Carotid Artery Atherosclerosis, MRI Indices of Brain Ischemia, Aging, and Cognitive Impairment

The goal of this study was to compare internal carotid artery (ICA) intima-media thickness (IMT) with common carotid artery (CCA) IMT as global markers of cardiovascular disease (CVD). Cross-sectional measurements of the mean CCA IMT and maximum ICA IMT were made on ultrasound images acquired from the Framingham Offspring cohort (n = 3316; mean age, 58 years; 52.7% women). Linear regression models were used to study the associations of the Framingham risk factors with CCA and ICA IMT. Multivariate logistic regression models and receiver operating characteristic (ROC) curve analysis were used to compare the associations of prevalent CVD with CCA and ICA IMT and determine sensitivity and specificity. The association between age and the mean CCA IMT corresponded to an increase of 0.007 mm/y; the increase was 0.037 mm/y for the ICA IMT. Framingham risk factors accounted for 28.6% and 27.5% of the variability in the CCA and ICA IMT, respectively. Age and gender contributed 23.5% to the variability of the CCA IMT and 22.5% to that of the ICA IMT, with the next most important factor being systolic blood pressure (1.9%) for the CCA IMT and smoking (1.6%) for the ICA IMT. The CCA IMT and ICA IMT were statistically significant predictors of prevalent CVD, with the ICA IMT having a larger area under the ROC curve (0.756 versus 0.695). Associations of risk factors with CCA and ICA IMT are slightly different, and both are independently associated with prevalent CVD. Their value for predicting incident cardiovascular events needs to be compared in outcome studies.

Other than the documented associations of risk factors and carotid artery wall thickness, the genetic basis of variation in carotid artery intimal-medial thickness (IMT) is unknown. The purpose of this study was to examine the extent to which variation in common carotid artery (CCA) IMT and internal carotid artery (ICA) IMT are under genetic control. The sibship data used for this analysis were part of an epidemiological survey in Mexico City. The CCA and ICA analyses were based on 46 and 44 sibships of various sizes, respectively. The CCA and ICA IMTs were measured with carotid ultrasonography. Using a robust variance decomposition method, we performed genetic analyses of CCA IMT and ICA IMT measurements with models incorporating several cardiovascular risk factors (eg, lipids, diabetes, blood pressure, and smoking) as covariates. After accounting for the effects of covariates, we detected high heritabilities for CCA IMT (h2 = 0.92 +/- 0.05, P = .001) and ICA IMT (h2 = 0.86 +/- 0.13, P = .029). Genes accounted for 66.0% of the total variation in CCA IMT, whereas 27.7% of variation was attributable to covariates. For ICA IMT, genes explained a high proportion (74.9%) of total phenotypic variation. The covariates accounted for 11.5% of variation in ICA IMT. Our results suggest that substantial proportions of phenotypic variance in CCA IMT and ICA IMT are attributable to shared genetic factors.

BackgroundCarotid artery intima‐media thickness (IMT) is associated with the risk of subsequent cardiovascular events in the general population. This association has not been established in type 1 diabetes.Methods and ResultsWe studied if carotid IMT is associated with the risk of a first coronary artery disease event in participants with type 1 diabetes in the EDIC (Epidemiology of Diabetes Interventions and Complications) study, the long‐term observational follow‐up of the DCCT (Diabetes Control and Complications Trial). Between 1994 and 1996, common carotid artery and internal carotid artery IMT were measured with high‐resolution ultrasound in 1309 study participants with a mean age of 35 years and diabetes duration of 13.8 years; 52% were men. Cox proportional hazards models evaluated the association of standardized common carotid artery IMT and internal carotid artery IMT with subsequent cardiovascular events over the next 17 years. Models were adjusted for age, sex, mean hemoglobin A1c levels, and traditional cardiovascular risk factors. Associations of common carotid artery IMT with subsequent CAD were significant after adjustment for imaging device, sex, and age (hazard ratio [HR], 1.23 per 0.09 mm [95% CI, [1.04–1.45]; P=0.0141), but did not remain significant after further adjustment for traditional risk factors and hemoglobin A1c (HR, 1.14 per 0.09 mm [95% CI, 0.97–1.33]; P=0.1206). No significant associations with subsequent coronary artery disease events were seen for internal carotid artery IMT.ConclusionsIn the DCCT/EDIC cohort with type 1 diabetes, common carotid artery IMT, but not internal carotid artery IMT, is weakly associated with subsequent coronary artery events, an association eliminated after adjusting for coexistent traditional cardiovascular risk factors.RegistrationURL: https://www.clinicaltrials.gov; Unique identifiers: NCT00360815 and NCT00360893.

We examined whether B-mode ultrasound-detected carotid artery intima-media thickness (IMT) was elevated before the onset of clinical diabetes. The study population for these analyses included 1127 nondiabetic participants, 66 prediabetic participants, and 303 diabetic participants with a mean age of 49.8 years who participated in the Mexico City Diabetes Study, a prospective cohort study. Common carotid artery (CCA) and internal carotid artery (ICA) IMTs were measured bilaterally by B-mode ultrasound. Age- and sex-adjusted mean ICA and CCA IMTs were both significantly higher among prediabetic individuals [0.81 mm [95% confidence interval (CI), 0.75-0.88] and 0.72 mm [95% CI, 0.69-0.75], respectively] than in individuals who remained free of diabetes [0.71 mm (95% CI, 0.69-0.72) and 0.69 mm (95% CI, 0.68-0.69), respectively]. However, after adjustment for established cardiovascular risk factors, ICA IMT, but not CCA IMT, remained significantly higher among prediabetic individuals [0.81 mm (95% CI, 0.75-0.88) and 0.71 mm (95% CI, 0.68-0.74)] than in individuals who remained free of diabetes [0.71 mm (95% CI, 0.69-0.72) and 0.69 mm (95% CI, 0.68-0.70)]. The present study provides direct evidence at the vascular level that atherosclerosis levels are elevated before the clinical onset of diabetes.

Association of Multiple Inflammatory Markers with Carotid Intimal Medial Thickness and Stenosis (from the Framingham Heart Study)

Genomewide Linkage Analysis for Internal Carotid Artery Intimal Medial Thickness: Evidence for Linkage to Chromosome 12

This study investigated the relationship between intima-media thickness (IMT) and immune parameters in obese children from five to 16 years of age. We enrolled 185 obese children with a mean age of 10.65 ± 2.10 years and 211 controls with a mean age of 10.32 ± 1.81 years. Glycometabolism, lipid metabolism, sex hormones, immune indices and carotid IMT were measured. Serum interleukin (IL)-6, IL-10, tumour necrosis factor (TNF)-alpha, white blood cells and common and internal carotid artery IMTs in the obese group were higher than those in the control group (p < 0.05, respectively). Bivariate correlation analysis showed that the common carotid arterial IMT was positively correlated with alanine aminotransferase, triglyceride, uric acid, apolipoprotein B, IL-6, IL-10, TNF-alpha, follicle-stimulating hormone and testosterone. Internal carotid artery IMT was positively correlated with alanine aminotransferase and follicle-stimulating hormone. Both common and internal carotid artery IMTs were inversely correlated with apolipoprotein A1 (p < 0.05, respectively). Stepwise multiple regression analysis showed that testosterone, alanine aminotransferase and TNF-alpha were the independent determinants of common carotid arterial IMT. Tumour necrosis factor-alpha, alanine aminotransferase and testosterone were associated with intima thickening in the early life in obese children and may increase later risks of premature atherogenicity and adult cardio-cerebrovascular diseases.

BackgroundChromosome 9p21 has recently been shown to be a risk region for a broad range of vascular diseases. Since carotid intima-media thickness (IMT) and plaque are independent predictors for vascular diseases, the association between 9p21 and these two phenotypes was investigated.Methodology/Principal FindingsCarotid segment-specific IMT and plaques were obtained in 1083 stroke- and myocardial infarction-free volunteers. We tested the genotypes and haplotypes of key single nucleotide polymorphisms (SNPs) on chromosome 9p21 for the associations with carotid IMT and plaque. Multivariate permutation analyses demonstrated that carriers of the T allele of SNP rs1333040 were significantly associated with thicker common carotid artery (CCA) IMT (p = 0.021) and internal carotid artery (ICA) IMT (p = 0.033). The risk G allele of SNP rs2383207 was associated with ICA IMT (p = 0.007). Carriers of the C allele of SNP rs1333049 were found to be significantly associated with thicker ICA IMT (p = 0.010) and the greater risk for the presence of carotid plaque (OR = 1.57 for heterozygous carriers; OR = 1.75 for homozygous carriers). Haplotype analysis showed a global p value of 0.031 for ICA IMT and 0.115 for the presence of carotid plaque. Comparing with the other haplotypes, the risk TGC haplotype yielded an adjusted p value of 0.011 and 0.017 for thicker ICA IMT and the presence of carotid plaque respectively. Further analyzing the data separated by sex, the results were significant only in men but not in women.ConclusionsChromosome 9p21 had a significant association with carotid atherosclerosis, especially ICA IMT. Furthermore, such genetic effect was in a gender-specific manner in the Han Chinese population.

Background and Purpose— We propose to study possible differences in the associations between risk factors for cardiovascular disease (myocardial infarction and stroke) and carotid intima-media thickness (IMT) measurements made at 3 different levels of the carotid bifurcation. Methods— We conducted a cross-sectional study of a cohort of whites and blacks of both genders with a mean age of 45 years. Traditional cardiovascular risk factors were determined in cohort members. Carotid IMT was measured from high-resolution B-mode ultrasound images at 3 levels: the common carotid artery, the carotid artery bulb (bulb), and the internal carotid artery. Associations with risk factors were evaluated by multivariate linear regression analyses. Results— Of 3258 who underwent carotid IMT measurements, common carotid artery, bulb, and internal carotid artery IMT were measured at all 3 separate levels in 3023 (92.7%). A large proportion of the variability of common carotid artery IMT was explained by cardiovascular risk factors (26.8%) but less so for the bulb (11.2%) and internal carotid artery (8.0%). Carotid IMT was consistently associated with age, low-density lipoprotein cholesterol, smoking, and hypertension in all segments. Associations with fasting glucose and diastolic blood pressure were stronger for common carotid artery than for the other segments. Hypertension, diabetes, and current smoking had qualitatively stronger associations with bulb IMT and low-density lipoprotein cholesterol with internal carotid artery IMT. Conclusion— In our cohort of relatively young white and black men and women, a greater proportion of the variability in common carotid IMT can be explained by traditional cardiovascular risk factors than for the carotid artery bulb and internal carotid arteries.

Association between carotid ultrasonographic parameters and microvascular and macrovascular complications in diabetes: A systematic review and meta-analysis

Type 2 diabetes mellitus (T2D) and cardiovascular disease share risk factors and subclinical atherosclerosis (SCA) predicts events in those with and without diabetes mellitus. T2D genetic risk may predict both T2D and SCA. We hypothesized that greater T2D genetic risk is associated with higher extent of SCA. In a cross-sectional analysis, including ≤9210 European Americans, 3773 African Americans, 1446 Hispanic Americans, and 773 Chinese Americans without known cardiovascular disease and enrolled in the Framingham Heart Study, Coronary Artery Risk Development in Young Adults, Multi-Ethnic Study of Atherosclerosis, and Genetic Epidemiology Network of Arteriopathy studies, we tested a 62 T2D-loci genetic risk score for association with measures of SCA, including coronary artery or abdominal aortic calcium score, common and internal carotid artery intima-media thickness, and ankle-brachial index. We used ancestry-stratified linear regression models, with random effects accounting for family relatedness when appropriate, applying a genetic-only (adjusted for sex) and a full SCA risk factors-adjusted model (significance, P<0.01=0.05/5, number of traits analyzed). An inverse association with coronary artery calcium score in Multi-Ethnic Study of Atherosclerosis Europeans (fully-adjusted P=0.004) and with common carotid artery intima-media thickness in the Framingham Heart Study (P=0.009) was not confirmed in other study cohorts, either separately or in meta-analysis. Secondary analyses showed no consistent associations with β-cell and insulin resistance genetic risk sub-scores in the Framingham Heart Study and in the Coronary Artery Risk Development in Young Adults. SCA does not have a major genetic component linked to a burden of 62 T2D loci identified by large genome-wide association studies. A shared T2D-SCA genetic basis, if any, might become apparent from better functional information about both T2D and cardiovascular disease risk loci.

ObjectiveWe assessed the correlation between intima-media thickness (IMT) and stiffness and test whether they are independent risk factors for atherosclerotic diseases.MethodsWe enrolled 2333 participants from the general population. Among the...

We assessed the correlation between intima-media thickness (IMT) and stiffness and test whether they are independent risk factors for atherosclerotic diseases. We enrolled 2333 participants from the general population. Among the study subjects, 197 subjects had a history of stroke or myocardial infarction (MI) and were treated as patients, and the rest were the control subjects. Intima-media thickness was measured at the common carotid artery (CCA), bifurcation, and internal carotid artery. Three parameters (arterial stiffness [beta], elastic modulus, and pulse wave velocity) were measured for carotid stiffness. Correlation between IMT and stiffness was first calculated. Multivariate regression model was used to evaluate whether inclusion of both IMT and stiffness can increase the prediction of cardiovascular events. Only CCA and bifurcation IMTs were significantly and positively correlated with stiffness. After adjusting for age and sex, the correlations were substantially attenuated. Common carotid artery IMT was most significantly associated with stroke and MI (P = 2.6 x 10) followed by bifurcation IMT (P = 5.5 x 10), and internal carotid artery IMT was least significant (P = 0.02). For stiffness, beta was most significant (P = 3.6 x 10) for stroke and MI, followed by elastic modulus (P = 1.1 x 10) and pulse wave velocity (P = 6.8 x 10). The best model for the combined effect was from beta (P < 0.03) and CCA (P = 0.056) or bifurcation IMT (P = 0.057). Carotid IMT and stiffness represent different properties of atherosclerotic vessel wall. Measuring both traits provides a better characterization of atherosclerosis.

To characterize abdominal visceral adipose tissue (VAT) trajectory relative to the final menstrual period (FMP), and to test whether menopause-related VAT accumulation is associated with greater average, common carotid artery intima-media thickness (cIMT) and/or internal carotid artery intima-media thickness (ICA-IMT). Participants were 362 women (at baseline: age was (mean ± SD) 51.1 ± 2.8 y; 61% White, 39% Black) with no cardiovascular disease from the Study of Women's Health Across the Nation Heart study. Women had up to two measurements of VAT and cIMT over time. Splines revealed a nonlinear trajectory of VAT with two inflection points demarcating three time segments: segment 1: >2 years before FMP; segment 2: 2 years before FMP to FMP; and segment 3: after FMP. Piecewise-linear random-effects models estimated changes in VAT. Random-effects models tested associations of menopause-related VAT with each cIMT measure separately. Estimates were adjusted for age at FMP, body mass index, and sociodemographic, lifestyle, and cardiovascular disease risk factors. VAT increased significantly by 8.2% (95% CI: 4.1%-12.5%) and 5.8% (3.7%-7.9%) per year in segments 2 and 3, respectively, with no significant change in VAT within segment 1. VAT predicted greater ICA-IMT in segment 2, such that a 20% greater VAT was associated with a 2.0% (0.8%-3.1%) greater ICA-IMT. VAT was not an independent predictor of ICA-IMT in the other segments or of the other cIMT measures after adjusting for covariates. Women experience an accelerated increase in VAT starting 2 years before menopause. This menopause-related increase in VAT is associated with greater risk of subclinical atherosclerosis in the internal carotid artery.

Background and ObjectivesCarotid intima-media thickness (IMT) is associated with chronic inflammation, and C-reactive protein (CRP) level is elevated in patients with atrial fibrillation (AF). We investigated the impacts of CRP and AF on carotid atherosclerosis and ischemic stroke in patients with suspected ischemic cerebrovascular disease.Subjects and MethodsOne-hundred forty patients (78 males) with suspected ischemic cerebrovascular disease underwent carotid ultrasonography. The mean common carotid artery IMT, mean internal carotid artery (ICA) IMT, and plaque score were measured. Patients were divided into four groups according to the presence of AF and elevated CRP level {n=46 for AF(-)CRP(-), n=38 for AF(-)CRP(+), n=43 for AF(+)CRP(-), and n=13 for AF(+)CRP(+)}.ResultsCommon carotid artery IMT was significantly higher in the AF(-)CRP(+) (0.98±0.51 mm) and AF(+)CRP(+) (0.96±0.27 mm) groups compared to the AF(-)CRP(-) (0.80±0.32 mm) and AF(+)CRP(-) (0.77±0.19 mm) groups (p=0.027). Although there was no significant difference in mean ICA IMT among the groups, plaque score was the highest in the AF(+)CRP(+) (4.18±3.84 mm) group, followed by AF(-)CRP(+) (3.87±2.78 mm), AF(+)CRP(-) (1.34±2.61 mm), and AF(-)CRP(-) (1.17±2.02 mm) (p<0.001). The AF(+)CRP(+) group showed significantly higher incidence of ischemic stroke than the other groups (all p<0.05). Binary logistic regression analysis showed that age {odds ratio (OR)=1.033, p=0.001}, elevated CRP (OR=3.884, p=0.001), and the presence of AF (OR=1.375, p=0.018) were significantly correlated with incidence of ischemic stroke.ConclusionElevated plasma CRP concentration may be a reliable surrogate marker for predicting carotid atherosclerosis in patients with AF, which may be related to increased risk of ischemic stroke.