Free fatty acids do not acutely increase asymmetrical dimethylarginine concentrations.

Concentrations of asymmetrical dimethylarginine (ADMA) and free fatty acids (FFAs) are elevated in insulin resistance which is associated with impaired vascular function. We hypothesized that FFAs could alter vascular tone by affecting ADMA concentrations. Plasma FFA levels were increased in seventeen healthy male volunteers by Intralipid/heparin infusion; hemodynamic and biochemical parameters were measured after 90 minutes. Plasma collected before and during Intralipid/heparin or equivalent synthetic FFAs was incubated with human umbilical vein endothelial cells (HUVECs) in vitro. Intralipid/heparin infusion resulted in an approximately seven-fold increase in plasma FFA levels to 1861 +/- 139 micromol/l, which was paralleled by increased systemic blood pressure and forearm blood flow. Intralipid/heparin did not affect ADMA (baseline mean 0.59 [95 % confidence interval [CI]: 0.54; 0.64] and 0.56 [CI: 0.51; 0.59] after 90 minutes), but slightly decreased SDMA (from 0.76, [CI: 0.70; 0.83] to 0.71 [CI: 0.64; 0.74], p < 0.05), and had no effect on ADMA/SDMA ratio. There was no correlation between ADMA and FFA concentrations or forearm blood flow. Incubation of HUVECs with FFA-rich plasma or synthetic FFAs induced an ADMA release after 24 hours, but not after 90 minutes. Acutely increased FFA levels caused hemodynamic effects but did not affect ADMA. Prolonged elevation of FFA levels might influence vascular function by increasing ADMA levels.     

Parathyroid hormone, but not vitamin D, is associated with the metabolic syndrome in morbidly obese women and men: a cross-sectional study

Background

Asymmetric dimethylarginine (ADMA) is a competitive inhibitor of endothelial nitric oxide synthase (eNOS) that is associated with endothelial dysfunction, and is a risk marker for cardiovascular disease, a significant problem in Type 1 diabetes. The aim of the present study was to measure circulating ADMA, and define its association with endothelial dysfunction and endothelial markers in people with Type 1 diabetes with low likelihood of macrovascular disease.

Methods

Sixty-one young people with Type 1 diabetes without macrovascular disease or nephropathy and 62 healthy volunteers underwent brachial artery flow-mediated dilatation (FMD) and assay of plasma ADMA and adhesion molecules.

Results

Age, gender, BMI, lipid profile and renal function were similar in the two groups. People with Type 1 diabetes had impaired FMD compared to healthy controls (5.0 ± 0.4 vs 8.9 ± 0.4%; p < 0.001). Plasma ADMA levels were significantly lower in the people with diabetes compared to healthy controls (0.52 ± 0.12 vs 0.66 ± 0.20 μmol/l, p < 0.001). Plasma ICAM-1, E-selectin and PAI-1 levels were significantly higher in people with diabetes compared to healthy controls (median 201 (IQR 172–226) vs 180 (156–216) μg/l, p = 0.027; 44.2 (32.6–60.9) vs. 33.1 (22.4–51.0) μg/l; p = 0.003 and 70.8 (33.3–85.5) vs 46.3 (23.9–76.8) μg/l, p = 0.035). Plasma ADMA and VCAM-1 levels were positively correlated (r = 0.37, p = 0.003) in people with diabetes. There was no correlation between the plasma ADMA and FMD.

Conclusion

ADMA levels are not associated with endothelial dysfunction in young adults with Type 1 diabetes without microalbuminuria or known macrovascular disease. This suggests that the impaired endothelial function in these individuals is not a result of eNOS inhibition by ADMA.     

Increased Asymmetric Dimethylarginine in Severe Falciparum Malaria: Association with Impaired Nitric Oxide Bioavailability and Fatal Outcome

Asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is a predictor of mortality in critical illness. Severe malaria (SM) is associated with decreased NO bioavailability, but the contribution of ADMA to the pathogenesis of impaired NO bioavailability and adverse outcomes in malaria is unknown. In adults with and without falciparum malaria, we tested the hypotheses that plasma ADMA would be: 1) increased in proportion to disease severity, 2) associated with impaired vascular and pulmonary NO bioavailability and 3) independently associated with increased mortality. We assessed plasma dimethylarginines, exhaled NO concentrations and endothelial function in 49 patients with SM, 78 with moderately severe malaria (MSM) and 19 healthy controls (HC). Repeat ADMA and endothelial function measurements were performed in patients with SM. Multivariable regression was used to assess the effect of ADMA on mortality and NO bioavailability. Plasma ADMA was increased in SM patients (0.85 µM; 95% CI 0.74–0.96) compared to those with MSM (0.54 µM; 95%CI 0.5–0.56) and HCs (0.64 µM; 95%CI 0.58–0.70; p<0.001). ADMA was an independent predictor of mortality in SM patients with each micromolar elevation increasing the odds of death 18 fold (95% CI 2.0–181; p = 0.01). ADMA was independently associated with decreased exhaled NO (r_s = −0.31) and endothelial function (r_s = −0.32) in all malaria patients, and with reduced exhaled NO (r_s = −0.72) in those with SM. ADMA is increased in SM and associated with decreased vascular and pulmonary NO bioavailability. Inhibition of NOS by ADMA may contribute to increased mortality in severe malaria.     

Asymmetric dimethylarginine, endothelial nitric oxide bioavailability and mortality in sepsis

Background

Plasma concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, are raised in patients with chronic vascular disease, causing increased cardiovascular risk and endothelial dysfunction, but the role of ADMA in acute inflammatory states is less well defined.

Methods and Results

In a prospective longitudinal study in 67 patients with acute sepsis and 31 controls, digital microvascular reactivity was measured by peripheral arterial tonometry and blood was collected at baseline and 2–4 days later. Plasma ADMA and L-arginine concentrations were determined by high performance liquid chromatography. Baseline plasma L-arginine: ADMA ratio was significantly lower in sepsis patients (median [IQR] 63 [45–103]) than in hospital controls (143 [123–166], p<0.0001) and correlated with microvascular reactivity (r = 0.34, R² = 0.12, p = 0.02). Baseline plasma ADMA was independently associated with 28-day mortality (Odds ratio [95% CI] for death in those in the highest quartile (≥0.66 µmol/L) = 20.8 [2.2–195.0], p = 0.008), and was independently correlated with severity of organ failure. Increase in ADMA over time correlated with increase in organ failure and decrease in microvascular reactivity.

Conclusions

Impaired endothelial and microvascular function due to decreased endothelial NO bioavailability is a potential mechanism linking increased plasma ADMA with organ failure and death in sepsis.     

Involvement of DDAH/ADMA/NOS pathway in nicotine-induced endothelial dysfunction

Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor, is a key contributor for endothelial dysfunction. Decrease in activity of dimethylarginine dimethylaminohydrolase (DDAH), a major hydrolase of ADMA, causes accumulation of ADMA under cardiovascular abnormalities. The study was to determine whether nicotine-induced endothelial dysfunction is related to modulating DDAH/ADMA/NOS pathway. Four-week oral nicotine treatment (5 mg/kg/day) significantly increased the plasma level of ADMA and decreased aortic DDAH expression as well as impaired endothelial function in Sprague-Dawley rats. Similarly, the medium levels of both ADMA and lactate dehydrogenase were markedly elevated in umbilical vein endothelial cells (HUVECs) treated with nicotine (10 microM) for 48 h. Nicotine-induced endothelial damages were markedly attenuated by L-arginine or overexpression of DDAH-II. Nicotine greatly downregulated both mRNA and protein levels of DDAH-II, and decreased DDAH activity in HUVECs. HUVECs express alpha7 nicotinic acetylcholine receptor (alpha7 nAChR), whose antagonists could block these effects of nicotine mentioned above. Intracellular Ca2+ chelator did not affect nicotine-induced decrease in DDAH-II mRNA level. In conclusion, nicotine modulates DDAH/ADMA/NOS pathway of endothelial cell via activation of alpha7 nAChR, which may be involved in endothelial dysfunction associated to smoking.     

Plasma levels of trace element status in early pregnancy and the risk of gestational diabetes mellitus: A nested case-control study

PurposeWe investigated the impacts of plasma levels of magnesium (Mg), zinc (Zn), calcium (Ca), iron (Fe), copper (Cu), selenium (Se), and chromium (Cr) on GDM risk and the potential mediation effect of blood glucose levels on the relationship between trace elements and GDM risk.MethodsThis nested case-control study was based on data from a birth cohort study conducted in Wuhan, China in 2013−2016. A total of 305 GDM cases and 305 individually-matched controls were included in the study. Conditional logistic regression models were used to estimate the associations between plasma trace element concentrations and GDM risk. A mediation analysis was conducted to explore whether blood glucose levels act as a mediator between trace element levels and GDM risk.ResultsAn IQR increment in plasma levels of Fe and Cu was associated with a significant increase in GDM risk [OR = 2.04 (95 % CI 1.62, 2.57) and OR = 1.52 (95 % CI 1.25, 1.82)], respectively. On the other hand, an IQR increment in plasma levels of Zn and Ca was associated with a significant decrease in GDM risk [OR = 0.55 (95 % CI 0.43, 0.71) and OR = 0.72 (95 % CI 0.56, 0.92)], respectively. The mediation analysis showed significant mediation of the association between Cu and GDM risk via the FBG (%mediated: 19.27 %), 1 h-PBG (12.64 %), 2h-PBG (28.44 %) pathways.ConclusionsPlasma levels of Zn and Ca were negatively associated with GDM risk, while Fe and Cu were positively associated. Blood glucose levels act as a mediator between plasma trace element exposures and GDM risk.     

Impairment of the extrusion transporter for asymmetric dimethyl-L-arginine: a novel mechanism underlying vasospastic angina

A 37-year old male patient presented with frequent angina attacks (up to 40/day) largely resistant to classical vasodilator therapy. The patient showed severe coronary and peripheral endothelial dysfunction, increased platelet aggregation and increased platelet-derived superoxide production. The endothelial nitric oxide synthase (eNOS)-inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) reduced superoxide formation in platelets identifying "uncoupled" eNOS as a superoxide source. Oral L-arginine normalized coronary and peripheral endothelial dysfunction and reduced platelet aggregation and eNOS-derived superoxide production. Plasma concentrations of the endogenous NOS inhibitor asymmetric dimethyl-L-arginine (ADMA), representing an independent risk factor for cardiovascular disease, were normal in the patient. However, immediately after oral administration of cationic amino acid (CAA), plasma ADMA levels rose markedly, demonstrating increased ADMA efflux from intracellular stores. ADMA efflux from mononuclear cells of the patient was accelerated by CAA, but not neutral amino acids (NAA) demonstrating impairment of y(+)LAT (whose expression was found reduced in these cells). These data suggest that impairment of y(+)LAT may cause intracellular (endothelial) ADMA accumulation leading to systemic endothelial dysfunction. This may represent a novel mechanism underlying vasospastic angina and vascular dysfunction in general. Moreover, these new findings contribute to the understanding of the l-arginine paradox, the improvement of eNOS activity by oral L-arginine despite sufficient cellular l-arginine levels to ensure proper function of this enzyme.     

Reduced renal plasma clearance does not explain increased plasma asymmetric dimethylarginine in hypertensive subjects with mild to moderate renal insufficiency

Plasma concentrations of the nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) increase already in the early stages of renal insufficiency. There is no agreement as to whether reduced renal plasma clearance (RPCL) contributes to this increase. Therefore, we investigated the relationship between estimated glomerular filtration rate (eGFR), RPCL, and plasma ADMA and SDMA in essential hypertensive patients with mild to moderate renal insufficiency. In 171 patients who underwent renal angiography, we drew blood samples from the aorta and both renal veins and measured mean renal blood flow (MRBF) using the (133)Xe washout technique. RPCL was calculated using arteriovenous concentration differences and MRBF. After correction for potential confounders, reduced eGFR was associated with higher plasma ADMA and SDMA [standardized regression coefficient (β) = -0.22 (95% confidence intervals: -0.41, -0.04) and β = -0.66 (95% confidence intervals: -0.83, -0.49), respectively]. However, eGFR was not independently associated with RPCL of ADMA. Moreover, reduced RPCL of ADMA was not associated with higher plasma ADMA. Contrary to ADMA, reduced eGFR was indeed associated with lower RPCL of SDMA [β = 0.21 (95% confidence intervals: 0.02, 0.40)]. In conclusion, our findings indicate that RPCL of ADMA is independent of renal function in hypertensive patients with mild to moderate renal insufficiency. Unlike the case for SDMA, reduced RPCL of ADMA is of minor importance for the increase in plasma ADMA in these patients, which indicates that increased plasma ADMA in this population is not a direct consequence of the kidneys failing as a plasma ADMA-regulating organ.     

Effect of diabetic duration on serum concentrations of endogenous inhibitor of nitric oxide synthase in patients and rats with diabetes

This study was designed to investigate the effect of diabetic duration on serum concentrations of endogenous inhibitor of nitric oxide synthase N(G), N(G)-asymmetric dimethylarginine (ADMA) in patients and rats with diabetes, and to determine whether elevated endogenous ADMA is implicated in endothelial dysfunction or macroangiopathy in diabetes. Experimental diabetic model was induced by a single intraperitoneal injection of streptozotocin to male Sprague-Dawley rats and fed for 2-, 4- and 8-week, respectively. Type 2 diabetic patients with different diabetic duration were recruited from Xiangya Hospital. Plasma glucose and serum ADMA levels were measured in both patients and rats. Moreover, endothelium-dependent relaxation of thoracic aortas and some parameters of metabolic control were examined in rats. Serum ADMA concentrations were significantly elevated in type 2 diabetic patients compared with healthy subjects (3.44 +/- 0.40 vs 1.08 +/- 0.14 micromol/L, n = 50 in diabetic patients and n = 40 in healthy subjects, P < 0.01). The serum levels of ADMA in patients with macroangiopathy were higher than the patients without macroangiopathy (P < 0.01). But no difference was observed in serum ADMA concentrations between groups of patients with different diabetic duration. Similarly, serum levels of ADMA in diabetic rats were also significantly elevated at 2-week duration compared with duration-matched control (3.71 +/- 0.20 vs 1.04 +/- 0.23 micromol/L, n = 5 approximately 6, P < 0.01). This elevation of ADMA was retained to 4- and 8-week (3.54 +/- 0.76 vs 0.95 +/- 0.06 micromol/L for 4-week, 3.21 +/- 0.50 vs 1.03 +/- 0. 09 micromol/L for 8-week, n = 5 approximately 6, all P < 0.01) and remained unchanged among three diabetic groups. The elevation of ADMA was accompanied by impairment of endothelium-dependent relaxation and poor metabolic control in diabetic rat. These results first reveal that the extent of elevation in serum ADMA in both rats and patients with diabetes is not proportion with the length of their diabetic duration but rather with the metabolic control of this disease. Elevated endogenous ADMA may be implicated in diabetes-induced endothelial dysfunction and macroangiopathy. This study is helpful to prevention and treatment of diabetic-induced endothelial dysfunction or macroangiopathy.     

Increased asymmetric dimethylarginine (ADMA) dimethylaminohydrolase (DDAH) activity in childhood hypercholesterolemia type II

Asymmetric dimethylarginine (ADMA) systemic concentrations are elevated in hypercholesterolemic adults and contribute to nitric oxide (NO) dependent endothelial dysfunction. Decreased activity of the key ADMA-hydrolyzing enzyme dimethylarginine dimethylaminohydrolase (DDAH) may be involved. Yet, the ADMA/DDAH/NO pathway has not been investigated in childhood hypercholesterolemia. We studied 64 children with hypercholesterolemia type II (HCh-II) and 54 normocholesterolemic (NCh) children (mean ± SD; age, years: 11.1 ± 3.5 vs. 11.9 ± 4.6). Plasma and urine ADMA was measured by GC-MS/MS. Dimethylamine (DMA), the ADMA metabolite, creatinine, nitrite and nitrate in urine were measured by GC-MS. The DMA/ADMA molar ratio in urine was calculated to estimate whole body DDAH activity. ADMA plasma concentration (mean ± SD; nM: 571 ± 85 vs. 542 ± 110, P = 0.17) and ADMA urinary excretion rate (mean ± SD: 7.1 ± 2 versus 7.2 ± 3 μmol/mmol creatinine, P = 0.6) were similar in HCh-II and NCh children. Both DMA excretion rate [median (25th-75th percentile): 56.3 (46.4-109.1) vs. 45.2 (22.2-65.5) μmol/mmol creatinine, P = 0.0004] and DMA/ADMA molar ratio [median (25th-75th percentile): 9.2 (6.0-16.3) vs. 5.4 (3.8-9.4), P = 0.0004] were slightly but statistically significantly increased in HCh-II children compared to NCh children. Plasma and urinary nitrite and nitrate were similar in both groups. In HCh-II whole body DDAH activity is elevated as compared to NCh. HCh-II children treated with drugs for hypercholesterolemia had lower plasma ADMA levels than untreated HCh-II or NCh children, presumably via increased DDAH activity. Differences between treated and untreated HCh-II children were not due to differences in age. In conclusion, HCh-II children do not have elevated ADMA plasma levels, largely due to an apparent increase in DDAH activity. While this would tend to limit development of endothelial dysfunction, it is not clear whether this might be medication-induced or represent a primary change in HCh-II children.     

Plasma nitrite concentrations reflect the degree of endothelial dysfunction in humans

A reduced nitric oxide availability is a hallmark of endothelial dysfunction occurring early in atherosclerosis. Recently, we have shown that plasma nitrite mirrors acute changes in endothelial nitric oxide synthase activity in various mammals, including humans. Here, we examined the hypothesis that plasma nitrite levels are reduced in humans with endothelial dysfunction and the decrease is correlated with increasing numbers of cardiovascular risk factors (RF). Plasma nitrite concentrations were quantified by flow-injection analysis. The coefficient of variation for repeated measurements of plasma nitrite was <8%, and heart rate and blood pressure at the time of blood sampling had no significant effect on nitrite values measured (n=10). Baseline levels of plasma nitrite followed a normal distribution in each group studied and decreased progressively with increasing numbers of cardiovascular risk factors (n=351, p<0.001): 351+/-13 (0 RF), 261+/-10 (1 RF), 253+/-11 (2 RF), 222+/-18 (3 RF), and 171+/-29 nmol/L (4 RF). Intima media thickness (IMT) and flow-mediated dilation (FMD) were determined via ultrasound. Plasma nitrite and FMD levels were lower, whereas IMT was greater in individuals with endothelial dysfunction (n=12) compared to healthy volunteers (n=12). Nitrite correlated significantly with FMD (r=0.56, p<0.001) and inversely with IMT (r= -0.49, p<0.01). Plasma nitrite levels are reliably measurable in humans, indicate endothelial dysfunction, and correlate with cardiovascular risk factors. Future studies are necessary to identify the prognostic relevance of plasma nitrite determination in patients suffering from cardiovascular disease.     

Elevated IL-10 plasma levels correlate with poor prognosis in diffuse large B-cell lymphoma

The aim of the study was to confirm whether plasma levels of interleukin-10 (IL-10) correlate with the prognosis in diffuse, large B-cell lymphoma (DLBCL) patients. Plasma IL-10 levels were determined at the time of diagnosis in a group of 157 consecutively treated, DLBCL patients. Of those, 122 patients (78%) had IL-10 plasma levels below the detection limit (< 5 pg/mL) and 35 (22%) above this value. The median value for patients with detectable IL-10 levels was 35 pg/mL (range, 5 to 2480 pg/mL). Detectable plasma IL-10 levels were significantly associated with age > 60 years, ECOG performance status > or = 2, Ann Arbor advanced disease stage, bulky tumor mass, elevated serum levels of LDH and beta2-microglobulin, presence of anemia and low serum albumin levels as well as the presence of B symptoms. The patients with detectable IL-10 levels had lower probability of CR achievement (OR = 0.23, 95% CI 0.1-0.5, p = 0.0003). In addition, detectable IL-10 levels were significantly associated with shorter PFS (OR = 2.5, 95% CI 1.5-4.4, p = 0.001) and OS (OR = 3.0, 95% CI 1.7-5.2, p = 0.0001). In conclusion, we confirmed in this large group of DLBCL patients that elevated plasma IL-10 levels correlated with adverse disease features and poor prognosis. The plasma concentration of IL-10 may be a useful marker for evaluation of disease activity.     

The Risk of Asthma in Patients with Ankylosing Spondylitis: A Population-Based Cohort Study

BackgroundThe relationship between asthma and ankylosing spondylitis (AS) is controversial. We examined the risk of asthma among AS patients in a nationwide population.MethodsWe conducted a retrospective cohort study using data from the National Health Insurance (NHI) system of Taiwan. The cohort included 5,974 patients newly diagnosed with AS from 2000 to 2010. The date of diagnosis was defined as the index date. A 4-fold of general population without AS was randomly selected frequency matched by age, gender and the index year. The occurrence and hazard ratio (HR) of asthma were estimated by the end of 2011.ResultsThe overall incidence of asthma was 1.74 folds greater in the AS cohort than in the non-AS cohort (8.26 versus 4.74 per 1000 person-years) with a multivariable Cox method measured adjusted HR of 1.54 (95% confidence interval (CI), 1.34–1.76). The adjusted HR of asthma associated with AS was higher in women (1.59; 95% CI, 1.33–1.90), those aged 50–64 years (1.66; 95% CI, 1.31–2.09), or those without comorbidities (1.82; 95% CI, 1.54–2.13).ConclusionPatients with AS are at a higher risk of developing asthma than the general population, regardless of gender and age. The pathophysiology needs further investigation.     

Interleukin-6 and Asymmetric Dimethylarginine Are Associated with Platelet Activation after Percutaneous Angioplasty with Stent Implantation

Data linking in vivo platelet activation with inflammation and cardiovascular risk factors are scarce. Moreover, the interrelation between endothelial dysfunction as early marker of atherosclerosis and platelet activation has not been studied, so far. We therefore sought to investigate the associations of inflammation, endothelial dysfunction and cardiovascular risk factors with platelet activation and monocyte-platelet aggregate (MPA) formation in 330 patients undergoing angioplasty with stent implantation for atherosclerotic cardiovascular disease. P-selectin expression, activation of glycoprotein IIb/IIIa and MPA formation were determined by flow cytometry. Interleukin (IL)-6, high sensitivity C-reactive protein and asymmetric dimethylarginine (ADMA) were measured by commercially available assays. IL-6 was the only parameter which was independently associated with platelet P-selectin expression and activated GPIIb/IIIa as well as with leukocyte-platelet interaction in multivariate regression analysis (all p<0.05). ADMA was independently associated with GPIIb/IIIa activation (p<0.05). Patients with high IL-6 exhibited a significantly higher expression of P-selectin than patients with low IL-6 (p=0.001), whereas patients with high ADMA levels showed a more pronounced activation of GPIIb/IIIa than patients with low ADMA (p=0.003). In conclusion, IL-6 and ADMA are associated with platelet activation after percutaneous angioplasty with stent implantation. It remains to be established whether they act prothrombotic and atherogenic themselves or are just surrogate markers for atherosclerosis with concomitant platelet activation.     

Mechanisms of endothelial dysfunction in resistance arteries from patients with end-stage renal disease

The study focuses on the mechanisms of endothelial dysfunction in the uremic milieu. Subcutaneous resistance arteries from 35 end-stage renal disease (ESRD) patients and 28 matched controls were studied ex-vivo. Basal and receptor-dependent effects of endothelium-derived factors, expression of endothelial NO synthase (eNOS), prerequisites for myoendothelial gap junctions (MEGJ), and associations between endothelium-dependent responses and plasma levels of endothelial dysfunction markers were assessed. The contribution of endothelium-derived hyperpolarizing factor (EDHF) to endothelium-dependent relaxation was impaired in uremic arteries after stimulation with bradykinin, but not acetylcholine, reflecting the agonist-specific differences. Diminished vasodilator influences of the endothelium on basal tone and enhanced plasma levels of asymmetrical dimethyl L-arginine (ADMA) suggest impairment in NO-mediated regulation of uremic arteries. eNOS expression and contribution of MEGJs to EDHF type responses were unaltered. Plasma levels of ADMA were negatively associated with endothelium-dependent responses in uremic arteries. Preserved responses of smooth muscle to pinacidil and NO-donor indicate alterations within the endothelium and tolerance of vasodilator mechanisms to the uremic retention products at the level of smooth muscle. We conclude that both EDHF and NO pathways that control resistance artery tone are impaired in the uremic milieu. For the first time, we validate the alterations in EDHF type responses linked to kinin receptors in ESRD patients. The association between plasma ADMA concentrations and endothelial function in uremic resistance vasculature may have diagnostic and future therapeutic implications.     

Association between Body Mass Index,Asymmetric Dimethylarginine and Risk of Cardiovascular Events and Mortality in Norwegian Patients with Suspected Stable Angina Pectoris

Background

Asymmetric dimethylarginine (ADMA) is associated with increased risk of atherosclerotic cardiovascular disease and mortality through inhibition of nitrogen oxide (NO) synthesis. As positive correlations between serum concentrations of NO and body mass index (BMI) have been observed, we aimed to explore whether the potential associations between plasma ADMA levels and the risk of acute myocardial infarction (AMI) and mortality were modified by BMI.

Methods

Multivariable Cox proportional hazard models were used to estimate the hazard ratios (HR) for AMI, cardiovascular death and all-cause mortality according to baseline plasma ADMA levels in 4122 patients with suspected stable angina pectoris. Analyses were subsequently repeated in patients with BMI below (low BMI) or above (high BMI) median.

Results

A total of 2982 patients (72%) were men. Median (range) age, plasma ADMA level and BMI were 62 (21–88) years, 0.54 (0.10–1.25) μmol/L and 26.3 (18.5–54.3) kg/m², respectively. During a mean (standard deviation) follow-up time of 4.7 (1.4) years, 337 (8%) patients suffered from an AMI, 300 (7%) died, whereof 165 (55%) due to cardiovascular disease. Each 0.1 μmol/L increment in plasma ADMA level was associated with an increased risk of AMI (HR (95% CI) 1.21 (1.08, 1.35) and cardiovascular death 1.30 (1.13, 1.49) in participants with low BMI only. Interactions were significant for AMI (p = 0.04) and CV death (p = 0.03). BMI did not modify the association between plasma ADMA levels and all-cause mortality.

Conclusion

Plasma ADMA levels were associated with risk of AMI and cardiovascular death among patients with low BMI only.     

Maternal plasma VEGF, sVEGF-R1, and PlGF concentrations in preeclamptic and normotensive pregnant Zimbabwean women

Vascular endothelial growth factor (VEGF), a disulphide-linked homodimeric glycoprotein that is selectively mitogenic for endothelial cells, plays an important role in vasculogenesis and angiogenesis. Preeclampsia, a relatively common complication of pregnancy that is characterized by diffuse endothelial dysfunction possibly secondary to impaired trophoblast invasion of the spiral arteries during implantation, has recently been associated with alterations in maternal serum/plasma concentrations of VEGF, and other related growth factors and their receptors. We examined the relationship of maternal plasma VEGF, sVEGF-R1 and PlGF levels to the risk of preeclampsia among women delivering at Harare Maternity Hospital, Zimbabwe. 131 pregnant women with preeclampsia and 175 controls were included in a case-control study. Maternal plasma concentrations of each biomarker were measured using enzymatic methods. We used logistic regression to calculate odds ratios (OR) and 95 % confidence intervals (CI). Preeclampsia risk was inversely related with quartiles of plasma VEGF (OR: 1.0, 1.0, 0.7, and 0.5, with the lowest quartile as reference; p for trend=0.06). We noted a strong positive association between preeclampsia risk and sVEGF-R1 concentrations (OR: 1.0, 6.5, 9.7, 31.6, with the first quartile as the referent group; p for trend<0.001). After adjusting for confounders, we noted that women with sVEGF-R1 concentrations in the highest quartile (>or=496 pg/ml), as compared with those in the lowest quartile (<62 pg/ml) had a 31.6-fold increased risk of preeclampsia (OR=31.6, 95 % CI 7.7-128.9). There was no clear evidence of a linear relation in risk of preeclampsia with PlGF concentrations. In conclusion, plasma VEGF, sVEGF-R1 and PlGF concentrations (measured at delivery) were altered among Zimbabwean women with preeclampsia as compared with normotensive women. Our results are consistent with some, though not all, previous reports. Prospective studies are needed to: 1) identify modifiable determinants of maternal plasma concentrations VEGF, sVEGF-R1, and PlGF; and 2) evaluate the temporal relationship between observed alterations of these biological markers in preeclamptic pregnancies.     

Asymmetric dimethylarginine, an endogenous NOS inhibitor, is actively metabolized in rat erythrocytes

N(G), N(G)-Dimethyl-L-arginine (asymmetric dimethylarginine: ADMA) is an endogenous competitive inhibitor of nitric oxide synthase (NOS). Plasma ADMA concentrations have been reported to increase in connection with diseases associated with an impaired endothelial L-arginine/NO pathway. In this study, we investigated the metabolism of ADMA in circulating blood cell populations to elucidate the regulatory mechanism of elevation of plasma ADMA, a novel risk factor for cardiovascular disease. We found by RT-PCR and Western blot analyses that protein arginine methyltransferase (PRMT)1 and dimethylarginine dimethylaminohydrolase (DDAH)-1, responsible for the biosynthesis and degradation of ADMA respectively, are expressed in erythrocytes (ECs), leukocytes, and platelets. We also identified a major ADMA-containing protein in ECs as catalase, confirmed by GST-pull down assay to bind to PRMT1 in vitro. This is the first report that the ADMA-metabolizing system, including the arginine methylation of proteins and the breakdown of free ADMA, occurs in circulating blood cell-populations, and that catalase in ECs might be a potential protein targeted by PRMT1.     

Effects of normalization of plasma testosterone levels in hypogonadal men on plasma levels and urinary excretion of asymmetric dimethylarginine (ADMA).

Elevated plasma levels of asymmetric dimethylarginine (ADMA) inhibit nitric oxide formation and exert a proatherogenic action. Low testosterone (T) levels are associated with increased cardiovascular risks. This study analyzed the effects of normalization of plasma T levels on plasma levels and urinary excretion of ADMA in hypgonadal men (n=10) receiving transdermal T administration. Plasma T levels, starting from clearly hypogonadal T plasma concentrations with a mean level of 4.0+/-2.72 nmol/l at baseline, rose to >10 nmol/l after 2 weeks, with plasma T levels within the normal range of men (mean level of 22.5+/-11.3 nmol/l) over the last 16 weeks of the 24 weeks of T administration. Normalization of plasma T led to a small but significant fall of plasma ADMA (519+/-55 vs. 472+/-59 nmol/l, p=0.031). The outcome of this study may be viewed as a favorable effect of normalization of plasma testosterone on plasma ADMA since even small elevations of plasma ADMA significantly increase cardiovascular risk. While this effect of normalization of plasma T may impress as favorable, most available studies on effects of T administration to hypogonadal men have not shown beneficial effects on functions of the vascular wall.