Diagnostic Value of Serum Asymmetric Dimethyl Arginine and Arginine Derivatives Levels in Distinguishing Potentially Life-Threatening Causes in Patients Presenting with Chest Pain to the Emergency Department

Asymmetric Dimethylarginine

Recent reports have demonstrated elevated serum homocysteine (Hcy) levels in children receiving valproic acid (VPA) therapy. Elevated Hcy levels might play a potential role in the resistance to antiepileptic drugs, and might lead to an increased risk for a vascular disease. It has been reported that elevated total homocysteine (tHcy) levels are associated with elevated asymmetric dimethylarginine (ADMA) levels, which are factors that may be better indicators of endothelial dysfunction compared to serum homocysteine levels, because they are less sensitive to changes, such as fasting status, physical activity, and other factors. In this study, we aim to evaluate serum ADMA, Hcy, lipid, folate, and vitamin B₁₂ levels in epileptic children, receiving VPA monotherapy. Forty-four epileptic children, receiving VPA monotherapy for at least 6 months and 28 healthy children aged between 4 and 16 years, were recruited. Serum lipids, lipoproteins, folate, vitamin B₁₂, Hcy, and ADMA levels were analyzed in both study groups. Serum Hcy, ADMA, and vitamin B₁₂ levels were higher in patients than in controls (p < 0.001 for tHcy and ADMA levels; p < 0.05 for vitamin B₁₂ levels); however, serum lipid, lipoprotein, and folate levels were similar. According to the duration of epilepsy, serum tHcy, ADMA, and triglyceride (TG) levels were higher in patients with epilepsy for ≥ 2 years than in patients with epilepsy for < 2 years (p < 0.001 for serum ADMA levels, p < 0.01 for tHcy levels, and p < 0.05 for serum TG levels). Similarly, with respect to the duration of VPA therapy, serum tHcy, ADMA, and TG levels were higher in patients who had received VPA therapy for more than 2 years (p < 0.001 for serum ADMA levels, p < 0.05 for serum tHcy levels, p < 0.01 for TG levels). Serum ADMA levels were significantly higher in patients receiving VPA at the dose of 25-30 mg/kg/day than in those receiving 20 mg/kg/day (p < 0.01). In conclusion, our study found increased serum ADMA levels and increased tHcy levels in epileptic children receiving VPA monotherapy. Increased serum ADMA levels were demonstrated in epileptic children who have had a seizure history greater than 2 years, and have used VPA therapy for more than 2 years, and have received higher doses of VPA. Routine monitoring of serum ADMA and tHcy levels might have beneficial effects for patients receiving long-term VPA therapy, especially in children who have other potential risk factors for vascular diseases. Further studies are needed to investigate serum ADMA and Hcy levels, and the presence of vascular disease, as well as the potential interactions between serum ADMA levels and seizure control.

Purpose: Hypertension (HTN) is considered a major health problem. Apelin (AP) a novel multifunction peptide implicated in regulation of the cardiovascular system, including blood pressure and cardiac function control, Evidence has accumulated that asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide (NO) synthase. ADMA inhibits vascular NO production at concentrations found in pathophysiological conditions. However, there is no data about ADMA and apelin levels in essential hypertension and any relationship between them and the effect of antihypertensive drugs from various classes on these parameters of endothelial function. The aim of this study is to assess the status of Apelin and Assymetric DiMethyl Arginine in essential Hypertension on various modalities of treatment. Methods: The present study is a cross-sectional study (2007/2008) at Al-Yarmouk Teaching Hospital. Includes measurement of serum AP and ADMA in patients with hypertension. a total of 80 patients with HTN were involved in this study, they were classified according to modality of treatment as Hypertensives on captopril G1: (n=40); Hypertensives on atenolol G2: (n=40). A matching group of eighty apparently healthy volunteers who were included as controls (n=80. Results: Serum AP was significantly reduced and serum ADMA was significantly elevated in hypertensive patients (G1 & G2) as compared with controls (G3) (p < 0.001), also the above significant alteration in these two parameters was found when hypertensives on atenolol (G2) were compared with hypertensives on captopril (G1) (p < 0.001). AP was negatively correlated with ADMA (r = -0.9, p

IntroductionAsymmetrical dimethyl arginine (ADMA) is an endogenous non-selective inhibitor of nitric oxide synthase that may influence the severity of organ failure and the occurrence of shock secondary to an infectious insult. Levels may be genetically determined by a promoter polymorphism in a regulatory gene encoding dimethylarginine dimethylaminohydrolase II (DDAH II), which functions by metabolising ADMA to citrulline. The aim of this study was to examine the association between ADMA levels and the severity of organ failure and shock in severe sepsis and also to assess the influence of a promoter polymorphism in DDAH II on ADMA levels.MethodsA prospective observational study was designed, and 47 intensive care unit (ICU) patients with severe sepsis and 10 healthy controls were enrolled. Serum ADMA and IL-6 were assayed on admission to the ICU and seven days later. Allelic variation for a polymorphism at position -449 in the DDAH II gene was assessed in each patient. Clinical and demographic details were also collected.ResultsOn day 1 more ADMA was detectable in the ICU group than in the control group (p = 0.005). Levels subsequently increased during the first week in ICU (p = 0.001). ADMA levels were associated with vasopressor requirements on day one (p = 0.001). ADMA levels and Sequential Organ Failure Assessment scores were directly associated on day one (p = 0.0001) and day seven (p = 0.002). The degree of acidaemia and lactaemia was directly correlated with ADMA levels at both time points (p < 0.01). On day seven, IL-6 was directly correlated with ADMA levels (p = 0.006). The variant allele with G at position -449 in the DDAH II gene was associated with increased ADMA concentrations at both time points (p < 0.05).ConclusionSeverity of organ failure, inflammation and presence of early shock in severe sepsis are associated with increased ADMA levels. ADMA concentrations may be influenced by a polymorphism in the DDAH II gene.

ADMA, proteinuria, and insulin resistance in non-diabetic stage I chronic kidney disease

Both elevated serum uric acid and serum asymmetric dimethylarginine (ADMA) are risk factors for cardiovascular disease. We hypothesized that combined elevation of uric acid and ADMA amplifies the risk of all-cause mortality and/or cardiovascular events (CVE) in patients with chronic kidney disease (CKD). A total of 259 patients with CKD stages 1-5 were followed up in a time-to-event analysis for all-cause mortality and fatal and non-fatal CVE (including death, stroke, and myocardial infarction). Baseline measurements included serum uric acid and ADMA and endothelial function [ultrasound determined flow-mediated dilatation (FMD)]. As a measure of endothelial function, log FMD value was positively associated with log eGFR, but negatively associated with log ADMA and log uric acid levels. During follow-up (median 38months), 24 (9.3%) deaths, 90 (34.7%) CVE, and 95 (36.7%) deaths and CVE (composite outcome) occurred. In the univariate Cox analysis, patients with both serum uric acid and ADMA levels above the median had an increased risk of all-cause mortality, CVE, and the composite outcome (HR 5.06, 95% CI 2.01-12.76; HR 4.75, 95% CI 2.98-7.59; and HR 4.13, 95% CI 2.66-6.43, respectively). However, after adjustment for renal-specific risk factors (glomerular filtration rate, proteinuria, and hsCRP), this association was maintained only for CVE and the composite outcome. The addition of both biomarkers into a model with traditional and renal-specific risk factors did not increase the prediction abilities of the model for none of the three outcomes. Elevated serum uric acid and ADMA levels are associated with an increased cardiovascular risk, but their combination does not improve risk prediction. The effects are not additive, possibly because uric acid may lie in the causal pathway by which ADMA acts.

Background: Nitric oxide (NO), synthesized from the amino acid L-arginine by the action of NO synthases (NOS), is a pulmonary vasodilator. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NOS. Preterm infants have higher plasma ADMA concentrations than term infants which could cause inhibition of NO synthesis and deterioration in pulmonary functions. We aimed to investigate the relationship between serum ADMA and L-arginine levels of preterm infants and respiratory distress syndrome (RDS), requirement of surfactant treatment, duration of mechanical ventilation, oxygen treatment, and development of bronchopulmonary dysplasia (BPD).Methods: A prospective cohort study was conducted including 80 preterm infants born with gestational age (GA) ≤ 32 weeks and birth weight (BW) ≤ 1500 g. Blood samples were obtained from all infants immediately after birth, and at postnatal 28th day of age. The relationship of first-day serum ADMA and L-arginine levels and surfactant requirement, duration of mechanical ventilation, oxygen treatment was investigated. Serum ADMA and L-arginine levels at 1st and 28th days were compared at patients with and without BPD. The role of serum ADMA levels at postnatal 28th day of age to predict the requirement of oxygen at postmenstrual 36 weeks of age was also investigated.Results: Eighty preterm infants (42 male, 38 female) were enrolled in the study. Mean BW and GA for the total cohort was 1144.81 ± 220.44 g and 28.3 ± 1.8 weeks, respectively. Sixty-one infants were diagnosed as RDS and 44 infants treated with surfactant. The first-day ADMA levels were significantly higher in infants with surfactant requirement (1.14 ± 0.23 versus 0.86 ± 0.37, p < 0.01). First-day L-arginine levels were lower in infants with surfactant requirement compared to infants without surfactant requirement (22.32 ± 2.33 versus 23.75 ± 2.42, p > 0.05) but not significantly. Serum ADMA and L-arginine concentrations at first day were not different among infants with and without BPD (p > 0.05). ADMA concentrations at 28th day was significantly higher in infants with BPD (1.00 ± 0.25 versus 0.81 ± 0.25, p < 0.05). The cutoff level of 0.875 μmol/L for ADMA at 28th day offered the best predictive value for oxygen requirement at postnatal 36 weeks of age with a sensitivity of 88% and a specificity of 54%.Conclusıon: Serum ADMA and L-arginine levels are related to pulmonary morbidities in newborn. The results of this study show that increased ADMA levels are associated with poor pulmonary outcomes in preterm infants.

Hyperhomocysteinemia, a well-known and independent risk factor for cardiovascular disease, has been related in several studies with psoriasis patients. It has been suggested that homocysteine leads to endothelial dysfunction by causing an accumulation of asymmetrical dimethyl arginine (ADMA), a potent endogenous nitric oxide (NO) synthase inhibitor of the L-arginine-NO pathway. However, limited data is available regarding the psoriasis and ADMA relationship. In this study, we aimed to investigate the serum levels of homocysteine, ADMA and other metabolites from the L-arginine-NO pathway in psoriasis patients. Forty-two patients with chronic plaque psoriasis and 48 controls were enrolled in the study. Serum homocysteine, ADMA, L-monomethyl-L-arginine (L-NMMA), symmetric dimethylarginine (SDMA) and L-arginine levels, and L-arginine/ADMA ratios of psoriasis patients and the control group were measured. The severity of psoriasis was assessed by the psoriasis area and severity index (PASI). The mean ADMA and homocysteine values were significantly higher, and citrulline and L-arginine/ADMA values were significantly lower in psoriasis patients compared to control subjects. However, there were no significant differences among the patient and control groups with respect to mean SDMA, L-NMMA and L-arginine values. PASI scores strongly correlated with the ADMA level and moderately correlated with L-arginine/ADMA ratio. This study suggests that the L-arginine-NO pathway metabolites, especially ADMA, may play an important role in the pathogenesis of psoriasis. Additionally, serum ADMA levels of psoriasis patients may be an indicator of the disease severity.

Increased symmetrical dimethylarginine in ischemic acute kidney injury as a causative factor of renal L-arginine deficiency

Background/aim: Asymmetric dimethyl arginine (ADMA) is a strong predictor of cardiovascular disease and mortality in patients under hemodialysis treatment. We aimed to investigate the relationship among volume status, endothelial dysfunction, and ADMA in hemodialysis patients. Materials and methods: A total of 120 patients with a history of hemodialysis treatment were included. ADMA and CRP were measured. Echocardiographic evaluation and carotid artery intima-media thickness (CIMT) measurements were performed. Patients were divided into two groups according to clinical evaluation, ultrafiltration rate, vena cava inferior diameter (VCI), and cardiothoracic index (CTI); the two groups were hypervolemic and normovolemic. Results: The hypervolemic group included 61 patients while the normovolemic group included 59 patients. CIMT was higher in the hypervolemic group, but this result was not statistically significant (0.95 mm versus 0.85 mm, P = 0.232). There was a statistically significant difference between the hypervolemic and normovolemic groups in terms of ADMA (P < 0.001) (0.69 ± 0.57 μmol/L and 0.41 ± 0.04 μmol/L, respectively). Positive correlations were observed between serum ADMA, VCI, CTI, CRP, CIMT, and cardiac mass (P < 0.001, P = 0.016, P < 0.001, P = 0.006, P = 0.022, respectively), and negative correlations were observed between ADMA and ejection fraction and albumin (P = 0.024, P = 0.024, respectively). In multiple linear regression analysis, ADMA was independently associated with age, systolic blood pressure, CTI, and volume status. Conclusion: ADMA may be a potential determinant of hypervolemia as well as atherosclerosis in patients under hemodialysis treatment.

Introduction:Patients with CKD have elevated plasma levels of Asymmetrical Dimethyl Arginine (ADMA), impaired EDRF/NO responses in isolated resistance vessels, and a marked increase in the frequency of cardiovascular events that are predicated by plasma levels of ADMA. ADMA is considered as a risk factor for endothelial dysfunction, progression of chronic kidney disease and a marked increase in the frequency of cardiovascular events that are predicated by plasma levels of ADMA. Elevated ADMA in CKD have been related to a combination of a reduced renal ADMA excretion and a reduced catabolism of ADMA by dimethylarginine dimethylaminohydrolase (DDAH). The current study was undertaken to determine whether there is a correlation between ADMA and SNPs at -449 DDAH 2.Subjects and Methods :It was a cross sectional analytic study, 56 hemodialysis patients and 30 healthy individuals were enrolled. Based on its etiology, HD patients group was further divided in to hypertension (HT) subgroup and non-HT subgroup. Genotyping of the polymorphisms was performed using PCR-based SNP detection methods based on 5’-exonuclease activity assays for rs805305.Results :Heterozygotes were observed as the most abundant genotypes in both groups, followed by GG genotype in the HD patients (30%) and CC (27%) healthy individuals. Among the HT subgroup, the mean plasma levels of ADMA were sequentially higher from genotypes CC, G/C and GG (p = 0.037). Further multiple comparisons between groups using post hoc test showed results that genotype GG and CC were different at 0.05 level of significance. These findings were not found among non HT subgroup.Conclusion: Genetic variation in the DDAH 2 genes is significantly associated with serum ADMA levels in hypertensive HD patients. We observed that carriage of a G at position -449 in the promoter region of the DDAH 2 gene is associated with higher ADMA levels.

Objective. Subarachnoid haemorrhage (SAH) is associated with an inflammatory systemic response and cardiovascular complications. Asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric oxide synthase, mediates vasoconstriction and might contribute to cerebral vasoconstriction and cardiovascular complications after SAH. ADMA is also involved in inflammation and induces endothelial dysfunction. The aim of this study was to evaluate whether and how CRP (marker for systemic inflammation) and ADMA increased in patients during the acute phase (first week) after SAH. The ADMA level was also assessed in the patients in a non-acute phase (three months), and in healthy controls. Methods. A prospective study of 20 patients with aneurysmal SAH. ADMA and CRP were followed daily during the first week after SAH and a follow up sample for ADMA was obtained 3 months later. A single blood sample for ADMA was collected from age- and sex-matched healthy controls (n = 40, two for each case). Results. CRP increased significantly from day 2; 16 (Confidence interval (CI) 10–23) mg/L to day 4; 84 (CI 47–120) mg/L, (p < 0.01). ADMA increased significantly from day 2; 0.22 (CI 0.17–0.27) μmol/L, to day 7; 0.37 (CI 0.21–0.54) μmol/L, p < 0.01. ADMA remained elevated at a 3-month follow-up: 0.36 (CI 0.31–0.42) μmol/L. ADMA in the first sample from the patients (day 1–3); 0.25 (CI 0.19–0.30) μmol/L, was not different from ADMA in matched healthy controls; 0.25 (CI 0.20–0.31), p > 0.05. Conclusion. After SAH, CRP and ADMA in serum increased significantly during the first week and ADMA remained elevated 3 months later.

Familial Mediterranean fever (FMF) is a chronic inflammatory disease, and it is thought that subclinical inflammation persists even when there are no attacks, eventually causing endothelial dysfunction (ED) and atherosclerosis. Limited data are available about serum endocan, asymmetric dimethylarginine (ADMA) and lipid profile in children with FMF, so we aimed to evaluate these markers in children with FMF during the attack-free period. A total of 50 patients diagnosed with FMF and 50 age and sex-matched healthy children were recruited. Serum endocan, ADMA and lipid profiles were measured. Also, atherogenic indices (Castelli's risk indices I and II [CRI I and II], atherogenic index of plasma [AIP] and atherogenic coefficient [AC]) were calculated. Serum endocan, ADMA levels, low-density lipoprotein cholesterol, triglycerides, CRI II and AIP of the FMF patients were significantly higher than controls (p < 0.001). Unlike serum endocan, serum ADMA showed a positive significant correlation with total cholesterol, non-high density lipoprotein cholesterol, CRI I, AIP and AC (p < 0.001, p < 0.001, p = 0.004, p = 0.028, p = 0.004 respectively). Serum ADMA and lipid profile might be used as potential markers for endothelial dysfunction and increased cardiovascular risk in FMF patients. Theoretically, serum ADMA may affect lipid profiles and serum endocan represents an intriguing biomarker related to inflammation. Coexistence of dyslipidemia represents an additional risk factor that contributes to the onset of early atherosclerosis. A few studies investigated the role of changes in lipid profile and lipid ratios in accelerated atherosclerosis pathogenesis in FMF patients. The relationship between colchicine and lipid profile is contradictory. Although colchicine can cause dyslipidemia, it also has anti-atherosclerosis effects. Elevated ADMA level and atherogenic indices in FMF children reflect their potential role in the early detection of cardiovascular affection in FMF patients.

Context: Melatonin, a pineal hormone and a potent antioxidant, has important roles in metabolic regulation.Objective: This study investigated serum asymmetric dimethylarginine (ADMA), homocysteine (Hcy), nitric oxide (NO) levels, known to be reliable markers of cardiovascular diseases, and determined possible protective effects of melatonin in fructose-fed rats.Materials and methods: Sprague–Dawley rats were divided into four groups: control, fructose, melatonin, and fructose plus melatonin. Metabolic syndrome was induced in rats by 20% (w/v) fructose solution in tap water, and melatonin was administered at the dose of 20 mg/kg bw per day by oral gavage. After 8 weeks, serum lipids, glucose, insulin, ADMA, Hcy, and NOx (the stable end products of NO) levels were quantified.Results: Fructose administration caused a statistically significant increase in systolic blood pressure (SBP), serum insulin, triglycerides, and very low-density lipoprotein (VLDL)–cholesterol levels compared with the control group and the metabolic syndrome model was successfully demonstrated. In comparison with the control group, fructose caused a significant increase in serum ADMA, Hcy, and NOx levels. Melatonin counteracted the changes in SBP, serum ADMA, and Hcy levels found in rats both alone and administered with fructose.Discussion and conclusion: These results show that high fructose consumption leads to elevated SBP, atherogenic lipid profile, increased serum ADMA, and Hcy levels and melatonin treatment has beneficial effects on these biochemical parameters in rats. Melatonin might be beneficial for the prevention and/or treatment of the cardiovascular complications of metabolic syndrome not only by reducing the well-known risk factors of the disease but also by diminishing blood ADMA and Hcy levels.

Background and Objectives: Heat shock proteins (HSPs) are stress proteins. The endogenous nitric oxide (NO) synthase inhibitor asymmetric dimethyl arginine (ADMA) is a mediator of endothelial dysfunction. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus causes endothelial dysfunction and coagulopathy through severe inflammation and oxidative stress. Using these markers, we analyzed the prognostic value of serum ADMA and HSP-90 levels for early prediction of severe coronavirus disease (COVID-19) patients. Materials and Methods: A total of 76 COVID-19 patients and 35 healthy control subjects were included in this case-control study. COVID-19 patients were divided into two groups: mild and severe. Results: Serum ADMA and HSP-90 levels were significantly higher in the COVID-19 patients compared to the control subjects (p < 0.001). Additionally, serum ADMA and HSP-90 levels were determined to be higher in a statistically significant way in severe COVID-19 compared to mild COVID-19 (p < 0.001). Univariable logistic regression analysis revealed that ADMA and HSP-90, respectively, were independent predictors of severe disease in COVID-19 patients (ADMA (OR = 1.099, 95% CI = 1.048-1.152, p < 0.001) and HSP-90 (OR = 5.296, 95% CI = 1.719-16.316, p = 0.004)). When the cut-off value for ADMA was determined as 208.94 for the prediction of the severity of COVID-19 patients, the sensitivity was 72.9% and the specificity was 100% (AUC = 0.938, 95%CI = 0.858-0.981, p < 0.001). When the cut-off value for HSP-90 was determined as 12.68 for the prediction of the severity of COVID-19 patients, the sensitivity was 88.1% and the specificity was 100% (AUC = 0.975, 95% CI= 0.910-0.997, p < 0.001). Conclusions: Increased levels of Heat shock proteins-90 (HSP-90) and ADMA were positively correlated with increased endothelial damage in COVID-19 patients, suggesting that treatments focused on preventing and improving endothelial dysfunction could significantly improve the outcomes and reduce the mortality rate of COVID-19. ADMA and HSP-90 might be simple, useful, and prognostic biomarkers that can be utilized to predict patients who are at high risk of severe disease due to COVID-19.