Oxidized low-density lipoprotein in plasma is a prognostic marker of subclinical atherosclerosis development in clinically healthy men

OBJECTIVE: To investigate the association between plasma oxidized low-density lipoprotein (OxLDL) and the progress of clinically silent atherosclerosis, as measured by ultrasound in the carotid arteries. DESIGN: Prospective, observational study with more than 3 years of follow-up. SETTING: One-centre study at university hospital. MATERIAL AND METHODS: The subjects (n = 326) were obtained by stratified sampling from a population sample of men who were 58 years old at baseline. Carotid artery intima-media thickness (IMT) was measured bilaterally by high-resolution B-mode ultrasound at baseline and after follow-up. Plasma OxLDL cholesterol concentrations and conventional cardiovascular risk factors were measured at study entry. Automated measurements of IMT were performed. Plaque occurrence and size were assessed (plaque status). Plasma OxLDL at entry was measured by a specific monoclonal antibody, mAb-4E6. RESULTS: OxLDL at entry, but not LDL cholesterol, was associated with the number and size of plaques at follow-up (P = 0.008), also after adjustment for plaque status at entry (P = 0.033). The plasma OxLDL concentration at entry was associated with change in carotid artery IMT (r = 0.17; P = 0.002) and in a stepwise multiple regression analysis this association remained after adjustment for other cardiovascular risk factors (P = 0.005). CONCLUSIONS: These results provide new information, supporting the concept that circulating OxLDL was associated with the silent phase of atherosclerosis progression in clinically healthy men independently of conventional risk factors.     

Evaluation of coronary calcium score by multidetector computed tomography in relation to endothelial function and inflammatory markers in asymptomatic individuals.

BACKGROUND: Coronary calcification has been correlated with the presence and extent of coronary artery disease (CAD), so in the present study the associations between coronary artery calcification score (CACS) and endothelial dysfunction, as well as the important inflammatory markers C-reactive protein (CRP), interleukin (IL)-6, and oxidized low-density lipoprotein (OxLDL), were studied in asymptomatic individuals at intermediate risk for CAD. METHODS AND RESULTS: The study group comprised 177 subjects (103 males) aged 50.6+/-5.9 years. CACS was measured by multidetector computed tomography using the Agatston method. Endothelium-dependent flow-mediated dilatation (FMD) and endothelium-independent nitroglycerin-mediated dilatation (NMD) were measured by high-resolution external brachial ultrasound. Coronary artery calcification (CAC) was detected in 82 subjects (52 males), and the median CACS was 143 [31-311.25] units. After adjusting for gender and body mass index, log (CACS +1) correlated positively with age (r=0.401, p<0.001) and IL-6 levels (r=0.442, p<0.001), and negatively with FMD (r=-0.511, p<0.001). The correlations of log (CACS +1) with CRP and OxLDL levels, and with NMD, were non-significant. In a multivariate-adjusted logistic regression model, age (odds ratio (OR) =1.083 [1.014-1.156]), serum IL-6 level (OR=3.837 [2.166-6.798]) and FMD (OR=0.851 [0.793-0.913]) were significantly and independently associated with CAC. CONCLUSIONS: Peripheral endothelial function inversely correlated with CACS, whereas IL-6 level was associated with CACS. Testing for endothelial function and IL-6 level may improve cardiovascular risk assessment and help target the therapeutic strategies in asymptomatic patients at intermediate CAD risk.     

Plasma fibronectin level and its association with coronary artery disease and carotid intima-media thickness

BACKGROUND: The exact relation of fibronectin with coronary atherosclerosis is unknown. The aim of the present study was to examine the association of fibronectin level with presence and extent of coronary artery disease (CAD) and intima-media thickness (IMT) of common carotid artery (CCA). DESIGN: The IMTs of CCA of 86 patients who underwent coronary angiography were measured; traditional vascular risk factors were also evaluated in these patients. Fibronectin, lipids, C-reactive protein (CRP) and fibrinogen levels were determined. RESULTS: Plasma fibronectin levels of the patients with CAD were found to be significantly elevated compared to patients with normal vessels (0.46+/-0.11 and 0.36+/-0.12 mg/dl respectively, P = 0.001). Fibronectin levels were not associated with extent of CAD. No significant association was observed between fibronectin level and traditional risk factors. IMTs of right and left CCA in patients with CAD were found to be elevated compared to patients with normal vessels (0.89+/-0.1 mm compared with 0.76+/-0.1 mm, P = 0.001 and 0.93+/-0.2 mm compared with 0.71+/-0.1 mm, respectively P < 0.001). Fibronectin levels were positively correlated with CRP (r = 0.45, P < 0.001), low-density lipoprotein-cholesterol (r = 0.23, P = 0.03) and total cholesterol (r = 0.21, P = 0.04) levels and negatively correlated with high-density lipoprotein-cholesterol (HDL-C) levels (r = -0.24, P = 0.02). IMT of left CCA was positively correlated with CRP levels (r = 0.23, P = 0.04) and negatively correlated with HDL-C levels (r = 0.2, P = 0.04). Logistic regression analysis showed that age (P < 0.01) and fibronectin levels (P = 0.01) were independent predictors for the existence of CAD. CONCLUSIONS: The results suggest that fibronectin levels may be a significant predictor of CAD. However, it was shown that fibronectin levels were not associated with extent of CAD and IMT of CCA.     

Lower plasma adiponectin is a marker of increased intima-media thickness associated with type 2 diabetes mellitus and with male gender

OBJECTIVE: We tested the extent to which altered plasma adipokine levels may contribute to the increased carotid artery intima-media thickness (IMT) associated with type 2 diabetes mellitus and with male gender, independently of conventional cardiovascular risk factors, insulin resistance, and plasma C-reactive protein (CRP). DESIGN: IMT (mean of three segments of both carotid arteries by ultrasonography), insulin resistance (homeostasis model assessment; HOMA(ir)), plasma CRP, lipids, adiponectin, leptin, resistin, and tumor necrosis factor-alpha (TNF-alpha) were measured in 84 type 2 diabetic patients and 85 control subjects. RESULTS: In diabetic patients, IMT (P<0.001), mean arterial pressure (P<0.001), HOMA(ir) (P<0.001), plasma CRP (P=0.003), triglycerides (P=0.037), leptin (P=0.023), resistin (P=0.003), and TNF-alpha (P=0.003) levels were higher, whereas high-density lipoproteins (HDL) cholesterol (P<0.001) and adiponectin (P<0.001) levels were lower compared with control subjects. Plasma adiponectin (P<0.001) and leptin (P<0.001) were substantially lower in men than in women. IMT was positively and independently associated with age (P<0.001), diabetes (P=0.049), and male gender (P=0.002) in a multivariate regression model, not including other variables. Further analyses showed that IMT was positively related to age (P<0.001) and plasma triglycerides (P=0.038) and negatively to adiponectin (P<0.001), without independent effects of diabetes, gender, and HOMA(ir). CONCLUSIONS: Increased IMT in type 2 diabetes may in part be explained by lower plasma adiponectin and higher triglycerides, but not by leptin, resistin, and TNF-alpha. The gender effect on IMT is related to lower plasma adiponectin.     

慢性肾脏病患者晚期氧化蛋白产物血症及其与动脉粥样硬化的关系

目的　观察慢性肾脏病(CKD)患者循环中晚期氧化蛋白产物(AOPP)水平,并探讨其与动脉粥样硬化的关系。方法　断面队列研究。选109例CKD患者和71例健康对照者,用高分辨B超测颈动脉内膜中层厚度(IMT)、切面内膜中层面积及粥样斑块。测血清AOPP、丙二醛、谷胱苷肽过氧化物酶活性(GSHPx)和C 反应蛋白水平。结果　CKD患者血清AOPP水平明显高于健康对照者(P<0 01), 62例透析者血清AOPP水平明显高于47例未透析者(P<0 01);未透析者血清AOPP水平与内生肌酐清除率呈负相关(r=-0 292, P<0 05)。38例有颈动脉粥样斑块者血清AOPP水平明显高于71例无颈动脉粥样斑块者(P<0 01)。单因素相关分析和多因素逐步回归分析均显示,血清AOPP水平与颈动脉IMT、切面内膜中层面积呈正相关(r=0 332,r=0 288,P值均小于0 05;β=0 313,P<0 001;β=0 301,P<0 01)。CKD患者血清AOPP水平与丙二醛、C 反应蛋白呈正相关(r=0 300,P=0 01;r=0 255,P<0 05 ),与血清GSHPx呈负相关(r=-0 647,P<0 01 )。结论CKD患者普遍存在高AOPP血症,血清AOPP水平随肾功能减退而增高,并与CKD患者动脉粥样硬化密切相关。     

Kalzifizierte Plaques der extrakraniellen hirnversorgenden Gefäße im Vergleich mit traditionellen Risikofaktoren als Prädiktor für relevante Koronararterienstenosen

BACKGROUND: Intima-media thickness (IMT) of carotid arteries, measured by vascular ultrasound, has widely been used as a surrogate marker for coronary atherosclerosis. As recent studies showed significant but only weak correlation between IMT and coronary artery stenoses, this study evaluated calcified plaques in the extracranial carotid arteries as a reasonable marker for coronary artery disease. PATIENTS AND METHOD: 139 patients underwent cardiac catheterization with selective coronary angiography and ultrasound examination (B-mode, standard Doppler, color Doppler) of the carotid arteries. In case of calcified plaques number and distribution among the extracranial cerebral arteries were determined (Figure 1). Coronary angiograms were analyzed for disease severity and extent (number of main vessels with > 50% stenosis). Besides the traditional vascular risk factors hypertension, diabetes, smoking and hypercholesterolemia as well as body mass index, age and sex were analyzed. RESULTS: Calcified plaques of carotid arteries were significantly correlated (r = 0.502, p < 0.001) with coronary artery stenoses as well as hypercholesterolemia (r = 0.410, p < 0.001), increasing age (r = 0.406, p < 0.001) and diabetes (r = 0.290, p < 0.001) in contrast to hypertension (r = 0.125, p = 0.075), smoking status (r = -0.043, p = 0.311), body mass index (r = -0.122, p = 0.083) and male sex (r = -0.103, p = 0.114) (Table 1). The number of calcified plaques was significantly correlated (r = 0.568, p < 0.001) with severity and extent of coronary artery disease, too (Figure 2). For two and more calcified plaques sensitivity concerning coronary artery stenoses was 80%, specificity 75%, positive predictive value 83%, negative predictive value 73% (Table 2). Multiple stepwise regression analysis was performed for all eight variables (calcified plaques, hypercholestrolemia, diabetes, hypertension, smoking status, age, sex, body mass index). Including calcified plaques the predictive value of all factors was higher (r = 0.644 to r = 0.607). CONCLUSIONS: Determination of calcified carotid plaques by ultrasound is useful to improve the predictive value of risk factor-based multivariate models based on traditional risk factors.     

强化治疗对2型糖尿病患者动脉内中膜厚度及其危险因素的影响

目的 评估强化控制血糖、血压、血脂对于新诊断2型糖尿病患者的颈、股动脉内中膜厚度(IMT)、血清晚期糖基化终末产物(AGE)及其可溶性受体(sRAGE)水平的影响.方法跟踪随访132例新诊断2型糖尿病患者5年,分3组:强化血糖、血压控制组(20例),强化血糖、血压、血脂控制组(80例),常规治疗组(32例).记录颈、股动脉IMT及其他相关指标水平变化情况,测定实验终点各组血清AGE和sRAGE水平.结果长期强化治疗较常规治疗,可明显减少颈、股动脉IMT增厚,同时可有效抑制血清中AGE的蓄积(P=0.009).经多元回归分析提示AGE为股动脉IMT的独立危险因素.sRAGE与研究终点HbA1C水平的比值,与5年间HbA1C的均数及波动情况呈负相关(P＜0.05).结论长期强化治疗较常规治疗可明显减少2型糖尿病患者颈、股动脉IMT增厚,同时可减少AGE在其体内的累积.

Abstract：

Objective To analyze the changes of the intima-media thickness(IMT)of carotid and femoral arteries, serum advanced glycosylation end-products(AGEs),and AGEs soluble receptor(sRAGE)after intensively controlling blood glucose, blood pressure, and lipid. Methods One hundred and thirty-two type 2 diabetic patients were divided into 3 groups and followed for 5 years: 20 patients were treated with intensive control of blood glucose and blood pressure, 80 patients with intensive control of blood glucose, blood pressure, and lipid; and 32 patients with conventional therapy. AGEs, sRAGE, and IMT of carotid and femoral arteries were measured and compared among different groups. Results The IMT of carotid and femoral arteries and serum level of AGEs were significantly decreased after intensive treatment. The ratio of sRAGE and HbA1C(sRAGE/HbA1C)were negatively correlated with the mean of HbA1Cin the past five years(r=-0.417, P＜0.001)and the fluctuation of HbA1C(r=-0.309,P＜0.001). Multinomial regression analysis showed that AGEs were the important risk factors of IMT of femoral artery(β=0.152,P=0.068). Conclusion Intensive treatment is significant in controlling the growing IMT of carotid and femoral arteries, while decreasing serum level of AGEs.     

Anticardiolipin antibody titre and plasma homocysteine level independently predict intima media thickness of carotid arteries in subjects with idiopathic antiphospholipid antibodies

This study evaluated whether IgG anticardiolipin antibody (aCL) titre and traditional risk factors for atherosclerosis bore any relationship to the intima media thickness (IMT) of carotid arteries of patients with idiopathic antiphospholipid antibodies (aPL). IMT was assessed by high-resolution sonography at the common carotid, carotid bifurcation and internal carotid in 42 (13 male, 29 female, mean age 31+/-10 years) aPL subjects, 29 with primary thrombotic antiphospholipid syndrome and 13 with persistence of aPL in the absence of any underlying disorder. In the same subjects the following were measured: plasma fibrinogen (FNG), von Willebrand factor (vWF), plasminogen activator inhibitor (PAI), homocysteine (HC), total cholesterol (CHO), triglycerides (TG), high density and low density lipoprotein (HDL and LDL), platelet numbers and aCL of IgG and IgM isotype. IMT of the internal carotid was greater in males than females (0.48+/-0.03 vs 0.39+/-0.01 mm, P=0.02). IMT of the carotid bifurcation was greater in thrombotic than nonthrombotic subjects (0.50+/-0.02 vs 0.42+/-0.02 mm, P=0.04). By simple regression, IMT of the common carotids correlated with age (P< 0.0001) IgG aCL titre (P=0.001), FNG (P=0.006), LDL (0.01), CHO (0.02) and PAI (P=0.02). IMT of the carotid bifurcation correlated with age (P=0.002), IgG aCL titre (P=0.0002), FNG (P=0.0001), HC (P=0.009), CHO (P=0.02), vWF (P=0.01) and number of thrombotic events (P=0.03). IMT of the internal carotids correlated with age (P=0.002), IgG aCL titre (P=0.0001), FNG (P=0.0008), PAI (P=0.002) and HC (P=0.01). By stepwise multiple regression analysis, IgG aCL titre independently predicted IMT at all carotid segments examined (P always <0.005). In addition, plasma FNG and HC also resulted independent predictors of IMT at the carotid bifurcation (P=0.001 and P<0.0001, respectively) and internal carotid (P=0.03 and P<0.0001, respectively). These data strongly support an atherogenic role for IgG aCL in patients with aPL. Measurement of plasma HC and FNG may help define aPL subjects at higher vascular risk who may require lowering of HC and FNG by vitamin and/or pharmacologic intervention.     

The influence of wave reflection on left ventricular hypertrophy in hypertensive patients is modified by age and gender

It has been established that a positive association exists between the augmentation index (AIx) and left ventricular mass (LVM) in hypertensives, but it remains unclear whether this association is affected by age or gender. The aim of the study was to assess the effect of age and gender on the association between carotid AIx and LVM in hypertensive patients. We performed arterial tonometry and echocardiography in 512 treated hypertensive patients who were divided into 4 groups by gender and age (older or younger than 65 years). Correlations between carotid AIx and echocardiographic indices were evaluated by univariable and multivariable models. In females, carotid AIx increased with age up to 60 years, but decreased thereafter. In univariable analyses, carotid AIx was positively correlated with the LVM index in younger females (r=0.25, p=0.04) and males (r=0.48, p<0.001), but not in the older age groups. Multivariable analyses showed that this positive correlation in younger males remained significant (beta=0.39, p<0.001) after adjusting for age, body mass index, and mean arterial pressure. In contrast, in the older subjects, carotid AIx was negatively correlated with relative wall thickness in females (beta= -0.14, p=0.034) and males (beta= -0.17, p=0.037) independent of age and mean arterial pressure. A significant association between carotid AIx and LVM index was seen only in younger males. The lack of any such association in older hypertensives can be explained by both the plateau in the values of carotid AIx, and the fact that LVM increased with age.     

Microcirculatory damage of common carotid artery wall in obese and non obese subjects

The objective of the present study was to determine whether the intima-media thickness (IMT) is independently related with obesity, and central fat accumulation in healthy subjects. Common carotid artery IMT, parameters of body fat accumulation and distribution (body mass index, waist circumference, waist-to-hip ratio), blood pressure levels, and circulating fasting insulin, glucose, and lipid (cholesterol, HDL-cholesterol, triglycerides, LDL-cholesterol) levels were determined in a population of non-diabetic normal weight and obese subjects. Smoking habits (packs-years) were also taken into account. 239 healthy subjects (143 women and 96 men), with age ranging between 18 and 45 years, were enrolled into the study. They were divided indo two groups according to the body mass index (BMI), obese (132 subjects, 77 woman and 55 men, with BMI greater than 27.0) and controls (107 subjects: 66 women and 41 men, with BMI lower than 27.0). Common carotid artery intima-media thickness was measured by B-mode ultrasound imaging. Fasting plasma metabolic parameters (glucose and lipids) and insulin levels were determined by enzymatic and radioimmunological assays, respectively. Insulin sensitivity was estimated by insulin tolerance test (ITT) and the rate constant for plasma glucose disappearance (KITT) during the 3- to 15-min period following the regular insulin injection was taken as a measure of in vivo insulin action. Obese patients showed higher IMT than controls, and IMT was significantly associated with BMI in the whole population (r = 0.316, p < 0.001). Age (r = 0.327, p < 0.001), KITT (r = -0.201, p < 0.01), fasting blood glucose (r = 0.187, p < 0.01), LDL-chol (r = 0.201, p < 0.01), smoking (r = 0.147, p < 0.05), MBP levels (r = 0.154, p < 0.05), cholesterol (r = 0.152, p < 0.05) and HDL-chol (r = -0.159, p < 0.05) were also significantly associated with IMT. Age (r = 0.330, p < 0.05), BMI (r = 0.299, p < 0.01), waist (r = 0.312, p < 0.001), WHR (r = 0.266, p < 0.001) and KITT (r = -0.259, p < 0.01) were the parameters most strongly correlated with IMT in women, and age (r = 0.324, p < 0.001), BMI (r = 0.338, p < 0.001) waist (r = 0.325, p < 0.001) and LDL-chol (r = 0.283, p < 0.01) where the parameters most strongly correlated with IMT in men. When a stepwise multiple regression analysis was performed for the whole population, only age (p < 0.001) and BMI (p < 0.001) maintained a significant positive relationship with IMT. When a stepwise multiple regression analysis was performed separately for men and women, BMI or waist circumference or WHR were alternatively entered into the model; interestingly, only age, BMI and waist were still significantly correlated with IMT, whereas WHR did not maintain a significant correlation with IMT. In conclusion, BMI and waist circumference, but not WHR, are strongly and independently associated with the IMT of common carotid artery. These results suggests that central fat accumulation may accelerate the development of earlier clinically silent stages of atherosclerosis, thus possibly explaining the higher prevalence of cardiovascular diseases in patients with abdominal obesity.     

Is high-sensitivity C-reactive protein associated with carotid atherosclerosis in healthy Koreans?

BACKGROUND: There is a positive association between chronic inflammation and the risk of cardiovascular disease, but whether there is an association between C-reactive protein (CRP) and carotid atherosclerosis is controversial. We investigated the relationship between high-sensitivity CRP (hsCRP) levels and carotid intima-media thickness (IMT) in healthy Koreans. DESIGN: We measured hsCRP levels, the carotid IMT, and conventional cardiovascular risk factors including obesity parameters, blood pressure, lipid profiles, insulin resistance, and smoking habits in 820 volunteers (35-79 years old) in a cross-sectional study. RESULTS: Higher hsCRP quartile groups had higher mean IMTs, as compared with the lowest quartile (P < 0.001 for the trend across quartiles). However, after adjustment for age, the relationship between hsCRP level and IMT was substantially weaker (P = 0.018). After additional adjustments for conventional cardiovascular risk factors, no significant association was observed (P = 0.548). The unadjusted risk for a high carotid IMT value (> or = 1.0 mm) was also positively related to hsCRP quartile, but this relationship was not significant after adjustment for age and other cardiovascular risk factors. CONCLUSIONS: Both hsCRP levels and the carotid IMT were strongly correlated with conventional cardiovascular risk factors, but there was no independent association between hsCRP levels and carotid IMT in healthy Korean adults.     

Relative influence of insulin resistance versus blood pressure on vascular changes in longstanding hypertension. ICARUS, a LIFE sub study. Insulin Carotids US Scandinavia

BACKGROUND: Insulin resistance is associated with hypertension. The relative influences of hyperinsulinaemia and high blood pressure on vascular hypertrophy and carotid distensibility is unclear in patients with longstanding hypertension. METHODS: In 88 unmedicated patients with stage II-III hypertension and left ventricular hypertrophy on electrocardiogram we measured blood pressure, minimal forearm vascular resistance (MFVR) using plethysmography, intima-media thickness (IMT) and the wall distensibility of the common carotid arteries using ultrasound, and insulin sensitivity using a 2-h isoglycaemic hyperinsulinaemic clamp. RESULTS: IMT was positively correlated to systolic blood pressure (r= 0.26, P < 0.05), whole body glucose uptake index (M/IG; r= 0.22, P< 0.05), age (r= 0.24, P< 0.05) and negatively correlated to body mass index (r= -0.24, P < 0.05); IMT did not correlate to fasting serum insulin (r= -0.14, NS). In men (n = 64) MFVR was positively correlated to systolic blood pressure (r = 0.30, P < 0.05), but was unrelated to M/G and serum insulin. The distensibility of the common carotid arteries was negatively correlated to systolic blood pressure (r = -0.40, P< 0.001) and in untreated patients (n = 22) positively correlated to M/IG (r = 0.47, P < 0.05). CONCLUSIONS: High systolic blood pressure was related to vascular hypertrophy, whereas hyperinsulinaemia and insulin resistance were not, suggesting that longstanding high blood pressure is a far more important determinant for structural vascular changes than insulin resistance at this stage of the hypertensive disease. However, hyperinsulinaemia and insulin resistance were associated with low distensibility of the common carotid arteries in the subgroup of never treated hypertensive patients.     

Association between carotid atherosclerosis and markers of inflammation in rheumatoid arthritis patients and healthy subjects

OBJECTIVE: To examine the relationship between markers of systemic inflammation and carotid atherosclerosis in patients with rheumatoid arthritis (RA) and healthy controls. METHODS: Carotid artery intima-media thickness (IMT) and carotid plaque were measured using high-resolution B-mode ultrasound in 204 patients with RA, ages 40-85, and 102 age- and sex-matched healthy persons. No subject in either group had ever smoked cigarettes. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were used to measure systemic inflammation. The relationship of the carotid artery IMT and carotid plaque to inflammation markers was examined, adjusting for age, sex, RA versus control status, and the cardiovascular (CV) risk factors hypercholesterolemia, systolic blood pressure, diabetes mellitus, and body mass index (BMI). RESULTS: A significant linear trend for increased carotid artery IMT was associated with increasing ESR and CRP categories (r = 0.16, P = 0.004 for ESR, and r = 0.13, P = 0.02 for CRP). These trends did not differ among RA cases and controls, and were independent of age, sex, and CV risk factors. The difference in carotid artery IMT between the lowest and highest categories of ESR was 0.221 mm (95% confidence interval [95% CI] 0.767-1.020, P = 0.02). The difference between extreme CRP categories was 0.275 mm (95% CI 0.039-0.509, P = 0.02). Both remained significant after CV risk factor adjustment. Carotid plaque displayed a similar relationship to markers of inflammation. CONCLUSION: Increased carotid artery IMT and the presence of carotid plaque are associated with markers of systemic inflammation in patients with RA and in healthy subjects. This observation is consistent with hypotheses that assign a role to systemic inflammation in atherosclerosis, and may have implications regarding RA and other chronic inflammatory diseases.     

Inflammation and arterial stiffness in systemic vasculitis: a model of vascular inflammation

OBJECTIVE: Arterial stiffness, an independent determinant of cardiovascular risk, is regulated by both structural and functional factors, including endothelium-derived nitric oxide. Endothelial dysfunction is associated with acute and chronic systemic inflammation. However, the role of systemic inflammation in arterial stiffening has not been determined. The aim of this study was to investigate the relationship between inflammation and arterial stiffness in patients with antineutrophil cytoplasmic antibody-associated systemic vasculitis (AASV) as a model of systemic inflammation. METHODS: Thirty-one patients with AASV (15 with active disease) and 32 age-matched controls were studied. Pulse wave velocity (PWV) and the augmentation index (AIx) were assessed noninvasively and related to serum levels of C-reactive protein (CRP), interleukin-6, and tumor necrosis factor alpha. RESULTS: In subjects with active disease, the AIx, PWV, and level of CRP were elevated compared with that in controls (mean +/- SEM 31 +/- 3% versus 22 +/- 2% [P = 0.003], 9.2 +/- 0.7 versus 7.5 +/- 0.3 meters/second [P = 0.03], and 16.0 +/- 4.0 versus 1.1 +/- 0.1 mg/liter [P < 0.001], respectively). However, PWV and the AIx were not significantly different between patients with disease in remission and controls (8.0 +/- 0.5 versus 7.5 +/- 0.3 meters/second and 19 +/- 3% versus 22 +/- 2%, respectively). The CRP level was positively correlated with both PWV and the AIx. Multiple regression analysis indicated that age, mean arterial pressure (MAP), and CRP were independently related to PWV, and that age, MAP, CRP, sex, and heart rate were associated with the AIx. CONCLUSION: These data indicate that AASV is associated with increased arterial stiffness, and that stiffness correlates with the degree of active inflammation.     

同型半胱氨酸对雌激素受体α基因甲基化调控及其与原发性高血压相关性分析

目的观察原发性高血压(EH)患者雌激素受体α(ER-α)基因启动子区域甲基化状态,分析其与血浆同型半胱氨酸(Hcy)水平和颈动脉内膜中层厚度(CIMT)的相关性。方法选择EH患者70例为EH组,其中高血压1级24例、高血压2级23例、高血压3级23例。选同期健康体检者50例为对照组。用直接化学发光法检测血浆Hcy水平,Hcy正常47例(Hcy<15μmol/L)和高同型半胱氨酸血症(HHcy,Hcy≥15μmol/L)23例。用巢式甲基化特异性PCR法检测ER-α基因启动子区甲基化状态,颈部血管超声测CIMT。用Spearman秩相关分析。结果EH组ER-α基因启动子区甲基化比例显著高于对照组(52.9%vs 30.0%,P=0.013),且高血压1级、高血压2级和高血压3级患者ER-α基因启动子区甲基化比例比较,差异有统计学意义(29.2%vs 52.2%vs 78.3%,P=0.003)。EH组血浆Hcy水平明显高于对照组[(13.34±4.22)μmol/L vs (10.34±3.10)μmol/L,P=0.000]。EH组中合并HHcy患者ER-α基因启动子区甲基化比例明显高于Hcy正常者(100.0%vs 29.8%,P=0.00)。EH组ER-α基因启动子区甲基化水平与血浆Hcy水平和CIMT呈正相关(r=0.722,r=0.718,P=0.00)。结论EH患者ER-α基因启动子区呈异常高甲基化,且其甲基化水平与血浆Hcy水平和CIMT具有显著的相关性。     

Detection of early atherosclerosis using the ultrasound parameter of the intima-media thickness of the common carotid artery in families with familial combined hyperlipidemia.

AIM: The aim of the present study was to quantify intima-media thickness (IMT) of the common carotid artery (CCA) in clinically asymptomatic members of familial combined hyperlipidemia (FCHL) families and to evaluate its association with lipids, apoproteins, blood pressure, surrogate markers of insulin resistance, fibrinogen and hs-CRP. METHODS: The group under study consisted of 82 individuals from 29 FCHL families (47 hyperlipidemic [HL] and 35 normolipidemic [NL]). They were compared with the age and sex adjusted control groups of healthy subjects (HL-c, n=20 and NL-c, n=20). IMT was measured by ultrasound at a far wall of both common carotid arteries. RESULTS: Hyperlipidemic subjects had increased IMT compared with healthy controls (0.695+/-0.118 vs 0.599+/-0.074 mm), with an age and sex corrected difference of 86 mm (p<0.001). No difference in IMT was recorded in NL FCHL members in comparison with their healthy controls. In HL subjects, significantly positive univariate correlations were observed between IMT and age, total cholesterol, LDL-cholesterol, non-HDL-cholesterol, apolipoprotein B, SBP, DBP, BMI, waist, fasting glycemia, C-peptide and proinsulin, whereas in NL subjects IMT correlated only with age. Multivariate regression analysis in FCHL subjects (HL+NL) revealed that age (p<0.001), sex (p<0.001), non-HDL-cholesterol (p<0.01) and BMI (p<0.05) were significant and independent predictors of IMT. CONCLUSIONS: The increase of IMT CCA in hyperlipidemic still clinically asymptomatic FCHL subjects corresponds to acceleration of the clinically 'silent' atherosclerosis by about 8-14 years and is in agreement with their increased risk of atherosclerosis.     

C-reactive protein is related to arterial wave reflection and stiffness in asymptomatic subjects from the community

BACKGROUND: Emerging data suggest that C-reactive protein (CRP), a marker of inflammation, is associated with functional properties of arteries. We investigated the relationship of CRP to measures of arterial wave reflection and stiffness (aortic augmentation index [AIX], carotid-femoral pulse wave velocity [PWV], and pulse pressure) in asymptomatic individuals from the community. METHODS: Subjects (n = 214) had a mean age of 59 years and 53% were men. CRP was measured by a high-sensitivity assay and values were log-transformed to reduce skewness. Radial artery waveforms were obtained by applanation tonometry, a validated transfer function was used to derive an ascending aortic pressure waveform, and AIX calculated. PWV was calculated from electrocardiogram-gated waveforms of the right carotid and right femoral artery obtained by applanation tonometry. RESULTS: Log CRP was correlated with AIX (r = 0.24, P = .0005), PWV (r = 0.25, P = .0002), and pulse pressure (r = 0.29, P < or = .0001). In separate backward elimination multiple regression analyses, log CRP was significantly associated with AIX (P = .038) and pulse pressure (P = .036), and marginally significantly associated with PWV (P = .054), after adjustment for heart rate, height, and coronary heart disease (CHD) risk factors (age, sex, body mass index, mean arterial pressure, total cholesterol, HDL cholesterol, diabetes, hypertension, and history of smoking). CONCLUSIONS: These results suggest that CRP, a marker of systemic inflammation, is related to measures of arterial wave reflection and stiffness in asymptomatic subjects from the community. Further studies are needed to understand the mechanisms underlying this association and the implications for assessment and management of CHD risk.     

Interrelationship between noninvasive predictors of atherosclerosis: transthoracic coronary flow reserve, flow-mediated dilation, carotid intima-media thickness, aortic stiffness, aortic distensibility, elastic modulus, and brachial artery diameter

BACKGROUND: In this study, we searched for a correlation between transthoracic coronary flow reserve (CFR) and well-established surrogates of coronary atherosclerosis. METHODS: The study was conducted on 136 healthy subjects (mean age: 39.9 +/- 7.3 years) who were free of coronary risk factors. Transthoracic echocardiography was used to measure the aortic stiffness index (AoSI), aortic distensibility (AoD), and aortic elastic modulus (AoEM). High-resolution ultrasound was used to measure brachial artery endothelium-dependent and independent vasomotion and carotid intima-media thickness (IMT). In addition, transthoracic second harmonic Doppler echocardiography was used to measure CFR. RESULTS: All of the parameters significantly correlated with each other except brachial endothelium-independent dilation. CFR correlated significantly with brachial endothelium-dependent dilation (EDD) (r = 0.302, P < 0.01), carotid IMT (r =-0.388, P < 0.01), brachial artery diameter (r = 0.340, P < 0.01), AoD (r = 0.275, P < 0.01), AoS (r =-0.299, P < 0.01), and AoEM (r =-0.30,7 P < 0.01). Carotid IMT correlated significantly with brachial EDD and modestly with brachial artery diameter, AoD, AoS, and AoEM.In multivariate analysis, carotid IMT (beta=-0.323, P < 0.0001) and brachial artery diameter (beta = -0.259, P = 0.001) were significant independent predictors of CFR. The left ventricular mass index (beta= 0.371, P < 0.0001), brachial EDD (beta = -0.232, P = 0.002), and CFR (beta = -0.228, P = 0.003) were significant predictors for IMT. CONCLUSION: Transthoracic CFR correlated significantly with well-established noninvasive predictors of atherosclerosis, and we suggest that it can be used as a surrogate for coronary atherosclerosis.     

The relationship between inflammation and arterial stiffness in patients with essential hypertension

BACKGROUND: Data about the correlation between augmentation index (AIx), timing of the reflected waveform (T(r)) and inflammatory markers in patients with essential hypertension are not yet well established. The aim of this study was to compare plasma high-sensitivity C-reactive protein (hsCRP), white blood cell count and fibrinogen in hypertensive patients and in normotensive controls and to assess the relationship between inflammatory markers and arterial stiffness. METHODS: Forty-two healthy middle-aged patients with untreated stage I-II essential hypertension and 42 sex- and age-matched controls were recruited in the study. Pulse wave analysis was used to assess AIx and T(r). RESULTS: Plasma hsCRP, white blood cell count, AIx and T(r) were significantly higher in the patients with essential hypertension. In multiple regression analysis, AIx correlated positively with age, female gender, mean arterial pressure and log(hsCRP), and negatively with heart rate and height (R(2)=0.75, p<0.001). T(r) correlated negatively with log(hsCRP) (r=-0.34, p=0.002) for the whole study group. However, after adjusting for mean arterial pressure, age, height, heart rate and sex to the regression model, no correlation was revealed between log(hsCRP) and T(r) (p=0.35) as the dependent variable (R(2)=0.48, p<0.001). CONCLUSIONS: Untreated hypertensive patients with low or moderate total cardiovascular risk had significantly increased blood hsCRP and white blood cell count and arterial stiffness, expressed as AIx and T(r). AIx correlated independently with hsCRP in multiple regression analysis. Measurement of arterial stiffness and inflammation can be suggested as an additional tool to assess cardiovascular risk in hypertensive patients with low or moderate total cardiovascular risk as estimated by traditional risk factors.     

Carotid atherosclerosis is associated with brain atrophy in Japanese elders

BACKGROUND: The relation between atherosclerosis and brain atrophy remains unclear in patients with risk factors for cardiovascular diseases. OBJECTIVE: This study was performed to clarify the relation between brain atrophy and carotid atherosclerosis. METHODS: A total of 142 patients (78 women and 64 men, mean age 74 years) with no neurologic disturbances were studied. Brain atrophy was evaluated on the basis of the brain atrophy index (BAI, BAI = brain parenchyma/intracranial space A 100%), calculated by means of digitized computed tomographic scans obtained at the level of the basal ganglia. Carotid atherosclerosis was evaluated on the basis of the plaque score (PS), defined as the sum of all plaque heights in both carotid arteries, intima-media thickness (IMT), and vessel diameter (VD) of the common carotid artery as assessed by ultrasonography. RESULTS: Age negatively correlated with BAI in both men (r = -0.587, p < 0.001) and women (r = -0.724, p < 0.001). PS of the carotid artery also negatively correlated with BAI in men (r = -0.502, p < 0.001) as well as women (r = -0.480, p < 0.001). VD and IMT of the right carotid artery negatively correlated with BAI in women (VD; -0.256, p < 0.05, IMT; -0.216, p < 0.05) but not in men. Other characteristics were unrelated to BAI. Multiple regression analysis showed that age and PS were independent predictors of brain atrophy in both sexes. The percentage of variance of BAI values explained by this model in women (51.9%) was much greater than that in men (35.5%). CONCLUSION: Carotid atherosclerosis may be a useful morphological index of brain atrophy.