dimethylarginine and Cardiovascular-Diseases

The Cardiorenal Syndrome type 4 (CRS-4) defines a pathological condition in which a primary chronic kidney disease (CKD) leads to a chronic impairment of cardiac function. The pathophysiology of CRS-4 and the role of arterial stiffness remain only in part understood. Several uremic toxins, such as uric acid, phosphates, advanced glycation end-products, asymmetric dimethylarginine, and endothelin-1, are also vascular toxins. Their effect on the arterial wall may be direct or mediated by chronic inflammation and oxidative stress. Uremic toxins lead to endothelial dysfunction, intima-media thickening and arterial stiffening. In patients with CRS-4, the increased aortic stiffness results in an increase of cardiac workload and left ventricular hypertrophy whereas the loss of elasticity results in decreased coronary artery perfusion pressure during diastole and increased risk of myocardial infarction. Since the reduction of arterial stiffness is associated with an increased survival in patients with CKD, the understanding of the mechanisms that lead to arterial stiffening in patients with CRS4 may be useful to select potential approaches to improve their outcome. In this review we aim at discussing current understanding of the pathways that link uremic toxins, arterial stiffening and impaired cardiac function in patients with CRS-4.

Topics: Aorta; Arginine; Autonomic Nervous System Diseases; Bone Diseases, Metabolic; Cardio-Renal Syndrome; Cardiovascular Diseases; Chronic Disease; Endothelium, Vascular; Glycation End Products, Advanced; Humans; Inflammation; Myocardial Infarction; Oxidative Stress; Phosphorus; Renal Insufficiency, Chronic; Toxins, Biological; Tunica Intima; Uric Acid; Vascular Stiffness; Vasculitis

The picture of HDL cholesterol (HDL-C) as the "good" cholesterol has eroded. This is even more surprising because there exists strong evidence that HDL-C is associated with cardiovascular disease (CVD) in the general population as well as in patients with impairment of kidney function and/or progression of CKD. However, drugs that dramatically increase HDL-C have mostly failed to decrease CVD events. Furthermore, genetic studies took the same line, as genetic variants that have a pronounced influence on HDL-C concentrations did not show an association with cardiovascular risk. For many, this was not surprising, given that an HDL particle is highly complex and carries >80 proteins and several hundred lipid species. Simply measuring cholesterol might not reflect the variety of biologic effects of heterogeneous HDL particles. Therefore, functional studies and the involvement of HDL components in the reverse cholesterol transport, including the cholesterol efflux capacity, have become a further focus of study during recent years. As also observed for other aspects, CKD populations behave differently compared with non-CKD populations. Although clear disturbances have been observed for the "functionality" of HDL particles in patients with CKD, this did not necessarily translate into clear-cut associations with outcomes.

Topics: Advanced Oxidation Protein Products; Apolipoprotein A-V; Apolipoprotein L1; Arginine; Cardiovascular Diseases; Cholesterol; Cholesterol, HDL; Glomerular Filtration Rate; Humans; Lipid Metabolism; MicroRNAs; Renal Insufficiency, Chronic; Serum Amyloid A Protein

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.

Topics: Arginine; Biomarkers; Cardiovascular Diseases; Humans; Nitric Oxide; Nitric Oxide Synthase; Proportional Hazards Models; Renal Dialysis; Risk Factors

Endothelial dysfunction occurs in chronic kidney disease (CKD) and increases the risk for cardiovascular disease. The mechanisms of endothelial dysfunction seem to evolve throughout kidney disease progression, culminating in reduced L-arginine transport and impaired nitric oxide bioavailability in advanced disease. This review examines the hypothesis that aerobic exercise may reverse endothelial dysfunction by improving endothelial cell L-arginine uptake in CKD.

Topics: Arginine; Biological Availability; Biological Transport; Cardiovascular Diseases; Disease Progression; Endothelium, Vascular; Exercise; Humans; Nitric Oxide; Oxidative Stress; Renal Insufficiency, Chronic; Risk Factors

Cardiovascular diseases are the most common diseases worldwide. They are responsible for one third of global deaths and they are the leading cause of disability, too. The usage of different levels of prevention in combination with effective risk assessment improved these statistical data. Risk assessment based on classic risk factors has recently been supported with several new markers, such as asymmetric dimethylarginine, which is an endogenous competitive inhibitor of nitric oxide synthase. Elevated levels of asymmetric dimethylarginine have been reported in obese, smoker, hypercholesterolemic, hypertensive and diabetic patients. According to previous studies, asymmetric dimethylarginine is a suitable indicator of endothelial dysfunction, which is held to be the preceding condition before atherosclerosis. Several researches found positive correlation between higher levels of asymmetric dimethylarginine and coronary artery disease onset, or progression of existing coronary disease. According to a study involving 3000 patients, asymmetric dimethylarginine is an independent risk factor of cardiovascular mortality in patients with coronary artery disease. This article summarizes the role of asymmetric dimethylarginine in prediction of cardiovascular diseases, and underlines its importance in cardiovascular prevention.

Topics: Arginine; Atherosclerosis; Biomarkers; Cardiovascular Diseases; Endothelium, Vascular; Humans; Nitric Oxide Synthase; Predictive Value of Tests; Risk Assessment; Risk Factors

Topics: Arginine; Biomarkers; Cardiovascular Diseases; Humans; Mortality; Percutaneous Coronary Intervention; Prospective Studies

An abnormal production of reactive oxygen species (ROS) and the subsequent decrease in vascular bioavailability of nitric oxide (NO) have long been proposed to be the common pathogenetic mechanism of the endothelial dysfunction, resulting from diverse cardiovascular risk factors such as hypercholesterolaemia, diabetes mellitus, chronic smoking, metabolic syndrome, and hypertension. Superoxide produced by the nicotinamide dinucleotide phosphate (NADPH) oxidase, mitochondrial sources, or the xanthine oxidase may react with NO, thereby resulting in excessive formation of peroxynitrite, a reactive nitrogen species that has been demonstrated to accelerate the atherosclerotic process by causing direct structural damage and by causing further ROS production. Despite this sound biological rationale and a number of pre-clinical and clinical lines of evidence, studies testing the effects of classical antioxidants such as vitamin C, vitamin E, or folic acid in combination with vitamin E have been disappointing. Rather, substances such as statins, angiotensin-converting enzyme inhibitors, or AT1-receptor blockers, which possess indirect antioxidant properties mediated by the stimulation of NO production and simultaneous inhibition of superoxide production (e.g. from the NADPH oxidase), have been shown to improve vascular function in pre-clinical and clinical studies and to reduce the incidence of cardiovascular events in patients with cardiovascular disease. Today, oxidative stress remains an attractive target for cardiovascular prevention and therapy. However, a deeper understanding of its source, and of its role in vascular pathology, is necessary before new trials are attempted.

Topics: Antioxidants; Arginine; Cardiovascular Diseases; Endothelium, Vascular; Humans; Mitochondria; NADPH Oxidases; Nitric Oxide Synthase; Oxidative Stress; Polyphenols; Prognosis; Prospective Studies; Reactive Oxygen Species; Risk Factors; Vitamins; Xanthine Oxidase

The amino acid L-arginine is the substrate for endothelial nitric oxide synthesis. The endothelium is capable of producing asymmetric dimethylargine (ADMA) (L-arginine methylated). ADMA is able to compete with L-arginine in nitric oxide (NO) production and inhibits oxide nitric synthase activity. Elevated blood levels of ADMA can block the synthesis of NO, and induce endothelial dysfunction, which may lead to the initiation and progression of atherosclerosic vascular disease. Prospective clinical studies in different patients populations suggest that ADMA is a new marker in cardiovascular disease and is to able to predict new cardiovascular events. Recently, intraindividual variations of ADMA in healthy subjects have been described. This fact induces to continue studying the diagnosis and prognosis value of this potential and novel marker of cardiovascular risk.

Topics: Arginine; Cardiovascular Diseases; Humans; Risk Factors

Decreased nitric oxide (NO) production and/or impaired NO bioavailability may occur in patients with chronic kidney disease (CKD), and could contribute to the elevation of blood pressure, cardiovascular disease (CVD) and the progression of renal injury in these patients. However, the underlying molecular mechanisms for reduced NO action in patients with CKD remains to be elucidated. Asymmetric dimethylarginine (ADMA) is a naturally occurring L-arginine analogue found in plasma and various types of tissues, acting as an endogenous NO synthase inhibitor in vivo. Further, plasma level of ADMA is elevated in patients with CKD and found to be a strong biomarker or predictor for future cardiovascular events. In addition, plasma level of ADMA could predict the progression of renal injury in these patients as well. These findings suggest that elevation of ADMA may be a missing link between CVD and CKD. In this review, we discuss the molecular mechanisms for the elevation of ADMA and its pathophysiological role for CVD in high-risk patients, especially focusing on patients with CKD.

Topics: Arginine; Cardiovascular Diseases; Humans; Kidney Failure, Chronic

Endothelial dysfunction is a key event in the pathophysiology of cardiovascular diseases and appears as a strong independent predictor of cardiovascular events. In this context, biological evaluation of endothelial circulating markers can be helpful. However, functional tests using pharmacological stimuli appear more specific for the study of resistance arteries. These methods consist in the evaluation of the endothelium-dependent changes in regional vascular flow in response to local infusion of substances that act through endothelial receptors without modification of systemic arterial pressure and in comparison with a non endothelium-dependent relaxation. Flow is measured by Doppler and intravascular ultrasound in coronary circulation, laser Doppler in skin and by venous occlusion plethysmography in peripheral muscular arteries. Similar studies can be performed ex vivo using isolated resistance arteries obtained from fat subcutaneous biopsies. In addition, other information can be obtained from reactive hyperemia and the study of the flow-mediated dilatation of conduit arteries to enable a selective and comprehensive approach of the heterogeneity of endothelial function in pathophysiology.

Topics: Acetylcholine; Adipose Tissue; Adrenergic beta-Agonists; Arginine; Arteries; Biomarkers; Blood Flow Velocity; Cardiovascular Diseases; Endothelium, Vascular; Forearm; Humans; Hyperemia; Laser-Doppler Flowmetry; Myography; Nitric Oxide; Plethysmography; Regional Blood Flow; Skin; Ultrasonography; Vascular Resistance; Vasodilator Agents; Vasomotor System

Dosing of most drugs must be adapted in renal insufficiency, making accurate assessment of renal function essential in clinical medicine. Furthermore, even modest impairment of renal function has been recognized as a cardiovascular risk factor. The purpose of this analysis was to identify the role of symmetric dimethylarginine (SDMA), the structural isomer of the cardiovascular risk marker asymmetric dimethylarginine, as an endogenous marker of renal function.. Comprehensive searches of Medline and the Cochrane Library from 1970 to February 2006 were performed to identify studies that evaluated the correlation between SDMA and renal function. The search was augmented by scanning references of identified articles and reviews. The correlation coefficients (R) were recorded from each study for the values of 1/SDMA and clearance estimates and for SDMA and creatinine levels. The summary correlation coefficients with 95% confidence intervals (CIs) were pooled using the random-effects method.. In 18 studies involving 2136 patients systemic SDMA concentrations correlated highly with inulin clearance [R = 0.85 (CI 0.76-0.91, P < 0.0001)], as well as with various clearance estimates combined [R = 0.77 (CI 0.65-0.85, P < 0.0001)] and serum creatinine [R = 0.75 (CI 0.46-089, P < 0.0001)].. SDMA exhibits some properties of a reliable marker of renal function. Future studies have to clarify whether SDMA is indeed suited to improve diagnosis and eventually optimize care of patients.

Topics: Arginine; Biomarkers; Cardiovascular Diseases; Creatinine; Female; Humans; Inulin; Male; Prognosis; Renal Insufficiency, Chronic; Retrospective Studies; Risk Factors

In 1992, asymmetrical dimethylarginine (ADMA) was first described as an endogenous inhibitor of the arginine-nitric oxide (NO) pathway. From then, its role in regulating NO production has attracted increasing attention. Nowadays, ADMA is regarded as a novel cardiovascular risk factor. The role of the kidney and the liver in the metabolism of ADMA has been extensively studied and both organs have proven to play a key role in the elimination of ADMA. Although the liver removes ADMA exclusively via degradation by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), the kidney uses both metabolic degradation via DDAH and urinary excretion to eliminate ADMA. Modulating activity and/or expression of DDAH is still under research and may be a potential therapeutic approach to influence ADMA plasma levels. Interestingly, next to its association with cardiovascular disease, ADMA also seems to play a role in other clinical conditions, such as critical illness, hepatic failure, and preeclampsia. To elucidate the clinical significance of ADMA in these conditions, the field of research must be enlarged.

Topics: Animals; Arginine; Cardiovascular Diseases; Endothelium, Vascular; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; Humans; Kidney; Liver; Nitric Oxide; Nitric Oxide Synthase; Risk Factors

Although the high risk for cardiovascular events in patients with end-stage renal disease (ESRD) is well known, recent data provide compelling evidence that even mild to moderate kidney disease is an important and independent risk factor for cardiac events. This increased risk does not seem to be explained by traditional risk factors as defined by the Framingham cohort. The examination of nontraditional risk factors has resulted in the identification of, among others, oxidant stress, hyperhomocystinemia, carbamylation, nitric oxide synthase inhibitors, and abnormal lipoproteins as potential pathways to explain the accelerated atherosclerosis in patients with kidney disease. Well-designed clinical trials should lead to the clarification of the relative importance of these factors in the pathogenesis of atherosclerotic disease.

Topics: Arginine; Cardiovascular Diseases; Humans; Hyperhomocysteinemia; Inflammation; Kidney Diseases; Kidney Failure, Chronic; Kidney Transplantation; Lipoproteins; Lipoproteins, LDL; Nitric Oxide Synthase; Oxidative Stress; Proteinuria; Renal Dialysis; Risk Factors

The uremic syndrome is the result of the retention of solutes, which under normal conditions are excreted by the healthy kidneys into the urine. The most practical classification of uremic toxins is based on their physicochemical characteristics that influence their dialytic removal, in (a) small water soluble compounds, (b) the larger "middle molecules," and (c) the protein bound compounds. Most small water soluble compounds are not very toxic and the toxic ones often show a kinetic behavior that is different from that of urea. The incidence of vascular disease and the morbidity and mortality related to it are extremely high in the population of uremic patients. A large proportion of uremic patients suffer from inflammation. Most often, the uremic solutes that play a role in inflammation and cardio-vascular complications are middle molecules and/or protein bound. Protein bound toxins inhibit several biochemical functions. High concentrations of cytokines with an immune activating potential are present in the plasma of uremic patients.

Topics: Arginine; Cardiovascular Diseases; Glycosylation; Homocysteine; Humans; Uremia

Elevated asymmetric dimethylarginine (ADMA) levels, an endogenous inhibitor of nitric oxide synthase, are an important cardiovascular risk factor. In patients with diabetes, increased ADMA levels have been reported, which may be associated with endothelial dysfunction. In this study, effect of nebivolol on serum ADMA levels in hypertensive patients with type 2 diabetes have been compared with metoprolol, an another beta-blocker.. A total of 54 patients (27 female, 27 male; mean age: 53.0+/-8.7 years) with type 2 diabetes and hypertension were included in this randomized, open-label, prospective study. Patients were randomized to receive either nebivolol 5 mg/day (n=28) or metoprolol 100 mg/day (n=26) for 12 weeks. When the patients could not reach target blood pressure levels at the end of week 4, indapamide (2.5 mg/day) was added. Enzyme Linked Immunosorbent Assay was used for serum ADMA measurements.. Similar reductions in blood pressure values were observed in both groups (p>0.05). In nebivolol group, there were no significant changes in serum ADMA levels compared to baseline (0.6+/-0.2 micromol/l vs 0.6+/-0.1 micromol/l, p>0.05), whereas in metoprolol group a 35.6% increase in serum ADMA levels was observed (0.6+/-0.1 micromol/l vs 0.7+/-0.2 micromol/l, p<0.01).. We observed a significant increase in ADMA levels, a marker of endothelial dysfunction, during metoprolol treatment, whereas nebivolol had neutral effects on ADMA levels in patients with type 2 diabetes mellitus and hypertension.

Topics: Administration, Oral; Adrenergic beta-Antagonists; Adult; Aged; Arginine; Benzopyrans; Biomarkers; Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Ethanolamines; Female; Humans; Hypertension; Male; Metoprolol; Middle Aged; Nebivolol; Prospective Studies; Treatment Outcome; Triglycerides

Asymmetric dimethylarginine (ADMA) is a recently identified potent cardiovascular risk factor. ADMA levels are increased in hyperhomocysteinaemia and the metabolism of ADMA is linked with that of homocysteine in several ways. Treatment with B vitamins effectively reduces homocysteine levels, but studies investigating the effect on ADMA levels are scarce and show conflicting results. In this study we evaluated the effect of treatment with B vitamins on ADMA levels in two high cardiovascular risk populations.. In study I, 110 siblings of patients with clinical atherosclerotic disease and postmethionine hyperhomocysteinaemia were treated with 5 mg of folic acid and 250 mg of pyridoxine or placebo, and were analysed after 1 year. In study II, 41 patients with type 2 diabetes and mild hyperhomocysteinaemia were analysed after 6 months treatment with 5 mg of folic acid or placebo.. A correlation between baseline homocysteine and ADMA levels was found, which was partly due to confounding by renal function. Homocysteine levels decreased by 43% in study I and by 28% in study II. In both studies, treatment with B vitamins had no effect at all on ADMA, arginine/ADMA ratio and SDMA levels. This result was confirmed in multiple linear regression analyses with adjustment for baseline values and gender.. Our studies indicate that B vitamins, despite causing a substantial reduction in plasma homocysteine levels, have no beneficial effect on ADMA levels.

Topics: Adolescent; Adult; Arginine; Atherosclerosis; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Female; Folic Acid; Humans; Hyperhomocysteinemia; Linear Models; Male; Middle Aged; Pyridoxine; Risk Factors; Time Factors; Treatment Failure; Vitamin B Complex

Levels of the endogenous nitric oxide synthase inhibitor asymmetrical dimethylarginine (ADMA) are elevated in patients with type 1 diabetes mellitus (DM1) and may contribute to vascular complications. In this study we tested the hypothesis that elevated ADMA in patients with DM1 can be reduced by regular physical exercise.. Plasma samples for analysis of L-arginine, ADMA, symmetrical dimethylarginine (SDMA) and metabolic parameters were obtained from 11 patients with DM1 who participated in a supervised aerobic exercise program for four months. Samples were collected before the training began, at two and four months after initiation, and eight months after cessation of regular training. Fifteen age- and sex-matched healthy persons who did not exercise regularly were examined once as controls and did not participate in the training program.. The patients with DM1 had higher ADMA levels than the controls before the training program began (0.54 +/- 0.02 vs. 0.44 +/- 0.03 micromol/l; P < 0.05). After two and four months of exercise, ADMA concentrations in the patients decreased to those seen in healthy persons (0.42 +/- 0.02 and 0.43 +/- 0.03 micromol/l; P < 0.001 and P < 0.05 compared with ADMA levels before training began). Eight months after cessation of the exercise program, ADMA levels in the patients reverted to those observed before the start of training. The L-arginine-to-ADMA ratio increased slightly after two months; L-arginine, symmetrical dimethylarginine, blood lipids and HbA1c were not affected by the training program.. Elevated ADMA levels in patients with DM1, who have a high risk for developing cardiovascular disease, can be lowered to those of healthy persons by regular physical exercise. This favorable effect on ADMA is not sustained when training is discontinued.

Topics: Adult; Arginine; Cardiovascular Diseases; Diabetes Mellitus, Type 1; Exercise Therapy; Female; Humans; Male; Treatment Outcome

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by systemic inflammation of the joints and extra-articular tissues. The incidence of cardiovascular disease (CVD) remains the main cause of morbidity and mortality in patients with RA. Despite the development of new therapeutics targeting the articular manifestations, the relief of the cardiovascular burden is still an unmet medical need during the management of RA. So, the early prognosis of RA-associated CVD plays a crucial role in improving the clinical outcomes of RA patients. Recently, circulating dimethylarginines have gained attention as potential biomarkers for CVDs. Here, we present the development and validation of a high-throughput liquid chromatography-tandem mass spectrometric (LC/MS/MS) method for simultaneous quantification of creatinine, arginine, and dimethylarginines in human serum within 2 mins by isotope dilution mass spectrometry. This method employed a protein precipitation method for rapid sample preparation, trichloroacetic acid (TCA)-based ion pairing chromatography for fast analyte separation, and multiple reaction monitoring (MRM) with stable isotope-labeled internal standards (ISs) for simultaneous quantitation. To assure the quality, our method was validated against the FDA guidelines for lower limit of quantitation (0.2 µM), linearity (square of coefficient correlation>0.99), precision (intra-&inter-assay imprecision < 10 %), accuracy (intra-&inter-assay inaccuracy < 10 %), sample preparation recovery (recovery ≥ 90 %), stability (instability < 10 %), matrix effect (signal suppression < 55 %), and carryover ( < 0.01 %). Afterward, we applied the validated method to a retrospective cross-sectional study. We aimed to evaluate the utility of serological dimethylarginines as potential cardiovascular biomarkers in the development of RA-associated CVD. Our results revealed that the serological ratio of asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), an indicator of physiological arginine methylation status, was significantly elevated in patients with RA. This finding might provide value in detecting CVD to improve clinical outcomes in RA management.

Topics: Arginine; Arthritis, Rheumatoid; Biomarkers; Cardiovascular Diseases; Chromatography, Liquid; Cross-Sectional Studies; Humans; Retrospective Studies; Tandem Mass Spectrometry

Arginine residues in proteins can be singly or doubly methylated post-translationally. Proteolysis of arginine-methylated proteins provides monomethyl arginine, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). ADMA and SDMA are considered cardiovascular risk factors, with the underlying mechanisms being not yet fully understood. SDMA lacks appreciable metabolism and is almost completely eliminated by the kidney, whereas ADMA is extensively metabolized to dimethylamine (DMA), with a minor ADMA fraction of about 10% being excreted unchanged in the urine. Urinary DMA and ADMA are useful measures of whole-body asymmetric arginine-dimethylation, while urinary SDMA serves as a whole-body measure of symmetric arginine-dimethylation. In renal transplant recipients (RTR), we previously found that higher plasma ADMA concentrations and lower urinary ADMA and SDMA concentrations were associated with a higher risk of all-cause mortality. Yet, in this RTR collective, no data were available for urinary DMA. For the present study, we additionally measured the excretion rate of DMA in 24-h collected urine samples of the RTR and of healthy kidney donors in the cohort, with the aim to quantitate whole-body asymmetric (ADMA, DMA) and symmetric (SDMA) arginine-dimethylation. We found that lower DMA excretion rates were associated with higher all-cause mortality, yet not with cardiovascular mortality. In the healthy donors, kidney donation was associated with considerable decreases in ADMA (by - 39%, P < 0.0001) and SDMA (by - 21%, P < 0.0001) excretion rates, yet there was no significant change in DMA (by - 9%, P = 0.226) excretion rate. Our results suggest that protein-arginine dimethylation is altered in RTR compared to healthy kidney donors and that it is pronouncedly shifted from symmetric to asymmetric arginine-dimethylation, with whole-body protein-arginine dimethylation being almost unaffected.

Topics: Adult; Aged; Arginine; Biomarkers; Cardiovascular Diseases; Cause of Death; Female; Heart Disease Risk Factors; Humans; Kidney Transplantation; Male; Methylation; Middle Aged; Protein Processing, Post-Translational; Tissue Donors; Transplant Recipients

Increased oxidative stress, leukocyte telomere length (LTL) shortening, endothelial dysfunction, and lower insulin-like growth factor (IGF)-1 concentrations reflect key molecular mechanisms of aging. We hypothesized that biomarkers representing these pathways are associated with measures of subclinical atherosclerosis and all-cause mortality.. We evaluated up to 2,314 Framingham Offspring Study participants (mean age 61 years, 55% women) with available biomarkers of aging: LTL, circulating concentrations of IGF-1, asymmetrical dimethylarginine (ADMA), and urinary F2-Isoprostanes indexed to urinary creatinine. We evaluated the association of each biomarker with coronary artery calcium [ln (CAC+1)] and carotid intima-media thickness (IMT). In multivariable-adjusted linear regression models, higher ADMA levels were associated with higher CAC values (βADMA per 1-SD increase 0.25; 95% confidence interval [CI] [0.11, 0.39]). Additionally, shorter LTL and lower IGF-1 values were associated with higher IMT values (βLTL -0.08, 95%CI -0.14, -0.02, and βIGF-1 -0.04, 95%CI -0.08, -0.01, respectively). During a median follow-up of 15.5 years, 593 subjects died. In multivariable-adjusted Cox regression models, LTL and IGF-1 values were inversely associated with all-cause mortality (hazard ratios [HR] per SD increase in biomarker, 0.85, 95% CI 0.74-0.99, and 0.90, 95% CI 0.82-0.98 for LTL and IGF-1, respectively). F2-Isoprostanes and ADMA values were positively associated with all-cause mortality (HR per SD increase in biomarker, 1.15, 95% CI, 1.10-1.22, and 1.10, 95% CI, 1.02-1.20, respectively).. In our prospective community-based study, aging-related biomarkers were associated with measures of subclinical atherosclerosis cross-sectionally and with all-cause mortality prospectively, supporting the concept that these biomarkers may reflect the aging process in community-dwelling adults.

Topics: Adult; Aged; Aged, 80 and over; Aging; Arginine; Atherosclerosis; Biomarkers; Cardiovascular Diseases; Carotid Intima-Media Thickness; Creatinine; Cross-Sectional Studies; Endothelial Cells; Female; Humans; Insulin-Like Growth Factor I; Isoprostanes; Male; Middle Aged; Oxidative Stress; Prospective Studies; Telomere Homeostasis; Telomere Shortening

Nitric oxide (NO) is an important mediator involved in vascular homeostasis. Changes in NO level are considered to be associated with obesity and its clinical consequences. Previous studies on NO levels in obese children provided inconclusive results, so this issue requires clarification.. One of the main goals of this study was to assess whether childhood excessive body weight (EBW) is associated with changes in serum NO level and whether features like age and gender are linked to NO levels in selected groups.. In the present study, the serum NO levels were compared in 43 children with EBW and 37 ageand gender-matched children with normal weight. Moreover, in both groups, body measurements and various clinical parameters, including the serum concentrations of arginine (Arg), a precursor of NO, were determined.. The mean serum NO level in EBW group (8.7 ±3.1 μmol/L) was significantly lower than in normal weight group (22.2 ±11.5 μmol/L). However, the serum Arg concentrations were higher in EBW children than in controls. Serum asymmetric dimethylarginine (ADMA) levels were higher in EBW group and inversely correlated with serum NO. The EBW female subgroup was characterized by slightly lower level of NO than the EBW male subgroup. There were no significant changes in serum NO level among different age subgroups in both groups.. Our results revealed that EBW in children is associated with significantly decreased level of serum NO. The decreased serum NO level in EBW children is not a result of depleted Arg in the blood. Asymmetric dimethylarginine may at least partially contribute to decreased NO levels in children with EBW. A decreased level of NO could be a potential early marker of the risk of cardiovascular disorders developing in children with EBW.

Topics: Adolescent; Arginine; Biomarkers; Body Weight; Cardiovascular Diseases; Case-Control Studies; Child; Child, Preschool; Female; Humans; Male; Nitric Oxide; Obesity

Cardiovascular disease (CVD) and chronic kidney disease (CKD) constitute substantial burdens for public health. The identification and validation of risk markers for CVD and CKD in epidemiological studies requires frequent adaption of existing analytical methods as well as development of new methods. In this study, an analytical procedure to simultaneously quantify ten endogenous biomarkers for CVD and CKD is described. An easy-to-handle sample preparation requiring only 20 µL of human plasma is followed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). The method was successfully validated according to established guidelines meeting required criteria for accuracy, precision, recovery, linearity, selectivity, and limits of quantification. The scalability of the method for application in larger cohorts was assessed using a set of plasma samples from healthy volunteers (n = 391) providing first reference values for the recently established biomarker N

Topics: Adolescent; Adult; Arginine; Biomarkers; Cardiovascular Diseases; Carnitine; Chromatography, Liquid; Citrulline; Creatinine; Female; Homoarginine; Humans; Lysine; Male; Middle Aged; Ornithine; Reference Values; Renal Insufficiency, Chronic; Tandem Mass Spectrometry; Young Adult

The vascular complications of diabetes are the most serious manifestations of the disease. The hyperglycemia can directly promote an inflammatory state where the increase C-reactive (CRP) and cytokines, such as interleukins (IL-1 and IL-6), which contribute to the development of cardiovascular diseases. The current study was aimed to evaluate the role of environmentally-synthesized zinc oxide nanocrystals (ZnO-NPs) in augmentation of hyperglycemia and its complications, as well as the preservation of asymmetrical dimethylarginine (ADMA) level as a specific marker for endothelial dysfunction in streptozotocin (STZ)-induced diabetic rats. ZnO-NPs was chemically-synthesized using environmental benign biodegradable hydroxyl ethyl cellulose (HES) as both a stabilizing and directing agent in the presence of potassium hydroxide. HES is a biomaterial compound used in many biomedical applications due to its biodegradability and biocompatibility in nature. Particle size, morphological structure, purity, and crystallinity of the as-prepared ZnO-NPs were evaluated through different techniques, such as transmission electron microscopy (TEM), X-ray diffraction (XRD), and scanning electron microscopy connected to energy-dispersive X-ray spectra (SEM-EDS). Sixty male albino rats were used in this study and divided into four groups: control, ZnO-NPs, diabetic and treated groups; after the experimental period, CRP and interleukin-1 (IL-1α) were determined by ELISA. ADMA was estimated by RP-HPLC using a fluorescence detector. The results obtained indicate that CRP, IL-1α, and ADMA levels increased significantly concomitant with a reduction in NO level in the diabetic group, whereas ZnO-NPs supplementation significantly attenuated these parameters. Based on these encouraging results, the reported approach of environmental synthesis and application has the potential of leading to a new generation of nanometerials for treatment of diabetic complications with considerably enhanced selectively towards atherosclerosis.

Topics: Animals; Arginine; Biocompatible Materials; Cardiovascular Diseases; Cellulose; Diabetes Mellitus, Experimental; Humans; Hyperglycemia; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission; Nanoparticles; Particle Size; Rats; Zinc Oxide

The association among serum homocysteine (HCY), symmetric dimethylarginine (SDMA), and asymmetric dimethylarginine (ADMA) is of interest in endothelial dysfunction, although the underlying pathology is not fully elucidated. We investigated the relationship of HCY with SDMA and ADMA regarding their long-time outcome and the age dependency of HCY, SDMA, and ADMA values in claudicant patients with lower extremity arterial disease. 120 patients were included in a prospective observational study (observation time 7.96 ± 1.3 years) with cardiovascular mortality as the main outcome parameter. Patients with intermittent claudication prior to their first endovascular procedure were included. HCY, SDMA, and ADMA were measured by high-performance liquid chromatography. Cutoff values for HCY (≤/>15 µmol/l), SDMA (≤/>0.75 µmol/l), and ADMA (≤/>0.8 µmol/l) differed significantly regarding cardiovascular mortality (p < 0.001, p < 0.001, p = 0.017, respectively). Age correlated significantly with HCY (r = 0.393; p < 0.001), SDMA (r = 0.363; p < 0.001), and ADMA (r = 0.210; p = 0.021). HCY and SDMA (r = 0.295; p = 0.001) as well as SDMA and ADMA (r = 0.380; p < 0.001) correlated with each other, while HCY and ADMA did not correlate (r = 0.139; p = 0.130). Patients older than 65 years had higher values of HCY (p < 0.001) and SDMA (p = 0.01), but not of ADMA (p = 0.133). In multivariable linear regression, age was the only significant independent risk factor for cardiovascular death (beta coefficient 0.413; 95% CI 0.007-0.028; p = 0.001). Age correlated significantly with HCY, SDMA, and ADMA. However, only age was an independent predictor for cardiovascular death. Older patients have higher values of HCY and SDMA than younger subjects suggesting age-adjusted cutoff values of HCY and SDMA due to strong age dependency.

Topics: Aged; Aging; Arginine; Austria; Cardiovascular Diseases; Female; Homocysteine; Humans; Incidence; Intermittent Claudication; Lower Extremity; Male; Prospective Studies; Risk Factors; Survival Rate

To evaluate symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA) as risk markers of cardiovascular disease, all-cause mortality and deterioration in renal function in a well characterised type 2 diabetic population with microalbuminuria and without symptoms of coronary artery disease.. 200 participants followed for 6.1 years. SDMA and ADMA were measured at baseline. Endpoints included (1) composite cardiovascular endpoint (n = 40); (2) all-cause mortality (n = 26); and (3) decline in eGFR of >30% (n = 42). Cox models were unadjusted and adjusted for traditional risk factors (sex, age, systolic blood pressure, LDL-cholesterol, smoking, HbA. Higher SDMA was associated with increased risk of all three endpoints (unadjusted: p ≤ 0.001; adjusted: p ≤ 0.02). Higher ADMA was associated with all-cause mortality (unadjusted: p = 0.002; adjusted: p = 0.006), but not cardiovascular disease or decline in eGFR (p ≥ 0.29).The c statistic was not significant for any of the endpoints for either SDMA or ADMA (p ≥ 0.10). The rIDI for SDMA was 15.0% (p = 0.081) for the cardiovascular endpoint, 52.5% (p = 0.025) for all-cause mortality and 48.8% (p = 0.007) for decline in eGFR; for ADMA the rIDI was 49.1% (p = 0.017) for all-cause mortality.. In persons with type 2 diabetes and microalbuminuria higher SDMA was associated with incident cardiovascular disease, all-cause mortality and deterioration in renal function. Higher ADMA was associated with all-cause mortality. SDMA and ADMA significantly improved risk prediction for all-cause mortality, and SDMA for deterioration in renal function beyond traditional risk factors.

Topics: Adult; Aged; Albuminuria; Arginine; Cardiovascular Diseases; Coronary Disease; Creatinine; Diabetes Mellitus, Type 2; Female; Glomerular Filtration Rate; Humans; Kidney; Male; Middle Aged; Risk Factors

It has been demonstrated that Cardiovascular Diseases (CVD) are a consequence of the combination of genetic and environmental factors and/or the interaction between them. Therefore, the aim of this study was to evaluate the impact of polycyclic aromatic hydrocarbon (PAHs) exposure and PON1 Q192R polymorphism (genetic susceptibility) on serum asymmetric dimethylarginine (ADMA) levels in Mexican women (n = 206). Urinary 1-hydroxypyrene concentrations (1-OHP; exposure biomarker for PAHs) were quantified using a high-performance liquid chromatography technique, PON1 Q192R polymorphism was genotyped using TaqMan probes and serum ADMA concentrations were evaluated using a commercially available ELISA kit. Urinary 1-OHP levels detected in this study ranged from 0.07 to 9.37 μmol/mol of creatinine (0.13-18.0 μg/g of creatinine). Regarding allele frequency (PON1 Q192R polymorphism), the 192Q-allele frequency was 0.43 and for the 192R-allele it was 0.57. In relation to serum ADMA levels, the levels ranged from 0.06 to 1.46 μmol/L. Moreover, multiple linear regression analysis was performed and associations between urinary 1-OHP levels (β = 0.05, p = 0.002), PON1 Q192R polymorphism (β = 0.04, p = 0.003) and serum ADMA concentrations were found. Besides, an interaction (gene-environment interaction) of both independent variables (1-OHP and PON1 polymorphism) on serum ADMA levels was found (β = 0.04, p = 0.02) in the constructed multiple linear model. Therefore, according to the significance of this research, it is necessary to execute health programs to reduce cardiovascular risk in the assessed population.

Topics: Adult; Alleles; Arginine; Aryldialkylphosphatase; Biomarkers; Cardiovascular Diseases; Creatinine; Environmental Exposure; Environmental Pollutants; Female; Gene Frequency; Gene-Environment Interaction; Genetic Predisposition to Disease; Genotype; Humans; Mexico; Polycyclic Aromatic Hydrocarbons; Polymorphism, Genetic; Pyrenes; Risk Factors

Atrial fibrillation (AF) is responsible for some thromboembolic events. Asymmetrical dimethylarginine(ADMA) increases in atrial fibrillation(AF) animals with dysfunction of endothelium, but its role in pro-thrombotic state of AF was unknown. The aim of our study was to explore the role of ADMA in predicting the pro-thrombotic state in AF and to reveal its mechanism.. One hundred and thirty-eight patients in the First Affiliated Hospital, Sun Yat-sen University, from 2010 to 2012, were enrolled (persistent atrial fibrillation group, PAF, n=80; paroxysmal atrial fibrillation group, Paf, n=30; sinus rhythm, SR, n=28). Plasma ADMA levels were detected by ELISA-kits. CHADS2 and CHA2DS2-VASc scores were estimated for each patient.14 Beagles (pacing group, n=8; sham group, n=6) were subjected to rapid atrial pacing (RAP). ADMA level was detected after 4 weeks of RAP.. ADMA level was elevated significantly in patients with atrial fibrillation especially in patients with persistent atrial fibrillation, and showed a significant linear correlation to CHADS2 and CHA2DS2-VASc score. With ADMA, ROC area under the curve was 0.865 in CHADS2 score ≥2 and was 0.959 in CHA2DS2-VASc score ≥2 (P<0.001 respectively). After 4 weeks of RAP, ADMA level was elevated compared to sham group and before operation. ADMA showed a linear correlation with atrial fibrillation susceptibility(r=0.686, P=0.007).. ADMA levels are elevated both in AF patients and RAP beagles. ADMA correlates with stroke risk concerning with CHADS2/CHA2DS2-VASc score. ADMA may become a new biomarker for predicting pro-thrombotic risk in AF.

Topics: Arginine; Atrial Fibrillation; Cardiovascular Diseases; Heart Atria; Humans; Stereoisomerism; Thrombosis

Elevated levels of circulating asymmetric and symmetric dimethylarginines (ADMA and SDMA) predict and potentially contribute to end organ damage in cardiovascular diseases. Alanine-glyoxylate aminotransferase 2 (AGXT2) regulates systemic levels of ADMA and SDMA, and also of beta-aminoisobutyric acid (BAIB)-a modulator of lipid metabolism. We identified a putative binding site for hepatic nuclear factor 4 α (HNF4α) in AGXT2 promoter sequence. In a luciferase reporter assay we found a 75% decrease in activity of Agxt2 core promoter after disruption of the HNF4α binding site. Direct binding of HNF4α to Agxt2 promoter was confirmed by chromatin immunoprecipitation assay. siRNA-mediated knockdown of Hnf4a led to an almost 50% reduction in Agxt2 mRNA levels in Hepa 1-6 cells. Liver-specific Hnf4a knockout mice exhibited a 90% decrease in liver Agxt2 expression and activity, and elevated plasma levels of ADMA, SDMA and BAIB, compared to wild-type littermates. Thus we identified HNF4α as a major regulator of Agxt2 expression. Considering a strong association between human HNF4A polymorphisms and increased risk of type 2 diabetes our current findings suggest that downregulation of AGXT2 and subsequent impairment in metabolism of dimethylarginines and BAIB caused by HNF4α deficiency might contribute to development of cardiovascular complications in diabetic patients.

Topics: Aminoisobutyric Acids; Animals; Arginine; Cardiovascular Diseases; Cell Line; Diabetes Mellitus, Type 2; Gene Expression Regulation; Hepatocyte Nuclear Factor 4; Humans; Liver; Mice; Mice, Inbred C57BL; Mice, Knockout; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Risk; RNA, Small Interfering; Transaminases

Arginine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), arginine/ADMA ratio and homoarginine could potentially affect nitric oxide production and have been studied in relation to cardiovascular risk (CVR) in various clinical populations. Prospective studies on the CVR associated with arginine/ADMA ratio and homoarginine in patients with moderate chronic kidney disease (CKD) are still scarce. We have studied how arginine, homoarginine and dimethylated arginine can predict cardiovascular events in such a population.. We measured plasma concentrations of arginine (P-arginine), ADMA (P-ADMA), SDMA (P-SDMA), homoarginine (P-homoarginine) and other covariates in 160 patients with predialytic CKD (mean age 57 years and mean eGFR 43 mL/min/1.73 m(2)) and followed them for 58 months in median. The risks of fatal and non-fatal cardiovascular events associated with the predictors were evaluated with multivariable Cox proportional hazard analysis.. There were 31 cardiovascular events during the observation period. In a multivariable model adjusted for age, sex, previous cardiovascular disease, P-cystatin C and P-homoarginine, the hazard ratio (HR) associated with an increase in arginine/ADMA ratio by 10 was 0.83 (P=0.03). The HR of a 1 μmol/L increase in P-homoarginine in the same model was 1.78 (P=0.01). A statistically significant interaction between P-homoarginine and P-cystatin C was found in an extended multivariable model. P-SDMA was not associated with increased CVR after adjustment for basic covariates.. This study demonstrates a negative association between arginine/ADMA ratio and CVR in CKD patients and a positive association between P-homoarginine and CVR. The latter is in contrast to what has been demonstrated by others.

Topics: Adult; Aged; Arginine; Biomarkers; Cardiovascular Diseases; Female; Follow-Up Studies; Homoarginine; Humans; Male; Middle Aged; Prospective Studies; Renal Insufficiency, Chronic; Risk Factors

To investigate determinants of asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), including single nucleotide polymorphisms (SNPs), in the DDAH1, DDAH2, and AGXT2 genes and their associations with prevalent and incident cardiovascular disease (CVD) in older adults with type 2 diabetes mellitus.. Prevalent CVD was assessed in men and women aged 60-75 years with type 2 diabetes as part of the Edinburgh Type 2 Diabetes Study (ET2DS), and the participants were prospectively followed up for 4 years for incident CVD. Dimethylarginines were measured in 783 of these subjects, and genotyping for tag SNPs in the DDAH1, DDAH2, and AGXT2 genes was performed in 935 subjects.. Plasma ADMA levels were significantly associated with SNPs in DDAH1 (top SNP rs1554597; P = 9.0E-09), while SDMA levels were associated with SNPs in AGXT2 (top SNP rs28305; P = 1.3E-04). Significant, independent determinants of plasma ADMA were sex, L-arginine, creatinine, fasting glucose, and rs1554597 (all P < 0.05; combined R(2) = 0.213). Determinants of SDMA were age, sex, creatinine, L-arginine, diabetes duration, prevalent CVD, and rs28305 (all P < 0.05; combined R(2) = 0.425). Neither dimethylarginine was associated with incident CVD. None of the investigated SNPs were associated with overall CVD, although subgroup analysis revealed a significant association of AGXT2 rs28305 with intermittent claudication.. Our study in a well-characterized population with type 2 diabetes does not support reported associations or causal relationship between ADMA and features of diabetes or CVD.

Topics: Aged; Arginine; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Environment; Female; Genotype; Humans; Intermittent Claudication; Male; Middle Aged; Polymorphism, Single Nucleotide; Risk Factors

Elevated plasma asymmetric dimethylarginine (ADMA) levels have been observed in patients with insulin resistance and diabetes, and have been reported to predict adverse cardiovascular events in type 2 diabetic patients. However, the relationship between ADMA and glycemic control in patients with type 2 diabetes remained controversial.. We evaluated 270 patients with type 2 diabetes and measured their plasma ADMA and hemoglobin A1c (HbA1c) levels by high performance liquid chromatography. The mean age was 67 ± 12 years. The mean plasma ADMA and HbA1c level were 0.46 ± 0.09 μmol/l and 7.8 ± 1.6%, respectively. There was no significant correlation between plasma ADMA level and HbA1c level (r = -0.09, p = 0.13). During the median follow-up period of 5.7 years (inter-quartile range: 5.0 - 7.3 years), major adverse cardiovascular event (MACE, including cardiovascular death, myocardial infarction and stroke) was observed in 55 patients (20.4%). Multivariate Cox regression analysis revealed that the ADMA tertile was an independent risk factor for MACE (ADMA tertile III versus ADMA tertile I: p = 0.026, HR: 2.31, 95% CI: 1.10 - 4.81). The prognosis predictive power of ADMA disappeared in patients with well glycemic control (HbA1c ≤6.5%), and the ADMA-HbA1c interaction p value was 0.01.. In patients with type 2 diabetes, ADMA might be an independent risk factor for long-term adverse cardiovascular events. However, ADMA was not correlated with serum HbA1c level, and in diabetic patients with HbA1c ≤6.5%, elevated ADMA level was no longer associated with increased risk of long-term prognosis. Our findings suggested that the prognosis predictive value of ADMA in type 2 diabetes might be modified by the glycemic control.

Topics: Aged; Aged, 80 and over; Arginine; Biomarkers; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Middle Aged; Prognosis; Prospective Studies; Risk Assessment; Risk Factors

There is growing evidence that increased levels of the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) may contribute to endothelial dysfunction. Studies in animal models as well as in humans have suggested that the increase in ADMA occurs at a time when vascular disease has not yet become clinically evident. ADMA competitively inhibits NO elaboration by displacing L-arginine from NO synthase. In a concentration-dependent manner, it thereby interferes not only with endothelium-dependent, NO-mediated vasodilation, but also with other biological functions exerted by NO. The upshot may be a pro-atherogenic state. Recently, several studies have investigated the effect of various therapeutical interventions on ADMA plasma concentrations.

Topics: Animals; Arginine; Cardiovascular Diseases; Humans; Inflammation; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Reactive Oxygen Species; Risk Factors

Plasma concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthesis from L-arginine and a cardiovascular risk factor, was found to be elevated in plasma of homocysteinemic adults. Enhanced cardiovascular risk due to homocystinuria and impaired renal function has been found in patients with phenylketonuria (PKU) on protein-restricted diet. However, it is still unknown whether ADMA synthesis is also elevated in children with homocystinuria due to cystathionine beta-synthase deficiency (classical homocystinuria), and whether ADMA may play a role in phenylketonuria in childhood. In the present study, we investigated the status of the L-arginine/NO pathway in six young patients with homocystinuria, in 52 young phenylketonuria patients on natural protein-restricted diet, and in age- and gender-matched healthy children serving as controls. ADMA in plasma and urine was determined by GC-MS/MS. The NO metabolites nitrate and nitrite in plasma and urine, and urinary dimethylamine (DMA), the dimethylarginine dimethylaminohydrolase (DDAH) metabolite of ADMA, were measured by GC-MS. Unlike urine ADMA excretion, plasma ADMA concentration in patients with homocystinuria was significantly higher than in controls (660±158 vs. 475±77 nM, P=0.035). DMA excretion rate was considerably higher in children with homocystinuria as compared to controls (62.2±24.5 vs. 6.5±2.9 μmol/mmol creatinine, P=0.068), indicating enhanced DDAH activity in this disease. In contrast and unexpectedly, phenylketonuria patients had significantly lower ADMA plasma concentrations compared to controls (512±136 vs. 585±125 nM, P=0.009). Phenylketonuria patients and controls had similar L-arginine/ADMA molar ratios in plasma. Urinary nitrite excretion was significantly higher in phenylketonuria as compared to healthy controls (1.7±1.7 vs. 0.7±1.2 μmol/mmol creatinine, P=0.003). Our study shows that the L-arginine/NO pathway is differently altered in children with phenylketonuria and homocystinuria. Analogous to hyperhomocysteinemic adults, elevated ADMA plasma concentrations could be a cardiovascular risk factor in children with homocystinuria. In phenylketonuria, the L-arginine/NO pathway seems not be altered. Delineation of the role of ADMA in childhood phenylketonuria and homocystinuria demands further investigation.

Topics: Adolescent; Amidohydrolases; Arginine; Cardiovascular Diseases; Child; Child, Preschool; Dimethylamines; Homocystinuria; Humans; Metabolic Networks and Pathways; Nitric Oxide; Phenylketonurias; Risk Factors; Young Adult

Free asymmetric dimethylarginine (ADMA) is a competitive inhibitor of the nitric oxide synthases (NOS). Suppression of nitric oxide (NO) synthesis increases the risk of atherosclerosis. Nevertheless, in the condition of oxidative stress, NOS blockade by ADMA may exert protective effects. Protein metabolism is altered in patients with phenylketonuria (PKU) on dietary treatment and as shown recently, oxidative stress is high in PKU. Since free ADMA concentrations are determined by both protein metabolism and oxidative stress we hypothesized, that free ADMA levels may be elevated in PKU patients.. Sixteen patientswith PKU on dietary treatment (mean age 10.1 ± 5.2 yrs), and 91 healthy children (mean age 11.6 ± 3.7 yrs) participated in a cross sectional study.. ADMA, total homocysteine (tHcy) and blood glucose were lower and the L-arginine/ADMA ratio was higher in PKU patients compared to controls. No significant correlation was present between phenylalanine (Phe) concentrations, protein intake, and lipid profile, history of cardiovascular disease or ADMA.. In contrast to our hypothesis, ADMAwas lower and the L-arginine/ADMA ratio was higher in PKU patients. Therefore, in PKU patients, the regulating function of ADMA on NO synthesis is altered and may thus contribute to oxidative stress.

Topics: Adolescent; Arginine; Atherosclerosis; Blood Glucose; Cardiovascular Diseases; Child; Cross-Sectional Studies; Female; Homocysteine; Humans; Lipid Metabolism; Male; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Phenylalanine; Phenylketonurias

We tested a biofermented nutraceutical (FPP) that has been previously shown to positively modulate nitric oxide (NO). Forty-two healthy middle-aged subjects were given 3 grams of FPP three times a day for 6 weeks, and tests were repeated at 3 and 6 weeks; the control group was given a placebo. Flow-mediated dilation (FMD) was measured together with NO compounds (nitrogen oxides [NOx]: NO(2)(-)+NO(3)(-)) plasma levels and asymmetrical dimethylarginine (ADMA). In the interventional group, overall FMD significantly increased from 4.2% to 7.3% (p<0.05 vs. placebo). A significant increase in plasma NO and a decrease in ADMA were detected after consumption of FPP (p<0.01). Although larger studies are awaited, it appears that, at least in healthy individuals, such nutraceutical intervention by positively acting on significant cardiovascular parameters can be considered in the armamentarium of a proactive age-management strategy.

Topics: Adult; Age Factors; Arginine; C-Reactive Protein; Cardiotonic Agents; Cardiovascular Diseases; Cardiovascular System; Dietary Supplements; Endothelium, Vascular; Female; Fermentation; Humans; Male; Middle Aged; Models, Biological; Nitric Oxide; Placebos; Time Factors

In HIV-infected patients, elevated plasma concentrations of the endogenous nitric oxide synthase inhibitor and cardiovascular risk factor asymmetric dimethylarginine (ADMA) are documented, and levels correlate with markers of immune activation, such as neopterin.. In this study, the effect of antiretroviral therapy (ART) on arginine, ADMA and symmetric dimethylarginine (SDMA) levels was investigated and related to changes of immune activation markers and lipids. Concentrations of ADMA, SDMA, arginine, C-reactive protein (CRP) and neopterin were determined in 112 HIV-infected patients after 12 months of successful ART, as reflected by undetectable HIV RNA levels, and compared to baseline levels. ADMA, SDMA, arginine and urine neopterin levels were determined by HPLC, and plasma neopterin concentrations by ELISA. Disease activity before and after treatment was monitored by determination of HIV RNA levels and CD4(+) T-cell counts. Lipids and CRP were determined by routine laboratory assays.. Under treatment with ART, concentrations of ADMA, SDMA and arginine dropped in parallel with decreasing HIV RNA levels and neopterin concentrations, while cholesterol, triglyceride levels and CD4(+) T-cell counts increased. CRP levels did not change. After ART, a significant inverse association between ADMA and plasma cholesterol was observed.. Successful ART, defined by HIV RNA levels below the limit of detection, leads to decreasing levels of methylated arginines and immune activation markers. Thus, it is unlikely that disturbances of dimethylarginine metabolism account for the increased risk of cardiovascular events of HIV-infected patients under ART.

Topics: Adult; Anti-HIV Agents; Arginine; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; CD4 Lymphocyte Count; Cholesterol; Chromatography, High Pressure Liquid; Enzyme-Linked Immunosorbent Assay; Female; HIV; HIV Infections; Humans; Limit of Detection; Male; Middle Aged; Neopterin; Prospective Studies; RNA, Viral; Treatment Outcome; Triglycerides

Hyperhomocysteinaemia represents an important cause of morbidity in recipients of renal transplants, but few investigations have been carried out to evaluate the status of the methylation cycle and its relation with levels of new cardiovascular biomarkers, such as asymmetric dimethylarginine (ADMA).. Twenty-six children and adolescents aged 7-18 years (17 male, 9 female) with stable renal transplants were recruited for the study. None had received treatment with folate, vitamin B(12) or statins. Levels of ADMA in plasma and of components of the methylation cycle and arginine (Arg)-creatine pathway in plasma and urine were analysed by specific analytical methods. Results were compared to those obtained by us with identical methods in healthy children of similar age.. Concentrations of homocysteine (Hcys), S-adenosylhomocysteine (SAH) and ADMA were significantly higher, while S-adenosylmethionine (SAM)/SAH and Arg/ADMA ratios were significantly lower than controls. Arg/ADMA ratio correlated with plasma guanidinoacetate. The components of the methylation cycle, Hcys and SAH correlated with renal function.. Children with renal transplant showed low methylation power (SAM/SAH) mainly due to increased levels of SAH which acts as a cardiovascular biomarker. Elevated values of ADMA and low Arg/ADMA coefficients also represent a novel finding because it inhibits nitric oxide synthesis contributing to endothelial dysfunction and cardiovascular risk in such patients.

Topics: Acute Kidney Injury; Adolescent; Arginine; Biomarkers; Cardiovascular Diseases; Case-Control Studies; Child; Creatine; Creatinine; Cystatin C; Female; Glomerular Filtration Rate; Humans; Kidney Function Tests; Kidney Transplantation; Male; Methylation; Prognosis; Risk Factors; Survival Rate

Dental infections might predispose toward the onset of cardiovascular disease (CVD). To date, only a few studies, yielding inconclusive findings, have investigated the potential correlation between apical periodontitis (AP) and CVD. The aim of this study (as the first part of a prospective study) was to evaluate, in the absence of CV risk factors, whether subjects with AP were more exposed to the pathogenetic indices of an atherosclerotic lesion.. Forty men between the ages of 20 and 40 years who were free from periodontal disease, CVD, and traditional CV risk factors were enrolled in the study; 20 subjects had AP, and 20 acted as controls. All subjects underwent dental examination and complete cardiac assessment: physical examination, electrocardiogram, conventional and tissue Doppler echocardiography, and measurement of endothelial flow reserve (EFR). The following laboratory parameters were tested: interleukins -1, -2, and -6 (IL-1, IL-2, IL-6), tumor necrosis factor alpha, and asymmetrical dimethylarginine (ADMA). Data were analyzed by using the 2-tailed Student's t test, Pearson t test (or Spearman t test for nonparametric variables), and multivariate linear regression analysis.. Echocardiography revealed no abnormalities in any of the subjects studied. ADMA levels were inversely correlated with EFR (P < .05) and directly correlated with IL-2 (P < .001). Patients with AP presented with significantly greater blood concentrations of IL-1 (P < .05), IL-2 (P < .01), IL-6 (P < .05), and ADMA (P < .05) and a significant reduction of EFR (P < .05).. Increased ADMA levels and their relationship with poor EFR and increased IL-2 might suggest the existence of an early endothelial dysfunction in young adults with AP.

Topics: Adult; Arginine; Cardiovascular Diseases; Chromatography, High Pressure Liquid; Coronary Circulation; Cross-Sectional Studies; Dental Pulp Diseases; Echocardiography, Doppler; Echocardiography, Doppler, Pulsed; Electrocardiography; Endothelium, Vascular; Humans; Interleukin-1; Interleukin-2; Interleukin-6; Male; Periapical Periodontitis; Physical Examination; Prospective Studies; Radiography, Bitewing; Radiography, Panoramic; Risk Factors; Stroke Volume; Tumor Necrosis Factor-alpha; Ventricular Function, Left; Young Adult

Asymmetric dimethylarginine (ADMA) has been suggested as a possible marker of endothelial dysfunction, and interest in its use in clinical practice is increasing. However, the potential role of symmetric dimethylarginine (SDMA) as an endogenous marker of renal function, has been less widely investigated. The aims of the present study were therefore to determine reference values for dimethylarginines in plasma after method validation, and to ascertain ADMA plasma concentrations in patients with disorders characterized by endothelial dysfunction; a further end-point was to investigate the relationship between SDMA plasma concentrations and estimated GFR (eGFR) as well as plasmatic creatinine in patients with chronic kidney disease (CKD).. HPLC with fluorescence detection was used for the determination of plasma dimethylarginines. To verify the clinical usefulness of ADMA and SDMA, values from 4 groups of patients at a high risk of cardiovascular complications as well renal dysfunction (chronic heart failure n=126; type II diabetes n=43; pulmonary arterial hypertension n=17; chronic kidney disease n=42) were evaluated, and compared with the reference values, obtained from 225 blood donors.. The intra- and inter-assay CVs (<5.2%), the absolute and relative recoveries (96-106%) were highly satisfactory. ADMA levels were significantly elevated in all groups of patients compared with controls (p<0.001) with the exception of samples from patients with type II diabetes. SDMA levels were significantly elevated both in the patients with chronic kidney disease and in the patients with type II diabetes complicated by renal insufficiency, the values being closely correlated with both eGFR (R=0.740) and plasmatic creatinine (R=0.700).. The findings made in the present study shows that ADMA levels are significantly increased in patients with diseases associated with endothelial dysfunction This molecule might, therefore, be used as a biochemical marker for the evaluation of endothelial function. Furthermore, the preliminary results reported suggest that SDMA might be a reliable marker of renal function, especially in peadiatric populations, for which the use of eGFR is not recommended.

Topics: Adolescent; Adult; Aged; Arginine; Cardiovascular Diseases; Chromatography, High Pressure Liquid; Creatine; Endothelium, Vascular; Female; Glomerular Filtration Rate; Humans; Kidney Function Tests; Male; Middle Aged; Renal Insufficiency, Chronic; Young Adult

Atherosclerosis is a chronic inflammatory disease, which selectively involves the arteries in the vascular system. Atherosclerosis develops because of reactions occurring in vessel wall beginning with response to endothelial injury. Endothelial dysfunction is characterized with impairment and loss of monolayer cells covering the inside of the vessels, which is endothelium. Endothelial dysfunction is the first stage in atherosclerosis. Coronary angiogenesis and collateral growth are chronic adaptations to myocardial ischemia to restore coronary blood flow and salvage myocardium in the ischemic region. Nitric oxide (NO) which represents the status of endothelial health plays a major role in collateral vessel development. Asymmetric dimethylarginine (ADMA) which is endogenous inhibitor of NO synthesis may impair the effective coronary collateral vessel development. Increased plasma ADMA levels are related with poor coronary collateral development. ADMA may be responsible for the difference in coronary collateral vessel development among similar patients with coronary artery disease. Nitric oxide inhibitors have a determinative relation with endothelial cell functions which may be integral prerequisite in all steps of collateral development. The aim of this review is to evaluate the interrelations between ADMA and collateral growth.

Topics: Arginine; Atherosclerosis; Cardiovascular Diseases; Collateral Circulation; Coronary Artery Disease; Humans; Male; Nitric Oxide; Nitric Oxide Synthase Type III; Risk Factors

The purpose of this study was to evaluate whether the mRNA expression profiles of three genes (PRMT1, DDAH2 and NOS3) are related to ADMA metabolism and signalling, and the potential relationships with anthropometrical, biochemical, lifestyle and inflammatory indicators in healthy young adults. An emphasis on the putative effect of different mRNA expression on cardiovascular risk-related features was paid. Anthropometrical measurements as well as lifestyle features were analyzed in 120 healthy young adults. Fasting blood samples were collected for the measurement of glucose and lipid profiles as well as the concentrations of selected inflammatory markers. Profiles of mRNA expression were assessed for PRMT1, DDAH2 and NOS3 genes from peripheral blood mononuclear cells. Regarding inflammatory biomarkers, DDAH2 was inversely associated with IL-6 and TNF-alpha. Moreover, subjects in the highest quintile of DDAH2 mRNA expression showed a reduced risk to have higher values of waist circumference, and to be more prone to show higher values of HDL-c. Interestingly, DDAH2 gene expression seemed to be related with some anthropometrical, biochemical, lifestyle and inflammatory indicators linked to cardiovascular risk in apparently healthy young adults, emerging as a potential disease marker.

Topics: Adult; Amidohydrolases; Anthropometry; Arginine; Biomarkers; Cardiovascular Diseases; Female; Humans; Interleukin-6; Life Style; Male; Nitric Oxide Synthase Type III; Protein-Arginine N-Methyltransferases; Repressor Proteins; Risk Factors; RNA, Messenger; Tumor Necrosis Factor-alpha; Young Adult

To investigate the correlation between concentrations of asymmetric dimethylarginine (ADMA) and neopterin (NP) as potential risk factors for cardiovascular diseases in chronic renal failure patients.. In this study, 33 patients with renal failure before and after haemodialysis were compared with healthy control subjects. Serum ADMA and NP levels were measured using high performance liquid chromatography (HPLC).. When ADMA and NP concentrations in renal failure patients were compared before and after dialysis, before dialysis ADMA and NP concentrations were higher than those in the control group. However, ADMA and NP levels showed a falling mean and clear after dialysis. While there is no correlation between ADMA and NP levels before dialysis, there is a mean and positive correlation between ADMA and NP levels after dialysis.. Potential risk factors for cardiovascular diseases include high concentrations of both ADMA and NP levels in chronic renal failure patients. A correlation mean between ADMA and NP levels after dialysis was found, but no correlation between ADMA and NP levels before haemodialysis was discovered. These can be evaluated as two different risk factors independent from each other.

Topics: Arginine; Cardiovascular Diseases; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Neopterin; Renal Dialysis; Risk Factors

Tobacco smoking, counted as one of the alternating external cardiovascular risk factors, can cause disadvantageous changes of concentration of compounds considered to be the new internal risk factors. The aim of the study was to determine the influence of tobacco smoke on concentration levels of homocysteine, dimethylarginine (ADMA), fibrinogen and C-reactive protein (CRP) in healthy smoking male's blood plasma. 71 healthy male volunteers, aged 30-59, were chosen for the study. Based on a questionnaire they were divided into non-smoking group (37 individuals) and active smokers group (34 individuals). The results obtained indicate the most significant increasing effect of tobacco smoke on blood plasma homocysteine levels (by 11.9%) and then, successively, on fibrinogen (by 10.1%) and ADMA (by 9.1%). Changes of CRP concentration, although differentiated similarly to other factors, were insignificant. Since the coexistence of elevated risk factors shows a synergistic effect on cardiovascular risk level in general, it is advisable to perform tests of new risk factors among people exposed to tobacco smoke. The tests will appoint the ones at risk of disease and help to cover them with a medical care.

Topics: Adult; Arginine; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Causality; Comorbidity; Environmental Monitoring; Epidemiological Monitoring; Fibrinogen; Homocysteine; Humans; Male; Middle Aged; Risk Factors; Smoking; Tobacco Smoke Pollution

Obstructive sleep apnea-hypopnea syndrome (OSAHS) with episodic hypoxia-reoxygenation is associated with increased cardiovascular morbidity and mortality. Therefore, increased homocysteine, asymmetric dimethylarginine (ADMA), oxidative status, and decreased nitric oxide levels have been implicated as possible mechanisms for development of cardiovascular diseases. We aimed to investigate changes in the levels of these substances in patients with OSAHS in comparison with nonapneic controls. Thirty-four OSAHS patients and 15 healthy controls were included in this study. In the blood samples, oxidative status and nitric oxide levels were measured with spectrophotometric methods. Plasma ADMA and homocysteine levels were determined by using high-performance liquid chromatography with fluorescence detection. Nitric oxide levels were significantly low in OSAHS patients (p < 0.05) and correlated with mean SaO(2) (r = 0.513, p < 0.002) and lowest SaO(2) (r = 0.363, p < 0.03). Oxidative status, ADMA, and homocysteine levels were higher in OSAHS patients, but difference did not reach statistical significance. After dividing patients into moderate (AHI = 5-29) and severe (AHI > or = 30) OSAHS groups, significantly increased homocysteine levels were observed in the severe OSAHS group (p < 0.05). Nitric oxide levels negatively correlated with oxidative status in total OSAHS patients (r = -0.415, p < 0.02) and also in severe OSAHS group (r = -0.641, p < 0.007). Hyperhomocysteinemia and diminished NO production may be causal factors in endothelial dysfunction seen in OSAHS and may explain the association between OSAHS and cardiovascular diseases. These modifiable factors should be monitored in patients suspected of having OSAHS.

Topics: Arginine; Body Mass Index; Cardiovascular Diseases; Female; Homocysteine; Humans; Male; Middle Aged; Nitric Oxide; Oxidative Stress; Polysomnography; Severity of Illness Index; Sleep Apnea, Obstructive

Left ventricular hypertrophy (LVH) is an early manifestation of cardiovascular target organ damage in patients with arterial hypertension. It is not only a target organ response to increased after-load, but is also the most potent cardiovascular risk factor. LVH is multifactorial sign which has several causative factors in addition to blood pressure. Asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of NO synthase. ADMA plasma levels have been shown to be elevated in diseases related to endothelial dysfunction such as hypertension, hyperlipidemia, diabetes mellitus. Because cardiac remodeling is associated with endothelial NO pathway, some recent studies investigated whether the plasma ADMA was related to LVH and found that there is a link between ADMA and left ventricular mass and geometry. ADMA was two times higher in patients with concentric LVH than in those normal controls. In many experimental systems, accumulation of ADMA is accompanied by reduced dimethylarginine dimethylaminohydrolase (DDAH) activity. Plasma ADMA is cleared in small part by urinary excretion, but the bulk of ADMA is degraded by DDAH. Therefore, we proposed that change in DDAH activity could disturb the metabolism of ADMA and result in hypertensive LVH through the ADMA/NO pathway.

Topics: Amidohydrolases; Animals; Arginine; Cardiovascular Diseases; Diabetes Mellitus; Endothelium; Humans; Hypertension; Hypertrophy, Left Ventricular; Mice; Models, Biological; Nitric Oxide; Nitric Oxide Synthase; Risk; Risk Factors

To investigate whether circulating asymmetric dimethylarginine (ADMA) levels are predictive of cardiovascular events, decline in glomerular filtration rate (GFR), end-stage renal disease (ESRD), and all-cause mortality in type 1 diabetic patients.. We performed a prospective observational follow-up study including 397 type 1 diabetic patients with overt diabetic nephropathy (243 men aged 42.1 +/- 10.5 years, GFR 76 +/- 34 ml/min per 1.73 m(2)) and a control group of 175 patients with longstanding type 1 diabetes and persistent normoalbuminuria (104 men aged 42.7 +/- 9.7 years, duration of diabetes 27.7 +/- 8.3 years). Patients were followed for a median 11.3 years (range 0.0-12.9) with yearly measurements of GFR ((51)Cr-EDTA plasma clearance) in patients with diabetic nephropathy. Endpoints were fatal and nonfatal cardiovascular disease (CVD), decline in GFR, ESRD, and all-cause mortality.. Among patients with diabetic nephropathy, 37 patients (19.4%) with ADMA levels below the median, compared with 79 patients (43.4%) above the median, suffered a major cardiovascular event during the follow-up period (P < 0.001). This effect persisted after adjustment for conventional CVD risk factors including baseline GFR (adjusted hazard ratio [HR] for elevated ADMA 2.05 [95% CI 1.31-3.20], P = 0.002). Furthermore, elevated ADMA levels predicted an increased rate of decline in GFR, development of ESRD, and all-cause mortality (P < 0.001). After adjustment for well-known progression promoters, including baseline GFR, the HR (adjusted) was 1.85 (95% CI 0.99-3.46, P = 0.055) for ESRD comparing upper and lower median ADMA levels.. Plasma ADMA levels predict fatal and nonfatal cardiovascular events in patients with type 1 diabetic nephropathy. Furthermore, increased ADMA levels tend to contribute to increased risk of progressive diabetic kidney disease.

Topics: Adult; Albuminuria; Arginine; Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Nephropathies; Female; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Kidney Failure, Chronic; Male; Middle Aged

Plasma accumulation of asymmetric dimethyl arginine (ADMA) is considered as a risk factor for endothelial dysfunction and a strong predictor for coronary heart diseases. Eicosapentaenoic (EPA) and docosahexaenoic (DHA) increasing plasma levels have been positively associated with reduced cardiovascular mortality with a mechanism( s) yet unclear. We hypothesised that ADMA reduction might be a part of EPA and DHA beneficial effects on the cardiovascular system.. To verify this hypothesis we measured ADMA plasma levels in aged spontaneously hypertensive rats (SHR) supplemented for 8 weeks with EPA and DHA.. 16-month-old SHR were supplemented with EPA and DHA (EPA-DHA) or with olive oil (1 g/kg/day; OLIVE). At the end of the treatments, the plasma of each animal was analysed for 1) the total fatty acid composition, by gas-cromatography, 2) ADMA levels, by high pressure liquid chromatography, 3) nitrite and homocysteine concentration by chemiluminescence and by polarisation immunoassay respectively. Moreover, the activity of dimethyl arginine dimethyl amino hydrolase, the main enzyme involved in ADMA metabolism, was measured spectrophotometrically in the kidney from each rat.. Animals supplemented with EPA and DHA showed: 1) lower ADMA and arachidonate plasma levels (587.4 +/- 113.7 nM and 0.49 +/- 0.11 mM respectively) than the values found in OLIVE rats (1365 +/- 399 nM and 1.07 +/- 0.07 mM respectively) 2) higher nitrite content (0.73 +/- 0.05 microM) than OLIVE (0.23 +/- 0.08 microM).. EPA and DHA supplementation reduced ADMA accumulation in SHR in parallel with a decrease of arachidonate availability. This finding suggests that the control of the inflammatory ground of endothelium might play an important role in EPA and DHA effect on this novel and highly predictive cardiovascular risk factor.

Topics: Aging; Animals; Arachidonic Acid; Arginine; Cardiovascular Diseases; Dietary Supplements; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Male; Rats; Rats, Inbred SHR; Risk Factors

An increasing number of reports in the literature indicate that endogenously produced inhibitors of nitric oxide synthase (NOS),particularly asymmetric dimethylarginine (ADMA), regulate nitric oxide generation in disease states. This article describes the biology of ADMA and the implications for cardiovascular physiology and pathophysiology.

Topics: Amidohydrolases; Arginine; Cardiovascular Diseases; Endothelium, Vascular; Enzyme Inhibitors; Humans; Models, Biological; Nitric Oxide; Nitric Oxide Synthase; Risk Factors

Increased plasma concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, has been associated with endothelial dysfunction, insulin resistance, and atherosclerosis in nondiabetic populations. In end-stage renal failure, circulating ADMA is elevated and a strong predictor of cardiovascular outcome. This study investigated the relation between ADMA and diabetic micro- and macrovascular complications in a large cohort of type 1 diabetic patients with and without early diabetic nephropathy.. ADMA concentrations in plasma were determined by a high-performance liquid chromatography method in 408 type 1 diabetic patients with overt diabetic nephropathy (252 men; mean age 42.7 years [SD 11.0], mean duration of diabetes 28 years [SD 9], median serum creatinine level 102 micromol/l [range 52-684]). A group of 192 patients with longstanding type 1 diabetes and persistent normoalbuminuria served as control subjects (118 men; mean age 42.6 years [SD 10.2], mean duration of diabetes 27 years [SD 9]).. In patients with diabetic nephropathy, mean +/- SD plasma ADMA concentration was elevated 0.46 +/- 0.08 vs. 0.40 +/- 0.08 micromol/l in normoalbuminuric patients (P<0.001). An increase in plasma ADMA of 0.1 micromol/l increased the odds ratio of nephropathy to 2.77 (95% CI 1.89-4.05) (P<0.001). Circulating ADMA increased in nephropathy patients with declining kidney function, as indicated by elevated values in the lower quartiles of glomerular filtration rate (<76 ml.min(-1).1.73 m(-2)) (P<0.001 ANOVA). Mean ADMA levels were similar in patients with or without diabetic retinopathy (P>0.2). However, in 44 patients with nephropathy and history of myocardial infarction and/or stroke, ADMA was significantly elevated at 0.48 +/- 0.08 micromol/l compared with 0.46 +/- 0.08 micromol/l in patients without major cardiovascular events (P=0.05).. Elevated circulating ADMA may contribute to the excess cardiovascular morbidity and mortality in early diabetic nephropathy.

Topics: Adult; Arginine; Biomarkers; Blood Pressure; Cardiovascular Diseases; Creatinine; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Nephropathies; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Morbidity; Nitric Oxide Synthase

Increased blood levels of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) predict cardiovascular mortality in patients with end-stage renal disease. Despite its low molecular weight, available information on the impact of hemodialysis (HD) on ADMA plasma levels is controversial.. We assessed plasma concentrations, dialyzer clearance and total amount of ADMA removed in 30 patients with end-stage renal disease during regular HD. In addition, plasma ADMA levels were assessed in 10 patients with acute renal failure treated with extended HD.. Regular HD decreased plasma creatinine (from 774 +/- 42 to 312 +/- 17 micromol/l) and urea (from 24.5 +/- 1.5 to 8.4 +/- 0.5 mmol/l) concentrations significantly (both p < 0.001), whereas plasma ADMA remained unchanged (4.35 +/- 0.19 vs. 4.76 +/- 0.24 micromol/l). ADMA clearance was 92 +/- 6 ml/min, and the total amount removed in the spent dialysate was 37 +/- 4 micromol. The clearances of creatinine (161 +/- 3 ml/min) and of urea (173 +/- 3 ml/min) were significantly higher. Furthermore, even during extended HD, plasma ADMA concentrations did not decrease significantly (1.73 +/- 0.22 vs. 1.63 +/- 0.18 micromol/l).. In conclusion, dialysance of ADMA is markedly lower than expected from its molecular weight because of significant protein binding of the substance. Since markedly increased ADMA blood concentrations have been linked to cardiovascular complications due to atherosclerosis in patients with ESRD, new strategies should be evaluated to remove this putative uremic toxin.

Topics: Arginine; Cardiovascular Diseases; Creatine; Female; Humans; In Vitro Techniques; Kidney Failure, Chronic; Male; Middle Aged; Protein Binding; Renal Dialysis; Urea