dimethylarginine and Coronary-Disease

Coronary artery disease is the major cause of death worldwide. Hypertension is a major risk factor for developing coronary disease. It is now recognized that endothelial dysfunction is an early marker of coronary artery disease before structural changes to the vessel wall are apparent on angiography or intravascular ultrasound and that it has a prognostic value in predicting cardiovascular events in hypertensive patients. This review addresses recent developments in hypertension-induced endothelial dysfunction.. Hyperaldosteronism causes endothelial dysfunction independent of high blood pressure. Exaggerated exercise blood pressure response has been related to endothelial dysfunction. Cyclosporin-A-induced endothelial dysfunction is related to reduced cholesterol content in caveolae. Chronic kidney disease induces changes in caveoli-1 and thus contributes to the reduced nitric oxide bioavailability, and causes oxidative stress independent of the high blood pressure. Asymmetric dimethylarginine plays a role in endothelial dysfunction in hypertensive patients independent of insulin resistance. 20-Hydroxyeicosatetraenoic acid is an independent predictor of hypertension in postmenopausal women. Endothelial dysfunction precedes and predicts the development of hypertension in postmenopausal women. Oral treatment with L-arginine improves endothelial dysfunction in hypertensives and lowers the blood pressure.. The pathophysiology of endothelial dysfunction in hypertension is multifactorial. Recent findings have contributed to our understanding of mechanisms of endothelial dysfunction and support a role for early intervention to prevent irreversible vascular and organ damage.

Topics: Angiotensin II; Antihypertensive Agents; Arginine; Coronary Disease; Endothelium, Vascular; Humans; Hydroxyeicosatetraenoic Acids; Hypertension; Nitric Oxide; Oxidants

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

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

We investigated the association of serum asymmetric dimethylarginine (ADMA) with metabolic syndrome (MetS), type-2 diabetes and coronary heart disease (CHD) in the general population.. Cross-sectional and, at 2000 person-years' follow-up, prospective analysis. Adults with measured serum ADMA level (n=848) were analyzed using tertiles or dichotomized values. ADMA concentrations were measured by a validated commercial ELISA kit.. Dichotomized subjects of combined sexes with low (≤0.68 µmol/L) ADMA values had significantly higher fasting glucose, total cholesterol, apolipoprotein B and lower diastolic blood pressure. In linear regression analyses comprising age, smoking, triglyceride, HDL-cholesterol, C-reactive protein and waist circumference as well, creatinine was significantly and independently associated with ADMA, further in women glucose (inversely). In logistic regression analyses uniformly adjusted for age, smoking status and waist girth, prevalent MetS tended to positive independent association with ADMA tertiles only in men. Combined prevalent and incident diabetes weakly tended to be associated with the lowest (vs mid- and highest) ADMA tertiles in combined gender; and prevalent and incident CHD was not associated with ADMA tertiles in either sex.. Apparently "low" circulating ADMA is independently associated with fasting glucose and tends to be so with type-2 diabetes. The lack of anticipated positive associations of ADMA with cardiometabolic disorders is likely due to autoimmune responses operating against serum ADMA under oxidative stress, rendering partial failure in immunoassay.

Topics: Adult; Anthropometry; Arginine; Biomarkers; Coronary Disease; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Humans; Male; Metabolic Syndrome; Prospective Studies

Patients with diabetes mellitus (DM) have been shown to have higher levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide (NO) synthase. Higher plasma levels of ADMA have been implicated in the pathogenesis of endothelial dysfunction and atherosclerosis by lowering NO levels. High baseline plasma levels of ADMA in patients with DM have been shown to predict diabetes related complications. However, there are limited data on the prognostic significance of baseline ADMA levels in patients with established DM.. The present study investigated the long-term prognostic significance of baseline plasma ADMA levels in a well-characterized cohort of 170 high-risk diabetic men with known or suspected coronary artery disease who were referred for coronary angiography. All patients were followed prospectively for the development of vascular outcomes, including all-cause mortality.. After controlling for a variety of baseline variables (including established biomarkers such as hs-CRP and fibrinogen), plasma ADMA levels (analyzed as the upper tertile of baseline values compared with the lower two tertiles) were a strong and independent predictor of all-cause mortality (HR 2.63, 95% CI 1.13-6.11, p=0.0247) when using a Cox proportional hazards model. In addition, baseline ADMA values were also an independent predictor of the composite outcome of all-cause mortality or MI (fatal or non-fatal) (HR 2.44, 95% CI 1.26-4.72, p=0.0079), as well as the composite outcome of all-cause mortality, MI (fatal or nonfatal), or stroke (HR 2.00, 95% CI 1.10-3.62, p=0.0232).. These data demonstrate that elevated baseline levels of ADMA are a strong and independent predictor of cardiovascular outcomes (including all-cause mortality) in patients with DM.

Topics: Aged; Arginine; Coronary Angiography; Coronary Disease; Diabetes Complications; Humans; Male; Myocardial Infarction; Prognosis; Proportional Hazards Models; Stroke

The concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is increased in patients with coronary heart disease (CHD). The potential effect of percutaneous coronary intervention (PCI) with stent placement on ADMA plasma level in CHD patients has not yet been investigated. Concentrations of ADMA, L-arginine, symmetric dimethylarginine (SDMA), and L-ornithine were measured in the plasma of 30 CHD patients 24 h before, and 1 h, 5 days, and 30 days following PCI with bare-metal stent or drug-eluting stent placement (stent group) and in the plasma of 20 patients without CHD who underwent angiography alone (control group). A repeated measures ANOVA revealed the significant time by group interaction for ADMA (F=12.8, p<0.0001), SDMA (F=5.5, p=0.013), L-ornithine (F=12.5, p<0.0001), L-aginine (F=4.7, p=0.013) and L-arginine/ADMA ratio (F=7.1, p<0.001). Post-hoc ANOVAs showed that this interaction was due to the fact that control patients without stent placement responded to the coronary angiography with a significant increase in ADMA (F=4.4, p=0.009), SDMA (F=4.7, p=0.007) and L-ornithine (F=28.3, p<0.0001) levels, whereas the stent implantation independent of the stent type used significantly reduced the cardiovascular risk factor ADMA (F=10.8, p<0.0001). Thus, the current study demonstrates that in patients with CHD, PCI stent placement markedly decreases the plasma level of cardiovascular risk factor ADMA. Coronary angiography alone results in an increase of ADMA. We conclude that the stent effect on ADMA level cannot be explained by unspecific effects of the coronary angiography and is independent of the stent type used.

Topics: Aged; Arginine; Cardiovascular Surgical Procedures; Case-Control Studies; Coronary Disease; Down-Regulation; Enzyme Inhibitors; Female; Follow-Up Studies; Humans; Male; Middle Aged; Nitric Oxide Synthase; Stents; Time Factors

(E)-4-Hydroxy-2-nonenal (HNE) is a highly electrophilic end-product of lipid peroxidation. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide synthase (NOS). ADMA is metabolised by dimethylarginine dimethylaminohydrolase (DDAH). DDAH contains a nucleophilic cysteine residue in its active site. There is an increase in lipid peroxidation in major depression. Major depression is associated with the development of coronary heart disease (CHD) and greatly increases morbidity and mortality. There is an increase in circulating ADMA in CHD and vascular risk factors.. To determine plasma HNE, ADME and nitric oxide (NO) concentrations in patients with major depression compared to normal volunteers and to examine the effect of HNE on ADMA formation and DDAH activity in cultured endothelial cells.. The study was conducted in 25 patients with major depression (DSM-IV criteria) and 25 healthy control subjects. Plasma concentrations of HNE were determined as the O-pentafluorylbenzyl oxime using capillary column GC-MS and deuterated HNE as the internal standard; ADME by LC-MS-MS using 13C6-L-arginine as the internal standard; and NO by GC-MS following reduction to nitrate and nitrite and derivatisation to the pentafluorobenzyl derivative using [15N]nitrate and [15N]nitrite as the internal standards. Human umbilical vein endothelial cells were incubated in serum-free medium in the presence of HNE. The concentration of ADMA in the medium was determined by LC-MS-MS. DDAH activity was determined by measuring L-citrulline in endothelial cell lysates using LC-MS.. There was a significant increase in the plasma concentration of HNE (P<0.0001) and ADMA (P<0.0002) in patients with major depression. There was a significant decrease in the plasma concentration of NO (P<0.0001). A significant positive correlation was found between the plasma concentrations of HNE and ADMA (r=0.63, P<0.0001). A significant negative correlation was detected between the plasma concentrations of ADMA and NO (r=-0.595, P<0.0001). HNE significantly increased ADMA formation (P<0.0001) and significantly decreased DDAH activity (P<0.0001) in cultured endothelial cells. The effects of HNE on DDAH activity were significantly attenuated by the addition of glutathione (P<0.0001).. No allowance was made for the phase of the menstrual cycle which could influence plasma nitric oxide concentrations.. There is an increase in circulating HNE in major depression. HNE inactivates the cysteine residue in the active site of endothelial DDAH leading to the accumulation of ADMA in the circulation. The ADMA then decreases the production of eNOS. This could reduce the amount of NO diffusing from cerebral blood vessels to nearby neurons and influence the release of neurotransmitters. ADMA also constricts cerebral blood vessels and may contribute to the decreased regional perfusion in major depression. The accumulation of ADMA could explain the increased risk of CHD in major depression. The preservation of DDAH activity and the reduction of ADMA accumulation may represent a novel therapeutic approach to the treatment of major depression.

Topics: Aldehydes; Arginine; Citrulline; Coronary Disease; Depressive Disorder, Major; Female; Glutathione; Humans; Lipid Peroxidation; Male; Middle Aged; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitrites