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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.  Association of the Complement Factor H Y402H Polymorphism With Cardiovascular Disease Is Dependent Upon Hypertension Status: The ARIC Study 
American journal of hypertension  2008;21(5):533-538.
Complement factor H (CFH) is a plasma protein that is essential in the regulation of the alternative complement pathway and has been implicated as taking part in complement inhibition in atherogenesis. We evaluated the association of the y402H polymorphism with incident coronary heart disease (CHD), incident ischemic stroke, and carotid artery wall thickness (intima-media thickness (IMT)) in the Atherosclerosis Risk in Communities (ARIC) cohort.
Incident ischemic stroke and CHD were identified through annual telephone calls and hospital and death certificate surveillance. Carotid IMT was measured by means of high-resolution B-mode ultrasound. Four hundred eighty-three validated ischemic stroke and 1,544 CHD events were identified. Because of allele frequency differences between whites and African Americans, analyses were performed separately according to the racial group.
The 402HH homozygous genotype was a significant predictor of incident ischemic stroke in whites (hazard rate ratio (HRR) 1.47, 95% confidence interval (CI) 1.05–2.05). Significant interaction effects between genotype and hypertension were observed for CHD in whites and for cIMT in whites and African Americans. In further analyses of incident CHD, genotypes carrying the 402H allele were a significant predictor of incident CHD in whites who had hypertension (402yH: HRR 1.19, 95% CI 1.01–1.40; 402HH: HRR 1.28, 95% CI 1.04–1.57). The 402H allele was also associated with higher cIMT measures for whites in the overall cohort, and for whites with hypertension.
The CFH 402H allele was associated with an increased risk for incident CHD and ischemic stroke in whites, with the strength and significance of the association dependent upon hypertension status.
PMCID: PMC2674647  PMID: 18292760
3.  Common carotid artery intima–media thickness is as good as carotid intima–media thickness of all carotid artery segments in improving prediction of coronary heart disease risk in the Atherosclerosis Risk in Communities (ARIC) study 
European Heart Journal  2011;33(2):183-190.
Carotid intima–media thickness (CIMT) and plaque information can improve coronary heart disease (CHD) risk prediction when added to traditional risk factors (TRF). However, obtaining adequate images of all carotid artery segments (A-CIMT) may be difficult. Of A-CIMT, the common carotid artery intima–media thickness (CCA-IMT) is relatively more reliable and easier to measure. We evaluated whether CCA-IMT is comparable to A-CIMT when added to TRF and plaque information in improving CHD risk prediction in the Atherosclerosis Risk in Communities (ARIC) study.
Methods and results
Ten-year CHD risk prediction models using TRF alone, TRF + A-CIMT + plaque, and TRF + CCA-IMT + plaque were developed for the overall cohort, men, and women. The area under the receiver operator characteristic curve (AUC), per cent individuals reclassified, net reclassification index (NRI), and model calibration by the Grønnesby–Borgan test were estimated. There were 1722 incident CHD events in 12 576 individuals over a mean follow-up of 15.2 years. The AUC for TRF only, TRF + A-CIMT + plaque, and TRF + CCA-IMT + plaque models were 0.741, 0.754, and 0.753, respectively. Although there was some discordance when the CCA-IMT + plaque- and A-CIMT + plaque-based risk estimation was compared, the NRI and clinical NRI (NRI in the intermediate-risk group) when comparing the CIMT models with TRF-only model, per cent reclassified, and test for model calibration were not significantly different.
Coronary heart disease risk prediction can be improved by adding A-CIMT + plaque or CCA-IMT + plaque information to TRF. Therefore, evaluating the carotid artery for plaque presence and measuring CCA-IMT, which is easier and more reliable than measuring A-CIMT, provide a good alternative to measuring A-CIMT for CHD risk prediction.
PMCID: PMC3258447  PMID: 21666250
CIMT; Plaque; Risk prediction
4.  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
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.  Atherosclerotic plaques occur in absence of intima-media thickening in both systemic sclerosis and systemic lupus erythematosus: a duplexsonography study of carotid and femoral arteries and follow-up for cardiovascular events 
The objective of this cross-sectional and retrospective cohort study was (1) to determine the usefulness of intima-media thickness (IMT) in contrast to plaque assessment, (2) to examine the value of additive femoral artery sonography and (3) to identify potential risk factors for atherosclerosis and incident cardiovascular events in systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) patients.
In this study, 90 SSc and 100 SLE patients were examined by duplexsonography. IMT was measured in common carotid and common femoral arteries, plaques were assessed in common, internal and external carotid and common, proximal superficial and deep femoral arteries. Different definitions of pathological IMT (pIMT) were compared with the presence of plaque. Results were evaluated in relation to traditional and non-traditional risk factors for baseline atherosclerosis (logistic regression) and their predictive value for cardiovascular events during follow-up (cox regression).
Definite atherosclerosis occurred frequently without signs of subclinical atherosclerosis in both diseases: pIMT >0.9 mm was present in only 17/59 (28.9%) SSc and 13/49 (26.5%) SLE patients with already present atherosclerotic plaques. Using age-adjusted pIMT definitions, this rate was even lower (5.1-10.3% in SSc, 14.3-26.5% in SLE). Plaques were located only at the carotid or only at the femoral arteries in 26 (13.7%) and 24 (12.6%) patients, respectively. Age and nicotine pack-years were independently associated with atherosclerotic plaques in SLE and SSc patients, as well as the cumulative prednisolone dose in SSc subgroup, and ssDNA positive SLE patients had a lower risk for atherosclerotic plaque. During follow-up (available for 129/190 (67.9%) patients, 650 person-years), cardiovascular events occurred more often in patients with coronary heart disease (adjusted-hazards ratio (HR) 10.19, 95% confidence interval (CI) 3.04 to 34.17, P <0.001), male patients (adjusted-HR 8.78, 95% CI 2.73 to 28.19, P <0.001) and in patients with coexistent carotid and femoral plaques (adjusted-HR 5.92, 95% CI 1.55 to 22.67, P = 0.009). Patients with solely carotid or femoral plaque were not at higher risk.
Atherosclerotic plaque lesions can be found frequently in absence of intima-media thickening in both SSc and SLE patients. As well as routine sonography of carotid arteries, the sonography of femoral arteries is recommended to identify additional atherosclerotic lesions and to detect patients at a high risk for cardiovascular events.
PMCID: PMC3978872  PMID: 24548804
7.  Coronary Artery Calcification Compared with Carotid Intima-Media Thickness in Prediction of Cardiovascular Disease Incidence: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Archives of internal medicine  2008;168(12):1333-1339.
Coronary artery calcium (CAC) and carotid intima-media thickness (IMT) are noninvasive measures of atherosclerosis that consensus panels have recommended as possible additions to risk factor assessment for predicting the probability of cardiovascular disease (CVD) occurrence.
To assess whether maximum carotid IMT or CAC (Agatston Score) is the better predictor of incident CVD.
Design, Setting, Patients
Prospective cohort study of 45–84 year-olds initially free of CVD (n = 6,698) in four ethnic groups, with standardized carotid IMT and CAC measures at baseline, in six field centers of the Multi-Ethnic Study of Atherosclerosis (MESA).
Main Outcome Measure(s)
Incident CVD events (coronary heart disease, stroke, and fatal CVD) over a maximum of 5.3 years of follow-up.
There were 222 CVD events during follow-up. CAC was associated more strongly than carotid IMT with risk of incident CVD. After adjustment for each other and traditional CVD risk factors, the hazard of CVD increased 2.1-fold (95% CI 1.8–2.5) for each standard deviation greater level of log-transformed CAC, versus 1.3-fold (95% CI 1.1–1.4) for each standard deviation greater maximum IMT. For coronary heart disease, the hazard ratios per standard deviation increment were 2.5-fold (95% CI 2.1–3.1) for CAC and 1.2-fold (95% CI 1.0–1.4) for IMT. An ROC analysis also suggested that CAC predicted incident CVD better than IMT did.
Although whether and how to clinically use bio-imaging tests of subclinical atherosclerosis remains a topic of debate, this study found that CAC predicts subsequent CVD events better than does carotid IMT.
PMCID: PMC2555989  PMID: 18574091
8.  Risk Factors for the Progression of Intima-Media Thickness of Carotid Arteries: A 2-Year Follow-Up Study in Patients with Newly Diagnosed Type 2 Diabetes 
Diabetes & Metabolism Journal  2013;37(5):365-374.
Intima-media thickness (IMT) of the carotid arteries is known to have a positive correlation with the risk of cardiovascular disease. This study was designed to identify risk factors affecting the progression of carotid IMT in patients with type 2 diabetes mellitus (T2DM).
Patients with newly diagnosed T2DM with carotid IMT measurements were enrolled, and their clinical data and carotid IMT results at baseline and 2 years later were compared.
Of the 171 patients, 67.2% of males and 50.8% of females had abnormal baseline IMT of the left common carotid artery. At baseline, systolic blood pressure, body mass index and smoking in male participants, and fasting plasma glucose and glycated hemoglobin levels in females were significantly higher in patients with abnormal IMT than in those with normal IMT. Low density lipoprotein cholesterol (LDL-C) levels in males and high density lipoprotein cholesterol (HDL-C) levels in females at the 2-year follow-up were significantly different between the nonprogression and the progression groups. Reduction of the United Kingdom Prospective Diabetes Study (UKPDS) 10-year coronary heart disease (CHD) risk score after 2 years was generally higher in the nonprogression group than the progression group.
LDL-C levels in males and HDL-C levels in females at the 2-year follow-up were significantly different between participants with and without progression of carotid IMT. Furthermore, a reduction in the UKPDS 10-year CHD risk score appeared to delay the advancement of atherosclerosis. Therefore, the importance of establishing the therapeutic goal of lipid profiles should be emphasized to prevent the progression of carotid IMT in newly diagnosed T2DM patients.
PMCID: PMC3816138  PMID: 24199166
Atherosclerosis; Carotid artery intima-media thickness; Diabetes mellitus type 2; Risk factors
9.  Changes in Carotid Intima-Media Thickness During the Cardiac Cycle: The Multi-Ethnic Study of Atherosclerosis 
Common carotid artery intima-media thickness (IMT), a measure of subclinical cardiovascular disease, changes during the cardiac cycle. The magnitude of this effect and its implications have not been well studied.
Methods and Results
Far-wall IMT measurements of the right common carotid artery were measured at end diastole and peak systole in 5633 individuals from the Multi-Ethnic Study of Atherosclerosis (MESA). Multivariable regression models were generated with end-diastolic IMT, peak-systolic IMT, and change in IMT during the cardiac cycle as dependent variables and traditional cardiovascular risk factors as independent variables. The average age of our population was 61.9 (45 to 84) years. Average change in carotid IMT during the cardiac cycle was 0.041 mm (95% confidence interval: 0.039 to 0.042 mm), with a mean IMT of 0.68 mm. End-diastolic IMT and peak-systolic IMT were similarly associated with risk factors. In a fully adjusted model, change in carotid IMT during the cardiac cycle was associated with ethnicity and pulse pressure (P=0.001) and not age, sex, or other risk factors. Chinese and Hispanics had less of a change in IMT than did non-Hispanic whites. With peak-systolic IMT reference values used as normative data, 31.3% more individuals were classified as being in the upper quartile of IMT and at high risk for cardiovascular disease than would be expected when IMT is measured at end diastole.
Measurable differences in IMT are seen during the cardiac cycle. This affects the interpretation of IMT measurements used for cardiovascular risk assessment, given published normative data with IMT measured at peak systole.
Clinical Trial Registration
URL: Unique identifier: NCT00063440. (J Am Heart Assoc. 2012;1:e001420 doi: 10.1161/JAHA.112.001420.)
PMCID: PMC3487346  PMID: 23130162
atherosclerosis; blood pressure; carotid arteries; diastole; epidemiology; risk factors; systole; ultrasonics
10.  Increased carotid artery intima-media thickness may be associated with stroke in primary antiphospholipid syndrome 
Annals of the Rheumatic Diseases  2003;62(7):607-610.
Objective: To investigate the prevalence and clinical significance of carotid artery intima-media thickness (IMT) in patients with primary antiphospholipid syndrome (APS).
Methods: 28 patients with primary APS with at least a five year follow up, and 28 healthy subjects, matched by age and sex, were included in the study. Colour Doppler with high resolution B mode carotid ultrasonography and spectral analysis were performed in patients and controls. Information on cardiovascular risk factors and the clinical course were collected.
Results: The mean (SD) age of patients and controls (12 male, 16 female in each group) was 40 (8.5) years; the mean (SD) disease duration 7.7 (3) years. Carotid artery IMT was found in 23/28 patients (2.6 (1.14) mm) and 7/28 controls (1.2 (0.44)) (p=0.0001). A decrease in the lumen diameter was also found in 11/28 patients with primary APS without carotid atherosclerotic plaque, and 2/28 controls (p=0.004). Hyperlipidaemia, diabetes, smoking, obesity, and hypertension were not associated with carotid artery IMT. Patients with carotid artery IMT had arterial vascular disease more often than patients without: 9/23 v 0/5 (p<0.009). These patients had stroke (seven patients), myocardial infarction (one), and mesenteric thrombosis (one). Subjects with IMT had a threefold higher risk for stroke than those without IMT (95% CI 0.78 to 14.3).
Conclusions: Patients with primary APS have a high prevalence of carotid artery IMT and a decreased lumen diameter. IMT in primary APS may be associated with stroke. Patients with primary APS with IMT must be considered as carriers of atherosclerosis.
PMCID: PMC1754607  PMID: 12810420
11.  Carotid Intima-Media Thickness and Plaque as a Predictor for Ischemic Etiology in Patients With Severe Left Ventricular Systolic Dysfunction 
Korean Circulation Journal  2010;40(12):665-670.
Background and Objectives
Coronary artery disease (CAD) is a major cause of heart failure associated with left ventricular systolic dysfunction (LVSD). The prognosis of LVSD is significantly influenced by the etiology of heart failure and therefore, differentiation of significant CAD from other etiologies is important. Carotid intima-media thickness (IMT) and plaque are useful predictors for cardiovascular events, including stroke and CAD. The purpose of this study was to evaluate the predictive value of carotid IMT and plaque for the diagnosis of CAD in LVSD patients.
Subjects and Methods
Seventy-three (n= 73, 47 male, 67.6±12.4 years) patients hospitalized for heart failure with severe LVSD were retrospectively enrolled. The severity of CAD was analyzed by the Duke Jeopardy Score system, and carotid IMT and plaque were measured according to the Mannheim Carotid IMT Consensus.
Significant CAD was found in 41 patients (56.1%, CAD group) on coronary angiography. Mean common carotid artery (CCA) IMT (0.74±0.05 mm vs. 1.04±0.04 mm, p<0.01) was significantly higher in the CAD group. Plaque in CCA (6.25% vs. 19.5%, p<0.01) and plaque in bulb (25.0% vs. 60.9%, p<0.001) were significantly higher in the CAD group. Mean CCA IMT {odds ratio (OR) 2.61, 95% confidence interval (CI) 1.134-4.469, p<0.01} and plaque in bulb (OR 4.69, 95% CI 1.702-12.965, p<0.01) were significant predictors for the diagnosis of CAD according to multivariate logistic regression analysis.
In patients with severe LVSD, mean CCA IMT and bulb plaque can be useful additional predictors for the diagnosis of CAD.
PMCID: PMC3025341  PMID: 21267390
Plaque; Intima-media thickness; Coronary artery disease
12.  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
13.  The Relationship of Atherosclerosis to the 10-Year Cumulative Incidence of Age-Related Macular Degeneration: The Beaver Dam Studies 
Ophthalmology  2013;120(5):1012-1019.
To describe the relationships of intima-media layer thickness (IMT), plaque in the carotid artery, angina, myocardial infarction (MI), and stroke to the 10-year cumulative incidence of early and late age-related macular degeneration (AMD) and progression of AMD.
Cohort study.
1700 persons aged 53–96 years who participated in both the Epidemiology of Hearing Loss Study and the Beaver Dam Eye Study in 1998–2000, with photographs gradable for AMD at a 5- (2003–2005) and/or 10-year (2008–2010) follow-up examination.
IMT and presence of plaque were assessed using B-mode ultrasonography of the carotid artery. Presence of angina, MI, and stroke were defined based on a self-reported history of physician diagnosis. Presence and severity of AMD were determined by systematic grading of stereoscopic color fundus photographs.
Main Outcome Measures
The 10-year cumulative incidence of early AMD was 15.7% and the 10-year cumulative incidence of late AMD was 4.0%. Adjusting for age, sex, body mass index, smoking status, Age-Related Maculopathy Susceptibility 2 and Complement Factor H genotypes and other factors, mean IMT was associated with the 10-year incidence of early AMD (odds ratio per 0.1 mm IMT 1.11, 95% confidence interval 1.00–1.21, P value=0.03) and late AMD (1.27, 1.10–1.47, P=0.001). Mean IMT was associated with the 10-year incidence of pure geographic atrophy (1.31, 1.05–1.64, P=0.02) but not exudative AMD (1.14, 0.97–1.34, P=0.11). Similar associations were found for maximum IMT. The number of sites with plaque was related to the incidence of late AMD (2.79 for 4–6 sites vs. none, 1.06–7.37, P=0.04) but not to early AMD. A history of angina, MI, or stroke was not related to any incident AMD outcome.
In these population-based data, carotid artery IMT and carotid plaques had a weak relationship to the incidence of late AMD, independent of systemic and genetic risk factors. Angina, MI, and stroke were not related to AMD. It is unclear whether the carotid IMT is a risk indicator of processes affecting Bruch’s membrane and the retinal pigment epithelium, or a measure of atherosclerosis affecting susceptibility to AMD.
PMCID: PMC3646961  PMID: 23399375
14.  Do stroke patients with normal carotid arteries require TEE for exclusion of relevant aortic plaques? 
Objectives: This study investigated (a) the hypothesis that stroke patients with aortic atheroma would show comparable atherosclerotic changes in the carotid arteries, which are easily accessible for ultrasound evaluation and (b) the possibility of carotid duplex sonography as a replacement for transoesophageal echocardiography (TEE) for the exclusion or prediction of relevant aortic plaques.
Methods: In 301 consecutive patients (mean age 62 years) with acute cerebral ischaemia, two dimensional ultrasound measurements were taken of common carotid artery intima media thickness (IMT) and maximal plaque area (PA) and the local degree of internal carotid artery (ICA) stenosis were determined. Maximal aortic wall thickness (AWT) was assessed by TEE.
Results: An IMT ⩽0.9 mm yielded a negative predictive value (NPV) of 95.8% for exclusion of aortic atheromas ⩾4 mm and an NPV of 100% for the exclusion of aortic thrombi. However, positive predictive value of IMT >0.9 mm was low (29.6%), increasing only slightly in the presence of carotid plaques (33%). Incidence of aortic thrombi was significantly higher with ⩾50% compared with <50% ICA stenosis (11.3% v 3.9%, respectively). IMT and PA correlated moderately with AWT (r = 0.47, r = 0.53, respectively; p<0.001). Systolic blood pressure, coronary heart disease and peripheral artery disease, increased IMT, and ICA stenosis ⩾50% were independently related to AWT ⩾4 mm.
Conclusions: A high NPV of normal carotid ultrasound does not support routine TEE for the exclusion of complex aortic plaques as a high risk source of cerebral embolism. However, in patients with carotid atherosclerosis, particularly in those with ICA stenosis ⩾50%, TEE should be performed to exclude an additional high risk source for stroke.
PMCID: PMC1739459  PMID: 16291889
15.  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
16.  Effects of Obesity, Body Composition, and Adiponectin on Carotid Intima-Media Thickness in Healthy Women 
Increased common carotid intima-media thickness (IMT) is predictive of coronary artery disease and stroke.
In this study, we investigated common carotid IMT by obesity category in a cohort of healthy women without previously known cardiovascular disease.
Design, Setting, Participants, and Main Outcome Measures
One hundred healthy women (aged 24-59 yr) from the general community enrolled in an observational study conducted at an academic medical center participated in the study. B-mode ultrasound imaging of the common carotid arteries was used to measure common carotid IMT in 99 subjects. Fat distribution was determined by computed tomography. Hormonal and inflammatory parameters related to cardiovascular disease and obesity were measured.
IMT was higher in obese [body mass index (BMI) ≥ 30 kg/m2], compared with overweight women (BMI ≥ 25 and < 30 kg/m2) [0.69 mm, interquartile range (IQR) 0.60-0.75 mm] vs. 0.62 mm [IQR 0.56-0.68 mm), P = 0.044] and in comparison with lean women (BMI < 25 kg/m2) [0.69 mm (IQR 0.60-0.75 mm) vs. 0.59 mm (IQR 0.54-0.67 mm), P = 0.016]. In multivariate modeling, age (beta = 0.0050 mm change in IMT per year of age, P = 0.003), smoking (beta = 0.0044 mm change in IMT per pack-year, P = 0.046), and sc abdominal adiposity (beta = 0.00026 mm change in IMT per square centimeter, P = 0.010) were positively associated with IMT, whereas adiponectin (beta =–0.0042 mm change in IMT per milligram per liter, P = 0.045) was negatively associated with IMT. Visceral adiposity (beta = 0.00048 mm change in IMT per square centimeter, P = 0.092) was not significantly associated with IMT after adjusting for age, race, smoking, sc abdominal adiposity, and adiponectin.
Obesity is associated with increased common carotid IMT in young and middle-aged women. Adiponectin and sc abdominal adiposity are associated with carotid IMT in this population.
PMCID: PMC3210448  PMID: 16522690
17.  Carotid artery plaque and progression of coronary artery calcium: the Multi-Ethnic Study of Atherosclerosis 
Carotid and coronary atherosclerosis are associated to each other in imaging and autopsy studies. We evaluated whether carotid artery plaque seen on carotid ultrasound can predict incident coronary artery calcification (CAC).
Materials and Methods
We repeated Agatston calcium score measurements in 5445 participants of the Multi-Ethnic Study of Atherosclerosis (MESA) (mean age 57.9 years; 62.9% female). Internal carotid artery lesions were graded as 0%, 1-24%, >25% diameter narrowing and intima-media thickness (IMT) was measured. Plaque was present for any stenosis > 0%. CAC progression was evaluated with multivariable relative risk regression in cases with CAC = 0 at baseline and with multivariable linear regression for CAC > 0 adjusting for cardiovascular risk factors, body mass index, ethnicity, and common carotid IMT.
CAC was positive at baseline in 2708/5445 (49.7%) participants and became positive in 458/2837 (16.1%) at mean interval of 2.4 years between repeat examinations. Plaque and ICA IMT were both strongly associated with presence of CAC. After statistical adjustment, presence of carotid artery plaque significantly predicted incident CAC with a relative risk(RR) of 1.37 (95% Confidence Intervals: 1.12, 1.67). Incident CAC was associated with ICA IMT with an RR of 1.13 (95% Confidence Intervals: 1.03, 1.25) for each mm increase. Progression of CAC was also significantly associated (p < 0.001) with plaque and ICA IMT.
In individuals free of cardiovascular disease, subjective and quantitative measures of carotid artery plaques by ultrasound imaging are associated with CAC incidence and progression.
PMCID: PMC4084492  PMID: 23522805
18.  Carotid intima-media thickness and presence or absence of plaque improves prediction of coronary heart disease risk in the Atherosclerosis Risk in Communities (ARIC) study 
We evaluated whether carotid intima-media thickness (C-IMT) and the presence or absence of plaque improved coronary heart disease (CHD) risk prediction when added to traditional risk factors (TRF).
Traditional CHD risk prediction schemes need further improvement as the majority of the CHD events occur in the “low” and “intermediate” risk groups. C-IMT and presence of plaque on an ultrasound are associated with CHD and therefore could potentially help improve CHD risk prediction.
Risk prediction models (overall, in men and women) considered included TRF-only, TRF+C-IMT, TRF+plaque, and TRF+C-IMT+ plaque. Model predictivity was determined by calculating the area under the receiver operating characteristic curve (AUC) adjusted for optimism. Cox-proportional hazards models were used to estimate 10-year CHD risk for each model, and the number of individuals reclassified determined. Observed events were compared with expected events; and, the net reclassification index (NRI) was calculated.
Of 13,145 eligible individuals (5,682 men; 7,463 women), ~23% were reclassified by adding C-IMT+plaque information. Overall, the addition of C-IMT and plaque separately or together to the TRF model improved the AUC which increased from 0.742 to 0.750, 0.751 and 0.755 for the TRF-only, TRF+C-IMT, TRF+plaque and TRF+C-IMT+plaque model respectively. The C-IMT+TRF+plaque model had a NRI of 9.9% when compared to TRF-only in the overall population. However, comparison of TRF+C-IMT+plaque with TRF+C-IMT or TRF+plaque only resulted in non-significant or modestly significant changes of the various statistical tests. Sex-specific analyses are presented in the manuscript.
Adding plaque and C-IMT to TRF improves CHD risk prediction in the ARIC study.
PMCID: PMC2862308  PMID: 20378078
C-IMT; plaque; risk prediction
19.  Prevalence and Significance of Carotid Plaques in Patients With Coronary Atherosclerosis 
Korean Circulation Journal  2009;39(8):317-321.
Background and Objectives
Carotid artery intima-media thickness (CIMT) has recently been recommended as a non-invasive tool for primary prevention of cardiovascular events; the association between CIMT and adverse cardiovascular events is well-known. We sought to evaluate the prevalence and significance of carotid artery plaque, especially in patients with coronary atherosclerosis.
Subjects and Methods
The study population consisted of 1,705 consecutive patients {933 males (54.7%); mean age, 59.7±10.9 years} who underwent coronary angiography and carotid artery scanning using high-resolution ultrasonography. Carotid plaque was defined as a focal structure encroaching into the arterial lumen by at least 50% of the surrounding IMT value or a thickness >1.2 mm.
Carotid plaque was identified in 30.3% (516/1,705) of the patients. Of patients in whom the plaque location could be evaluated (n=1,027), carotid plaque was located at the common carotid artery {n=64/267 (24.0%)}, carotid bulb {n=194/267 (72.7%)}, and at both sites {n=9/267 (3.4%)}. The prevalence of hypertension (58.5% vs. 45.2%, p<0.001) and diabetes mellitus (30.6% vs. 23.5%, p=0.007) was higher in patients with carotid plaques. The patients with carotid plaques were older (65.4±8.9 years vs. 57.2±10.7 years, p<0.0001), had a thicker CIMT (0.89±0.20 mm vs. 0.77±0.16 mm, p<0.001), and higher fasting blood sugar (FBS) levels (132.1±60.7 mg/dL vs. 121.6±47.1 mg/dL, p<0.001) than those without carotid plaque. Patients with carotid plaque more frequently presented with acute coronary syndrome (32.4% vs. 23.9%, p<0.001) than those without carotid plaque. Significant coronary artery stenosis by coronary angiography (75.4% vs. 58.3%, p<0.001), especially multi-vessel disease (46.3% vs. 27.2%, p<0.001), was more frequent in patients with carotid plaques. On multivariate analysis, old age (≥65 years), hypertension, and increased CIMT (≥1.0 mm) were independent predictors of carotid plaque. Carotid plaque (odds ratio, 1.85; 95% confidence interval, 1.39-2.45; p<0.001) was an independent predictor of multivessel disease based on multivariate regression analysis.
Carotid plaque was common (30.3%) in Korean patients with coronary atherosclerosis, but it is still relatively uncommon compared to Western populations. Carotid plaque was associated with old age, hypertension, and increased IMT, and was an independent predictor of multi-vessel disease.
PMCID: PMC2771847  PMID: 19949637
Carotid arteries; Atherosclerosis; Coronary artery disease
20.  Carotid Intima‐Media Thickness is Associated With Incident Heart Failure Among Middle‐Aged Whites and Blacks: The Atherosclerosis Risk in Communities Study 
Increased carotid intima‐media thickness (IMT) is associated with subclinical left ventricular myocardial dysfunction, suggesting a possible role of carotid IMT in heart failure (HF) risk determination.
Methods and Results
Mean far wall carotid IMT, measured by B‐mode ultrasound, was available for 13 590 Atherosclerosis Risk in Communities study participants aged 45 to 64 years and free of HF at baseline. HF was defined using ICD‐9 428 and ICD‐10 I‐50 codes from hospitalization records and death certificates. The association between carotid IMT and incident HF was assessed using Cox proportional hazards analysis with models adjusted for demographic variables, major CVD risk factors, and interim CHD. There were 2008 incident HF cases over a median follow‐up of 20.6 years (8.1 cases per 1000 person‐years). Mean IMT was higher in those with HF than in those without (0.81 mm±0.23 versus 0.71 mm±0.17, P<0.001). Unadjusted rate of HF for the fourth compared with the first quartile of IMT was 15.4 versus 3.9 per 1000 person‐years; P<0.001. In multivariable analysis, after adjustment, each standard deviation increase in IMT was associated with incident HF (HR 1.20 [95% CI: 1.16 to 1.25]). After adjustment, the top quartile of IMT was associated with HF (HR 1.60 [95% CI: 1.37 to 1.87]). Results were similar across race and gender groups.
Increasing carotid IMT is associated with incident HF in middle‐aged whites and blacks, beyond risks explained by major CVD risk factors and CHD. This suggests that carotid IMT may be associated with HF through mechanisms different from myocardial ischemia or infarction.
PMCID: PMC4309069  PMID: 24815496
carotid intima‐media thickness; heart failure; subclinical atherosclerosis
21.  Correlation between the intima-media thickness and Framingham risk score in patients with sleep apnea syndrome 
Journal of Thoracic Disease  2013;5(6):751-757.
In the present study, we want to demonstrate the correlation between obstructive sleep apnea syndrome (OSAS) whose independent effect on carotid artery intima-media thickness (IMT) was demonstrated, with Framingham risk score (FRS) showing the overall cardiovascular risk.
IMT of the carotid artery was measured with ultrasonography and 10-year risk of coronary heart disease (CHD) was defined with FRS in 90 consecutive patients referred to our sleep clinic and who underwent polysomnography (PSG), with vascular risk factors and without a clinical atherosclerotic disease.
IMT and FRS were found to be statistically significantly increased in the severe OSAS group compared to the other two groups. Carotid IMT was found to be significantly positively correlated with, apnea-hypopnea index (AHI), oxygen desaturation index (ODI) and time duration with oxygen saturation (SpO2) <90%, and negatively correlated with minimum oxygen saturation at sleep (minimum SpO2) and mean SpO2. In control and mild OSAS group IMT and FRS have significantly positive correlation (r: 0.501, P: 0.027; r: 0.625, P<0.001), while in severe OSAS group no significant correlation was detected between IMT and FRS (r: 0.321, P: 0.06). In the regression analysis AHI and ODI were found to be an independent predictor of carotid IMT. ODI was found to have an independent effect on the progression of atherosclerosis.
Increased carotid IMT in severe OSAS group could not be explained with the classical risk factors. In this respect, FRS might be insufficient to determine correctly the cardiovascular risk and protection strategies against the disease in OSAS patients.
PMCID: PMC3886707  PMID: 24409351
Carotid artery; Framingham risk score (FRS); sleep apnea
22.  Lack of Associations of Ten Candidate Coronary Heart Disease Risk Genetic Variants and Subclinical Atherosclerosis in Four U.S. Populations: the Population Architecture using Genomics and Epidemiology (PAGE) Study 
Atherosclerosis  2013;228(2):390-399.
A number of genetic variants have been discovered by recent genome-wide association studies for their associations with clinical coronary heart disease (CHD). However, it is unclear whether these variants are also associated with the development of CHD as measured by subclinical atherosclerosis phenotypes, ankle brachial index (ABI), carotid artery intima-media thickness (cIMT) and carotid plaque.
Ten CHD risk single nucleotide polymorphisms (SNPs) were genotyped in individuals of European American (EA), African American (AA), American Indian (AI), and Mexican American (MA) ancestry in the Population Architecture using Genomics and Epidemiology (PAGE) study. In each individual study, we performed linear or logistic regression to examine population-specific associations between SNPs and ABI, common and internal cIMT, and plaque. The results from individual studies were meta-analyzed using a fixed effect inverse variance weighted model.
None of the ten SNPs was significantly associated with ABI and common or internal cIMT, after Bonferroni correction. In the sample of 13,337 EA, 3,809 AA, and 5,353 AI individuals with carotid plaque measurement, the GCKR SNP rs780094 was significantly associated with the presence of plaque in AI only (OR = 1.32, 95% confidence interval: 1.17, 1.49, P = 1.08 × 10−5), but not in the other populations (P = 0.90 in EA and P = 0.99 in AA). A 9p21 region SNP, rs1333049, was nominally associated with plaque in EA (OR = 1.07, P = 0.02) and in AI (OR = 1.10, P = 0.05).
We identified a significant association between rs780094 and plaque in AI populations, which needs to be replicated in future studies. There was little evidence that the index CHD risk variants identified through genome-wide association studies in EA influence the development of CHD through subclinical atherosclerosis as assessed by cIMT and ABI across ancestries.
PMCID: PMC3717342  PMID: 23587283
ankle brachial index; carotid artery intima-media thickness; carotid plaque; coronary heart disease; genetic association study; multiethnic populations; subclinical atherosclerosis
23.  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
24.  Carotid Intima-Media Thickness, Electrocardiographic Left Ventricular Hypertrophy and Incidence of Intracerebral Hemorrhage 
Background and Purpose
Carotid intima-media thickness (IMT) and electrocardiographic left ventricular hypertrophy (ECG-LVH) are two subclinical cardiovascular disease measures associated with increased risk of total and ischemic strokes. Increased IMT and ECG-LVH also may reflect end-organ hypertensive effects. Information is scant on the associations of these subclinical measures with intracerebral hemorrhage (ICH). We hypothesized that greater carotid IMT and the presence of ECG-LVH would be independently associated with increased ICH incidence.
Among 18,155 participants initially free of stroke in the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS), we assessed carotid IMT, carotid plaque, and ECG-LVH. Over a median of 18 years of follow-up, 162 incident ICH events occurred.
After adjustment for other ICH risk factors, carotid IMT was associated positively with incidence of ICH in both ARIC and CHS. The risk was lowest in study-specific quartile 1, elevated 1.6 to 2.6-fold in quartiles 2–3, and elevated 2.5 to 3.7-fold in quartile 4 (p<0.05 for both studies). In CHS, having a carotid plaque was associated with a 2-fold (95% CI = 1.1–3.4) greater ICH risk than having no plaque, but only 1.2-fold (95% CI = 0.76–2.0) greater ICH risk in ARIC. ECG-LVH carried a hazard ratio of ICH of 1.7 (95% CI = 0.77–3.7) in CHS and 2.8 (95% CI = 1.2–6.4) in ARIC.
Our data suggest that people with carotid atherosclerosis and possibly LVH are at increased risk not only of ischemic stroke but also of ICH.
PMCID: PMC3202073  PMID: 21940954
atherosclerosis; left ventricular hypertrophy; intracerebral hemorrhage; prospective study; risk factors
25.  The Impacts of C-Reactive Protein and Atrial Fibrillation on Carotid Atherosclerosis and Ischemic Stroke in Patients with Suspected Ischemic Cerebrovascular Disease: A Single-Center Retrospective Observational Cohort Study 
Korean Circulation Journal  2013;43(12):796-803.
Background and Objectives
Carotid intima-media thickness (IMT) is associated with chronic inflammation, and C-reactive protein (CRP) level is elevated in patients with atrial fibrillation (AF). We investigated the impacts of CRP and AF on carotid atherosclerosis and ischemic stroke in patients with suspected ischemic cerebrovascular disease.
Subjects and Methods
One-hundred forty patients (78 males) with suspected ischemic cerebrovascular disease underwent carotid ultrasonography. The mean common carotid artery IMT, mean internal carotid artery (ICA) IMT, and plaque score were measured. Patients were divided into four groups according to the presence of AF and elevated CRP level {n=46 for AF(-)CRP(-), n=38 for AF(-)CRP(+), n=43 for AF(+)CRP(-), and n=13 for AF(+)CRP(+)}.
Common carotid artery IMT was significantly higher in the AF(-)CRP(+) (0.98±0.51 mm) and AF(+)CRP(+) (0.96±0.27 mm) groups compared to the AF(-)CRP(-) (0.80±0.32 mm) and AF(+)CRP(-) (0.77±0.19 mm) groups (p=0.027). Although there was no significant difference in mean ICA IMT among the groups, plaque score was the highest in the AF(+)CRP(+) (4.18±3.84 mm) group, followed by AF(-)CRP(+) (3.87±2.78 mm), AF(+)CRP(-) (1.34±2.61 mm), and AF(-)CRP(-) (1.17±2.02 mm) (p<0.001). The AF(+)CRP(+) group showed significantly higher incidence of ischemic stroke than the other groups (all p<0.05). Binary logistic regression analysis showed that age {odds ratio (OR)=1.033, p=0.001}, elevated CRP (OR=3.884, p=0.001), and the presence of AF (OR=1.375, p=0.018) were significantly correlated with incidence of ischemic stroke.
Elevated plasma CRP concentration may be a reliable surrogate marker for predicting carotid atherosclerosis in patients with AF, which may be related to increased risk of ischemic stroke.
PMCID: PMC3875695  PMID: 24385990
Atrial fibrillation; C-reactive protein; Carotid atherosclerosis

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