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1.  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
2.  Associations of Carotid Artery Intima-Media Thickness (IMT) With Risk Factors and Prevalent Cardiovascular Disease 
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.
PMCID: PMC3186063  PMID: 21098848
atherosclerosis; carotid artery; disease prevalence; intima-media thickness; risk factors
3.  Predictors of Carotid Thickness and Plaque Progression Over a Decade: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Background and Purpose
Carotid artery intima-media thickness (IMT) and plaque are non-invasive markers of subclinical arterial injury that predict incident cardiovascular disease. We evaluated predictors of longitudinal changes in IMT and new plaque over a decade in a longitudinal multiethnic cohort.
Carotid IMT and plaque were evaluated in Multi-Ethnic Study of Atherosclerosis participants at exams 1 and 5, a mean (standard deviation) of 9.4 (0.5) years later. Far wall carotid IMT was measured in both common (CCA) and internal carotid arteries. A plaque score was calculated from all carotid segments. Mixed effects longitudinal and multivariate regression models evaluated associations of baseline risk factors and time-updated medication use with IMT progression and plaque formation.
The 3,441 MESA participants were 60.3 (9.4) years old (53% female; 26% African-American, 22% Hispanic, 13% Chinese); 1,620 (47%) had carotid plaque. Mean CCA IMT progression was 11.8 (12.8) μm/year. 1,923 (56%) of subjects developed new plaque. IMT progressed more slowly in Chinese (β=−2.89, p=0.001) and Hispanic participants (β=−1.81, p=0.02), and with higher baseline high-density lipoprotein cholesterol (per 5 mg/dL, β=−0.22, p=0.03), antihypertensive use (β=−2.06, p=0.0004), and time on antihypertensive medications (years) (β=−0.29, p<0.0001). Traditional risk factors were associated with new plaque formation, with strong associations for cigarette use (odds ratio 2.31, p<0.0001) and protection by African-American ethnicity (odds ratio 0.68, p<0.0001).
In a large, multi-ethnic cohort with a decade of follow-up, ethnicity is a strong, independent predictor of carotid IMT and plaque progression. Anti-hypertensive medication use was associated with less subclinical disease progression.
PMCID: PMC4213289  PMID: 25213342
Carotid arteries; Risk Factors; Epidemiology; Atherosclerosis
4.  C-reactive protein is an independent predictor for carotid artery intima-media thickness progression in asymptomatic younger adults (from the Bogalusa Heart Study) 
Conflicting information exists regarding the association between hsCRP and the progression of early stages of atherosclerosis. The purpose of the study was to investigate the association of high sensitiviy c-reactive protein (hsCRP) along with major cardiovascular (CV) risk factors on early carotid atherosclerosis progression in a large, population-based cohort study.
The study cohort included 839 young adults (aged 24 to 43 years, 70% white, 42% men) enrolled in Bogalusa Heart Study, who in 2001-2002 attended baseline examination with measurements of CV risk factors. Progression of carotid artery intima-media thickness (IMT) was assessed during a mean follow-up of 2.4 years.
Carotid artery IMT progression rates were as follows: composite carotid artery = 9.2 ± 52 μm/y, common carotid artery = 0.0 ± 51 μm/y, carotid bulb = 8.8 ± 103 μm/y, and internal carotid artery = 18.9 ± 81 μm/y. Elevated baseline hsCRP, reflecting an inflammatory state, showed independent association with composite carotid artery IMT progression. Increased age, systolic blood pressure, fasting glucose, LDL cholesterol, and current smoking were other risk associates of carotid artery IMT progression in young adults, indicating an underlying burden on the CV system by multiple risk factors.
In this population-based study, we observed independent categorical association of increased hsCRP with carotid artery IMT progression in young adults. This study underlines the importance of assesssing hsCRP levels along with smoking and traditional CV risk factor profiles in asymptomatic young adults.
PMCID: PMC3264529  PMID: 22208681
Carotid artery intima-media thickness progression; cardiovascular risk; c-reactive protein; epidemiology; young adults
5.  Relationship Between Brachial Flow - Mediated Dilation and Carotid Intima- Media Thickness in an Elderly Cohort: The Cardiovascular Health Study 
Atherosclerosis  2007;197(2):840-845.
The aim of this study was to determine the relationship between brachial flow-mediated dilation (FMD) and carotid intima-media thickness (IMT) in a large multi-ethnic elderly cohort.
Brachial flow-mediated dilation (FMD) is a physiologic measure and Carotid IMT is an anatomic structural measure of subclinical atherosclerosis. Both brachial FMD and carotid IMT have been associated with cardiovascular risk factors and cardiovascular events. The relationship between brachial FMD and carotid IMT is less clear especially in older adults.
Brachial FMD, carotid IMT and traditional cardiovascular risk factors were measured in 2338 adults, age 72–98 years who were participants in the Cardiovascular Health Study. The relationship between FMD and IMT was assessed both unadjusted and also after adjusting for age, gender, race/ethnicity. BMI, HDL, LDL, systolic and diastolic blood pressure, serum creatinine, current smoking, diabetes mellitus, hormone therapy and prior CVD.
Both brachial FMD and carotid IMT correlated significantly with age, HDL levels, waist/hip ratio, serum cholesterol and number of CV risk factors. Brachial FMD was not associated with CCA IMT in this elderly cohort (Pearson partial correlation coefficient= −0.0252, p=0.222). In the adjusted linear regression model with CCA IMT as the dependent variable, brachial FMD was also not associated with CCA IMT (beta coefficient= −0.006, p=0.470)
Brachial FMD and CCA IMT are not related in population-based older adults. Brachial FMD and CCA IMT may be distinct and independent stages in the complex atherosclerotic process.
PMCID: PMC4115586  PMID: 17804000
Brachial flow-mediated dilation; carotid intima-media thickness; endothelial function; atherosclerosis; elderly
6.  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
7.  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
8.  Coronary Calcification is More Predictive of Carotid Intimal Medial Thickness in Black Compared to White Middle Aged Men 
Atherosclerosis  2007;196(2):913-918.
Race-specific data for the association between coronary artery calcification (CAC) and carotid intimal medial thickness (IMT) are limited. We sought to compare black-white specific associations of these two measures.
We conducted a population-based study of 379 randomly-selected men aged 40–49 years (84 black and 295 white) from Allegheny County, US (2004–2006). Agatston CAC score was evaluated by electron-beam tomography and carotid IMT was evaluated by ultrasonography.
Compared to white men, black men had similar prevalence of CAC (p=0.56) and higher total carotid IMT (p<0.001). In black and white men, CAC score had significant positive correlations with total carotid IMT (r=0.47 & r=0.24 respectively, p<0.001 for both) as well as the IMT for the common carotid artery (CCA), internal carotid artery and carotid bulb. The associations of CAC with total and CCA IMT were significantly stronger in black (beta=0.07 & beta=0.05 respectively) than white men (beta=0.03 & beta=0.01 respectively) after adjustment for traditional coronary risk factors (p=0.046 & p=0.036 respectively).
In black and white middle-aged men, CAC score had significant positive correlations with total and segmental carotid IMT. CAC was more predictive of total and CCA IMT in black than white men independent of coronary risk factors.
PMCID: PMC3089019  PMID: 17350026
Epidemiology; atherosclerosis; coronary calcification; carotid intimal medial thickness; Caucasian; black
9.  Occupational Mobility and Carotid Artery Intima-Media Thickness: Findings from the Coronary Artery Risk Development in Young Adults (CARDIA) Study 
Psychosomatic medicine  2011;73(9):795-802.
To examine whether 10-year change in occupational mobility is related to carotid artery intima-media thickness (IMT) 5 years later.
Data were obtained from 2350 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Occupational standing was measured at the Year 5 and 15 CARDIA follow-up exams when participants were 30.2+3.6 and 40.2+3.6 years of age, respectively. IMT (common (CCA), internal (ICA), and bulb) was measured at Year 20. Occupational mobility was defined as the change in occupational standing between Years 5 and 15 using two semi-continuous variables. Analyses controlled for demographics, CARDIA center, employment status, parents’ medical history, own medical history, Year 5 Framingham risk score, physiological risk factors and health behaviors averaged across the follow-up, and sonography reader.
Occupational mobility was unrelated to IMT save for an unexpected association of downward mobility with less CCA-IMT (β= −.04, p=.04). However, associations differed depending on initial standing (Year 5) and sex. For those with lower initial standings upward mobility was associated with less CCA-IMT (β= −.07, p=.003) and downward mobility with greater CCA-IMT and bulb-ICA-IMT (β= .14, p=.01 and β= .14, p=.03, respectively); for those with higher standings, upward mobility was associated with greater CCA-IMT (β= .15, p=.008) but downward mobility was unrelated to either IMT measure (ps>.20). Sex-specific analyses revealed associations of upward mobility with less CCA-IMT and bulb-ICA-IMT among men only (ps<.02).
Occupational mobility may have implications for future cardiovascular health. Effects may differ depending on initial occupational standing and sex.
PMCID: PMC3216404  PMID: 22021461
CARDIA; IMT; occupational mobility; occupational social class; socioeconomic status
10.  Associations of common carotid intima-media thickness (IMT) with coronary heart disease risk factors and events vary with distance from the carotid bulb 
Common carotid artery (CCA) intima-media thickness (IMT) can be measured by ultrasound near to or below the carotid bulb. This might affect associations of IMT with coronary heart disease (CHD) risk factors and events.
We performed IMT measurements near and below the divergence of the CCA bulb, in 279 white individuals, aged 45–54 years, free of CHD at baseline and a subset of the Multi-Ethnic Study of Atherosclerosis (MESA), a cohort composed of Whites, Blacks, Chinese and Hispanics. Participants were followed for an average of 8.2 years. Far wall mean of the maximum IMT (MMaxIMT) and mean of the mean IMT (MMeanIMT) of the right and left CCA were averaged. Framingham risk factors were used in multivariable linear regression models. Parsimonious Cox proportional regression models included first time CHD as outcome.
MMeanIMT below the bulb was smaller than near the bulb (0.51 mm +/− 0.078 mm versus 0.56 +/− 0.088 mm; p < 0.001) and had similar associations with risk factors (model R2 of 0.215 versus 0.186). MMaxIMT below the bulb was associated with risk factors (model R2: 0.211), MMaxIMT near to the bulb was not (R2: 0.025). MMeanIMT and MMaxIMT below the bulb were associated with CHD events (HR 1.67; p = 0.047 and 1.72; p= 0.037, respectively) but not when measured near the bulb.
CCA IMT measurements made below the bulb are smaller but have more consistent associations with CHD risk factors and outcomes as compared to IMT measured near the bulb.
PMCID: PMC4149919  PMID: 24944141
risk factors; common carotid artery; ultrasound; coronary heart disease; intima media thickness; carotid artery bifurcation
11.  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
12.  Contrast of the impact of multiple cardiovascular risk factors on the femoral and carotid intima-media thickness in asymptomatic young adults: The Bogalusa Heart Study 
Atherosclerosis  2011;216(2):359-364.
Impact of multiple cardiovascular (CV) risk factors on the intima-media thickness (IMT) of femoral and carotid artery segments measured simultaneously has not been studied in asymptomatic adults. This study examined the impact of multiple CV risk factors on the IMT in asymptomatic adults.
Femoral and carotid IMT were measured by B-mode ultrasonography in 1080 asymptomatic subjects (aged 24–43 years) of the Bogalusa Heart Study.
In multivariate analyses, systolic blood pressure, age, male, total cholesterol/HDL cholesterol ratio and smoking were common independent predictor variables for the femoral and carotid IMT. Systolic blood pressure followed by age were the major determinant risk factors for the IMT of all arterial segments except carotid bulb for which age was the major predictor. The independent variables listed explained 11% of the variability in femoral IMT, 28% in common carotid, 18% in carotid bulb, 10% in internal carotid and 27% in composite carotid segments. Mean IMT increased with increasing number of risk factors in all arterial segments; p for trend = 0.003 for femoral and 0.001 for all carotid segments.
The observed deleterious trend of increasing IMT of the femoral and different segments of the carotid artery with increasing number of CV risk factors provide evidence of silent systemic atherosclerosis in asymptomatic young adults. These findings underscore the importance of multiple for risk factors profiling in early life. Studies of the femoral and carotid IMT may be helpful along with measurements of risk factors for evaluation of asymptomatic atherosclerotic disease.
PMCID: PMC3110625  PMID: 21376319
femoral and carotid artery; intima-media thickness; risk factors; ultrasonography; arterial disease
13.  Colour Doppler Evaluation of Extracranial Carotid Arteries: A Clinical and Radiological Correlation 
Atherosclerosis (i.e. hardening and thickening of arteries) causes vascular remodeling, obstruction of lumen, abnormalities of blood flow and reduced oxygenation of target tissues. Manifestation of atherosclerosis in the form of either Myocardial Infarction or Stroke is the major cause of morbidity and mortality. This study evaluated extracranial carotid arteries of patients (>60 years) who presented with risk factors of atherosclerosis and determined the association of risk factors with carotid abnormalities.
To evaluate the prevalence of atherosclerosis, haemodynamic and morphological changes that take place in extra cranial portion of carotid arteries in patients with risk factors of atherosclerosis (Diabetes Mellitus, Hypertension, Smoking, Stroke, Coronary Artery Disease, Hypercholesterolaemia) and determine the association of risk factors with carotid abnormalities.
Materials and Methods
The prospective cross-sectional analytical study included the examination of Extracranial carotid arteries of 1043 patients over a period of 2 years (2013-2015) using duplex ultrasound. Assessment of CCA-IMT, ICA-IMT and percent stenosis was done using a linear probe of 8-12 MHz.
Statistical Analysis
Correlation between risk factors of atherosclerosis, wall thickness of common carotid (CCA-IMT), internal carotid arteries (ICA-IMT) and stenosis was studied using statistical tools like multiple logistic regression analysis and analysis of variance (p<0.05) using SPSS 17.0.
Maximum percent stenosis increased with increase in age. Prevalence of severe stenosis (>70%) was low while the prevalence of mild stenosis (<50%) was quite high. In all age groups, stenosis was more prevalent and more severe in men as compared to women. Hypertension showed the strongest positive correlation with all three measures of interest CCA-IMT, ICA-IMT and maximum percent stenosis. Stroke history showed strong positive correlation with CCA-IMT and stenosis. Smoking, Diabetes Mellitus, Hypercholesterolaemia, Heart disease showed strong association with all three measures as well. Atherosclerotic plaques were mostly found at the site of carotid bifurcation.
CCA-IMT was strongly associated with hypertension, smoking and diabetes mellitus. ICA-IMT was strongly associated with hypertension and history of heart disease. Percent stenosis was strongly associated with smoking and history of heart disease.
PMCID: PMC4740669  PMID: 26894141
Atherosclerosis; Intima-media thickness; Plaque; Stroke; Stenosis; Ultrasound
14.  Reappraisal of velocity criteria for carotid bulb/internal carotid artery stenosis utilizing high-resolution B-mode ultrasound validated with computed tomography angiography 
Journal of vascular surgery  2008;48(1):104-113.
Reliability of the most commonly used duplex ultrasound (DUS) velocity thresholds for internal carotid artery (ICA) stenosis has been questioned since these thresholds were developed using less precise methods to grade stenosis severity based on angiography. In this study, maximum percent diameter carotid bulb ICA stenosis (European Carotid Surgery Trial [ECST] method) was objectively measured using high resolution B-mode DUS validated with computed tomography angiography (CTA) and used to determine optimum velocity thresholds for ≥50% and ≥80% bulb internal carotid artery stenosis (ICA).
B-mode DUS and CTA images of 74 bulb ICA stenoses were compared to validate accuracy of the DUS measurements. In 337 mild, moderate, and severe bulb ICA stenoses (n = 232 patients), the minimal residual lumen and the maximum outer bulb/proximal ICA diameter were determined on longitudinal and transverse images. This in contrast to the North American Symptomatic Carotid Endarterectomy Trial (NASCET) method using normal distal ICA lumen diameter as the denominator. Severe calcified carotid segments and patients with contralateral occlusion were excluded. In each study, the highest peak systolic (PSV) and end-diastolic (EDV) velocities as well as ICA/common carotid artery (CCA) ratio were recorded. Using receiver operating characteristic (ROC) analysis, the optimum threshold for each hemodynamic parameter was determined to predict ≥50% (n = 281) and ≥80% (n = 62) bulb ICA stenosis.
Patients mean age was 74 ± 8 years; 49% females. Clinical risk factors for atherosclerosis included coronary artery disease (40%), diabetes mellitus (32%), hypertension (70%), smoking (34%), and hypercholesterolemia (49%). Thirty-three percent of carotid lesions (n = 110) presented with ischemic cerebrovascular symptoms and 67% (n = 227) were asymptomatic. There was an excellent agreement between B-mode DUS and CTA (r = 0.9, P = .002). The inter/intraobserver agreement (κ) for B-mode imaging measurements were 0.8 and 0.9, respectively, and for CTA measurements 0.8 and 0.9, respectively. When both PSV of ≥155 cm/s and ICA/CCA ratio of ≥2 were combined for the detection of ≥50% bulb ICA stenosis, a positive predictive value (PPV) of 97% and an accuracy of 82% were obtained. For a ≥80% bulb ICA stenosis, an EDV of ≥140 cm/s, a PSV of ≥370 cm/s and an ICA/CCA ratio of ≥6 had acceptable probability values.
Compared with established velocity thresholds commonly applied in practice, a substantially higher PSV (155 vs 125 cm/s) was more accurate for detecting ≥50% bulb/ICA stenosis. In combination, a PSV of ≥155 cm/s and an ICA/CCA ratio of ≥2 have excellent predictive value for this stenosis category. For ≥80% bulb ICA stenosis (NASCET 60% stenosis), an EDV of 140 cm/s, a PSV of ≥370 cm/s, and an ICA/CCA ratio of ≥6 are equally reliable and do not indicate any major change from the established criteria. Current DUS ≥50% bulb ICA stenosis criteria appear to overestimate carotid bifurcation disease and may predispose patients with asymptomatic carotid disease to untoward costly diagnostic imaging and intervention.
PMCID: PMC3506188  PMID: 18486416
15.  Risk Factors Associated with Aortic and Carotid Intimal-Medial Thickness in Adolescents and Young Adults: the Muscatine Offspring Study 
To determine whether cardiovascular risk factors are associated with aortic and carotid intimal-medial thickness (aIMT and cIMT) in adolescents and young adults.
Atherosclerotic lesions begin developing in youth, first in the distal abdominal aorta and later in the carotid arteries. Knowledge of how risk factors relate to aIMT and cIMT may help in the design of early interventions to prevent cardiovascular disease.
Participants were 635 members of the Muscatine Offspring cohort. The mean aIMT and cIMT were measured using an automated reading program.
The means (SDs) of aIMT and cIMT were 0.63 (0.14) mm and 0.49 (0.04) mm, respectively. In adolescents (ages 11 to 17), aIMT was associated with triglycerides, systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), and waist/hip ratio, after adjusting for age, gender, and height. In young adults (ages 18 to 34), aIMT was associated with those same five risk factors, plus HDL-cholesterol and pulse pressure. In adolescents, cIMT was associated with SBP, pulse pressure, heart rate, BMI, and waist/hip ratio. In young adults, cIMT was associated total cholesterol, LDL-cholesterol, triglycerides, SBP, .DBP, BMI, waist/hip ratio, and HbA1C. In both age groups, aIMT and cIMT were significantly correlated with the PDAY coronary artery risk score.
Both aIMT and cIMT are associated with cardiovascular risk factors. Using aIMT in adolescents gives information beyond that obtained from cIMT alone. Measurement of aIMT and cIMT may help identify those at risk for premature cardiovascular disease.
PMCID: PMC2747309  PMID: 19520251
Atherosclerosis; Ultrasound; Preclinical disease; Abdominal aorta; IMT
16.  Bone mineral density and atherosclerosis: The Multi-Ethnic Study of Atherosclerosis, Abdominal Aortic Calcium Study 
Atherosclerosis  2009;209(1):283-289.
Molecular and cell biology studies have demonstrated an association between bone and arterial wall disease, but the significance of a population-level association is less clear and potentially confounded by inability to account for shared risk factors.
To test population-level associations between atherosclerosis types and bone integrity.
Main Outcome Measures
Volumetric trabecular lumbar bone mineral density (vBMD), ankle-brachial index (ABI), intima-media thickness of the common carotid (CCA-IMT) and internal carotid (ICA-IMT) arteries, and carotid plaque echogenicity.
Design, Setting and Participants
A random subset of participants from the Multi-Ethnic Study of Atherosclerosis (MESA) assessed between 2002 and 2005.
904 post-menopausal female (62.4 years; 62% non-white; 12% ABI<1; 17% CCA-IMT>1mm; 33% ICA-IMT>1mm) and 929 male (61.4 years; 58% non-white; 6% ABI<1; 25% CCA-IMT>1mm; 40% ICA-IMT>1mm) were included. In serial, sex-specific regression models adjusting for age, ethnicity, body mass index, dyslipidemia, hypertension, smoking, alcohol consumption, diabetes, homocysteine, interleukin-6, sex hormones, and renal function, lower vBMD was associated with lower ABI in men (p for trend <0.01) and greater ICA-IMT in men (p for trend <0.02). CCA-IMT was not associated with vBMD in men or women. Carotid plaque echogenicity was independently associated with lower vBMD in both men (trend p=0.01) and women (trend p<0.04). In all models, adjustment did not materially affect results.
Lower vBMD is independently associated with structural and functional measures of atherosclerosis in men and with more advanced and calcified carotid atherosclerotic plaques in both sexes.
PMCID: PMC4254856  PMID: 19819456
17.  Lipids and lipoprotein ratios: The contribution to carotid intima media thickness in adolescents and young adults with type 2 diabetes mellitus 
Journal of clinical lipidology  2013;7(5):441-445.
Dyslipidemia is common among adolescents with type 2 diabetes (T2D).
To assess whether the lipoprotein ratios LDL/HDL or TG/HDL (low density lipoprotein cholesterol/ high density lipoprotein cholesterol or triglycerides/HDL) or non-HDL cholesterol are more useful than the traditional lipid panel to predict increased arterial thickness in adolescents and young adults T2D. .
We evaluated 244 T2D adolescents and young adults in a cross sectional study (mean age 18 years, 56% African American, 65% female). Demographics, anthropometrics, and laboratory data were collected. Arterial thickness was assessed using carotid intima media thickness (IMT). Bivariate correlations and general linear models were used to determine the independent contributions of the various lipid parameters to carotid IMT.
Bivariate correlations revealed LDL/HDL ratio was the strongest predictor carotid IMT (p<0.02). After adjustment for potential covariates LDL/HDL was no longer significant. HDL cholesterol was the only lipid to independently (negatively) contribute to carotid IMT. Other risk factors that were independently associated with carotid IMT included age, race, sex and body mass index z score and hemoglobin A1C. Together these cardiovascular risk factors explained less than 20% of the variance in carotid IMT.
HDL cholesterol is the only lipid to independently associate with carotid IMT. Lipoprotein ratios and non-HDL did not provide additional information. The low variance in carotid IMT explained by traditional risk factors suggests nontraditional risk factors may be important to assess to better understand the contributors to early stage atherosclerosis in adolescents and young adults with T2D.
PMCID: PMC3788355  PMID: 24079285
type 2 diabetes; lipids; lipoproteins; adolescents; pediatrics; carotid intima media thickness; vascular disease
18.  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
19.  Alcohol consumption and carotid artery structure in Korean adults aged 50 years and older 
BMC Public Health  2009;9:358.
Epidemiologic studies of the association between alcohol consumption and carotid artery structure have reported conflicting results. We investigated the association between alcohol consumption and carotid atherosclerosis by evaluating the effects of alcohol intake on carotid artery enlargement.
The study population consisted of 4302 community-dwelling Koreans (1577 men and 2725 women) aged 50 years and over. All the subjects had participated in the baseline survey of the Dong-gu Study conducted between 2007 and 2008. Daily alcohol consumption was determined by the number and frequency of alcoholic beverages consumed. We measured common carotid artery intima-media thickness (CCA-IMT), common carotid and bulb IMT (CB-IMT), carotid plaques, and the diameter of the common carotid artery (CCA-diameter) using high-resolution B-mode ultrasonography. We used analysis of covariance and multiple logistic regressions to determine the relationship between alcohol consumption and carotid artery parameters.
CCA-IMT and CB-IMT were negatively correlated with alcohol consumption after controlling for cardiovascular risk factors in men (p for linear trend = 0.009 and = 0.038, respectively). The multivariate-adjusted odds ratio (OR) for carotid plaques was significantly higher in men who consumed >40.0 g/d (OR = 1.81, 95% CI = 1.13-2.91), although a significant positive correlation was observed between alcohol consumption and carotid plaques (p for linear trend = 0.027). Neither carotid IMT nor carotid plaques were correlated with alcohol intake in women. Alcohol intake was positively correlated with CCA-diameter adjusted for carotid IMT and plaques in the multivariate-adjusted model in both sexes (p for linear trend <0.001 for men and 0.020 for women).
The results of our study indicate that alcohol consumption is inversely related to carotid IMT and positively related to carotid plaques in men, but not women. However, alcohol intake is positively associated with CCA-diameter in both men and women. Additional large population-based prospective studies are needed to confirm the effects of alcohol consumption on carotid artery structure.
PMCID: PMC2761892  PMID: 19775442
20.  Genetic polymorphisms at SIRT1 and FOXO1 are associated with carotid atherosclerosis in the SAPHIR cohort 
BMC Medical Genetics  2014;15:112.
SIRT1 and FOXO1 interact with each other in multiple pathways regulating aging, metabolism and resistance to oxidative stress and control different pathways involved in atherosclerotic process. It is not known, if genetic polymorphisms (SNPs) at the SIRT1 and FOXO1 have an influence on carotid atherosclerosis.
Intima-media thickness (IMT) was measured on the common and internal carotid arteries. Morphological alterations of the carotid arteries and size of these alterations were included in the B-score grading on a five point scale. Eleven SNPs at SIRT1 and FOXO1 gene loci were genotyped in the SAPHIR cohort (n = 1742). The association of each SNP with common carotid IMT, internal carotid IMT and B-score was analyzed using linear regression models.
A significant association was found between common carotid IMT and two SNPs at FOXO1 - rs10507486, rs2297627 (beta = -0.00168, p = 0.0007 and beta = -0.00144, p = 0.0008 respectively) and at least a trend for rs12413112 at SIRT1 (beta = 0.00177, p = 0.0157) using an additive model adjusting for age and sex. Additional adjustment for traditional cardiovascular risk factors and markers (BMI, smoking status, hypertension, total cholesterol, HDL-cholesterol, hsCRP) even improved the strength of this association (p = 0.0037 for SIRT1 and p = 0.0002 for both SNPs at FOXO1). Analysis for internal carotis IMT and B-score did not reveal any significant association. One haplotype in FOXO1 showed a moderate effect on common carotid IMT and B-score in comparison to the reference haplotype of this gene. Several SNPs within SIRT1 showed differential effects for men and women with higher effect sizes for women: rs3740051 on all three investigated phenotypes (interaction p-value < 0.0069); rs2236319 on common and internal carotid IMT (interaction p-value < 0.0083), rs10823108, rs2273773 on common carotid IMT and rs1467568 on B-score (interaction p-value = 0.0007). The latter was significant in women only (betawomen = 0.111, pwomen = 0.00008; betamen = -0.009, pmen = 0.6464).
This study demonstrated associations of genetic variations at the SIRT1 and FOXO1 loci with carotid atherosclerosis and highlighted the need for further investigation by functional studies.
PMCID: PMC4411770  PMID: 25273948
21.  Effect of Intensive Diabetes Treatment on Carotid Artery Wall Thickness in the Epidemiology of Diabetes Interventions and Complications 
Diabetes  1999;48(2):383-390.
The Epidemiology of Diabetes Interventions and Complications (EDIC) is a multicenter longitudinal observational study of the Diabetes Control and Complications Trial (DCCT) cohort. One of the major objectives of EDIC is to study the development and progression of atherosclerotic cardiovascular disease in type 1 diabetes. In this study, we evaluated the role of cardiovascular risk factors and antecedent therapy in the DCCT on carotid intima-media wall thickness (IMT) in type 1 diabetes. At ~18 months after the end of the DCCT, high-resolution B-mode ultrasonography was used to assess the carotid arteries of 1,325 patients with type 1 diabetes, 19–51 years of age, with duration of diabetes ranging from 6.3 to 26.1 years. An age- and sex-matched nondiabetic population (n = 153) was studied with the same protocol. The ultrasound protocol was carried out in 28 EDIC clinics by centrally trained and certified sonographers using one of three scanning systems. Determination of IMT from videotaped images was performed by a single reader at the Central Ultrasound Reading Unit. Univariate associations with greater IMT were strongest for older age and longer diabetes duration, greater waist-to-hip ratio (men only), higher blood pressure, higher LDL cholesterol, and smoking. The DCCT therapy group (intensive versus conventional) and HbA1c, measured at the time of the ultrasound or the mean HbA1c during the DCCT, were not significantly related to IMT. Multivariate analyses suggest that age, height, smoking, and BMI were the major predictors of common carotid IMT, whereas age, smoking, and LDL cholesterol predicted internal carotid IMT. There were significant differences between the IMT values of the internal carotid artery in the EDIC male cohort and similarly aged male nondiabetic control subjects. There were no significant differences between the IMT values in the EDIC female cohort and similarly aged female nondiabetic control subjects. At this point in the planned 10-year follow-up of the DCCT cohort, neither intensive therapy nor HbA1c level appears to influence the early signs of atherosclerosis. Traditional risk factors, including age, smoking, and LDL cholesterol, were related to IMT. As the cohort is only now entering the age interval during which rapid progression and clinical expression of atherosclerosis are expected, further follow-up will help to determine the role of hyperglycemia, and its interaction with other risk factors, on the development of atherosclerosis.
PMCID: PMC2622732  PMID: 10334318
22.  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
23.  Cardiovascular Risk Factor Profiles for Peripheral Artery Disease and Carotid Atherosclerosis among Chinese Older People: A Population-Based Study 
PLoS ONE  2014;9(1):e85927.
Epidemiological data concerning atherosclerotic disease among older people in rural China are sparse. We seek to determine prevalence and cardiovascular risk factor profiles for peripheral artery disease (PAD) and carotid atherosclerosis (CAS) among Chinese older people living in a rural community.
This cross-sectional study included 1499 participants (age ≥60 years, 59.0% women) of the Confucius Hometown Aging Project in Shandong, China. From June 2010–July 2011, data were collected through interviews, clinical examinations, and laboratory tests. PAD was defined as an ankle-brachial index ≤0.9. Carotid intima-media thickness (cIMT) and carotid artery stenosis were assessed by ultrasonography. We defined moderate stenosis as carotid stenosis ≥50%, and severe stenosis as carotid stenosis ≥70%. cIMT≥1.81 mm was considered as an increased cIMT (a measure of CAS). Data were analyzed with multiple logistic models.
The prevalence was 5.7% for PAD, 8.9% for moderate stenosis, 1.8% for severe stenosis, and 11.2% for increased cIMT. After controlling for multiple potential confounders, diabetes, an increased low-density lipoprotein cholesterol (LDL-C)/high-density lipoprotein cholesterol (HDL-C) ratio, and hypertension were significantly or marginally associated with PAD. Ever smoking, hypertension, and an increased LDL-C/HDL-C ratio were significantly associated with an increased likelihood of increased cIMT. An increasing number of those cardiovascular risk factors were significantly associated with an increasing odds ratio of PAD and increased cIMT, respectively (p for linear trend <0.001).
Among Chinese older people living in a rural community, PAD, carotid artery stenosis, and an increased cIMT are relatively uncommon. Cardiovascular risk factor profiles for PAD and CAS are slightly different, with hypertension and an increased LDL-C/HDL-C ratio being associated with an increased likelihood of both PAD and increased cIMT.
PMCID: PMC3895010  PMID: 24465793
24.  Pulse Pressure and Subclinical Cardiovascular Disease in the Multi-Ethnic Study of Atherosclerosis 
American Journal of Hypertension  2013;26(5):636-642.
Brachial pulse pressure (PP) has been found to be associated with markers of subclinical cardiovascular disease, including carotid intima–media thickness and left-ventricular mass index (LVMI), but it is unclear whether these associations are independent of traditional cardiovascular risk factors and of the steady, nonpulsatile component of blood pressure (BP). Moreover, it is unknown whether these associations are modified by gender, age, or race/ethnicity.
We used multivariate linear regression models to assess the relationship between brachial PP and three markers of subclinical cardiovascular disease (CVD) (common carotid intima–media thickness (CC-IMT), internal carotid intima–media thickness (IC-IMT), and LVMI) in four race/ethnic groups in the Multi-Ethnic Study of Atherosclerosis. The models were adjusted for traditional Framingham risk factors (age, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, diabetes, smoking status), use of lipid-lowering medication, use of antihypertensive medication, study site, and mean arterial pressure (MAP).
The assessment was done on 6,776 participants (2,612 non-Hispanic white, 1,870 African-American, 1,494 Hispanic, and 800 Chinese persons). The associations between brachial PP and CC-IMT, IC-IMT, and LVMI were significant in fully adjusted models. The three subclinical markers also showed significant interactions with gender (P < 0.0001), with stronger interactions in men. There was an interaction with age for LVMI (P = 0.004) and IC-IMT (P = 0.008). Race/ethnicity modified the association of PP with CC-IMT.
Brachial PP was independently associated with subclinical CVD after adjustment for cardiovascular risk factors and mean arterial pressure (MAP). The strength of the association differed significantly for strata of gender, age, and race/ethnicity.
PMCID: PMC3657481  PMID: 23388832
pulse pressare; subclinical cardiovascular disease; carotid intima–media thickness; left ventricular mass index; aging; hypertension; arterial stiffness; blood pressure.
25.  Angle between the common and internal carotid arteries detected by ultrasound is related to intima-media thickness among those with atherosclerotic disease 
Although carotid artery structural variations have been detected by ultrasound, their clinical significance is not fully understood. The objective of this study was to determine whether the angle between the common carotid artery (CCA) and the internal carotid artery (ICA), designated angle α, an ultrasound-detectable carotid artery structural variation, is related to carotid artery intima-media thickness (IMT), a surrogate marker for carotid atherosclerosis.
As a cross-sectional study, we measured angle α in routine carotid artery ultrasounds from 176 subjects (130 men) with atherosclerotic disease/risk factors that attended Kouseiren Hospital in Kagoshima City, Japan between August 2007 and April 2009. We evaluated the correlation between the angle α and CCA- or ICA-IMT.
Angle α was weakly correlated with age but significantly correlated with ICA-IMT. The correlation was stronger in subjects with an ICA-IMT ≥ 0.5 mm than in those with an ICA-IMT < 0.5 mm (Right side r = 0.475 vs. 0.246, Left side r = 0.498 vs. 0.301, respectively). Upon multivariate logistic regression analysis, angle α and serum low-density lipoprotein cholesterol were independent explanatory variables for ICA-IMT.
Angle α is related to ICA-IMT in subjects with atherosclerotic disease or risk factors in this study.
Electronic supplementary material
The online version of this article (doi:10.1007/s12199-015-0453-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4434238  PMID: 25773682
Atherosclerotic risk; Cross-sectional study; Intima-media thickness; Vessel structural variations

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