Metabolic syndrome (MetS) is a primary risk factor for cardiovascular disease and is associated with a proinflammatory state. Here, we assessed the contribution of inflammatory and oxidative stress markers towards prediction of MetS. A total of 2316 individuals were recruited in Phase I of the Indian Atherosclerosis Research Study (IARS). Modified ATPIII guidelines were used for classification of subjects with MetS. Among the inflammatory and oxidative stress markers studied, levels of hsCRP (P < .0001), Neopterin (P = .036), and oxLDL (P < .0001) were significantly higher among subjects with MetS. Among the markers we tested, oxLDL stood out as a robust predictor of MetS in the IARS population (OR 4.956 95% CI 2.504–9.810; P < .0001) followed by hsCRP (OR 1.324 95% CI 1.070–1.638; P = .010). In conclusion, oxLDL is a candidate predictor for MetS in the Asian Indian population.
Background. There is an association between chronic kidney disease (CKD) and metabolic syndrome (MetS). We examined the joint association of CKD and MetS with incident cardiovascular (CVD) events in the Multiethnic Study of Atherosclerosis (MESA) cohort. Methods. We analyzed 2,283 Caucasians, 363 Chinese, 1,449 African-Americans, and 1,068 Hispanics in the MESA cohort. CKD was defined by cystatin C estimated glomerular filtration rate ≤ 60 mL/min/1.73 m2 and MetS was defined by NCEP criteria. Cox proportional regression adjusting for age, ethnicity, gender, study site, education, income, smoking, alcohol use, physical activity, and total and LDL cholesterol was performed to assess the joint association of CKD and MetS with incident CVD events. Participants were divided into four groups by presence of CKD and/or MetS and compared to the group without CKD and MetS (CKD−/MetS−). Tests for additive and multiplicative interactions between CKD and MetS and prediction of incident CVD were performed. Results. During follow-up period of 5.5 years, 283 participants developed CVD. Multivariate Cox regression analysis demonstrated that CKD and MetS were independent predictors of CVD (hazard ratio, 2.02 for CKD, and 2.55 for MetS). When participants were compared to the CKD−/MetS− group, adjusted HR for the CKD+/MetS+ group was 5.56 (95% CI 3.72–8.12). There was no multiplicative interaction between CKD and MetS (P = 0.2); however, there was presence of additive interaction. The relative excess risk for additive interaction (RERI) was 2.73, P = 0.2, and the attributable portion (AP) was 0.49 (0.24–0.74). Conclusion. Our findings illustrate that the combination of CKD and MetS is a strong predictor of incident clinical cardiovascular events due to presence of additive interaction between CKD and MetS.
Biomarkers of inflammation and hemostasis have been associated with left ventricular (LV) mass. We studied relationships of C-reactive protein (CRP), interleukin-6 (IL6), D-dimer, soluble intercellular adhesion molecule-1 (sICAM-1), plasminogen activator inhibitor 1 (PAI-1), soluble thrombomodulin (sTM), soluble tumor necrosis factor type 1 receptor (sTNFR1), von Willebrand factor (vWF), soluble E-selectin (sE-selectin), factor VIII, fibrinogen, matrix metalloproteinase 3 (MMP3), and matrix metalloproteinase 9 (MMP9) with LV mass in an asymptomatic population. Multi-Ethnic Study of Atherosclerosis participants underwent magnetic resonance imaging to characterize LV mass; biomarkers were measured using standardized protocols (N = 763 to 4979). Adjusted models were used to associate each biomarker with LV mass while correcting for potential confounding.
LV mass was associated with many biomarkers after adjustment for demographic characteristics and traditional cardiovascular risk factors. Although the demographic and risk factor adjustments attenuated the association of CRP and IL6 with LV mass, further adjustment for weight changed regression coefficients from positive to negative for CRP and IL6 for LV mass. sTM, Factor VIII, and vWF were directly associated with LV mass in fully-adjusted models. For sTNFR1, sICAM-1, D-dimer, fibrinogen, and PAI-1, adjustment for risk factors and weight rendered associations with LV mass nonsignificant.
In this large cohort free of clinical cardiovascular disease, several hemostasis and inflammation markers were associated with LV mass. The unusual finding of a negative relationship of CRP and IL6 with LV mass only after adjustment for weight suggests that the effects of inflammation on LV mass are strongly influenced by obesity.
Left ventricle; biomarker; hemostasis; inflammation
We examined the association of biomarkers of inflammation and endothelial dysfunction with diabetes and metabolic syndrome (MetS) in persons from Inner Mongolia.
A cross-sectional study was conducted among 2,536 people aged 20 years and older from Inner Mongolia, China. Overnight fasting blood samples were obtained to measure plasma concentrations of high sensitivity C-reactive protein (hsCRP), soluble inter-cellular adhesion molecule-1 (sICAM-1), sE-selectin, angiotensin II, high density lipoprotein cholesterol, triglycerides, and blood glucose. Waist circumference and blood pressure were measured by trained staff. MetS was defined according to the modified ATP III definition for Asians. Elevated level of the biomarker was defined as values in the upper tertile of the distribution. Participants were categorized into one of four groups based on the presence or absence of metabolic and glycemic abnormalities: 1) free of prediabetes, diabetes and MetS (reference group), 2) prediabetes or diabetes only, 3) MetS without prediabetes or diabetes, and 4) MetS plus prediabetes or diabetes. The multivariable models are adjusted for age, gender, smoking, drinking, family history of hypertension, and body mass index.
Among study participants, 18.5% had prediabetes, 3.6% had diabetes, and 27.4% of the entire study population had 3 or more components of the MetS. Elevated hsCRP was associated with an increased odds of prediabetes or diabetes only, MetS without prediabetes or diabetes, and MetS plus prediabetes or diabetes with multivariable adjusted odds ratios (95% confidence intervals) of 2.3 (1.7-3.1), 3.0 (2.4-3.8), and 5.8 (4.5-7.5), respectively. Elevated sICAM-1 was associated with increased odds (95% CI) of prediabetes or diabetes only (2.1, 1.6-2.9) and MetS plus prediabetes or diabetes (4.2, 3.2-5.3) but was not associated with MetS alone. Elevated sE-selectin was associated with a modestly increased risk of MetS (OR 1.7, 95% CI 1.4-2.2). Elevated levels of Angiotensin II were not associated with the MetS plus prediabetes or diabetes in this study.
Diabetes and the MetS are common in the Inner Mongolia population. The biomarkers of inflammation and endothelial dysfunction are associated with increased risk for diabetes and MetS in this population. These results are consistent with results from other populations.
metabolic syndrome; diabetes; inflammation; endothelial dysfunction; C-reactive protein; intercellular adhesion molecule-1; E-selectin
Erectile dysfunction (ED), impaired arterial elasticity, elevated resting heart rate as well as increased levels of oxidized LDL and fibrinogen associate with future cardiovascular events. Physical activity is crucial in the prevention of cardiovascular diseases (CVD), while metabolic syndrome (MetS) comprises an increased risk for CVD events. The aim of this study was to assess whether markers of subclinical atherosclerosis are associated with the presence of ED and MetS, and whether physical activity is protective of ED.
57 MetS (51.3 ± 8.0 years) and 48 physically active (PhA) (51.1 ± 8.1 years) subjects participated in the study. ED was assessed by the International Index of Erectile Function (IIEF) questionnaire, arterial elasticity by a radial artery tonometer (HDI/PulseWave™ CR-2000) and circulating oxLDL by a capture ELISA immunoassay. Fibrinogen and lipids were assessed by validated methods. The calculation of mean daily energy expenditure of physical exercise was based on a structured questionnaire.
ED was more often present among MetS compared to PhA subjects, 63.2% and 27.1%, respectively (p < 0.001). Regular physical exercise at the level of > 400 kcal/day was protective of ED (OR 0.12, 95% CI 0.017-0.778, p = 0.027), whereas increased fibrinogen (OR 4.67, 95% CI 1.171-18.627, p = 0.029) and elevated resting heart rate (OR 1.07, 95% CI 1.003-1.138, p = 0.04) were independently associated with the presence of ED. In addition, large arterial elasticity (ml/mmHgx10) was lower among MetS compared to PhA subjects (16.6 ± 4.0 vs. 19.6 ± 4.2, p < 0.001), as well as among ED compared to non-ED subjects (16.7 ± 4.6 vs. 19.0 ± 3.9, p = 0.008). Fibrinogen and resting heart rate were highest and large arterial elasticity lowest among subjects with both MetS and ED.
Markers of subclinical atherosclerosis associated with the presence of ED and were most evident among subjects with both MetS and ED. Thus, especially MetS patients presenting with ED should be considered at high risk for CVD events. Physical activity, on its part, seems to be protective of ED.
Metabolic syndrome (MetS) has been associated with increased prevalence of aortic valve calcium (AVC) and with increased progression of aortic stenosis. The purpose of this study was to determine whether MetS is associated with increased risks for the development of new (“incident”) AVC or for progression of established AVC as assessed by CT.
RESEARCH DESIGN AND METHODS
The relationships of MetS or its components as well as of diabetes to risks for incident AVC or AVC progression were studied among participants with CT scans performed at baseline and at either year 2 or year 3 examinations in the Multi-Ethnic Study of Atherosclerosis (MESA).
Of 5,723 MESA participants meeting criteria for inclusion, 1,674 had MetS by Adult Treatment Panel III criteria, whereas 761 had diabetes. Among the 5,123 participants without baseline AVC, risks for incident AVC, adjusted for time between scans, age, sex, race/ethnicity, LDL cholesterol, lipid-lowering medications, and smoking, were increased significantly for MetS (odds ratio [OR] 1.67 [95% CI 1.21–2.31]) or diabetes (2.06 [1.39–3.06]). In addition, there was an increase in incident AVC risk with increasing number of MetS components. Similar results were found using the International Diabetes Federation MetS criteria. Among the 600 participants (10.5%) with baseline AVC, neither MetS nor diabetes was associated with AVC progression.
In the MESA cohort, MetS was associated with a significant increase in incident (“new”) AVC, raising the possibility that MetS may be a potential therapeutic target to prevent AVC development.
The metabolic syndrome (MetS) is associated with an increased incidence of diabetes and coronary heart disease. Postprandial lipemia is a prominent feature of dyslipidemia in both type 2 diabetes mellitus and MetS and is also associated with coronary heart disease. Oxidative stress and inflammation are pivotal in all stages of atherosclerosis; however, there is a paucity of data on postprandial oxidative stress and inflammation in subjects with MetS. Thus, the primary aim of this study was to compare the postprandial effects of an energy-dense, high-fat, fast-food–style (FFS) meal with an American Heart Association (AHA)–recommended heart-healthy meal on biomarkers of oxidative stress and inflammation in subjects with MetS. A total of 11 subjects with MetS completed the study. Glucose levels were significantly increased 2 hours after both FFS and AHA diets (P <.0001), and high-density lipoprotein cholesterol levels significantly decreased in FFS diet but not in the AHA diet (P for interaction <.05). Total triglyceride levels significantly increased postprandially only in the FFS meal but not in the AHA meal (P for interaction =.03). Plasma thiobarbituric acid reactive substances and malondialdehyde + hydroxynonenal increased significantly with time in both dietary groups, and the postprandial increase was greater in the FFS diet compared to the AHA diet (P <.0005). Serum high-sensitivity C-reactive protein, interleukin 6, and tumor necrosis factor levels did not change with time or dietary treatment. The postprandial increase in interleukin 1b was significantly higher with the FFS meal, thus resulting in significant differences between both treatments (P for interaction = .03). Thus, in subjects with MetS, consumption of an energy-dense, fatty meal (FFS breakfast) results in increased postprandial oxidative stress compared to a heart-healthy meal (AHA).
Current smoking is associated with type 2 diabetes mellitus and impaired glucose tolerance but its association with the metabolic syndrome (metS), particularly with sufficiently sampled African American representation, has not been clearly established.
To assess whether a) metS is associated with smoking; b) any increased risk of metS among smokers is independent of body mass index (BMI) compared with non-smokers; c) smoking status is differentially associated with the metS and its components across different ethnic groups.
Cross sectional analysis of the Multi-Ethnic Study of Atherosclerosis (MESA) a community population-based sample free of cardiovascular disease.
Current smokers (N = 769) had higher risk of metS (odds ratio [OR, 95% confidence interval]: 1.4, 1.1-1.7) versus never (reference, N = 2981) and former smokers (1.0, 0.8-1.1, N = 2163) and for metS components: high waist circumference (WC) (OR:1.9, 1.2-2.1), low high density lipoprotein cholesterol (HDL-C) (1.5, 1.3-1.8), elevated plasma triglycerides (TG) (OR:1.4, 1.2-1.7) as well as high C-reactive protein (CRP, an inflammatory marker) concentration (OR: 1.6,1.3-2.0) compared to never and former smokers after adjustment for BMI. A smoking status by ethnicity interaction occurred such that African American current and former smokers had greater likelihood of low HDL-C than White counterparts.
This study found that smoking is associated with the metS and despite the lower BMI of current smokers the prevalence of low HDL-C, elevated TG and CRP is higher among them than among non-smokers. African Americans generally have higher HDL-C than Whites but smoking wipes out this advantage.
Multi-Ethnic Study of Atherosclerosis (MESA) ClinicalTrials.gov Identifier: NCT00005487
Metabolic syndrome; Smoking; Ethnic groups; Body mass index
Vascular endothelial dysfunction induced by oxidative stress has been demonstrated to be the initiation step of atherosclerosis (AS), and flavonoids may play an important role in AS prevention and therapy. Twenty-three flavonoids categorized into flavones, flavonols, isoflavones, and flavanones, all with 4-oxo-pyronenucleus, were examined for what structural characteristics are required for the inhibitory effects on endothelial dysfunction induced by oxidized low-density lipoprotein (oxLDL). Human vascular endothelial cells EA.hy926 were pretreated with different 4-oxo-flavonoids for 2 hs, and then exposed to oxLDL for another 24 hs. Cell viability and the level of malondialdehyde (MDA), nitric oxide (NO) and soluble intercellular adhesion molecule-1 (sICAM-1) were measured, respectively. Then, correlation analysis and paired comparison were used to analyze the structure–activity relationships. Significant correlations were observed between the number of −OH moieties in total or in B-ring and the inhibitory effectson endothelial dysfunction. Furthermore, 3′,4′-ortho-dihydroxyl on B-ring, 3-hydroxyl on C-ring and 2,3-double bondwere correlated closely to the inhibitory effects of flavonolson cell viability decrease and lipid peroxidation. 5,7-meta-dihydroxyl group on A-ring was crucial for the anti-inflammatory effects of flavones and isoflavones in endothelial cells. Moreover, the substituted position of B-ring on C3 rather than C2 was important for NO release. Additionally, hydroxylation at C6 position significantly attenuated the inhibitory effects of 4-oxo-flavonoids on endothelial dysfunction. Our findings indicated that the effective agents in inhibiting endothelial dysfunction include myricetin, quercetin, luteolin, apigenin, genistein and daidzein. Our work might provide some evidence for AS prevention and a strategy for the design of novel AS preventive agents.
flavonoids; endothelial dysfunction; oxidized low-density lipoprotein; structure-activity analysis; atherosclerosis; reactive oxygen species
Predicting the development of veno-occlusive disease of the liver (VOD) remains challenging. We hypothesized that biomarkers of endothelial injury in myeloablative allogeneic transplant recipients could predict VOD occurrence. We evaluated 4 biomarkers (von Willebrand Factor (vWF), thrombomodulin, E-selectin and soluble intercellular adhesion molecule-1 (sICAM-1) weekly in the peri-transplant period in an attempt to predict VOD. Among patients who received sirolimus, vWF, thrombomodulin and sICAM-1 levels were significantly elevated in VOD patients in comparison with patients without VOD on day −1 (p≤0.035), day+7 (p≤0.0001) and day+14 (p≤0.004). E-selectin was predictive on day+7 (p=0.007). vWF ≥1400 IU/ml and TM ≥ 100 ng/ml levels on day +7 were both 100% sensitive and 100% specific in predicting VOD. These biomarkers were informative when adjusted for other risk factors for VOD in regression analysis. Among non-sirolimus patients, biomarkers of endothelial injury were not informative. We conclude that vWF, thrombomodulin and sICAM-1 elevations before and early after transplantation may be useful in predicting VOD in patients receiving sirolimus.
Recent studies have suggested a relationship of the increased circulating adipokines and inflammatory cytokine, and the risk of metabolic syndrome (MetS). The objective of this study was to identify adiposity-related factors that reflect MetS in order to establish early intervention targets. We performed a cross-sectional study which included 108 MetS subjects and 91 controls. Blood adiponectin, leptin, vascular-, and intercellular adhension molecules (VCAM, ICAM), monocyte chemoattractant protein 1 (MCP1), high-sensitivity C-reactive protein (hsCRP), oxidized LDL (oxLDL), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) were measured. The correlation analysis indicated that the MetS score (sum of the number of MetS risk factors) had an inverse relationship with adiponectin (p < 0.0001), and positive correlations with leptin (p < 0.05), ICAM (p < 0.01), MCP1 (p < 0.05), oxLDL (p < 0.05), TNF-α (p < 0.0001), IL-6 (p < 0.05) and hsCRP (p < 0.01). In multivariate logistic regression analyses, plasma triglyceride (TG) was independently associated with adiponectin, ICAM and TNF-α with the standardized β coefficients of -0.213, 0.197, and 0.193, respectively. Plasma HDL-cholesterol was independently associated with ICAM and hsCRP with the standardized β coefficients of -0.150 and -0.173. Adiponectin, TNF-α, and hsCRP were the most proximate markers reflecting MetS. Among MetS components, TG and HDL-cholesterol concentrations displayed the relationship with inflammatory markers measured in this study.
Metabolic syndrome; Adiposity; Adipokines; Inflammatory cytokines; Abdominal fat
Background: Arsenic exposure is a risk factor for atherosclerosis in adults, but there is little information on arsenic and early risk biomarkers for atherosclerosis in children. Carotid intima-media thickness (cIMT) is an indicator of subclinical atherosclerotic burden that has been associated with plasma asymmetric dimethylarginine (ADMA), a predictor of cardiovascular disease risk.
Objectives: The aim of this study was to investigate associations of arsenic exposure with cIMT, ADMA, and endothelial adhesion molecules [soluble intercellular cell adhesion molecule-1 (sICAM-1); soluble vascular cell adhesion molecule-1 (sVCAM-1)] in children who had been exposed to environmental inorganic arsenic (iAs).
Methods: We conducted a cross-sectional study in 199 children 3–14 years of age who were residents of Zimapan, México. We evaluated cIMT using ultrasonography, and plasma lipid profiles by standard methods. We analyzed ADMA, sICAM-1, and sVCAM-1 by ELISA, and measured the concentrations of total speciated arsenic (tAs) in urine using hydride generation cryotrapping atomic absorption spectrometry.
Results: In the multiple linear regression model for cIMT, tAs categories were positively associated with cIMT increase. The estimated cIMT diameter was greater in 35- to 70-ng/mL and > 70-ng/mL groups (0.035 mm and 0.058 mm per 1-ng/mL increase in urinary tAs, respectively), compared with the < 35-ng/mL group. In addition to tAs level, plasma ADMA was a significant predictor of cIMT. In the adjusted regression model, cIMT, percent iAs, and plasma sVCAM-1 were significant predictors of ADMA levels (e.g., 0.419-μmol/L increase in ADMA per 1-mm increase in cIMT).
Conclusions: Arsenic exposure and plasma ADMA levels were positively associated with cIMT in a population of Mexican children with environmental arsenic exposure through drinking water.
Citation: Osorio-Yáñez C, Ayllon-Vergara JC, Aguilar-Madrid G, Arreola-Mendoza L, Hernández-Castellanos E, Barrera-Hernández A, De Vizcaya-Ruíz A, Del Razo LM. 2013. Carotid intima-media thickness and plasma asymmetric dimethylarginine in Mexican children exposed to inorganic arsenic. Environ Health Perspect 121:1090–1096; http://dx.doi.org/10.1289/ehp.1205994
While metabolic syndrome (MetS) and diabetes confer greater cardiovascular disease (CVD) risk, recent evidence suggests that individuals with these conditions have a wide range of risk. We evaluated whether screening for coronary artery calcium (CAC) and carotid intimal-medial thickness (CIMT) can improve CVD risk stratification over traditional risk factors (RFs) in people with MetS and diabetes.
RESEARCH DESIGN AND METHODS
We assessed CAC and CIMT in 6,603 people aged 45–84 years in the Multi-Ethnic Study of Atherosclerosis (MESA). Cox regression examined the association of CAC and CIMT with coronary heart disease (CHD) and CVD over 6.4 years in MetS and diabetes.
Of the subjects, 1,686 (25%) had MetS but no diabetes and 881 (13%) had diabetes. Annual CHD event rates were 1.0% among MetS and 1.5% for diabetes. Ethnicity and RF-adjusted hazard ratios for CHD for CAC 1–99 to ≥400 vs. 0 in subjects with neither MetS nor diabetes ranged from 2.6 to 9.5; in those with MetS, they ranged from 3.9 to 11.9; and in those with diabetes, they ranged from 2.9 to 6.2 (all P < 0.05 to P < 0.001). Findings were similar for CVD. CAC increased the C-statistic for events (P < 0.001) over RFs and CIMT in each group while CIMT added negligibly to prediction over RFs.
Individuals with MetS or diabetes have low risks for CHD when CAC or CIMT is not increased. Prediction of CHD and CVD events is improved by CAC more than by CIMT. Screening for CAC or CIMT can stratify risk in people with MetS and diabetes and support the latest recommendations regarding CAC screening in those with diabetes.
Early features in the pathogenesis of atherosclerosis include accumulation of oxidized LDL (oxLDL) and endothelial expression of the vascular adhesion molecule VCAM-1. Because antioxidants inhibit endothelial VCAM-1 expression, we tested the hypothesis that oxLDL functions as a prooxidant signal in atherogenesis to augment VCAM-1 activation by inflammatory signals. Cultured human aortic endothelial cells (HAECs) or human umbilical vein endothelial cells (HUVECs) were incubated with unmodified LDL, oxLDL, or glycated LDL for 48 h. No change in VCAM-1, intercellular cell adhesion molecule-1 (ICAM-1), or E-selectin expression from control was observed by ELISA. However, dose-response and time course studies demonstrated that oxLDL enhanced VCAM-1 expression induced by the cytokin tumor necrosis factor alpha (TNF alpha) 63% in HAECs and 45% in HUVECs over unmodified LDL or control. Using flow cytometry analysis, oxLDL augmented TNF alpha-induced VCAM-1 expression in a uniform HAEC population. oxLDL had no effect on E-selection induction. oxLDL augmented TNF alpha-induced ICAM-1 expression 44% in HAECs but not in HUVECs. Glycated LDL augmented TNF alpha-induced VCAM-1 expression 35% in HAECs but not HUVECs. Similar results were obtained with 13-HPODE or lysophosphatidylcholine, significant components of oxLDL. 13-HPODE augmented TNF alpha-induced mRNA accumulation and transcriptional activation of VCAM-1 in HAECs. These results suggest that as long-term regulatory signals, specific oxidized fatty acid and phospholipid components of oxLDL augment the ability of vascular endothelial cells to express cytokine-mediated VCAM-1. These studies link oxidant signals conferred by oxLDL to oxidation-sensitive regulatory mechanisms controlling the expression of endothelial cell adhesion molecules involved in early atherosclerosis.
The metabolic syndrome (MetS) is a precursor of diabetes. Physical activity (PA) improves endothelial dysfunction and may benefit patients with MetS. Aims. To evaluate the effect of a physical activity (PA) program on markers of endothelial dysfunction and oxidative stress in adolescents with (MetS). Methods. We carried out a cohort study of 38 adolescents with and without MetS (18 females and 20 males). All participants completed a 3-month PA program. All variables of the MetS as well as markers of endothelial dysfunction and oxidative stress tests were evaluated. Results. Females with and without MetS showed significant differences for almost all components of the MetS, whereas males were significantly different in half of the components. After the PA program, components of the MetS were not different from baseline values except for HDL-C levels. Some baseline endothelial dysfunction markers were significantly different among adolescents with and without MetS; however, after the PA program, most of these markers significantly improved in subjects with and without MetS. Conclusion. PA improves the markers of endothelial dysfunction in adolescents with MetS although other changes in the components of the MetS were not observed. Perhaps the benefits of PA on all components of MetS would appear after a PA program with a longer duration.
Defined as estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2, chronic kidney disease (CKD) is strongly and independently associated with cardiovascular and overall mortality. We hypothesized that reduced kidney function would be characterized by abnormalities of hemostasis.
We tested cross-sectional associations between (eGFR) and multiple hemostatic markers among 6751 participants representing a broad spectrum of kidney function in the Multi-Ethnic Study of Atherosclerosis (MESA). Kidney function was measured using cystatin C (eGFRcys) or creatinine, using CKD Epidemiology Collaboration (eGFRcr). Hemostatic markers included soluble thrombomodulin (sTM), soluble tissue factor (sTF), D-Dimer, von Willebrand factor (vWF), factor VIII, plasmin-antiplasmin complex (PAP), tissue factor pathway inhibitor (TFPI), plasminogen activator inhibitor-1 (PAI-1), and fibrinogen. Associations were tested using multivariable linear regression with adjustment for demographics and comorbidities.
In comparison to persons with eGFRcys >90 ml/min/1.73 m2, subjects with eGFRcys < 60 ml/min/1.73 m2 had adjusted levels of sTM, sTF, D-Dimer, PAP, Factor VIII, TFPI, vWF and fibrinogen that were respectively 86%, 68%, 44%, 22%, 17%, 15%, 12% and 6% higher. Subjects with eGFRcys 60-90 ml/min/1.73 m2 had adjusted levels that were respectively 16%, 14%, 12%, 6%, 6%, 6%, 11% and 4% higher (p < 0.05 for all). Percent differences were not significantly different when groups were categorized by eGFRcr.
Throughout a broad spectrum of kidney function, lower eGFR was associated with higher levels of hemostatic markers. Dysregulation of hemostasis may be a mechanism by which reduced kidney function promotes higher cardiovascular risk.
Although metabolic syndrome (MetS) is associated with increased cardiovascular mortality and the development of atherosclerosis, consensus is still lacking on the status of cardiovascular function and geometry in MetS patients. We investigated the relation between MetS and left ventricle (LV) geometry and function, carotid intima-media thickness (IMT) and arterial stiffness in a community-based cohort of 702 adult subjects. Subjects were categorized into three groups according to the number of MetS components present, as defined by the Adult Treatment Panel III guidelines: 1) Absent (0 criteria), 2) Pre-MetS (1-2 criteria) or 3) MetS (≥3 criteria). In female subjects, LV mass, LV mass/height2.7, deceleration time, and aortic pulse wave velocity increased, and E/A ration decreased in a stepwise manner across the three groups. These changes were not observed in male subjects. The mean carotid IMT was higher in the MetS group than in the other two groups. The degree of MetS clustering is found to be strongly correlated with geometric eccentricity of LV hypertrophy, diastolic dysfunction and arterial changes irrespective of age and blood pressure status, particularly in females. Waist circumference is found to have the most powerful effect on cardiovascular parameters.
Metabolic Syndrome; Heart Ventricles; Geometry; Intima-media Thickness; Pulse Wave Velocity
OBJECTIVE: To describe the association between intima-media thickness (IMT) and metabolic syndrome (MetS) and to examine if the addition of IMT to a traditional MetS definition adds value to the assessment of predicted cardiovascular disease (CVD) risk in a large multiethnic population.
PARTICIPANTS AND METHODS: In this cross-sectional study, carotid IMT was measured in 2268 men and women as part of a wellness physical examination between August 1, 2000, and October 1, 2001. The wellness examination included a fasting lipid panel, physical examination, and medical history. Mean IMT was described by sex, ethnicity, and the MetS. Predicted risk for CVD was determined with IMT as a component of the diagnostic criteria for MetS.
RESULTS: Intima-media thickness increased with each additional component of the MetS, increasing from 0.516 mm for 0 components to 0.688 mm for 4 or more components (P<.001). In each ethnic group (non-Hispanic whites, blacks, Hispanics, and Asians), those with the MetS had higher mean IMT (increased by 0.084 mm to 0.134 mm) than those without MetS. The addition of IMT as a “new” component in the diagnosis of MetS allowed us to identify 78 (3.4%) participants who were not previously diagnosed as having MetS but who had a high 10-year estimated risk of MetS as measured by the Framingham risk score (11.67%).
CONCLUSION: The addition of IMT to the traditional criteria for the diagnosis of the MetS may help identify individuals who otherwise would not have been identified to be at high risk of CVD.
This article describes the association between intima-media thickness and metabolic syndrome and concludes that the addition of intima-media thickness to the traditional criteria for the diagnosis of the metabolic syndrome may help identify individuals who otherwise would not have been identified to be at high risk of cardiovascular disease.
Common carotid artery inter-adventitial diameter (IAD) and intima-media thickness (IMT) are measurable by ultrasound. IAD may be associated with left ventricular mass (LV mass) while IMT is a marker of subclinical atherosclerosis. It is not clear if IAD is associated with LV mass after accounting for IMT and traditional cardiovascular risk factors.
IAD and IMT were measured on participants of the Multi-Ethnic Study of Atherosclerosis (MESA) IMT progression study. A total of 5641 of the originally enrolled 6814 MESA participants were studied. LV mass was measured by magnetic resonance imaging. Multivariable linear regression was used with IAD as the outcome and adjustment for risk factors, as well as IMT and LV mass.
Traditional cardiovascular risk factors, height, weight and ethnicity were significantly associated with IAD. After adjustment for risk factors, a one mm difference in IMT was associated with a 1.802 mm (95% CI: 1.553, 2.051) higher mean IAD. A one gm difference in LV mass was associated with a 0.006 mm (95% CI: 0.005, 0.007) higher mean IAD. LV mass was independently associated with IAD after adjusting for cardiovascular risk factors and IMT. These associations were slightly different for men and women.
Inter-adventitial diameters are associated with left ventricular mass after adjusting for cardiovascular risk factors and IMT. IAD might serve as a surrogate for left ventricular mass and have predictive value for cardiovascular outcomes.
carotid arteries; ultrasonics; hypertrophy; magnetic resonance imaging; remodeling; risk factors; left ventricle
Aortic distensibility (AD) is a marker of the elastic properties of the aorta. Reduction of AD occurs early in subjects with type 2 diabetes mellitus (T2DM) and it is associated with subclinical generalized atherosclerosis. Metabolic syndrome (MetS) is common in subjects with T2DM and predicts cardiovascular morbidity and mortality. This study examined the potential relationship between MetS and AD in a cohort of subjects with T2DM.
Methods and results
A total of 210 subjects with T2DM were studied. MetS was diagnosed using the NCEP/ATP-III criteria. AD was assessed non-invasively by ultrasonography. The prevalence of MetS was 64.8%. AD was not significantly different between subjects with and without MetS (1.80 ± 0.54 vs. 1.84 ± 0.53 10-6 dyn-1 cm2, p = 0.55). Univariate linear regression analysis showed that AD was associated positively with male sex (p = 0.02) as well as glomerular filtration rate (p < 0.001), and negatively with age (p = 0.04), history of hypertension (p = 0.001), as well as duration of diabetes (p < 0.001). After multivariate adjustment, AD was associated independently and significantly only with age (p = 0.02), duration of diabetes p < 0.001), and history of hypertension (p = 0.004); no significant relationship was found with MetS status, the sum of the components of the MetS or the individual components-besides hypertension-of the MetS.
In subjects with T2DM, MetS status per se is not associated with reduction of AD. In addition, it was shown that besides ageing, duration of glycemia was a strong predictor of AD. From the components of the MetS only hypertension was associated with reduction of the elastic properties of the aorta.
Oxidized low-density lipoprotein (LDL) may act as an atheroprotective (anti-atherosclerotic) agent under some conditions. While the α1-antitrypsin (AT)-LDL complex is considered a type of oxidized LDL, its clinical relevance remains unknown. The aim of the present study was to investigate the association between AT-LDL and anti-atherosclerotic variables such as HDL-cholesterol and adiponectin in subjects with and without metabolic syndrome (MetS).
In asymptomatic females (n = 194; mean age, 54 years) who were divided into non-MetS (n = 108) and MetS groups (n = 86), the fasting levels of serum AT-LDL, adiponectin and glucose/lipid panels were measured, in addition to body mass index (BMI) and blood pressure.
The MetS group showed significantly higher BMI, blood pressure, glucose and triglyceride levels as well as significantly lower levels of HDL-cholesterol and adiponectin than the non-MetS group. A multivariate-adjusted analysis revealed that in the non-MetS group, AT-LDL was significantly, independently and positively correlated with adiponectin (β = 0.297, P < 0.05), along with HDL-cholesterol (β = 0.217, P < 0.05). In the MetS group, AT-LDL was significantly, independently and positively correlated with LDL-cholesterol only (β = 0.342, P < 0.05).
These data suggest that AT-LDL may exert anti-atherosclerotic effects in female subjects without MetS. More studies are required to clarify the clinical roles of AT-LDL in relation to the pathophysiology of MetS.
This study was aimed at assessing oxidative stress in LDL from obese patients with metabolic syndrome (MetS) compared with LDL from type 2 diabetic patients or control volunteers, and determining their effects on platelets.
The profiles of lipids, fatty acids and fatty acid oxidation products were determined in LDL isolated from plasma of MetS patients, type 2 diabetic patients and volunteers (n=10 per group). The effects of LDL isolated from these participants on platelet arachidonic acid signaling cascade and aggregation were investigated.
Compared with LDL from control volunteers, LDL from obese MetS and type 2 diabetic patients contained lower cholesteryl esters, higher triacylglycerols and lower ethanolamine plasmalogens levels. Proportions of linoleic acid were decreased in phosphatidylcholine and cholesteryl esters in patients’ LDL. Among the markers of lipid peroxidation, oxidation products of linoleic acid (hydroxy-octadecadienoic acids) and malondialdehyde were increased by 59% and 2-fold, respectively in LDL from MetS patients and to the same extent in LDL from type 2 diabetic patients. LDL from MetS patients were as potent as LDL from type 2 diabetic patients in activating platelet arachidonic acid signaling cascade through increased phosphorylation of p38 MAPK and cytosolic phospholipase A2, and increased thromboxane B2 formation. LDL from patients with MetS and type 2 diabetes potentiated 3-fold and 3.5-fold respectively platelet aggregation whereas control LDL had no activating effects on platelets.
MetS in obese patients, without or with diabetes, is associated with increased oxidative stress in LDL, which trigger platelet activation.
The protocol is registered in ClinicalTrials.gov as NCT00932087.
Adult; Aged; Arachidonic Acid; metabolism; Biological Markers; blood; Blood Platelets; enzymology; metabolism; Diabetes Mellitus, Type 2; blood; complications; metabolism; Humans; Lipid Peroxidation; Lipids; blood; Lipoproteins, LDL; blood; chemistry; metabolism; Male; Metabolic Syndrome X; complications; Middle Aged; Obesity; blood; complications; metabolism; Oxidative Stress; Phospholipases A2, Secretory; blood; metabolism; Platelet Activation; Signal Transduction; Lipid peroxidation; Fatty acids; LDL; Oxidized LDL; Platelets; Metabolic syndrome; Type 2 diabetes; Obesity
Rosiglitazone may be useful for the treatment of antiretroviral therapy-associated lipoatrophy, but an association with cardiovascular disease (CVD) has been questioned in diabetics. We evaluated rosiglitazone's effect on surrogate markers of CVD in HIV-infected individuals with lipoatrophy. HIV+ patients with lipoatrophy on thymidine-sparing regimens were randomized to rosiglitazone vs. placebo for 48 weeks. We serially assessed carotid IMT, fasting metabolic profiles, tumor necrosis factor (TNF)-α, soluble receptors (sTNFRI and II), interleukin (IL)-6, high-sensitivity C-reactive protein (hsCRP), myeloperoxidase (MPO), and endothelial activation markers [von Willebrand factor (vWF), soluble intercellular cell adhesion molecules-1 (sICAM-1), and vascular cell adhesion molecules-1 (sVCAM-1)]. Seventy-one subjects enrolled: 17% were female and 51%were white. Baseline characteristics were similar between groups except for higher total cholesterol in the placebo group (p = 0.04). At 48 weeks, common carotid artery (CCA) IMT changed significantly (p ≤ 0.05) within but not between the groups (p = 0.36): the median (IQR) increase was 0.10 (0.05, 0.25) mm and 0.15 (0, 0.25) mm in the rosiglitazone and placebo groups, respectively. hsCRP, sTNFRI and II, sVCAM-1, and vWF changed significantly (p ≤ 0.02) within but not between groups. Total cholesterol increased significantly in the rosiglitazone group (p = 0.008). In our study of virologically controlled subjects with lipoatrophy, rosiglitazone did not independently increase carotid IMT, endothelial activation, and inflammatory cytokines.
Recent studies have confirmed inflammatory factors and metabolic syndrome (MetS) as important cardiovascular disease (CVD) risk factors. Recently measurement of carotid intima-media thickness (IMT) has been used for evaluation of early atherosclerosis. This study was designed to assess the correlation between IMT with some inflammatory biomarkers, ghrelin and adiponectin in people with and without MetS in a cohort sample in Isfahan province.
Among participants of Isfahan Cohort Study (ICS) by random sampling, 88 participants were selected and divided into case (with MetS) and control (without MetS) groups. A questionnaire including demographic data and CVD risk factors was completed for all of the participants. Physical examination and blood pressure, height, weight and waist circumference measurements were done for all subjects. Vascular echocardiography was done for evaluation of IMT of each carotid artery of both sides. Interlukin-6 (IL-6), interlukin-10 (IL-10), highly sensitive C-reactive protein (hs-CRP), ghrelin and adiponectin levels were measured using ELIZA method. Data were entered in SPSS15 software and analyzed by t-test, chi square, Pearson correlation and linear regression analyze.
The mean waist circumference, BMI, systolic blood pressure, diastolic blood pressure, hs-CRP and IMT of left carotid artery were significantly higher in participants with Mets. There was significant correlation between left carotid IMT and IL-6 level in all patients (P = 0.03). After adjustment for age and sex, significant relationship in groups with MetS was only reported between the left IMT and IL-6 (P = 0.02). There was no relation between IMT and other inflammatory markers in subjects with and without MetS.
Significant correlation between IL-6 and IMT was reported in patients with MetS. While no significant correlation between IL-10, adiponectin and ghrelin with IMT was observed in metabolic syndrome group.
Intima-media thickness (IMT); Carotid artery; hs-CRP; Ghrelin; Adiponectin IL-6; IL-10
The metabolic syndrome (MetS) is associated with increased risk of cardiovascular disease. In this study, we examine if metabolic syndrome predicts progression of atherosclerosis over 13 years.
Participants were 1442 men and 1532 women in the population-based Tromsø Study who underwent carotid ultrasound examinations at baseline in the 4th (1994–5) and at follow-up in the 6th survey (2007–8). Of these, 278 men and 273 women fulfilled the criteria for the MetS, defined according to a modified version of the National Cholesterol Education Program Adult Treatment Panel III (NCEP, ATPIII). Carotid atherosclerosis was assessed as total plaque area (TPA) and mean intima-media thickness (IMT) at follow-up and as change in IMT and TPA from baseline to follow-up. Associations between MetS and its components and carotid atherosclerosis were assessed in linear regression models adjusted for age, total cholesterol and daily smoking, stratified by sex.
IMT and TPA levels at follow-up (p < 0.0001) and progression of TPA (p = 0.02) were higher in the MetS group compared to the non-MetS group. In stepwise multivariable models, MetS was associated with TPA (β = 0.372 mm2, p = 0.009) and IMT (β = 0.051 mm, p < 0.0001) in men, and with IMT (β = 0.045 mm, p = 0.001) in women after 13 years of follow-up, but not with progression of IMT or TPA. In analyses stratified by age, MetS predicted progression of IMT (β = 0.043 mm, p = 0.046) and TPA (β = 1.02 mm2, p = 0.002) in men below 50 years of age. Hypertension was predictive of follow-up TPA and IMT in both genders and of progression of TPA in women. Impaired glucose tolerance was associated with follow up levels of IMT and TPA as well as progression in IMT in men. None of the other components of MetS were associated with progression of atherosclerosis.
Subjects with MetS had higher levels of IMT and TPA at follow up than those without MetS. Mets predicted progression of IMT and TPA in those below 50 years of age, but not in other age groups, indicating that MetS may be involved in the initiation of the atherosclerotic process.
Metabolic syndrome; Carotid artery; Atherosclerosis; Intima-media thickness; Plaque; Progression; Risk factor; Prospective; Population study