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1.  Determination of site-specific carotid-intima media thickness: common –carotid artery and carotid bifurcation in hypercholesterolemia patients 
Pakistan Journal of Medical Sciences  2013;29(5):1249-1252.
Objective: To determine site specific carotid intima-media thickness: common–carotid artery and carotid bifurcation in hypercholesterolemia patients as a marker for atherosclerosis.
Methods: Fifty patients with hypercholesterolemia and twenty controls were selected after getting informed consent regarding the investigation of carotid- intima media thickness by B-mode ultrasound. All the patients of hypercholesterolemia with LDL-C > 160mg/dL had family history of coronary artery diseases. This procedure was carried out in the Radiology Department of Dr. Ziauddin Hospitals. Measurement of carotid -intima media thickness, B-mode ultrasonography of common carotid artery, carotid bifurcation and internal carotid artery (left and right carotid arteries) was performed with Toshiba (M# SSA-580A/E2) ultrasound scanner with linear probe. The posterior or far wall of the carotid artery is, the distance between the leading edge first bright line (lumen -intima interface) and the leading edge of the second bright line (media-adventitia interface) of far wall was recorded as intima -media thickness. The average mean of six segments of intima-media thickness was taken as mean CIMT of right and left common carotid, bifurcation and internal carotid arteries.
Results: Maximal CIMT was significantly increased at sites common carotid, carotid bifurcation and internal carotid arteries in fifty patients with hypercholesterolemia as compared to controls. At carotid bifurcation mean of maximal CIMT was (0.9+ 0.3mm). Range of maximum CIMT in hypercholesterolemia patients was (0.8- 3.3mm) and in controls (0.4- 0.8 mm). The thickness was more frequently increased at site of bifurcation.
Conclusions: Carotid intima- media thickness in hypercholesterolemia patients was increased and carotid bifurcation was site that has shown greater increase in intima-media thickness and plaques in these patients predict high risk for atherosclerosis.
PMCID: PMC3858954  PMID: 24353730
CIMT- Carotid- intima media thickness; CCA- Common carotid artery; BULB – Bifurcation of carotid artery; B-mode ultrasound
2.  Intensive Diabetes Therapy and Carotid Intima–Media Thickness in Type 1 Diabetes Mellitus 
The New England journal of medicine  2003;348(23):2294-2303.
Cardiovascular disease causes severe morbidity and mortality in type 1 diabetes, although the specific risk factors and whether chronic hyperglycemia has a role are unknown. We examined the progression of carotid intima–media thickness, a measure of atherosclerosis, in a population with type 1 diabetes.
As part of the Epidemiology of Diabetes Interventions and Complications (EDIC) study, the long-term follow-up of the Diabetes Control and Complications Trial (DCCT), 1229 patients with type 1 diabetes underwent B-mode ultrasonography of the internal and common carotid arteries in 1994–1996 and again in 1998–2000. We assessed the intima–media thickness in 611 subjects who had been randomly assigned to receive conventional diabetes treatment during the DCCT and in 618 who had been assigned to receive intensive diabetes treatment.
At year 1 of the EDIC study, the carotid intima–media thickness was similar to that in an age- and sex-matched nondiabetic population. After six years, the intima–media thickness was significantly greater in the diabetic patients than in the controls. The mean progression of the intima–media thickness was significantly less in the group that had received intensive therapy during the DCCT than in the group that had received conventional therapy (progression of the intima–media thickness of the common carotid artery, 0.032 vs. 0.046 mm; P=0.01; and progression of the combined intima–media thickness of the common and internal carotid arteries, −0.155 vs. 0.007; P=0.02) after adjustment for other risk factors. Progression of carotid intima–media thickness was associated with age, and the EDIC base-line systolic blood pressure, smoking, the ratio of low-density lipoprotein to high-density lipoprotein cholesterol, and urinary albumin excretion rate and with the mean glycosylated hemoglobin value during the mean duration (6.5 years) of the DCCT.
Intensive therapy during the DCCT resulted in decreased progression of intima–media thickness six years after the end of the trial.
PMCID: PMC2701300  PMID: 12788993
3.  Atherosclerotic plaques occur in absence of intima-media thickening in both systemic sclerosis and systemic lupus erythematosus: a duplexsonography study of carotid and femoral arteries and follow-up for cardiovascular events 
The objective of this cross-sectional and retrospective cohort study was (1) to determine the usefulness of intima-media thickness (IMT) in contrast to plaque assessment, (2) to examine the value of additive femoral artery sonography and (3) to identify potential risk factors for atherosclerosis and incident cardiovascular events in systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) patients.
In this study, 90 SSc and 100 SLE patients were examined by duplexsonography. IMT was measured in common carotid and common femoral arteries, plaques were assessed in common, internal and external carotid and common, proximal superficial and deep femoral arteries. Different definitions of pathological IMT (pIMT) were compared with the presence of plaque. Results were evaluated in relation to traditional and non-traditional risk factors for baseline atherosclerosis (logistic regression) and their predictive value for cardiovascular events during follow-up (cox regression).
Definite atherosclerosis occurred frequently without signs of subclinical atherosclerosis in both diseases: pIMT >0.9 mm was present in only 17/59 (28.9%) SSc and 13/49 (26.5%) SLE patients with already present atherosclerotic plaques. Using age-adjusted pIMT definitions, this rate was even lower (5.1-10.3% in SSc, 14.3-26.5% in SLE). Plaques were located only at the carotid or only at the femoral arteries in 26 (13.7%) and 24 (12.6%) patients, respectively. Age and nicotine pack-years were independently associated with atherosclerotic plaques in SLE and SSc patients, as well as the cumulative prednisolone dose in SSc subgroup, and ssDNA positive SLE patients had a lower risk for atherosclerotic plaque. During follow-up (available for 129/190 (67.9%) patients, 650 person-years), cardiovascular events occurred more often in patients with coronary heart disease (adjusted-hazards ratio (HR) 10.19, 95% confidence interval (CI) 3.04 to 34.17, P <0.001), male patients (adjusted-HR 8.78, 95% CI 2.73 to 28.19, P <0.001) and in patients with coexistent carotid and femoral plaques (adjusted-HR 5.92, 95% CI 1.55 to 22.67, P = 0.009). Patients with solely carotid or femoral plaque were not at higher risk.
Atherosclerotic plaque lesions can be found frequently in absence of intima-media thickening in both SSc and SLE patients. As well as routine sonography of carotid arteries, the sonography of femoral arteries is recommended to identify additional atherosclerotic lesions and to detect patients at a high risk for cardiovascular events.
PMCID: PMC3978872  PMID: 24548804
4.  Progression of Carotid Intima-Media Thickness and Coronary Artery Calcium over Six Years in an HIV-infected Cohort 
Journal of acquired immune deficiency syndromes (1999)  2013;64(1):10.1097/QAI.0b013e31829ed726.
To evaluate changes in cardiovascular disease risk surrogate markers in a longitudinal cohort of HIV-infected adults over 6 years.
Internal and common carotid artery intima-media thickness, coronary artery calcium, vascular and HIV risk factors were prospectively examined over 6 years in HIV-infected adults from 2002 to 2010.
Longitudinal cohort study with participants from urban center and surrounding communities.
Subjects, participants
345 HIV-infected participants were recruited from a longitudinal cohort study. 211 participants completed the study and were included in this analysis.
Main Outcome Measures
Total and yearly internal and common carotid artery intima-media thickness change; coronary artery calcium score progression.
Participants were 27% female and 49% non-white; mean age at start was 45 ± 7 years. The median change in internal and common carotid arteries over six years was 0.15mm (0.08,0.28) and 0.12mm (0.09,0.15), respectively. Age, baseline triglycerides ≥ 150mg/dL, and pack-years smoking were associated with internal carotid artery intima-media thickness change; age, cholesterol, nadir CD4+ count, and protease inhibitor use were associated with common carotid artery intima-media thickness change. Diabetes, HIV viral load, and HAART duration were associated with coronary artery calcium progression.
Carotid intima-media thickness and coronary artery calcium progressed in this HIV-infected cohort. Some HIV-specific characteristics were associated with surrogate marker changes, but the majority of risk factors continue to be traditional. Aggressive identification and management of modifiable risk factors may reduce progression of cardiovascular disease risk in this population.
PMCID: PMC3815556  PMID: 23945252
5.  Associations of Carotid Artery Intima-Media Thickness (IMT) With Risk Factors and Prevalent Cardiovascular Disease 
The goal of this study was to compare internal carotid artery (ICA) intima-media thickness (IMT) with common carotid artery (CCA) IMT as global markers of cardiovascular disease (CVD).
Cross-sectional measurements of the mean CCA IMT and maximum ICA IMT were made on ultrasound images acquired from the Framingham Offspring cohort (n = 3316; mean age, 58 years; 52.7% women). Linear regression models were used to study the associations of the Framingham risk factors with CCA and ICA IMT. Multivariate logistic regression models and receiver operating characteristic (ROC) curve analysis were used to compare the associations of prevalent CVD with CCA and ICA IMT and determine sensitivity and specificity.
The association between age and the mean CCA IMT corresponded to an increase of 0.007 mm/y; the increase was 0.037 mm/y for the ICA IMT. Framingham risk factors accounted for 28.6% and 27.5% of the variability in the CCA and ICA IMT, respectively. Age and gender contributed 23.5% to the variability of the CCA IMT and 22.5% to that of the ICA IMT, with the next most important factor being systolic blood pressure (1.9%) for the CCA IMT and smoking (1.6%) for the ICA IMT. The CCA IMT and ICA IMT were statistically significant predictors of prevalent CVD, with the ICA IMT having a larger area under the ROC curve (0.756 versus 0.695).
Associations of risk factors with CCA and ICA IMT are slightly different, and both are independently associated with prevalent CVD. Their value for predicting incident cardiovascular events needs to be compared in outcome studies.
PMCID: PMC3186063  PMID: 21098848
atherosclerosis; carotid artery; disease prevalence; intima-media thickness; risk factors
6.  Carotid artery plaque and progression of coronary artery calcium: the Multi-Ethnic Study of Atherosclerosis 
Carotid and coronary atherosclerosis are associated to each other in imaging and autopsy studies. We evaluated whether carotid artery plaque seen on carotid ultrasound can predict incident coronary artery calcification (CAC).
Materials and Methods
We repeated Agatston calcium score measurements in 5445 participants of the Multi-Ethnic Study of Atherosclerosis (MESA) (mean age 57.9 years; 62.9% female). Internal carotid artery lesions were graded as 0%, 1-24%, >25% diameter narrowing and intima-media thickness (IMT) was measured. Plaque was present for any stenosis > 0%. CAC progression was evaluated with multivariable relative risk regression in cases with CAC = 0 at baseline and with multivariable linear regression for CAC > 0 adjusting for cardiovascular risk factors, body mass index, ethnicity, and common carotid IMT.
CAC was positive at baseline in 2708/5445 (49.7%) participants and became positive in 458/2837 (16.1%) at mean interval of 2.4 years between repeat examinations. Plaque and ICA IMT were both strongly associated with presence of CAC. After statistical adjustment, presence of carotid artery plaque significantly predicted incident CAC with a relative risk(RR) of 1.37 (95% Confidence Intervals: 1.12, 1.67). Incident CAC was associated with ICA IMT with an RR of 1.13 (95% Confidence Intervals: 1.03, 1.25) for each mm increase. Progression of CAC was also significantly associated (p < 0.001) with plaque and ICA IMT.
In individuals free of cardiovascular disease, subjective and quantitative measures of carotid artery plaques by ultrasound imaging are associated with CAC incidence and progression.
PMCID: PMC4084492  PMID: 23522805
7.  The Role of Carotid Intimal Thickness Testing and Risk Prediction for the Development of Coronary Atherosclerosis 
Carotid Ultrasound is a safe and available non invasive diagnostic tool that provides information about the carotid arteries’ characteristics and may be used for early detection of coronary artery disease as well as cardiovascular and stroke event risk stratifications. We performed a systematic search of the articles discussing carotid ultrasound in English literature, published in PubMed from the year2010 to September 2012. Generally, the studies showed that Internal carotid artery intima media thickness is a more powerful variable than common carotid artery intima media thickness. Moreover, the presence of carotid plaque and plaque volumes are more reliable and accurate estimators of coronary artery disease and risk of a stroke or cardiovascular event than intima media thickness.
PMCID: PMC3583351  PMID: 23328906
Carotid Ultrasound; Coronary Artery Disease; Risk Prediction; Intima Media Thickness
8.  Clinical utility of brachial-ankle pulse wave velocity in the prediction of cardiovascular events in diabetic patients 
Cardiovascular Diabetology  2014;13(1):128.
Brachial-ankle pulse wave velocity (baPWV) is a method to estimate arterial stiffness, which reflects the stiffness of both the aorta and peripheral artery; it would be applicable to general practice, since its measurementis automated. The aim of this study was to evaluate whether baPWV can be predictors of future cardiovascular events (CVE) in diabetic patients.
We prospectively evaluated the association between baPWV or carotid intima-media thickness (carotid IMT) at baseline and new onset of CVE in 1040 type 2 diabetic patients without CVE. The predictability of baPWV and/or carotid IMT for identifying patients at high risk for CVE was evaluated by time-dependent receiver-operating-characteristic (ROC) curve analysis.
During a median follow-up of 7.5 years, 113 had new CVD events. The cumulative incidence rates of CVE were significantly higher in patients with high baPWV values (≥1550 cm/s) as compared to those with low baPWV values (<1550 cm/s) (p < 0.001, log-rank test). Similarly, the cumulative incidence rate of CVE was significantly higher in patients with higher maximum carotid IMT (maxIMT) values (≥1.0 mm) as compared to those with lower maxIMT values (<1.0 mm) (p < 0.001, log-rank test). Subjects with both “high PWV” and “high IMT” had a significantly higher risk of developing CVE as compared to those with either “high PWV” or “high IMT,” as well as those with neither. A multivariate Cox proportional hazards regression model revealed that both baPWV (HR = 1.30, [95%CI: 1.07-1.57]; p = 0.009) and maxIMT (HR = 1.20, [95%CI: 1.01-1.41]; p = 0.033) were independent predictors for CVE, even after adjustment for the conventional risk factors. Time-dependent ROC curve analyses revealed that the addition of maxIMT to the Framingham risk score resulted in significant increase in AUC (from 0.60 [95%CI: 0.54-0.67] to 0.63 [95%CI: 0.60-0.82]; p = 0.01). Notably, the addition of baPWV to the Framingham risk score and maxIMT resulted in further and significant (p = 0.02) increase in AUC (0.72 [95%CI: 0.67-0.78]).
Evaluation of baPWV, in addition to carotid IMT and conventional risk factors, improved the ability to identify the diabetic individuals with high risk for CVE.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-014-0128-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4172854  PMID: 25186287
Brachial-ankle pulse wave velocity (baPWV); Carotid intima-media thickness (carotid IMT); Cardiovascular risk; Diabetes mellitus
9.  Common carotid artery intima–media thickness is as good as carotid intima–media thickness of all carotid artery segments in improving prediction of coronary heart disease risk in the Atherosclerosis Risk in Communities (ARIC) study 
European Heart Journal  2011;33(2):183-190.
Carotid intima–media thickness (CIMT) and plaque information can improve coronary heart disease (CHD) risk prediction when added to traditional risk factors (TRF). However, obtaining adequate images of all carotid artery segments (A-CIMT) may be difficult. Of A-CIMT, the common carotid artery intima–media thickness (CCA-IMT) is relatively more reliable and easier to measure. We evaluated whether CCA-IMT is comparable to A-CIMT when added to TRF and plaque information in improving CHD risk prediction in the Atherosclerosis Risk in Communities (ARIC) study.
Methods and results
Ten-year CHD risk prediction models using TRF alone, TRF + A-CIMT + plaque, and TRF + CCA-IMT + plaque were developed for the overall cohort, men, and women. The area under the receiver operator characteristic curve (AUC), per cent individuals reclassified, net reclassification index (NRI), and model calibration by the Grønnesby–Borgan test were estimated. There were 1722 incident CHD events in 12 576 individuals over a mean follow-up of 15.2 years. The AUC for TRF only, TRF + A-CIMT + plaque, and TRF + CCA-IMT + plaque models were 0.741, 0.754, and 0.753, respectively. Although there was some discordance when the CCA-IMT + plaque- and A-CIMT + plaque-based risk estimation was compared, the NRI and clinical NRI (NRI in the intermediate-risk group) when comparing the CIMT models with TRF-only model, per cent reclassified, and test for model calibration were not significantly different.
Coronary heart disease risk prediction can be improved by adding A-CIMT + plaque or CCA-IMT + plaque information to TRF. Therefore, evaluating the carotid artery for plaque presence and measuring CCA-IMT, which is easier and more reliable than measuring A-CIMT, provide a good alternative to measuring A-CIMT for CHD risk prediction.
PMCID: PMC3258447  PMID: 21666250
CIMT; Plaque; Risk prediction
10.  Stress-Induced Cardiovascular Reactivity and Atherogenesis in Adolescents 
Atherosclerosis  2011;215(2):465-470.
To examine the association between cardiovascular reactivity to a set of psychological stressors and carotid artery intima-media thickness, a marker of subclinical cardiovascular disease in healthy adolescents.
Participants were 25 boys and 23 girls age 14.2±0.9 years who were measured for heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressure reactivity to mirror-tracing, reaction time, speech preparation and ad lib speech tasks and for common carotid artery intima-media thickness. Sequential regression analyses were used to establish the incremental increase in R2 (R2inc) for the prediction of intima-media thickness due to cardiovascular reactivity independent of age, BMI percentile, sex, socioeconomic status, and resting HR or BP.
SBP reactivity while preparing (β= 0.0019, R2inc = 0.09) and giving the speech (β = 0.0014, R2inc = 0.10) and an aggregate reactivity score based on all 4 tasks (β= 0.0026, R2inc = 0.11) independently predicted (p ≤ 0.05) mean carotid artery intima-media thickness. Neither DBP reactivity nor HR reactivity during any task were independent predictors of intima-media thickness.
Stress-induced cardiovascular reactivity, and especially SBP reactivity, is associated with carotid intima-media thickness and the early pathogenesis of cardiovascular disease. The use of an aggregate stress reactivity index provides a more reliable reflection of trait SBP reactivity to psychological stress and increases the confidence that youth with greater cardiovascular stress reactivity may indeed have greater progression of subclinical cardiovascular disease.
PMCID: PMC3072778  PMID: 21296350
psychological stress; cardiovascular disease; atherosclerosis; carotid artery intima media thickness
11.  Do Carotid Artery Diameters Manifest Early Evidence of Atherosclerosis in Women with Rheumatoid Arthritis? 
Journal of Women's Health  2009;18(1):21-29.
Given the high incidence of cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA), we examined the associations between RA diagnosis and characteristics and evidence of carotid atherosclerosis. We take a unique approach by evaluating lumen and interadventitial diameters in addition to intima-media thickness and plaque.
Ninety-three women with RA were matched with 93 healthy women by age, race, and menopause status. In cross-sectional analyses, we compared common carotid artery measures between groups and examined their relationships with measures of RA severity and activity.
Mean age was 53.3 years, and median RA duration was 14 years. Lumen diameter in patients was significantly greater than in healthy women (5.50 vs. 5.19 mm, p < 0.001), as was interadventitial diameter (6.92 vs. 6.61 mm, p < 0.001). Having RA also was independently associated with greater lumen (β = 0.256, p < 0.01) and interadventitial (β = 0.261, p < 0.01) diameters, after controlling for cardiovascular risk factors and intima-media thickness. Carotid intima-media thickness (0.70 vs. 0.71 mm) was similar, and the prevalence of carotid plaque in patients (21%) was higher but not statistically different from healthy women (15%). In patients with RA, we found positive associations between methotrexate dose and interadventitial diameter, between hypothyroidism and intima-media thickness, and between hypothyroidism and soluble endothelial adhesion molecule and plaque, independent of cardiovascular risk factors.
Women with RA have increased carotid artery diameters compared with healthy women. This may reflect premature vascular aging and may be an early indicator of increased cardiovascular risk.
PMCID: PMC2897697  PMID: 19105681
12.  Cardiovascular risk scores in the prediction of subclinical atherosclerosis in young adults: Evidence from the Cardiovascular Risk in Young Finns Study 
To study the utility of risk scores in prediction of subclinical atherosclerosis in young adults.
Methods and results
Participants were 2,204 healthy Finnish adults aged 24–39 years in 2001 from population-based follow-up study Cardiovascular Risk in Young Finns. We examined the performance of the Framingham, Reynolds, SCORE (Systematic Coronary Risk Evaluation), PROCAM, and Finrisk cardiovascular risk scores to predict subclinical atherosclerosis, i.e. carotid artery intima-media thickness(IMT) and plaque, carotid artery distensibility (CDist) and brachial artery flow-mediated dilatation (FMD) 6 years later. In 6-year prediction of high IMT (highest decile or plaque), areas under the receiver operating characteristic curves (AUC) for baseline Finrisk (0.733), SCORE (0.726), PROCAM (0.712) and Reynolds (0.729) risk scores were similar as for Framingham risk score (0.728, P always ≥0.15). All risk scores had similar discrimination in predicting low CDist (lowest decile) (0.652, 0.642, 0.639, 0.658, 0.652 respectively, P always ≥0.41). In prediction of low FMD (lowest decile), Finrisk, PROCAM, Reynolds and Framingham scores had similar AUCs (0.578, 0.594, 0.582, 0.568, P always ≥0.08) and SCORE discriminated slightly better (AUC=0.596, P<0.05). Prediction of subclinical outcomes was consistent when estimated from other statistical measures of discrimination, reclassification, and calibration.
CVD risk scores had equal performance in predicting subclinical atherosclerosis measured by IMT and CDist in young adults. SCORE was more accurate at predicting low FMD than Framingham risk score.
PMCID: PMC2907448  PMID: 20354441
cardiovascular risk score; subclinical atherosclerosis; ultrasound
Echocardiography (Mount Kisco, N.Y.)  2012;29(10):1224-1232.
Framingham Risk Scores (FRS) were validated in a mostly Caucasian population. Evaluation of subclinical atherosclerosis by carotid ultrasound may improve ascertainment of risk in non-White populations. This study aimed to evaluate carotid intima-media thickness (cIMT) and carotid plaquing among Mexican Americans, and to correlate these markers with coronary risk factors and the FRS.
Participants (n=141) were drawn from the Cameron County Hispanic Cohort. Carotid artery ultrasound was performed and cIMT measured. Carotid plaque was defined as areas of thickening >50% of the thickness of the surrounding walls. Mean age was 53.1±11.7 years (73.8% female). Most were overweight or obese (88.7%) and more than half (53.2%) had the metabolic syndrome. One third (34.8%) had abnormal carotid ultrasound findings (either cIMT ≥75th percentile for gender and age or presence of plaque). Among those with abnormal carotid ultrasound, the majority were classified as being at low 10-year risk for cardiovascular events. Carotid ultrasound reclassified nearly a third of the cohort as being at high risk. This discordance between 10-year FRS and carotid ultrasound was noted whether risk was assessed for hard coronary events or global risk. Concordance between FRS and carotid ultrasound findings was best when long-term (30-year) risk was assessed and no subject with an abnormal carotid ultrasound was categorized as low risk by the 30-year FRS algorithm.
Integration of carotid ultrasound findings to coronary risk assessments and use of longer term prediction models may provide better risk assessment in this minority population, with earlier initiation of appropriate therapies.
PMCID: PMC3687003  PMID: 22747630
Carotid ultrasound; Subclinical atherosclerosis; Framingham risk score; Minority population; Risk assessment
14.  Comparison of Novel Risk Markers for Improvement in Cardiovascular Risk Assessment in Intermediate Risk Individuals. The Multi-Ethnic Study of Atherosclerosis 
Risk markers including coronary artery calcium (CAC), carotid intima-media thickness (CIMT), ankle-brachial Index (ABI), brachial flow-mediated dilation (FMD), high sensitivity C -reactive protein (hs-CRP) and family history (FH) of coronary heart disease (CHD) have been reported to improve on the Framingham risk score (FRS) for prediction of CHD. However, there are no direct comparisons of these markers for risk prediction in a single cohort.
We compared improvement in prediction of incident CHD/cardiovascular disease (CVD) of these 6 risk markers within intermediate risk participants (5 % < FRS < 20%) in the Multi-Ethnic Study of Atherosclerosis (MESA).
Design, Setting and Participants
Of 6814 MESA participants from 6 US field centers, 1330 were intermediate risk, without diabetes mellitus, and had complete data on all 6 markers. Recruitment spanned July 2000 to September 2002; follow-up extended through May 2011. Probability- weighted Cox proportional hazard models were used to estimate hazard ratios (HR). Area under the receiver operator characteristic curve (AUC) and net reclassification improvement (NRI) were used to compare incremental contributions of each marker when added to the FRS + race/ethnicity.
Main Outcome Measures
Incident CHD defined as MI, angina followed by revascularization, resuscitated cardiac arrest or CHD death. Incident CVD additionally included stroke or CVD death.
After median follow-up of 7.6 years (IQR 7.3 – 7.8 years), 94 CHD and 123 CVD events occurred. CAC, ABI, hs-CRP and FH were independently associated with incident CHD in multivariable analyses [HR (95%CI: 2.60(1.94-3.50), 0.79(0.66-0.95), 1.28(1.00-1.64) and 2.18(1.38-3.42) respectively]. CIMT and FMD were not associated with incident CHD in multivariable analyses [HR (95%CI) 1.17(0.95- 1.45) and 0.95(0.78 −1.14) respectively]. Although the addition of the markers individually to the FRS +race/ethnicity improved the AUC, CAC afforded the highest increment (0.623 vs. 0.784) while FMD afforded the least [0.623 vs. 0.639]. For incident CHD, the NRI with CAC was 0.659, FMD 0.024, ABI 0.036, CIMT 0.102, FH 0.160 and hs-CRP 0.079. Similar results were obtained for incident CVD.
CAC, ABI, hs-CRP and FH are independent predictors of incident CHD/CVD in intermediate risk individuals. CAC provides superior discrimination and risk reclassification compared with other risk markers.
PMCID: PMC4141475  PMID: 22910756
15.  The Carotid Intima Media Thickness: A Predictor of the Clincal Coronary Events 
Background: The Carotid Intima-Media Thickness (CIMT) is a simple and an inexpensive tool which can be used to assess the cumulative effect of atherosclerotic risk factors and it is also an independent predictor of the future cardiovascular risk. Nevertheless, criticism has been raised throughout the scientific community, based on the observations which indicated a weak correlation between CIMT and coronary atherosclerosis.
It has been suggested by the International Atherosclerosis Project, that the atherosclerotic process occurs at the same time in the carotid, cerebral and the coronary arteries. Measurement of the Carotid Intima-Media Thickness (CIMT) of the Common Carotid Artery (CCA) by B-mode ultrasound was found to be a suitable non-invasive method, to visualize the arterial walls and to monitor the early stages of the atherosclerotic process.
Aim: This study sought to determine the usefulness of B-mode ultrasound as a non-invasive marker to examine the association between CIMT and the extent and the severity of coronary artery disease and its association with the cardiovascular risk factors, if any.
Methods: A cross-sectional study was done among hundred cases and hundred age and sex matched controls who were in the age group of 30-65 years. The cases included those who had undergone coronary angiography. The controls included non-diabetic non-hypertensives with no cardiovascular risk factors. The CIMT was assessed by using a 7MHz linear array transducer. Fasting blood samples were collected for measuring the blood sugar and the lipid profiles.
Results: The statistical analysis was done by using the Student’s t test and ANOVA and a p value of <0.001 was considered to be significant. The Average Carotid Intima Media Thickness (AVCIMT) was higher in the cases (0.90 vs 0.47 in controls, p<0.001, very highly significant). The AVCIMT was found to be higher in those with triple vessel disease (1.00mm)
Conclusion: The easy applicability and the non invasive nature of B-mode ultrasonography make it suitable for use as a surrogate endpoint for measuring the atherosclerotic burden in people with cardiovascular risk factors. Even in this present study, we found a significant association between the extent of carotid atherosclerosis which was measured by B-mode ultrasound, and the presence, its extent, or the lack of coronary atherosclerosis which was documented by coronary angiography.
PMCID: PMC3708203  PMID: 23905108
Atherosclerosis; Carotid; Intima; Coronary
Patients with type-2 diabetes mellitus have greater carotid intima media thickness and they are at risk for generalized atherosclerosis. This study aimed to compare the thickness of carotid artery intima media in type-2 diabetes mellitus patients with and without nonblood pressure component metabolic syndrome.
This was a comparative observational study conducted in the Departments of Pharmacology and Physiology in the College of Medicine, Al-Mustansiriyia University in cooperation with Baghdad Teaching Hospital.
Forty-six diabetic patients of both sexes with systolic blood pressure < 130 mm Hg and diastolic blood pressure < 85 mm Hg were subjected to high resolution B-mode ultrasonography of the common and internal carotid arteries. Patients were grouped into those without metabolic syndrome (Group I) and with nonblood pressure component metabolic syndrome (Group II).
The two-tailed unpaired Student's t-test was used in this study.
Significantly high mean thickness was observed in the common carotid intima media (0.824 ± 0.155 mm) but not in the internal carotid arteries in group II patients compared to group I patients (0.708 ± 0.113 mm). Group II also had a significant number of patients with increased lesion intima media thickness (≥ 1.1 mm).
The greater carotid intima media thickness observed in type 2 diabetes mellitus patients is related to the metabolic syndrome even in the absence of the blood pressure component.
PMCID: PMC2802360  PMID: 20062559
Intima media thickness; metabolic syndrome; type 2 diabetes mellitus
Mayo Clinic Proceedings  2009;84(3):229-233.
OBJECTIVE: To determine the ability of carotid intima-media thickness (CIMT) and coronary artery calcium score (CACS) to detect subclinical atherosclerosis in a young to middle-aged, low-risk, primary-prevention population.
PATIENTS AND METHODS: Patients aged 36 to 59 years who underwent determination of CIMT and CACS at our institution between May 1, 2004, and April 1, 2008, were included in the study. Those with diabetes mellitus or a history of coronary, peripheral, or cerebral vascular disease were excluded. Other information, such as Framingham risk score (FRS), was obtained by a review of clinical and laboratory data.
RESULTS: Of 118 patients, 89 (75%) had a CACS of zero and 94 (80%) were men; mean ± SD age was 48.9±5.7 years. The mean FRS of this group was 4.0; 86 patients (97%) were considered at low risk (<1% annualized rate) of cardiovascular events. Evidence of carotid atherosclerosis was found in 42 (47%; 95% confidence interval, 37%-58%) of these 89 patients; carotid plaque was found in 30 (34%); and CIMT above the 75th percentile was found in 12 (13%) of age-, sex-, and race-matched control patients. Of the 40 patients with low-risk CIMT (below the 50th percentile), 4 (10%) had a CACS at or above the 50th percentile.
CONCLUSION: Subclinical vascular disease can be detected by CIMT evaluation in young to middle-aged patients with a low FRS and a CACS of zero. These findings have important implications for vascular disease screening and the implementation of primary-prevention strategies.
Subclinical vascular disease can be detected by carotid intima-media thickness evaluation in young to middle-aged patients with a low Framingham risk score and a coronary artery calcium score of zero; these findings have important implications for vascular disease screening and the implementation of primary-prevention strategies.
PMCID: PMC2664607  PMID: 19252109
BMC Medical Genetics  2012;13:32.
The role of cyclooxygenase-2 (COX-2) single nucleotide polymorphisms has mostly been studied in relation to advanced atherosclerosis, but little is known how they contribute to preclinical disease. In the present study we analyzed whether COX-2 gene variants associate independently with the early subclinical markers of atherosclerosis, carotid intima-media thickness and carotid artery distensibility in a population of young healthy Caucasian adults.
SNPs for association analysis were collected from the COX-2 gene and 5 kb up- and downstream of it. There were 19 SNPs available for analysis, four genotyped and fifteen imputed. Genotype data was available for 2442 individuals participating in the Cardiovascular Risk in Young Finns Study. Genotype imputation was performed using MACH 1.0 and HapMap II CEU (release 22) samples as reference. Association analysis was performed using linear regression with an additive model. PLINK was used for true genotyped SNPs and ProbABEL for imputed genotype dosages. False discovery rate was used to take into account multiple testing bias.
Two of the COX-2 variants (rs689470, rs689462) associated with distensibility (p = 0.005) under the linear regression additive model. After adjustment with gender, age, body mass index and smoking status, association between these SNPs and distensibility remained significant (p = 0.031). Subjects carrying the minor alleles had higher value of carotid artery distensibility compared to the major allele homozygotes. However, after correcting p-values for multiple testing bias using false discovery rate, association was lost. Another COX-2 variant rs4648261 associated with mean carotid intima-media thickness (p = 0.046) and maximal carotid intima-media thickness (p = 0.048) in the linear regression model. Subjects carrying the minor allele of rs4648261 had lower values of mean and maximal carotid intima-media thickness compared to subjects homozygote for major allele. After adjustments the associations were lost with both mean and maximal carotid intima-media thickness. Thus, no statistically significant associations of the studied COX-2 variants with carotid artery distensibility or carotid intima-media thickness were found.
Our results suggest that in a Finnish population, there are no significant associations between COX-2 variants and early atherosclerotic changes in young adulthood.
PMCID: PMC3388005  PMID: 22551325
Higher plasma total homocysteine (tHcy) is an established risk factor for cardiovascular disease. The relation between tHcy and carotid artery intima-media thickness (IMT) at the internal carotid artery (ICA)/bulb-IMT and common carotid artery (CCA)-IMT has not been systematically examined. Since the ICA/bulb segment is more prone to plaque formation than the CCA segment, differential associations with tHcy at these sites might suggest mechanisms of tHcy action.
We examined the cross-sectional segment-specific relations of tHcy to ICA/bulb-IMT and CCA-IMT in 2,499 participants from the Framingham Offspring Study, free of cardiovascular disease.
In multivariable linear regression analysis, ICA/bulb-IMT was significantly higher in the fourth tHcy quartile category compared to the other quartile categories, in both the age- and sex-adjusted and in the multivariable-adjusted model (P for trend <0.0001 and <0.01, respectively). We observed a significant age by tHcy interaction for ICA/bulb-IMT (P=0.03) and therefore stratified the analyses by median age (58 years). There was a significant positive trend between tHcy and ICA/bulb-IMT in individuals 58 years of age or older (P-trend <0.01), but not in the younger individuals (P-trend=0.24). For CCA-IMT, no significant trends were observed in any of the analyses.
The segment-specific association between elevated tHcy levels and ICA/bulb-IMT suggests an association between tHcy and plaque formation.
PMCID: PMC3011043  PMID: 20580253
carotid artery; intima-media thickness; homocysteine; atherosclerosis; Framingham Offspring Study
Arthritis Research & Therapy  2005;7(3):R634-R643.
Cardiovascular event rates are markedly increased in rheumatoid arthritis (RA), and RA atherogenesis remains poorly understood. The relative contributions of traditional and nontraditional risk factors to cardiovascular disease in RA await elucidation. The present study comprises three components. First, we compared biomarkers of endothelial dysfunction (vascular cell adhesion molecule [VCAM]-1, intercellular adhesion molecule [ICAM]-1 and endothelial leucocyte adhesion molecule [ELAM]-1) in 74 RA patients and 80 healthy control individuals before and after controlling for traditional and nontraditional cardiovascular risk factors, including high-sensitivity C-reactive protein (hs-CRP), IL-1, IL-6 and tumor necrosis factor-α. Second, we investigated the potential role of an extensive range of patient characteristics in endothelial dysfunction in the 74 RA patients. Finally, we assessed associations between biomarkers of endothelial dysfunction and ultrasonographically determined common carotid artery intima–media thickness and plaque in RA. The three biomarkers of endothelial dysfunction, as well as hs-CRP, IL-1, IL-6 and tumor necrosis factor-α, were higher in patients than in control individuals (P < 0.0001). Patients were also older, exercised less and had a greater waist circumference, blood pressure and triglyceride levels (P ≤ 0.04). Five patients had diabetes. Differences in endothelial function were no longer significant between patients and controls (P = 0.08) only after both traditional and nontraditional cardiovascular risk factors were controlled for. In the 74 RA patients, IL-6 predicted levels of all three biomarkers (P ≤ 0.03), and rheumatoid factor titres and low glomerular filtration rate (GFR) both predicted levels of VCAM-1 and ICAM-1, independent of traditional cardiovascular risk factors (P ≤ 0.02). VCAM-1 was associated with common carotid artery intima–media thickness (P = 0.02) and plaque (P = 0.04) in RA. Patients had impaired endothelial function, less favourable traditional cardiovascular risk factor profiles, and higher circulating concentrations of hs-CRP and cytokines compared with healthy control individuals. Both traditional and nontraditional cardiovascular risk factors contributed to the differences in endothelial function between RA patients and healthy control individuals. IL-6, rheumatoid factor titres and low GFR were independently predictive of endothelial dysfunction in RA. Disease-modifying agents that effectively suppress both cytokine and rheumatoid factor production, and interventions aimed at preserving renal function may attenuate cardiovascular risk in RA.
PMCID: PMC1174955  PMID: 15899050
Non-alcoholic fatty liver disease shares many features of metabolic syndrome and its presence could signify a substantial cardiovascular risk above and beyond that conferred by individual risk factors. This study is an attempt to investigate the association of non-alcoholic fatty liver disease with carotid intima-media thickness and plaque as surrogate measures of increased cardiovascular risk. The study was conducted on 645 non diabetic, non alcoholic subjects in the age range of 20–60 years. Metabolic syndrome was assessed by using ATP III and ADA (2005) criteria. Anthropometric factors—waist circumference and blood pressure were measured. Fasting serum samples were analyzed for glucose, triglyceride, cholesterol and its fractions, insulin, alanine and aspartate transaminases, gamma glutamyl transferase and free fatty acids. Insulin resistance and secretion were calculated by homeostasis model and insulin sensitivity by QUICKI index. Liver ultrasonographic scanning was used for assessing fatty liver. Carotid atherosclerosis was assessed by B-mode ultrasonography of common carotid artery and internal carotid artery. The prevalence of non-alcoholic fatty liver disease was 15.6 % in non alcoholic population and 68.5 % of non-alcoholic fatty liver disease had metabolic syndrome, which was associated with hyperinsulinemia, insulin resistance, insulin insensitivity along with elevated levels of waist circumference, blood pressure, triglyceride, FFA and decreased HDL cholesterol. NAFLD patients had markedly greater carotid intima media thickness than non NAFLD subjects with MCIMT of 591.6 ± 108 and 489.5 ± 132.4 μm (P < 0.001) and plaque prevalence of 19.2 and 2.2 %, respectively, thus the carotid intima media thickness is associated with NAFLD.
PMCID: PMC3547443  PMID: 24381427
NAFLD; CIMT; Metabolic syndrome; Carotid atherosclerosis
BMJ : British Medical Journal  2000;320(7230):273-278.
To quantify the direct and indirect effects of fetal life, childhood, and adult life on risk of cardiovascular disease at age 49-51 years.
Follow up study of the “Newcastle thousand families” birth cohort established in 1947.
154 men and 193 women who completed a health and lifestyle questionnaire and attended for clinical examination between October 1996 and December 1998.
Main outcome measures
Correlations between mean intima-media thickness of the carotid artery (carotid intima-media thickness) and family history, birth weight, and socioeconomic position around birth; socioeconomic position, growth, illness, and adverse life events in childhood; and adult socioeconomic position, lifestyle, and biological risk markers. Proportions of variance in carotid intima-media thickness that were accounted for by each stage of the lifecourse.
Socioeconomic position at birth and birth weight were negatively associated with carotid intima-media thickness, although only social class at birth in women was a statistically significant covariate independent of adult lifestyle. These early life variables accounted directly for 2.2% of total variance in men and 2.0% in women. More variation in carotid intima-media thickness was explained by adult socioeconomic position and lifestyle, which accounted directly and indirectly for 3.4% of variance in men (95% confidence interval 0.5% to 6.2%) and 7.6% in women (2.1% to 13.0%). Biological risk markers measured in adulthood independently accounted for a further 9.5% of variance in men (2.4% to 14.2%) and 4.9% in women (1.6% to 7.4%).
Adult lifestyle and biological risk markers were the most important determinants of the cardiovascular health of the study members of the Newcastle thousand families cohort at age 49-51 years. The limited overall effect of early life factors may reflect the postwar birth year of this cohort.
PMCID: PMC27272  PMID: 10650022
American Journal of Hypertension  2013;26(5):636-642.
Brachial pulse pressure (PP) has been found to be associated with markers of subclinical cardiovascular disease, including carotid intima–media thickness and left-ventricular mass index (LVMI), but it is unclear whether these associations are independent of traditional cardiovascular risk factors and of the steady, nonpulsatile component of blood pressure (BP). Moreover, it is unknown whether these associations are modified by gender, age, or race/ethnicity.
We used multivariate linear regression models to assess the relationship between brachial PP and three markers of subclinical cardiovascular disease (CVD) (common carotid intima–media thickness (CC-IMT), internal carotid intima–media thickness (IC-IMT), and LVMI) in four race/ethnic groups in the Multi-Ethnic Study of Atherosclerosis. The models were adjusted for traditional Framingham risk factors (age, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, diabetes, smoking status), use of lipid-lowering medication, use of antihypertensive medication, study site, and mean arterial pressure (MAP).
The assessment was done on 6,776 participants (2,612 non-Hispanic white, 1,870 African-American, 1,494 Hispanic, and 800 Chinese persons). The associations between brachial PP and CC-IMT, IC-IMT, and LVMI were significant in fully adjusted models. The three subclinical markers also showed significant interactions with gender (P < 0.0001), with stronger interactions in men. There was an interaction with age for LVMI (P = 0.004) and IC-IMT (P = 0.008). Race/ethnicity modified the association of PP with CC-IMT.
Brachial PP was independently associated with subclinical CVD after adjustment for cardiovascular risk factors and mean arterial pressure (MAP). The strength of the association differed significantly for strata of gender, age, and race/ethnicity.
PMCID: PMC3657481  PMID: 23388832
pulse pressare; subclinical cardiovascular disease; carotid intima–media thickness; left ventricular mass index; aging; hypertension; arterial stiffness; blood pressure.
Preventive cardiology has expanded beyond coronary heart disease towards prevention of a broader spectrum of cardiovascular diseases. Ethnic minorities are at proportionately greater risk for developing extracoronary vascular disease including heart failure and cerebrovascular disease.
We performed a cross sectional study of Latino and White hypertension patients in a safety-net healthcare system. Framingham risk factors, markers of inflammation (hsCRP, LPpLA2), arterial stiffness (Pulse wave velocity, augmentation index, and central aortic pressure), and endothelial function (brachial artery flow-mediated dilatation) were measured. Univariate and multivariable associations between these parameters and an index of extracoronary atherosclerosis (carotid intima media thickness) was performed.
Among 177 subjects, mean age was 62 years, 67% were female, and 67% were Latino. In univariate analysis, markers associated with carotid intima media thickness (IMT) at p < 0.25 included pulse wave velocity (PWV), augmentation index (AIx), central aortic pressure (cAP), and LpPLA2 activity rank. However, AIx, cAP, and LpPLA2 activity were not significantly associated with carotid IMT after adjusting for Framingham risk factors (all p > .10). Only PWV retained a significant association with carotid IMT independent of the Framingham general risk profile parameters (p = .016). No statistically significant interactions between Framingham and other independent variables with ethnicity (all p > .05) were observed.
In this safety net cohort, PWV is a potentially useful adjunctive atherosclerotic risk marker independent of traditional risk factors and irrespective of ethnicity.
PMCID: PMC3080337  PMID: 21481252
Pulse wave velocity; hypertension; atherosclerosis; carotid intima media thickness; Latino; inflammatory markers; augmentation index; central aortic pressure; C-reactive protein
Lancet  2012;379(9831):2053-2062.
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.
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.
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).
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.
Deutsche Forschungsgemeinschaft.
PMCID: PMC3918517  PMID: 22541275

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