Plasma Asymmetric Dimethylarginine Levels Research Articles

Asymmetric dimethylarginine predicts perioperative cardiovascular complications in patients undergoing medium-to-high risk non-cardiac surgery.

ObjectivesPerioperative cardiovascular events remain an important factor that affects surgery outcome. We assessed if asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthesis, predicts perioperative risk, and if pre-operative supplementation with L-arginine/L-citrulline improves the plasma L-arginine/ADMA ratio.MethodsIn this prospective study, planned thoracic and/or abdominal surgery patients were randomized to receive L-arginine/L-citrulline (5 g/day) or placebo 1 to 5 days before surgery. We measured perioperative plasma ADMA and L-arginine levels. The primary outcome was a 30-day combined cardiovascular endpoint.ResultsAmong 269 patients, 23 (8.6%) experienced a major adverse cardiovascular event. ADMA and C-reactive protein were significantly associated with the incidence of cardiovascular complications in the multivariable-adjusted analysis. The L-arginine plasma concentration was significantly higher on the day of surgery with L-arginine/L-citrulline supplementation compared with placebo. In patients with high pre-operative ADMA, there was a non-significant trend towards reduced incidence of the primary endpoint with L-arginine/L-citrulline supplementation (six vs. nine events).ConclusionsADMA is a predictor of major adverse cardiovascular complications in the perioperative period for patients who are undergoing major abdominal and/or thoracic surgery. Supplementation with L-arginine/L-citrulline increased the L-arginine plasma concentration, enhanced the L-arginine/ADMA ratio, and induced a trend towards fewer perioperative events.

Role of Serum Asymmetric Dimethylarginine Level in Cardiovascular Diseases Early Prognostic in Patients with Obstructive Sleep Apnea-Hypopnea Syndrome

The purpose of this paper was to investigate the role of serum asymmetric dimethylarginine (ADMA) in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) and identify its clinical significance in OSAHS related cardiovascular diseases. A total of 75 patients with OSAHS were enrolled and divided into mild (n=25), moderate (n=27), and severe group (n=23) according to their apnea hypopnea index (AHI) and minimal oxygen saturation (SaO2 min), respectively. Thirty healthy individuals were enrolled as normal control. Serum ADMA was measured with enzyme-linked immunosorbent assay (ELISA). Nitric oxide (NO) level was assayed with colorimetric method. Nasal continuous positive airway pressure (nCPAP) treatment was performed to the patients, and the follow up lasted for 2 months. Serum ADMA level increased with the severity of patients. Serum NO level decreased with severity of patients. A negative correlation was noticed between serum NO and mean SaO2 (SaO2 mean) and minimal SaO2 (SaO2 min). Serum ADMA was positively correlated with AHI, tSaO2<90%, and morbidity of cardiovascular diseases. After nCPAP therapy, the serum ADMA level was remarkably decreased and NO was remarkably increased in patients with OSAHS. Serum ADMA may be correlated with OSAHS and OSAHS related cardiovascular diseases. Reducing the plasma ADMA level by nCPAP therapy can reduce the morbidity of OSAHS-related cardiovascular diseases.

Assessment of ADMA, IMA, and Vitamin A and E Levels in Patients with Acne Vulgaris.

Acne vulgaris is a common skin disease in adolescents known to be associated with oxidative stress. However, the number of studies in which oxidative stress and antioxidants are evaluated together is limited. In this study, we aimed to investigate L-arginine/nitric oxide (NO) pathway metabolites, ischemia-modified albumin (IMA), and vitamin A and E levels in patients with acne and its association with disease severity. Ninety patients with acne and 30 healthy adults were included in the study. The serum levels ofL-arjinin, L-arginine metabolites, IMA, and vitamins A and E measured in the patient and control groups. Asymmetric dimethylarginine (ADMA), LNG -monomethyl-L-arginine (L-NMMA) and symmetric dimethylarginine (SDMA), and IMA levels were significantly higher in the patients with acne than in the control group (P˂.05). The L-arginine/ADMA ratio and citrulline and vitamin A levels were significantly lower in patients with acne than those of the controls (P˂.05). ADMA and IMA plasma levels were increased in parallel with the disease severity (P˂.05). L-arginine/ADMA ratio, L-arginine, citrulline, and vitamin A plasma levels decreased as the disease became severe (P˂.05). Although L-arginine and vitamin E levels were lower in the patient group compared to the control group, the difference was not statistically significant (P˃.05). These results suggest that IMA and L-arginine-NO pathway associated with ischemia and oxidative stress may play an important role in the pathogenesis and progression of acne vulgaris.

Determination of Endothelial Nitric Oxide Synthase Gene Polymorphism and Plasma Asymmetric Dimethyl Arginine Concentrations in Patients with Lung Cancer.

Genetic factors can contribute to both the occurrence and development of lung cancer. This study aimed to investigate endothelial nitric oxide synthase (eNOS) G894T and T-786C polymorphisms and plasma asymmetric dimethylarginine (ADMA) levels of lung cancer patients in comparison with healthy subjects. A total of 200 subjects, 100 patients with lung cancer and 100 healthy volunteers were included in this study. To determine eNOS gene polymorphisms, we collected and analyzed blood samples with polymerase chain reaction (PCR). Plasma ADMA levels were evaluated by high-performance liquid chromatography (HPLC). The difference in gene polymorphisms between lung cancer patients and healthy controls were insignificant. However, lung cancer patients had statistically significantly higher plasma ADMA levels than healthy controls. The patients and control groups with CC polymorphisms and TT polymorphisms on eNOS T-786C and G894T gene regions had higher plasma ADMA levels. The CC polymorphisms and plasma ADMA levels were higher in patients with small-cell lung cancer compared to those in patients with non-small-cell lung cancer. Although eNOS gene polymorphisms had no significant difference between lung cancer patients and healthy controls, plasma ADMA levels were higher in lung cancer patients compared to healthy controls. Our study suggests that CC genotypes and elevated plasma ADMA levels might be associated with small-cell lung cancer.

Elevated plasma levels of asymmetric dimethylarginine and the risk for arrhythmic death in ischemic and non-ischemic, dilated cardiomyopathy – A prospective, controlled long-term study

IntroductionElevated plasma levels of asymmetric dimethylarginine (ADMA), an inhibitor of NO synthase, are associated with adverse outcome. There is no data available, whether ADMA levels are associated with arrhythmic death (AD) in patients with ischemic cardiomyopathy (ICM) or non-ischemic, dilated cardiomyopathy (DCM). Methods and resultsA total of 110 ICM, 52 DCM and 30 control patients were included. Primary outcome parameter of this prospective study was arrhythmic death (AD) or resuscitated cardiac arrest (RCA). Plasma levels of ADMA were significantly higher in ICM (p < 0.001) and in DCM (p < 0.001) patients compared to controls. During a median follow-up of 7.0 years, 62 (32.3%) patients died. AD occurred in 26 patients and RCA was observed in 22 patients. Plasma levels of ADMA were not associated with a significantly increased risk of AD or RCA in ICM (hazard ratio (HR) = 1.37, p = 0.109) or in DCM (HR = 1.06, p = 0.848) patients. No significant association was found with overall mortality in ICM (HR = 1.39, p = 0.079) or DCM (HR = 1.10, p = 0.666) patients. Stratified Kaplan-Meier curves for ADMA levels in the upper tertile (>0.715 µmol/l) or the two lower tertiles (≤0.715 µmol/l) did not show a higher risk for AD or RCA (p = 0.221) or overall mortality (p = 0.548). In patients with left ventricular ejection fraction ≤ 35%, ADMA was not associated with AD or RCA (HR = 1.35, p = 0.084) or with overall mortality (HR = 1.24, p = 0.162). ConclusionsPlasma levels of ADMA were elevated in patients with ICM or DCM as compared to controls, but were not significantly predictive for overall mortality or the risk for arrhythmic death.

Effect of Selective Antegrade Cerebral Perfusion with Moderately Hypothermic Lower Body Circulatory Arrest on Biomarkers Related to Endothelial Function

Aim: This study aims to compare biomarkers related to endothelial function during selective antegrade cerebral perfusion with moderate hypothermic lower body circulatory arrest with that of standard cardiac surgery.Material and Methods: Thirty-six consecutive patients who underwent selective antegrade cerebral perfusion with moderately hypothermic lower body circulatory arrest at 28°C (study group) for aneurysms of the ascending aorta were prospectively compared with 36 patients who underwent standard cardiac surgery (control group) with conventional cardiopulmonary bypass. Nitric oxide, asymmetric dimethylarginine, hydrogen sulfide and total antioxidant capacity status and lactate levels in blood specimens obtained from the vena cava inferior were studied. Clinical results and biochemical parameters were evaluated.Results: Biomarkers related to endothelial function were found to be similar between the groups except for asymmetric dimethylarginine. The asymmetric dimethylarginine levels were lower, while lactate levels were significantly higher compared to the control group. When the patients with coronary artery disease were excluded from the analysis to rule out the predominance of coronary artery disease patients in one group as a confounding factor, the asymmetric dimethylarginine levels were found to be similar between the two subgroups.Conclusion: Low plasma levels of asymmetric dimethylarginine in the study group may have a protective role in endothelial nitric oxide synthesis. When patients with coronary artery disease were excluded from both group, biomarkers related to endothelial function were similar in both groups. We consider that endothelial functions are not affected adversely during short periods of moderately hypothermic lower body circulatory arrest.

SAT-252 The association of genotype polymorphisms of endothelial function-related genes with restenosis of arteriovenous access after angioplasty in hemodialysis patients

Venous intimal hyperplasia is more aggressive than arterial intimal hyperplasia after angioplasty. Veins tend to produce less nitric oxide, which could predispose to endothelial dysfunction. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase and contributes to vascular disease. In human, dimethylarginine dimethylaminohydrolase 1 (DDAH1) is the major enzyme degrading ADMA. We aimed to determine whether venous intimal hyperplasia in dialysis vascular access is influenced by common polymorphisms in the DDAH1 genes. This is a prospective observational cohort study. A total of 473 hemodialysis patients referred for angioplasty of hemodialysis vascular accesses were enrolled. There were 190 grafts and 283 native fistulas. Follow-up lasted for two years after interventions. Seven single nucleotide polymorphisms in DDAH1 were genotyped and ADMA were measured at baseline. Primary outcome was restenosis after angioplasty. Among the seven single nucleotide polymorphisms, plasma ADMA levels were significantly different in DDAH1 rs233112 (GA+GG vs. AA, 0.86 ± 0.23 vs. 0.82 ± 0.19μM, P=0.03) and rs1498373 (CT+TT vs. CC, 0.87 ± 0.23 vs. 0.82 ± 0.20 μM, P=0.02) genotypes. The native-access group with GG+GA genotype of rs233112 and CT+TT genotype of rs1498373 had higher risks of early restenosis at 3 months. In graft-access groups, only GG+GA genotype of rs233112 was associated with early restenosis. Combined analysis of graft- and native- access groups showed that patients with rs233112 GA+GG genotype and rs1498373 CT+TT genotype had higher risks of early restenosis (both p <0.001). In the multivariate analysis, the association of these genotypes with early restenosis is independent of clinical, access or biochemical Our findings suggest that certain DDAH1 polymorphisms modulate circulating ADMA levels and are associated with venous intimal hyperplasia.

Raised Plasma Levels of Asymmetric Dimethylarginine Are Associated with Pathological Type and Predict the Therapeutic Effect in Lupus Nephritis Patients Treated with Cyclophosphamide

Background: Lupus nephritis (LN) is one of the most serious complications of systemic lupus erythematosus (SLE). Asymmetric dimethylarginine (ADMA) has been associated with cardiovascular events in SLE patients and is a strong predictor of the progression of chronic kidney disease. However, whether ADMA can provide a predictive value for the diagnosis and treatment of LN patients remains unclear. This study evaluated the clinical significance of ADMA in LN patients. Methods: Blood samples of 114 patients with LN, 52 patients with primary glomerular disease, and 20 healthy people were collected. Plasma ADMA was measured via enzyme-linked immunosorbent assay. The relationship between plasma ADMA levels and pathological types and renal function and efficacy in LN patients were further analyzed. Results: There was no significant difference in plasma ADMA levels between LN and primary glomerular disease, but both were significantly higher than the values in healthy people (p < 0.05). Plasma ADMA levels in LN patients were negatively correlated with baseline estimated glomerular filtration rate (eGFR) and serum superoxide dismutase and positively correlated with serum cystatin C and serum β₂-microglobulin (p < 0.05). The plasma ADMA levels of diffuse proliferative LN patients were significantly higher than those of other histopathological classes of LN. High plasma ADMA levels in LN patients (OR = 1.012; 95% CI 1.003–1.022; p = 0.010) is a risk factor for diffuse proliferative LN. The area under the receiver operating characteristic (ROC) curve of diagnosing diffuse proliferative LN by plasma ADMA was 0.707 (95% CI 0.610–0.805). The area under the ROC curve of combination with plasma ADMA, serum complement C3, and eGFR for diffuse proliferative LN was 0.796 (95% CI 0.713–0.879), which was significantly higher than that of ADMA, complement C3, and eGFR for diffuse proliferative LN alone, respectively (p < 0.05). Low plasma ADMA is an independent protective factor for proliferative LN patients achieving complete remission with cyclophosphamide as induction therapy (OR = 0.978; 95% CI 0.961–0.996; p < 0.05). Conclusion: High plasma ADMA levels in combination with eGFR and complement C3 may be useful to diagnose diffuse proliferative LN. Low plasma ADMA may help to predict complete remission in proliferative LN patients treated with cyclophosphamide as induction therapy. Plasma ADMA may be a new biomarker to determine the pathological type of LN and predict the therapeutic effect.

62 Time course of improvement in secretory unbalance of asymmetric dimethylarginine and nitric oxide productions in response to exercise training in middle-aged and older adults

Abstract Funding Acknowledgements Supported by Grants-in-Aid for Scientific Research (#17H02182, #16K13059, M. Iemitsu; #18J01024, S. Fujie) Introduction Aging is well known to elevate risks of cardiovascular diseases. As a mechanism of these increased risks with aging, a reduction of nitric oxide (NO) production via augmented secretion of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthesis is related. Habitual aerobic exercise has shown to improve secretory unbalance of endothelium-derived regulating factors with aging, such as increase in NO and decrease in ADMA, resulting in the reduction of arterial stiffness. However, the time course of improvement in secretory unbalance of NO and ADMA productions in response to exercise training in middle-aged and older adults remains unclear. Purpose This study aimed to determine the time course of changes in plasma nitrite/nitrate (NOx) and ADMA levels related to exercise-training effects of arterial stiffness in healthy middle-aged and older adults. Methods Thirty-two Japanese healthy middle-aged and older subjects (67 ± 1 years) were randomly divided into two groups: exercise intervention and sedentary controls. Subjects in the training group completed 8-week of aerobic exercise training (60-70% peak oxygen uptake [VO2peak] for 45 min, 3 days/week). We evaluated plasma NOx and ADMA concentrations and carotid-femoral pulse wave velocity (cfPWV) as an index of arterial stiffness, measured every 2 weeks for 8-week in the training group. Results cfPWV was gradually declined from baseline to 8-week and significantly decreased from baseline at weeks 6 (P &amp;lt; 0.05) and 8 (P &amp;lt; 0.01). Plasma NOx level was gradually elevated during exercise intervention and significantly increased from baseline at weeks 6 (P &amp;lt; 0.05) and 8 (P &amp;lt; 0.01). Interestingly, plasma ADMA level was significantly decreased at 8-week intervention (P &amp;lt; 0.05). Furthermore, the exercise training-induced reduction in plasma ADMA level was negatively correlated with the change in plasma NOx level before and after the 8-week (r = -0.483, P &amp;lt; 0.05). The exercise training-induced change in plasma ADMA concentration was positively correlated with training-induced change in cfPWV before and after the 8-week (r = 0.633, P &amp;lt; 0.01). Additionally, there was a negative correlation between the changes in plasma NOx level and cfPWV before and after the 8-week (r = -0.642, P &amp;lt; 0.05). Conclusions These results suggest that habitual aerobic exercise can normalize the secretory unbalance of NO and ADMA productions in 6 to 8 weeks, and these balance normalizations may be contributed to the reduction of arterial stiffness in the middle-aged and older adults.

An exploratory, randomised, placebo-controlled, 14\xa0day trial of the soluble guanylate cyclase stimulator praliciguat in participants with type 2 diabetes and hypertension

Aims/hypothesisPraliciguat (IW-1973), a soluble guanylate cyclase stimulator, amplifies nitric oxide signalling. This exploratory trial investigated the safety, tolerability, pharmacokinetic profile and pharmacodynamic effects of praliciguat in individuals with type 2 diabetes and hypertension.MethodsThis Phase IIA, double-blind, placebo-controlled trial investigated praliciguat in 26 participants with type 2 diabetes and hypertension on stable glucose- and BP-lowering therapies. Participants were randomly allocated in a 3:5:5 ratio to three groups: placebo (n = 6), praliciguat 40 mg once daily for days 1–14 (n = 10), or praliciguat 20 mg twice daily for days 1–7 then 40 mg once daily for days 8–14 (n = 10). Assessments were made in clinic and included treatment-emergent adverse events, pharmacokinetics, metabolic variables, 24 h BP and heart rate, platelet function, reactive hyperaemia index (RHI) and plasma biomarkers. Participants, the sponsor, the investigator and clinic study staff (except designated pharmacy personnel) were blinded to group assignment.ResultsParticipants treated for 14 days with praliciguat had least-square mean change-from-baseline differences vs placebo (95% CI) of −0.7 (−1.8, 0.4) mmol/l for fasting plasma glucose, −0.7 (−1.1, −0.2) mmol/l for total cholesterol, −0.5 (−1.0, −0.1) mmol/l for LDL-cholesterol, −23 (−56, 9) for HOMA-IR in those not being treated with insulin, and −5 (−10, 1) mmHg and 3 (−1, 6) beats/min for average 24 h mean arterial pressure and heart rate, respectively. Apart from one serious adverse event (SAE; upper gastrointestinal haemorrhage), praliciguat was well tolerated. Praliciguat did not affect platelet function or RHI. Among exploratory biomarkers, plasma levels of asymmetric dimethylarginine decreased in praliciguat vs placebo recipients.Conclusions/interpretationIn participants with type 2 diabetes and hypertension on standard therapies, over 14 days praliciguat was well tolerated, except for a single SAE, and showed positive trends in metabolic and BP variables. These results support further clinical investigation of praliciguat.Trial registrationClinicalTrials.gov NCT03091920.FundingThis trial was funded by Cyclerion Therapeutics.

ADMA elevation does not exacerbate development of diabetic nephropathy in mice with streptozotocin-induced diabetes mellitus

Background and aimsCardiovascular disease is nowadays the major cause of mortality and morbidity worldwide. The risk of developing cardiovascular disease is significantly increased in patients with diabetic nephropathy. It has been suggested that asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthases (NOS), may play an important role in the pathogenesis of diabetic nephropathy. ADMA is mainly metabolized by dimethylarginine dimethylaminohydrolase 1 (DDAH1). The goal of this study was to test the hypothesis that elevation of systemic ADMA levels by knocking out DDAH1 would exacerbate functional and structural glomerular abnormalities in a murine model of diabetic nephropathy. MethodsStreptozotocin (STZ) was used to induce diabetes in adult DDAH1 knock-out and wild type mice. Healthy mice served as controls. Mice were sacrificed after 20 weeks of diabetes. Plasma ADMA levels were assessed by isotope-dilution tandem mass spectrometry and albumin by ELISA. Kidneys were used for FACS analysis and were also stained for markers of inflammation, cell proliferation, glomerular cells and cell matrix. ResultsSTZ led to development of diabetes mellitus in all injected animals. Deficiency of DDAH1 led to a significant increase in plasma ADMA levels in healthy and diabetic mice. The diabetic state itself did not influence systemic ADMA levels. Diabetic mice of both genotypes developed albuminuria and had increased glomerulosclerosis index. There were no changes in desmin expression, glomerular cell proliferation rate, matrix expansion and expression of Mac-2 antigen in the diabetic mice of both genotypes as compared to the healthy ones. ConclusionsIn summary, STZ-induced diabetes led to the development of early features of diabetic nephropathy. Deficiency of DDAH1 and subsequent increase in systemic ADMA levels did not exacerbate these changes, indicating that ADMA is not the major mediator of diabetic nephropathy in this experiment model.

Serum Asymmetric Dimethylarginine Levels in Patients with Vasovagal Syncope.

Background and Objectives: Vasovagal syncope (VVS) is the most common cause of syncope and has multiple pathophysiological mechanisms. Asymmetric dimethylarginine (ADMA) is the major inhibitor of nitric oxide (NO). In this study, we aimed to investigate the relationship between plasma ADMA levels and syncope during the head-up tilt (HUT) test. Materials and Methods: Overall, 97 patients were included in this study. They were above 18 years of age and were admitted to our clinic with the complaint of at least one episode of syncope consistent with VVS. The HUT test was performed in all patients. Patients were divided into the following two groups based on the HUT test results: group 1 included 57 patients with a positive HUT test and group 2 included 35 patients with a negative HUT test. Blood samples were taken before and immediately after the HUT test to measure ADMA levels. Results: No significant intergroup differences were observed concerning gender and age (female gender 68% vs 60%; mean age 24.85 ± 4.01 vs 25.62 ± 3.54 years, respectively, for groups 1 and 2). ADMA values were similar between groups 1 and 2 before the HUT test [ADMA of 958 (544–1418) vs 951 (519–1269); p = 0.794]. In the negative HUT group, no significant differences were observed in ADMA levels before and after the HUT test [ADMA of 951 (519–1269) vs 951 (519–1566); p = 0.764]. However, in the positive HUT group, ADMA levels were significantly decreased following the HUT test [pretest ADMA of 958 (544–1418) vs post-test ADMA of 115 (67–198); p < 0.001]. Conclusion: ADMA levels significantly decreased after the HUT test in patients with VVS.

Dimethylarginine Dimethylaminohydrolase 1 Polymorphisms and Venous Intimal Hyperplasia in Hemodialysis Patients

Background: After angioplasty, veins are more prone to intimal hyperplasia than arteries. Veins tend to produce less nitric oxide (NO), which could lead to endothelial dysfunction. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthase and contributes to cardiovascular disease. In humans, dimethylarginine dimethylaminohydrolase 1 (DDAH1) is the major enzyme for ADMA degradation. In this study, we aim to determine whether venous intimal hyperplasia in hemodialysis (HD) vascular access is influenced by common polymorphisms in the DDAH1 genes. Methods: This is a prospective observational cohort study. A total of 473 HD patients referred for the angioplasty of vascular access were enrolled. There were 190 arteriovenous grafts (AVG) and 283 arteriovenous fistulas (AVF). The follow-up lasted for 2 years after the interventions. Seven single nucleotide polymorphisms (SNPs) in DDAH1 were genotyped and ADMA were measured at baseline. The primary outcome was restenosis after angioplasty. Results: Among the 7 SNPs, plasma ADMA levels were significantly different in DDAH1 rs233112 (GA + GG vs. AA, 0.86 ± 0.23 vs. 0.82 ± 0.19 μM, p = 0.03) and rs1498373 (CT + TT vs. CC, 0.87 ± 0.23 vs. 0.82 ± 0.20 μM, p = 0.02) genotypes. The AVF group with GG + GA genotype of rs233112 and CT + TT genotype of rs1498373 had higher risks of early restenosis at 3 months. In the AVG group, only GG + GA genotype of rs233112 was associated with early restenosis. A combined analysis of AVG and AVF groups showed that patients with rs233112 GA + GG genotype and rs1498373 CT + TT genotype had higher risks of early restenosis (both p < 0.001). The multivariate analysis results showed that the association of these genotypes with early restenosis is independent of clinical, access, or biochemical factors. Conclusions: Our findings suggest that certain DDAH1 polymorphisms modulate circulating ADMA levels and are associated with venous intimal hyperplasia.

The Vascular Wall State and Microcirculation Parameters in Patients with Controlled and Uncontrolled Arterial Hypertension

Aim. To study the rigidity of the vascular wall and microcirculation parameters in patients with uncontrolled (UCAH) and controlled arterial hypertension (CAH).Material and methods. 134 patients with essential hypertension were included, among them 88 (65.7%) patients with UCAH and 46 (34.3%) patients with CAH. Patients in both groups were similar by sex, age, duration of hypertension and some biochemical parameters. Patients had a study of the parameters of stiffness of the vascular wall, microcirculation parameters, as well as an evaluate of the plasma level of asymmetric dimethylarginine (ADMA).Results. Pulse wave velocity (PWV) did not differed between the UCAH and CAH, both in absolute values (1144 [1000-1290] vs 1138 [10281279] cm/sec; p=0.385) and in the frequency of exceeding the normal values (95% vs 92%; p=0.784). Microcirculation index (MI) in CAH was significantly higher than in the UCAH group: 30.55 [27.08-34.4] and 22.82 [18.62-26.05], respectively (p &lt;0.05). ADMA plasma concentration was significantly higher 0.69 [0.62-0.81] μmol/l in UCAH, than in the CAH group 0.62 [0.58-0.70] µmol/l (p &lt;0.05), that shows the presence of endothelial dysfunction. There were detected significant relation between MI and cognitive status.Conclusion. The results of our study indicate the presence of signs of endothelial dysfunction in patients with UCAH with changes in the stiffness of the vascular wall comparable with the CAH group. This may reflect the slower effect of antihypertensive therapy on the remodeling processes of large vessels in comparison with the microvasculature.

Protection of Male Rat Offspring against Hypertension Programmed by Prenatal Dexamethasone Administration and Postnatal High-Fat Diet with the Nrf2 Activator Dimethyl Fumarate during Pregnancy.

Hypertension can originate from early-life exposure to oxidative stress. As reported, dimethyl fumarate (DMF) activates nuclear factor erythroid-derived 2-related factor 2 (Nrf2) and protects against oxidative stress damage. We examined whether maternal DMF therapy protects adult offspring against hypertension programmed by prenatal dexamethasone (DEX) and postnatal high-fat (HF) diet exposure. We examined male Sprague Dawley rat offspring at 4 months of age from five groups (n = 11–13/group): control, DEX (0.1mg/kg i.p. from gestational day 16 to 22), HF (D12331 diet from weaning to 16 weeks of age), DEX+HF, and DEX+HF+DMF (50mg/kg/day via gastric gavage for 3 weeks during pregnancy). Maternal DMF therapy prevented male offspring against hypertension programmed by combined DEX and HF exposures. The protective effects of maternal DMF include reduced oxidative stress, decreased plasma asymmetric dimethylarginine (ADMA) levels, downregulated the renin-angiotensin system (i.e. Ren, Agt, Ace, and Agtr1a), increased renal protein levels of certain nutrient-sensing signals, and promoted autophagy. In conclusion, maternal Nrf2 activation by DMF protects male adult offspring against hypertension programmed by combined DEX and HF exposures. Our results cast a new light on the therapeutic potential of targeting Nrf2 signaling pathway as reprogramming strategies to prevent programmed hypertension in children exposed to antenatal corticosteroids and postnatally excessive consumption of fat.

A functional variant of the dimethylarginine dimethylaminohydrolase-2 gene is associated with myocardial infarction in type 2 diabetic patients

BackgroundMyocardial infarction is the main mortality cause in patients with type 2 diabetes (T2DM). Endothelial dysfunction due to reduced bioavailability of nitric oxide (NO) is an early step of atherogenesis. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthesis, and it is metabolized by the enzymes dimethylarginine dimethylaminohydrolase (DDAH) 1 and 2. The functional variant rs9267551 C, in the promoter region of DDAH2, has been linked to increased DDAH2 expression, and lower ADMA plasma levels, and was associated with lower risk of coronary artery disease in large-scale genome-wide association studies (GWAS) performed in the general population. However, it is unknown whether this association holds true in T2DM patients. To address this issue, we investigated whether rs9267551 is associated with risk of myocardial infarction in two cohorts of T2DM patients.MethodsSNP rs9267551 was genotyped in 1839 White T2DM patients from the Catanzaro Study (CZ, n = 1060) and the Gargano Heart Study-cross sectional design (GHS, n = 779). Cases were patients with a previous myocardial infarction, controls were asymptomatic patients with neither previous myocardial ischemia nor signs of it at resting and during a maximal symptom limited stress electrocardiogram.ResultsCarriers of allele rs9267551 C showed a dose dependent reduction in the risk of myocardial infarction [(CZ = OR 0.380, 95% CI 0.175–0.823, p = 0.014), (GHS = 0.497, 0.267–0.923, p = 0.027), (Pooled = 0.458, 0.283–0.739, p = 0.001)] which remained significant after adjusting for sex, age, BMI, smoking, HbA1c, total cholesterol HDL, and triglyceride levels [(CZ = 0.307, 0.106–0.885, p = 0.029), (GHS = 0.512, 0.270–0.970, p = 0.040), (Pooled = 0.458, 0.266–0.787, p = 0.005)].ConclusionsWe found that rs9267551 polymorphism is significantly associated with myocardial infarction in T2DM patients of European ancestry from two independent cohorts. It is possible that in subjects carrying the protective C allele less ADMA accumulates in endothelial cells causing vascular protection as a consequence of higher nitric oxide availability.

DDAH1 and DDAH2 polymorphisms associate with asymmetrical dimethylarginine plasma levels in erectile dysfunction patients but not in healthy controls

Erectile Dysfunction (ED) is one of the main complaints of aging male. A reduced production of Nitric Oxide (NO) may be involved in ED pathogenesis. NO is synthesized from l-Arginine, and asymmetrical dimethylarginine inhibits all NO synthases. DDAH1 and DDAH2 are genes that encode enzymes responsible for metabolizing ADMA. We aimed to assess whether: 1) ADMA and nitrite levels associated with ED risk and with symptoms intensity; and whether 2) DDAH1 and DDAH2 gene polymorphisms associate with changes in biochemical data, and with ED risk and symptoms intensity. In this study were included 98 healthy controls and 130 ED patients. ADMA levels were measured by ELISA and nitrite levels by Chemiluminescence. DDAH1 and DDAH2 polymorphisms were assessed by Taqman assays. We found that ED had increased nitrite levels and lower ADMA levels than Control group (P < 0.05). We found a significant correlation of ADMA with Nitrite levels only in ED (B = -0.57, P < 0.001). Genotypes and haplotypes of DDAH1 were associated with ADMA levels in ED (P < 0.05), while haplotypes of DDAH2 were associated with levels of nitrite in ED (P < 0.05). Erectile dysfunction patients show an association between DDAH1 and DDAH2 polymorphisms with ADMA levels, which in turn are negatively correlated with nitrite levels. This is not evident on healthy controls.

Asymmetric dimethylarginine predicts impaired epicardial coronary vasomotion in patients with angina in the absence of obstructive coronary artery disease

BackgroundImpaired epicardial coronary vasomotion is a potential mechanism of angina and a predictor of adverse cardiovascular outcomes in patients without angiographic evidence of obstructive coronary artery disease (CAD). We sought to evaluate the association of asymmetric dimethylarginine (ADMA)—a marker of nitric oxide-mediated vascular dysfunction—with epicardial coronary vasomotor dysfunction in this select population. MethodsInvasive testing for epicardial vasomotor dysfunction was performed using intracoronary acetylcholine in the left anterior descending coronary artery. Impaired vasomotor response was defined as a luminal constriction of >20% on quantitative coronary angiography. Plasma ADMA levels were measured using high performance liquid chromatography. A robust multivariate linear mixed-effect model approach and Akaike information criterion were used to determine predictors of vasomotor dysfunction. ResultsIn 191 patients with angina in the absence of obstructive CAD, abnormal epicardial vasomotion was observed in 137 (71.7%) patients. Median ADMA rose as the extent of impairment progressed: none (0.48 [0.44–0.59] μM), any (0.51 [0.46–0.60] μM, p = 0.12), focal (0.54 [0.49,0.61] μM, p = 0.17), and diffuse (0.55 [0.49,0.63] μM, p = 0.02). In unadjusted analysis, ADMA was highly predictive of vasomotor dysfunction (χ2=15.1, p = 0.002). Notably, ADMA remained a significant predictor even after adjusting for other factors in the best fit model (χ2=10.0, p = 0.02). ConclusionsADMA is an independent predictor of epicardial coronary vasomotor dysfunction in patients with angina in the absence of obstructive CAD. These data support a very early mechanistic role of ADMA in the continuum of atherosclerotic heart disease.

Evaluation of homocystein and asymmetric dimethyl arginine levels in patients with coronary slow flow phenomenon

BackgroundPrevious studies have demonstrated that homocysteine and asymmetric dimethyl arginine (ADMA) levels were strongly associated with cardiovascular diseases including coronary artery disease. The aim of this study was to investigate the role of plasma homocysteine and ADMA levels in the pathogenesis of coronary slow flow (CSF) phenomenon.MethodsTwenty-three patients with CSF and 25 controls with normal coronary flow were included in this study. The quantitative measurement of coronary blood flow was performed using the thrombolysis in myocardial infarction frame count method. Plasma homocysteine and ADMA levels were determined using enzymatic assays from venous blood samples.ResultsThe patients with CSF had significantly higher plasma homocysteine levels than controls (16.2 ± 7.6 vs. 12.2 ± 2.2 μM/L; p = 0.023). The uric acid levels were significantly higher in CSF group than controls (5.4 ± 1.1 vs. 4.6 ± 0.9 mg/dl; p = 0.011). Plasma ADMA levels were also higher in the CSF group; however, this was not statistically significant (0.6 ± 0.1 vs. 0.5 ± 0.2 μM/L; p = 0.475).ConclusionsIncreased homocysteine and uric acid levels may play an important role in the pathogenesis of CSF. Further large scale studies are required to determine the relationship between ADMA levels and CSF.

Reference intervals of urinary creatine and guanidinoacetate in children

The aim of this paper is to review the possible relationship of restricted phenylalanine (Phe) diet, a diet primarily comprising low-protein foods and Phe-free protein substitutes, with major cardiovascular risk factors (overweight/obesity, blood lipid profile, plasma levels of homocysteine, adiponectin and free asymmetric dimethylarginine (ADMA), oxidative stress and blood pressure) in PKU children.In PKU children compliant with diet, blood total cholesterol, low-density lipoprotein cholesterol (LDL-C), plasma ADMA levels and diastolic pressure were reported to be lower and plasma adiponectin levels to be higher compared to healthy controls. No difference was observed in overweight prevalence and in high-density lipoprotein cholesterol (HDL-C) levels. Inconsistent results were found for plasma homocysteine levels and antioxidant status.PKU children compliant with diet seem to display non-different cardiovascular risks compared with the healthy population. Well-designed longitudinal studies are required to clarify the potential underlying mechanisms associated with PKU and cardiovascular risk factors.