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.     

Impact of plasma adiponectin levels to the presence and severity of coronary artery disease in patients with metabolic syndrome

OBJECTIVES: Adiponectin is thought to serve a protective function for the coronary endothelium by inhibiting many of the crucial steps in atherosclerotic process. Previous research has indicated an increased risk of coronary artery disease (CAD) in patients with metabolic syndrome (MetS). The objective of this study was to investigate whether plasma adiponectin concentrations were associated with the presence and severity of CAD in patients with MetS undergoing coronary angiography. METHODS: We measured plasma adiponectin levels in 167 consecutive patients with MetS undergoing coronary angiography. The severity of coronary atherosclerosis was defined by using Gensini score system. RESULTS: CAD was found in 70.1% of the patients. Patients with significant CAD had lower plasma adiponectin concentrations than those without CAD (4.14+/-3.83 vs. 8.94+/-6.63 microg/ml, P<0.001). Multiple regression analysis demonstrated that plasma adiponectin level was independently associated with CAD (odds ratio: 0.86; 95% confidence interval: 0.78-0.94; P=0.001). Plasma adiponectin levels were inversely related to the Gensini score (rho: -0.480, P<0.001) and predicted the severity of coronary atherosclerosis independent of other risk factors (beta: -0.054; 95% confidence interval: -0.074--0.034; P<0.001). CONCLUSIONS: These findings suggest that hypoadiponectinemia may play a role in the development of coronary atherosclerosis and the observation of adiponectin levels may be indicative of the presence of significant CAD in patients with MetS.     

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.     

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.     

Relationship between aortic valve sclerosis and the extent of coronary artery disease in patients undergoing diagnostic coronary angiography

BACKGROUND: Aortic valve sclerosis (AVS) is considered to be a manifestation of coronary atherosclerosis. Recent studies demonstrated an association between AVS and significant coronary artery disease (CAD). AIM: We sought to determine the association between AVS and the extent of coronary atherosclerosis by means of the Gensini score system, which was calculated to yield a measure of the extent and severity of coronary atherosclerosis in patients referred for coronary angiography. METHODS: A total of 160 consecutive patients referred for coronary angiography were subjected to echocardiography for screening of AVS and coronary risk assessment. Absence (group 1, n = 110) and presence of AVS (Group 2, n = 50) was established. The cardiac risk factors considered in this study were age, gender, family history of CAD, diabetes mellitus, hypertension, hypercholesterolemia and history of smoking. The body mass index was also measured. Atherosclerotic plaque burden was determined using the Gensini score. Significant CAD was defined as >50% reduction in the internal diameter of at least one coronary artery. Multivessel coronary disease was based on the presence of 2- or 3-vessel disease. RESULTS: The AVS patients had a higher rate of 3-vessel disease (AVS group vs. non AVS: 40 vs. 13.6%; p < 0.001). No significant correlations were found between AVS and 1- and 2-vessel disease. Individuals with AVS were found to have a higher Gensini score (40.7 +/- 38.05 vs. 18 +/- 16.4; p < 0.001). Multivariate analysis identified age (p < 0.001), male sex (p = 0.01), triglycerides (p = 0.02), LDL cholesterol (p = 0.001) and Gensini score (p = 0.003) as independent predictors of AVS. CONCLUSION: AVS is strongly interrelated with the coronary angiographic Gensini score. Echocardiographic detection of AVS in patients undergoing coronary angiography can provide a new surrogate marker of the extent of coronary atherosclerosis.     

Increased serum glycated albumin level is associated with the presence and severity of coronary artery disease in type 2 diabetic patients.

BACKGROUND: Glycated albumin is the predominant circulating Amadori-type glycated protein in vivo and plays a major role in the development of diabetic vascular complications. The aim of this study was to assess the relationship between increased serum glycated albumin level and the presence and severity of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM). METHODS AND RESULTS: In a total of 320 consecutive patients with T2DM, coronary angiography revealed normal coronary arteries in 83 patients (control group) and significant coronary stenosis (> or = 70% luminal diameter narrowing) in 237, of whom 51 patients had 1-vessel disease (Group I), 80 had 2-vessel disease (Group II), and 106 had 3-vessel disease (Group III). Serum glycated albumin, hemoglobin A(1c) (HbA(1c)) and tumor necrosis factor (TNF)-alpha levels, lipid profile, and renal function were measured. Logistic regression analysis was performed to determine the relative risk of serum glycated albumin level for the presence and severity of CAD. Multivariate stepwise linear regression analysis was done to identify independent determinants of the glycated albumin level. Serum glycated albumin (21.2+/-5.3% vs 19.4+/-4.3%, p=0.005) and TNF-alpha levels (123 +/-115 pg/ml vs 65+/-59 pg/ml, p<0.001) were significantly higher in patients with CAD than in controls, but serum HbAlc level did not significantly differ between them (7.6+/-1.3% vs 7.4+/-1.2%, p=0.19). There was a significant difference in serum glycated albumin level between Groups I and III (19.5+/-3.3% vs 21.8+/-5.7%, p<0.001). The serum glycated albumin level correlated with the number of diseased arteries (Spearman r=0.205, p<0.001), and was closely related to serum levels on admission of glucose (r=0.495, p<0.001), TNF-alpha (r=0.123, p=0.028), blood urea nitrogen (r=0.167, p=0.004), triglycerides (r=0.129, p=0.021), and HbA(1c) (r=0.795, p<0.001). Multivariate analysis indicated that serum levels of glucose (p<0.0001), TNF-alpha (p=0.001), blood urea nitrogen (p=0.004) and triglycerides (p=0.035) were independent determinants for glycated albumin. Logistic regression analysis revealed that glycated albumin > or = 19% (odds ratio (OR) 2.9, p<0.001) was an independent predictor for CAD and glycated albumin > or = 21% (OR 2.3, p=0.032) for 3-vessel disease prediction. The area under the receiver-operating characteristic curve for glycated albumin (0.620, 95% confidence interval (CI) 0.548 to 0.691, p=0.001) was superior to that for HbA(1c) (0.543, 95% CI 0.473 to 0.613, p=0.243). CONCLUSIONS: An increased serum level of glycated albumin is associated with the presence and severity of CAD, and may be useful in screening patients with T2DM.     

Asymmetric dimethylarginine plasma concentrations and L-arginine/asymmetric dimethylarginine ratio in patients with slow coronary flow

OBJECTIVE: Elevated levels of nitric oxide synthase inhibitor, asymmetric dimethylarginine (ADMA) is considered to be a marker of endothelial dysfunction and increased risk of cardiovascular disease. Recent reports have implicated endothelial dysfunction as an underlying pathophysiological mechanism of slow coronary flow (SCF) phenomenon. Accordingly, we investigated plasma L-arginine, ADMA concentrations and L-arginine/ADMA ratio in patients with SCF in comparison with participants having normal coronary flow. METHODS: We measured plasma levels of L-arginine and ADMA by high-performance liquid chromatography in 31 participants with SCF and 31 age and sex matched control participants with normal coronary flow. Coronary flow was quantified using the thrombolysis in myocardial infarction (TIMI) frame count method. RESULTS: The patients with SCF were detected to have significantly higher concentrations of plasma ADMA (P=0.006) and lower L-arginine/ADMA ratio compared with participants with normal coronary flow (P=0.002). In addition, both ADMA and L-arginine/ADMA ratio were significantly correlated with mean TIMI frame count and TIMI frame count for each coronary artery in patients with SCF and multivariate regression analysis identified plasma ADMA as an independent predictor for SCF. In the receiver operator characteristics curve analysis, patients with SCF were detected by plasma ADMA level with a sensitivity, specificity of 64.5%, 74.2%, at a cut-off of >2.4 micromol/l and L-arginine/ADMA ratio with a sensitivity, specificity of 77.4%, 67.7% at a cut-off of <36.6. CONCLUSION: Our findings provide evidence to support the hypothesis that endothelial dysfunction may be an important factor in the pathogenesis of SCF.     

Relationship of metabolic syndrome with quantum of coronary artery disease in Indian patients with chronic stable angina

Background: The current study was aimed to ascertain presence and severity of coronary artery lesions in patients of Type 2 diabetic mellitus (DM) with coronary artery disease (CAD), in our population, by using scoring system analysis of the coronary angiography. Methods: 147 consecutive patients with Type 2 DM of chronic stable angina (CSA) were enrolled in the study with 147 age- and sex-matched patients of CSA who did not have diabetes to serve as control. All of them underwent coronary angiography and were evaluated by using four scores to quantify the coronary artery lesions. The scores analyzed were coronary score, extent score, severity score, and atherosclerosis score. Other major risk factors such as smoking and hypertension lipid profile were also evaluated. Results: Type 2 diabetics with CAD had higher coronary score (0.91 +/- 0.63 in diabetics vs. 0.43 +/- 0.39, p < 0.001), extent score (4.91 +/- 3.1 vs. 2.3 +/- 1.8, p < 0.001), severity score (1.85 +/- 0.41 vs. 1.2 +/- 0.32, p < 0.001), and atherosclerosis score (0.52 +/- 0.31 vs. 0.21 +/- 0.26, p < 0.001) as compared to non-diabetics with CAD. Left main stem involvement, 2-vessel disease, and 3-vessel disease were also more frequent in the diabetics. These diabetes also had higher incidence of obesity, hypertension, and dyslipidemia. Conclusions: In our population, diabetics suffer from higher prevalence of diffuse and extensive coronary atherosclerosis. The grades of stenosis in coronary arteries are also higher in diabetic patients when compared with non-diabetics with CAD, as was the prevalence of other components of the metabolic syndrome.     

Long-term angiotensin-converting enzyme inhibition reduces plasma asymmetric dimethylarginine and improves endothelial nitric oxide bioavailability and coronary microvascular function in patients with syndrome X

Angiotensin-converting enzyme (ACE) inhibition has been shown to improve clinical myocardial ischemia in patients with syndrome X (angina pectoris, positive treadmill exercise test, normal coronary angiograms, and no evidence of coronary spasm). This study was conducted to investigate the effects of long-term ACE inhibitors on endothelial nitric oxide (NO) metabolism and coronary microvascular function in patients with syndrome X. After a 2-week washout period, 20 patients with syndrome X were randomized to receive either enalapril, an ACE inhibitor, 5 mg twice daily (n = 10) or placebo (n = 10) in a double-blind design for 8 weeks. Another 6 age- and gender-matched subjects with negative treadmill exercise tests were also studied as controls. Compared with control subjects, patients with syndrome X had significantly reduced coronary flow reserve, reduced plasma levels of nitrate and nitrite (NOx), and a reduced plasma L-arginine to asymmetric dimethylarginine (ADMA) ratio (an index of systemic NO metabolism), as well as reduced endothelial function. These patients also had increased plasma levels of ADMA, which is an endogenous inhibitor of NO synthase and of von Willebrand factor, a marker of endothelial injury. Baseline characteristics including exercise performance and coronary flow reserve were similar between enalapril and placebo groups. After an 8-week treatment period, exercise duration (p = 0.001) and coronary flow reserve (p = 0.001) significantly improved with enalapril but not with placebo. Enalapril treatment, but not placebo, reduced plasma von Willebrand factor (p = 0.03) and ADMA levels (p = 0.01) and increased NOx levels (p = 0.01) and the ratio of L-arginine to ADMA (p <0.01). In patients with syndrome X, the plasma NOx level was positively and ADMA level inversely correlated with coronary flow reserve before and after the treatment. In conclusion, long-term ACE inhibitor treatment with enalapril improved coronary microvascular function as well as myocardial ischemia in patients with syndrome X. This may be related to the improvement of endothelial NO bioavailability with the reduction of plasma ADMA levels.     

Endothelium-dependent vasodilation is independent of the plasma L-arginine/ADMA ratio in men with stable angina: lack of effect of oral L-arginine on endothelial function, oxidative stress and exercise performance

OBJECTIVES: This study was designed to determine the effect of two weeks' treatment with L-arginine on the ratio of plasma L-arginine to asymmetric dimethylarginine (ADMA), oxidative stress, endothelium-dependent vasodilatation to acetylcholine, exercise performance and heart rate variability in men with stable angina. BACKGROUND: The ratio of plasma L-arginine:ADMA has been proposed as a determinant of endothelium-dependent dilation; dietary supplementation with L-arginine has been shown to improve endothelium-dependent vasodilation and symptoms in some conditions. METHODS: Men (n = 40) with stable angina, at least one epicardial coronary artery with a stenosis >50% and a positive exercise test were randomized to receive L-arginine (15 g daily) or placebo for two weeks according to a double-blind parallel-group design. Plasma L-arginine, ADMA, 8-epi-prostaglandin F2alpha (a marker of oxidative stress) and forearm vasodilator responses to brachial artery infusion of nitroprusside and acetylcholine (+/-L-arginine) were measured. A standard Bruce protocol exercise test was performed before and at the end of the treatment period. RESULTS: Plasma L-arginine increased after oral L-arginine, whereas ADMA remained unchanged, leading to an increase in the L-arginine/ADMA ratio of 62 +/- 11% (mean +/- SE, p < 0.01). Despite a significant enhancement in acetylcholine response by intra-arterial L-arginine at baseline, this response remained unchanged after oral L-arginine. Measures of oxidative stress and exercise performance after L-arginine/placebo were similar in placebo and active groups. CONCLUSIONS: In men with stable angina, an increase in plasma L-arginine/ADMA ratio after two weeks' oral supplementation with L-arginine is not associated with an improvement in endothelium-dependent vasodilatation, oxidative stress or exercise performance.     

Nontraditional atherosclerotic risk factors and extent of coronary atherosclerosis in patients with combined impaired fasting glucose and impaired glucose tolerance

Partially inconsistent data exist on mutual relations between nontraditional atherosclerotic risk factors, including the magnitude of insulin resistance (IR), as well as on their relevance for atherogenesis in the metabolic syndrome. Subjects exhibiting combined impaired fasting glucose and impaired glucose tolerance (IFG/IGT) are exposed to an exceptionally high risk for atherogenesis and development of type 2 diabetes mellitus. Because of islet Beta-cell dysfunction, the usefulness of commonly used indices of IR is limited in IFG/IGT. Our aim was to assess the relationship between extent of angiographic coronary artery disease (CAD) and nontraditional atherosclerotic risk factors (including IR by a clamp-based golden standard method) in IFG/IGT. Fifty-three subjects (32 men, 21 women; mean age, 55 +/- 11 years) with stable angina, preserved left ventricular systolic function, and IFG/IGT were divided into 3 groups: group A (no coronary stenoses >50%, n = 22), group B (1-vessel CAD, n = 15), and group C (2/3-vessel CAD, n = 16). Insulin sensitivity was quantified by a hyperinsulinemic euglycemic clamp technique and expressed as M. M value, plasma homocysteine (Hcy) level, and asymmetric dimethyl-L-arginine (ADMA)/L-arginine ratio were independent determinants of CAD extent as shown by forward stepwise discriminant function analysis. Compared with group A (M = 32.7 +/- 9.3 micromol/kg fat-free mass [FFM] per minute; Hcy, 8.1 +/- 1.4 micromol/L), lower M and higher Hcy levels were found in group B (M = 16.9 +/- 8.2 micromol/kg FFM per minute, P < .001; Hcy, 11.2 +/- 2.9 micromol/L, P = .003) and C (M = 16.4 +/- 7.8 micromol/kg FFM per minute, P < .001; Hcy, 12.8 +/- 3.9 micromol/L, P < .001). The ADMA/L-arginine ratio was increased in group C (0.0078 +/- 0.0011) compared with group A (0.0063 +/- 0.0013, P = .03) and B (0.0058 +/- 0.0012, P = .01). Multivariate correlates (P < .05) of plasma Hcy concentrations were M (beta = -.34 +/- .12, P = .008), creatinine clearance (beta = -.23 +/- .10, P = .03) and fasting insulin (beta = .25 +/- .12, P = .04). This indicates an additive contribution of IR, plasma Hcy, and elevated ADMA/L-arginine ratio to the extent of angiographic CAD in combined IFG/IGT.     

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.     

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.     

Revisiting the frequency of peripheral arterial disease in patients with coronary artery disease: is there a difference between diabetic and non-diabetic patients?

BACKGROUND: The aim of this study was to investigate whether frequency of concomitant peripheral arterial disease (PAD) is associated with angiographic severity of coronary artery disease (CAD), as well as to ascertain if diabetic patients differ from those without diabetes in the association between these two manifestations of atherosclerosis. PATIENTS AND METHODS: This study included 302 patients (229 men, mean age 62.2 +/- 11.5 years) with documented CAD, divided into groups I-III, according to the angiographic severity of coronary atherosclerosis. Group I comprised 140 patients (104 men) with severe CAD, group II comprised 63 patients (48 men) with moderate CAD and group III comprised 99 patients (77 men) with mild CAD. Each of the groups I-III was further divided into the subgroups of diabetic and non-diabetic patients. Included were also 88 patients (42 men, mean age 61.7 +/- 9.5 years) without CAD and a control group of 60 healthy volunteers (30 men), aged 18-40 years. PAD was diagnosed by means of a Doppler apparatus. RESULTS: Frequency of PAD was associated with angiographic severity of CAD (p = 0.0001). This association was shown both in diabetic (p = 0.012) and in non-diabetic patients (p = 0.0041). Significantly (p < or = 0.01) higher frequency of PAD among diabetic patients was found in each of the groups I-III. CONCLUSIONS: Among patients with CAD, frequency of concomitant PAD is associated with angiographic severity of coronary atherosclerosis. This association is demonstrated both in diabetic and in non-diabetic patients. Finally, PAD is significantly more frequent in diabetic patients, irrespective of the angiographic severity of CAD.     

Elevation of asymmetric dimethylarginine in patients with unstable angina and recurrent cardiovascular events.

AIMS: We investigated the role of asymmetric dimethylarginine (ADMA) for clinical outcome of patients with unstable angina. METHODS AND RESULTS: Forty-five patients with stable angina, 36 patients with unstable angina, and 40 healthy controls were included in this study. Coronary artery disease (CAD) patients were prospectively followed for 1 year. ADMA levels were measured at baseline and after 6 weeks using a validated ELISA. Baseline ADMA concentration in controls was significantly lower than in patients with CAD (0.59+/-0.23 vs. 0.76+/-0.17 micromol/L; P<0.001). Patients with unstable angina had significantly higher baseline ADMA levels than patients with stable angina (0.82+/-0.18 vs. 0.73+/-0.15 micromol/L; P=0.01). There was a significant reduction of ADMA levels at 6 weeks after percutaneous coronary intervention (PCI) in patients with unstable angina who experienced no recurrent cardiovascular event (from 0.81+/-0.14 to 0.73+/-0.19 micromol/L; P<0.05). In contrast, patients with unstable angina who had an event showed no significant decrease in ADMA at 6 weeks. Actuarial survival analysis showed a significantly higher event rate in patients with persistently elevated ADMA plasma concentrations. CONCLUSION: ADMA is significantly elevated in patients with unstable angina. A reduced ADMA level at 6 weeks after PCI may indicate a decreased risk of recurrent cardiovascular events.     

Thyroid function is associated with presence and severity of coronary atherosclerosis

BACKGROUND: Overt hypothyroidism has been found to be associated with cardiovascular disease. Moreover, subclinical hypothyroidism is a strong indicator of risk for aortic atherosclerosis and myocardial infarction. HYPOTHESIS: We hypothesized that variation of thyroid function within the normal range may influence the presence and severity of coronary atherosclerosis. METHODS: We studied a total of 100 consecutive men and women (59 men, 41 women, age 63.7 +/- 11.0 years) who underwent coronary angiography. Blood was tested for serum thyrotropin concentrations and for free tri-iodothyronine and free thyroxine concentrations. In addition to the assessment of thyroid function, conventional risk factors for coronary artery disease (CAD), clinical characteristics, serum lipid levels, fasting total homocysteine, and angiographic results of coronary artery assessment were obtained. Two experienced cardiologists blinded to clinical and laboratory data reviewed the cinefilms. The severity of CAD was scored as 0 for those with smooth normal epicardial coronary arteries, 0.5 for plaquing (< 50% diameter stenosis), and 1, 2, or 3 for those with single-, double-, or triple-vessel epicardial coronary artery stenosis of > 50%, respectively. RESULTS: The severity of CAD was scored as 0, 0.5, 1, 2, and 3 in 14, 26, 25, 22, and 13 patients, respectively. Higher levels of serum-free thyroid hormone concentrations were associated with decreased severity of coronary atherosclerosis. Serum-free tri-iodothyronine was 2.99 +/- 0.33 pg/ml in patients with a CAD severity score of 0 to 1 and 2.74 +/- 0.49 pg/ml in patients with CAD severity scores of 2 and 3 (p < 0.01). Moreover, serum-free thyroxine concentrations showed a trend toward higher levels in patients with CAD severity score 0 to 1 compared with patients with CAD severity scores 2 and 3 (11.65 +/- 1.87 pg/ml vs. 10.9 +/- 2.3 pg/ml; p = 0.09). Higher levels of serum thyrotropin concentrations were associated with increased severity of coronary atherosclerosis (1.37 +/- 1.02 mU/l vs. 1.98 +/- 2.13 mU/l in patients with CAD severity score 0 to 1 versus CAD severity scores 2 and 3; p = 0.049). When grouped into three subsets according to their serum free tri-iodothyronine levels (< 2.79, 2.8 to 3.09, and +/- 3.1 pg/ml), the prevalence of CAD scores 2 and 3 was significantly higher in the subset of patients with low serum free tri-iodothyronine levels (48.5%) than in the subsets of patients with medium or high tri-iodothyronine concentrations (32.25 and 25%, respectively, p for trend < 0.05). CONCLUSION: These data in patients referred for coronary angiography suggest that variation of thyroid function within the statistical normal range may influence the presence and severity of coronary atherosclerosis.     

Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease

OBJECTIVES: The purpose of this study was to determine whether lowering homocysteine levels with folic acid, with or without antioxidants, will improve endothelial dysfunction in patients with coronary artery disease (CAD). BACKGROUND: Elevated plasma homocysteine levels are a risk factor for atherosclerosis. Homocysteine may promote atherogenesis through endothelial dysfunction and oxidative stress. METHODS: In a double-blind, placebo-controlled, randomized trial, we used vascular ultrasound to assess the effect of folic acid alone or with antioxidants on brachial artery endothelium-dependent flow-mediated dilation (FMD). Seventy-five patients with CAD (screening homocysteine level > or =9 micromol/liter) were randomized equally to one of three groups: placebo, folic acid alone or folic acid plus antioxidant vitamins C and E. Patients were treated for four months. Plasma folate, homocysteine, FMD and nitroglycerin-mediated dilation were measured before and after four months of treatment. RESULTS: Plasma folate, homocysteine and FMD were unchanged in the placebo group. Compared with placebo, folic acid alone increased plasma folate by 475% (p < 0.001), reduced plasma homocysteine by 11% (p = 0.23) and significantly improved FMD from 3.2 +/- 3.6% to 5.2 +/- 3.9% (p = 0.04). The improvement in FMD correlated with the reduction in homocysteine (r = 0.5, p = 0.01). Folic acid plus antioxidants increased plasma folate by 438% (p < 0.001), reduced plasma homocysteine by 9% (p = 0.56) and insignificantly improved FMD from 2.6 +/- 2.4% to 4.0 +/- 3.7% (p = 0.45), as compared with placebo. Nitroglycerin-mediated dilation did not change significantly in any group. CONCLUSIONS: Folic acid supplementation significantly improved endothelial dysfunction in patients with coronary atherosclerosis. Further clinical trials are required to determine whether folic acid supplementation may reduce cardiovascular events.     

Plasma asymmetric dimethylarginine concentrations in newly diagnosed patients with acute myocardial infarction or unstable angina pectoris during two weeks of medical treatment

A high concentration of plasma asymmetric dimethylarginine (ADMA) has been associated with several risk factors for atherosclerosis, and this may increase the risk for acute coronary syndromes (ACSs). We measured plasma ADMA concentrations in patients who had newly diagnosed ACS (n = 48), and we followed the changes in ADMA concentrations during these patients' short-term medical therapy, which included various combination of drugs with or without percutaneous coronary interventions according to the needs of each patient. Concentrations of plasma ADMA were found to be high in patients who had ACS compared with 48 age-matched healthy control subjects (3.13 +/- 0.85 vs 1.57 +/- 0.85 mumol/L, p <0.0001). Follow-up measurements of ADMA showed dramatic decreases in plasma ADMA concentrations over 2 weeks of medical therapy for ACS (from 3.27 +/- 0.87 to 1.52 +/- 0.47 mumol/L, p <0.0001). Plasma ADMA at baseline showed a significant positive correlation with serum C-reactive protein and plasma insulin and a significant negative correlation with serum levels of high-density lipoprotein and plasma alpha-tocopherol. During therapy, changes in plasma ADMA concentrations were significantly correlated with changes in the ratio of total cholesterol to high-density lipoprotein cholesterol and in serum C-reactive protein concentrations but not with changes in insulin levels. This study provides the first evidence that plasma ADMA concentrations are significantly high in patients who have ACS and that ADMA concentrations rapidly decrease after short-term medical therapy.     

Circulating endothelial progenitor cells, C-reactive protein and severity of coronary stenosis in Chinese patients with coronary artery disease.

We sought to investigate whether numbers and activity of circulating endothelial progenitor cells (EPCs) correlate with severity of coronary stenosis as well as cardiovascular risk factors in patients with stable coronary artery disease (CAD). Number of circulating EPCs was analyzed in 104 consecutive patients with proven or clinically suspected CAD. Adhesive and migratory activity was also determined. The number of EPCs was lower in patients with a single diseased coronary artery (Group II, n=35, p<0.05 vs. Group I) or multiple diseased arteries (Group III, n=25, p<0.01 vs. Group I, p<0.05 vs. Group II) compared to those with normal coronary arteries (Group I, n=44). The number of EPCs was also related with angiographic Gensini score (r=-0.355, p=0.006). In addition, concentrations of C-reactive protein (CRP) were elevated in patients with CAD, and positively correlated with Gensini score (r=0.476, p=0.001). As for the risk factors, the number of EPCs was also inversely correlated with age (p=0.001), high sensitivity-CRP (p=0.012), hypertension (p=0.042) and family history of CAD (p=0.043). Most importantly, the migratory capacity of EPCs was compromised in patients with CAD, and inversely correlated with the angiographic Gensini score (r=-0.315, p=0.021). EPCs isolated from patients with CAD also showed an impaired adhesive activity (p<0.05). In conclusion, in patients with stable CAD, reduction in the number and impairment in the function of circulating EPCs were correlated with the severity of coronary stenosis. CRP may play an important role in reducing the number of EPCs and accelerating atherosclerosis. Given the important role of EPCs in neovascularization of ischemic tissue, a decrease in the number and activity of EPCs may contribute to the impaired vascularization in patients with CAD.     

Hyperhomocysteinemia is associated with human coronary atherosclerosis through the reduction of the ratio of endothelium-bound to basal extracellular superoxide dismutase.

BACKGROUND: Homocysteine is involved in coronary atherosclerosis through oxidative stress, so the present study investigated the association between plasma concentrations of homocysteine and extracellular superoxide dismutase (EC-SOD) in coronary artery disease (CAD). METHODS AND RESULTS: The study group comprised 154 consecutive male patients with suspected CAD who had undergone angiography. Plasma concentrations of homocysteine and EC-SOD, which was determined before (basal) and after heparin therapy, were measured and the difference was designated as endothelium-bound EC-SOD. The EC-SOD ratio (endothelium-bound/basal EC-SOD) was also evaluated as an index of binding capacity. The plasma homocysteine concentration in the stenosis (+) group (n=97, 12.0+/-4.6 micromol/L) was significantly higher than that of the stenosis (-) group (n=57, 10.2+/-3.0 micromol/L, p=0.004). Plasma homocysteine correlated positively with the basal EC-SOD (r=0.377, p<0.001) and negatively with the EC-SOD ratio (r=-0.199, p=0.014). When the group was subdivided according to either homocysteine or the EC-SOD ratio, there were 2 groups with high homocysteine concentration and of these atherosclerosis was reduced in the group with a high EC-SOD ratio. CONCLUSIONS: In CAD patients, homocysteine is involved in the significant release of EC-SOD from the endothelium. Furthermore, the higher EC-SOD binding capacity, even at high concentrations of homocysteine, suggested that homocysteine-induced atherosclerosis was suppressed.