Symmetric Dimethylarginine Levels Research Articles

Nitric Oxide-Related Biological Pathways in Patients with Major Depression.

BackgroundMajor depression is a well-known risk factor for cardiovascular diseases and increased mortality following myocardial infarction. However, biomarkers of depression and increased cardiovascular risk are still missing. The aim of this prospective study was to evaluate, whether nitric-oxide (NO) related factors for endothelial dysfunction, such as global arginine bioavailability, arginase activity, L-arginine/ADMA ratio and the arginine metabolites asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) might be biomarkers for depression-induced cardiovascular risk.MethodsIn 71 in-patients with major depression and 48 healthy controls the Global Arginine Bioavailability Ratio (GABR), arginase activity (arginine/ornithine ratio), the L-arginine/ADMA ratio, ADMA, and SDMA were determined by high-pressure liquid chromatography. Psychiatric and laboratory assessments were obtained at baseline at the time of in-patient admittance and at the time of hospital discharge.ResultsThe ADMA concentrations in patients with major depression were significantly elevated and the SDMA concentrations were significantly decreased in comparison with the healthy controls. Even after a first improvement of depression, ADMA and SDMA levels remained nearly unchanged. In addition, after a first improvement of depression at the time of hospital discharge, a significant decrease in arginase activity, an increased L-arginine/ADMA ratio and a trend for increased global arginine bioavailability were observed.ConclusionsOur study results are evidence that in patients with major depression ADMA and SDMA might be biomarkers to indicate an increased cardiovascular threat due to depression-triggered NO reduction. GABR, the L-arginine/ADMA ratio and arginase activity might be indicators of therapy success and increased NO production after remission.

Nitric oxide synthesis capacity, ambulatory blood pressure and end organ damage in a black and white population: the SABPA study.

Nitric oxide (NO) synthesis capacity is determined by the availability of substrate(s) such as L-arginine and the influence of nitric oxide synthase (NOS) inhibitors, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). These factors may be important in black South Africans with a very high prevalence of hypertension. We compared ambulatory blood pressure (BP), markers of end organ damage and NO synthesis capacity markers [L-arginine, L-homoarginine, L-citrulline, L-arginine:ADMA, ADMA, SDMA and dimethylarginine (DMA)], between black and white teachers (n = 390). Associations of nighttime BP and markers of end organ damage with NO synthesis capacity markers were also investigated. Although black men and women had higher BP and albumin-to-creatinine ratio (ACR) (all p < 0.001), they also had higher L-arginine, L-homoarginine, L-arginine:ADMA and lower SDMA and DMA levels (all p < 0.05). Only in white men ADMA concentrations associated positively with nighttime systolic blood pressure (R (2) = 0.20, β = 0.26, p = 0.009), nighttime diastolic blood pressure (R (2) = 0.23, β = 0.27, p = 0.007), carotid intima media thickness (cIMT) (R (2) = 0.36, β = 0.22, p = 0.008) and ACR (R (2) = 0.14, β = 0.32, p = 0.001). Our findings suggest that despite an adverse cardiovascular profile in blacks, their NO synthesis capacity profile seems favourable, and that other factors, such as NO inactivation, may prove to be more important.

L-Arginine and SDMA Serum Concentrations Are Associated with Subclinical Atherosclerosis in the Study of Health in Pomerania (SHIP).

ObjectiveEven though ˪-arginine (ARG) derivatives can predict cardiovascular mortality, their role as atherosclerotic biomarkers is unclear. We tested the hypothesis if asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and the sum of both (DMA) are positively, while ARG and ARG/ADMA ratio are inversely associated with carotid intima-media thickness (cIMT) and atherosclerotic plaque in the carotid artery.Approach and ResultsCross-sectional data of 1999 subjects (age: 45–81 years; 48.2% ♀) from the population-based Study of Health in Pomerania (SHIP-0) was used. Analysis of variance and logistic regression models were calculated and all adjusted models were corrected for sex, age, smoking status, waist-to-hip ratio and estimated glomerular filtration rate. Increased cIMT (>75th age-sex specific percentile) was found in 517 subjects (25.7%), while atherosclerotic plaque was detected in 1413 subjects (70.4%). SDMA tertiles were significantly positively associated with larger cIMT among subjects with high SDMA levels [>66th: 0.82 (95%-CI 0.80; 0.85) mm]. High SDMA levels were related to a higher odds ratio (OR) of increased cIMT [OR 1.39 (95%-CI 1.08; 1.79)]. Furthermore, ARG was positively associated with atherosclerotic plaques [OR 1.41 (95%-CI 1.07; 1.85)]. No relation was found for ADMA and atherosclerosis.ConclusionsIn conclusion, the hypothesis of a positive association between SDMA with an increased cIMT was confirmed. Unexpectedly, ARG was positively related to atherosclerotic plaque. In view of these inconsistent findings, the impact of ARG derivatives as atherosclerotic biomarkers deserves further research.

Association of homoarginine and methylarginines with liver dysfunction and mortality in chronic liver disease.

Previous studies on arginine metabolites reported an association of asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) with liver dysfunction and an inverse relation of homoarginine (hArg) with cardiovascular risk. The aim of the present study was to investigate the relationships between hArg, ADMA, SDMA, and the dimethylarginine score (DAS, i.e., ADMA + SDMA) and liver dysfunction and survival in chronic liver disease. In 94 consecutive cirrhotic patients admitted to our outpatient liver clinic, serum levels of hArg, ADMA, and SDMA were measured by HPLC at baseline. Patients were followed with respect to mortality. In the entire study cohort (age 58.5 ± 11.2 years; 31 % females), the serum concentrations were 1.94 ± 0.90 µM for homoarginine, 0.90 ± 0.22 µM for ADMA, and 0.70 (0.60-0.93) µM for SDMA. ADMA correlated with both Child-Pugh and MELD scores, while SDMA, DAS, and hArg correlated with MELD score only. Thirty patients (32 %) died during a median follow-up of 3.5 years. Age- and sex-adjusted Cox proportional hazard ratios (HR) per µM (with 95 % confidence intervals) showed that hArg was associated with decreased mortality [HR 0.59 (0.37-0.96)], whereas mortality was increased in patients with higher ADMA [HR 3.78 (0.98-14.60)], SDMA [HR 6.54 (3.15-13.59)] and DAS [HR 4.13 (2.26-7.56)]. Only SDMA and DAS remained significantly associated with mortality after additional adjustments for either Child-Pugh stage or MELD score. In conclusion, in cirrhotic patients seen in an outpatient liver clinic, hArg as well as the dimethylarginines ADMA and SDMA was related to long-term mortality. In particular, SDMA predicts mortality independently of both Child-Pugh stage and MELD score.

Changes in plasma levels of asymmetric dimethylarginine, symmetric dimethylarginine, and arginine after a single dose of vardenafil in patients with pulmonary hypertension

ObjectiveWe investigated whether vardenafil, a phosphodiesterase-5 inhibitor, alters plasma levels of asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and arginine. Patients and methodsADMA, SDMA, and arginine were measured (0–540min) in 12 patients with pulmonary hypertension after a single oral dose of vardenafil. Invasive hemodynamic data were collected at baseline and after 60min. ResultsA reduction in ADMA was observed at 30 and 45min with a median change of −11.1% (P=0.021) and −12.5% (P=0.002). SDMA decreased with a median −5.3% change (P=0.032) at 45min. An increase in arginine, median 40.3% (P=0.002), 45.0% (P=0.010), and 77.1% (P=0.008) was observed at 120, 300, and 540min respectively. An increase in the arginine/ADMA ratio, median 11.7% (P=0.012), 32.5% (P=0.003), 26.5% (P=0.021), 33% (P=0.007), 48.5% (P=0.007), and 63.1% (P=0.008) was observed at 15, 45, 60, 120, 300, and 540min respectively. There was a positive correlation between vardenafil exposure and the percent change in the arginine/ADMA ratio from baseline to 540min (r=0.80; P=0.01). A correlation between baseline mean right atrial pressure (mRAP) and baseline ADMA (r=0.65; P=0.023), and baseline SDMA (r=0.61; P=0.035) was observed. A correlation between the baseline arginine/ADMA ratio and baseline cardiac output (CO) (r=0.59; P=0.045) and baseline cardiac index (CI) (r=0.61; P=0.036) was observed. Baseline arginine/ADMA ratio correlated with baseline mRAP (r=−0.79; P=0.002). A correlation between change (0–60min) in CI and change in arginine (r=0.77; P=0.003) as well as change in the arginine/ADMA ratio (r=0.61; P=0.037) was observed. ConclusionsVardenafil induced changes in ADMA, SDMA, arginine, and the arginine/ADMA ratio in patients with PH. An increase in arginine and the arginine/ADMA ratio was associated with improvement in CI.

Increased levels of symmetric dimethyl-arginine are associated with all-cause mortality in patients with symptomatic peripheral arterial disease

Recent interest has focused on the role of the methyl-arginines, endogenous inhibitors of nitric oxide, as adverse prognostic indicators. To date, few studies have assessed the role of symmetric dimethyl-arginine (SDMA) in patients with peripheral arterial disease. We aimed to determine the relationship, if any, of SDMA to all-cause mortality and disease severity as assessed by the ankle-brachial index (ABI) in patients with symptomatic peripheral arterial disease (PAD). In 238 patients with symptomatic PAD and an ABI of <0.8, l-arginine, asymmetric dimethyl-arginine (ADMA) and SDMA levels were measured by hydrophilic-interaction liquid chromatography-electrospray tandem mass spectrometry. The median follow-up was 6 years 11 months (interquartile range [IQR], 4 years 5 months-7 years 10 months). SDMA and ADMA levels were higher in those who died compared with those who survived (0.51 [IQR, 0.44-0.66] μmol/L vs 0.46 [IQR, 0.39-0.55] μmol/L, P ≤ .001; and 0.48 [IQR, 0.41-0.55] μmol/L vs 0.45 [IQR, 0.39-0.50] μmol/L, P = .007, respectively). l-arginine levels were similar in the two groups. On multivariate analysis, SDMA and ADMA as continuous variable were significantly associated with mortality (P = .001). For SDMA and ADMA, the highest compared with the lowest quartile levels were significantly associated with mortality (SDMA: hazard ratio, 3.855; 95% confidence interval, 1.625-9.143; P = .002; ADMA: hazard ratio, 2.277; 95% confidence interval, 1.114-4.654; P = .024). ADMA and SDMA showed a negative correlation with severity of PAD as assessed by ABI (r = -0.236, N = 216, P < .001; r = -0.209, N = 208, P = .002, respectively). The novel finding of this study is that SDMA levels were predictive of all cause-mortality and correlated with disease severity. Further studies should assess the role of nitric oxide donors in patients with high levels of SDMA.

The Role of Asymmetric and Symmetric Dimethylarginine in Acute Deep Vein Thrombosis

In this study, we aimed to determine the importance of asymmetric dimethylarginine (ADMA), symmetric dimethyl arginine (SDMA), and l-arginine levels which are influenced by the endothelial dysfunction in acute deep vein thrombosis (DVT), and compare their pretreatment and post-treatment levels. A total of 34 cases (19 men and 15 women, age range 42 ± 14 years) diagnosed with acute DVT and 34 control subjects (22 men and 12 women, age range 45 ± 11 years) without any vascular disorders were included in the study. The patients were administered low-molecular-weight heparin subcutaneously. Blood samples were obtained to measure ADMA, SDMA, and arginine levels before treatment and during the treatment (on 10th day). ADMA, SDMA, and l-arginine levels were measured using high performance liquid chromatography method. The ADMA and SDMA levels were significantly higher in acute DVT patients when compared with the controls (P = 0.001). Post-treatment decrease of ADMA and SDMA levels when compared with the pretreatment levels were found as statistically significant (P = 0.001). Increase in l-arginine levels were not found significant when compared with the control group (P = 0.12) or post-treatment levels (P = 0.16). We concluded that ADMA and SDMA levels can be used as parameters in clinical follow-up for determining the efficacy of treatment in acute DVT patients, and further studies are needed to further clarify the subject.

Scientific Prize Papers

Objective Recent interest has focused on the role of the methyl-arginines, endogenous inhibitors of nitric oxide, as adverse prognostic indicators. To date, few studies have assessed the role of symmetric dimethyl-arginine (SDMA) in patients with peripheral arterial disease. We aimed to determine the relationship, if any, of SDMA to all-cause mortality and disease severity as assessed by the ankle-brachial index (ABI) in patients with symptomatic peripheral arterial disease (PAD). Methods In 238 patients with symptomatic PAD and an ABI of Results The median follow-up was 6 years 11 months (interquartile range [IQR], 4 years 5 months-7 years 10 months). SDMA and ADMA levels were higher in those who died compared with those who survived (0.51 [IQR, 0.44-0.66] μmol/L vs 0.46 [IQR, 0.39-0.55] μmol/L, P ≤ .001; and 0.48 [IQR, 0.41-0.55] μmol/L vs 0.45 [IQR, 0.39-0.50] μmol/L, P = .007, respectively). l-arginine levels were similar in the two groups. On multivariate analysis, SDMA and ADMA as continuous variable were significantly associated with mortality ( P = .001). For SDMA and ADMA, the highest compared with the lowest quartile levels were significantly associated with mortality (SDMA: hazard ratio, 3.855; 95% confidence interval, 1.625-9.143; P = .002; ADMA: hazard ratio, 2.277; 95% confidence interval, 1.114-4.654; P = .024). ADMA and SDMA showed a negative correlation with severity of PAD as assessed by ABI ( r = −0.236, N = 216, P r = −0.209, N = 208, P = .002, respectively). Conclusions The novel finding of this study is that SDMA levels were predictive of all cause-mortality and correlated with disease severity. Further studies should assess the role of nitric oxide donors in patients with high levels of SDMA.

Serum homocysteine, asymmetric dimethyl arginine (ADMA) and other arginine-NO pathway metabolite levels in patients with psoriasis.

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.

Soluble CD14 is associated with markers of vascular dysfunction in bariatric surgery patients.

Chronic endotoxemia has been proposed to contribute to obesity-related complications. We aimed to investigate the potential impact of lipopolysaccharide (LPS) and subsequent monocyte activation measured as soluble CD14 (sCD14) on markers of vascular dysfunction in obese subjects undergoing bariatric surgery. This was a prospective study of 49 obese patients and 17 controls, assessed by plasma levels of LPS, sCD14, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA). Levels of ADMA were increased in obese subjects compared to controls, but were not significantly reduced after bariatric surgery. In obese subjects at baseline, there was a significant trend to increasing levels of ADMA and SDMA through tertiles of sCD14 and decreasing levels of both markers through tertiles of LPS. In models adjusting for age and gender, sCD14 but not LPS remained independently associated with ADMA and SDMA. For every 10% age- and gender-adjusted increase in sCD14, ADMA increased 0.031 μM (5.6%), whereas SDMA increased 0.039 μM (10.8%). Our results suggest that monocyte activation as measured by sCD14 is associated with obesity-related vascular dysfunction, whereas potential upstream triggers including microbial products should be investigated in future studies.

Physical exercise reduces synthesis of ADMA, SDMA, and L-Arg.

Increased levels of asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and low plasma level of L-arginine (L-ARG) are all conditions likely to decrease nitric oxide (NO) production. Aim of this study is to evaluate ADMA, SDMA, and L-ARG plasmatic levels before and after physical exercise in patients with coronary artery disease (CAD). We studied 30 patient with mean age 52 + 4.5 years. After inclusion in the study, before the execution of physical exercise, heparinized blood sample was drawn from an indwelling arterial line for determination of ADMA, L-ARG and SDMA (baseline values). Subsequently a blood sample was drawn after the physical exercise. The mean plasma concentrations of ADMA (0.68 + 0.06 vs 0.48 + 0.05 µmol/L) and SDMA (0.45 + 0.03 vs 0.30 + 0.03 µmol/L) were significantly lower after physical exercise in comparison to baseline value, while L-ARG mean levels were increased (44.20 + 10.5 vs 74.13 + 11.2 µmol/L). Physical exercise has a beneficial effect by reducing plasmatic ADMA and SDMA levels, and increasing L-ARG substrate for endothelial NO.

Physical exercise reduces synthesis of ADMA SDMA and L-Arg

Increased levels of asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and low plasma level of L-arginine (L-ARG) are all conditions likely to decrease nitric oxide (NO) production. Aim of this study is to evaluate ADMA, SDMA, and L-ARG plasmatic levels before and after physical exercise in patients with coronary artery disease (CAD). We studied 30 patient with mean age 52 ± 4.5 years. After inclusion in the study, before the execution of physical exercise, heparinized blood sample was drawn from an indwelling arterial line for determination of ADMA, L-ARG and SDMA (baseline values). Subsequently a blood sample was drawn after the physical exercise. The mean plasma concentrations of ADMA (0.68 ± 0.06 vs 0.48 ± 0.05 µmol/L) and SDMA (0.45 ± 0.03 vs 0.30 ± 0.03 µmol/L) were significantly lower after physical exercise in comparison to baseline value, while L-ARG mean levels were increased (44.20 ± 10.5 vs 74.13 ± 11.2 µmol/L). Physical exercise has a beneficial effect by reducing plasmatic ADMA and SDMA levels, and increasing L-ARG substrate for endothelial NO.

Symmetric Dimethylarginine Is Not Associated with Cumulative Inflammatory Load or Classical Cardiovascular Risk Factors in Rheumatoid Arthritis: A 6-Year Follow-Up Study.

Symmetric dimethylarginine (SDMA) indirectly inhibits nitric oxide (NO) synthesis and predicts cardiovascular and all-cause mortality in high-risk patients. The aim of our study was to investigate the associations of cumulative inflammatory burden (assessed by serial measurements of inflammatory markers) and classical cardiovascular (CV) disease risk factors with SDMA in RA patients. 201 RA patients (155 females, median age 67 (59–73)) were assessed at baseline (2006). Classical CV disease risk factors were recorded and systemic inflammation was determined by the measurement of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). At follow-up (2012) SDMA levels were measured by enzyme-linked immunosorbent assay. Mean SDMA levels in RA population were 0.40 (0.40–0.53) μmol/L. No significant association between SDMA and cumulative inflammatory load was established in the analysis. SDMA levels were not found to be significantly related to CV disease risk factors. We explored the potential relationship between SDMA and cumulative inflammatory burden in patients with RA and obtained negative results. SDMA did not relate to CV disease risk factors in our population and its clinical significance as a surrogate marker of endothelial dysfunction in patients with RA remains to be determined.

Metabolomic Profiling of Arginine Metabolome Links Altered Methylation to Chronic Kidney Disease Accelerated Atherosclerosis.

Atherosclerotic cardiovascular disease is the leading cause of death in patients with chronic kidney disease (CKD), but the mechanisms underlying vascular disease has not been fully understood. As the nitrogen donor in nitric oxide (NO·) synthesis, arginine and its metabolic products are integrally linked to vascular health and information. We hypothesized that derangements in this pathway could explain, in part, increased atherosclerotic risk in CKD. We developed a targeted metabolomic platform to profile quantitatively arginine metabolites in plasma by liquid chromatography tandem mass spectrometry (LC/MS). Male low-density lipoprotein receptor defcient (LDLr−/−) mice at age 6 weeks were subjected to sham or 5/6 nephrectomy surgery to induce CKD. Subsequently, the animals were maintained on high fat diet for 24 weeks. Targeted metabolomic analysis of arginine metabolites in plasma was performed by isotope dilution LC/MS including asymmetric dimethyl arginine (ADMA), symmetric dimethyl arginine (SDMA), N-mono-methylarginine (NMMA), arginine and citrulline. Although elevated plasma levels of ADMA and SDMA were found in the CKD mice, only higher ADMA level correlated with degree of atherosclerosis. No significant differences were noted in levels of NMMA between the groups. CKD mice had high levels of citrulline and arginine, but ADMA levels had no correlation with either of these metabolites. These fndings strongly implicate altered arginine methylation and accumulation of ADMA, may in part contribute to CKD accelerated atherosclerosis. It raises the possibility that interrupting pathways that generate ADMA or enhance its metabolism may have therapeutic potential in mitigating atherosclerosis.

Plasma levels of dimethylarginines in preterm very low birth weight neonates: its relation with perinatal factors and short-term outcome.

Endogenously produced inhibitors of nitric oxide (NO) synthase, in particular asymmetric dimethylarginine (ADMA), are currently considered of importance in various disease states characterized by reduced NO availability. We investigated the association between plasma levels of ADMA, symmetric dimethylarginine (SDMA), l-arginine, and citrulline and perinatal factors and outcome in 130 preterm (gestational age ≤30 weeks) very low birth weight (VLBW, <1500 g) infants. Plasma samples were collected 6–12 h after birth. We did not find significant correlations between ADMA, SDMA, l-arginine, and citrulline levels and gestational age or birth weight. However, the arginine:ADMA ratio (AAR, a better indicator of NO availability than either arginine or ADMA separately) was positively correlated with gestational age. ADMA and arginine levels were not significantly different between males and females but males showed a negative correlation between ADMA levels and gestational age. Perinatal factors such as preeclampsia, chrorioamnionitis, prolonged rupture of membranes, or form of delivery did not significantly alter dimethylarginine levels or AAR. In contrast, the AAR was significantly reduced in the infants with respiratory distress, mechanical ventilation, and systemic hypotension Therefore, our data suggest that altered NO availability may play a role in the respiratory and cardiovascular adaptation in preterm VLBW infants.

Symmetric dimethylarginine as predictor of graft loss and all-cause mortality in renal transplant recipients.

Elevated symmetric dimethylarginine (SDMA) has been shown to predict cardiovascular events and all cause mortality in diverse populations. The potential role of SDMA as a risk marker in renal transplant recipients (RTR) has not been investigated. We analyzed SDMA in the placebo arm of the Assessment of Lescol in Renal Transplantation study, a randomized controlled trial of fluvastatin in RTR. Mean follow-up was 5.1 years. Patients were grouped into quartiles based on SDMA levels at study inclusion. Relationships between SDMA and traditional risk factors for graft function and all-cause mortality were analyzed in 925 RTR using univariate and multivariate survival analyses. In univariate analysis, SDMA was significantly associated with renal graft loss, all-cause death, and major cardiovascular events. After adjustment for established risk factors including estimated glomerular filtration rate, an elevated SDMA-level (4th quartile, >1.38 μmol/L) was associated with renal graft loss; hazard ratio (HR), 5.51; 95% confidence interval (CI), 1.95-15.57; P=0.001, compared to the 1st quartile. Similarly, SDMA in the 4th quartile was independently associated with all-cause mortality (HR, 4.56; 95% CI, 2.15-9.71; P<0.001), and there was a strong borderline significant trend for an association with cardiovascular mortality (HR, 2.86; 95% CI, 0.99-8.21; P=0.051). In stable RTR, an elevated SDMA level is independently associated with increased risk of all-cause mortality and renal graft loss.

Monocyte activation, but not microbial translocation, is independently associated with markers of endovascular dysfunction in HIV-infected patients receiving cART.

Microbial translocation has been suggested as a driver of cardiovascular disease in HIV infection. We hypothesized that microbial translocation and the resulting monocyte activation would be associated with markers of endovascular dysfunction. In 60 HIV-infected patients on combination antiretroviral therapy, plasma levels of lipopolysaccharide, soluble CD14 (sCD14), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) were measured. ADMA and SDMA were associated with sCD14 but not lipopolysaccharide. There was a significant increase in ADMA and SDMA through tertiles of sCD14, and both markers were associated with sCD14 in multivariate linear regression analyses. Monocyte activation as measured by sCD14 is associated with endovascular dysfunction in HIV infection.

Skin autofluorescence as a novel marker of vascular damage in children and adolescents with chronic kidney disease.

BackgroundSkin autofluorescence (sAF) was examined as a marker of the accumulation of advanced glycation end products (AGEs) in tissues of children with chronic kidney disease (CKD) in relation to renal function, dialysis modality and markers of endothelial inflammation and dysfunction.MethodsA total of 76 children with CKD were enrolled in the study, of whom 20 children were on hemodialysis (HD), 20 were on peritoneal dialysis (PD) and 36 were treated conservatively. A control group of 26 healthy subjects was also included in the study. In all children, sAF intensity, carotid intima-media (cIMT) thickness and plasma concentrations of sE-selectin, matrix metalloproteinase 9 (MMP-9), tissue inhibitor of metalloproteinase 1 (TIMP-1), asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and plasminogen activator inhibitor type 1 (PAI-1) were measured.ResultsCompared to the controls, children with CKD had significantly elevated sAF levels. sAF in the children with CKD was positively correlated with sE-selectin, MMP-9, TIMP-1, ADMA, SDMA and PAI-1 levels. In the predialysis group (conservative treatment) sAF levels were positively correlated with sE-selectin and ADMA levels and negatively correlated with glomerular filtration rate. Multiple regression analysis showed a significant association of sAF with sE-selectin and MMP-9 in CKD children.ConclusionsThe results reveal that AGEs were accumulated in the children with CKD. This accumulation was related to early vascular changes and a number of biochemical vascular risk markers. sAF measurement, as a noninvasive method, may be useful for identification of clinical risk factors of vascular disease in CKD children.

Endothelial dysfunction and oxidative stress in polycystic kidney disease.

Cardiovascular disease (CVD) is the leading cause of premature mortality in ADPKD patients. The aim was to identify potential serum biomarkers associated with the severity of ADPKD. Serum samples from a homogenous group of 61 HALT study A ADPKD patients [early disease group with estimated glomerular filtration rate (eGFR) >60 ml·min(-1)·1.73 m(-2)] were compared with samples from 49 patients from the HALT study B group with moderately advanced disease (eGFR 25-60 ml·min(-1)·1.73 m(-2)). Targeted tandem-mass spectrometry analysis of markers of endothelial dysfunction and oxidative stress was performed and correlated with eGFR and total kidney volume normalized to the body surface area (TKV/BSA). ADPKD patients with eGFR >60 ml·min(-1)·1.73 m(-2) showed higher levels of CVD risk markers asymmetric and symmetric dimethylarginine (ADMA and SDMA), homocysteine, and S-adenosylhomocysteine (SAH) compared with the healthy controls. Upon adjustments for age, sex, systolic blood pressure, and creatinine, SDMA, homocysteine, and SAH remained negatively correlated with eGFR. Resulting cellular methylation power [S-adenosylmethionine (SAM)/SAH ratio] correlated with the reduction of renal function and increase in TKV. Concentrations of prostaglandins (PGs), including oxidative stress marker 8-isoprostane, as well as PGF2α, PGD₂, and PGE₂, were markedly elevated in patients with ADPKD compared with healthy controls. Upon adjustments for age, sex, systolic blood pressure, and creatinine, increased PGD₂ and PGF₂α were associated with reduced eGFR, whereas 8-isoprostane and again PGF₂α were associated with an increase in TKV/BSA. Endothelial dysfunction and oxidative stress are evident early in ADPKD patients, even in those with preserved kidney function. The identified pathways may provide potential therapeutic targets for slowing down the disease progression.

Associations of Methylarginines and Homoarginine With Diastolic Dysfunction and Cardiovascular Risk Factors in Patients With Preserved Left Ventricular Ejection Fraction

BackgroundAsymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and homoarginine are considered to modulate nitric oxide synthesis. We evaluated whether ADMA, SDMA, and homoarginine are associated with diastolic dysfunction. Methods and ResultsWe investigated primary care patients at cardiovascular risk with preserved left ventricular ejection fraction from the multicenter DIAST-CHF study. We measured serum concentrations of ADMA, SDMA, and homoarginine and performed standardized echocardiographic examinations. Among 1,396 patients (mean age 65.3 ± 8.3 y, 54.6% women), diastolic dysfunction was ruled out in 261 patients (18.7%). Mild and moderate/severe grades of diastolic dysfunction were present in 900 (64.5%) and 235 (16.8%) study participants, respectively. After adjustments for cardiovascular risk factors, ADMA and SDMA were positively and homoarginine negatively associated with N-terminal pro–B-type natriuretic peptide and midregional pro-adrenomedullin (P < .05 for all). Lower homoarginine levels were associated with diastolic dysfunction, and higher ADMA and SDMA levels were associated with the severity of diastolic dysfunction (P < .05 for all). ConclusionsHigher levels of ADMA and SDMA and lower levels of homoarginine are associated with an adverse cardiovascular risk profile and diastolic dysfunction. Further studies should clarify the potential of these amino acid derivatives for the therapy of cardiovascular diseases.