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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.  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
3.  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
4.  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
5.  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
6.  Previous gestational diabetes is independently associated with increased carotid intima-media thickness, similarly to metabolic syndrome – a case control study 
Background
Women with previous gestational diabetes mellitus (pGDM) face a higher risk of developing type 2 diabetes and, consequently, a higher cardiovascular risk. This study aimed to compare the carotid intima-media thickness (cIMT) from young women with pGDM to those with metabolic syndrome (MS) and to healthy controls (CG) to verify whether a past history of pGDM could be independently associated with increased cIMT.
Methods
This is a cross-sectional study performed in two academic referral centers. Seventy-nine women with pGDM, 30 women with MS, and 60 CG aged between 18 and 47 years were enrolled. They all underwent physical examination and had blood glucose, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDLc), and triglycerides determined. The cIMT was measured by ultrasound in several carotid segments. The primary endpoint was cIMT and clinically relevant parameters included as predictors were: age, systolic blood pressure, waist, BMI, total cholesterol, LDLc, triglycerides, fasting glucose, previous history of GDM as a whole group, previous history of GDM without MS, presence of DM, presence of MS, and parity.
Results
cIMT was significantly higher in pGDM when compared to CG in all sites of measurements (P < 0.05) except for the right common carotid. The pGDM women showed similar cIMT measurements to MS in all sites of measurements, except for the left carotid bifurcation, where it was significantly higher than MS (P < 0.001). In a multivariate analysis which included classical cardiovascular risk factors and was adjusted for confounders, pGDM was shown to be independently associated with increased composite cIMT (P < 0.01). The pGDM without risk factors further showed similar cIMT to MS (P > 0.05) and an increased cIMT when compared to controls (P < 0.05).
Conclusions
Previous GDM was independently associated with increased composite cIMT in this young population, similarly to those with MS and regardless the presence of established cardiovascular risk factors.
doi:10.1186/1475-2840-11-59
PMCID: PMC3403942  PMID: 22651701
Atherosclerosis; Gestational diabetes; Intima-media thickness; Carotid doppler ultrasonography; Metabolic syndrome
7.  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
8.  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
9.  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
10.  Relationship between Carotid Intima-Media Thickness and Left Ventricular Mass in Type 1 Diabetes: results from the Epidemiology of Diabetes Interventions and Complications (EDIC) Study 
The American journal of cardiology  2012;110(10):1534-1540.
Introduction
Type 1 diabetes mellitus is associated with early atherosclerosis and enhanced cardiovascular mortality. The relationship between carotid IMT (cIMT), a marker of subclinical atherosclerosis and left ventricular (LV) mass, an independent predictor of cardiovascular morbidity has not been previously studied in type 1 diabetics.
Methods
The Epidemiology of Diabetes Interventions and Complications (EDIC) study is a multicenter observational study designed to follow up the Diabetes Control and Complications Trial (DCCT) cohort. LV mass was measured with cardiac MRI at EDIC year 15 and common cIMT was assessed using B-mode ultrasound at EDIC year 12. Multivariable linear regression models were used to assess the relationship between cIMT at year 12 and LV mass at year 15.
Results
A total of 889 participants had both cardiac MRI and cIMT measures available for these analyses. At EDIC year 15, the mean age of the participants was 49 (±7) years; mean diabetes duration was 28 (±5) years and 52% were males. Spearman correlation coefficient (r) between LV mass and cIMT was 0.33 (p<0.0001). After adjusting for basic covariates (machine, reader, age and gender), a significant association between LV mass and cIMT (estimate 2.0 g/m2 per 0.1 mm cIMT increment, p < 0.0001) was observed. This association was diminished by the addition of systolic blood pressure in particular 1.15 g/m2 per 0.1 mm cIMT increment, p<0.0001) and to a lessor extent other cardiovascular disease (CVD) risk factors. The relationship observed between LV mass and cIMT was stronger (HOW MUCH) in patients with shorter diabetes duration.
Conclusion
In a well characterized population with type 1 diabetes, cIMT was an independent predictor of higher LV mass. These findings suggest a common pathway, possibly mediated by blood pressure dependent mechanisms, for vascular and myocardial structural change in T1DM.
doi:10.1016/j.amjcard.2012.07.014
PMCID: PMC3488435  PMID: 22884107
11.  Carotid Intima-Media Thickness and Plasma Asymmetric Dimethylarginine in Mexican Children Exposed to Inorganic Arsenic 
Environmental Health Perspectives  2013;121(9):1090-1096.
Background: Arsenic exposure is a risk factor for atherosclerosis in adults, but there is little information on arsenic and early risk biomarkers for atherosclerosis in children. Carotid intima-media thickness (cIMT) is an indicator of subclinical atherosclerotic burden that has been associated with plasma asymmetric dimethylarginine (ADMA), a predictor of cardiovascular disease risk.
Objectives: The aim of this study was to investigate associations of arsenic exposure with cIMT, ADMA, and endothelial adhesion molecules [soluble intercellular cell adhesion molecule-1 (sICAM-1); soluble vascular cell adhesion molecule-1 (sVCAM-1)] in children who had been exposed to environmental inorganic arsenic (iAs).
Methods: We conducted a cross-sectional study in 199 children 3–14 years of age who were residents of Zimapan, México. We evaluated cIMT using ultrasonography, and plasma lipid profiles by standard methods. We analyzed ADMA, sICAM-1, and sVCAM-1 by ELISA, and measured the concentrations of total speciated arsenic (tAs) in urine using hydride generation cryotrapping atomic absorption spectrometry.
Results: In the multiple linear regression model for cIMT, tAs categories were positively associated with cIMT increase. The estimated cIMT diameter was greater in 35- to 70-ng/mL and > 70-ng/mL groups (0.035 mm and 0.058 mm per 1-ng/mL increase in urinary tAs, respectively), compared with the < 35-ng/mL group. In addition to tAs level, plasma ADMA was a significant predictor of cIMT. In the adjusted regression model, cIMT, percent iAs, and plasma sVCAM-1 were significant predictors of ADMA levels (e.g., 0.419-μmol/L increase in ADMA per 1-mm increase in cIMT).
Conclusions: Arsenic exposure and plasma ADMA levels were positively associated with cIMT in a population of Mexican children with environmental arsenic exposure through drinking water.
Citation: Osorio-Yáñez C, Ayllon-Vergara JC, Aguilar-Madrid G, Arreola-Mendoza L, Hernández-Castellanos E, Barrera-Hernández A, De Vizcaya-Ruíz A, Del Razo LM. 2013. Carotid intima-media thickness and plasma asymmetric dimethylarginine in Mexican children exposed to inorganic arsenic. Environ Health Perspect 121:1090–1096; http://dx.doi.org/10.1289/ehp.1205994
doi:10.1289/ehp.1205994
PMCID: PMC3764073  PMID: 23757599
12.  Risk factors and their impact on carotid intima-media thickness in young and middle-aged ischemic stroke patients and controls: The Norwegian Stroke in the Young Study 
BMC Research Notes  2014;7:176.
Background
Vascular morbidity and mortality due to cardiovascular disease (CVD) are high after ischemic stroke at a young age. Data on carotid intima-media thickness (cIMT) as marker of atherosclerosis are scarce for young stroke populations. In this prospective case–control study, we examined cIMT, the burden of vascular risk factors (RF) and their associations among young and middle-aged ischemic stroke patients and controls. We aimed to detect clinical and sub-clinical arterial disease.
Methods
This study was conducted in 150 patients aged 15–60 years and 84 controls free of CVD. We related RF to ultrasonographic B-mode cIMT-measurements obtained from 12 standardized multiangle measurements in the common carotid artery (CCA), carotid bifurcation (BIF) and internal carotid artery (ICA).
Results
RF burden was higher among patients than among controls (p < 0.001). In multivariate analyses of all 234 participants, increased cIMT was associated with age in each carotid segment. Incident stroke was associated with increased ICA-IMT. ICA-IMT increase was associated with a family history of CVD among patients aged 15–44 years, and with RF at mid-age. The overall cIMT difference between patients and controls was 12% for CCA, 17% for BIF and 29% for ICA. Further, increased CCA-IMT was associated with male sex and hypertension. Increased BIF-IMT was associated with dyslipidemia, coronary heart disease and smoking. Increased ICA-IMT was associated with dyslipidemia and stroke.
Conclusions
Ischemic stroke is associated with increased ICA-IMT, related to a family history of CVD among patients aged <45 years, and to increasing RF burden with increasing age. Preventive strategies and aggressive RF treatment are indicated to avoid future cardiovascular events.
Trial registration
NOR-SYS is registered in ClinicalTrials.gov (NCT01597453).
doi:10.1186/1756-0500-7-176
PMCID: PMC3986875  PMID: 24669965
Young stroke; Ischemic stroke; Risk factors; Carotid intima-media thickness; Atherosclerosis; Ultrasound
13.  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
14.  Carotid intima media thickness in type 2 diabetes mellitus with ischemic stroke 
Background:
Diabetes mellitus is associated with high cardiovascular risk. Carotid intima media thickness (CIMT) is used commonly as a noninvasive test for the assessment of degree of atherosclerosis. The objective of this study was to find out the cut-off point for CIMT for ischemic stroke in patients with type 2 diabetes mellitus (T2DM) and to correlate CIMT with various parameters like smoking, hypertension, lipid profile and duration of T2DM.
Materials and Methods:
A total of 80 subjects in the age group of 30–75 years (M:F = 57:23) were selected and divided into three groups, i.e. diabetes with ischemic stroke, diabetes and healthy subjects. All the participants were subjected to B-mode ultrasonography of both common carotid arteries to determine CIMT, along with history taking, physical examination and routine laboratory investigations including included fasting and 2-hour postprandial blood sugar, blood urea, serum creatinine, lipid profile, glycated hemoglobin, and microalbuminuria.
Results:
Patients with T2DM with or without ischemic stroke were found to have significantly higher prevalence of increased CIMT and a value greater than 0.8 mm was found to be associated with the occurrence of stroke. The mean carotid IMT of the group as a whole was 0.840 ± 0.2 mm. The mean carotid IMT was not significantly different between T2DM patients with or without ischemic stroke (1.06 ± 0.2 vs. 0.97 ± 0.26 mm, P = 0.08). However, the mean CIMT was significantly higher in diabetic subjects compared to healthy subjects (1.01 ± 0.28 mm vs. 0.73 ± 0.08, P = 0.006). Other parameters like higher age, smoking, hypertension, hyperlipidemia, low HDL cholesterol, the glycemic parameters and the duration of diabetes were independently and significantly related to CIMT.
Conclusion:
A high CIMT is a surrogate and reliable marker of higher risk of ischemic stroke amongst type 2 diabetic patients. Our study demonstrates the utility of carotid IMT as a simple non-invasive screening test for the assessment of atherosclerosis risk/prognosis in type 2 diabetics.
doi:10.4103/2230-8210.113767
PMCID: PMC3743376  PMID: 23961492
B-mode ultrasonography; carotid intima media thickness; diabetes mellitus; ischemic stroke
15.  Early signs of atherosclerosis are associated with insulin resistance in non-obese adolescent and young adults with type 1 diabetes 
Background
Patients with type 1 diabetes have a substantial risk of developing cardiovascular complications early in life. We aimed to explore the role of insulin sensitivity (Si) as an early factor of atherosclerosis in young type 1 diabetes vs. non-diabetic subjects.
Methods
Forty adolescent and young adult individuals (20 type 1 diabetics and 20 non-diabetics), age 14–20 years, without characteristics of the metabolic syndrome, participated in this cross-sectional study. After an overnight fast, Si was measured by hyperinsulinemic euglycemic clamp (40 mU/m2) and calculated by glucose infusion rate (GIR). Carotid intima-media thickness (cIMT) was measured in the common carotid artery with high-resolution ultrasonography. Risk factors of atherosclerosis (Body mass index [BMI], waist circumference, systolic blood pressure [sBP], triglycerides, low HDL-cholesterol and HbA1c) were also investigated.
Results
cIMT was increased (0.52 ± 0.1 vs. 0.47 ± 0.1 mm, P < 0.01), whereas GIR was decreased (5.0 ± 2.1 vs. 7.1 ± 2.2 mg/kg/min, P < 0.01) in type 1 diabetics vs. non-diabetics. The differences in cIMT were negatively associated with Si (r = −0.4, P < 0.01) and positively associated with waist circumference (r = 0.34, P = 0.03), with no such associations between BMI (r = 0.15, P = 0.32), sBP (r = 0.09, P = 0.58), triglycerides (r = 0.07, P = 0.66), HDL-cholesterol (r = 0.10, P = 0.55) and HbA1c (r = 0.24, P = 0.13). In a multivariate regression model, between cIMT (dependent) and group (explanatory), only adjustment for Si affected the significance (ß = 0.08, P = 0.11) vs. (ß = 0.07, P < 0.01) for the whole model. No interaction between cIMT, groups and Si was observed.
Conclusions
cIMT is increased and associated with insulin resistance in adolescent, non-obese type 1 diabetic subjects. Although, no conclusions toward a causal relationship can be drawn from current findings, insulin resistance emerges as an important factor reflecting early signs of atherosclerosis in this small cohort.
doi:10.1186/1475-2840-11-145
PMCID: PMC3538551  PMID: 23185996
Adolescent; Atherosclerosis; Carotid intima-media thickness; Insulin sensitivity; Type 1 diabetes
16.  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
17.  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
18.  Association between Obesity, hsCRP ≥2 mg/L, and Subclinical Atherosclerosis: Implications of JUPITER from the Multi-Ethnic Study of Atherosclerosis (MESA) 
Objective
High-sensitivity C-reactive protein (hsCRP) levels are closely associated with abdominal obesity, metabolic syndrome, and atherosclerotic cardiovascular disease. The JUPITER trial has encouraged using hsCRP ≥2 mg/L to guide statin therapy; however the association of hsCRP to atherosclerosis, independent of obesity, remains unknown.
Methods and Results
We studied 6,760 participants from the Multi-Ethnic Study of Atherosclerosis (MESA). Participants were stratified into 4 groups: non-obese/low hsCRP, non-obese/high hsCRP, obese/low hsCRP, and obese/high hsCRP. Using multivariable logistic and robust linear regression, we described the association with subclinical atherosclerosis, using coronary artery calcium (CAC) and carotid intima-media thickness (cIMT). Mean BMI was 28.3 ± 5.5 kg/m2, and median hsCRP was 1.9 mg/L (0.84 – 4.26). High hsCRP, in the absence of obesity, was not associated with CAC and was mildly associated with cIMT. Obesity was strongly associated with CAC and cIMT independent of hsCRP. When obesity and high hsCRP were both present, there was no evidence of multiplicative interaction. Similar associations were seen among 2,083 JUPITER-eligible individuals.
Conclusions
High hsCRP, as defined by JUPITER, was not associated with CAC and was mildly associated with cIMT in the absence of obesity. In contrast, obesity was associated with both measures of subclinical atherosclerosis independent of hsCRP status.
doi:10.1161/ATVBAHA.111.223768
PMCID: PMC3130297  PMID: 21474823
obesity; hsCRP; high sensitivity C-reactive protein; subclinical atherosclerosis; coronary artery calcium; carotid intima-media thickness
19.  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
20.  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
21.  Polymorphisms of the methylenetetrahydrofolate reductase, vascular endothelial growth factor, endothelial nitric oxide synthase, monocyte chemoattractant protein-1 and apolipoprotein E genes are not associated with carotid intima-media thickness 
BACKGROUND:
Single nucleotide polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR), vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), monocyte chemoattractant protein-1 (MCP-1) and apolipoprotein E (ApoE) genes appear to be a genetic risk factor for atherosclerosis. Common carotid intima-media thickness (cIMT) provides information on the severity of atherosclerosis.
OBJECTIVE:
To investigate the relationship between cIMT and gene polymorphisms associated with atherosclerosis in Turkish patients with coronary artery disease (CAD).
METHODS:
Sixty-two patients with angiographically diagnosed stable CAD were divided into two groups according to their cIMT values (group 1: n=35, cIMT of 1 mm or greater; group 2: n=27, cIMT of less than 1 mm). MTHFR 677 C/T, VEGF–460 C/T, eNOS 894 G/T, MCP-1–2518 A/G and ApoE (E2, E3 and E4) gene polymorphisms (where A is adenine, C is cytosine, G is guanine and T is thymine) were analyzed by polymerase chain reaction and restriction fragment length polymorphism. Evaluations of cardiovascular risk factors and coronary atherosclerotic lesions were performed in all patients. Serum homocysteine and high-sensitivity C-reactive protein were measured and compared between the two groups.
RESULTS:
Serum high-sensitivity C-reactive protein (P=0.04) and homocysteine (P=0.006) levels were higher in group 1 than in group 2. The ratio of multivessel CAD and previous myocardial infarction was significantly higher in group 1 than in group 2 (P=0.014). In the study population, no significant difference in cIMT was observed according to the polymorphisms studied. Only hyperhomocysteinemia (OR 1.17 [95% CI 1.01 to 1.35], P=0.033) and previous myocardial infarction (OR 3.76 [95% CI 1.10 to 12.81], P=0.034) maintained a significant correlation with cIMT on multiple logistic regression analysis.
CONCLUSION:
cIMT is increased in patients with hyperhomocysteinemia, inflammation and extended CAD. MTHFR 677 C/T, VEGF–460 C/T, eNOS 894 G/T, MCP-1–2518 A/G and ApoE single nucleotide polymorphisms were not associated with increased cIMT.
PMCID: PMC2691882  PMID: 19148342
Atherosclerosis-related genes; Carotid intima-media thickness; Coronary artery disease; Homocysteine
22.  Evaluation of endothelial function and subclinical atherosclerosis in association with hepatitis C virus in HIV-infected patients: a cross-sectional study 
BMC Infectious Diseases  2011;11:265.
Background
Relationship of hepatitis C virus (HCV) infection with an increased risk of cardiovascular disease (CVD) in HIV-infected patients remains controversial. We evaluated endothelial function and subclinical atherosclerosis in HIV-infected patients with and without HCV.
Methods
Flow-mediated dilatation (FMD) of the brachial artery and circulating levels of cell adhesion molecules (CAM) were measured in HCV/HIV-coinfected and HIV-monoinfected patients. Subclinical atherosclerosis was assessed by carotid intima-media thickness (cIMT).
Results
63 (31%) HCV/HIV-coinfected and 138 (69%) HIV-monoinfected patients were included. Median soluble vascular CAM-1 (sVCAM-1) and intercellular CAM-1 (sICAM-1) levels were significantly higher in HIV/HCV-coinfected patients (P < 0.001 for both cases). Median (interquartile range) FMD was 6.21% (2.86-9.62) in HCV/HIV-coinfected and 5.54% (2.13-9.13) in HIV-monoinfected patients (P = 0.37). Adjustment for variables associated with HCV and FMD disclosed similar results. FMD correlated inversely with cIMT and age. Carotid IMT did not differ between HCV/HIV-coinfected and HIV-monoinfected patients in unadjusted (0.61 [0.55-0.65] mm vs 0.60 [0.53-0.72] mm; P = 0.39) or adjusted analyses.
Conclusion
HCV infection was associated with higher levels of sICAM-1 and sVCAM-1, but no evidence of increased subclinical atherosclerosis was found when endothelial function was evaluated through FMD, or when assessing the cIMT.
doi:10.1186/1471-2334-11-265
PMCID: PMC3198698  PMID: 21967471
23.  Comparison of Factors Associated with Carotid Intima-Media Thickness in the Multi-Ethnic Study of Atherosclerosis (MESA) and the Heinz Nixdorf Recall Study (HNR) 
Background
The measurement of carotid intima-media thickness (CIMT) is a valid method to quantify levels of atherosclerosis. The present study was conducted to compare the strengths of associations between CIMT and cardiovascular risk factors in two different populations.
Methods
The Multi-Ethnic Study of Atherosclerosis (MESA) and the Heinz Nixdorf Recall Study (HNR) are two population-based prospective cohort studies of subclinical cardiovascular disease. All Caucasian subjects aged 45 to 75 years from these cohorts who were free of baseline cardiovascular disease (n = 2,820 in HNR, n = 2,270 in MESA) were combined. CIMT images were obtained using B-mode sonography at the right and left common carotid artery and measured 1 cm starting from the bulb.
Results
In both studies, age, male sex, and systolic blood pressure showed the strongest association (P < .0001 for each) for a higher CIMT. The mean of mean far wall CIMT was slightly higher in MESA participants (0.71 vs 0.67 mm). Almost all significant variables were consistent between the two cohorts in both magnitude of association with CIMT and statistical significance, including age, sex, smoking, diabetes, cholesterol levels, and blood pressure. For example, the association with systolic blood pressure was (ΔSD = 0.011; 95% confidence interval, 0.0009 to 0.014) per mm Hg in MESA and (ΔSD = 0.010; 95% confidence interval, 0.005 to 0.021) per mm Hg in HNR. This consistency persisted throughout the traditional (Framingham) risk factors.
Conclusions
A comparison of the associations between traditional cardiovascular risk factors and CIMT across two culturally diverse populations showed remarkable consistency.
doi:10.1016/j.echo.2013.03.011
PMCID: PMC3694173  PMID: 23611058
Carotid intima-media thickness; Subclinical atherosclerosis; Multi-Ethnic Study of Atherosclerosis; MESA; Heinz Nixdorf Recall Study; HNR
24.  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
25.  Changes in Carotid Intima-Media Thickness During the Cardiac Cycle: The Multi-Ethnic Study of Atherosclerosis 
Background
Common carotid artery intima-media thickness (IMT), a measure of subclinical cardiovascular disease, changes during the cardiac cycle. The magnitude of this effect and its implications have not been well studied.
Methods and Results
Far-wall IMT measurements of the right common carotid artery were measured at end diastole and peak systole in 5633 individuals from the Multi-Ethnic Study of Atherosclerosis (MESA). Multivariable regression models were generated with end-diastolic IMT, peak-systolic IMT, and change in IMT during the cardiac cycle as dependent variables and traditional cardiovascular risk factors as independent variables. The average age of our population was 61.9 (45 to 84) years. Average change in carotid IMT during the cardiac cycle was 0.041 mm (95% confidence interval: 0.039 to 0.042 mm), with a mean IMT of 0.68 mm. End-diastolic IMT and peak-systolic IMT were similarly associated with risk factors. In a fully adjusted model, change in carotid IMT during the cardiac cycle was associated with ethnicity and pulse pressure (P=0.001) and not age, sex, or other risk factors. Chinese and Hispanics had less of a change in IMT than did non-Hispanic whites. With peak-systolic IMT reference values used as normative data, 31.3% more individuals were classified as being in the upper quartile of IMT and at high risk for cardiovascular disease than would be expected when IMT is measured at end diastole.
Conclusions
Measurable differences in IMT are seen during the cardiac cycle. This affects the interpretation of IMT measurements used for cardiovascular risk assessment, given published normative data with IMT measured at peak systole.
Clinical Trial Registration
URL: www.ClinicalTrials.gov. Unique identifier: NCT00063440. (J Am Heart Assoc. 2012;1:e001420 doi: 10.1161/JAHA.112.001420.)
doi:10.1161/JAHA.112.001420
PMCID: PMC3487346  PMID: 23130162
atherosclerosis; blood pressure; carotid arteries; diastole; epidemiology; risk factors; systole; ultrasonics

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