Association between human paraoxonase 1 activity and intima-media thickness in subjects under 55 years of age with carotid artery disease.

BACKGROUND: Human serum paraoxonase (PON1) protects lipoproteins against oxidation by hydrolyzing lipid peroxides in oxidized low-density lipoprotein (oxLDL); therefore, it may protect against atherosclerosis. PON1 activity and polymorphisms have been inconsistently associated with carotid artery disease. The goal of this study was to clarify the role of PON1 activity and phenotype on carotid artery disease and its correlation with some inflammatory and immune markers in subjects under 55 years with early-onset carotid atherosclerosis. METHODS: Sixty patients with occlusive carotid artery disease and 30 healthy controls were enrolled. Intima-media thickness (IMT) was measured by high-resolution ultrasound of both common carotid arteries. Anti-oxLDL antibody levels were determined by ELISA. RESULTS: In the whole study population we found a negative correlation between PON1 activity and IMT (r = -0.27, p = 0.011), and between salt-stimulated PON1 activity and IMT (r = -0.24, p = 0.02). Both PON1 activity and salt-stimulated PON1 activity negatively correlated with anti-oxLDL levels (r = -0.28, p = 0.008; r = -0.26, p = 0.01). PON1 activity was lower in patients compared to controls; however, the difference was not significant.PON1 phenotype distribution of patients and controls did not differ significantly. CONCLUSION: The importance of PON1 activity as a predictive risk factor for early-onset occlusive carotid artery disease should be assessed in future studies.

Severity of carotid atherosclerosis unrelated to Chlamydia pneumoniae infection in acute ischemic stroke patients: a clinicopathological study.

BACKGROUND: Both clinical and pathological alterations of the carotid arteries were correlated with Chlamydia pneumoniae infection in 67 acute ischemic stroke patients with severe neurological symptoms. METHODS: In the clinical study, intima-media thickness (IMT) of the common carotid arteries was determined in vivo by B-mode ultrasound measurement and C. pneumoniae-specific IgG and IgA responses were detected. In the pathological study, the absolute wall thickness of the common, internal and external carotid arteries was measured postmortem in specimens obtained at the autopsy of patients who died due to complications of acute stroke. In the atherosclerotic plaques of the autopsy specimens, C. pneumoniae genomic DNA was detected by polymerase chain reaction amplification. RESULTS: The Spearman's rho correlation coefficient of IMT with the average wall thickness of the common, internal and external carotid arteries was 0.51 (p = 0.002), 0.34 (p = 0.052) and 0.58 (p < 0.001), respectively. Anti-C. pneumoniae IgG and IgA antibodies were detected in 43 (73%) and 29 (49%) patients, but neither antibody marker correlated with IMT (median: 0.91 mm in IgG positives vs. 0.90 mm in IgG negatives, p = 0.86; 0.88 mm in IgA positives vs. 0.90 mm in IgA negatives, p = 0.53). The presence of C. pneumoniae DNA was detected in the carotid plaques of 21 (54%) of the 39 tested patients, independently of either IMT values or the average wall thickness of all carotid arteries. CONCLUSIONS: In acute ischemic stroke patients, C. pneumoniae infection was frequently detected in the arteriosclerotic plaques of the carotid arteries but it did not correlate with the severity of carotid arteriosclerosis.

Dimethylarginines at the crossroad of insulin resistance and atherosclerosis.

We tested if asymmetric dimethylarginine (ADMA) contributes to the simultaneous evolution of atherosclerosis and insulin resistance. We investigated the significant predictors of insulin resistance in the context of atherosclerosis, focusing on the role ADMA, symmetric dimethylarginine (SDMA), and l-arginine play in a cohort of young atherosclerotic patients and their age-matched controls. In a case-control study, 60 patients younger than 55 years having at least 30% stenosis of the internal carotid artery and 30 age- and sex-matched controls were recruited at a community-based neurosonologic laboratory. We found a strong positive association between the homeostasis model assessment of beta-cell function and insulin resistance and the ADMA/SDMA ratio that remained statistically significant even after adjusting for all significant and a priori identified determinants (beta = 6.76; 95% confidence interval [CI], 2.13-11.39; P = .005). Interestingly, this relationship was even more pronounced in the atherosclerotic stratum (beta = 8.29; 95% CI, 1.43-15.15; P = .019), whereas, on multiple linear regression, lack of association was seen in subjects free of carotid atherosclerosis (beta = 1.39; 95% CI, -5.46 to 8.26; P = .671). We conclude that ADMA/SDMA ratio is a significant determinant of insulin resistance and may be a better parameter to monitor than ADMA alone. By accounting for the competition at the y+ transporters, ADMA/SDMA ratio could be an indicator of intracellular ADMA level.

Early-onset carotid atherosclerosis is associated with increased intima-media thickness and elevated serum levels of inflammatory markers.

BACKGROUND AND PURPOSE: Several factors have been held responsible for the development of atherosclerosis. To avoid the masking effect of age, we evaluated correlates of carotid atherosclerosis in patients <55 years of age. METHODS: Plasma lipids, oxidative resistance of low-density lipoprotein, homocysteine, inflammatory markers, plasma viscosity, and red cell deformability were measured in fasting blood samples of 100 subjects: 45 patients with >30% stenosis of the internal carotid artery, 20 patients with carotid occlusion, and 35 control subjects. Stenosis and intima-media thickness (IMT) of the carotid artery were evaluated by duplex ultrasound. RESULTS: White blood cell (WBC) count, plasma fibrinogen, C-reactive protein (CRP), and lipoprotein(a) levels were significantly higher in patients than in control subjects, and patients had increased IMT (P<0.01 for all comparisons). There was a tendency for higher homocysteine levels in patients. Smokers had higher WBC, fibrinogen, and CRP levels. After the effect of smoking was controlled for, WBC count, natural logarithmic transform of homocysteine, and online-measured IMT remained significantly higher in patients than in control subjects. WBC, fibrinogen, and CRP levels were highest in the highest IMT quartile (P=0.012, P=0.007, and P=0.036, respectively). CONCLUSIONS: Inflammatory markers and homocysteine have a more important role than lipid factors in early-onset carotid atherosclerosis. We cannot recommend the measurement of low-density lipoprotein peroxidation as a routine screening test to identify high-risk patients for early-onset carotid atherosclerosis. The confounding effect of smoking on inflammatory markers should be considered in studies on atherosclerosis.

Increased levels of platelet activation markers are positively associated with carotid wall thickness and other atherosclerotic risk factors in obese patients.

The role of platelets in the development of atherosclerosis and obesity-related prothrombotic state is still under investigation. In this cross-sectional cohort study, we measured the levels of different platelet activation markers and evaluated their relationship with carotid intima-media thickness (IMT) along with other atherosclerotic risk factors in obese patients with or without atherosclerotic co-morbidities. We enrolled 154 obese patients, including 98 with either hypertension, type 2 diabetes mellitus or dyslipidaemia, 56 without these co-morbidities and 62 age- and sex-matched healthy controls. Platelet P-selectin expression and the number of platelet-derived microparticles (PMPs) were measured by flow cytometry; soluble P-selectin levels were analysed by ELISA and Thr715Pro P-selectin polymorphism was determined by PCR-RFLP. Carotid IMT was examined by ultrasonography. The levels of platelet activation parameters were significantly elevated in all obese subjects with increased carotid IMT compared to healthy controls. There was no effect of Thr715Pro genotype on soluble P-selectin levels in obese individuals contrary to normal subjects. Significant and positive association was revealed between carotid IMT and platelet P-selectin (p<0.0001), soluble P-selectin (p=0.039) and PMP (p=0.0001) levels. After adjusting for multiple variables, independent association was found between soluble P-selectin and fibrinogen (p=0.007), PMP levels and body mass index (p<0.0001) as well as platelet P-selectin and carotid IMT (p=0.012) plus plasminogen activator inhibitor-1 (p=0.009). In conclusion, P-selectin and PMP levels showed positive associations with abnormal carotid IMT and other risk factors in obesity suggesting a critical role of enhanced platelet reactivity in atherosclerotic wall alteration.

Endothelial cell markers reflecting endothelial cell dysfunction in patients with mixed connective tissue disease.

INTRODUCTION: The aim of the present study was to investigate the association between cardiovascular risk factors and endothelial dysfunction in patients with mixed connective tissue disease (MCTD) and to determine which biomarkers are associated with atherosclerotic complications, such as cardiovascular disease. METHODS: Fifty MCTD patients and 38 healthy age-matched and sex-matched controls were enrolled in this study. In order to describe endothelial dysfunction, we assessed flow-mediated dilation (FMD), nitrate-mediated dilation (NMD) and carotid artery intima-media thickness (IMT). We investigated FMD of the brachial artery after reactive hyperemia and NMD after sublingual nitroglycerin administration, while the IMT of the common carotid artery was determined by ultrasound. Anti-U1 ribonucleoprotein (anti-U1RNP) antibodies, anti-cardiolipin (anti-CL) antibodies, anti-endothelial cell antibody (AECA) and endothelial cell markers, such as soluble thrombomodulin (TM) and von Willebrand factor antigen (vWFAg), were assessed. RESULTS: The endothelium-dependent vasodilation (FMD) was significantly impaired in patients with MCTD, as compared with controls (%FMD: 4.7+/-4.2% vs. 8.7+/-5.0%; P<0.001), while the percentage NMD did not differ (%NMD: 14.3+/-6.6% vs. 17.1+/-6.7%; P=0.073). Mean carotid IMT values were higher in patients than in controls (IMT: MCTD, 0.64+/-0.13 mm vs. controls, 0.53+/-0.14 mm; P<0.001). FMD negatively correlated with disease duration, the levels of apolipoprotein A1, the paraoxonase-1 activity, and systolic blood pressure in MCTD patients. The percentage FMD was significantly lower in MCTD patients with cardiovascular diseases (CVD), than in those without CVD (%FMD: 3.5+/-2.9 vs. 5.8+/-4.8, P<0.0002), while percentage NMD did not differ between patients with and without CVDs. Serum levels of autoantibodies (anti-U1RNP, AECA and anti-CL) were significantly higher in MCTD patients and differed between MCTD patients with and without CVD. Endothelial cell markers such as soluble TM (12.2+/-8.1 ng/ml vs. 3.2+/-1.3 ng/ml; P<0.001) and vWFAg (224.1+/-115% vs. 89.4+/-27.1%, P<0.001) were the highest in MCTD patients with CVD. CONCLUSIONS: FMD is a reliable sensitive marker of endothelial cell dysfunction in MCTD. Beside the traditional risk factors, anti-U1RNP, AECA and anti-CL antibodies may be important not only in the pathogenesis of MCTD but in the induction of endothelial cell activation, and may play crucial roles in the development of early atherosclerosis in MCTD.

Correlations between the atherosclerotic changes of femoral, carotid and coronary arteries: a post mortem study.

OBJECTIVE: To compare the severity of atherosclerosis in the carotid, coronary and femoral arteries in autopsy findings of stroke patients. METHODS AND RESULTS: 40 patients (age: 75.2 (12.3) years, 21 men, 19 women) were investigated, who died of ischemic stroke. Carotid, femoral and coronary arteries were removed and cut into slices. Atherosclerotic changes were scored and compared. The severity of atherosclerotic changes of the common carotid artery did not correlate with any other arteries. Atherosclerotic parameters of the internal carotid artery correlated with those of the deep femoral and common femoral arteries (r=0.457-0.459; P=0.022-0.028 respectively). We found significant correlations between the deep femoral artery and left anterior descendent coronary arteries (r=0.513; P=0.012). External carotid artery correlated with both the left anterior descendent coronary and deep femoral arteries (r=0.458-0.473 and P=0.028-0.017 respectively). CONCLUSIONS: The severity of atherosclerosis in the external carotid arteries and/or the femoral arteries showed a stronger correlation with the atherosclerosis in the coronaries than that of the common carotid arteries.

Serum cholesterols have a more important role than triglycerides in determining intima-media thickness of the common carotid artery in subjects younger than 55 years of age.

OBJECTIVE: The role of serum cholesterol and triglycerides in carotid artery atherosclerosis is controversial. We measured carotid artery intima-media thickness (IMT), a marker of atherosclerosis in subjects younger than 55 years of age with a 6-fold range of serum cholesterol levels (3.93-25.03 mmol/L) and a 200-fold range of triglyceride levels (0.36-75.97 mmol/L). METHODS: Eighty-six patients with increased serum lipid values and 30 subjects with normal lipid values were included. Serum lipids were measured after an overnight fast. High-resolution sonographic investigations of the carotid arteries of all patients were videotaped. Intima-media thickness was measured offline at 1-mm increments in the distal 10-mm segments of both common carotid arteries by a reader blinded to patient characteristics. First, IMT was compared among groups defined by their cholesterol and triglyceride levels with the use of traditional cutoff values. Next, all subjects were pooled, and general regression analysis was performed to identify significant predictors of IMT with age, body mass index, lipid values, sex, diabetes, hypertension, and smoking status as independent variables. RESULTS: Intima-media thickness was larger in patient groups with high cholesterol levels (ie, the hypercholesterolemic and combined hyperlipidemic groups) than in the control, borderline, and isolated hypertriglyceridemic groups (P < .01). In the general multiple regression model, IMT correlated positively with total cholesterol level (beta = 0.343; P = .002) and age (beta = 0.3; P = .006) but not with triglyceride level. CONCLUSIONS: Both the group comparisons and the general regression analysis of the pooled data suggest that hypercholesterolemia has an important role in early onset IMT changes in the common carotid artery, whereas hypertriglyceridemia does not have an appreciable role.