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OBJECTIVE - Understanding the interplay between adiposity, inflammation, and cardiovascular complications in type 2 diabetes mellitus (T2DM) remains a challenge. Signaling from adipocytes is considered important in this context. Adiponectin is the most abundant adipocytokine and has been associated with various measures of cardiovascular disease (CVD). This study examines the relationships between genetic variants in the adiponectin (ADIPOQ) and adiponectin-related signaling pathway genes and measures of subclinical CVD (vascular calcified plaque and carotid intima-media thickness), plasma lipids, and inflammation in T2DM.
DESIGN AND METHODS - Single-nucleotide polymorphisms (SNPs) in ADIPOQ (n = 45), SNPs tagging ADIPOR1 (n = 6), APIPOR2 (n = 8), APPL1 (n = 6) and known rare coding variants in KNG1 (n = 3) and LYZL1 (n = 3) were genotyped in 1220 European Americans from the family-based Diabetes Heart Study. Associations between SNPs and phenotypes of interest were assessed using a variance components analysis with adjustment for age, sex, T2DM-affected status, and body mass index.
RESULTS - There was minimal evidence of association between SNPs in the adiponectin signaling pathway genes and measures of calcified plaque; eight of the 71 SNPs showed evidence of association with subclinical CVD (P = 0.007-0.046) but not with other phenotypes examined. Nine additional SNPs were associated with at least one of the plasma lipid measures (P = 0.008-0.05).
CONCLUSION - Findings from this study do not support a significant role for variants in the adiponectin signaling pathway genes in contributing to risk for vascular calcification in T2DM. However, further understanding the interplay between adiposity, plasma lipids, and inflammation may prove important in the prediction and management of cardiovascular complications in T2DM.
Copyright © 2012 The Obesity Society.
OBJECTIVE - To determine the association of coffee, decaffeinated coffee, caffeine, and tea consumption in young adulthood with the presence and progression of coronary artery calcified (CAC) plaque and carotid intima-media thickness later in life.
METHODS AND RESULTS - The Coronary Artery Risk Development in Young Adults (CARDIA) Study is a cohort of 5115 white and black adults who were aged 18 to 30 years when they completed a baseline clinic examination from 1985 to 1986. Subsequent examinations were conducted 2, 5, 7, 10, 15, and 20 years later. After multivariable adjustment, no association was observed between average coffee, decaffeinated coffee, or caffeine consumption (years 0 and 7) and presence of CAC (score, >0 Agatston units at year 15 or 20), CAC progression (incident CAC at year 20 or increase in CAC score by ≥20 Agatston units), or high carotid intima-media thickness (>80th percentile, year 20). However, tea consumption displayed a nonsignificant trend for an inverse association with CAC (P=0.08 for trend) and an inverse association with CAC progression (P=0.04 for trend) but no association with high carotid intima-media thickness (P>0.20 for trend). Stratification of the coffee analyses by sex, race, or smoking yielded similar nonsignificant patterns.
CONCLUSIONS - We observed no substantial association between coffee or caffeine intake and coronary and carotid atherosclerosis. However, our results suggested an inverse association between tea and CAC but not carotid atherosclerosis.
INTRODUCTION - Carotid intima-media thickness (IMT) is a subclinical marker of atherosclerosis and a strong predictor of stroke. Pericardial fat (PF), the fat depot around the heart, has been associated with several atherosclerosis risk factors. We sought to examine the association between carotid IMT and PF, and to examine whether such an association is independent from common atherosclerosis risk factors including measures of overall adiposity.
METHODS - Unadjusted and multivariable-adjusted linear regression analysis was used to examine associations between common carotid artery (CCA) IMT and internal carotid artery (ICA) IMT with PF in a random sample of 996 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) who underwent carotid ultrasound and chest computed tomography at baseline examination.
RESULTS - A significant positive correlation was observed between PF and CCA-IMT (r=0.27, P < .0001) and ICA-IMT (r=0.17, P < .0001). In an unadjusted sex-specific linear regression analysis, there was a significant association between PF (1-SD difference) and CCA-IMT (mm) in both women (beta coefficient [95% confidence interval]: 0.06 [0.04, 0.08], P < .0001) and men (0.03 [0.01, 0.05], P < .0002), an association that persisted after further adjusting for age and ethnicity (0.02 [+0.00, 0.04], P=.0120 for women, and 0.02 [+0.00, 0.03], P=.0208 for men). However, after additional adjustment for atherosclerosis risk factors and either body mass index or waist circumference, these relations were no longer significant in either sex. In similar analyses, PF was significantly associated with ICA-IMT in both men (0.11 [0.06, 0.15], P < .0001) and women (0.08 [0.02, 0.13], P=.0041). These relations were no longer significant in women in multivariable-adjusted models, but persisted in men in all models except after adjusting for age, ethnicity, and waist circumference.
CONCLUSIONS - In the general population PF is associated with carotid IMT, an association that possibly is not independent from markers of overall adiposity or common atherosclerosis risk factors.
(c) 2010 National Stroke Association. Published by Elsevier Inc. All rights reserved.
Inflammatory markers, particularly C-reactive protein (CRP), predict incident cardiovascular disease and are associated with the presence of subclinical atherosclerosis. The relations between multiple inflammatory markers and direct measures of atherosclerosis are less well established. Participants in the Offspring Cohort of the Framingham Heart Study (n = 2,885, 53% women, mean age 59 years) received routine assessments of common carotid artery intima-media thickness (CCA-IMT), internal carotid artery intima-media thickness (ICA-IMT), and the presence or absence of > or =25% carotid stenosis by ultrasonography. Circulating inflammatory markers assessed from an examination 4 years later included CRP, interleukin-6 (IL-6), intercellular adhesion molecule-1, monocyte chemoattractant protein-1, P-selectin, and CD40 ligand. Assessed as a group, inflammatory markers were significantly associated with ICA-IMT (p = 0.01), marginally with carotid stenosis (p = 0.08), but not with CCA-IMT. Individually, with an increase from the 25th to 75th percentile in IL-6, there were significant increases in ICA-IMT and carotid stenosis (for ICA-IMT, estimated fold increase 1.04, 95% confidence interval 1.03 to 1.06, p = 0.0004; for carotid stenosis, odds ratio 1.25, 95% confidence interval 1.06 to 1.47, p = 0.007) after adjustment for age, gender, and established risk factors for atherosclerosis. There was a similar significant multivariate-adjusted association of CRP with ICA-IMT but not with carotid stenosis. Smoking appeared to modify the associations of ICA-IMT with CRP (p = 0.009) and with IL-6 (p = 0.006); the association was more pronounced in current (vs former or never) smokers. In conclusion, there were modest associations of inflammatory markers, particularly IL-6, with carotid atherosclerosis. This association appears more pronounced in current smokers than in former smokers and nonsmokers.
OBJECTIVE - Increased carotid artery intima-media thickness (IMT) and increased coronary artery calcium (CAC) are noninvasive surrogate indices of prevalent coronary artery disease (CAD). We compared CAC to IMT for noninvasive detection of prevalent CAD in participants whose coronary status was identified by coronary angiography.
METHODS AND RESULTS - Male and female CAD patients (> or =50% stenosis in one or more coronary artery, n=79) and controls (no lumen irregularities, n=93) were identified using coronary angiography. Mean maximum carotid IMT was quantified using B-mode ultrasound and total CAC was measured using ECG-gated helical computed tomography (HCT). Carotid IMT was approximately 20% higher in CAD cases compared with controls (P<0.001), whereas mean CAC was 1000% higher in CAD cases than controls (P<0.0001). In multivariable models adjusted for age and sex, IMT greater than the median (1.13 mm) was associated with 2-fold increase in likelihood of prevalent CAD compared with scores below that cut point (P=0.015). CAC scores that exceeded the median score of 92 were associated with 28-fold increase in likelihood of prevalent CAD (P<0.0001). Although associations of increased IMT with prevalent CAD were similar in males and females, CAC scores above the median in females were associated with 39-fold increase in odds of prevalent CAD, whereas males with elevated CAC had 19-fold risk of CAD.
CONCLUSIONS - HCT-measured CAC compares favorably with carotid IMT measured by B-mode ultrasound as a noninvasive index of prevalent CAD.
BACKGROUND - A family history of coronary heart disease (CHD) is an independent risk factor for cardiovascular events. However, the mechanisms underlying this susceptibility have not been fully elucidated. We hypothesized that an important mediator of the familial predisposition to CHD is subclinical atherosclerosis, which is detectable by noninvasive imaging.
METHODS AND RESULTS - We studied 1662 subjects (mean age 57, 51% women) in the Framingham Offspring Study who underwent carotid ultrasonography and had both biological parents in the original (parental) cohort. Parental CHD events were validated prospectively by a physician endpoint committee. The associations of carotid intima-media thickness (IMT) with premature parental CHD (occurring before age 60) and any parental CHD (no age restriction) were examined in age- and multivariable-adjusted analyses. Age-adjusted mean internal carotid IMT was higher in subjects who had at least one parent with premature CHD than in those without a validated parental history of premature CHD (men 1.13 versus 1.04 mm, P<0.01; women 0.92 versus 0.85 mm, P=0.03). In both sexes, these differences remained significant after adjustment for cardiovascular risk factors. In analyses without a restriction on parental age of CHD onset, the association between carotid IMT and parental CHD was not statistically significant. There was also no significant association of common carotid IMT with premature or any parental CHD.
CONCLUSIONS - These findings suggest that subclinical atherosclerosis, assessed in the carotid arteries, is more prevalent in individuals with a family history of CHD. Early-onset parental CHD, in particular, identifies offspring with a strong familial predisposition to atherosclerosis.
BACKGROUND - Although atherosclerosis often leads to lumen narrowing and symptomatic cardiovascular disease, it is now recognized that arteries have the potential to compensate by enlarging in response to atherosclerosis. We tested the hypotheses that carotid arterial interadventitial (IA) and lumen diameters were related to wall thickness and that carotid arterial diameters of individuals with coronary artery disease (CAD) differed from those of CAD-free controls.
METHODS AND RESULTS - We measured lumen diameter, IA diameter, and intima-media thickness (IMT) using B-mode ultrasound in the common and internal carotid arteries of 141 CAD case patients and 139 disease-free control subjects. Common carotid IA diameter was greater in CAD cases than controls after adjustment for age, height, and sex (P<0.01). Common carotid lumen diameter was marginally larger in individuals with greater IMT (P=0.06) but was not associated with case status. Conversely, mean internal carotid IA and lumen diameters were smaller in CAD cases than controls in both univariable and multivariable models (both P<0.001), and lumina were smaller in individuals with greater IMT. Despite these cross-sectional differences in carotid artery dimensions, we were unable to detect any statistically significant interactive effects of CAD case status on the association of IMT with arterial dimensions.
CONCLUSIONS - Internal carotid artery lumen and IA diameters are both smaller in CAD cases than controls. The association of increased IMT with arterial dimensions varies in a manner that is segment-specific for the common and internal carotid arteries.
BACKGROUND - Intimal medial thickness of the extracranial carotid arteries (IMT) is related to coronary artery disease (CAD) and CAD risk factors. Few studies have explored the association of risk factors with progression of IMT, and none have evaluated their associations with IMT progression specifically in patients with and without CAD.
METHODS AND RESULTS - We used coronary angiography to identify 280 patients equally divided between men and women and those with either > or =50% coronary artery stenosis or no CAD. Risk factors were measured at baseline and IMT was measured at baseline and yearly for 3 years in 241 of these individuals. Baseline risk factors and CAD status were related to IMT progression. IMT of patients with CAD progressed 3 times faster than that of patients with no CAD (mean+/-SEM, 33.7+/-7.4 versus 8.9+/-7.1 microm/year; P=0.02), and CAD status and high-density lipoprotein (HDL) cholesterol were independently associated with IMT progression. Male sex, increased waist to hip ratio, cigarette smoking, increased triglycerides, and decreased HDL cholesterol were associated with increased progression in CAD patients.
CONCLUSIONS - Patients with CAD have more rapid progression of IMT than CAD-free controls, and risk factors are related to progression in them.
BACKGROUND AND PURPOSE - Carotid artery intima-medial thickness (IMT), a marker of subclinical atherosclerosis, is a strong predictor of subsequent cardiovascular morbidity. The role of genetic factors in thickening of the carotid wall remains largely unknown. We hypothesize that in families with multiple members having diabetes, carotid IMT is likely to be associated with both inherited and environmental factors.
METHODS - To determine the extent of the familial aggregation of carotid IMT in the presence of type 2 diabetes, we studied 252 individuals with type 2 diabetes (mean age 60.6 years) from 122 families. Common carotid artery IMT was measured by high-resolution B-mode ultrasonography. Other measured factors included lipid levels, body mass index, fasting glucose, hemoglobin A1c, albumin/creatinine ratio, and self-reported medical history. Heritability estimates were obtained by using variance component methodology, as implemented in the SOLAR software package. Tests for association between carotid IMT and variables were performed by using mixed model analysis while accounting for the correlation due to family structure.
RESULTS - The age-, sex-, and race-adjusted heritability estimate for carotid IMT was 0.32 (SE 0.17, P=0.02). Further adjustment for total cholesterol, hypertension status, and current smoking status resulted in a heritability estimate of 0.41 (SE 0.16, P=0.004). The strongest predictors of carotid IMT, after adjusting for age and sex, were ethnicity (African American versus white), total cholesterol, and smoking status.
CONCLUSIONS - These data provide empirical evidence that subclinical cardiovascular disease has a significant genetic component and merits a search for the genes involved in susceptibility to the atherosclerotic complications of diabetes.
BACKGROUND AND PURPOSE - It is generally assumed that risk factors affect extracranial carotid intimal-medial thickness similarly among all arterial segments. This assumption underlies use of single segments or walls of segments as outcome variables for risk factor studies and clinical trials. However, if the impact of risk factors was unequal for various segments or circumferentially asymmetrical within segments, then inferences drawn from a single segment or wall might not be generalizable; furthermore, since individual segments and walls have unique histological characteristics and are differentially exposed to turbulent flow, risk factor relationships with a particular segment or wall may provide inferences regarding pathogenesis of atherosclerosis.
METHODS - We evaluated associations of risk factors with intimal-medial thickness at the near and far walls of the common carotid artery, bifurcation, and internal carotid artery in 280 individuals older than 45 years equally divided between coronary artery disease cases and controls and between men and women.
RESULTS - The patterns of differences in mean intimal-medial thickness among segments vary, depending on age, history of hypertension, body mass index in women, and coronary (case-control) status. The asymmetry of disease depended on blood glucose concentrations, prior history of diabetes, smoking, and coronary status. Sex, postmenopausal status, LDL cholesterol, systolic blood pressure, and history of myocardial infarction all had statistically significant relationships with intimal-medial thickness that were fairly homogeneous among arterial sites.
CONCLUSIONS - Focus on an individual segments or walls of the extracranial carotid arteries may lead to overestimation or underestimation of associations of risk factors with extracranial carotid intimal-medial thickness.