Higher Asymmetric Dimethylarginine Concentrations Research Articles

Asymmetric and Symmetric Dimethylarginines as Renal Function Parameters in Paediatric Kidney Diseases: A Literature Review from 2003 to 2022.

Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), inhibitors of nitric oxide synthase, play important roles in many processes in the body. Most data in the literature concern their importance in adult chronic kidney disease (CKD). According to them, SDMA well reflects the glomerular filtration rate (GFR), and higher ADMA concentrations are associated with hypertension and higher mortality. In addition, both substances are recognised cardiovascular risk factors in CKD. The purpose of this review was to summarise the studies on dimethylarginines in renal diseases in children, about which we have much fewer data. The review focuses specifically on dimethylarginine's relation to routinely used renal function parameters. Finally, we analysed 21 of the 55 articles published between 2003 and 2022 on dimethylarginines in kidney diseases in children (from birth to 18 years of age), obtained by searching PubMed/MEDLINE (search terms: "dimethylarginine" and "kidney").

The relationship of serum asymmetric dimethylarginine concentrations and lung involvement in patients with COVID-19 infection

Aim: COVID-19 infections the tissue through angiotensin converting enzyme 2 receptor, which is also expressed on endothelial cells. Endothelial dysfunction may be associated with lung involvement. Asymmetric dimethylarginine (ADMA) is an indirect marker of endothelial dysfunction. The aim of our study was to evaluate ADMA concentrations and to identify its association with lung involvement in patients with COVID-19 disease. Methods: We included 42 patients with COVID-19 infection and lung involvement (Group 1). Forty-two age and sex matched patients without pneumonia acted as the control group (Group 2). All patients gave blood samples for ADMA at the 1st month control visit after discharge. We compared C-reactive protein (CRP) and ADMA concentrations in addition to routine biochemical parameters between groups. Results: Patients with lung involvement had higher admission glucose, CRP, and ADMA concentrations, and displayed lower hemoglobin concentration and lymphocyte count compared to patients without lung involvement. Although patients with lung involvement had higher ADMA concentrations with respect to those without; plasma ADMA levels were also higher than normal values in control group. Multivariate analysis identified log CRP concentration (OR= 3.047, 95% CI=1.881-5.023, p<0.001) as the independent predictor for lung involvement. And, there was a correlation between ADMA and CRP (r: 0.318, p: 0.003). Conclusion: We revealed elevated ADMA concentrations as the surrogate of endothelial dysfunction in COVID-19 patients whether they have pneumonia or not.

Upregulation of DDAH2 Limits Pulmonary Hypertension and Right Ventricular Hypertrophy During Chronic Hypoxia in Ddah1 Knockout Mice.

Objective: Chronic hypoxia causes pulmonary vasoconstriction leading to pulmonary hypertension and right ventricular hypertrophy. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthesis; its level increases in hypoxia (HX) concomitantly with reduced activity of dimethylarginine dimethylaminohydrolases (DDAH-1 and DDAH-2), enzymes metabolizing ADMA. Ddah1 knockout (KO) mice may therefore help to understand the pathophysiological roles of this enzyme and its substrate, ADMA, in the development of hypoxia-associated pulmonary hypertension.Methods: Ddah1 KO mice and their wild-type (WT) littermates were subjected to normoxia (NX) or for 21 days. We measured ADMA concentration in plasma and lungs, DDAH1 and DDAH2 mRNA and protein expression in the lungs, right ventricular systolic pressure (RVSP), right ventricular hypertrophy by the Fulton index, and cardiomyocyte hypertrophy by dystrophin staining of the heart.Results: Ddah1 KO mice had higher ADMA concentrations in plasma and in lung tissue than WT in NX (p < 0.05). ADMA significantly increased in WT-HX in plasma and lungs, while there were no significant differences in WT-HX vs. KO-HX. This finding was paralleled by a 38 ± 13% reduction in Ddah1 but not Ddah2 mRNA expression, and reduced DDAH1 protein expression but stable DDAH2 protein levels in WT mice. Ddah1 KO mice showed significant elevation of DDAH2 protein but not mRNA levels, which further increased in HX. HX led to increased RVSP and right ventricular hypertrophy in both, WT and KO mice, with no significant differences between both genotypes.Conclusions: Chronic hypoxia causes an elevation of ADMA, which may impair NO production and lead to endothelial dysfunction and vasoconstriction. Downregulation of DDAH1 expression and activity may be involved in this; however, knockout of the Ddah1 gene does not modify the hypoxia-induced pathophysiological changes of pulmonary blood pressure and right ventricular hypertrophy, possibly due to compensatory upregulation of DDAH2 protein.

Arginine derivatives in atrial fibrillation progression phenotypes

Arginine, homoarginine (hArg), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) affect nitric oxide metabolism and altered concentrations are associated with cardiovascular morbidity and mortality. We analyzed these metabolites using liquid chromatography–tandem mass spectrometry in patients with atrial fibrillation (AF) (n = 241) with a focus on heart rhythm at blood withdrawal, AF progression phenotypes, and successful sinus rhythm (SR) restoration (n = 22). AF progression phenotypes were defined as paroxysmal AF with/without low voltage areas (LVA) and persistent AF with/without LVA. While arginine, ADMA, and hArg were within reference limits for healthy controls, SDMA was higher in the AF cohort (0.57 ± 0.12 vs. 0.53 μmol/L (97.5th percentile in reference cohort)). SR restoration in AF patients resulted in normalization of SDMA concentrations (0.465 ± 0.082 vs. 0.570 ± 0.134 μmol/L at baseline, p < 0.001). Patients with AF at the time of blood sampling had significantly lower hArg (1.65 ± 0.51 vs. 1.85 ± 0.60 μmol/L, p = 0.006) and higher ADMA concentrations (0.526 ± 0.08 vs. 0.477 ± 0.08 μmol/L, p < 0.001) compared with AF patients in SR. hArg concentrations were lower in patients with advanced AF progression phenotypes (persistent AF with LVA (p = 0.046)) independent of heart rhythm at blood sampling. Summarizing, arginine metabolism imbalance is associated with AF in general and AF progression and may contribute to associated risk.Key messages• Heart rhythm at blood withdrawal affects ADMA and hArg level in AF patients.• SDMA is higher in AF patients.• SDMA levels normalize after sinus rhythm restoration.• hArg levels decrease in advanced AF progression phenotypes.

Pre-Analytical and Clinical Validation of a Dried Blood Spot Assay for Asymmetric Dimethylarginine and L-Arginine.

Asymmetric dimethylarginine (ADMA) inhibits nitric oxide (NO) synthesis. It is a risk marker for cardiovascular events and mortality in patients with cardiometabolic diseases and in population-based studies. Plasma or serum analysis of ADMA may be hampered by pre-analytical sample handling. We validated a dried blood spot (DBS) assay for ADMA and L-arginine and show here that this assay has excellent variabilities and reproducibilities. Filter paper is impregnated with the arginase inhibitor nor-NOHA (Nω-hydroxy-nor-Arginine) to avoid L-arginine degradation. Clinical validation of this DBS assay confirms elevated ADMA concentration in hemodialysis patients as compared to healthy controls, higher ADMA concentrations in men versus women, and elevated L-arginine concentration in subjects supplemented with L-arginine. The DBS assay was used in a cohort study involving 100 primarily healthy subjects in the Andean region to assess the impact of chronic intermittent hypoxia on ADMA and L-arginine; ADMA DBS concentration at sea level was prospectively associated with pulmonary hypertension after six months of exposure to 3500 m. In a cohort of 753 individuals, L-arginine/ADMA ratio significantly decreased with increasing number of traditional cardiovascular risk factors. Analysis of ADMA and L-arginine in DBS is a reliable and reproducible method for quantitation of these markers in field studies.

Asymmetric Dimethylarginine (ADMA) and Soluble Vascular Cell Adhesion Molecule 1(sVCAM-1) as Circulating Markers for Endothelial Dysfunction in Patients with Pheochromocytoma

Endothelial dysfunction is a common feature of hypertension and is associated with reduced nitric oxide bioavailability. The endogenous inhibitor of nitric oxide syntase, asymmetric dimethylarginine (ADMA), and soluble adhesion molecules such as vascular cell adhesion molecule 1 (sVCAM-1) have been established as markers of endothelial dysfunction in a number of pathologic conditions including essential hypertension. There is little information, however, about these markers in endocrine hypertension. To investigate the levels of circulating ADMA and sVCAM-1 in patients with pheochromocytoma. Serum ADMA and sVCAM-1 concentrations were assayed by ELISA technique in 18 patients with pheochromocytoma, 18 patients with essential hypertension (EH) and 18 healthy subjects serving as a control group. ADMA and sVCAM-1 levels were significantly elevated in pheochromocytoma patients compared to normotensive healthy controls (0.479 ± 0.072 vs. 0.433 ± 0.054 µmol/l, p=0.037 and 690 ± 181 vs. 577 ± 108 ng/ml, p=0.03, respectively). Patients with EH also had higher ADMA concentrations than the control group, but the difference was not significant (0.476 ± 0.075 vs. 0.433 ± 0.054 µmol/l, p=0.06). No associations were found between the levels of ADMA, sVCAM-1 and some potential risk factors for endothelial dysfunction. Endothelial function is impaired in patients with pheochromocytoma as indicated by the elevated circulating levels of ADMA and sVCAM-1. The lack of association of these markers with cateholamines, glucose and lipid abnormalities together with their comparable levels in EH patients suggests that endothelial dysfunction is most likely related to hypertension itself.

Plasma asymmetric dimethylarginine concentrations in sickle cell disease are related to the hemolytic phenotype

Asymmetric dimethylarginine (ADMA) is associated with pulmonary hypertension (PHT) in sickle cell disease (SCD). We studied the relationship of ADMA to other SCD-related complications. Plasma ADMA and associated parameters were determined in 52 HbSS/HbSβ 0-thalassemia and 24 HbSC/HbSβ +-thalassemia patients. As expected ADMA levels were higher in HbSS/HbSβ 0-thalassemia patients with PHT ( p = 0.018), but also in those with other hemolysis-associated complications such as leg ulcers ( p = 0.012), cholelithiasis ( p = 0.008) and priapism ( p = 0.02) compared with counterparts without these complications. ADMA levels did not differ between patients with and without other disease related complications such as retinopathy and avascular osteonecrosis. Higher ADMA concentrations therefore seem to be associated to the hemolytic phenotype of SCD.

Significance of asymmetric dimethylarginine (ADMA) concentrations during coronary circulation in patients with vasospastic angina.

The basal activity of nitric oxide (NO) is reduced in spastic arteries of patients with vasospastic angina (VSA). Elevated concentrations of ADMA are associated with reduced NO production and impaired endothelium-dependent vasodilatation. The aim of this study was to elucidate the role of ADMA and its relationship to NO end-products (NOx; nitrate + nitrite) during coronary circulation in patients with VSA. The plasma ADMA and NOx concentrations during coronary circulation were evaluated in 16 VSA and 16 control patients. Blood samples were obtained from the coronary sinus (V) and the ostium of the left coronary artery (A), and the (V-A) differences of ADMA and NOx were determined. The coronary sinus plasma ADMA concentration in patients with VSA was higher than that in the control. The coronary sinus - arterial (V-A) difference of NOx was negative in the VSA group and approximately zero in the control group (VSA group =-1.4 micromol/L, control group =-0.1 micromol/L, p=0.0005). Furthermore, in the VSA patients, there was a negative correlation between the (V-A) difference of NOx and the basal coronary artery tone at the site of spasm (r=-0.60, p=0.015). A significant negative correlation between the (V-A) differences of NOx and ADMA was observed in patients with VSA (r=-0.52, p<0.05), but not in those of the control. Higher ADMA concentrations might cause the reduced formation of NO that underlies the pathophysiology of coronary vasospasm.