Symmetric dimethylarginine is an independent predictor of intradialytic hypotension

BACKGROUND: Hemodialysis (HD) is associated with significant reductions in the plasma concentrations of the nitric oxide (NO) inhibitors N(G)-monomethyl L-arginine (L-NMMA), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA). We sought to determine whether elevated concentrations of these NO inhibitors pre-HD and/or their acute decrease during HD might mediate intradialytic hypotension (IDH). METHODS: Systolic blood pressure (SBP), L-arginine, L-NMMA, ADMA, and SDMA were measured at the beginning (pre-HD) and at the end (end-HD) in 52 consecutive HD patients (age 64.4 +/- 13.4 years). IDH was defined as a SBP reduction of >20 mm Hg end-HD vs. pre-HD. RESULTS: Fourteen patients demonstrated IDH. The mean SBP reduction during HD in this group was -35 +/- 13 mm Hg compared to an increase of +2 +/- 12 mm Hg among the 38 patients without IDH (no-IDH). Baseline demographic, clinical, and biochemical parameters did not differ between the IDH and no-IDH groups. However, the IDH group had higher pre-HD SBP (155 +/- 17 vs. 132 +/- 14 mm Hg, P < 0.001), pre-HD plasma SDMA concentrations (1.98 +/- 0.61 vs. 1.64 +/- 0.46 micromol/l, P = 0.04), and greater SDMA reductions during HD (-0.78 +/- 0.43 vs. -0.56 +/- 0.32 micromol/l, P = 0.06) than the no-IHD group. After adjusting for pre-HD SBP, the odds of IDH occurring were higher with increased pre-HD SDMA plasma concentrations (OR = 1.31 per 0.1 micromol/l SDMA increase; 95% CI = 1.04-1.65, P = 0.02) and with decreases in SDMA during HD (OR = 1.39 per 0.1 micromol/l SDMA decrease; 95% CI = 1.02-1.91, P = 0.04). CONCLUSION: Increased pre-HD SDMA plasma concentrations and greater SDMA reductions during HD independently predict IDH after adjusting for demographic and clinical variables, pre-HD SBP, and other methylated forms of L-arginine.     

Effects of combined supplementation with B vitamins and antioxidants on plasma levels of asymmetric dimethylarginine (ADMA) in subjects with elevated risk for cardiovascular disease

Elevated plasma asymmetric dimethylarginine (ADMA) concentrations have been suggested as a potential risk factor for cardiovascular disease (CVD). Studies indicate a linkage between hyperhomocysteinemia, oxidative stress and ADMA metabolism. We tested the hypothesis that combined supplementation of B vitamins and antioxidants reduces ADMA concentrations in subjects with at least two CVD risk factors. A total of 123 men and women (58+/-8.1 years) were randomly assigned to take either a preparation including B vitamins and antioxidants (verum) or placebo for 6 months in a double-blind design. Blood concentrations of ADMA, symmetric dimethylarginine (SDMA), L-arginine, B vitamins, total homocysteine (tHcy), alpha-tocopherol, antioxidant capacity (TEAC), and oxLDL were measured pre- and post-intervention. Treatment with verum significantly decreased tHcy (-2.14 micromol/L; P<0.001) and significantly increased TEAC values (+39.3 microM; P<0.022), but no effect on ADMA was observed. OxLDL was significantly reduced in verum (-7.3 U/L; P=0.001) and placebo (-9.2U/L; P<0.001). At baseline, significant correlations were found only between ADMA and SDMA (r=0.281; P=0.002), L-arginine/ADMA and SDMA (r=-0.294; P<0.001), L-arginine/ADMA and oxLDL (r=-0.281; P=0.016), and L-arginine/ADMA and age (r=-0.231; P=0.010). Our results indicate that combined supplementation of B vitamins and antioxidants is not an adequate strategy to reduce ADMA plasma levels in subjects with elevated CVD risk.     

Asymmetric dimethylarginine and coronary collateral vessel development

INTRODUCTION: Nitric oxide (NO) plays a major role in collateral vessel development. Asymmetric dimethylarginine (ADMA) that is an endogenous inhibitor of NO synthesis may impair the effective coronary collateral vessel development. The aim of this study was to evaluate the relationship between plasma ADMA level and coronary collateral vessel development. METHODS: The patients with a greater than or equal to 95% obstruction in at least one epicardial coronary artery were included in the study. Degree of coronary collateral development was determined according to Rentrop method. Patients with grade 2-3 collateral development were regarded as good collateral group and formed group I. The patients with grade 0-1 collateral development were regarded as poor collateral group and were included in group II. Group III that had been formed as a control group included the patients with a normal coronary angiogram. We compared the plasma ADMA, symmetric dimethylarginine, L-arginine/ADMA ratio among three groups. RESULTS: Seventy-four patients have been included in the study. Patients with good collateral development had lower plasma ADMA level in comparison with patients with poor collateral development (0.41+/-0.25 micromol/l vs. 0.70+/-0.23 micromol/l, P=0.001) and had similar plasma ADMA levels with the patients who have normal coronary arteries. When we compared L-arginine/ADMA ratio between good and poor collateral groups, we found that the patients with higher L-arginine/ADMA ratio have significantly better collateral development (270.8+/-168.0 vs. 120.9+/-92.1, P<0.001). In the analyses comparing Rentrop score with ADMA level and L-arginine/ADMA ratio, there were significant correlations (r=-0.444, P=0.008 and r=0.553, P=0.001, respectively). In multivariate analysis, ADMA level (odds ratio, 0.009; 95% confidence interval, 0.000-0.466, P=0.020) and L-arginine/ADMA ratio (odds ratio, 1.010; 95% confidence interval, 1.001-1.020, P=0.032) were independent predictors of collateral development. CONCLUSION: Increased plasma ADMA levels are related with poor coronary collateral development. ADMA may be responsible for the difference in coronary collateral vessel development among different patients with coronary artery disease. NO inhibitors that have a determinative relation with endothelial cell functions may be integral prerequisite in all steps of collateral development.     

Asymmetric dimethylarginine levels in thyroid diseases

Thyroid diseases may lead to endothelial dysfunction; however, the mechanism underlying the endothelial dysfunction in thyroid disease is not clear yet. Asymmetric dimethylarginine (ADMA), a novel inhibitor of endothelial nitric oxide synthase (eNOS), blocks nitric oxide (NO) synthesis from L-arginine. Symmetric dimethylarginine (SDMA) is the structural isomer of the eNOS inhibitor ADMA. SDMA does not directly inhibit eNOS but is a competitive inhibitor of arginine transport. Increased plasma ADMA, SDMA concentrations, and low L-arginine/ADMA ratio were considered as possible contributing factors for endothelial dysfunction in hyperthyroid patients. On the other hand, plasma ADMA, SDMA levels and L-arginine/ADMA ratio in the hypothyroid group were unexpectedly found to be similar to those of the control subjects. The aim of this study is to evaluate and compare the plasma ADMA levels in hyperthyroid, hypothyroid and healthy subjects. Plasma ADMA, SDMA, and L-arginine levels were measured by high performance liquid chromatography. Plasma ADMA levels were significantly higher in both patients with hyperthyroidism and hypothyroidism than in the control group. SDMA concentrations were significantly increased in hypothyroid patients compared to control subjects. Patients with hyperthyroidism and hypothyroidism had significantly higher plasma L-arginine levels compared with healthy controls. L-arginine/ADMA ratio, which shows NO bioavailability, was significantly lower in hyperthyroid patients than in both hypothyroid and control subjects. In hyperthyroidism, plasma ADMA levels were related to age, L-arginine, and SDMA levels. SDMA was associated with age and L-arginine. L-arginine/ADMA ratio was negatively associated with freeT4 levels. There was a relationship between ADMA and L-arginine in hypothyroid patients. SDMA was significantly related to L-arginine, total cholesterol, and LDL. In conclusion, not only hyperthyroidism but also hypothyroidism was associated with alterations of ADMA and SDMA metabolism.     

Uncomplicated type 1 diabetes is associated with increased asymmetric dimethylarginine concentrations

CONTEXT: Asymmetric dimethylarginine (ADMA) has recently emerged as an independent risk marker for cardiovascular disease, but studies investigating the ADMA levels in type 1 diabetes mellitus (DM) are scarce. OBJECTIVE: We aimed to evaluate plasma ADMA, L-arginine concentrations, and L-arginine to ADMA ratio in uncomplicated type 1 diabetic patients and controls. DESIGN AND SUBJECTS: Forty patients with type 1 DM who did not have clinical evidence of vascular complications and 35 healthy controls were included in the study. RESULTS: Plasma ADMA concentrations were higher (2.6 +/- 1.9 vs. 1.7 +/- 0.7 micromol/liter, P < 0.01), and L-arginine levels were lower (79.3 +/- 22.6 vs. 89.6 +/- 19.4 micromol/liter, P < 0.05) in the diabetic group, compared with controls. The L-arginine to ADMA ratio was also lower in the diabetic group (38.7 +/- 17.1 vs. 62.0 +/- 27.9, P < 0.0001). In diabetic patients, logADMA correlated positively with body mass index (BMI) (P = 0.01), fasting blood glucose (P = 0.006), and low-density lipoprotein cholesterol (LDL-c) (P = 0.01) and negatively with high-density lipoprotein cholesterol (P = 0.03). L-arginine to ADMA ratio correlated negatively with BMI (P = 0.004), fasting blood glucose (P = 0.02), and LDL-c (P = 0.01) and positively with high-density lipoprotein cholesterol (P = 0.04). In controls, logADMA and L-arginine to ADMA ratio correlated with BMI and LDL-c (P < 0.05). In regression analysis, BMI predicted 15% variance of ADMA levels (P = 0.02). CONCLUSIONS: We demonstrated that ADMA increases and L-arginine to ADMA ratio decreases, even before the development of vascular complications in type 1 DM.     

The L-Arginine–Asymmetric Dimethylarginine Ratio is an Independent Predictor of Mortality in Dilated Cardiomyopathy

BackgroundAsymmetric dimethylarginine (ADMA) is associated with increased mortality in patients with chronic heart failure but it remains unclear if the etiology of heart failure influences the prognostic value of dimethylarginines.Methods and ResultsL-Arginine, ADMA, and symmetric dimethylarginine (SDMA) were measured by liquid chromatography–tandem mass spectrometry in 341 patients with chronic heart failure due to dilated cardiomyopathy (DCM; n = 226) or ischemic cardiomyopathy (ICM; n = 115). Median (interquartile range [IQR]) ADMA and SDMA plasma levels were higher, L-arginine and the L-arginine–ADMA ratio were lower in patients with severe forms of heart failure (New York Heart Association (NYHA) functional class III or IV) compared with milder forms (NYHA functional class I or II) (ADMA 0.57 (0.14) μmol/L vs 0.54 (0.12) μmol/L [P < .001]; SDMA 0.47 (0.27) μmol/L vs 0.37 (0.13) μmol/L [P < .001]; L-arginine 81.8 (39.1) μmol/L vs 92.6 (39.3) μmol/L [P < .01]), but no significant differences were observed between the different etiologies. The L-arginine–ADMA ratio was associated with outcome only in patients with DCM. In multivariate analysis, the mortality risk of DCM patients was significantly lower for those in the highest quartile compared with the lowest quartile during a median observation time of 3.3 years (hazard ratio 0.31, 95% CI 0.11–0.88; P = .028, adjusted for other risk factors).ConclusionsDCM patients with unfavourable L-arginine–ADMA ratio are at increased risk for death.     

Plasma asymmetric dimethylarginine level and extent of lesion at coronary angiography

BACKGROUND: Given that the endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine, can decrease nitric oxide bioavailability and lead to atherosclerosis, its concentration can be a good predictor for coronary artery disease. In this study, we investigated the relationship of plasma asymmetric dimethylarginine concentration with lesion distribution and severity at coronary artery angiography. METHOD: Ninety-eight patients with stable angina were enrolled prospectively. We divided the patients into two groups. Group I (n=37) included the patients with normal coronary arteries. All the other patients were included in group II (n=61). We calculated coronary atherosclerotic score and coronary vessel score. Plasma asymmetric dimethylarginine, L-arginine and symmetric dimethylarginine concentrations were measured and L-arginine/asymmetric dimethylarginine ratio was calculated. RESULTS: Plasma L-arginine and symmetric dimethylarginine concentrations did not differ in the two groups. The plasma asymmetric dimethylarginine level, however, was higher in group II patients than in group I patients (0.43+/-0.26 vs. 0.59+/-0.28 micromol/l, P=0.004) and L-arginine/asymmetric dimethylarginine ratio was lower in group II patients than in group I patients (262.0+/-186.4 vs. 176.6+/-139.8, P=0.019). Asymmetric dimethylarginine was positively correlated with the coronary atherosclerotic score (rs=0.273, P=0.006). Moreover, asymmetric dimethylarginine was an important predictor of angiographically defined coronary artery disease (odds ratio=14.42, P=0.004). CONCLUSION: Our findings support the hypothesis that the plasma asymmetric dimethylarginine concentration may be a good indicator of predicting coronary artery disease.     

Plasma asymmetric dimethylarginine and L-arginine levels in patients with cardiac syndrome X

BACKGROUND: Endothelial dysfunction and subsequently impaired microvascular circulation are the leading mechanisms in the development of cardiac syndrome X (CSX). The study evaluated the plasma asymmetric dimethylarginine (ADMA) and L-arginine levels of the patients with CSX and the control group and aimed to determine any relationship between these parameters and epicardial coronary blood flow and myocardial tissue perfusion. METHODS: The study group consisted of 32 patients (mean age: 52.6+/-9.4 years, 14 men) with typical exertional angina, positive exercise test, and normal coronary arteries diagnosed as CSX. Plasma ADMA, L-arginine levels, and L-arginine/ADMA ratio were compared with the values of the control group, which consisted of 17 age-matched and sex-matched individuals. Concentrations of L-arginine and ADMA were measured by high-performance liquid chromatography. In all the coronary territories, epicardial coronary flow was assessed by thrombolysis in myocardial infarction (TIMI) frame count (TFC) method, and tissue level perfusion, by myocardial blush grade (MBG) method. A MBG score less than 3 was considered an impaired myocardial perfusion, and a MBG score of '3' in all the coronary territories, a normal myocardial perfusion. RESULTS: The plasma ADMA levels of the study group were higher than those of the control group (0.83+/-0.38 vs. 0.55+/-0.44 micromol/l, P=0.03), whereas plasma L-arginine levels were similar in both groups (70.25+/-21.89 vs. 76.09+/-18.22 micromol/l, P=0.36), resulting in a diminished L-arginine/ADMA ratio in the patients with CSX [82.3 (60.2-128.8) vs. 242.2 (76.7-386.4), P=0.003]. In CSX group, the patients with abnormal myocardial tissue perfusion had increased plasma ADMA levels compared with those with normal tissue perfusion (0.99+/-0.37 vs. 0.69+/-0.34 micromol/l, P=0.02), whereas plasma L-arginine levels were similar in both groups. No correlations were observed between TFC values and plasma ADMA, L-arginine levels, and L-arginine/ADMA ratio. Plasma ADMA levels, however, were negatively correlated with MBG scores (r=-0.349, P=0.014). CONCLUSION: We have shown for the first time that in the patients with CSX, increased plasma ADMA levels might be associated with impaired myocardial tissue perfusion when assessed by MBG.     

Metformin treatment lowers asymmetric dimethylarginine concentrations in patients with type 2 diabetes

This study was initiated to see if plasma asymmetric dimethylarginine (ADMA) concentrations decreased in hyperglycemic patients with type 2 diabetes following metformin treatment, either as monotherapy or following its addition to sulfonylurea-treated patients. Fasting plasma glucose, dimethylarginine, and L-arginine concentrations were measured before and 3 months after the administration of a maximally effective dose of metformin to 31 patients with type 2 diabetes in poor glycemic control (fasting plasma concentrations > 9.7 mmol/L), while being treated with either diet (n = 16) or a maximal amount of a sulfonylurea compound (n = 15). Fasting plasma glucose concentration (mean +/- SEM) decreased to a similar degree (P <.01) in patients treated with either metformin alone (12.4 +/- 0.5 to 9.5 +/- 0.5 mmol/L) or when it was added to a sulfonylurea compound (14.1 +/- 0.5 to 10.6 +/- 0.9 mmol/L). The improvement in glycemic control was associated with similar decreases (P <.01) in ADMA concentrations in metformin (1.65 +/- 0.21 to 1.18 +/- 0.13 micromol/L) and sulfonylurea + metformin-treated patients (1.75 +/- 0.13 to 1.19 +/- 0.08 micromol/L). Plasma L-arginine concentrations were similar in the 2 groups at baseline and did not change in response to metformin. Thus, metformin treatment was associated with a favorable increase in the plasma L-arginine/ADMA ratio. These results provide the first evidence that plasma ADMA concentrations decrease in association with improved glycemic control in patients with type 2 diabetes and demonstrate that the magnitude of the change in metformin-treated patients was similar, irrespective of whether it was used as monotherapy or in combination with sulfonylurea treatment.     

The role of asymmetric and symmetric dimethylarginines in renal disease

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthases. By inhibiting nitric oxide formation, ADMA causes endothelial dysfunction, vasoconstriction, elevation of blood pressure, and aggravation of experimental atherosclerosis. Levels of ADMA and its isomer symmetric dimethylarginine (SDMA), which does not inhibit nitric oxide synthesis, are both elevated in patients with kidney disease. Currently available data from prospective clinical trials in patients with chronic kidney disease suggest that ADMA is an independent marker of progression of renal dysfunction, vascular complications and death. High SDMA levels also negatively affect survival in populations at increased cardiovascular risk, but the mechanisms underlying this effect are currently only partly understood. Beyond glomerular filtration, other factors influence the plasma concentrations of ADMA and SDMA. Elevated plasma concentrations of these dimethylarginines might also indirectly influence the activity of nitric oxide synthases by inhibiting the uptake of cellular L-arginine. Other mechanisms may exist by which SDMA exerts its biological activity. The biochemical pathways that regulate ADMA and SDMA, and the pathways that transduce their biological function, could be targeted to treat renal disease in the future.     

Asymmetrical dimethylarginine is related to renal function, chronic inflammation and macroangiopathy in patients with Type 2 diabetes and albuminuria.

AIMS: Patients with Type 2 diabetes mellitus (T2DM) and micro- and macroalbuminuria are at increased cardiovascular risk. The endogenous nitric oxide synthase inhibitor asymmetrical dimethylarginine (ADMA) is increased in renal failure and could promote atherosclerosis. To determine the relationship between ADMA, renal albumin excretion rate (AER) and cardiovascular risk, we studied 103 T2DM patients. METHODS: ADMA, symmetrical dimethylarginine (SDMA) and L-arginine were determined by high-performance liquid chromatography in plasma from 36 normo-, 40 micro- and 27 macroalbuminuric patients with T2DM (age 64 +/- 11 years; 38 women) who had comparable age, sex and metabolic parameters. Forty-six patients had macrovascular disease (MVD). RESULTS: ADMA was significantly increased in patients with micro- and macroalbuminuria [median 0.61 (interquartile range 0.55-0.70) micromol/l and 0.62 (0.50-0.79) micromol/l, respectively] compared with those with normoalbuminuria [0.55 (0.48-0.63) micromol/l; both P < 0.05]. SDMA was elevated in micro- and macroalbuminuria [0.57 (0.42-0.80) micromol/l and 0.64 (0.50-0.96) micromol/l] compared with normoalbuminuric subjects [0.44 (0.37-0.53) micromol/l; both P < 0.01]. Patients with increased AER and MVD had higher ADMA and SDMA compared with those without MVD (both P < 0.001). L-arginine was comparable between all groups. ADMA correlated significantly with high-sensitivity C-reactive protein (hsCRP) and glomerular filtration rate (GFR) but not with the extent of albumin excretion, body mass index, fasting glucose, HbA(1c) or plasma lipids. CONCLUSIONS: Increased ADMA in T2DM patients with albuminuria is linked to cardiovascular disease and is associated with renal dysfunction and subclinical inflammation.     

Dietary composition as a determinant of plasma asymmetric dimethylarginine in subjects with mild hypercholesterolemia

Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase inhibitor that participates in the regulation of vasodilatory function and is also linked to hypertension, whereas its stereoisomere, symmetric dimethylarginine (SDMA), is biologically inactive. Dietary components influence vascular functions and a high-fat meal seems to increase postprandial plasma ADMA levels. However, it has not been published whether diet influences plasma ADMA levels. In this study, we investigated the impact of diet on plasma ADMA and SDMA levels. Thirty-four mildly hypercholesterolemic, otherwise healthy women (n = 14) and men (n = 20) with a mean age of 46.2 years (range, 35 to 62 years) participated in the study. The subjects were examined twice at intervals of 2 months. Seven-day food records were used to analyze diet and alcohol intake. ADMA was measured by using high-performance liquid chromatography (HPLC)-tandem mass spectrometry. In a multivariate analysis (R2 = 0.20, P < .002), low amount of energy received from carbohydrates (r = -0.31, P = .009) and high plasma triglycerides (r = 0.30, P = .01) were predictors of high ADMA plasma levels. Alcohol drinkers had higher plasma ADMA concentrations than abstainers (0.50 +/- 0.13 v 0.42 +/- 0.11 micromol/L, P = .04). Plasma ADMA correlated with systolic (r = 0.60, P = .005) and diastolic blood pressure (r = 0.53, P = .02) in abstainers but not in alcohol drinkers. Plasma SDMA was not associated with any dietary components or with blood pressure. In conclusion, a high amount of dietary carbohydrates is strongly associated with low levels of plasma ADMA. Concentration of ADMA in plasma seems to be higher in alcohol drinkers than in abstainers.     

Plasma concentrations of nitric oxide and asymmetric dimethylarginine in human alcoholic cirrhosis

BACKGROUND/AIMS: The liver plays a prominent role in the metabolism of asymmetric dimethyl-l-arginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthase. This study was designed to determine whether plasma levels of ADMA and NO production are altered in patients with compensated and decompensated alcoholic cirrhosis. METHODS: Plasma levels of l-arginine, ADMA, symmetric dimethylarginine (SDMA) and NO (nitrite plus nitrate, NOx) were measured in nine patients with compensated alcoholic cirrhosis (Child-Pugh A) and 11 patients with advanced cirrhosis (Child-Pugh B-C). Seven healthy volunteers served as controls. RESULTS: ADMA and NOx concentrations in decompensated cirrhosis were higher than in the compensated group and control group (ADMA: 1.12+/-0.08 vs. 0.58+/-0.05 and 0.58+/-0.07micromol/l, respectively; P<0.05; NOx 97.90+/-10.27 vs. 37.42+/-3.91 and 40.43+/-5.30micromol/l, respectively; P<0.05). There was a positive correlation between the clinical score of the patients and concentrations of ADMA (r(2)=0.547, P<0.01) and NOx (r(2)=0.689, P<0.01). SDMA and l-arginine levels were not significantly different between the three groups. CONCLUSIONS: The results suggest that hepatocellular damage is a main determinant of elevated ADMA concentration in advanced alcoholic cirrhosis. By inhibiting NO release from vascular endothelium, ADMA might oppose the peripheral vasodilation caused by excessive NO production in severe cirrhosis.     

Unchanged plasma levels of dimethylarginines and nitric oxide in chronic hepatitis C

Objective. Previous studies have shown that asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and nitric oxide (NO) play a prominent role in liver dysfunction. The objective of this study was to determine whether plasma levels of ADMA, SDMA and NO are altered in patients with chronic hepatitis C. Material and methods. Plasma levels of ADMA, SDMA and NO (nitrite plus nitrate) were measured in 22 patients with chronic hepatitis C and 24 patients with sustained virologic response after treatment with peginterferon plus ribavirin. Seven healthy volunteers served as controls. Results. Plasma levels of ADMA, SDMA and NO were not significantly different between groups: chronic hepatitis C, ADMA 0.55±0.06, SDMA 0.22±0.03, NO 36.3±5.9 µmol/l; treated patients, ADMA 0.60±0.15, SDMA 0.31±0.05, NO 36.1±5.5 µmol/l; controls, ADMA 0.65±0.08, SDMA 0.28±0.05, NO 40.7±8.9 µmol/l). Conclusions. Our results show that plasma NO, ADMA and SDMA concentrations are not changed in patients with chronic hepatitis C without superimposed signs of acute inflammatory activity. Furthermore, no significant differences in plasma values of NO and dimethylarginines were observed between the group of untreated patients and the group of patients treated with interferon plus ribavirin     

ADMA: a novel risk factor that explains excess cardiovascular event rate in patients with end-stage renal disease

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthase. By competitively displacing L-arginine from the substrate binding site of NO synthase, ADMA interferes with many of the physiological functions of NO, like endothelium-dependent vasodilation and leukocyte adhesion. ADMA, like its biologically inactive regioisomer, symmetric dimethylarginine (SDMA), can be found in human plasma and urine in low concentrations. The concentrations of both dimethylarginines are increased in patients with end-stage renal disease, which may explain at least in part endothelial dysfunction and cardiovascular complications in this patient population. In addition, the metabolism of ADMA, but not SDMA, occurs via hydrolytic degradation to citrulline and dimethylamine by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). Data from experimental studies suggest that ADMA inhibits vascular NO elaboration at concentrations that can be measured in plasma of patients with renal disease. Interestingly, ADMA and SDMA are poorly eliminated during hemodialysis. This is probably due to a high level of binding of both molecules to plasma proteins. High ADMA concentrations in patients with end-stage renal disease may contribute to their excess cardiovascular event rate, as in clinical studies a relationship between ADMA and carotid artery intimal thickening was found. Moreover, in a prospective study we demonstrated recently that determination of ADMA plasma concentration is useful to predict future cardiovascular event rate and total mortality in this patient population. As other researchers reported observations that are in line with our findings, there is evidence that ADMA may be a novel cardiovascular risk factor.     

Asymmetric dimethylarginine, derangements of the endothelial nitric oxide synthase pathway, and cardiovascular diseases

Analogues of L-arginine that are chemically modified at the terminal guanidino nitrogen group, such as Nomega-monomethy-L-arginine (L-NMMA), have been used for nitric oxide synthase inhibition. However, L-NMMA and other methylated L-arginine analogues are also endogenously formed. Among these, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) have been shown to be the most abundant. Like L-NMMA, ADMA is an inhibitor of NO synthase, whereas SDMA is inactive. ADMA is synthesized by N-methyltransferases, a family of enzymes that methylate L-arginine residues within specific proteins. Free ADMA is released during proteolytic cleavage of methylated proteins; it can be detected in plasma and urine, but its intracellular concentrations appear to be much higher. ADMA is metabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), and inhibition of DDAH activity has been shown to lead to increased ADMA levels and endothelial dysfunction. Plasma levels of ADMA are elevated in endstage renal failure, in atherosclerosis and hypercholesterolemia, in hypertension, and in heart failure. Although the molecular cause for elevation of ADMA concentration in these diseases has not been fully elucidated, evidence is accumulating that ADMA is one cause of endothelial dysfunction in these diseases. Moreover, it may be a marker or even a risk factor for cardiovascular disease. Therefore, pharmacological modulation of ADMA concentration may be a novel therapeutic target in cardiovascular diseases.     

Asymmetrical dimethylarginine: a novel risk factor for coronary artery disease

BACKGROUND: Asymmetrical dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide synthase and has been associated with systemic atherosclerosis; however, the role of ADMA in patients with coronary artery disease (CAD) has not been investigated. HYPOTHESIS: The present study was designed to determine whether the plasma ADMA level predicts the presence of CAD independently, and whether the plasma ADMA level correlates with the extent and severity of coronary atherosclerosis. METHODS: In all, 97 consecutive patients with angina and positive exercise stress test were enrolled prospectively for coronary angiography. According to the result of angiography, the subjects were divided into two groups: Group I (n = 46): patients with normal coronary artery or mild CAD (< 50% stenosis of major coronary arteries); Group 2 (n = 51): patients with significant CAD (> or = 50% stenosis of majorcoronary arteries). Plasma levels of ADMA and L-arginine were determined by high-performance liquid chromatography. In addition, we used coronary atherosclerotic score to assess the extent and severity of CAD. RESULTS: The plasma levels of ADMA in Group 2 patients were significantly higher than those in Group 1 patients (0.66 +/- 0.17 microM vs. 0.44 +/- 0.09 microM, p < 0.001); these were accompanied by significantly lower plasma L-arginine/ADMA ratio in patients with significant CAD (Group 1 vs. 2: 194.0 +/- 55.3 vs. 136.7 +/- 50.3, p < 0.001). In a multivariate stepwise logistic regression analysis, both plasma ADMA level and plasma L-arginine/ADMA ratio were identified as independent predictors for CAD. Moreover, there were significant positive and negative correlations between coronary atherosclerotic score and plasma ADMA level as well as plasma L-arginine/ADMA ratio, respectively (plasma ADMA level: r = 0.518, p < 0.001; L-arginine/ADMA ratio: r = -0.430, p < 0.001). CONCLUSIONS: Both plasma ADMA level and plasma L-arginine/ADMA ratio were useful in predicting the presence of significant CAD and correlated significantly with the extent and severity of coronary atherosclerosis. Our findings suggest that plasma ADMA level may be a novel marker of CAD.     

Asymmetric dimethylarginine determines the improvement of endothelium-dependent vasodilation by simvastatin: Effect of combination with oral L-arginine.

OBJECTIVES: We hypothesized that the level of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide (NO) synthase (eNOS), might determine the endothelial effects of statins. BACKGROUND: Endothelial NO synthase is up-regulated by statins. However, statins failed to improve endothelial function in some studies. Asymmetric dimethylarginine inhibits eNOS by a mechanism that is reversible by L-arginine. METHODS: Ninety-eight clinically asymptomatic elderly subjects had their plasma ADMA levels screened. Those in the highest (high ADMA, n = 15) and lowest quartiles of the ADMA distribution (low ADMA, n = 13) were eligible to receive, in a randomized order, simvastatin (40 mg/day), L-arginine (3 g/day), or a combination of both, each for 3 weeks. Endothelium-dependent vasodilation (EDD) was assessed by brachial artery ultrasound. RESULTS: Simvastatin had no effect on EDD in subjects with high ADMA (6.2 +/- 1.2% vs. 6.1 +/- 0.9%), whereas simvastatin plus L-arginine significantly improved EDD (9.8 +/- 1.5% vs. 5.3 +/- 0.8%; p < 0.01). In subjects with low ADMA, simvastatin improved endothelial function when given alone (9.5 +/- 3.2% vs. 6.1 +/- 3.8%; p < 0.001) or in combination with L-arginine (9.0 +/- 3.1% vs. 6.3 +/- 3.3%; p = 0.001). L-arginine alone improved endothelial function in both groups. Endothelium-independent vasodilation was not affected. CONCLUSIONS: Simvastatin does not enhance endothelial function in subjects with elevated ADMA, whereas it does so in patients with low ADMA. Combination of simvastatin with oral L-arginine improves endothelial function in subjects with high ADMA, but has no additional effect in subjects with low ADMA. As NO-mediated effects may play a major role in the therapeutic effects of statins, ADMA concentration is an important factor that influences the "pleiotropic" effects of simvastatin.     

Homocyst(e)ine-lowering therapy does not affect plasma asymmetrical dimethylarginine concentrations in patients with peripheral artery disease

BACKGROUND: Elevated plasma asymmetrical dimethylarginine (ADMA) is suggested to contribute to hyperhomocyst(e)ine-related vascular dysfunction in patients with peripheral artery disease (PAD). The present trial investigated whether homocyst(e)ine (Hcy)-lowering therapy with vitamin-B (vit-B) and folic acid affects plasma concentrations of ADMA in patients with PAD and hyperhomocyst(e)inemia. SUBJECTS AND METHODS: Forty-nine subjects (15 women, 34 men) with PAD and fasting plasma total Hcy concentrations greater than 15 micromol/liter were randomized to receive either oral vit-B and folic acid therapy (n = 27) or placebo (n = 22) for 6 wk. Fasting venous blood samples were monitored for plasma total Hcy, vit-B12 and folate, ADMA, symmetric dimethylarginine, L-arginine, and high-sensitivity C-reactive protein. RESULTS: After 6 wk, plasma Hcy concentrations were decreased, and concentrations of vit-B12 and folate were elevated in patients with vitamin supplementation (all P < 0.05 vs. baseline) and unchanged in the placebo group. Dimethylarginine plasma concentrations were not affected by treatment. High-sensitivity C-reactive protein correlated with ADMA plasma concentrations (r = 0.29; P < 0.01). CONCLUSION: The lack of vit-B and folic acid therapy on plasma concentrations of ADMA renders a role of extracellular methylarginines unlikely to be involved in the pathophysiology of hyperhomocyst(e)inemia and its complications.     

Unchanged asymmetric dimethylarginine levels in non-diabetic, premenopausal obese women who have common risk factors for cardiovascular disease

This study was performed to test whether plasma asymmetric dimethylarginine (ADMA) concentrations are related to obesity and obesity complications including decrement in insulin sensitivity and adiponectin levels, dyslipidemia and low-grade inflammation. Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) concentrations were analyzed by HPLC in 17 overweight (BMI ≥ 25 kg/m²) and 40 obese (BMI ≥ 30 kg/m²) premenopausal women. Age-matched healthy women were studied as controls. Obesity did not give rise to a significant change in circulating ADMA levels but reduced in SDMA levels. As compared with control subjects (0.441 ± 0.102 μM), ADMA values in overweight and obese subjects were found to be as 0.412 ± 0.102 and 0.436 ± 0.093, respectively. No Pearson’s association of ADMA with relevant risk variables for cardiovascular disease, including blood pressure, insulin sensitivity, inflammatory markers, lipid and adiponectin levels. However, in linear regression analysis, BMI, diastolic blood pressure, glucose, insulin, and IL-8 emerged as significant predictors of ADMA. In spite of obese women have elevated hs-CRP, triglyceride levels and decreased insulin sensitivity, adiponectin and HDL-cholesterol levels, all of which is closely linked risk factors for cardiovascular disease, circulating ADMA levels remained unchanged in obese individuals as compared with controls.