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1.  Serum Carotenoids Reduce Progression of Early Atherosclerosis in the Carotid Artery Wall among Eastern Finnish Men 
PLoS ONE  2013;8(5):e64107.
Several previous epidemiologic studies have shown that high blood levels of carotenoids may be protective against early atherosclerosis, but results have been inconsistent. We assessed the association between atherosclerotic progression, measured by intima-media thickness of the common carotid artery wall, and serum levels of carotenoids.
We studied the effect of carotenoids on progression of early atherosclerosis in a population-based study. The association between concentrations of serum carotenoids, and intima-media thickness of the common carotid artery wall was explored in 840 middle-aged men (aged 46–65 years) from Eastern Finland. Ultrasonography of the common carotid arteries were performed at baseline and 7-year follow-up. Serum levels of carotenoids were analyzed at baseline. Changes in mean and maximum intima media thickness of carotid artery wall were related to baseline serum carotenoid levels in covariance analyses adjusted for covariates.
In a covariance analysis with adjustment for age, ultrasound sonographer, maximum intima media thickness, examination year, body mass index, systolic blood pressure, smoking, physical activity, serum LDL cholesterol, family history of coronary heart disease, antihypertensive medication and serum high sensitivity C-reactive protein, 7-year change in maximum intima media thickness was inversely associated with lycopene (p = 0.005), α-carotene (p = 0.002) and β-carotene (p = 0.019), respectively.
The present study shows that high serum concentrations of carotenoids may be protective against early atherosclerosis.
PMCID: PMC3660262  PMID: 23700460
2.  Ultrasound study of carotid and cardiac remodeling and cardiac-arterial coupling in normal pregnancy and preeclampsia: a case control study 
Cardiovascular adaptions, such as cardiac and uterine spiral arterial remodeling, and aortic arterial stiffening during pregnancy have been extensively investigated, while the interactions between the elastic artery and the left ventricle are poorly understood. This study was to evaluate the cardiac-arterial coupling in both normal pregnancy and preeclampsia using ultrasound techniques.
Twenty-three preeclamptic women with no antihypertensive treatment prior to admission, and 40 age- (27.2 ± 3.0 y vs. 29.1 ± 5.7 y, p = 0.0805) and gestational week- (35.6 ± 3.4 wk vs. 34.8 ± 3.6 wk, p = 0.3573) matched normotensive pregnant women were included. All women signed informed consent. All were nulliparas, had singleton pregnancies, and had no other risk factors for arterial stiffening. Carotid and cardiac ultrasound was performed using a MylabTwice ultrasound unit (Esaote, Italy). Cardiac and carotid remodeling and their associations were analyzed. Left ventriculo-carotid coupling was characterized by the ratio between the arterial elastance (Ea) and the left ventricular systolic elastance (Ees). Follow-up study was performed 16–20 months after parturition.
Left ventricular and carotid arterial remodeling was seen more frequently in preeclamptic women than in normal pregnant controls (96% vs. 40%, 82% vs. 48%, both p < 0.0001). The relative carotid arterial wall thickness showed no significant difference between the two groups. However, the carotid cross-sectional area, a surrogate for carotid arterial mass, was significantly greater in preeclampsia than that in normal controls (11.23 ± 0.17 mm2 vs. 8.58 ± 1.88 mm2, p < 0.00001). Carotid arterial stiffness and intima-media thickness correlated significantly with cardiac diastolic function parameters and blood pressures (p < 0.05). Both Ea and Ees were significantly greater in preeclampsia, compared with values in normal pregnant controls (Ea: 2.41 ± 0.57 mmHg/ml vs. 1.98 ± 0.46 mmHg/ml, p = 0.0005; Ees: 11.68 ± 9.51 m/s2 vs. 6.91 ± 6.13 m/s2, p = 0.002). However, there was no significant difference in the left ventriculo-carotid coupling index, Ea/Ees, between the two groups. Carotid remodeling persisted in both preeclamptic women and normal pregnant controls 16–20 months after parturition.
Significant cardiac and carotid remodeling and similar left ventriculo-carotid coupling were observed in both preeclampsia and normal pregnancy. Carotid remodeling may persist postpartum. Further studies with larger populations are needed to confirm these findings.
PMCID: PMC4000894  PMID: 24666973
Preeclampsia; Ventriculo-arterial coupling; Ultrasound; Diastolic function; Arterial stiffness
3.  Carotid-Wall Intima–Media Thickness and Cardiovascular Events 
The New England journal of medicine  2011;365(3):213-221.
Intima–media thickness of the walls of the common carotid artery and internal carotid artery may add to the Framingham risk score for predicting cardiovascular events.
We measured the mean intima–media thickness of the common carotid artery and the maximum intima–media thickness of the internal carotid artery in 2965 members of the Framingham Offspring Study cohort. Cardiovascular-disease outcomes were evaluated for an average follow-up of 7.2 years. Multivariable Cox proportional-hazards models were generated for intima–media thickness and risk factors. We evaluated the reclassification of cardiovascular disease on the basis of the 8-year Framingham risk score category (low, intermediate, or high) after adding intima–media thickness values.
A total of 296 participants had a cardiovascular event. The risk factors of the Framingham risk score predicted these events, with a C statistic of 0.748 (95% confidence interval [CI], 0.719 to 0.776). The adjusted hazard ratio for cardiovascular disease with a 1-SD increase in the mean intima–media thickness of the common carotid artery was 1.13 (95% CI, 1.02 to 1.24), with a nonsignificant change in the C statistic of 0.003 (95% CI, 0.000 to 0.007); the corresponding hazard ratio for the maximum intima–media thickness of the internal carotid artery was 1.21 (95% CI, 1.13 to 1.29), with a modest increase in the C statistic of 0.009 (95% CI, 0.003 to 0.016). The net reclassification index increased significantly after addition of intima–media thickness of the internal carotid artery (7.6%, P<0.001) but not intima–media thickness of the common carotid artery (0.0%, P = 0.99). With the presence of plaque, defined as intima–media thickness of the internal carotid artery of more than 1.5 mm, the net reclassification index was 7.3% (P = 0.01), with an increase in the C statistic of 0.014 (95% CI, 0.003 to 0.025).
The maximum internal and mean common carotid-artery intima–media thicknesses both predict cardiovascular outcomes, but only the maximum intima–media thickness of (and presence of plaque in) the internal carotid artery significantly (albeit modestly) improves the classification of risk of cardiovascular disease in the Framingham Offspring Study cohort. (Funded by the National Heart, Lung, and Blood Institute.)
PMCID: PMC3153949  PMID: 21774709
4.  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
5.  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
6.  Interaction of workplace demands and cardiovascular reactivity in progression of carotid atherosclerosis: population based study. 
BMJ : British Medical Journal  1997;314(7080):553-558.
OBJECTIVE: To examine the combined influence of workplace demands and changes in blood pressure induced by stress on the progression of carotid atherosclerosis. DESIGN: Population based follow up study of unestablished as well as traditional risk factors for carotid atherosclerosis, ischaemic heart disease, and other outcomes. SETTING: Eastern Finland. SUBJECTS: 591 men aged 42-60 who were fully employed at baseline and had complete data on the measures of carotid atherosclerosis, job demands, blood pressure reactivity, and covariates. MAIN OUTCOME MEASURES: Change in ultrasonographically assessed intima-media thickness of the right and left common carotid arteries from baseline to 4 year follow up. RESULTS: Significant interactions between workplace demands and stress induced reactivity were observed for all measures of progression (P < 0.04). Men with large changes in systolic blood pressure (20 mm Hg or greater) in anticipation of a maximal exercise test and with high job demands had 10-40% greater progression of mean (0.138 v 0.123 mm) and maximum (0.320 v 0.261 mm) intima-media thickness and plaque height (0.347 v 0.264) than men who were less reactive and had fewer job demands. Similar results were obtained after excluding men with prevalent ischaemic heart disease at baseline. Findings were strongest among men with at least 20% stenosis or non-stenotic plaque at baseline. In this subgroup reactive men with high job demands had more than 46% greater atherosclerotic progression than the others. Adjustment for atherosclerotic risk factors did not alter the results. CONCLUSIONS: Men who showed stress induced blood pressure reactivity and who reported high job demands experienced the greatest atherosclerotic progression, showing the association between dispositional risk characteristics and contextual determinants of disease and suggesting that behaviourally evoked cardiovascular reactivity may have a role in atherogenesis.
PMCID: PMC2126071  PMID: 9055713
7.  C-reactive protein is an independent predictor for carotid artery intima-media thickness progression in asymptomatic younger adults (from the Bogalusa Heart Study) 
Conflicting information exists regarding the association between hsCRP and the progression of early stages of atherosclerosis. The purpose of the study was to investigate the association of high sensitiviy c-reactive protein (hsCRP) along with major cardiovascular (CV) risk factors on early carotid atherosclerosis progression in a large, population-based cohort study.
The study cohort included 839 young adults (aged 24 to 43 years, 70% white, 42% men) enrolled in Bogalusa Heart Study, who in 2001-2002 attended baseline examination with measurements of CV risk factors. Progression of carotid artery intima-media thickness (IMT) was assessed during a mean follow-up of 2.4 years.
Carotid artery IMT progression rates were as follows: composite carotid artery = 9.2 ± 52 μm/y, common carotid artery = 0.0 ± 51 μm/y, carotid bulb = 8.8 ± 103 μm/y, and internal carotid artery = 18.9 ± 81 μm/y. Elevated baseline hsCRP, reflecting an inflammatory state, showed independent association with composite carotid artery IMT progression. Increased age, systolic blood pressure, fasting glucose, LDL cholesterol, and current smoking were other risk associates of carotid artery IMT progression in young adults, indicating an underlying burden on the CV system by multiple risk factors.
In this population-based study, we observed independent categorical association of increased hsCRP with carotid artery IMT progression in young adults. This study underlines the importance of assesssing hsCRP levels along with smoking and traditional CV risk factor profiles in asymptomatic young adults.
PMCID: PMC3264529  PMID: 22208681
Carotid artery intima-media thickness progression; cardiovascular risk; c-reactive protein; epidemiology; young adults
8.  Cholesterol Is Associated with the Presence of a Lipid Core in Carotid Plaque of Asymptomatic, Young-to-Middle-Aged African Americans with and without HIV Infection and Cocaine Use Residing in Inner-City Baltimore, Md., USA 
Stroke remains a leading cause of death in the United States. While stroke-related mortality in the USA has declined over the past decades, stroke death rates are still higher for blacks than for whites, even at younger ages. The purpose of this study was to estimate the frequency of a lipid core and explore risk factors for its presence in asymptomatic, young-to-middle-aged urban African American adults recruited from inner-city Baltimore, Md., USA.
Between August 28, 2003, and May 26, 2005, 198 African American participants aged 30-44 years from inner-city Baltimore, Md., were enrolled in an observational study of subclinical atherosclerosis related to HIV and cocaine use. In addition to clinical examinations and laboratory tests, B-mode ultrasound for intima-media thickness of the internal carotid arteries was performed. Among these 198, 52 were selected from the top 30th percentile of maximum carotid intima-media thickness by ultrasound, and high-resolution black blood MRI images were acquired through their carotid plaque before and after the intravenous administration of gadodiamide. Of these 52, 37 with maximum segmental thickness by MRI >1.0 mm were included in this study. Lumen and outer wall contours were defined using semiautomated analysis software. The frequency of a lipid core in carotid plaque was estimated and risk factors for lipid core presence were explored using logistic regression analysis.
Of the 37 participants in this study, 12 (32.4%) were women. The mean age was 38.7 ± 4.9 years. A lipid core was present in 9 (17%) of the plaques. Seventy percent of the study participants had a history of cigarette smoking. The mean total cholesterol level was 176.1 ± 37.3 mg/dl, the mean systolic blood pressure was 113.1 ± 13.3 mm Hg, and the mean diastolic blood pressure was 78.9 ± 9.5 mm Hg. There were 5 participants with hypertension (13.5%). Twelve (32%) participants had a history of chronic cocaine use, and 23 (62%) were HIV positive. Among the factors investigated, including age, sex, blood pressure, cigarette smoking, C-reactive protein, fasting glucose, triglycerides, serum total cholesterol, coronary calcium, cocaine use, and HIV infection, only total cholesterol was significantly associated with the presence of a lipid core.
This study revealed an unexpectedly high rate of the presence of lipid core in carotid plaque and highlights the importance of cholesterol lowering to prevent cerebrovascular disease in this population. Further population-based studies are warranted to confirm these results.
PMCID: PMC3355645  PMID: 22327293
Carotid artery; Cholesterol; Lipid core; Risk factors; Stroke
9.  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
10.  Carotid intima-media thickness and arterial stiffness in type 1 diabetic patients with and without microangiopathy 
The aim of the study was to assess carotid intima-media thickness (CIMT) as a subclinical marker of atherosclerosis and arterial stiffness in type 1 diabetic patients in relation to microangiopathy.
Material and methods
We included 87 type 1 diabetic patients (44 women, 43 men), median age 34 years (interquartile range [IQR] 29-43), median disease duration 10 years (IQR: 9-14), mean ± standard deviation (SD) glycated haemoglobin (HbA1c) 8.4 ±1.4%. Fifty patients had at least one microangiopathic complication. Intima-media thickness (IMT) of the common carotid artery was measured using high resolution ultrasonography. Arterial stiffness was assessed using digital volume pulse analysis and tonometric measurement of wave reflection and central haemodynamics.
Subjects with microangiopathy compared with those without had higher values of CIMT (median [IQR]: 0.53 mm [0.45-0.60 mm] vs 0.47 mm [0.34-0.52 mm], p = 0.002), higher central augmentation index (CAIx) (mean ± SD: 120.2 ±19.4% vs. 110.5 ±17.1%, p = 0.016) and higher peripheral augmentation index (PAIx) (65.7 ±18.1% vs. 57.2 ±14.9%, p = 0.023). In the logistic regression analysis, the duration of diabetes, systolic and diastolic blood pressure, postprandial glycaemia, HbA1c and triglycerides predicted the presence of diabetic microangiopathy independently of age and sex. The CIMT, CAIx and PAIx were associated with the presence of diabetic microangiopathy only in the univariate model.
In type 1 diabetic patients with microangiopathic complications, increased carotid IMT and arterial stiffness were observed. The study confirms the role of traditional risk factors for late diabetic complications, such as the duration of the disease and metabolic control in the development of microangiopathy.
PMCID: PMC3400914  PMID: 22852004
type 1 diabetes; carotid intima-media thickness; arterial stiffness; microangiopathy
11.  Circulating Levels of Persistent Organic Pollutants (POPs) and Carotid Atherosclerosis in the Elderly 
Background and objective: Increased circulating levels of persistent organic pollutants (POPs) have been associated with myocardial infarction. Because myocardial infarction is an atherosclerotic disease, we investigated, in a cross-sectional study, whether POP levels are related to atherosclerosis.
Methods: In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (n = 1,016 participants 70 years of age), the prevalence of carotid artery plaques was determined by ultrasound. The number of carotid arteries with plaques (0, 1, or 2) was recorded. Also, the intima-media thickness (IMT) and gray scale median of the intima-media complex (IM-GSM) were measured. Twenty-three POPs, comprising 16 polychlorinated biphenyls (PCBs), 5 pesticides, 1 dioxin, and 1 brominated compound (brominated diphenyl ether congener BDE-47), were analyzed by high-resolution chromatography coupled to high-resolution mass spectrometry.
Results: Seven of the POPs (PCB congeners 153, 156, 157, 170, 180, 206, and 209) were significantly associated with the number of carotid arteries with plaques even after adjusting for multiple risk factors (sex, waist circumference, body mass index, fasting blood glucose, systolic and diastolic blood pressure, high-density lipoprotein and low-density lipoprotein cholesterol, serum triglycerides, smoking, antihypertensive treatment, and statin use; p = 0.002–0.0001). Highly chlorinated PCBs (congeners 194, 206, and 209) were associated with an echolucent IM-GSM (p < 0.0001 after adjustment), whereas associations between POPs and IMT were modest.
Conclusions: Circulating levels of PCBs were associated with atherosclerotic plaques and echogenicity of the intima-media complex independent of cardiovascular risk factors, including lipids. This suggests that POPs may be a risk factor for myocardial infarction, but associations need to be confirmed in prospective studies.
PMCID: PMC3261941  PMID: 22222676
atherosclerosis; atherosclerotic plaques; persistent organic pollutants (POPs); pesticides
12.  Large-vessel correlates of cerebral small-vessel disease 
Neurology  2013;80(7):662-669.
Our aim was to investigate the relationship of carotid structure and function with MRI markers of cerebral ischemic small-vessel disease.
The study comprised 1,800 participants (aged 72.5 ± 4.1 years, 59.4% women) from the 3C-Dijon Study, a population-based, prospective cohort study, who had undergone quantitative brain MRI and carotid ultrasound. We used multivariable logistic and linear regression adjusted for age, sex, and vascular risk factors.
Presence of carotid plaque and increasing carotid lumen diameter (but not common carotid artery intima-media thickness) were associated with higher prevalence of lacunar infarcts: odds ratio (OR) = 1.60 (95% confidence interval [CI]: 1.09–2.35), p = 0.02 and OR = 1.24 (95% CI: 1.02–1.50), p = 0.03 (by SD increase). Carotid plaque was also associated with large white matter hyperintensity volume (WMHV) (age-specific top quartile of WMHV distribution): OR = 1.32 (95% CI: 1.04–1.67), p = 0.02, independently of vascular risk factors. Increasing Young elastic modulus and higher circumferential wall stress, reflecting augmented carotid stiffness, were associated with increasing WMHV (effect estimate [β] ± standard error: 0.0003 ± 0.0001, p = 0.024; β ± standard error: 0.005 ± 0.002, p = 0.008). Large WMHV was also associated with increasing Young elastic modulus (OR = 1.22 [95% CI: 1.04–1.42], p = 0.01) and with decreasing distensibility coefficient (OR = 0.83 [95% CI: 0.69–0.99], p = 0.04), independently of vascular risk factors. Associations of carotid lumen diameter with lacunar infarcts and of carotid stiffness markers with WMHV were independent of carotid plaque.
In addition to and independently of carotid plaque, increasing carotid lumen diameter and markers of carotid stiffness were associated with increasing prevalence of lacunar infarcts and increasing WMHV, respectively.
PMCID: PMC3590057  PMID: 23345633
13.  Association of SERPINA9 gene variants with carotid artery atherosclerosis: the Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study 
The SNP rs11628722 in the SERPINA9 gene was previously associated with incident ischemic stroke in the Atherosclerosis Risk in Communities (ARIC) study. Centerin, the protein encoded by SERPINA9, is involved in maturation and maintenance of naïve B cells, which play a role in atherogenesis. We investigated whether 21 tag SNPs in the SERPINA9 gene are associated with features of carotid artery atherosclerotic plaque measured by magnetic resonance imaging (MRI). Carotid MRI data were obtained from 1,282 European Americans and 341 African Americans of the ARIC Carotid MRI study, which recruited participants from ARIC by a stratified sampling plan that over-sampled participants with carotid intima-media thickening. Five MRI measures, focused on carotid wall volume, wall thickness, and lipid core, were analyzed. Genetic associations between the MRI measurements and each of the 21 SNPs were analyzed in linear regression models with adjustment for sample weights and traditional risk factors. Rs11628722 was tested a priori. In African Americans, rs11628722 was significantly associated with carotid wall volume (p < 0.05). Among the other 20 SNPs, adjusted for multiple testing, rs4905204, which encodes an Ala to Val amino acid change, was significantly associated with maximum wall thickness (p < 0.000625) and suggestively associated with total wall volume (p < 0.0026) in European Americans. In conclusion, SNPs in the SERPINA9 gene showed race-specific associations with characteristics of carotid atherosclerotic plaques. Replications in other populations are needed to validate findings of this study and to establish the SERPINA9 gene as a candidate in the etiology of carotid atherosclerosis.
PMCID: PMC3852645  PMID: 24319541
SERPINA9 gene; carotid atherosclerosis; MRI; genetic association
14.  Common carotid artery intima-media thickness (IMT) progression as a predictor of stroke in MESA (Multi-Ethnic Study of Atherosclerosis) 
Carotid artery intima-media thickness (IMT) is a marker of cardiovascular disease associated with incident stroke. We study whether IMT rate-of-change is associated with stroke.
Materials and Methods
We studied 5028 participants of the Multi-Ethnic Study of Atherosclerosis (MESA) composed of whites, Chinese, Hispanic and African-Americans free of cardiovascular disease. In this MESA IMT progression study, IMT rate-of-change (mm/year) was the difference in right common carotid artery (CCA) far-wall IMT (mm) divided by the interval between two ultrasound examinations (median interval of 32 months). CCA IMT was measured in a region free of plaque. Cardiovascular risk factors and baseline IMT were determined when IMT rate-of-change was measured. Multivariable Cox proportional hazards models generated Hazard risk Ratios (HR) with cardiovascular risk factors, ethnicity and education level/income as predictors.
There were 42 first time strokes seen during a mean follow-up of 3.22 years (median 3.0 years). Average age was 64.2 years, with 48% males. In multivariable models, age (HR: 1.05 per year), systolic blood pressure (HR 1.02 per mmHg), lower HDL cholesterol levels (HR: 0.96 per mg/dL) and IMT rate-of-change (HR 1.23 per 0.05 mm/year; 95% C.L. 1.02, 1.48) were significantly associated with incident stroke. The upper quartile of IMT rate-of-change had an HR of 2.18 (95% C.L.: 1.07, 4.46) compared to the lower three quartiles combined.
Common carotid artery IMT progression is associated with incident stroke in this cohort free of prevalent cardiovascular disease and atrial fibrillation at baseline.
PMCID: PMC3202068  PMID: 21885840
Ultrasonography; Risk Factors; Carotid Arteries; Carotid Intima Media Thickness; stroke
15.  Comparison of Factors Associated with Carotid Intima-Media Thickness in the Multi-Ethnic Study of Atherosclerosis (MESA) and the Heinz Nixdorf Recall Study (HNR) 
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.
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.
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.
A comparison of the associations between traditional cardiovascular risk factors and CIMT across two culturally diverse populations showed remarkable consistency.
PMCID: PMC3694173  PMID: 23611058
Carotid intima-media thickness; Subclinical atherosclerosis; Multi-Ethnic Study of Atherosclerosis; MESA; Heinz Nixdorf Recall Study; HNR
16.  Determinants of Functional and Structural Properties of Large Arteries in Healthy Individuals 
Arquivos Brasileiros de Cardiologia  2014;103(5):426-432.
Changes in the properties of large arteries correlate with higher cardiovascular risk. Recent guidelines have included the assessment of those properties to detect subclinical disease. Establishing reference values for the assessment methods as well as determinants of the arterial parameters and their correlations in healthy individuals is important to stratify patients.
To assess, in healthy adults, the distribution of the values of pulse wave velocity, diameter, intima-media thickness and relative distensibility of the carotid artery, in addition to assessing the demographic and clinical determinants of those parameters and their correlations.
This study evaluated 210 individuals (54% women; mean age, 44 ± 13 years) with no evidence of cardiovascular disease. The carotid-femoral pulse wave velocity was measured with a Complior® device. The functional and structural properties of the carotid artery were assessed by using radiofrequency ultrasound.
The means of the following parameters were: pulse wave velocity, 8.7 ± 1.5 m/s; diameter, 6,707.9 ± 861.6 μm; intima-media thickness, 601 ± 131 μm; relative distensibility, 5.3 ± 2.1%. No significant difference related to sex or ethnicity was observed. On multiple linear logistic regression, the factors independently related to the vascular parameters were: pulse wave velocity, to age (p < 0.01) and triglycerides (p = 0.02); intima-media thickness, to age (p < 0.01); diameter, to creatinine (p = 0.03) and age (p = 0.02); relative distensibility, to age (p < 0.01) and systolic and diastolic blood pressures (p = 0.02 and p = 0.01, respectively). Pulse wave velocity showed a positive correlation with intima media thickness (p < 0.01) and with relative distensibility (p < 0.01), while diameter showed a positive correlation with distensibility (p = 0.03).
In healthy individuals, age was the major factor related to aortic stiffness, while age and diastolic blood pressure related to the carotid functional measure. The carotid artery structure was directly related to aortic stiffness, which was inversely related to the carotid artery functional property.
PMCID: PMC4262104  PMID: 25211201
Arteries; Arterial Pressure; Vascular Stiffness; Pulse Wave Analysis; Carotid Intima-Media Thickness
The Journal of surgical research  2011;176(1):329-336.
The mechanical environment and properties of the carotid artery play an important role in the formation and progression of atherosclerosis in the carotid bifurcation. The purpose of this work was to measure and compare the range and variation of circumferential stress and tangent elastic moduli in the human common (CCA), external (ECA) and internal (ICA) carotid arteries over the cardiac cycle in vivo.
Measurements were performed in the surgically exposed proximal cervical CCA, distal ECA and distal ICA of normotensive patients (n = 16) undergoing carotid endarterectomy. All measurements were completed in vivo over the cardiac cycle in the repaired carotid bifurcation after the atherosclerotic plaque was successfully removed. B-mode Duplex ultrasonography was used for measurement of arterial diameter and wall thickness, and an angiocatheter placed in the CCA was used for concurrent measurement of blood pressure. A semi-automatic segmentation algorithm was used to track changes in arterial diameter and wall thickness in response to blood pressure. These measurements were then used to calculate the variation of circumferential (hoop) stresses, tangent elastic moduli (the slope of the stress-strain curve at specified stresses), and stress-induced stiffness of the arterial wall (stiffening in response to intraluminal blood pressure fluctuation) for each patient.
The diameter and wall thickness of the segments (CCA, ECA and ICA) of the carotid bifurcation were found to decrease and stress-induced stiffness to increase from proximal CCA to distal ECA and ICA. The circumferential stress from end-diastole (minimum pressure) to peak-systole (maximum pressure) varied nonlinearly from 25±7 to 63±23 kPa (CCA), from 22±7 to 57±19 kPa (ECA) and from 28±8 to 67±23 kPa (ICA). Tangent elastic moduli also varied nonlinearly from end-diastole to peak-systole as follows: from 0.40±0.25 to 1.50±2.05 MPa (CCA), from 0.49±0.34 to 1.14±0.52 MPa (ECA) and from 0.68±0.31 to 1.51±0.69 MPa (ICA). The stress-induced stiffness of CCA and ECA increased more than 3-fold and the stiffness of ICA increased more than 2.5-fold at peak-systole compared to end-diastole.
The in vivo mechanical behavior of the three segments of the carotid bifurcation was qualitatively similar, but quantitatively different. All three arteries – CCA, ECA and ICA – exhibited nonlinear variations of circumferential stress and tangent elastic moduli within the normal pressure range. The variability in the properties of the three segments of the carotid bifurcation indicates a need for development of carotid models that match the in vivo properties of the carotid segments. Finally, the observed nonlinear behavior of the artery points to the need for future vascular mechanical studies to evaluate the mechanical factors of the arterial wall over the entire cardiac cycle.
PMCID: PMC3470810  PMID: 22099586
common carotid artery; external carotid artery; internal carotid artery; in vivo mechanical properties; circumferential stress; stiffening
18.  Heritability of Carotid Intima-Media Thickness: A Twin Study 
Atherosclerosis  2007;197(2):814-820.
To estimate the heritability of carotid intima-media thickness (IMT), a surrogate marker for atherosclerosis, independent of traditional coronary risk factors.
Methods and Results
We performed a classical twin study of carotid IMT using 98 middle-aged male twin pairs, 58 monozygotic (MZ) and 40 dizygotic (DZ) pairs, from the Vietnam Era Twin Registry. All twins were free of overt cardiovascular disease. Carotid IMT was measured by ultrasound. Bivariate and multivariate analyses were used to determine the association between traditional cardiovascular risk factors and carotid IMT. Intraclass correlation coefficients and genetic modeling techniques were used to determine the relative contributions of genes and environment to the variation in carotid IMT. In our sample, the mean of the maximum carotid IMT was 0.75 ± 0.11. Age, systolic blood pressure and HDL were significantly associated with carotid IMT. The intraclass correlation coefficient for carotid IMT was larger in MZ (0.66; 95% confidence interval [CI], 0.62–0.69) than in DZ twins (0.37; 95% CI, 0.29–0.44), and the unadjusted heritability was 0.69 (95% CI, 0.54–0.79). After adjusting for traditional coronary risk factors, the heritability of carotid IMT was slightly reduced but still of considerable magnitude (0.59; 95% CI, 0.39–0.73).
Genetic factors have a substantial influence on the variation of carotid IMT. Most of this genetic effect occurs through pathways independent of traditional coronary risk factors.
PMCID: PMC2387097  PMID: 17825306
heritability; carotid intima-media thickness; twin study; atherosclerosis
19.  Prevalence and Predictors of Carotid Wall Triple Line Pattern in a General Population Sample 
Carotid intima-media thickness (IMT) and plaques are markers of atherosclerosis and predict cardiovascular events. A specific sonographic triple line pattern (TLP) of the carotid wall has been identified in different conditions, but its origin and clinical significance are unclear. We examined the prevalence and predictors of TLP in a general population.
Methods and Results
The study was conducted in random sample of the general population of Novosibirsk, Russia, within the international Health, Alcohol and Psychosocial Factors in Eastern Europe project. In a subsample of 418 men (aged 45 to 69), carotid IMT, the presence of atherosclerotic plaques, and the presence of TLP were assessed by ultrasound. The prevalence of TLP was 21%. It was associated with IMT (odds ratio=9.53 per 1 SD, P<0.001) and the presence of plaques (odds ratio=2.42, P=0.002). Other predictors of TLP in multivariate models included age, systolic blood pressure, total cholesterol, and smoking. In addition, infrequent consumption of high amounts of alcohol approximately doubled the risk of triple pattern.
Our findings showed high prevalence of TLP of carotid wall in a general male population sample from a typical Russian city. This sonographic pattern was strongly associated with cardiovascular risk factors and diseases, bioimaging indicators of atherosclerosis, and episodic heavy drinking.
PMCID: PMC3951865  PMID: 21493889
alcohol; carotid arteries; Doppler ultrasound; risk factors; intima-media thickness
20.  B-mode ultrasound common carotid artery intima-media thickness and external diameter: cross-sectional and longitudinal associations with carotid atherosclerosis in a large population sample 
Arterial diameter and intima-media thickness (IMT) enlargement may each be related to the atherosclerotic process. Their separate or combined enlargement may indicate different arterial phenotypes with different atherosclerosis risk.
We investigated cross-sectional (baseline 1987–89: n = 7956) and prospective (median follow-up = 5.9 years: n = 4845) associations between baseline right common carotid artery (RCCA) external diameter and IMT with existing and incident carotid atherosclerotic lesions detected by B-mode ultrasound in any right or left carotid segments. Logistic regression models (unadjusted, adjusted for IMT, or adjusted for IMT and risk factors) were used to relate baseline diameter to existing carotid lesions while comparably adjusted parametric survival models assessed baseline diameter associations with carotid atherosclerosis progression (incident carotid lesions). Four baseline arterial phenotypes were categorized as having 1) neither IMT nor diameter enlarged (reference), 2) isolated IMT thickening, 3) isolated diameter enlargement, and 4) enlargement of both IMT and diameter. The association between these phenotypes and progression to definitive carotid atherosclerotic lesions was assessed over the follow-up period.
Each standard deviation increment of baseline RCCA diameter was associated with increasing carotid lesion prevalence (unadjusted odds ratio [OR] = 1.54, 95% confidence interval [CI] = 1.47–1.62) and with progression of carotid atherosclerosis (unadjusted hazards ratio (HR) = 1.37, 95% CI = 1.28–1.46); and the associations remained significant even after adjustment for IMT and risk factors (prevalence OR = 1.11, 95% CI = 1.04–1.18; progression HR = 1.11, 95% CI = 1.03–1.19). Controlling for gender, age and race, persons with both RCCA IMT and diameter in the upper 50th percentiles had the greatest risk of progressing to clearly defined carotid atherosclerotic lesions (all HR = 1.71, 95% CI = 1.47–2.0; men HR = 1.88, 95% CI = 1.48–2.39; women HR = 1.59, 95% CI = 1.31–1.95) while RCCA IMT or diameter alone in the upper 50th percentile produced significantly lower estimated risks.
RCCA IMT and external diameter provide partially overlapping information relating to carotid atherosclerotic lesions. More importantly, the RCCA phenotype of coexistent wall thickening with external diameter enlargement indicates higher atherosclerotic risk than isolated wall thickening or diameter enlargement.
PMCID: PMC2277382  PMID: 18321381
21.  Carotid intima-media thickness in young patients with familial hypercholesterolaemia. 
Heart  1996;76(4):321-325.
OBJECTIVE: To assess the extent of early atherosclerotic changes of the carotid arteries in young patients with familial hypercholesterolaemia (FH) detected as increased intima-media thickness (IMT), and to determine the relations between IMT and some clinical and blood variables such as lipid and lipoprotein(a) (Lp(a)) concentration and haemostatic factors. DESIGN: The IMT of the carotid bifurcation, the proximal 1 cm of the internal carotid artery, and the distal 1 cm of the common carotid artery was determined in all subjects using B mode ultrasonography. Blood lipids, fasting glucose, and several haemostatic variables were also analysed. SUBJECTS: 28 patients with FH (12 males and 16 females aged 11 to 27 years, one homozygote, 27 heterozygotes) and 28 sex and age matched normolipidaemic healthy subjects. RESULTS: The mean carotid IMT (the average of six measurements of the maximum far wall IMT in the three carotid segments on each side) was significantly greater in patients with FH than in controls (mean (SD) 0.71 (0.15) v 0.49 (0.08) mm, P < 0.001). In all subjects, the mean IMT was significantly correlated with total cholesterol (r = 0.59), low density lipoprotein (LDL) cholesterol (r = 0.60), triglycerides (r = 0.27), and systolic blood pressure (r = 0.47). No correlation was found between the mean IMT and Lp(a), fibrinogen, tissue plasminogen activator, and plasminogen activator inhibitor 1. CONCLUSIONS: The majority of young patients with FH have a greater intima-media thickness of the carotid arteries than healthy subjects. Since the individual susceptibility of patients with FH to increased LDL cholesterol is different, B mode ultrasonography could provide a useful tool to identify those who are more likely to develop premature atherosclerotic disease.
PMCID: PMC484543  PMID: 8983678
22.  The Association between Within-Visit Blood Pressure Variability and Carotid Artery Atherosclerosis in General Population 
PLoS ONE  2014;9(5):e97760.
To determine whether within-visit blood pressure (BP) variability based on three measurements over minutes is associated with increased carotid intima-media thickness (IMT) and plaque in a general population.
A cross-sectional survey was performed in 2007, and a total of 1222 Beijing community residents aged 50–79 years belonging to part of the Chinese Multi-Provincial Cohort Study (CMCS) were recruited in this study. BP was measured three times at 5-minute intervals during a single visit, and the maximum absolute difference (MAD) between any two readings of three measurements was used to indicate within-visit BP variability. Carotid IMT and plaque scanned by B-mode ultrasound were identified as the surrogate end points in the intermediate stage of atherosclerosis.
After adjustment for established cardiovascular risk factors, the odds ratio (OR) (95% confidence interval (CI)) for increased carotid IMT and internal carotid plaque associated with the highest within-visit diastolic BP (DBP) variability (MAD > mean + standard deviation (SD)) compared with participants in the lowest within-visit DBP variability (MAD ≤ mean −SD) was 4.92 (1.48–16.42) and 6.07 (1.31–28.10), respectively, in the normotensives (P = 0.01; P = 0.02). The OR (95% CI) for internal carotid plaque associated with the highest within-visit systolic BP (SBP) variability (MAD >mean +SD) compared with participants in the lowest within-visit SBP variability (MAD ≤ mean −SD) was 3.54 (1.26–10.00) in the hypertensives on antihypertensive therapy (P = 0.02).
Within-visit DBP variability was associated with increased carotid IMT and internal carotid plaque in the normotensive population, and within-visit SBP variability was associated with internal carotid plaque in hypertensive patients undergoing antihypertensive therapy.
PMCID: PMC4024014  PMID: 24835667
23.  Socioeconomic position in childhood and adult cardiovascular risk factors, vascular structure, and function: cardiovascular risk in young Finns study 
Heart  2005;92(4):474-480.
To examine the association of childhood socioeconomic position (SEP) with adult cardiovascular risk factors, vascular structure, and vascular function in a contemporary population of young adults.
Population based prospective cohort study with baseline assessment in 1980.
856 men and 1066 women whose childhood SEP was determined by parental occupational status (manual, lower non‐manual, upper non‐manual) at age 3–18 years.
Main outcome measures
Cardiovascular risk factors, carotid artery intima–media thickness, and brachial artery flow mediated vasodilatation, assessed at age 24–39 years.
After adjustment for age and adult SEP, systolic pressure was 2.3 mm Hg higher (p  =  0.0002), high density lipoprotein (HDL) cholesterol 0.03 mmol/l lower (p  =  0.02), and insulin resistance score (homeostasis model assessment index) 0.12 units greater (p  =  0.05) among men; and systolic pressure was 1.3 mm Hg higher (p  =  0.02), diastolic pressure 1.1 mm Hg higher (p  =  0.01), and height 1.1 cm lower (p < 0.0001) among women for each step down the childhood SEP hierarchy. Lower childhood SEP was associated with a 20% increase in the odds of having a waist circumference > 102 cm in men and > 88 cm in women (overall p  =  0.05). Childhood SEP was not associated with intima–media thickness, flow mediated vasodilatation, the metabolic syndrome, low density lipoprotein cholesterol, triglycerides, body mass index, alcohol consumption, or smoking.
Among adults under 40, low childhood SEP predicted higher blood pressure and central obesity and, among men, unfavourable HDL cholesterol and insulin resistance, independent of current SEP. No independent effects were found on adult vascular structure, vascular function, or health related behaviours at this life stage.
PMCID: PMC1860895  PMID: 16159979
socioeconomic status; cardiovascular diseases; atherosclerosis; endothelial function; risk factors
24.  Association between circulating leukocyte subtype counts and carotid intima-media thickness in Japanese subjects with type 2 diabetes 
An increased leukocyte count is an independent risk factor for cardiovascular events, but the association between leukocyte subtype counts and carotid atherosclerosis in patients with diabetes has not been determined. We therefore investigated the correlation between leukocyte subtype counts and intima-media thickness of the common carotid artery (CCA-IMT) in subjects with type 2 diabetes.
This cross-sectional study involved 484 in-patients with type 2 diabetes (282 males and 202 females), who were hospitalized for glycemic control and underwent carotid ultrasonography at Kumamoto University Hospital between 2005 and 2011. Mean and maximum CCA-IMT was measured by high-resolution B-mode ultrasonography.
Univariate analyses revealed that mean CCA-IMT was positively correlated with age, systolic blood pressure, brachial-ankle pulse wave velocity (PWV), urinary albumin excretion and duration of diabetes, but was negatively correlated with diastolic blood pressure and fasting plasma glucose. Maximum CCA-IMT was positively and negatively correlated with the same factors as mean CCA-IMT except for fasting plasma glucose. Mean CCA-IMT was positively correlated with total leukocyte (r = 0.124, p = 0.007), monocyte (r = 0.373, p < 0.001), neutrophil (r = 0.139, p = 0.002) and eosinophil (r = 0.107, p = 0.019) counts. Maximum CCA-IMT was positively correlated with total leukocyte (r = 0.154, p < 0.001), monocyte (r = 0.398, p < 0.001), neutrophil (r = 0.152, p < 0.001) and basophil counts (r = 0.102, p = 0.027). Multiple regression analyses showed that monocyte count, age and PWV were significant and independent factors associated with mean CCA-IMT (adjusted R2 = 0.239, p < 0.001), and that monocyte count, age and urinary albumin excretion were significant and independent factors associated with maximum CCA-IMT (adjusted R2 = 0.277, p < 0.001).
Monocyte counts were positively correlated with both mean CCA-IMT and maximum CCA-IMT in patients with type 2 diabetes. Monocyte count may be a useful predictor of macrovascular complications in patients with type 2 diabetes.
Trial registration
Trial registry no: UMIN000003526.
PMCID: PMC3878795  PMID: 24373412
Leukocyte subtype counts; Carotid intima-media thickness; Diabetic macrovascular complication; Type 2 diabetes
25.  Albuminuria as a Marker of Cardiovascular Risk in HIV-Infected Individuals Receiving Stable Antiretroviral Therapy 
Albuminuria (urinary excretion of more than 30 milligram of albumin per gram of creatinine) serves as an indicator of microvascular injury, which has been associated with atherosclerosis and cardiovascular disease in HIV-seronegative individuals. Albuminuria has been reported to be prevalent among HIV-seropositive individuals, however, the relationship between albuminuria and risk for cardiovascular disease in this population has not been well-studied. We examined the relationships between albuminuria and parameters of atherosclerosis including carotid intima-media thickness and traditional cardiovascular risk assessment among HIV-seropositive individuals receiving stable antiretroviral therapy. We utilized a cross-sectional baseline data from the Hawai‘i Aging with HIV-Cardiovascular Study cohort.
Data was available on 111 HIV-infected patients (median age of 52 (Q1,Q3: 46, 57), male 86%; diabetes 6%; hypertension 33%; dyslipidemia 50%; median CD4 count of 489 cells/mm3 (341, 638); HIV RNA PCR < 48 copies/ml of 85%). Eighteen subjects (16.2%) had microalbuminuria, and two subjects (1.8%) had macroalbuminuria. Albuminuria was significantly associated with increased Framingham Risk Score (P=.002), insulin resistance by HOMA-IR (P=.02), diastolic blood pressure (P=.01), and carotid intima-media thickness (P =.04). The correlation between the amount of albuminuria and carotid intima-media thickness remained significant even after adjusting for age, gender, ethnicity, current smoking status, diabetes mellitus, diastolic blood pressure, fasting insulin level, CD4 count, and HIV-RNA viral load.
Albuminuria is prevalent among HIV-infected patients receiving stable antiretroviral therapy. It is significantly related to previously defined markers of cardiovascular disease and metabolic syndrome among HIV-infected patients receiving stable antiretroviral therapy.
PMCID: PMC3764546  PMID: 24052917
HIV; albuminuria; CD4 count; HIV viral load; atherosclerosis; aging; cardiovascular disease

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