Soluble intercellular adhesion molecule-1 (sICAM-1) is associated with endothelial dysfunction and clinical cardiovascular disease. We investigated the relationship of subclinical atherosclerosis with sICAM-1 concentration.
sICAM-1 concentration was assayed at year 15 of the Coronary Artery Risk Development in Young Adults (CARDIA) Study (black and white men and women, average age 40 years). We assessed progression of coronary artery calcification through year 20 (CAC, n=2378), and both carotid artery stenosis (n=2432) and intima media thickness at year 20 (IMT, n = 2240).
Median sICAM-1 was 145.9 ng/ml. Among a subgroup with advanced atherosclerotic plaque (either CAC or stenosis), IMT was 0.010 (95% confidence interval (CI) 0.003–0.017 mm) higher per standard deviation of sICAM-1 (44 ng/ml) in a model adjusted for age, race, sex, clinic, smoking, exercise, body size, education, blood pressure, antihypertensive medication, plasma lipids, and cholesterol lowering medication. With the same adjustment, the odds ratios (OR) for the presence of year 20 carotid artery stenosis per SD of sICAM-1 was 1.12 (CI 1.01–1.25, p<0.04), while for occurrence of CAC progression the OR was 1.16 (CI 1.04–1.31, p<0.01). The associations with CAC and carotid stenosis were strongest in the top 20th of the sICAM-1 distribution.
sICAM-1 concentration may be an early biomarker that indicates changes in the artery wall that accompany atherosclerosis, as well as the presence of advanced plaque in the coronary and carotid arteries. This finding holds in people with low total burden of atherosclerosis, decades prior to the development of clinical CVD.
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.
To evaluate associations between total serum γ-glutamyltransferase activity (GGT) and biomarkers of arteriosclerosis in the Multi-Ethnic Study of Atherosclerosis (MESA), including 6,783 participants from four ethnic subgroups, i.e., White, Chinese, Black and Hispanic.
Associations between fasting total serum GGT activity and oxidized low-density lipoproteins (oxLDL), interleukin-6 (IL-6), C-reactive protein (CRP), and soluble intercellular adhesion molecule-1 (sICAM-1) were assessed. Following evaluation of linear trends between GGT and biomarkers of interest, multivariable linear regression models were serially adjusted for age, gender, site, ethnicity (M1); M1+lifestyle variables (M2); M2+traditional cardiovascular risk factors plus medications (M3); and M3+metabolic status (M4). Interactions were evaluated between GGT and age and ethnicity in all models.
Linear trends were positive and significant between GGT and oxLDL, IL-6, CRP and sICAM-1 in crude models, and trends remained significant in all ethnic subgroups for CRP (p<0.0001) and sICAM-1 (p<0.001), and for IL-6 except in the Chinese. Trends between GGT and oxLDL were significant in the entire cohort and the White subgroup (p<0.0001), but not in other ethnic subgroups. Multivariable models demonstrated continuous strong, positive associations between GGT and CRP, IL-6 and sICAM-1. Associations between GGT and oxLDL were attenuated upon adjustment for LDL-C and other traditional risk factors. All models were attenuated with adjustment for metabolic status. No age interactions were evident.
Our findings support the hypothesis that total serum GGT activity represents the impact of metabolic disease on vascular injury and atherosclerosis.
GGT; oxidative stress; oxidized LDL; sICAM; CRP; endothelial dysfunction
Polymorphisms within the ICAM1 structural gene have been shown to influence circulating levels of soluble intercellular adhesion molecule -1 (sICAM-1) but their relation to atherosclerosis has not been clearly established. We sought to determine whether ICAM1 SNPs are associated with circulating sICAM-1 concentration, coronary artery calcium (CAC), and common and internal carotid intima medial thickness (IMT).
Methods and Results
3,550 black and white Coronary Artery Risk Development in Young Adults (CARDIA) Study subjects who participated in the year 15 and/or 20 examinations and were part of the Young Adult Longitudinal Study of Antioxidants (YALTA) ancillary study were included in this analysis. In whites, rs5498 was significantly associated with sICAM-1 (p < 0.001) and each G-allele of rs5498 was associated with 5% higher sICAM-1 concentration. In blacks, each C-allele of rs5490 was associated with 6 % higher sICAM-1 level; this SNP was in strong linkage disequilibrium with rs5491, a functional variant. Subclinical measurements of atherosclerosis in either year 15 or year 20 were not significantly related to ICAM1 SNPs.
In CARDIA, ICAM1 DNA segment variants were associated with sICAM-1 protein level including the novel finding that levels differ by the functional variant rs5491. However, ICAM1 SNPs were not strongly related to either IMT or CAC. Our findings in CARDIA suggest that ICAM1 variants are not major early contributors to subclinical atherosclerosis.
cell adhesion molecules; atherosclerosis; coronary calcium; genetics; inflammation
Tissue factor pathway inhibitor (TFPI) is an endothelial membrane-associated anticoagulant protein. Higher circulating levels might reflect endothelial damage.
We hypothesized an association of higher total TFPI with subclinical atherosclerosis.
Total TFPI was measured in 1000 participants of the Multi-Ethnic Study of Atherosclerosis, a cohort of 6814 men and women without clinical vascular disease, aged 45–84, from 4 ethnic groups. Subclinical atherosclerosis measures were coronary artery calcium (CAC), carotid intima-media thickness (IMT) and ankle-brachial index (ABI).
TFPI was higher with age, male gender, higher LDL-cholesterol, smoking and diabetes, but not ethnicity. Adjusting for risk factors, TFPI in the 4th versus 1st quartile was associated with a 1.2-fold increased risk of detectable CAC (95% CI 1.0–1.4), a 2.1-fold increased risk of CAC >400 Agatston units (95% CI 1.1–4.0) and a 1.6-fold (95% CI 1.1–2.5) increased risk of internal carotid IMT above the 80th percentile, but not with external carotid IMT or low ABI. Findings were consistent across ethnic groups.
In this diverse population, higher total TFPI was associated with prevalent CAC (limited to levels >400 units), and elevated internal carotid IMT, independent of other factors. Higher TFPI may indicate endothelial dysfunction. Further study is needed of TFPI and progression of atherosclerosis.
atherosclerosis; coronary heart disease; tissue factor pathway inhibitor; risk factor
The purpose of the study was to examine and compare the incidence and progression of coronary artery calcium (CAC) among persons with metabolic syndrome (MetS) and diabetes mellitus (DM), compared to those with neither condition.
MetS and DM are associated with subclinical atherosclerosis as evidenced by coronary artery calcium (CAC).
The Multiethnic Study of Atherosclerosis included 6,814 African-American, Asian, Caucasian, and Hispanic adults aged 45–84 free of cardiovascular disease at baseline. 5,662 subjects (51% female, mean age 61.0 ± 10.3 years) received baseline and follow-up (mean 2.4 years) cardiac CT scans. We compared the incidence of CAC in 2,927 subjects without CAC at baseline and progression of CAC in 2,735 subjects with CAC at baseline in those with MetS without DM (25.2%), DM without MetS (3.5%), or both DM and MetS (9.0%), compared to neither MetS nor DM (58%). Progression of CAC was also examined in relation to coronary heart disease events over an additional 4.9 years.
Relative to those with neither MetS nor DM, adjusted relative risks (95% confidence intervals) for incident CAC were 1.7 (1.4–2.0), 1.9 (1.4–2.4), and 1.8 (1.4–2.2) (all p<0.01) and absolute differences in mean progression (volume score) were 7.8 (4.0–11.6; p<0.01), 11.6 (2.7–20.5; p<0.05), and 22.6 (17.2–27.9; p<0.01) for those with MetS without DM, DM without MetS, and both DM and MetS, respectively. Similar findings were seen in analysis using Agatston calcium score. In addition, progression predicted CHD events in those with MetS without DM (adjusted hazard ratio 4.1, 95% CI=2.0–8.5, p<0.01) and DM (4.9 [1.3–18.4], p<0.05) among those in highest tertile of CAC increase vs. no increase).
Individuals with MetS and DM have a greater incidence and absolute progression of CAC compared to individuals without these conditions, with progression also predicting CHD events in those with MetS and DM.
atherosclerosis; diabetes; risk factors; calcification
Data accumulated from mouse studies and in vitro studies of human arteries support the notion that soluble intercellular adhesion molecule-1 (sICAM-1) and monocyte chemoattractant protein-1 (MCP-1) play important roles in the inflammation process involved in atherosclerosis. However, at the population level, the utility of sICAM-1 and MCP-1 as biomarkers for subclinical atherosclerosis is less clear. In the follow-up exam of the NHLBI Family Heart Study, we evaluated whether plasma levels of sICAM-1 and MCP-1 were associated with coronary artery calcification (CAC), a measure of the burden of coronary atherosclerosis.
CAC was measured using the Agatston score with multidetector computed tomography. Information on CAC and MCP-1 was obtained in 2246 whites and 470 African Americans (mean age 55 years) without a history of coronary heart disease (CHD). Information on sICAM-1 was obtained for white participants only.
In whites, after adjustment for age and gender, the odds ratios (ORs) of CAC (CAC > 0) associated with the second, third, fourth, and fifth quintiles of sICAM-1 compared to the first quintile were 1.22 (95% confidence interval [CI]: 0.91–1.63), 1.15 (0.84–1.58), 1.49 (1.09–2.05), and 1.72 (1.26–2.36) (p = 0.0005 for trend test), respectively. The corresponding ORs for the second to fifth quintiles of MCP-1 were 1.26 (0.92–1.73), 0.99 (0.73–1.34), 1.42 (1.03–1.96), and 2.00 (1.43–2.79) (p < 0.0001 for trend test), respectively. In multivariable analysis that additionally adjusted for other CHD risk factors, the association of CAC with sICAM-1 and MCP-1 was attenuated and no longer statistically significant. In African Americans, the age and gender-adjusted ORs of CAC associated with the second and third tertiles of MCP-1 compared to the first tertile were 1.16 (0.64–2.08) and 1.25 (0.70–2.23) (p = 0.44 for trend test), respectively. This result did not change materially after additional adjustment for other CHD risk factors. Test of race interaction showed that the magnitude of association between MCP-1 and CAC did not differ significantly between African Americans and whites. Similar results were obtained when CAC ≥ 10 was analyzed as an outcome for both MCP-1 and sICAM-1.
This study suggests that sICAM-1 and MCP-1 are biomarkers of coronary atherosclerotic burden and their association with CAC was mainly driven by established CHD risk factors.
Carotid and coronary atherosclerosis are associated to each other in imaging and autopsy studies. We evaluated whether carotid artery plaque seen on carotid ultrasound can predict incident coronary artery calcification (CAC).
Materials and Methods
We repeated Agatston calcium score measurements in 5445 participants of the Multi-Ethnic Study of Atherosclerosis (MESA) (mean age 57.9 years; 62.9% female). Internal carotid artery lesions were graded as 0%, 1-24%, >25% diameter narrowing and intima-media thickness (IMT) was measured. Plaque was present for any stenosis > 0%. CAC progression was evaluated with multivariable relative risk regression in cases with CAC = 0 at baseline and with multivariable linear regression for CAC > 0 adjusting for cardiovascular risk factors, body mass index, ethnicity, and common carotid IMT.
CAC was positive at baseline in 2708/5445 (49.7%) participants and became positive in 458/2837 (16.1%) at mean interval of 2.4 years between repeat examinations. Plaque and ICA IMT were both strongly associated with presence of CAC. After statistical adjustment, presence of carotid artery plaque significantly predicted incident CAC with a relative risk(RR) of 1.37 (95% Confidence Intervals: 1.12, 1.67). Incident CAC was associated with ICA IMT with an RR of 1.13 (95% Confidence Intervals: 1.03, 1.25) for each mm increase. Progression of CAC was also significantly associated (p < 0.001) with plaque and ICA IMT.
In individuals free of cardiovascular disease, subjective and quantitative measures of carotid artery plaques by ultrasound imaging are associated with CAC incidence and progression.
Circulating adiponectin has been associated with both clinical and subclinical cardiovascular disease (CVD). Variants of the adiponectin gene (ADIPOQ) are associated with clinical CVD, but little is known about associations with subclinical CVD. We studied the association of 11 ADIPOQ SNPs with common and internal carotid intima media thickness (cIMT), presence of coronary artery calcification (CAC), and CAC scores (in those with CAC) in 2847 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Participants were Caucasian (n=712), African-American (n=712), Chinese (n=718), and Hispanic (n=705). All models were adjusted for age, sex, and field site, and stratified by race/ethnic group. African-Americans with genotypes AG/GG of rs2241767 had 36% greater (95% CI (16%, 59%), p=0.0001) CAC prevalence; they also had a larger common cIMT (p=0.0043). Also in African-Americans, genotypes AG/AA of rs1063537 were associated with a 35% (95% CI (14%, 59%), p=0.0005) greater CAC prevalence. Hispanics with the AA genotype of rs11711353 had a 37% (95% CI (14%, 66%), p=0.0011), greater CAC prevalence compared to those with the GG genotype. Additional adjustment for ancestry in African-American and Hispanic participants did not change the results. No single SNP was associated with subclinical CVD phenotypes in Chinese or Caucasian participants. There appears to be an association between ADIPOQ SNPs and subclinical CVD in African-American and Hispanics. Replication as well as assessment of other ADIPOQ SNPs appears warranted.
Metabolic syndrome (MetS) is associated with incident myocardial infarction and stroke and is linked with subclinical inflammation. However, prospective data pertaining to MetS and future peripheral artery disease (PAD) are sparse with few studies examining the role of inflammation. We therefore evaluated the relationship between MetS, inflammation, and incident PAD.
Methods and Results
We conducted a prospective cohort study among 27,111 women free of baseline cardiovascular disease participating in the Women’s Health Study. Subjects were followed for incident symptomatic PAD (n=114; median cohort follow-up=13.3 years). We used Cox proportional hazards models to compare PAD risk among women with and without MetS. We also evaluated relationships between MetS and subclinical inflammation as measured by high sensitivity C-reactive protein (hsCRP) and soluble intercellular adhesion molecule-1 (sICAM-1) and adjusted for these biomarkers in multivariable models. Women with MetS had a 62% increased risk of future PAD (HR 1.62; 95% CI 1.10–2.38). After multivariable adjustment, MetS remained significantly associated with PAD (adj HR 1.48; 95% CI 1.01–2.18) with a 21% risk increase per additional MetS-defining trait (adj HR 1.21; 95% CI 1.06–1.39). Median levels of hsCRP were 4.0 versus 1.5 mg/L (p<0.0001) and 374 versus 333 ng/mL for sICAM-1(p<0.0001) in women with and without MetS, respectively. When hsCRP and sICAM-1 were added to multivariable models, risk associated with the MetS was substantially attenuated and no longer significant (HR 1.14, 95% CI 0.75–1.73).
MetS is associated with an increased risk of future symptomatic PAD in women. This risk appears largely mediated by the effects of inflammation and endothelial activation.
Peripheral artery disease; metabolic syndrome; inflammation; endothelial dysfunction; women
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.
Coronary artery calcium (CAC) and carotid intima-media thickness (IMT) are noninvasive measures of atherosclerosis that consensus panels have recommended as possible additions to risk factor assessment for predicting the probability of cardiovascular disease (CVD) occurrence.
To assess whether maximum carotid IMT or CAC (Agatston Score) is the better predictor of incident CVD.
Design, Setting, Patients
Prospective cohort study of 45–84 year-olds initially free of CVD (n = 6,698) in four ethnic groups, with standardized carotid IMT and CAC measures at baseline, in six field centers of the Multi-Ethnic Study of Atherosclerosis (MESA).
Main Outcome Measure(s)
Incident CVD events (coronary heart disease, stroke, and fatal CVD) over a maximum of 5.3 years of follow-up.
There were 222 CVD events during follow-up. CAC was associated more strongly than carotid IMT with risk of incident CVD. After adjustment for each other and traditional CVD risk factors, the hazard of CVD increased 2.1-fold (95% CI 1.8–2.5) for each standard deviation greater level of log-transformed CAC, versus 1.3-fold (95% CI 1.1–1.4) for each standard deviation greater maximum IMT. For coronary heart disease, the hazard ratios per standard deviation increment were 2.5-fold (95% CI 2.1–3.1) for CAC and 1.2-fold (95% CI 1.0–1.4) for IMT. An ROC analysis also suggested that CAC predicted incident CVD better than IMT did.
Although whether and how to clinically use bio-imaging tests of subclinical atherosclerosis remains a topic of debate, this study found that CAC predicts subsequent CVD events better than does carotid IMT.
Adaptive immunity has been implicated in atherosclerosis in animal models and small clinical studies. Whether chronic immune activation is associated with atherosclerosis in otherwise healthy individuals remains underexplored. We hypothesized that activation of adaptive immune responses, as reflected by higher proportions of circulating CD4+ memory cells and lower proportions of naive cells, would be associated with subclinical atherosclerosis.
Methods and Findings
We examined cross-sectional relationships of circulating CD4+ naive and memory T cells with biomarkers of inflammation, serologies, and subclinical atherosclerosis in 912 participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Circulating CD4+ naive cells were higher in women than men and decreased with age (all p-values <0.0001). European-Americans had higher levels of naive cells and lower levels of memory cells compared with African-Americans and Hispanic-Americans (all p-values ≤0.0005). Lower naive/higher memory cells were associated with interleukin-6 levels. In multivariate models, cytomegalovirus (CMV) and H. Pylori titers were strongly associated with higher memory and lower naive cells (all p-values <0.05). Higher memory cells were associated with coronary artery calcification (CAC) level in the overall population [β-Coefficient (95% confidence interval (CI)) = 0.20 (0.03, 0.37)]. Memory and naive (inversely) cells were associated with common carotid artery intimal media thickness (CC IMT) in European-Americans [memory: β = 0.02 (0.006, 0.04); naive: β = −0.02 (−0.004, −0.03)].
These results demonstrate that the degree of chronic adaptive immune activation is associated with both CAC and CC IMT in otherwise healthy individuals, consistent with the known role of CD4+ T cells, and with innate immunity (inflammation), in atherosclerosis. These data are also consistent with the hypothesis that immunosenescence accelerates chronic diseases by putting a greater burden on the innate immune system, and suggest the importance of prospective studies and research into strategies to modulate adaptive immune activation in chronic disease states such as atherosclerosis.
In this study we aimed to investigate whether there are indications of premature atherosclerosis, as measured by endothelial dependent flow-mediated dilation (ED-FMD) and intima media thickness (IMT), in patients with very early RA, and to analyze its relation to biomarkers of endothelial dysfunction, taking inflammation and traditional cardiovascular disease (CVD) risk factors into account.
Patients from the three northern counties of Sweden diagnosed with early RA are followed in an ongoing prospective study of CVD co-morbidity. Of these, all patients aged ≤60 years were consecutively included in this survey of CVD risk factors (n = 79). Forty-four age and sex matched controls were included. IMT of common carotid artery and ED-FMD of brachial artery were measured using ultrasonography. Blood was drawn for analysis of lipids, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA)-mass, VonWillebrand factor (VWF), soluble intercellular adhesion molecule-1 (sICAM), soluble vascular cell adhesion molecule-1 (sVCAM), sE-selectin, sL-selectin and monocyte chemotactic protein-1 (MCP-1). In a subgroup of 27 RA patients and their controls the ultrasound measurements were reanalysed after 18 months.
There were no significant differences between RA patients and controls in terms of IMT or ED-FMD at the first evaluation. However after 18 months there was a significant increase in the IMT among the patients with RA (P < 0.05). Patients with RA had higher levels of VWF, sICAM-1 (P < 0.05) and of MCP-1 (P = 0.001) compared with controls. In RA, IMT was related to some of the traditional CVD risk factors, tPA-mass, VWF (P < 0.01) and MCP-1 and inversely to sL-selectin (P < 0.05). In RA, ED-FMD related to sL-selectin (P < 0.01). DAS28 at baseline was related to PAI-1, tPA-mass and inversely to sVCAM-1 (P < 0.05) and sL-selectin (P = 0.001).
We found no signs of atherosclerosis in patients with newly diagnosed RA compared with controls. However, in patients with early RA, IMT and ED-FMD were, to a greater extent than in controls, related to biomarkers known to be associated with endothelial dysfunction and atherosclerosis. After 18 months, IMT had increased significantly in RA patients but not in controls.
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
Differences in cardiovascular disease (CVD) burden exist among racial/ethnic groups in the United States, with African Americans having the highest prevalence. Subclinical CVD measures have also been shown to differ by race/ethnicity. In the United States, there has been significant intermixing among racial/ethnic groups creating admixed populations. Very little research exists on the relationship of genetic ancestry and subclinical CVD measures.
Methods and Results
These associations were investigated in 712 African-American and 705 Hispanic participants from the MESA candidate gene sub-study. Individual ancestry was estimated from 199 genetic markers using STRUCTURE. Associations of ancestry and coronary artery calcium (CAC) and common and internal carotid intima media thickness (cIMT) were evaluated using log-binomial and linear regression models. Splines indicated linear associations of ancestry with subclinical CVD measures in African-Americans, but presence of threshold effects in Hispanics. Among African Americans, each standard deviation (SD) increase in European ancestry was associated with an 8% (95% CI (1.02, 1.15), p=0.01) greater CAC prevalence. Each SD increase in European ancestry was also associated with a 2% (95% CI (−3.4%, −0.5%), p=0.008) lower common cIMT in African Americans. Among Hispanics, the highest tertile of European ancestry was associated with a 34% greater CAC prevalence, p=0.02 as compared to lowest tertile.
The linear association of ancestry and subclinical CVD suggests that genetic effects may be important in determining CAC and cIMT among African-Americans. Our results also suggest that CAC and common cIMT may be important phenotypes for further study with admixture mapping.
atherosclerosis; calcium; ancestry; epidemiology; genetics
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
Inflammation, endothelial activation and oxidative stress have been established as key events in the initiation and progression of atherosclerosis. High-density lipoprotein cholesterol (HDL-c) is protective against atherosclerosis and coronary heart disease, but its association with inflammation, endothelial activation and oxidative stress is not well established.
(1) To compare the concentrations of biomarkers of inflammation, endothelial activation and oxidative stress in subjects with low HDL-c compared to normal HDL-c; (2) To examine the association and correlation between HDL-c and these biomarkers and (3) To determine whether HDL-c is an independent predictor of these biomarkers.
422 subjects (mean age±SD = 43.2±11.9years) of whom 207 had low HDL-c concentrations (HDL-c <1.0mmol/L and <1.3mmol/L for males and females respectively) and 215 normal controls (HDL-c ≥1.0 and ≥1.3mmol/L for males and females respectively) were recruited in this study. The groups were matched for age, gender, ethnicity, smoking status, diabetes mellitus and hypertension. Fasting blood samples were collected for analysis of biomarkers of inflammation [high-sensitivity C-reactive protein (hsCRP) and Interleukin-6 (IL-6)], endothelial activation [soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1), soluble Intercellular Adhesion Molecule-1 (sICAM-1) and E-selectin)] and oxidative stress [F2-Isoprostanes, oxidized Low Density Lipoprotein (ox-LDL) and Malondialdehyde (MDA)].
Subjects with low HDL-c had greater concentrations of inflammation, endothelial activation and oxidative stress biomarkers compared to controls. There were negative correlations between HDL-c concentration and biomarkers of inflammation (IL-6, p = 0.02), endothelial activation (sVCAM-1 and E-selectin, p = 0.029 and 0.002, respectively), and oxidative stress (MDA and F2-isoprostane, p = 0.036 and <0.0001, respectively). Multiple linear regression analysis showed HDL-c as an independent predictor of IL-6 (p = 0.02) and sVCAM-1 (p<0.03) after correcting for various confounding factors.
Low serum HDL-c concentration is strongly correlated with enhanced status of inflammation, endothelial activation and oxidative stress. It is also an independent predictor for enhanced inflammation and endothelial activation, which are pivotal in the pathogenesis of atherosclerosis and atherosclerosis-related complications.
The aim of the present study was to determine whether serum urate (sUA) concentration is positively associated with subclinical atherosclerosis, independent of body mass index (BMI), among generally healthy adults.
Design and setting
The CARDIA study followed 5115 black and white individuals aged 18–30 years in 1985–1986 (year 0). Subclinical atherosclerosis comprised coronary artery calcified plaque (CAC; years 15, 20 and 25) and maximum common carotid intima–media thickness (IMT; year 20). sUA (years 0, 10, 15 and 20) was modelled as gender-specific quartiles that were pooled. Discrete-time hazard regressions and generalized linear regressions were used for analyses.
Mean sUA concentration was lower in women than in men, and increased with age. Adjusting for demographic and lifestyle factors, the highest versus lowest quartile of sUA at year 0 was associated with a 44% [95% confidence interval (CI) 20%, 73%] greater risk of CAC progression from year 15 to 25 (Ptrend < 0.001), which was attenuated by adjustment for BMI at year 0 (Ptrend = 0.45). A stronger association was found between sUA at year 15 and CAC progression at year 20 or 25 (hazard ratio 2.07, 95% CI 1.66, 2.58 for the highest versus lowest sUA quartile Ptrend < 0.001), which was attenuated but remained significant with additional adjustment for BMI at year 15 (Ptrend = 0.01). A greater increment in sUA concentration from year 0 to year 15, independent of change in BMI, was related to a higher risk of CAC progression (Ptrend < 0.001). Similar associations were found between sUA and IMT, but only in men.
sUA may be an early biomarker for subclinical atherosclerosis in young adults; starting in early middle age, sUA predicts subclinical atherosclerosis independently of BMI.
calcified plaque; intima–media thickness; subclinical atherosclerosis; urate; uric acid
The present study examines the association between carotid and coronary atherosclerosis and metabolic syndrome in human immunodeficiency virus (HIV)–infected adults.
We measured the common and internal carotid intima-media thickness (c-IMT) using B-mode ultrasonography, and we measured coronary artery calcium (CAC) using high-resolution, electrocardiographic, synchronized, computed tomography, for 314 HIV-infected men and women. Metabolic syndrome was defined by National Cholesterol Education Program/Adult Treatment Panel III criteria. We compared the c-IMT measurements and CAC scores of patients with metabolic syndrome with the scores of those without metabolic syndrome using a Wilcoxon test for continuous variables and a χ2 test for categorical variables. To examine the association between surrogate markers and metabolic syndrome, we used logistic regression analysis.
Participants with metabolic syndrome were more likely to have a common c-IMT measurement >0.8 mm than were those without metabolic syndrome (17% vs.7%; P=.009), but both groups were equally likely to have an internal c-IMT measurement >1.0 mm (20% vs. 13%; P=.15). Any positive CAC score was more likely to occur for participants with metabolic syndrome (80.3% vs. 46.7%; P < .0001). In a multivariate model adjusted for sex, age, ethnicity, and smoking status, participants with metabolic syndrome were more likely than those without metabolic syndrome to have an abnormal common c-IMT measurement (odds ratio [OR], 2.9; P= .020) and detectable CAC scores (OR, 4.9; P < .0001) but not a higher internal c-IMT measurement (OR, 1.6; P=.255).
Our study demonstrates that HIV-infected individuals with metabolic syndrome may be at increased risk for subclinical atherosclerosis and supports screening for metabolic syndrome among HIV-infected patients at risk for cardiovascular disease.
The objective of this study was to investigate the association between nonalcoholic fatty liver disease (NAFLD) and carotid artery atherosclerosis beyond metabolic disorders.
We studied 320 non-diabetic patients with ultrasonographically diagnosed NAFLD and 313 non-diabetic patients without NAFLD who have less than 40 g alcohol/week drinking history. Carotid atherosclerotic burden was assessed by carotid intima-media thickness (IMT) and plaque. All subjects were divided to the metabolic syndrome (MetS) according to International Diabetes Federation criteria.
NAFLD patients had a significantly increased mean carotid IMT (0.79 ± 0.18 vs. 0.73 ± 0.13 mm; p < 0.001) than those without the condition. The prevalence of increased IMT, defined as IMT ≥ 1 mm, and carotid plaque were 52.5% and 34.1% in the patients with NAFLD vs. 35.8% and 18.8% in the patients without this condition (p < 0.001). The difference in IMT and prevalence of plaque was also significant even in patients without MetS as well as those with MetS (all p < 0.05). NAFLD-associated adjusted odds ratio for increased IMT was 1.236 [95% confidence interval (CI), 1.023-1.467, p = 0.016] without MetS and 1.178 (95% CI, 1.059-1.311, p = 0.003) with MetS. NAFLD-associated adjusted odds ratio of carotid plaque was 1.583 (95% CI, 1.309-1.857, p = 0.024) without MetS and 1.536 (95% CI, 0.512-4.604, p = 0.444) with MetS.
NAFLD is significantly associated with carotid atherosclerosis in non-diabetic outpatients even without MetS. Carotid screening for NAFLD might be beneficial for assessment of future atherosclerotic complications.
Fatty liver; Carotid intima media thickness; Metabolic syndrome
To examine whether the inflammatory markers, C-reactive protein (CRP) and fibrinogen, are associated with biomarkers of atherosclerosis [carotid intima-media thickness (IMT) and coronary artery calcification (CAC)] in the general male population, including Asians.
Population-based samples of 310 Japanese, 293 Japanese-American and 297 White men aged 40-49 years without clinical cardiovascular disease had IMT, CAC, CRP and fibrinogen levels, and other conventional risk factors measured using standardized methods. Statistical associations between the variables were evaluated using multiple linear or logistic regression models.
The Japanese group had significantly lower levels of inflammatory markers and subclinical atherosclerosis than the Japanese-American and White groups (P-values all <0.001). The mean levels of CRP were 0.66 vs. 1.11 and 1.47 mg/L, and fibrinogen 255.0 vs. 313.0 and 291.5 mg/dl, respectively. Mean carotid IMT was 0.61 vs. 0.73 and 0.68 mm, and the prevalence of CAC 11.6% vs. 32.1% and 26.3%, respectively. Body mass index (BMI) showed significant positive associations with both CRP and fibrinogen levels. Although CRP showed a significant positive association with IMT in Japanese men, this association became non-significant after adjustment for traditional risk factors or BMI. In all three populations, CRP was not associated significantly with the prevalence of CAC. Similarly, fibrinogen did not show a significant association with either IMT or the prevalence of CAC.
The associations of inflammatory markers with subclinical atherosclerosis may merely reflect the strong association of BMI with inflammatory markers and subclinical atherosclerosis in both Eastern and Western populations.
obesity; C-reactive protein; fibrinogen; intima-media thickness; coronary artery calcification
Background. The NCEP metabolic syndrome (MetS) is a combination of dichotomized interrelated risk factors from predominantly Caucasian populations. We propose a continuous MetS score based on principal component analysis (PCA) of the same risk factors in a multiethnic cohort and compare prediction of incident CVD events with NCEP MetS definition. Additionally, we replicated these analyses in the Health, Aging, and Body composition (Health ABC) study cohort. Methods and Results. We performed PCA of the MetS elements (waist circumference, HDL, TG, fasting blood glucose, SBP, and DBP) in 2610 Caucasian Americans, 801 Chinese Americans, 1875 African Americans, and 1494 Hispanic Americans in the multiethnic study of atherosclerosis (MESA) cohort. We selected the first principal component as a continuous MetS score (MetS-PC). Cox proportional hazards models were used to examine the association between MetS-PC and 5.5 years of CVD events (n = 377) adjusting for age, gender, race, smoking and LDL-C, overall and by ethnicity. To facilitate comparison of MetS-PC with the binary NCEP definition, a MetS-PC cut point was chosen to yield the same 37% prevalence of MetS as the NCEP definition (37%) in the MESA cohort. Hazard ratio (HR) for CVD events were estimated using the NCEP and Mets-PC-derived binary definitions. In Cox proportional models, the HR (95% CI) for CVD events for 1-SD (standard deviation) of MetS-PC was 1.71 (1.54–1.90) (P < 0.0001) overall after adjusting for potential confounders, and for each ethnicity, HRs were: Caucasian, 1.64 (1.39–1.94), Chinese, 1.39 (1.06–1.83), African, 1.67 (1.37–2.02), and Hispanic, 2.10 (1.66-2.65). Finally, when binary definitions were compared, HR for CVD events was 2.34 (1.91–2.87) for MetS-PC versus 1.79 (1.46–2.20) for NCEP MetS. In the Health ABC cohort, in a fully adjusted model, MetS-PC per 1-SD (Health ABC) remained associated with CVD events (HR = 1.21, 95%CI 1.12–1.32) overall, and for each ethnicity, Caucasian (HR = 1.24, 95%CI 1.12–1.39) and African Americans (HR = 1.16, 95%CI 1.01–1.32). Finally, when using a binary definition of MetS-PC (cut point 0.505) designed to match the NCEP definition in terms of prevalence in the Health ABC cohort (35%), the fully adjusted HR for CVD events was 1.39, 95%CI 1.17–1.64 compared with 1.46, 95%CI 1.23–1.72 using the NCEP definition. Conclusion. MetS-PC is a continuous measure of metabolic syndrome and was a better predictor of CVD events overall and in individual ethnicities. Additionally, a binary MetS-PC definition was better than the NCEP MetS definition in predicting incident CVD events in the MESA cohort, but this superiority was not evident in the Health ABC cohort.
People with type 1 diabetes are at high risk of premature atherosclerosis. Existing evidence suggests that impaired vitamin D metabolism may contribute to the development of atherosclerosis. We tested associations of circulating vitamin D metabolite concentrations with subclinical atherosclerosis among 1,193 participants with type 1 diabetes in the DCCT/EDIC study.
RESEARCH DESIGN AND METHODS
We measured plasma concentrations of 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D, and 24,25-dihydroxyvitamin D by mass spectrometry at the end of the DCCT. In a staggered cross-sectional design, we tested associations with coronary artery calcium (CAC), measured by computed tomography a median of 10 years later, and with common and internal carotid intima-media thickness (IMT), measured by B-mode ultrasonography on two occasions a median of 4 years later and a median of 10 years later. We hypothesized that lower concentrations of each vitamin D metabolite would be associated with increased risk of CAC and greater carotid IMT.
At the time metabolites were measured, mean age was 32.4 years and mean duration of diabetes was 7.5 years. The prevalence and severity of CAC tended to be lower—not higher—with lower concentrations of each vitamin D metabolite. For instance, in a fully adjusted multinomial logistic model, a 25 nmol/L lower 25-hydroxyvitamin D was associated with a 0.8-fold decrease in the odds of having higher CAC (95% CI 0.68–0.96, P = 0.01). No vitamin D metabolite was associated with either common or internal mean IMT.
We did not find evidence linking impaired vitamin D metabolism with increased subclinical atherosclerosis in type 1 diabetes.
High-sensitivity C-reactive protein (hsCRP) levels are closely associated with abdominal obesity, metabolic syndrome, and atherosclerotic cardiovascular disease. The JUPITER trial has encouraged using hsCRP ≥2 mg/L to guide statin therapy; however the association of hsCRP to atherosclerosis, independent of obesity, remains unknown.
Methods and Results
We studied 6,760 participants from the Multi-Ethnic Study of Atherosclerosis (MESA). Participants were stratified into 4 groups: non-obese/low hsCRP, non-obese/high hsCRP, obese/low hsCRP, and obese/high hsCRP. Using multivariable logistic and robust linear regression, we described the association with subclinical atherosclerosis, using coronary artery calcium (CAC) and carotid intima-media thickness (cIMT). Mean BMI was 28.3 ± 5.5 kg/m2, and median hsCRP was 1.9 mg/L (0.84 – 4.26). High hsCRP, in the absence of obesity, was not associated with CAC and was mildly associated with cIMT. Obesity was strongly associated with CAC and cIMT independent of hsCRP. When obesity and high hsCRP were both present, there was no evidence of multiplicative interaction. Similar associations were seen among 2,083 JUPITER-eligible individuals.
High hsCRP, as defined by JUPITER, was not associated with CAC and was mildly associated with cIMT in the absence of obesity. In contrast, obesity was associated with both measures of subclinical atherosclerosis independent of hsCRP status.
obesity; hsCRP; high sensitivity C-reactive protein; subclinical atherosclerosis; coronary artery calcium; carotid intima-media thickness