypertensive subjects in comparison to normotensive control subjects (p < 0.0001). Intra-arterial coinfusion of L-arginine induced a further significant enhancement in ACh-stimulated vasodilation in hypertensive patients. In these, ADMA was strongly and inversely associated with the peak increase in FBF. In a multivariate model, only ADMA and L-arginine were independent correlates, accounting for 33.9% and 8.9% of the variability in the peak FBF response to ACh (p < 0.0001), respectively.ConclusionsThe main finding in this study is that in essential hypertensives the L-arginine and endogenous inhibitor of nitric oxide synthase, ADMA, are inversely related to endothelial function

Alterations in Rev-ERBα/BMAL1 ratio and glycated hemoglobin in rotating shift workers: the EuRhythDia study

Objective: To detect premature gluco-metabolic defects among night shift workers with disturbances in circadian rhythms. Design and methods: We performed a hypothesis-generating, cross-sectional analysis of anthropometric, metabolic, lipid, and inflammation parameters, comparing active (a-NSW, n = 111) and former (f-NSW, n = 98) rotating night shift workers with diurnal workers (controls, n = 69). All participants were hospital nurses. We also evaluated the Pittsburgh Sleep Quality Index (PSQI) and assessed expression of transcription factors REV-ERBα and BMAL1 in peripheral blood mononuclear cells (PBMCs), as indicators of the molecular clock. Results: Both a-NSW and f-NSW participants had significantly higher glycated hemoglobin (HbA1c) and white blood cell counts (WBC) (p &lt; 0.001 for both), PSQI global score (p = 0.001) and diastolic blood pressure levels (p = 0.024) compared with controls. Expression of REV-ERBα/BMAL1 RNA in PBMC was significantly higher in a-NSW (p = 0.05) than in f-NSW or control participants. Multivariate regression analysis showed that working status and PSQI were independent determinants of higher HbA1c levels (p &lt; 0.001). Conclusions: We demonstrated that young, healthy night shift workers show subclinical abnormalities in HbA1c and changes in peripheral clock gene expression

Genome-wide association and functional follow-up reveals new loci for kidney function

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD

Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits

Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.Peer reviewe

Asymmetric dimethylarginine predicts outcome and time of stay in hospital in patients attending an internal medicine emergency room

Introduction: For patients attending the emergency room (ER) valid diagnostic criteria which identify patients at risk for an adverse outcome are needed. We investigated the predictive value of asymmetric dimethylarginine (ADMA) in unselected patients attending an internal medicine ER regarding outcome of the patients and duration of stay in the hospital.\ud \ud Patients and methods: Patients (n = 417) attending the ER were classified according to their primary diagnosis. Routine laboratory tests were performed and ADMA was determined. Patients were followed for a primary endpoint of in hospital death and complicated outcome.\ud \ud Results: ADMA levels were highest in patients with a cancer-related diagnosis (0.76 (0.63–0.93) µmol/L) and in patients with a cardiovascular diagnosis (0.69 (0.60–0.80) µmol/L; p < 0.001). Overall, we found increasing proportions of patients experiencing the primary end point over the quartiles of ADMA (4.6%, 8.2%, 9.6%, and 15.8%; p = 0.007). ADMA had the highest predictive value for the primary endpoint in patients with cardiovascular disease (odds ratio 19.4; p = 0.029). In a Cox proportional hazard model ADMA was an independent predictor of the length of hospitalization (hazard ratio 2.0 (95% CI: 1.3–3.3); p = 0.006) in the entire cohort.\ud \ud Conclusion: We conclude that ADMA independently predicts future complications and hospitalization in patients attending an ER