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1.  Associations of antiretroviral drug use and HIV-specific risk factors with carotid intima–media thickness 
AIDS (London, England)  2010;24(14):2201-2209.
Background
Previous research has demonstrated an increase in carotid intima–media thickness (cIMT) in HIV-infected individuals compared to controls. However, the reason for this increased level of subclinical vascular disease is unknown.
Objective
To identify HIV-related risk factors for increased cIMT.
Methods
We evaluated the relationship between HIV-related characteristics (including markers of HIV disease severity and use of antiretroviral therapy) and cIMT measurements in the internal/bulb and common carotid regions among 538 HIV-infected participants from the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM). We used Bayesian model averaging to estimate the posterior probability of candidate HIV and non-HIV-related risk factors being true predictors of increased cIMT. Variables with a posterior probability of more than 50% were used to develop a selected regression model for each of the anatomic regions.
Results
For common cIMT, the Bayesian model selection process identified age, African-American race, and systolic and diastolic blood pressure with probability more than 95%, HDL cholesterol with probability 85% and Hispanic ethnicity with probability 51%. Among the HIV-related factors included in the analysis, only tenofovir use was selected (51% probability). In the selected model, duration of tenofovir use was associated with lower common cIMT (−0.0094 mm/year of use; 95% confidence interval: −0.0177 to −0.0010). For internal cIMT, no HIV-related risk factors were above the 50% posterior probability threshold.
Conclusion
We observed an inverse association between duration of tenofovir use and common carotid cIMT. Whether this association is causal or due to confounding by indication needs further investigation.
doi:10.1097/QAD.0b013e32833d2132
PMCID: PMC3224487  PMID: 20671544
atherosclerosis; carotid intima–media thickness; HIV; tenofovir
2.  Normative values and correlates of carotid artery intima-media thickness and carotid atherosclerosis in Andean-Hispanics: The PREVENCION Study 
Atherosclerosis  2010;211(2):499-505.
Objectives
Carotid intima-media thickness (cIMT) is an independent predictor of cardiovascular risk. Furthermore, ethnicity and gender-specific normative data are required to assess cIMT, which are not available for Andean-Hispanics. In addition, data regarding correlates of subclinical atherosclerosis in ethnic population are needed.
Methods
We studied 1448 adults enrolled in a population-based study in Peru. cIMT and carotid plaque were measured with high-resolution ultrasonography. A healthy reference sample (n=472) with no cardiovascular disease, normal weight and normal metabolic parameters was selected to establish normative cIMT values. Correlates of abnormal cIMT and carotid plaque were assessed in the entire population.
Results
In the reference sample, 95th-percentile cIMT values were both age and gender-dependent. In stepwise regression, selected predictors of increasing cIMT were: older age, impaired fasting glucose, diabetes mellitus, higher systolic blood pressure, higher LDL-cholesterol, smoking and male gender. Predictors of carotid plaque included older age, male gender, higher systolic blood pressure, lower diastolic blood pressure and higher LDL-cholesterol. HDL-cholesterol and C-reactive protein were not associated with cIMT or carotid plaque. The lack of association with HDL-cholesterol was confirmed using high performance liquid chromatography.
Conclusions
We present ethnic-specific cutoffs for abnormal cIMT applicable to Andean-Hispanics and correlates of subclinical atherosclerosis in this population. Pending longitudinal studies, our data supports several risk associations seen in other populations and can be used to identify Andean-Hispanics at increased risk for atherosclerotic cardiovascular disease. The lack of association between HDL-C and cIMT or carotid plaque in this population requires further investigation.
doi:10.1016/j.atherosclerosis.2010.04.009
PMCID: PMC2928715  PMID: 20510418
carotid intima-media thickness; Andean-Hispanics; definitions; cardiovascular disease; Latin America
3.  Associations of edge detected and manual traced common carotid intima-media thickness (IMT) measurements with Framingham risk factors: the Multi-Ethnic Study of Atherosclerosis 
Background
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.
Methods
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.
Results
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%).
Conclusion
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.
doi:10.1161/STROKEAHA.110.603449
PMCID: PMC3169166  PMID: 21546477
Ultrasonography; Risk Factors; Carotid Arteries; Carotid Intima Media Thickness
4.  Clinical Factors Associated with Carotid Plaque and Intima-Medial Thickness in HIV-Infected Patients 
Yonsei Medical Journal  2013;54(4):990-998.
Purpose
HIV-infected patients are at increased risk for cardiovascular disease, which may be mediated in part by inflammation. This study aimed to evaluate the risk factors of carotid plaque, and clinical factors associated with carotid atherosclerosis measured by carotid intima-medial thickness (cIMT) in HIV patients.
Materials and Methods
Clinical and cardiometabolic factors as well as cIMT were prospectively measured in 145 HIV-infected participants who had received combined antiretroviral therapy for ≥6 months. The mean value of the bilateral average cIMT level was used as Mean-IMT in the analysis, and the greatest value among the measured cIMT levels was used as Max-IMT.
Results
Among 145 patients, 34 (23.4%) had carotid plaque. Multivariate logistic regression analysis revealed three independent risk factors of carotid plaque: old age [odds ratio (OR) 6.16, 95% confidence interval (CI) 1.09-34.88; p=0.040], hypertension (OR 12.62, 95% CI 1.72-92.49; p=0.013) and higher low-density lipoprotein cholesterol (LDL-C) (OR 1.08, 95% CI 1.01-1.16; p=0.039). Levels of estimated glomerular filtration rate were inversely associated with Mean-IMT (r=-0.379, p<0.001) and Max-IMT (r=-0.389, p<0.001). Stepwise multivariate regression analyses revealed that age, total cholesterol and fasting glucose were positively correlated with cIMT, independent of other risk factors.
Conclusion
The presence of hypertension, old age and a higher level of LDL-C were independent risk factors of carotid plaque among HIV-infected subjects.
doi:10.3349/ymj.2013.54.4.990
PMCID: PMC3663240  PMID: 23709436
Carotid plaque; carotid artery intima-media thickness; atherosclerosis; combined antiretroviral therapy; HIV infection
5.  Pre-Clinical Atherosclerosis due to HIV Infection: Carotid Intima-Medial Thickness Measurements from the FRAM Study 
AIDS (London, England)  2009;23(14):1841-1849.
Background
Cardiovascular disease (CVD) is an increasing cause of morbidity and mortality in HIV-infected patients. However, it is controversial whether HIV infection contributes to accelerated atherosclerosis independent of traditional CVD risk factors.
Methods
Cross-sectional study of HIV-infected and control subjects without pre-existing CVD from the study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) and the Multi-Ethnic Study of Atherosclerosis (MESA). Pre-clinical atherosclerosis was assessed by carotid intima-medial thickness (IMT) measurements in the internal/bulb and common regions in HIV-infected and control subjects after adjusting for traditional CVD risk factors.
Results
For internal carotid, mean IMT was 1.17±0.50mm for HIV-infected participants and 1.06±0.58mm for controls (p<0.0001). After multivariable adjustment for demographic characteristics, the mean difference of HIV-infected vs. controls was +0.188mm (95%CI 0.113-0.263, p<0.0001). Further adjustment for traditional CVD risk factors modestly attenuated the HIV association (+0.148mm, 95%CI 0.072-0.224, p=0.0001). For the common carotid, HIV infection was independently associated with greater IMT (+0.033mm, 95%CI 0.010, 0.056, p=0.005). The association of HIV infection with IMT was similar to that of smoking which was also associated with greater IMT (internal +0.173mm, common +0.020mm).
Conclusions
Even after adjustment for traditional CVD risk factors, HIV infection was accompanied by more extensive atherosclerosis measured by IMT. The stronger association of HIV infection with IMT in the internal/bulb region compared to the common carotid may explain previous discrepancies in the literature. The association of HIV infection with IMT was similar to that of traditional CVD risk factors, such as smoking.
doi:10.1097/QAD.0b013e32832d3b85
PMCID: PMC3156613  PMID: 19455012
HIV; carotid IMT; smoking; cholesterol; diabetes; atherosclerosis
6.  Effects of Aging and Smoking on Carotid Intima Media Thickness in HIV-infection 
AIDS (London, England)  2013;27(1):49-57.
Objectives
To investigate the effects of aging and smoking on carotid intima-media thickness (cIMT) among patients with and without HIV.
Methods
Data from a community sample of HIV-infected and HIV-uninfected participants were analyzed. Carotid intima-media thickness was measured via carotid ultrasound and smoking history was obtained via patient interview.
Results
Data on 166male and female participants with stable HIV-infection and 152 healthy HIV-uninfected participants were analyzed. Among the HIV-infected and HIV-uninfected participants, a significant association was observed between age and cIMT [r=0.51, P<0.0001 (HIV), r=0.39, P<0.0001, (non-HIV)], and between smoking burden and cIMT [r=0.42, P<0.0001 (HIV), r=0.24, P=0.003 (non-HIV)]. In multivariate regression modeling among all participants (HIV and non-HIV), a significant three-way interaction was observed between age, smoking burden, and HIV status with respect to cIMT (P<0.010), controlling for gender, race and traditional cardiovascular disease (CVD) risk factors, such that increased cIMT was associated with increased smoking burden and age to a greater degree among HIV-infected vs. HIV-uninfected participants. Among HIV-infected participants a significant interaction between smoking burden and age with respect to cIMT was seen (P=0.027), controlling for race, gender, CVD risk factors, immunological function and antiretroviral therapy use.
Conclusion
A significant interaction between HIV, age and smoking on cIMT was observed, suggesting that HIV-infection modifies the relationship of age and smoking on cIMT in this population. These findings emphasize the need to encourage smoking cessation in this population, due to its deleterious effect on subclinical atherosclerosis in older HIV-infected patients.
doi:10.1097/QAD.0b013e328358b29c
PMCID: PMC3690796  PMID: 22874518
HIV; Aging; Cardiovascular Diseases; Smoking
7.  Reduced Kidney Function and Preclinical Atherosclerosis in HIV-Infected Individuals: The Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) 
American Journal of Nephrology  2011;33(5):453-460.
Background/Aims
Reduced kidney function and albuminuria are associated with higher risk for cardiovascular disease (CVD) and mortality in HIV-infected individuals. We investigated whether reduced estimated glomerular filtration rate (eGFR) and albuminuria are associated with subclinical vascular disease, as assessed by carotid intima-medial thickness (cIMT).
Methods
Cross-sectional analysis of 476 HIV-infected individuals without clinical evidence of CVD enrolled in the Fat Redistribution and Metabolic Change in HIV infection (FRAM) study, using multivariable linear regression. eGFRCys and eGFRCr were calculated from cystatin C and creatinine levels. Albuminuria was defined as a positive urine dipstick (≥1+) or urine albumin-to-creatinine ratio ≥30 mg/g. Common and internal cIMT were measured by high-resolution B-mode ultrasound.
Results
In unadjusted analyses, eGFRCys and eGFRCr were strongly associated with common and internal cIMT. Each 10 ml/min/1.73 m2 decrease in eGFRCys and eGFRCr was associated with a 0.008 mm higher common cIMT (p = 0.003, p = 0.01) and a 0.024 and 0.029 mm higher internal cIMT (p = 0.003), respectively. These associations were eliminated after adjustment for age, gender, and race. Albuminuria showed little association with common or internal cIMT in all models.
Conclusions
In HIV-infected individuals without prior CVD, reduced kidney function and albuminuria were not independently associated with subclinical vascular disease, as assessed by cIMT. These results suggest that research should focus on searching for novel mechanisms by which kidney disease confers cardiovascular risk in HIV-infected individuals.
doi:10.1159/000327606
PMCID: PMC3100378  PMID: 21508633
Cystatin C; Intima-medial thickness; HIV; Atherosclerosis; Cardiovascular disease; Kidney
8.  Common carotid artery intima-media thickness (IMT) progression as a predictor of stroke in MESA (Multi-Ethnic Study of Atherosclerosis) 
Background
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.
Results
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.
Conclusion
Common carotid artery IMT progression is associated with incident stroke in this cohort free of prevalent cardiovascular disease and atrial fibrillation at baseline.
doi:10.1161/STROKEAHA.111.625186
PMCID: PMC3202068  PMID: 21885840
Ultrasonography; Risk Factors; Carotid Arteries; Carotid Intima Media Thickness; stroke
9.  Carotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project): a meta-analysis of individual participant data 
Lancet  2012;379(9831):2053-2062.
Summary
Background
Carotid intima-media thickness (cIMT) is related to the risk of cardiovascular events in the general population. An association between changes in cIMT and cardiovascular risk is frequently assumed but has rarely been reported. Our aim was to test this association.
Methods
We identified general population studies that assessed cIMT at least twice and followed up participants for myocardial infarction, stroke, or death. The study teams collaborated in an individual participant data meta-analysis. Excluding individuals with previous myocardial infarction or stroke, we assessed the association between cIMT progression and the risk of cardiovascular events (myocardial infarction, stroke, vascular death, or a combination of these) for each study with Cox regression. The log hazard ratios (HRs) per SD difference were pooled by random effects meta-analysis.
Findings
Of 21 eligible studies, 16 with 36 984 participants were included. During a mean follow-up of 7·0 years, 1519 myocardial infarctions, 1339 strokes, and 2028 combined endpoints (myocardial infarction, stroke, vascular death) occurred. Yearly cIMT progression was derived from two ultrasound visits 2–7 years (median 4 years) apart. For mean common carotid artery intima-media thickness progression, the overall HR of the combined endpoint was 0·97 (95% CI 0·94–1·00) when adjusted for age, sex, and mean common carotid artery intima-media thickness, and 0·98 (0·95–1·01) when also adjusted for vascular risk factors. Although we detected no associations with cIMT progression in sensitivity analyses, the mean cIMT of the two ultrasound scans was positively and robustly associated with cardiovascular risk (HR for the combined endpoint 1·16, 95% CI 1·10–1·22, adjusted for age, sex, mean common carotid artery intima-media thickness progression, and vascular risk factors). In three studies including 3439 participants who had four ultrasound scans, cIMT progression did not correlate between occassions (reproducibility correlations between r=−0·06 and r=−0·02).
Interpretation
The association between cIMT progression assessed from two ultrasound scans and cardiovascular risk in the general population remains unproven. No conclusion can be derived for the use of cIMT progression as a surrogate in clinical trials.
Funding
Deutsche Forschungsgemeinschaft.
doi:10.1016/S0140-6736(12)60441-3
PMCID: PMC3918517  PMID: 22541275
10.  Impaired Lung Function Is Associated with Increased Carotid Intima-Media Thickness in Middle-Aged and Elderly Chinese 
PLoS ONE  2013;8(2):e53153.
Background
Impairment of lung function was reported to be associated with cardiovascular disease (CVD). The aim of the present study is to evaluate the relationship between lung function and carotid intima-media thickness (cIMT) in participants without chronic pulmonary disease.
Methodology and Principal Findings
A total of 6,423 participants aged 40 years and above were recruited from Jiading District, Shanghai, China. Lung function, evaluated by forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) was measured with standard spirometry. CIMT was measured with high-resolution ultrasonography by trained physicians. Mean values of FVC (% pred) and FEV1 (% pred) in participants with elevated cIMT were significantly lower than in those without (0.92±0.20 vs. 0.99±0.19, 0.83±0.24 vs. 0.90±0.22; both p-values < 0.0001). The levels of cIMT in the lowest quartile of FVC (% pred) and FEV1 (% pred) were markedly higher than in the second, third and fourth quartile, respectively (p < 0.0001 for all). The lowest quartile of FVC (% pred) and FEV1 (% pred) was associated with increased odds of elevated cIMT, with the fully adjusted odds ratio of 1.34 and 1.41 (95% confidence interval (CI) 1.09–1.65, p  =  0.006, 95% CI 1.15–1.72, p  =  0.0008), respectively.
Conclusions and Significance
Impaired lung function is associated with elevated cIMT in middle-aged and elderly Chinese. These findings suggest the need to screen impairment of lung function in people without respiratory disease for the presence of subclinical atherosclerosis in CVD prevention.
doi:10.1371/journal.pone.0053153
PMCID: PMC3574141  PMID: 23457443
11.  A Genome-wide Association Study of Carotid Atherosclerosis in HIV-infected Men 
AIDS (London, England)  2010;24(4):583-592.
Background
The role of host genetics in the development of subclinical atherosclerosis in the context of HIV infected persons who are being treated with highly active antiretroviral therapy (HAART) is not well understood.
Methods
The present genome-wide association study (GWAS) is based on 177 HIV-positive Caucasian males receiving HAART who participated in the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) Study. Common and internal carotid intima-media thicknesses (cIMT) measured by B-mode ultrasound were used as a subclinical measure of atherosclerosis. Single nucleotide polymorphisms (SNPs) were assayed using the Illumina HumanCNV370-quad beadchip. Copy Number Variants (CNV) were inferred using a hidden Markov Model (PennCNV). Regression analyses were used to assess the association of common and internal cIMT with individual SNPs and CNVs, adjusting for age, duration of antiretroviral treatment, and principal components to account for potential population stratification.
Results
Two SNPs in tight linkage disequilibrium, rs2229116 (a missense, nonsynonymous polymorphism (IIe to Val)) and rs7177922, located in the Ryanodine receptor (RYR3) gene on chromosome 15 were significantly associated with common cIMT (p-value<1.61×10−7). The RYR gene family has been known to play a role in the etiology of cardiovascular disease and has been shown to be regulated by HIV TAT protein.
Conclusions
These results suggest that in the context of HIV infection and HAART, a functional SNP in a biologically plausible candidate gene, RYR3, is associated with increased common carotid IMT, which is a surrogate for atherosclerosis.
doi:10.1097/QAD.0b013e3283353c9e
PMCID: PMC3072760  PMID: 20009918
HIV; HAART; atherosclerosis; GWAS; intima-media thickness
12.  Evaluation of Clinical Variables Associated with Increased Carotid Intima-Media Thickness in Middle-Aged Hypertensive Women 
It has been previously documented that carotid intima-media thickness (cIMT) is a predictor of cardiovascular disease. The aim of this study was to identify clinical parameters associated with an increased cIMT treated hypertensive women. Female patients (n = 116) with essential hypertension, aged 40–65 years, were included in this study. Vascular ultrasound was performed and the patients were divided into two groups according to the values of cIMT (< or ≥0.9 mm). Patients with greater cIMT presented significantly higher systolic blood pressure and pulse pressure. Serum HDL-cholesterol was significantly lower and CRP was significantly higher in the same group. There was a significant correlation between cIMT and age (r = 0.25, P = 0.007), systolic blood pressure (r = 0.19, P = 0.009), pulse pressure (r = 0.30, P = 0.001), and LDL-cholesterol (r = 0.19, P = 0.043). cIMT was correlated to CRP (r = 0.31, P = 0.007) and negatively correlated to HDL-cholesterol (r = 0.33, P = 0.001). In logistic regression, only HDL-cholesterol, CRP, and pulse pressure were shown to be independent variables associated to increased cIMT. In conclusion, pulse pressure, HDL-cholesterol, and CRP are variables correlated with cIMT in treated hypertensive women.
doi:10.1155/2012/257501
PMCID: PMC3371681  PMID: 22701780
13.  Associations of cardiovascular risk factors, carotid intima-media thickness and left ventricular mass with inter-adventitial diameters of the common carotid artery: the Multi-Ethnic Study of Atherosclerosis (MESA) 
Atherosclerosis  2011;218(2):344-349.
Background
Common carotid artery inter-adventitial diameter (IAD) and intima-media thickness (IMT) are measurable by ultrasound. IAD may be associated with left ventricular mass (LV mass) while IMT is a marker of subclinical atherosclerosis. It is not clear if IAD is associated with LV mass after accounting for IMT and traditional cardiovascular risk factors.
Methods
IAD and IMT were measured on participants of the Multi-Ethnic Study of Atherosclerosis (MESA) IMT progression study. A total of 5641 of the originally enrolled 6814 MESA participants were studied. LV mass was measured by magnetic resonance imaging. Multivariable linear regression was used with IAD as the outcome and adjustment for risk factors, as well as IMT and LV mass.
Results
Traditional cardiovascular risk factors, height, weight and ethnicity were significantly associated with IAD. After adjustment for risk factors, a one mm difference in IMT was associated with a 1.802 mm (95% CI: 1.553, 2.051) higher mean IAD. A one gm difference in LV mass was associated with a 0.006 mm (95% CI: 0.005, 0.007) higher mean IAD. LV mass was independently associated with IAD after adjusting for cardiovascular risk factors and IMT. These associations were slightly different for men and women.
Conclusions
Inter-adventitial diameters are associated with left ventricular mass after adjusting for cardiovascular risk factors and IMT. IAD might serve as a surrogate for left ventricular mass and have predictive value for cardiovascular outcomes.
doi:10.1016/j.atherosclerosis.2011.05.033
PMCID: PMC3186064  PMID: 21726862
carotid arteries; ultrasonics; hypertrophy; magnetic resonance imaging; remodeling; risk factors; left ventricle
14.  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.
Results
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.
Conclusion
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.
doi:10.4070/kcj.2009.39.8.317
PMCID: PMC2771847  PMID: 19949637
Carotid arteries; Atherosclerosis; Coronary artery disease
15.  Markers of Atherosclerosis and Inflammation and Mortality in Patients with HIV Infection 
Atherosclerosis  2010;214(2):468-473.
Objective
HIV-infected patients are at increased risk for cardiovascular disease, which may be mediated in part by inflammation. Surrogate marker studies suggest an increased prevalence of vascular abnormalities in HIV infection. We examined the association of all-cause mortality in HIV-infected patients with carotid artery intima-media thickness (cIMT) and high-sensitivity C-reactive protein (hsCRP).
Design and Methods
Baseline risk factors, cIMT and hsCRP were prospectively measured in 327 HIV-infected participants. Follow-up time with median of 3.1 years was calculated from baseline to death or censored dated 7/31/07. Cox Proportional Hazards models were used to study risk factors associated with mortality.
Results
Thirty eight (11.6 %) of participants have died since study enrollment. CIMT was significantly higher in those who died and decedents were significantly more likely to have cIMT above the 75th percentile. Those who died had higher hsCRP than those alive and more had hsCRP values above 3 mg/L. CD4 count was lower and log10 viral load was higher in decedents, but antiretroviral regimens were similar in both groups. CIMT and hsCRP levels were significantly associated with mortality (HR=2.74, 95% CI 1.26 to 5.97, p=0.01; HR=2.38, 95% CI 1.15 to 4.9, p=0.02).
Conclusions
Our study demonstrated a strong association of carotid IMT and hsCRP with all-cause death in this HIV-infected population despite being similar with respect to exposure to antiretroviral medications. Together these surrogate markers may be indices of chronic inflammation and unfavorable outcomes in HIV-positive patients.
doi:10.1016/j.atherosclerosis.2010.11.013
PMCID: PMC3034311  PMID: 21130995
16.  Increased Carotid Intima-Media Thickness and Reduced Distensibility in Human Class III Obesity: Independent and Differential Influences of Adiposity and Blood Pressure on the Vasculature 
PLoS ONE  2013;8(1):e53972.
Carotid intima-media-thickness (cIMT) and carotid distensibility (distensibility), structural and functional properties of carotid arteries respectively, are early markers, as well as strong predictors of cardiovascular disease (CVD). The characteristic of these two parameters in individuals with BMI>40.0 kg/m2 (Class III obesity), however, are largely unknown. The present study was designed to document cIMT and distensibility in this population and to relate these to other factors with established association with CVD in obesity. The study included 96 subjects (65 with BMI>40.0 kg/m2 and 31, age- and gender-matched, with BMI of 18.5 to 30.0 kg/m2). cIMT and distensibility were measured by non-invasive high resolution ultrasonography, circulatory CD133+/KDR+ angiogenic cells and endothelial microparticles (EMP) by flow cytometry, and plasma levels of adipokines, growth factors and cytokines by Luminex immunoassay kits. The study results demonstrated increased cIMT (0.62±0.11 mm vs. 0.54±0.08 mm, P = 0.0002) and reduced distensibility (22.52±10.79 10−3kpa−1 vs. 29.91±12.37 10−3kpa−1, P<0.05) in individuals with BMI>40.0 kg/m2. Both cIMT and distensibility were significantly associated with traditional CVD risk factors, adiposity/adipokines and inflammatory markers but had no association with circulating angiogenic cells. We also demonstrated, for the first time, elevated plasma EMP levels in individuals with BMI>40.0 kg/m2. In conclusion, cIMT is increased and distensibility reduced in Class III obesity with the changes predominantly related to conventional CVD risk factors present in this condition, demonstrating that both cIMT and distensibility remain as CVD markers in Class III obesity.
doi:10.1371/journal.pone.0053972
PMCID: PMC3546965  PMID: 23342053
17.  Association Between Carotid Intima-Media Thickness and Pericardial Fat in the Multi-Ethnic Study of Atherosclerosis (MESA) 
Introduction
Carotid intima-media thickness (IMT) is a sub-clinical marker of atherosclerosis and a strong predictor of stroke. Pericardial fat (PF), the fat depot around the heart, has been associated with several atherosclerosis risk factors. We sought to examine the association between carotid IMT and PF, and to examine whether such an association is independent from common atherosclerosis risk factors including measures of overall adiposity.
Methods
Unadjusted and multivariable adjusted linear regression analysis was used to examine associations between common (CCA-IMT) and internal (ICA-IMT) carotid IMT with PF in a random sample of 996 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) who underwent carotid ultrasound and chest CT at baseline examination.
Results
A significant positive correlation was observed between PF and CCA-IMT (r =0.27, P<0.0001) and ICA-IMT (r =0.17, P<0.0001). In an unadjusted sex-specific linear regression analysis, there was a significant association between PF (1-SD difference) and CCA-IMT (mm) in both women (β coefficient (95% CI): 0.06 (0.04, 0.08), P<0.0001) and men (0.03 (0.01, 0.05), P<0.0002), an association that persisted after further adjusting for age and ethnicity (0.02 (+0.00, 0.04), P=0.0120 for women, and 0.02 (+0.00, 0.03), P=0.0208 for men). However, after additional adjustment for atherosclerosis risk factors and either BMI or waist circumference, these relations were no longer significant in either sex. In similar analyses, PF was significantly associated with ICA-IMT in both men (0.11 (0.06, 0.15), P<0.0001) and women (0.08 (0.02, 0.13), P=041). These relations were no longer significant in women in multivariable adjusted models, but persisted in men in all models except after adjusting for age, ethnicity and waist circumference.
Conclusions
In the general population PF is associated with carotid IMT, an association that possibly not independent from markers of overall adiposity or common atherosclerosis risk factors.
doi:10.1016/j.jstrokecerebrovasdis.2009.03.008
PMCID: PMC2817960  PMID: 20123228
18.  Genetic ancestry is associated with subclinical cardiovascular disease in African Americans and Hispanics from the Multi-Ethnic Study of Atherosclerosis (MESA) 
Background
Differences in cardiovascular disease (CVD) burden exist among racial/ethnic groups in the United States, with African Americans having the highest prevalence. Subclinical CVD measures have also been shown to differ by race/ethnicity. In the United States, there has been significant intermixing among racial/ethnic groups creating admixed populations. Very little research exists on the relationship of genetic ancestry and subclinical CVD measures.
Methods and Results
These associations were investigated in 712 African-American and 705 Hispanic participants from the MESA candidate gene sub-study. Individual ancestry was estimated from 199 genetic markers using STRUCTURE. Associations of ancestry and coronary artery calcium (CAC) and common and internal carotid intima media thickness (cIMT) were evaluated using log-binomial and linear regression models. Splines indicated linear associations of ancestry with subclinical CVD measures in African-Americans, but presence of threshold effects in Hispanics. Among African Americans, each standard deviation (SD) increase in European ancestry was associated with an 8% (95% CI (1.02, 1.15), p=0.01) greater CAC prevalence. Each SD increase in European ancestry was also associated with a 2% (95% CI (−3.4%, −0.5%), p=0.008) lower common cIMT in African Americans. Among Hispanics, the highest tertile of European ancestry was associated with a 34% greater CAC prevalence, p=0.02 as compared to lowest tertile.
Conclusions
The linear association of ancestry and subclinical CVD suggests that genetic effects may be important in determining CAC and cIMT among African-Americans. Our results also suggest that CAC and common cIMT may be important phenotypes for further study with admixture mapping.
doi:10.1161/CIRCGENETICS.109.876243
PMCID: PMC2795643  PMID: 20031644
atherosclerosis; calcium; ancestry; epidemiology; genetics
19.  Perturbation of hyaluronan metabolism predisposes patients with type 1 diabetes mellitus to atherosclerosis 
Diabetologia  2007;50(6):1288-1293.
Aims/hypothesis
Cardiovascular disease contributes to mortality in type 1 diabetes mellitus, but the specific pathophysiological mechanisms remain to be established. We recently showed that the endothelial glycocalyx, a protective layer of proteoglycans covering the endothelium, is severely perturbed in type 1 diabetes, with concomitantly increased plasma levels of hyaluronan and hyaluronidase. In the present study, we evaluated the relationship between hyaluronan and hyaluronidase with carotid intima-media thickness (cIMT), an established surrogate marker for cardiovascular disease.
Subjects and methods
Non-smoking type 1 diabetes patients without micro- or macrovascular complications and matched controls were recruited and cIMT of both carotid arteries was measured. To evaluate the relationship between cIMT and hyaluronan and hyaluronidase as well as other parameters, uni- or multivariate regression analyses were performed.
Results
We included 99 type 1 diabetes patients (age 10–72 years) and 99 age- and sex-matched controls. Mean cIMT, HbA1c, high sensitivity C-reactive protein, hyaluronan and hyaluronidase were significantly increased in type 1 diabetes vs controls. Plasma hyaluronan and hyaluronidase were correlated in type 1 diabetes. In univariate regression analyses, mean IMT was associated with plasma hyaluronan, age and male sex, whereas after multivariate analysis only age and sex remained statistically significant.
Conclusions/interpretation
We conclude that type 1 diabetes patients show structural changes of the arterial wall associated with increased hyaluronan metabolism. These data may lend further support to altered glycosaminoglycan metabolism in type 1 diabetes as a potential mechanism involved in accelerated atherogenesis.
doi:10.1007/s00125-007-0666-4
PMCID: PMC1914278  PMID: 17415544
Hyaluronan; Hyaluronidase; Intima-media thickness; Type 1 diabetes mellitus
20.  Associations of SNPs in ADIPOQ and subclinical cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis (MESA) 
Obesity (Silver Spring, Md.)  2010;19(4):840-847.
Circulating adiponectin has been associated with both clinical and subclinical cardiovascular disease (CVD). Variants of the adiponectin gene (ADIPOQ) are associated with clinical CVD, but little is known about associations with subclinical CVD. We studied the association of 11 ADIPOQ SNPs with common and internal carotid intima media thickness (cIMT), presence of coronary artery calcification (CAC), and CAC scores (in those with CAC) in 2847 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Participants were Caucasian (n=712), African-American (n=712), Chinese (n=718), and Hispanic (n=705). All models were adjusted for age, sex, and field site, and stratified by race/ethnic group. African-Americans with genotypes AG/GG of rs2241767 had 36% greater (95% CI (16%, 59%), p=0.0001) CAC prevalence; they also had a larger common cIMT (p=0.0043). Also in African-Americans, genotypes AG/AA of rs1063537 were associated with a 35% (95% CI (14%, 59%), p=0.0005) greater CAC prevalence. Hispanics with the AA genotype of rs11711353 had a 37% (95% CI (14%, 66%), p=0.0011), greater CAC prevalence compared to those with the GG genotype. Additional adjustment for ancestry in African-American and Hispanic participants did not change the results. No single SNP was associated with subclinical CVD phenotypes in Chinese or Caucasian participants. There appears to be an association between ADIPOQ SNPs and subclinical CVD in African-American and Hispanics. Replication as well as assessment of other ADIPOQ SNPs appears warranted.
doi:10.1038/oby.2010.229
PMCID: PMC3510267  PMID: 20930713
21.  Variations in Common Carotid Artery Intima-Media Thickness (cIMT) during the Cardiac Cycle: Implications for Cardiovascular Risk Assessment 
Introduction
Common carotid artery (CCA) intima-media thickness (cIMT), a measure of atherosclerosis, varies between peak-systole (PS) and end-diastole (ED). This difference might affect cardiovascular risk assessment.
Materials and methods
IMT measurements of the right and left CCA were synchronized with an electrocardiogram: R-wave for ED and T-wave for PS. IMT was measured in 2930 members of the Framingham Offspring Study. Multivariable regression models were generated with ED-IMT, PS-IMT and change in IMT as dependent variables and Framingham risk factors as independent variables. ED-IMT estimates were compared to the upper quartile of IMT based on normative data obtained at PS.
Results
The average age of our population was 57.9 years. Average difference in IMT during the cardiac cycle was 0.037 mm (95% CI: 0.035–0.038 mm). ED-IMT and PS-IMT had similar associations with Framingham risk factors (total R2= 0.292 versus 0.275) and were significantly associated with all risk factors. In a fully adjusted multivariable model, a thinner IMT at peak-systole was associated with pulse pressure (p < 0.0001), LDL-cholesterol (p = 0.0064), age (p = 0.046), and no other risk factors. Performing ED-IMT measurements while using upper quartile PS-IMT normative data lead to inappropriately increasing by 42.1% the number of individuals in the fourth IMT quartile (high cardiovascular risk category).
Conclusion
The difference in IMT between peak-systole and end-diastole is associated with pulse pressure, LDL-cholesterol, and age. In our study, mean IMT difference during the cardiac cycle lead to an overestimation by 42.1% of individuals at high risk for cardiovascular disease.
doi:10.1016/j.echo.2012.05.007
PMCID: PMC3544292  PMID: 22721828
Ultrasonics; Risk Factors; Carotid Arteries; Blood Pressure; systole; diastole
22.  The I405V and Taq1B polymorphisms of the CETP gene differentially affect sub-clinical carotid atherosclerosis 
Background
Cholesteryl ester transfer protein (CETP) plays a major role in lipid metabolism, but studies on the association of CETP polymorphisms with risks of cardiovascular disease are inconsistent. This study investigated whether the CETP gene I405V and Taq1B polymorphisms modified subclinical atherosclerosis in an asymptomatic Brazilian population sample.
Methods
The polymorphisms were analyzed using polymerase chain reaction in 207 adult volunteers. Serum lipid profiles, oxLDL Ab titers, C-reactive protein and tumor necrosis factor-α concentrations and CETP and phospholipid transfer protein (PLTP) activities were determined, and common carotid artery intima-media thickness (cIMT) was measured using ultrasonography.
Results
No differences in cIMT were observed between the presence or absence of the minor B2 and V alleles in either polymorphism. However, inverse correlations between mean cIMT and CETP activity in the presence of these polymorphisms were observed, and positive correlations of these polymorphisms with PLTP activity and oxLDL Ab titers were identified. Moreover, logistic multivariate analysis revealed that the presence of the B2 allele was associated with a 5.1-fold (CI 95%, OR: 1.26 – 21.06) increased risk for cIMT, which was equal and above the 66th percentile and positively interacted with age. However, no associations with the V allele or CETP and PLTP activities were observed.
Conclusions
None of the studied parameters, including CETP activity, explained the different relationships between these polymorphisms and cIMT, suggesting that other non-determined factors were affected by the genotypes and related to carotid atherosclerotic disease.
doi:10.1186/1476-511X-11-130
PMCID: PMC3503625  PMID: 23039379
Carotid atherosclerosis; Carotid intima-media thickness; Cholesteryl ester transfer protein; Genetic polymorphism
23.  Cardiovascular Risk Factor Profiles for Peripheral Artery Disease and Carotid Atherosclerosis among Chinese Older People: A Population-Based Study 
PLoS ONE  2014;9(1):e85927.
Objectives
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1371/journal.pone.0085927
PMCID: PMC3895010  PMID: 24465793
24.  Atherogenic Lipid Profile and Systolic Blood Pressure are Associated with Carotid Artery Intima-media Thickness in Children with Turner Syndrome 
Objective: Women with Turner syndrome (TS) have greater carotid artery intima-media thickness (cIMT) known to be a risk factor for atherosclerosis in adults. To determine whether there are risk factors for atherosclerosis in children with TS, we compared cIMT, anthropometric and metabolic parameters between children with TS and healthy controls.
Methods: Data of children with TS with XO karyotype (n=24, mean age: 11.6±3.6) were compared with those of healthy children (n=24, mean age: 10.5±3.6) with respect to anthropometric parameters, lipid levels, insulin resistance and cIMT which was measured by high resolution B-mode ultrasonography.
Results: Mean age and cIMT values were similar in the two groups of children. However in children with TS, fasting glucose (p=0.01), total cholesterol (p=0.006), triglyceride (p=0.04) levels and HDL-cholesterol (p=0.002) levels were higher than those of controls. In the TS group, cIMT correlated positively with LDL-cholesterol (r=0.435, p=0.034) and with systolic blood pressure (r=0.430, p=0.036) and negatively with HDL-cholesterol (r=-0.518, p=0.01). In stepwise regression analysis, HDL-cholesterol emerged as a significant predictor of cIMT (b= -0.518, p=0.01) contributing to 26.8 % of its variability.
Conclusion: The systolic blood pressure and dyslipidaemia were shown to be risk factors for atherosclerosis in children with TS.
Conflict of interest:None declared.
doi:10.4008/jcrpe.v1i2.9
PMCID: PMC3005644  PMID: 21318066
children; Turner syndrome; cardiovascular disease; carotid intima-media thickness
25.  Implications of Nocturnal Hypertension in Children and Adolescents With Type 1 Diabetes 
Diabetes Care  2011;34(10):2180-2185.
OBJECTIVE
Diabetes is associated with atherogenic risk factors. Hypertension has a major influence on cardiovascular disease in diabetic patients. Ambulatory blood pressure monitoring (ABPM) is useful for identifying nocturnal hypertension. Carotid intima-media thickness (cIMT) is a good measure for identifying subclinical atherosclerosis. This study aimed to evaluate whether nocturnal hypertension affects atherosclerosis in children and adolescents with type 1 diabetes and to investigate the relationship between atherogenic risk factors and cIMT.
RESEARCH DESIGN AND METHODS
ABPM and cIMT were measured in 82 diabetic children and adolescents. We reviewed the hemoglobin A1c levels, 24-h urine microalbumin excretion, lipid profiles, and duration of diabetes. Nocturnal hypertension was defined as hypertension observed only at night.
RESULTS
Forty-three (52%) subjects were hypertensive, and 30 subjects were classified as having nocturnal hypertension. cIMT was higher in the nocturnal hypertensive group than in the normotensive group (0.44 ± 0.03 vs. 0.42 ± 0.04 mm, P = 0.026). Among children and adolescents with nonhypertensive blood pressure levels in clinic blood pressure monitoring, cIMT and daytime blood pressure were higher in the nocturnal hypertensive group. All ABPM parameters were significantly related to cIMT in multiple linear regression analysis.
CONCLUSIONS
This study showed significantly increased cIMT and daytime blood pressure in diabetic children and adolescents with nocturnal hypertension. ABPM may be a useful method for detecting the macrovascular complications of type 1 diabetes. Longitudinal studies are needed to find the causes of nocturnal hypertension and to evaluate the effect of nocturnal hypertension on atherosclerosis in type 1 diabetes.
doi:10.2337/dc11-0830
PMCID: PMC3177721  PMID: 21911774

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