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1.  Segment-specific association between plasma homocysteine and carotid artery intima-media thickness in the Framingham Heart Study 
Higher plasma total homocysteine (tHcy) is an established risk factor for cardiovascular disease. The relation between tHcy and carotid artery intima-media thickness (IMT) at the internal carotid artery (ICA)/bulb-IMT and common carotid artery (CCA)-IMT has not been systematically examined. Since the ICA/bulb segment is more prone to plaque formation than the CCA segment, differential associations with tHcy at these sites might suggest mechanisms of tHcy action.
We examined the cross-sectional segment-specific relations of tHcy to ICA/bulb-IMT and CCA-IMT in 2,499 participants from the Framingham Offspring Study, free of cardiovascular disease.
In multivariable linear regression analysis, ICA/bulb-IMT was significantly higher in the fourth tHcy quartile category compared to the other quartile categories, in both the age- and sex-adjusted and in the multivariable-adjusted model (P for trend <0.0001 and <0.01, respectively). We observed a significant age by tHcy interaction for ICA/bulb-IMT (P=0.03) and therefore stratified the analyses by median age (58 years). There was a significant positive trend between tHcy and ICA/bulb-IMT in individuals 58 years of age or older (P-trend <0.01), but not in the younger individuals (P-trend=0.24). For CCA-IMT, no significant trends were observed in any of the analyses.
The segment-specific association between elevated tHcy levels and ICA/bulb-IMT suggests an association between tHcy and plaque formation.
PMCID: PMC3011043  PMID: 20580253
carotid artery; intima-media thickness; homocysteine; atherosclerosis; Framingham Offspring Study
2.  Segment-Specific Associations of Carotid IMT with Cardiovascular Risk Factors: The Coronary Artery Risk Development in Young Adults (CARDIA) Study 
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 three different levels of the carotid bifurcation. Methods: Cross-sectional study of a cohort of Whites and African Americans of both genders with mean age 45 years. Traditional cardiovascular risk factors were determined in cohort members. Carotid IMT was measured from high-resolution B-mode ultrasound images at three levels: the common carotid artery (CCA), the carotid artery bulb (Bulb) and the internal carotid artery (ICA). Associations with risk factors were evaluated by multivariate linear regression analyses.
Of 3258 who underwent carotid IMT measurements, CCA, Bulb, and ICA IMT were measured at all three separate levels in 3023 (92.7%). A large proportion of the variability of CCA IMT was explained by cardiovascular risk factors (26.8%) but less so for the Bulb (11.2%) and ICA (8.0%). Carotid IMT was consistently associated with age, LDL-cholesterol, smoking and hypertension in all segments. Associations with fasting glucose and diastolic blood pressure were stronger for CCA than for the other segments. Hypertension, diabetes and current smoking had qualitatively stronger associations with Bulb IMT, and LDL cholesterol with ICA IMT. Conclusion: In our cohort of relatively young white and African-American 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.
PMCID: PMC3163306  PMID: 19910544
Carotid Intimal Medial Thickness; Risk Factors; Carotid Ultrasound
3.  Variations in Common Carotid Artery Intima-Media Thickness (cIMT) during the Cardiac Cycle: Implications for Cardiovascular Risk Assessment 
Common carotid artery (CCA) intima-media thickness (cIMT), a measure of atherosclerosis, varies between peak-systole (PS) and end-diastole (ED). This difference might affect cardiovascular risk assessment.
Materials and methods
IMT measurements of the right and left CCA were synchronized with an electrocardiogram: R-wave for ED and T-wave for PS. IMT was measured in 2930 members of the Framingham Offspring Study. Multivariable regression models were generated with ED-IMT, PS-IMT and change in IMT as dependent variables and Framingham risk factors as independent variables. ED-IMT estimates were compared to the upper quartile of IMT based on normative data obtained at PS.
The average age of our population was 57.9 years. Average difference in IMT during the cardiac cycle was 0.037 mm (95% CI: 0.035–0.038 mm). ED-IMT and PS-IMT had similar associations with Framingham risk factors (total R2= 0.292 versus 0.275) and were significantly associated with all risk factors. In a fully adjusted multivariable model, a thinner IMT at peak-systole was associated with pulse pressure (p < 0.0001), LDL-cholesterol (p = 0.0064), age (p = 0.046), and no other risk factors. Performing ED-IMT measurements while using upper quartile PS-IMT normative data lead to inappropriately increasing by 42.1% the number of individuals in the fourth IMT quartile (high cardiovascular risk category).
The difference in IMT between peak-systole and end-diastole is associated with pulse pressure, LDL-cholesterol, and age. In our study, mean IMT difference during the cardiac cycle lead to an overestimation by 42.1% of individuals at high risk for cardiovascular disease.
PMCID: PMC3544292  PMID: 22721828
Ultrasonics; Risk Factors; Carotid Arteries; Blood Pressure; systole; diastole
4.  Associations of edge detected and manual traced common carotid intima-media thickness (IMT) measurements with Framingham risk factors: the Multi-Ethnic Study of Atherosclerosis 
Carotid intima-media thickness (IMT) is a marker of cardiovascular disease derived from ultrasound images of the carotid artery. In most outcome studies, human readers identify and trace the key IMT interfaces. We evaluate an alternate approach using automated edge detection.
We study a subset of 5640 participants with an average age 61.7 years (48% men) of the Multi-Ethnic Study of Atherosclerosis composed of whites, Chinese, Hispanic and African-Americans that are part of the MESA IMT progression study. Manual tracing IMT (mt_IMT) and edge-detected IMT (ed_IMT) measurements of the far wall of the common carotid artery (CCA) served as outcome variables for multivariable linear regression models using Framingham cardiovascular risk factors and ethnicity as independent predictors.
Measurements of mt_IMT was obtainable in 99.9% (5633/5640) and of ed_IMT in 98.9% (5579/5640) of individuals. Average ed_IMT was 0.19 mm larger than mt_IMT. Inter-reader systematic differences (bias) in IMT measurements were apparent for mt_IMT but not ed_IMT. Based on complete data on 5538 individuals, associations of IMT with risk factors were stronger (p < 0.0001) for mt_IMT (model r2: 19.5%) than ed_IMT (model r2: 18.5%).
We conclude that this edge-detection process generates IMT values equivalent to manually traced ones since it preserves key associations with cardiovascular risk factors. It also decreases inter-reader bias, potentially making it applicable for use in cardiovascular risk assessment.
PMCID: PMC3169166  PMID: 21546477
Ultrasonography; Risk Factors; Carotid Arteries; Carotid Intima Media Thickness
5.  Common carotid artery intima-media thickness (IMT) progression as a predictor of stroke in MESA (Multi-Ethnic Study of Atherosclerosis) 
Carotid artery intima-media thickness (IMT) is a marker of cardiovascular disease associated with incident stroke. We study whether IMT rate-of-change is associated with stroke.
Materials and Methods
We studied 5028 participants of the Multi-Ethnic Study of Atherosclerosis (MESA) composed of whites, Chinese, Hispanic and African-Americans free of cardiovascular disease. In this MESA IMT progression study, IMT rate-of-change (mm/year) was the difference in right common carotid artery (CCA) far-wall IMT (mm) divided by the interval between two ultrasound examinations (median interval of 32 months). CCA IMT was measured in a region free of plaque. Cardiovascular risk factors and baseline IMT were determined when IMT rate-of-change was measured. Multivariable Cox proportional hazards models generated Hazard risk Ratios (HR) with cardiovascular risk factors, ethnicity and education level/income as predictors.
There were 42 first time strokes seen during a mean follow-up of 3.22 years (median 3.0 years). Average age was 64.2 years, with 48% males. In multivariable models, age (HR: 1.05 per year), systolic blood pressure (HR 1.02 per mmHg), lower HDL cholesterol levels (HR: 0.96 per mg/dL) and IMT rate-of-change (HR 1.23 per 0.05 mm/year; 95% C.L. 1.02, 1.48) were significantly associated with incident stroke. The upper quartile of IMT rate-of-change had an HR of 2.18 (95% C.L.: 1.07, 4.46) compared to the lower three quartiles combined.
Common carotid artery IMT progression is associated with incident stroke in this cohort free of prevalent cardiovascular disease and atrial fibrillation at baseline.
PMCID: PMC3202068  PMID: 21885840
Ultrasonography; Risk Factors; Carotid Arteries; Carotid Intima Media Thickness; stroke
6.  Association Between Carotid Intima-Media Thickness and Pericardial Fat in the Multi-Ethnic Study of Atherosclerosis (MESA) 
Carotid intima-media thickness (IMT) is a sub-clinical 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.
Unadjusted and multivariable adjusted linear regression analysis was used to examine associations between common (CCA-IMT) and internal (ICA-IMT) carotid IMT with PF in a random sample of 996 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) who underwent carotid ultrasound and chest CT at baseline examination.
A significant positive correlation was observed between PF and CCA-IMT (r =0.27, P<0.0001) and ICA-IMT (r =0.17, P<0.0001). 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 (β coefficient (95% CI): 0.06 (0.04, 0.08), P<0.0001) and men (0.03 (0.01, 0.05), P<0.0002), an association that persisted after further adjusting for age and ethnicity (0.02 (+0.00, 0.04), P=0.0120 for women, and 0.02 (+0.00, 0.03), P=0.0208 for men). However, after additional adjustment for atherosclerosis risk factors and either BMI 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<0.0001) and women (0.08 (0.02, 0.13), P=041). 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.
In the general population PF is associated with carotid IMT, an association that possibly not independent from markers of overall adiposity or common atherosclerosis risk factors.
PMCID: PMC2817960  PMID: 20123228
7.  Association of the Endogenous Nitric Oxide Synthase Inhibitor ADMA with Carotid Artery Intimal Media Thickness in the Framingham Heart Study Offspring Cohort 
Background and Purpose
Higher plasma concentrations of the endogenous nitric oxides synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) are associated with increased risk of cardio- and cerebrovascular events and death, presumably by promoting endothelial dysfunction and subclinical atherosclerosis. We hypothesized that plasma ADMA concentrations are positively related to common carotid artery intimal media thickness (CCA-IMT) and to internal carotid (ICA)/bulb-IMT.
We investigated the cross-sectional relations of plasma ADMA with CCA-IMT and ICA/bulb-IMT in 2958 Framingham Heart Study participants (mean age 58 years, 55% women).
In unadjusted analyses, ADMA was positively related to both CCA-IMT (β per SD increment 0.012, p<0.001) and ICA/bulb IMT (β per SD increment 0.059, p<0.001). In multivariable analyses (adjusting for age, sex, systolic blood pressure, antihypertensive treatment, smoking status, diabetes, body mass index (BMI), Total to HDL cholesterol ratio, log C-reactive protein, and serum creatinine), plasma ADMA was not associated with CCA-IMT (p=0.991), but remained significantly and positively related to ICA/bulb IMT (β per SD increment 0.0246, p=0.002).
In our large community-based sample, we observed that higher plasma ADMA concentrations were associated with greater ICA/bulb-IMT but not with CCA-IMT. These data are consistent with the notion that ADMA promotes subclinical atherosclerosis in a site-specific manner, with a greater proatherogenic influence at known vulnerable sites in the arterial tree.
PMCID: PMC2749947  PMID: 19498184
Carotid Intimal Medial Thickness; Endothelium; Epidemiology; Risk Factors; Nitric Oxide
8.  Carotid Artery Atherosclerosis, MRI Indices of Brain Ischemia and Aging and Cognitive Impairment: The Framingham Study 
Background and Purpose
Carotid atherosclerosis has been associated with increased risk of stroke, and poorer cognitive performance in older adults. The relation of carotid atherosclerosis to cognitive impairment and MRI indices of ischemia and aging in midlife is less clear.
We studied 1,975 Framingham Offspring Study participants free of stroke and dementia with available carotid ultrasound, brain MRI and neuropsychological testing. We related common and internal carotid artery intima-media thickness (ICA-IMT and CCA-IMT respectively) and internal carotid stenosis (CAS) to large white matter hyperintensity (>1-SD above age-specific mean; LWMH), total brain volume (TCBV), hippocampal volume, silent cerebral infarcts (SCI) and neuropsychological measures of verbal memory, executive function and non-verbal memory measures.
We observed that ICA-IMT, but not CCA-IMT, was associated with higher prevalence of SCI (OR 1.21, 95% CI 1.03–1.43, p<0.05), LWMH (OR 1.19, 95% CI 1.03–1.38, p<0.05), lower TCBV (−0.05 per SD, p<0.05) and poorer performance in verbal memory (−0.06 per SD; p<0.05) and non-verbal memory measures (−0.08 per SD; p<0.01), but not with hippocampal volume. CAS ≥25% was associated with a higher prevalence of LWMH (adjusted OR 1.77, 95% CI 1.25–2.53) and lower TCBV (−0.11 per SD, p=0.042) but not with SCI or hippocampal volume. CAS ≥50% was associated with higher prevalence of SCI (OR 2.53, 95% CI 1.17 – 5.44), LWMH (OR 2.35, 95% CI 1.08–5.13) and poorer performance on executive function (−0.39 per SD; p<0.05) but not with TCBV or hippocampal volume.
Carotid atherosclerosis markers were associated with MRI indices of brain ischemia and aging and with cognitive impairment in a community-based sample of middle-aged adults. Our data suggest that ICA-IMT may be a better marker for cognitive impairment than CCA-IMT.
PMCID: PMC2705324  PMID: 19265054
Carotid atherosclerosis; brain MRI; cognitive performance
9.  Risk factors and their impact on carotid intima-media thickness in young and middle-aged ischemic stroke patients and controls: The Norwegian Stroke in the Young Study 
BMC Research Notes  2014;7:176.
Vascular morbidity and mortality due to cardiovascular disease (CVD) are high after ischemic stroke at a young age. Data on carotid intima-media thickness (cIMT) as marker of atherosclerosis are scarce for young stroke populations. In this prospective case–control study, we examined cIMT, the burden of vascular risk factors (RF) and their associations among young and middle-aged ischemic stroke patients and controls. We aimed to detect clinical and sub-clinical arterial disease.
This study was conducted in 150 patients aged 15–60 years and 84 controls free of CVD. We related RF to ultrasonographic B-mode cIMT-measurements obtained from 12 standardized multiangle measurements in the common carotid artery (CCA), carotid bifurcation (BIF) and internal carotid artery (ICA).
RF burden was higher among patients than among controls (p < 0.001). In multivariate analyses of all 234 participants, increased cIMT was associated with age in each carotid segment. Incident stroke was associated with increased ICA-IMT. ICA-IMT increase was associated with a family history of CVD among patients aged 15–44 years, and with RF at mid-age. The overall cIMT difference between patients and controls was 12% for CCA, 17% for BIF and 29% for ICA. Further, increased CCA-IMT was associated with male sex and hypertension. Increased BIF-IMT was associated with dyslipidemia, coronary heart disease and smoking. Increased ICA-IMT was associated with dyslipidemia and stroke.
Ischemic stroke is associated with increased ICA-IMT, related to a family history of CVD among patients aged <45 years, and to increasing RF burden with increasing age. Preventive strategies and aggressive RF treatment are indicated to avoid future cardiovascular events.
Trial registration
NOR-SYS is registered in (NCT01597453).
PMCID: PMC3986875  PMID: 24669965
Young stroke; Ischemic stroke; Risk factors; Carotid intima-media thickness; Atherosclerosis; Ultrasound
10.  Longitudinal Predictors of Progression of Carotid Atherosclerosis in Rheumatoid Arthritis 
Arthritis and rheumatism  2011;63(11):3216-3225.
To explore predictors of change in measures of carotid atherosclerosis among rheumatoid arthritis (RA) patients without known cardiovascular disease (CVD) at baseline
RA patients underwent carotid ultrasonography at two timepoints, separated by an average of 3.2 ± 0.3 years. The associations of baseline and average patient characteristics with the average yearly change in mean maximal intima-medial thickness (IMT) of the common (CCA) and internal carotid arteries (ICA), and with incident or progressive plaque in the ICA/carotid bulb, were explored.
Among the 158 RA patients, maxCCA-IMT increased in 82% (median=16 μm/year; p<0.001) and maxICA-IMT increased in 70% (median=25 μm/year; p<0.001). Incident plaque was observed in 14% without baseline plaque [incidence rate=4.2/100 person-years (95% CI 1.61–6.82)]. Plaque progression was observed in 5% with baseline plaque. Among RA predictors, the adjusted average yearly change in maxCCA-IMT was significantly greater in patients with earlier RA vs. longer disease. Those prescribed TNF inhibitors at baseline had a 37% lower adjusted rate of maxCCA-IMT progression vs. non-users (14 vs. 22 μm/year; p=0.026). For maxICA-IMT, cumulative prednisone exposure was associated with progression [1.2 μm/year per gram (95% CI 0.1–2.4)] after adjustment, and was lower in patients prescribed statins concomitant with prednisone. Higher swollen joint count and higher average CRP were both associated with incident or progressive plaque, primarily in patients with elevated baseline CVD risk based on the Framingham score.
These prospective data provide evidence for inflammation as a contributor to subclinical atherosclerosis progression in RA, potentially modified favorably by TNF inhibitors and detrimentally by glucocorticoids.
PMCID: PMC3205252  PMID: 21965129
Atherosclerosis; Inflammation; prediction; carotid ultrasound
11.  Morphological macrovascular alterations in complex regional pain syndrome type I demonstrated by increased intima-media thickness 
BMC Neurology  2013;13:14.
Although intima-media thickness (IMT) was increased in several inflammatory diseases, studies investigating whether the inflammatory processes lead to macrovascular alteration with increased IMT in complex regional pain syndrome (CRPS) lack.
Using ultrasound (high-resolution B-mode), we compared bilaterally the IMT of the common carotid artery (CCA-IMT), the radial artery (RA-IMT), the brachial artery (BRA-IMT) and the quotient QRA/CCA, in CRPS type I (n=17), peripheral nerve injury (PNI, n=17) and pain-free controls (PFC, n=22, matched to CRPS by gender, age and traditional cardiovascular risk factors). Statistics: Spearman’s correlation, paired t-test, ANOVA (p<0.05).
Compared to PFC, RA-IMT were significantly increased in both patient groups bilaterally (mean±standard deviation, CRPS affected side vs. PFC dominant side: 0.32±0.08 mm vs. 0.19±0.08 mm, p<0.001; PNI affected side vs. PFC dominant side: 0.27±0.09 mm vs. 0.19±0.08 mm, p< 0.05; CRPS non-affected side vs. PFC non-dominant side: 0.30±0.10 mm vs. 0.19±0.09 mm, p<0.001; PNI non-affected side vs. PFC non-dominant side: 0.25±0.10 mm vs. 0.19±0.09 mm, p<0.05) and QRA/CCA (CRPS affected-side vs. PFC dominant side: 0.49±0.12 vs. 0.30±0.11, p<0.001; PNI affected side vs. PFC dominant side: 0.41±0.10 vs. 0.30±0.11, p<0.05; CRPS non-affected side vs. PFC non-dominant side: 0.43±0.19 vs. 0.30±0.13, p<0.001; PNI non-affected side vs. PFC non-dominant side: 0.39±0.14 vs. 0.30±0.13, p<0.05), and BRA-IMT - only on the affected side in CRPS (CRPS: 0.42±0.06 mm vs. PFC: 0.35±0.08 mm; p<0.05). In CRPS, QRA/CCA was significantly higher on the affected side compared to PNI (p<0.05). However, only CRPS displayed within-group side-to-side differences with a significantly increased RA-IMT and QRA/CCA on the affected side (p<0.05). The CCA-IMT was comparable between all groups and sides.
The increased IMT of peripheral arteries in CRPS suggests ongoing inflammatory process. Until now, only endothelial dysfunction has been reported. The presented morphological macrovascular alterations might explain the treatment resistance of some CRPS patients.
PMCID: PMC3570292  PMID: 23383716
Complex regional pain syndrome; Macrovascular changes; Intima-media thickness; Inflammatory alterations
12.  Bilateral common carotid artery ultrasound for prediction of incident strokes using intima-media thickness and external diameter: an observational study 
External common carotid artery (CCA) diameter and intima-media thickness (IMT) are independently associated with incident stroke and other cardiovascular events. Arterial geometry such as large IMT and large diameter may reflect vulnerable plaques and so impact stroke risk. Finally, arterial changes that exist bilaterally may increase stroke risk.
We studied middle-aged men and women (n=7276) from a prospective observational study who had right (R) and left (L) CCA IMT and external diameters measured via B-mode ultrasound (1987–89) in order to categorize CCA geometry. Using side- and gender-specific IMT and diameter medians, we categorized each measurement as large (≥ median) vs. not large (< median) and defined four geometries: both IMT and diameter were large, only one parameter was large, or neither was large (reference group). Participants were followed for first time stroke through December 31, 1999. We used proportional hazards models to assess associations between right and left CCA geometries with new stroke. We also calculated positive and negative likelihood ratios (+LR and -LR) for CCA bilateral phenotypes as a measure of diagnostic accuracy.
Presence of both large CCA IMT and large diameter on one side was associated with strong stroke risk even after risk factor adjustment (men: RCCA hazard ratio [HR]=3.7 95% confidence interval [CI]=1.9-7.4; LCCA HR=2.4 95% CI=1.4-4.4; women: RCCA HR=4.0 95% CI=1.5-10.5; LCCA HR=5.7 95% CI=1.7-19.0). Presence of both large IMT and large diameter bilaterally was the strongest predictor of stroke identifying 64% of women and 44% of men who developed strokes. This phenotype showed potential for predicting stroke among individuals (women: +LR=3.1, 95% CI=2.6-3.8; men: +LR=2.3, 95% CI=1.8-2.8).
Bilateral carotid artery geometries may be useful for stroke risk prediction.
PMCID: PMC3686606  PMID: 23768019
Stroke; Atherosclerosis; Carotid arteries; Ultrasound; Intima-media thickness; Arterial diameter; Arterial geometry; Bilateral; Prospective study
13.  Association between circulating leukocyte subtype counts and carotid intima-media thickness in Japanese subjects with type 2 diabetes 
An increased leukocyte count is an independent risk factor for cardiovascular events, but the association between leukocyte subtype counts and carotid atherosclerosis in patients with diabetes has not been determined. We therefore investigated the correlation between leukocyte subtype counts and intima-media thickness of the common carotid artery (CCA-IMT) in subjects with type 2 diabetes.
This cross-sectional study involved 484 in-patients with type 2 diabetes (282 males and 202 females), who were hospitalized for glycemic control and underwent carotid ultrasonography at Kumamoto University Hospital between 2005 and 2011. Mean and maximum CCA-IMT was measured by high-resolution B-mode ultrasonography.
Univariate analyses revealed that mean CCA-IMT was positively correlated with age, systolic blood pressure, brachial-ankle pulse wave velocity (PWV), urinary albumin excretion and duration of diabetes, but was negatively correlated with diastolic blood pressure and fasting plasma glucose. Maximum CCA-IMT was positively and negatively correlated with the same factors as mean CCA-IMT except for fasting plasma glucose. Mean CCA-IMT was positively correlated with total leukocyte (r = 0.124, p = 0.007), monocyte (r = 0.373, p < 0.001), neutrophil (r = 0.139, p = 0.002) and eosinophil (r = 0.107, p = 0.019) counts. Maximum CCA-IMT was positively correlated with total leukocyte (r = 0.154, p < 0.001), monocyte (r = 0.398, p < 0.001), neutrophil (r = 0.152, p < 0.001) and basophil counts (r = 0.102, p = 0.027). Multiple regression analyses showed that monocyte count, age and PWV were significant and independent factors associated with mean CCA-IMT (adjusted R2 = 0.239, p < 0.001), and that monocyte count, age and urinary albumin excretion were significant and independent factors associated with maximum CCA-IMT (adjusted R2 = 0.277, p < 0.001).
Monocyte counts were positively correlated with both mean CCA-IMT and maximum CCA-IMT in patients with type 2 diabetes. Monocyte count may be a useful predictor of macrovascular complications in patients with type 2 diabetes.
Trial registration
Trial registry no: UMIN000003526.
PMCID: PMC3878795  PMID: 24373412
Leukocyte subtype counts; Carotid intima-media thickness; Diabetic macrovascular complication; Type 2 diabetes
14.  Adipokines, inflammation, insulin resistance, and carotid atherosclerosis in patients with rheumatoid arthritis 
Arthritis Research & Therapy  2013;15(6):R194.
Cardiovascular (CV) morbidity and mortality are increased in patients with rheumatoid arthritis (RA). Inflammation is thought to be an important factor in accelerated atherosclerosis in RA, whereas insulin resistance is a known risk factor for atherosclerosis in RA. We hypothesised that adipokines could be a link between inflammation, insulin resistance, and atherosclerosis in RA.
The common carotid artery (CCA) intima-media thickness (IMT), CCA resistive index (RI), and carotid plaques were measured by ultrasonography in 192 patients with RA. Insulin resistance was assessed by the homeostasis model assessment for insulin resistance (HOMA-IR). Serum adiponectin, leptin, resistin, tumor necrosis factor-α, and interleukin (IL)-6 concentrations were determined.
The CCA RI was associated with CCA IMT and the estimated total plaque volume after adjustment for conventional CV risk factors. Among adipokines, resistin and IL-6 were correlated with inflammatory parameters. Leptin and leptin:adiponectin (L:A) ratio were correlated with metabolic risk factors, including HOMA-IR. And L:A ratio was related to the CCA RI after adjustment for conventional and nonconventional CV risk factors, including HOMA-IR, erythrocyte sedimentation rate and C-reactive protein.
L:A ratio was associated with HOMA-IR and carotid RI. L:A ratio might be an independent factor for predicting cardiovascular risk in patients with RA.
PMCID: PMC3978659  PMID: 24245495
15.  Sex Differential Genetic Effect of Chromosome 9p21 on Subclinical Atherosclerosis 
PLoS ONE  2010;5(11):e15124.
Chromosome 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 Findings
Carotid 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.
Chromosome 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.
PMCID: PMC2994883  PMID: 21152093
16.  Heritability of Carotid Intima-Media Thickness: A Twin Study 
Atherosclerosis  2007;197(2):814-820.
To estimate the heritability of carotid intima-media thickness (IMT), a surrogate marker for atherosclerosis, independent of traditional coronary risk factors.
Methods and Results
We performed a classical twin study of carotid IMT using 98 middle-aged male twin pairs, 58 monozygotic (MZ) and 40 dizygotic (DZ) pairs, from the Vietnam Era Twin Registry. All twins were free of overt cardiovascular disease. Carotid IMT was measured by ultrasound. Bivariate and multivariate analyses were used to determine the association between traditional cardiovascular risk factors and carotid IMT. Intraclass correlation coefficients and genetic modeling techniques were used to determine the relative contributions of genes and environment to the variation in carotid IMT. In our sample, the mean of the maximum carotid IMT was 0.75 ± 0.11. Age, systolic blood pressure and HDL were significantly associated with carotid IMT. The intraclass correlation coefficient for carotid IMT was larger in MZ (0.66; 95% confidence interval [CI], 0.62–0.69) than in DZ twins (0.37; 95% CI, 0.29–0.44), and the unadjusted heritability was 0.69 (95% CI, 0.54–0.79). After adjusting for traditional coronary risk factors, the heritability of carotid IMT was slightly reduced but still of considerable magnitude (0.59; 95% CI, 0.39–0.73).
Genetic factors have a substantial influence on the variation of carotid IMT. Most of this genetic effect occurs through pathways independent of traditional coronary risk factors.
PMCID: PMC2387097  PMID: 17825306
heritability; carotid intima-media thickness; twin study; atherosclerosis
17.  Despeckle Filtering for Multiscale Amplitude-Modulation Frequency-Modulation (AM-FM) Texture Analysis of Ultrasound Images of the Intima-Media Complex 
The intima-media thickness (IMT) of the common carotid artery (CCA) is widely used as an early indicator of cardiovascular disease (CVD). Typically, the IMT grows with age and this is used as a sign of increased risk of CVD. Beyond thickness, there is also clinical interest in identifying how the composition and texture of the intima-media complex (IMC) changed and how these textural changes grow into atherosclerotic plaques that can cause stroke. Clearly though texture analysis of ultrasound images can be greatly affected by speckle noise, our goal here is to develop effective despeckle noise methods that can recover image texture associated with increased rates of atherosclerosis disease. In this study, we perform a comparative evaluation of several despeckle filtering methods, on 100 ultrasound images of the CCA, based on the extracted multiscale Amplitude-Modulation Frequency-Modulation (AM-FM) texture features and visual image quality assessment by two clinical experts. Texture features were extracted from the automatically segmented IMC for three different age groups. The despeckle filters hybrid median and the homogeneous mask area filter showed the best performance by improving the class separation between the three age groups and also yielded significantly improved image quality.
PMCID: PMC3966465  PMID: 24734038
18.  Combination of the Framingham Risk Score and Carotid Intima-Media Thickness Improves the Prediction of Cardiovascular Events in Patients With Type 2 Diabetes 
Diabetes Care  2011;35(1):178-180.
The aim of this study was to investigate whether carotid intima-media thickness (IMT) and brachial-ankle pulse wave velocity (baPWV) add value to the Framingham risk score (FRS) in predicting the development of cardiovascular diseases (CVDs) in type 2 diabetic patients with a negative history of CVD.
Type 2 diabetic patients (n = 783) were retrospectively recruited and followed for CVD.
During a 5.4-year follow-up period, 85 incidences of CVD were recorded (10.9%). After adjustment for conventional arterial risk factors, multivariate analysis with the Cox proportional hazards model identified IMT, but not baPWV, as a significant determinant of CVD. In addition, the combination of FRS with IMT, but not with baPWV, improved the prediction of CVD.
Carotid IMT is a significant predictor of CVD in asymptomatic type 2 diabetic patients, and the combination of FRS and IMT improves the prediction of CVD in these patients.
PMCID: PMC3241317  PMID: 22028278
19.  Associations of cardiovascular risk factors, carotid intima-media thickness and left ventricular mass with inter-adventitial diameters of the common carotid artery: the Multi-Ethnic Study of Atherosclerosis (MESA) 
Atherosclerosis  2011;218(2):344-349.
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.
PMCID: PMC3186064  PMID: 21726862
carotid arteries; ultrasonics; hypertrophy; magnetic resonance imaging; remodeling; risk factors; left ventricle
20.  Does Carotid Intima-media Thickness have Relationship with Polycystic Ovary Syndrome? 
Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder associated with cardiovascular disease (CVD) risk factors and metabolic disturbances and a genetically heterogeneous disease. Intima-media thickness (IMT) is an indicator of atherosclerosis. This study aimed to determine the relation between IMT and PCOS in women.
This cross-sectional study was performed on 44 PCOS patients and 44 healthy women. Data collection included lipid profiles, blood pressure, waist circumference, body mass index (BMI), and common and internal IMT of carotid artery which were measured in studied subjects. IMT was measured by a radiologist using a linear 12 MHz ultrasound probe (LOGIC S6, GE) in carotid setting.
IMT of common carotid artery (56.8 ± 7.6 in cases versus 49.8 ± 7.3 in controls), internal carotid artery (56.9 ± 6.03 in cases versus 49.6 ± 6.9 in controls), and both common and internal carotid artery (56.6 ± 6.7 in cases versus 49.7 ± 6.9 in controls) were significantly higher in PCOS patients than healthy women (P < 0.001).
In summary, results demonstrated that carotid artery thickness as a risk for premature atherosclerosis in patients with PCOS is higher than healthy subjects. And hence care and monitoring of PCOS women with these risk factors sounds to be important and necessary.
PMCID: PMC3883250  PMID: 24404360
Carotid intima-media thickness; carotid artery thickness; intima-media thickness; oligomenorrehea; polycystic ovarian syndrome
21.  Influence of a family history of type 2 diabetes, demographic and clinical data on carotid intima-media thickness in patients with type 1 diabetes: a cross-sectional study 
Intima-media thickness (IMT) of the common carotid artery is a surrogate end point of cardiovascular disease (CVD). Identifying the factors associated with a higher IMT may contribute to the identification of subjects with higher CVD risk. Our objective was to compare the common carotid IMT of type 1 diabetes patients to healthy control subjects. The secondary objective was to determine factors associated with a higher carotid IMT.
We conducted a cross-sectional study between March 2009 and October 2013, comprising 127 type 1 diabetes patients and 125 control subjects matched by age, gender and body mass index (BMI). Carotid IMT was measured using semi-automated edge detection software.
Type 1 diabetes patients had a higher median IMT compared with control subjects (0.538; IQR: 0.500-0.607 vs 0.513 mm; IQR: 0.481-0.557, respectively p = 0.001). Women with type 1 diabetes had a higher median IMT difference compared to the control group (0.537; IQR: 0.495-0.596 vs 0.502 mm; IQR: 0.472-0.543, respectively p = 0.003) than did men with type 1 diabetes (0.547; IQR: 0.504-0.613 vs 0.528 mm; IQR: 0.492-0.575, respectively p = 0.2). Age and diabetes duration had an additive effect on the IMT of type 1 diabetes patients. Multivariate gamma regression model analysis showed that in type 1 diabetes patients, the IMT was associated with age (Exp (β) = 1.006, p < 0.001), duration of diabetes (Exp (β) = 1.004, p = 0.001), BMI (Exp (β) = 1.005, p = 0.021), family history of type 2 diabetes (Exp (β) = 1.044, p = 0.033), total cholesterol (Exp (β) = 0.999, p = 0.001) and creatinine clearance (Exp (β) = 1.000, p = 0.043).
Patients with type 1 diabetes have increased IMT, a marker of subclinical atherosclerosis. The CVD risk may be similar between men and women with type 1 diabetes, suggesting a loss of gender protection. Also, CVD risk may be higher in those with a family history of type 2 diabetes. Prospective studies are needed to confirm the predictive value of these findings and the causal effect between IMT and CVD in patients with type 1 diabetes.
PMCID: PMC4016785  PMID: 24886106
Type 1 diabetes; Carotid IMT; CVD risk; Women with type 1 diabetes; Family history of type 2 diabetes
22.  Long-term effects on carotid intima-media thickness after radiotherapy in patients with nasopharyngeal carcinoma 
Vascular abnormalities are the predominant histologic changes associated with radiation in nasopharyngeal carcinoma (NPC). This study examined if the duration after radiotherapy correlates with the progression of carotid intima-media thickness (IMT) and investigated its relationship with inflammatory markers.
One hundred and five NPC patients post-radiotherapy for more than one year and 25 healthy control subjects were examined by B-mode ultrasound for IMT measurement at the far wall of the common carotid artery (CCA). Surrogate markers including lipid profile, HbA1c, and high sensitive C-reactive protein (hs-CRP) were assessed.
The IMT of CCA was significantly increased in NPC patients and carotid plaque was detected in 38 NPC patients (38/105, 36.2%). Significant risk factors for carotid plaques included age, duration after radiotherapy, and HbA1c levels. Age, duration after radiotherapy, hs-CRP, HbA1c, and platelet count positively correlated with IMT. The cut-off value of age and duration after radiotherapy for the presence of plaque was 52.5 years and 42.5 months, respectively. In NPC subjects, multiple linear regression analysis revealed that age, gender, duration after radiotherapy and platelet counts were independently associated with CCA IMT. After adjustments for age, gender and platelet counts, IMT increased in a linear manner with duration after radiotherapy.
Radiation-induced vasculopathy is a dynamic and progressive process due to late radiation effects. Extra-cranial color-coded duplex sonography can be part of routine follow-up in NPC patients aged ≥50 years at 40 months post-radiotherapy.
PMCID: PMC3827874  PMID: 24196030
Atherosclerosis; Nasopharyngeal carcinoma; Radiotherapy; Risk factors
23.  Coronary Artery Calcium, Carotid Artery Wall Thickness and Cardiovascular Disease Outcomes in Adults 70 to 99 Years Old 
The American journal of cardiology  2008;101(2):186-192.
Few population studies have evaluated the associations of both coronary artery calcium (CAC) and carotid ultrasound with cardiovascular events, especially in adults > 70 years of age. At the Pittsburgh Field Center of the Cardiovascular Health Study, 559 men and women, mean age 80.2 (SD 4.1) years had CAC score assessed by electron beam computerized tomography scan and common and internal carotid intimal-medial wall thickness (CCA-IMT and ICA-IMT) by carotid ultrasound between 1998−2000 and were followed for total and incident cardiovascular disease events through June 2003. Crude rates and hazard ratios for total and incident events were examined with and without adjustment for cardiovascular risk factors. After 5 years, there were 127 cardiovascular disease events, 48 myocardial infarctions or cardiovascular disease deaths and 28 strokes or stroke deaths. Total and incident cardiovascular disease event rates were higher in each quartile of CAC and CCA-IMT, but not ICA-IMT. For total cardiovascular disease, the adjusted hazard ratio for the 4th vs. 1st quartile of CAC was 2.1 (95% CI = 1.2−3.9) and for CCA-IMT was 2.3 (95% CI = 1.3−4.1). The CCA-IMT was more strongly related to stroke risk than was CAC, though CAC was also an important predictor of stroke. No significant sex differences were found, though relative risks appeared to be stronger in women, especially for stroke. In conclusion, in these adults > 70 years of age, CAC and CCA-IMT had similar hazard ratios for total cardiovascular disease and coronary heart disease. The CCA-IMT was more strongly related to stroke than was CAC, but CAC was also a predictor of stroke.
PMCID: PMC2213559  PMID: 18178404
calcium; cardiovascular diseases; coronary disease; prognosis
24.  Segment-Specific Genetic Effects on Carotid Intima-Media Thickness: The Northern Manhattan Study 
Background and Purpose
Carotid intima-media thickness (IMT) is a surrogate marker of subclinical atherosclerosis and a strong predictor of stroke and myocardial infarction. The object of this study was to determine the association between carotid IMT and 702 single nucleotide polymorphisms in 145 genes.
B-mode carotid ultrasound was performed among 408 Hispanics from the Northern Manhattan Study. The common carotid artery IMT and bifurcation IMT were phenotypes of interest. Genetic effects were evaluated by the multivariate regression model adjusting for traditional vascular risk factors. For each individual, we calculated a gene risk score (GRS) defined as the total number of the significant single nucleotide polymorphisms in different genes. Subjects were then divided into 3 GRS categories using the 2 cutoff points: mean GRS ±1 SD.
We identified 6 significant single nucleotide polymorphisms in 6 genes for common carotid artery IMT and 7 single nucleotide polymorphisms in 7 genes for bifurcation IMT using the probability value of 0.005 as the significant level. There were no common significant genes for both phenotypes. The most significant genes were the tissue plasminogen activator (P=0.0005 for common carotid artery IMT) and matrix metallopeptidase-12 genes (P=0.0004 for bifurcation IMT). Haplotype analysis did not yield a more significant result. Subjects with GRS ≥9 had significantly increased IMT than those with GRS ≤5 (P<0.001). GRS was an independent predictor of both common carotid artery IMT (P=2.3×10−9) and bifurcation MT (P=7.2×10−8).
Multiple genes contributed to the variation in carotid IMT. IMT in different carotid segments may be regulated by different sets of susceptibility genes.
PMCID: PMC2676928  PMID: 18787196
atherosclerosis; carotid intima-media thickness; genetics; polymorphism
25.  The Epidemiology of Subclavian Stenosis and its Association with Markers of Subclinical Atherosclerosis: the Multi-Ethnic Study of Atherosclerosis (MESA) 
Atherosclerosis  2010;211(1):266-270.
Recent studies indicate that subclavian stenosis (SS), diagnosed by a large systolic blood pressure difference (SBPD) between the right and left brachial arteries, is associated with cardiovascular disease (CVD) risk factors and outcomes. We sought to describe the epidemiology of SS and determine its association with markers of subclinical CVD in the baseline cohort of the Multi-Ethnic Study of Atherosclerosis.
We defined SS by an absolute SBPD ≥15 mmHg. Peripheral artery disease (PAD) was defined by an ankle-brachial index ≤0.90. The coronary artery calcium score (CAC) and the common-carotid artery intima-media thickness (CCA-IMT) were measured by computed tomography and B-mode ultrasound, respectively. Odds ratios for the associations of SS with risk factors and subclinical disease were estimated using logistic regression.
Of 6,743 subjects studied, 307 participants (4.6%) had SS, with a higher prevalence in women (5.1%) than men (3.9%), and in African-Americans (7.4%) and non-Hispanic whites (5.1%) than Hispanic (1.9%) or Chinese (1.0%) participants (p<0.01). In a model including age, gender, ethnicity, traditional and novel CVD risk factors, significant associations with SS were observed for C-reactive protein (highest vs. three lower quartiles: OR=1.41; 95%CI: 1.06-1.87) and brachial artery pulse pressure (OR=1.12 /10 mmHg; 95%CI: 1.03-1.21). Adjusted for age, gender, ethnicity, traditional and novel CVD risk factors, SS was significantly associated with PAD (OR=2.35; 1.55-3.56), with CCA-IMT (highest vs. the lower three quartiles: OR=1.32; 1.00-1.75), and high CAC (score >100 vs. score=0; OR=1.43; 1.03-2.01).
The subclavian stenosis is positively associated with other markers of subclinical atherosclerosis.
PMCID: PMC2925848  PMID: 20138280
subclavian artery; blood pressure; atherosclerosis; epidemiology

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