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1.  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
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.  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
4.  IQ in childhood and atherosclerosis in middle-age: 40 Year follow-up of the Newcastle Thousand Families Cohort Study 
Atherosclerosis  2013;231(2):234-237.
Carotid intima-media thickness (IMT) is a known precursor to coronary heart disease (CHD) and other relevant health outcomes such as stroke and cognitive impairment. In addition, higher childhood intelligence has been associated with lower risk of coronary heart disease events in later life, although the mechanisms of effect are unclear. We therefore examined the association between childhood intelligence and atherosclerosis using carotid IMT as a marker of the atherosclerotic process.
Participants were 412 members of the Newcastle Thousand Families Study, a prospective cohort study of all 1142 births in the city of Newcastle in May and June 1947, who took an IQ test and English and arithmetic tests at age 11 years. Study members participated in a medical examination and lifestyle assessment at age 49–51 years during which IMT was measured using ultrasound techniques.
Individuals with higher childhood IQ score had a lower mean IMT in middle-age. A standard deviation higher score in childhood overall IQ was associated with a 0.053 mm (95% CI −0.102, −0.004) lower IMT in men and a 0.039 mm (95% CI −0.080, −0.002) lower IMT in women. Similar levels of association were found for the English and arithmetic tests. After adjustment for a range of covariates including education, the size of effect was undiminished in men but increased in women.
In the present study, higher childhood IQ scores were associated with a lower degree of atherosclerosis by middle-age.
PMCID: PMC3918147  PMID: 24267233
Childhood IQ; Atherosclerosis; Intima-media thickness; Cognitive epidemiology; CHD, coronary heart disease, IMT, intima-media thickness
5.  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
6.  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
7.  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
8.  Comparison of the Framingham Risk Score, UKPDS Risk Engine, and SCORE for Predicting Carotid Atherosclerosis and Peripheral Arterial Disease in Korean Type 2 Diabetic Patients 
Korean Journal of Family Medicine  2011;32(3):189-196.
To compare the predictability of the Framingham Risk Score (FRS), United Kingdom Prospective Diabetes Study (UKPDS) risk engine, and the Systematic Coronary Risk Evaluation (SCORE) for carotid atherosclerosis and peripheral arterial disease in Korean type 2 diabetic patients.
Among 1,275 registered type 2 diabetes patients in the health center, 621 subjects with type 2 diabetes participated in the study. Well-trained examiners measured the carotid intima-media thickness (IMT), carotid plaque, and ankle brachial index (ABI). The subject's 10-year risk of coronary heart disease was calculated according to the FRS, UKPDS, and SCORE risk scores. These three risk scores were compared to the areas under the curve (AUC).
The odds ratios (ORs) of all risk scores increased as the quartiles increased for plaque, IMT, and ABI. For plaque and IMT, the UKPDS risk score provided the highest OR (95% confidence interval) at 3.82 (2.36, 6.17) and at 6.21 (3.37, 11.45). For ABI, the SCORE risk estimation provided the highest OR at 7.41 (3.20, 17.18). However, no significant difference was detected for plaque, IMT, or ABI (P = 0.839, 0.313, and 0.113, respectively) when the AUCs of the three risk scores were compared. When we graphed the Kernel density distribution of these three risk scores, UKPDS had a higher distribution than FRS and SCORE.
No significant difference was observed when comparing the predictability of the FRS, UKPDS risk engine, and SCORE risk estimation for carotid atherosclerosis and peripheral arterial disease in Korean type 2 diabetic patients.
PMCID: PMC3383126  PMID: 22745854
Risk Assessment; Peripheral Arterial Disease; Carotid Artery Thrombosis; Diabetes Mellitus, Type 2
9.  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
10.  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
11.  Significance of the Intima-Media Thickness of Carotid and Thoracic Aorta in Coronary Artery Disease in the South Indian Population 
Ultrasound detected intima-media thickness (IMT) of the carotid artery and thoracic aorta are possible screening tests to assess the risk of coronary artery disease (CAD) in asymptomatic individuals.
Aim of the study was to assess the utility of carotid and aortic IMT as a predictor of CAD and to assess the extent of IMT with severity of CAD in a South Indian population.
Patients and Methods:
A cross-sectional and analytical study was carried out among 40 cases, who had angiographic evidence of CAD against 30 healthy control subjects with a normal treadmill test. At plaque-free regions, the carotid IMT was evaluated by B-mode ultrasonography and thoracic aorta IMT was evaluated by trans-esophageal echocardiography (TEE). The significance of difference in means between two groups was analyzed using one-way ANOVA F-test and the significance of difference in proportions by Chi-square test. Multiple comparisons were done by Bonferroni t test. The correlation between IMT and severity of CAD was assessed by Spearman's method.
There were 38 males and 2 females among cases with age 51.7 ± 8.3 years, and 28 males and 2 females among control subjects with age 52.2 ± 7.1 years. Increased carotid IMT was noted among 24 cases and 2 control subjects, and the association was significant for CAD [P < 0.001, Chi-square = 20.89, odds ratio (OR) = 21.00, and 95% confidence interval (CI) = 4.78-89.59]. Similarly, 19 cases and one control subject had abnormal IMT with positive correlation for CAD (P < 0.001, Chi-square = 16.39, OR = 28.24, and 95% CI = 4.06-163.21). There was no association between IMT and diabetes, hypertension, or smoking; however, IMT was significantly associated with age and dyslipidemia. Also, there was no correlation between extent of IMT and severity of CAD.
IMT of the carotid and thoracic aorta is strongly associated with risk of CAD in a South Indian population, and may be used as a non-invasive screening tool for coronary atherosclerosis in resource-limited settings. The presence of dyslipidemia influenced IMT and may be used as a tool to follow patients on hypolipidemic drugs.
PMCID: PMC3345149  PMID: 22574240
Aorta; atherosclerosis; CAD; carotid; coronary artery; intima-media thickness
12.  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
13.  Carotid Atherosclerosis in Ischemic Cerebrovascular Patients 
Cerebral emboli resulting from atherosclerosis at the carotid bifurcation is a major cause of ischemic stroke. A convenient and prompt evaluation is necessary for secondary prevention and treatment.
In this study, one hundred and thirty eight patients with cerebral ischemic events were enrolled; 100 patients with nonischemic cerebral diseases were enrolled as controls. Noninvasive ultrasound was used to measure the atherosclerotic plaques and intima-media thickness (IMT) of carotid and femoral artery.
Our results showed that patients in study group had higher incidence and severity of carotid and femoral plaques, and higher mean intima-media thickness (IMT) at both the carotid and femoral sites compared with that of controls (p < 0.01). Carotid atherosclerosis were highly prone to have instability plaques in study group(p < 0.001).
This cross-sectional study showed that, the prevalence of carotid atherosclerosis and the unstable plaques were higher in cerebral ischemic patients.
Carotid artery; Atherosclerosis; Intima-media thickness; Cerebral ischemic stroke
PMCID: PMC3318868  PMID: 22505964
14.  The Role of Carotid Intimal Thickness Testing and Risk Prediction for the Development of Coronary Atherosclerosis 
Carotid Ultrasound is a safe and available non invasive diagnostic tool that provides information about the carotid arteries’ characteristics and may be used for early detection of coronary artery disease as well as cardiovascular and stroke event risk stratifications. We performed a systematic search of the articles discussing carotid ultrasound in English literature, published in PubMed from the year2010 to September 2012. Generally, the studies showed that Internal carotid artery intima media thickness is a more powerful variable than common carotid artery intima media thickness. Moreover, the presence of carotid plaque and plaque volumes are more reliable and accurate estimators of coronary artery disease and risk of a stroke or cardiovascular event than intima media thickness.
PMCID: PMC3583351  PMID: 23328906
Carotid Ultrasound; Coronary Artery Disease; Risk Prediction; Intima Media Thickness
Atherosclerosis  2006;195(1):129-137.
Some studies have suggested that asthma may be a risk factor for coronary heart disease and stroke, particularly in women. Child and adult-onset asthma differ according to inflammatory characteristics and gender distribution. We examined whether childhood-onset and adult-onset asthma were associated with carotid artery intima-media thickness (IMT) in men and women in the Atherosclerosis Risk in Communities (ARIC) study. In unadjusted analyses, the weighted mean far wall IMT thickness for women with history of adult-onset asthma was significantly greater than that of women without history of asthma (0.731mm vs. 0.681mm; p<0.0001) while IMT for women with history of childhood-onset asthma (IMT=0.684mm) did not differ substantially from non-asthmatic women. Mean IMT did not differ significantly according to asthma history among men. When the data were fitted to a linear model, the interaction between asthma status and gender was significant (p=0.006). After adjusting for age, race, BMI, smoking status, smoking pack years, diabetes, hypertension, physical activity, education level, and high and low density lipoprotein levels, the mean IMT difference between women with adult-onset asthma and no history of asthma was attenuated but remained significant (0.713mm vs. 0.687mm, p=0.008). In conclusion, adult-onset asthma but not child-onset asthma is associated with increased carotid atherosclerosis among women but not among men.
PMCID: PMC2128256  PMID: 17045272
16.  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
17.  The estimated GFR, but not the stage of diabetic nephropathy graded by the urinary albumin excretion, is associated with the carotid intima-media thickness in patients with type 2 diabetes mellitus: a cross-sectional study 
To study the relationship between the intima-media thickness (IMT) of the carotid artery and the stage of chronic kidney disease (CKD) based on the estimated glomerular filtration rate (eGFR) and diabetic nephropathy graded by the urinary albumin excretion (UAE) in the patients with type 2 diabetes mellitus.
A cross-sectional study was performed in 338 patients with type 2 diabetes mellitus. The carotid IMT was measured using an ultrasonographic examination.
The mean carotid IMT was 1.06 ± 0.27 mm, and 42% of the subjects showed IMT thickening (≥ 1.1 mm). Cerebrovascular disease and coronary heart disease were frequent in the patients with IMT thickening. The carotid IMT elevated significantly with the stage progression of CKD (0.87 ± 0.19 mm in stage 1, 1.02 ± 0.26 mm in stage 2, 1.11 ± 0.26 mm in stage 3, and 1.11 ± 0.27 mm in stage 4+5). However, the IMT was not significantly different among the various stages of diabetic nephropathy. The IMT was significantly greater in the diabetic patients with hypertension compared to those without hypertension. The IMT positively correlated with the age, the duration of diabetes mellitus, and the brachial-ankle pulse wave velocities (baPWV), and negatively correlated with the eGFR. In a stepwise multivariate regression analysis, the eGFR and the baPWV were independently associated with the carotid IMT.
Our study is the first report showing a relationship between the carotid IMT and the renal parameters including eGFR and the stages of diabetic nephropathy with a confirmed association between the IMT and diabetic macroangiopathy. Our study further confirms the importance of intensive examinations for the early detection of atherosclerosis and positive treatments for hypertension, dyslipidaemia, obesity, as well as hyperglycaemia are necessary when a reduced eGFR is found in diabetic patients.
PMCID: PMC2877657  PMID: 20470427
18.  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
19.  Retinal Microvascular Signs and Risk of Stroke: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Background and Purpose
Small vessel disease contributes to the pathophysiology of stroke, and retinal microvascular signs have been linked to risk of stroke. We examined the relationship of retinal signs with incident stroke in a multi-ethnic cohort.
The Multi-Ethnic Study of Atherosclerosis (MESA) is a prospective cohort study that enrolled participants without clinical cardiovascular diseases from six United States communities between 2000–02. Of the participants, 4,849 (71.2%) had fundus photography performed in 2002–04. Retinopathy and retinal vessel caliber were assessed from retinal images. Stroke risk factors including high-sensitivity C-reactive protein (hsCRP), carotid artery intima-media thickness (IMT) and coronary artery calcium (CAC) were measured using standardized protocols. Incident stroke was confirmed from medical record review and death certificates.
After 6 years of follow-up, there were 62 incident strokes. Narrower retinal arteriolar caliber was associated with increased risk of stroke after adjusting for conventional cardiovascular risk factors (adjusted incidence rate ratio [IRR] 2.83, 95% confidence interval [CI] 1.34–5.95, p=0.006; adjusted hazard ratio [HR] 3.01, 95% CI 1.29–6.99, p=0.011). Retinopathy in persons without diabetes was associated with increased risk of stroke (adjusted IRR 2.96, 95% CI 1.50–5.84, p=0.002; adjusted HR 3.07, 95%CI 1.17–8.09, p=0.023). These associations remained significant after adjusting for hsCRP, carotid IMT or CAC.
Narrower retinal arteriolar caliber and retinopathy in non-diabetic persons were associated with increased risk of stroke in this relatively healthy multi-ethnic cohort independent of traditional risk factors and measures of atherosclerosis. The association between narrower retinal arteriolar caliber and stroke warrants further investigation.
PMCID: PMC3508325  PMID: 23111439
Stroke; Retinal microvascular signs; Retinopathy; Retinal vessel caliber
20.  Less subclinical atherosclerosis in Japanese men in Japan than in white men in the United States in the post World-War-II birth cohort 
American journal of epidemiology  2007;165(6):617-624.
Coronary heart disease (CHD) incidence and mortality remain very low in Japan despite major dietary changes and increases in CHD risk factors that should have resulted in substantial increase in CHD rates (Japanese paradox). Primary genetic effects are unlikely, given the substantial increase in CHD in migrant Japanese to the U.S. For men aged 40–49, levels of total cholesterol and blood pressure have been similar in Japan and the U.S. throughout their lifetime. The authors tested the hypothesis that levels of subclinical atherosclerosis, coronary artery calcification and intima-media thickness of the carotid artery (IMT), in men aged 40–49 are similar in Japan and the U.S. The authors conducted a population-based study of 493 randomly-selected men: 250 men in Kusatsu, Shiga, Japan, and 243 white men in Allegheny County, Pennsylvania, U.S. in 2002–2005. The Japanese had a less favorable profile of many risk factors than the whites. Prevalence ratio for the presence of coronary calcium score ≥10 in the Japanese compared to the whites was 0.52 (95% CI, 0.35, 0.76). Mean (SE) IMT was significantly lower in the Japanese (0.616 (0.005) versus 0.672 (0.005) mm, p<0.01). Both associations remained significant after adjusting for risk factors. The findings warrant further investigations.
PMCID: PMC3660737  PMID: 17244636
Atherosclerosis; epidemiology; men; risk factors
21.  Managing hypercholesterolemia and preventing cardiovascular events in elderly and younger Chinese adults: focus on rosuvastatin 
Coronary heart disease (CHD) is the leading cause of death worldwide. The efficacy and safety of statins in primary and secondary prevention of CHD is confirmed in several large studies, and rosuvastatin is the latest statin on market. We review the published literature on rosuvastatin in Chinese people. The pharmacokinetics of rosuvastatin in Chinese is somewhat different from that in Caucasians, but this does not influence the linear relationship between dosage and efficacy and with no drug accumulation. Rosuvastatin 5–20 mg/day is effective and safe in decreasing low-density lipoprotein cholesterol in both younger and elderly patients with hypercholesterolemia, even in very elderly patients. Rosuvastatin also shows anti-inflammatory and antiatherosclerosis features, such as reducing carotid intima-media thickness and plaque area. Rosuvastatin can also improve the prognosis of Chinese CHD patients, such as in the case of acute myocardial infarction. Its adverse-event rate is low and comparable to other statins. In conclusion, rosuvastatin is effective and safe for younger or elderly Chinese patients.
PMCID: PMC3861292  PMID: 24353409
rosuvastatin; Chinese; younger; elderly
22.  Sex-differential genetic effect of phosphodiesterase 4D (PDE4D) on carotid atherosclerosis 
BMC Medical Genetics  2010;11:93.
The phosphodiesterase 4D (PDE4D) gene was reported as a susceptibility gene to stroke. The genetic effect might be attributed to its role in modulating the atherogenic process in the carotid arteries. Using carotid intima-media thickness (IMT) and plaque index as phenotypes, the present study sought to determine the influence of this gene on subclinical atherosclerosis.
Carotid ultrasonography was performed on 1013 stroke-free subjects who participated in the health screening programs (age 52.6 ± 12.2; 47.6% men). Genotype distribution was compared among the high-risk (plaque index ≥ 4), low-risk (index = 1-3), and reference (index = 0) groups. We analyzed continuous IMT data and further dichotomized IMT data using mean plus one standard deviation as the cutoff level. Because the plaque prevalence and IMT values displayed a notable difference between men and women, we carried out sex-specific analyses in addition to analyzing the overall data. Rs702553 at the PDE4D gene was selected because it conferred a risk for young stroke in our previous report. Previous young stroke data (190 cases and 211 controls) with an additional 532 control subjects without ultrasonic data were shown as a cross-validation for the genetic effect.
In the overall analyses, the rare homozygote of rs702553 led to an OR of 3.1 (p = 0.034) for a plaque index ≥ 4. When subjects were stratified by sex, the genetic effect was only evident in men but not in women. Comparing male subjects with plaque index ≥ 4 and those with plaque index = 0, the TT genotype was over-represented (27.6% vs. 13.4%, p = 0.008). For dichotomized IMT data in men, the TT genotype had an OR of 2.1 (p = 0.032) for a thicker IMT at the common carotid artery compared with the (AA + AT) genotypes. In women, neither IMT nor plaque index was associated with rs702553. Similarly, SNP rs702553 was only significant in young stroke men (OR = 1.8, p = 0.025) but not in women (p = 0.27).
The present study demonstrates a sex-differential effect of PDE4D on IMT, plaque index and stroke, which highlights its influence on various aspects of atherogenesis.
PMCID: PMC2895592  PMID: 20540798
23.  Association of Carotid Artery Parameters of Atherosclerosis in Coronary Artery Disease 
Although carotid intima-media thickness (IMT) is the most commonly used ultrasonic measurement of atherosclerosis, plaque burden can be also assessed by ultrasound (US). We investigated the relationship between IMT, total plaque area (TPA) and total plaque volume (TPV) in patients with coronary artery disease (CAD).
One hundred and seven patients with suspected CAD and carotid plaques identified by duplex ultrasound underwent 3-dimensional US and coronary angiography. The mean IMT, TPA, and TPV were analyzed for patients with CAD according to the severity of CAD.
In the 107 participants, IMT, TPA and TPV averaged 0.90 ± 0.26 mm, 0.42 ± 0.39 cm2 and 237.0 ± 301.2 mm3, respectively. We found significant correlations for mean IMT : TPA, mean IMT : TPV and TPA : TPV of 0.448, 0.587 and 0.873, respectively (all p < 0.005). Although there was no significant association of IMT and the severity of CAD, TPA and TPV showed significant positive correlation with CAD severity (r = 0.340, p = 0.0003 for TPA and r = 0.465, p < 0.0001 for TPV). Multivariate linear regression analysis showed age was the only significant attributor to IMT, TPA, and TPV. Mean IMT was significantly associated only with hypertension. TPA was significantly associated with male sex, hypertension, and low density lipoprotein-cholesterol (LDL-C). TPV was significantly associated with male sex, C-reactive protein, and LDL-C.
Although there were significant correlations among the various US measures of carotid artery morphology, there seemed to be different biological determinants of IMT, TPA, and TPV. We might need to be selective about the particular measurements for specific applications.
PMCID: PMC3701782  PMID: 23837117
Atherosclerosis; Carotid arteries; Imaging; Plaque; Ultrasonography
24.  Ultrasonographic markers of vascular risk in patients with asymptomatic carotid stenosis 
Six-hundred twenty-one subjects with unilateral asymptomatic severe internal carotid artery (ICA) stenosis were prospectively evaluated with a median follow-up of 27 months (min=6, max=68). Vascular risk profile, plaque characteristic, stenosis progression, and common carotid artery intima-media thickness (IMT) were investigated in all patients. Outcome measures were occurrence of ischemic stroke ipsilateral to ICA stenosis and vascular death, while myocardial infarction, contralateral strokes, and transient ischemic attack were considered as competing events. A total of 99 subjects (15.9%) suffered from a vascular event. Among them, 39 were strokes ipsilateral to the stenosis (6.3%). Degree of stenosis, stenosis progression, and common carotid artery IMT resulted as independent predictive factors of ipsilateral stroke. Considering a stenosis of 60% to 70% as reference, a degree between 71% and 90% increased the risk by 2.45, while a degree between 91% and 99% increased the risk by 3.26. The progression of stenosis was a strong risk factor (hazard ratio=4.32). Finally, the role of carotid IMT was confirmed as crucial additional measure, with an increased risk by 25% for each 0.1 mm IMT increase. Our data suggest that IMT, stenosis progression and severity should be considered as risk factors for cerebrovascular events in asymptomatic subjects with severe ICA stenosis.
PMCID: PMC3618401  PMID: 23361391
atherosclerosis; carotid artery; cerebrovascular disease; risk factors; ultrasound
25.  Comparison of intensive and low‐dose atorvastatin therapy in the reduction of carotid intimal–medial thickness in patients with coronary heart disease 
Heart  2007;93(8):933-939.
Intensive statin therapy has been shown to improve prognosis in patients with coronary heart disease (CHD). It is unknown whether such benefit is mediated through the reduction of atherosclerotic plaque burden.
To examine the efficacy of high‐dose atorvastatin in the reduction of carotid intimal–medial thickness (IMT) and inflammatory markers in patients with CHD.
Randomised trial.
Single centre.
112 patients with angiographic evidence of CHD.
A high dose (80 mg daily) or low dose (10 mg daily) of atorvastatin was given for 26 weeks.
Main outcome measures
Carotid IMT, C‐reactive protein (CRP) and proinflammatory cytokine levels were assessed before and after therapy.
The carotid IMT was reduced significantly in the high‐dose group (left: mean (SD), 1.24 (0.48) vs 1.15 (0.35) mm, p = 0.02; right: 1.12 (0.41) vs 1.01 (0.26) mm, p = 0.01), but was unchanged in the low‐dose group (left: 1.25 (0.55) vs 1.20 (0.51) mm, p = NS; right: 1.18 (0.54) vs 1.15 (0.41) mm, p = NS). The CRP levels were reduced only in the high‐dose group (from 3.92 (6.59) to 1.35 (1.83) mg/l, p = 0.01), but not in the low‐dose group (from 2.25 (1.84) to 3.36 (6.15) mg/l, p = NS). A modest correlation was observed between the changes in carotid IMT and CRP (r = 0.21, p = 0.03).
In patients with CHD, intensive atorvastatin therapy results in regression of carotid atherosclerotic disease, which is associated with reduction in CRP levels. On the other hand, a low‐dose regimen only prevents progression of the disease.
PMCID: PMC1994404  PMID: 17344325

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