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.
Common carotid artery (CCA) intima-media thickness (cIMT), a measure of atherosclerosis, varies between peak-systole (PS) and end-diastole (ED). This difference might affect cardiovascular risk assessment.
Materials and methods
IMT measurements of the right and left CCA were synchronized with an electrocardiogram: R-wave for ED and T-wave for PS. IMT was measured in 2930 members of the Framingham Offspring Study. Multivariable regression models were generated with ED-IMT, PS-IMT and change in IMT as dependent variables and Framingham risk factors as independent variables. ED-IMT estimates were compared to the upper quartile of IMT based on normative data obtained at PS.
The average age of our population was 57.9 years. Average difference in IMT during the cardiac cycle was 0.037 mm (95% CI: 0.035–0.038 mm). ED-IMT and PS-IMT had similar associations with Framingham risk factors (total R2= 0.292 versus 0.275) and were significantly associated with all risk factors. In a fully adjusted multivariable model, a thinner IMT at peak-systole was associated with pulse pressure (p < 0.0001), LDL-cholesterol (p = 0.0064), age (p = 0.046), and no other risk factors. Performing ED-IMT measurements while using upper quartile PS-IMT normative data lead to inappropriately increasing by 42.1% the number of individuals in the fourth IMT quartile (high cardiovascular risk category).
The difference in IMT between peak-systole and end-diastole is associated with pulse pressure, LDL-cholesterol, and age. In our study, mean IMT difference during the cardiac cycle lead to an overestimation by 42.1% of individuals at high risk for cardiovascular disease.
Ultrasonics; Risk Factors; Carotid Arteries; Blood Pressure; systole; diastole
Increasing adiposity increases the risk for left ventricular hypertrophy. Adipokines are hormone-like substances from adipose tissue that influence several metabolic pathways relevant to LV hypertrophy. Data was from participants enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA) who underwent magnetic resonance imaging of the heart and who also had fasting venous blood assayed for 4 distinct adipokines (adiponectin, leptin, tumor necrosis factor – alpha and resistin). 1,464 MESA participants had complete data. The mean age was 61.5 years, the mean body mass index was 27.6 kg/m2 and 49% were female. With adjustment for age, sex, race, height and weight, multivariable linear regression modeling revealed that a 1-SD increment in leptin was significantly associated with smaller LV mass (ß: −4.66 % predicted, p-value: < 0.01), LV volume (−5.87 % predicted, < 0.01), stroke volume (−3.23 ml, p < 0.01) and cardiac output (−120 mL/min, p = 0.01) as well as a lower odds ratio for the presence of LV hypertrophy (OR: 0.65, p < 0.01), but a higher ejection fraction (0.44%, p = 0.05). Additional adjustment for the traditional cardiovascular disease (CVD) risk factors, insulin resistance, physical activity, education, income, inflammatory biomarkers, other selected adipokines and pericardial fat did not materially change the magnitude or significance of the associations. The associations between the other adipokines and LV structure and function were inconsistent and largely non-significant. In conclusion, the results indicate that higher levels of leptin are associated with more favorable values of several measures of LV structure and function.
leptin; left ventricle; hypertrophy; mass
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.
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.
Resting heart rate is an easily measured, non-invasive vital sign that is associated with cardiovascular disease events. The pathophysiology of this association is not known. We investigated the relationship between resting heart rate and stiffness of the carotid (a peripheral artery) and the aorta (a central artery) in an asymptomatic multi-ethnic population. Resting heart rate was recorded at baseline in the Multi-Ethnic Study of Atherosclerosis (MESA). Distensibility was used as a measure of arterial elasticity, with a lower distensibility indicating an increase in arterial stiffness. Carotid distensibility was measured in 6,484 participants (98% of participants) using B-mode ultrasound and aortic distensibility was measured in 3,512 participants (53% of participants) using cardiac MRI. Heart rate was divided into quintiles and we used progressively adjusted models that included terms for physical activity and AV-nodal blocking agents. Mean resting heart rate of participants (mean age 62 years, 47% male) was 63 beats per minute (SD 9.6 beats per minute). In unadjusted and fully adjusted models, carotid distensibility and aortic distensibility decreased monotonically with increasing resting heart rate (p for trend <0.001 and 0.009 respectively). The relationship was stronger for carotid versus aortic distensibility. Similar results were seen using the resting heart rate taken at the time of MRI scanning. Our results suggest that a higher resting heart rate is associated with an increased arterial stiffness independent of AV-nodal blocker use and physical activity level, with a stronger association for a peripheral (carotid) compared to a central (aorta) artery.
heart rate; cardiovascular disease; stiffness; ultrasound; cardiac magnetic resonance imaging
Stiffening of the central elastic arteries is one of the earliest detectable manifestations of adverse change within the vessel wall. While an association between carotid artery stiffness and adverse events has been demonstrated, little is known about the relationship between stiffness and atherosclerosis. Even less is known about the impact of age, gender, and race on this association. To elucidate this question, we used baseline data from the Multi-Ethnic Study of Atherosclerosis (MESA, 2000-2002). Carotid artery distensibility coefficient (DC) was calculated after visualization of the instantaneous waveform of common carotid diameter using high resolution B-mode ultrasound. Thoracic aorta calcification (TAC) was identified using non-contrast cardiac CT. We found a strong association between decreasing DC (increasing carotid stiffness) and increasing TAC as well as a graded increase in TAC score (p<0.001). After controlling for age, gender, race, and traditional and emerging cardiovascular risk factors, individuals in the stiffest quartile had a prevalence ratio of 1.52 (95% CI 1.15-2.00) for TAC compared to the least stiff quartile. In exploratory analysis, carotid stiffness was more highly correlated with calcification of the aorta than calcification of the coronary arteries (ρ=0.32 vs. 0.22, p<0.001 for comparison). In conclusion, there is a strong independent association between carotid stiffness and thoracic aorta calcification. Carotid stiffness is more highly correlated with calcification of the aorta, a central elastic artery, than calcification of the coronary arteries. The prognostic significance of these findings requires longitudinal follow-up of the MESA cohort.
Carotid stiffness; carotid compliance; subclinical atherosclerosis; thoracic aorta calcification; coronary calcification
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.
Ultrasonography; Risk Factors; Carotid Arteries; Carotid Intima Media Thickness; stroke
Although higher visit-to-visit variability (VVV) of blood pressure (BP) is associated with increased cardiovascular disease risk, the physiological basis for VVV of BP is incompletely understood.
We examined the associations of aortic distensibility (assessed by magnetic resonance imaging) and artery elasticity indices (determined by radial artery pulse contour analysis) with VVV of BP in 2,640 and 4,560 participants, respectively, from the Multi-Ethnic Study of Atherosclerosis. Arterial measures were obtained at exam 1. BP readings were taken at exam 1 and at 3 follow-up visits at 18-month intervals (exams 2, 3, and 4). VVV was defined as the SD about each participant’s mean systolic BP (SBP) across visits.
The mean SDs of SBP were inversely associated with aortic distensibility: 7.7, 9.9, 10.9, and 13.2mm Hg for quartiles 4, 3, 2, and 1 of aortic distensibility, respectively (P trend < 0.001). This association remained significant after adjustment for demographics, cardiovascular risk factors, mean SBP, and antihypertensive medication use (P trend < 0.01). In a fully adjusted model, lower quartiles of large artery and small artery elasticity (LAE and SAE) indices were also associated with higher mean SD of SBP (P trend = 0.02 for LAE; P trend < 0.001 for SAE).
In this multiethnic cohort, functional alterations of central and peripheral arteries were associated with greater long-term VVV of SBP.
arteries; blood pressure; epidemiology; hypertension; vasculature.
To investigate the association between salivary cortisol and two markers of subclinical cardiovascular disease (CVD), coronary calcification (CAC), and ankle-brachial index (ABI).
Data from an ancillary study to the Multi-Ethnic Study of Atherosclerosis (MESA), the MESA Stress Study, were used to analyze associations of salivary cortisol data collected six times per day over three days with CAC and ABI. The authors used mixed models with repeat cortisol measures nested within persons to determine if specific features of the cortisol profile were associated with CAC and ABI.
total of 464 participants were included in the CAC analysis and 610 in the ABI analysis. The mean age of participants was 65.6 years. A 1-unit increase in log coronary calcium was associated with a 1.77% flatter early decline in cortisol (95% CI: 0.23, 3.34) among men and women combined. Among women low ABI was associated with a steeper early decline (−13.95% CI:−25.58, −3.39) and a marginally statistically significant flatter late decline (1.39% CI: −0.009, 2.81). The cortisol area under the curve and wake to bedtime slope were not associated with subclinical CVD.
This study provides weak support for the link between cortisol and measures of subclinical atherosclerosis. We found an association between some features of the diurnal cortisol profile and coronary calcification and ABI but associations were not consistent across subclinical measures. There are methodological challenges in detecting associations of cortisol measures at a point in time with health outcomes that develop over a lifetime. Studies of short-term mechanisms linking stress to physiological processes related to the development of early atherosclerosis may be more informative.
salivary cortisol; ankle brachial index; coronary calcification; atherosclerosis; stress; cortisol awakening response; cortisol diurnal pattern; Multi-Ethnic Study of Atherosclerosis
Common carotid artery inter-adventitial diameter (IAD) and intima-media thickness (IMT) are measurable by ultrasound. IAD may be associated with left ventricular mass (LV mass) while IMT is a marker of subclinical atherosclerosis. It is not clear if IAD is associated with LV mass after accounting for IMT and traditional cardiovascular risk factors.
IAD and IMT were measured on participants of the Multi-Ethnic Study of Atherosclerosis (MESA) IMT progression study. A total of 5641 of the originally enrolled 6814 MESA participants were studied. LV mass was measured by magnetic resonance imaging. Multivariable linear regression was used with IAD as the outcome and adjustment for risk factors, as well as IMT and LV mass.
Traditional cardiovascular risk factors, height, weight and ethnicity were significantly associated with IAD. After adjustment for risk factors, a one mm difference in IMT was associated with a 1.802 mm (95% CI: 1.553, 2.051) higher mean IAD. A one gm difference in LV mass was associated with a 0.006 mm (95% CI: 0.005, 0.007) higher mean IAD. LV mass was independently associated with IAD after adjusting for cardiovascular risk factors and IMT. These associations were slightly different for men and women.
Inter-adventitial diameters are associated with left ventricular mass after adjusting for cardiovascular risk factors and IMT. IAD might serve as a surrogate for left ventricular mass and have predictive value for cardiovascular outcomes.
carotid arteries; ultrasonics; hypertrophy; magnetic resonance imaging; remodeling; risk factors; left ventricle
Common carotid artery intima-media thickness (IMT), a measure of subclinical cardiovascular disease, changes during the cardiac cycle. The magnitude of this effect and its implications have not been well studied.
Methods and Results
Far-wall IMT measurements of the right common carotid artery were measured at end diastole and peak systole in 5633 individuals from the Multi-Ethnic Study of Atherosclerosis (MESA). Multivariable regression models were generated with end-diastolic IMT, peak-systolic IMT, and change in IMT during the cardiac cycle as dependent variables and traditional cardiovascular risk factors as independent variables. The average age of our population was 61.9 (45 to 84) years. Average change in carotid IMT during the cardiac cycle was 0.041 mm (95% confidence interval: 0.039 to 0.042 mm), with a mean IMT of 0.68 mm. End-diastolic IMT and peak-systolic IMT were similarly associated with risk factors. In a fully adjusted model, change in carotid IMT during the cardiac cycle was associated with ethnicity and pulse pressure (P=0.001) and not age, sex, or other risk factors. Chinese and Hispanics had less of a change in IMT than did non-Hispanic whites. With peak-systolic IMT reference values used as normative data, 31.3% more individuals were classified as being in the upper quartile of IMT and at high risk for cardiovascular disease than would be expected when IMT is measured at end diastole.
Measurable differences in IMT are seen during the cardiac cycle. This affects the interpretation of IMT measurements used for cardiovascular risk assessment, given published normative data with IMT measured at peak systole.
Clinical Trial Registration
URL: www.ClinicalTrials.gov. Unique identifier: NCT00063440. (J Am Heart Assoc. 2012;1:e001420 doi: 10.1161/JAHA.112.001420.)
atherosclerosis; blood pressure; carotid arteries; diastole; epidemiology; risk factors; systole; ultrasonics
Subclinical atherosclerosis measured by coronary artery calcium (CAC) is associated with increased risk for multiple cardiovascular disease (CVD) outcomes and non-CVD death simultaneously, and we sought to determine the competing risks of specific cardiovascular disease (CVD) events and non-CVD death associated with varying burdens of subclinical atherosclerosis. We included 3095 men and 3486 women from the Multi-Ethnic Study of Atherosclerosis, aged 45–84 years, and from 4 ethnic groups. Participants were stratified by CAC scores: 0, 1–99, and ≥ 100. We used competing Cox models to determine competing cumulative incidences and hazards ratios within a group (e.g., among those with CAC ≥ 100) and hazards ratios for specific events between groups (e.g., CAC ≥ 100 vs. CAC = 0). We compared risks for specific CVD events and also compared against non-CVD death. In women, during a mean follow up of 7.1 years, the hazards ratios (HR) for any CVD event compared with a non-CVD death occurring first for CAC = 0 and CAC ≥ 100 were 1.40 (95% CI, 0.97–2.04) and 3.07 (2.02–4.67), respectively. CHD was the most common first CVD event type at all levels of CAC, and CHD rates were 9.5% vs. 1.6% (HR 6.24; 3.99–9.75) for women with CAC ≥100 compared with CAC = 0. We observed similar results in men. In conclusion, at all levels of CAC, CHD was the most common first CVD event and this analysis represents a novel approach to understanding the temporal sequence of cardiovascular events associated with atherosclerosis.
coronary artery calcium; competing risks
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.
Carotid intima-media thickness; Subclinical atherosclerosis; Multi-Ethnic Study of Atherosclerosis; MESA; Heinz Nixdorf Recall Study; HNR
Carotid intima-media thickness (IMT) is a marker of cardiovascular disease derived from ultrasound images of the carotid artery. In most outcome studies, human readers identify and trace the key IMT interfaces. We evaluate an alternate approach using automated edge detection.
We study a subset of 5640 participants with an average age 61.7 years (48% men) of the Multi-Ethnic Study of Atherosclerosis composed of whites, Chinese, Hispanic and African-Americans that are part of the MESA IMT progression study. Manual tracing IMT (mt_IMT) and edge-detected IMT (ed_IMT) measurements of the far wall of the common carotid artery (CCA) served as outcome variables for multivariable linear regression models using Framingham cardiovascular risk factors and ethnicity as independent predictors.
Measurements of mt_IMT was obtainable in 99.9% (5633/5640) and of ed_IMT in 98.9% (5579/5640) of individuals. Average ed_IMT was 0.19 mm larger than mt_IMT. Inter-reader systematic differences (bias) in IMT measurements were apparent for mt_IMT but not ed_IMT. Based on complete data on 5538 individuals, associations of IMT with risk factors were stronger (p < 0.0001) for mt_IMT (model r2: 19.5%) than ed_IMT (model r2: 18.5%).
We conclude that this edge-detection process generates IMT values equivalent to manually traced ones since it preserves key associations with cardiovascular risk factors. It also decreases inter-reader bias, potentially making it applicable for use in cardiovascular risk assessment.
Ultrasonography; Risk Factors; Carotid Arteries; Carotid Intima Media Thickness
It is unclear if associations between a parental history of premature CVD (pCVD) and subclinical atherosclerosis are attenuated by adjustment for long-term risk factors levels through middle adulthood.
Prospective community-based cohort study
CARDIA participants who attended the year 20 exam (N=2283, mean age 45 years) were grouped by pCVD status: maternal only, paternal only, any parental, and no parental history (referent). We used separate logistic regression models, adjusted for average risk factor levels over 20 years' follow-up to assess associations of parental pCVD and subclinical atherosclerosis in offspring.
White participants with any parental history of pCVD had a higher odds of CAC>0 than participants with no parental history (OR 1.55; 95% CI, 1.01-2.37). This was largely driven by the association of a paternal history of pCVD with CAC>0 (OR 2.15; 95% CI, 1.42-3.23), which was minimally attenuated by multivariable adjustment (OR 2.09; 95% CI, 1.31-3.32). Similarly, adjusted associations between parental pCVD and IMT > 90%tile were observed in white participants with a paternal history of pCVD (OR=1.93; 95% CI, 1.10-3.39) and any parental history pCVD (OR 1.67; 95% CI, 1.02-2.74). No significant associations between a parental history of pCVD and the odds of subclinical atherosclerosis were observed in black participants.
Parental pCVD is independently associated with early development of subclinical atherosclerosis; these associations may be race-specific for participants in their 5th decade of life.
Family History of Premature Cardiovascular Disease; Coronary Artery Calcium; Carotid Intima-Media Thickness
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.
pulse pressare; subclinical cardiovascular disease; carotid intima–media thickness; left ventricular mass index; aging; hypertension; arterial stiffness; blood pressure.
Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped ∼50 000 single-nucleotide polymorphisms (SNPs) that capture variation in ∼2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P < 2.4 × 10−6). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.
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.
atherosclerosis; carotid artery; disease prevalence; intima-media thickness; risk factors
Background and Purpose
We propose to study possible differences in the associations between risk factors for cardiovascular disease (myocardial infarction and stroke) and Carotid Intima-Media thickness (IMT) measurements made at three different levels of the carotid bifurcation. Methods: Cross-sectional study of a cohort of Whites and African Americans of both genders with mean age 45 years. Traditional cardiovascular risk factors were determined in cohort members. Carotid IMT was measured from high-resolution B-mode ultrasound images at three levels: the common carotid artery (CCA), the carotid artery bulb (Bulb) and the internal carotid artery (ICA). Associations with risk factors were evaluated by multivariate linear regression analyses.
Of 3258 who underwent carotid IMT measurements, CCA, Bulb, and ICA IMT were measured at all three separate levels in 3023 (92.7%). A large proportion of the variability of CCA IMT was explained by cardiovascular risk factors (26.8%) but less so for the Bulb (11.2%) and ICA (8.0%). Carotid IMT was consistently associated with age, LDL-cholesterol, smoking and hypertension in all segments. Associations with fasting glucose and diastolic blood pressure were stronger for CCA than for the other segments. Hypertension, diabetes and current smoking had qualitatively stronger associations with Bulb IMT, and LDL cholesterol with ICA IMT. Conclusion: In our cohort of relatively young white and African-American men and women, a greater proportion of the variability in common carotid IMT can be explained by traditional cardiovascular risk factors than for the carotid artery bulb and internal carotid arteries.
Carotid Intimal Medial Thickness; Risk Factors; Carotid Ultrasound
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
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
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
This study evaluated the association of long- and short-term air pollutant exposures with flow-mediated dilation (FMD) and baseline arterial diameter (BAD) of the brachial artery using ultrasound in a large multicity cohort.
Exposures to ambient air pollution, especially long-term exposure to particulate matter <2.5 μm in aerodynamic diameter (PM2.5), are linked with cardiovascular mortality. Short-term exposure to PM2.5 has been associated with decreased FMD and vasoconstriction, suggesting that adverse effects of PM2.5 may involve endothelial dysfunction. However, long-term effects of PM2.5 on endothelial dysfunction have not been investigated.
FMD and BAD were measured by brachial artery ultrasound at the initial examination of the Multi-Ethnic Study of Atherosclerosis. Long-term PM2.5 concentrations were estimated for the year 2000 at each participant’s residence (n = 3,040) using a spatio-temporal model informed by cohort-specific monitoring. Short-term PM2.5 concentrations were based on daily central-site monitoring in each of the 6 cities.
An interquartile increase in long-term PM2.5 concentration (3 μg/m3) was associated with a 0.3% decrease in FMD (95% confidence interval [CI] of difference: −0.6 to −0.03; p = 0.03), adjusting for demographic characteristics, traditional risk factors, sonographers, and 1/BAD. Women, nonsmokers, younger participants, and those with hypertension seemed to show a greater association of PM2.5 with FMD. FMD was not significantly associated with short-term variation in PM2.5 (−0.1% per 12 μg/m3 daily increase [95% CI: −0.2 to 0.04] on the day before examination).
Long-term PM2.5 exposure was significantly associated with decreased endothelial function according to brachial ultrasound results. These findings may elucidate an important pathway linking air pollution and cardiovascular mortality.
air pollution; atherosclerosis; cardiovascular mortality; endothelial function; flow-mediated dilation; traffic
Recent reports suggest that nephrolithiasis and atherosclerosis share a number of risk factors. There has been no previous examination of the relationship between kidney stones and subclinical atherosclerotic disease Here we assessed the relationship between nephrolithiasis and carotid wall thickness and carotid stenosis assessed by B-mode ultrasound in the general community using data from The Coronary Artery Risk Development in Young Adults (CARDIA) study.
CARDIA is a U.S. population-based, observational study of 5,115 white and African-American men and women between the ages of 18 and 30 years at recruitment in 1985-1986.
By the year 20 exam, 200 (3.9%) of CARDIA participants had reported ever having kidney stones. Symptomatic kidney stones were associated with greater carotid wall thickness measured at the year 20 exam, particularly of the internal carotid/bulb region. Using a composite dichotomous endpoint of carotid stenosis and/or upper quartile of internal carotid/bulb wall thickness, the association of kidney stones with carotid atherosclerosis was significant (odds ratio=1.6; 95% confidence interval 1.1-2.3; p=0.01) even after adjusting for major atherosclerotic risk factors.
The association between a history of kidney stones and subclinical carotid atherosclerosis in young adults adds further support to the notion that nephrolithiasis and atherosclerosis share common systemic risk factors and/or pathophysiology.
Coronary heart disease (CHD) is the major cause of death in the United States. Coronary artery calcification (CAC) scores are independent predictors of CHD. African Americans (AA) have higher rates of CHD but are less well-studied in genomic studies. We assembled the largest AA data resource currently available with measured CAC to identify associated genetic variants.
We analyzed log transformed CAC quantity (ln(CAC + 1)), for association with ~2.5 million single nucleotide polymorphisms (SNPs) and performed an inverse-variance weighted meta-analysis on results for 5,823 AA from 8 studies. Heritability was calculated using family studies. The most significant SNPs among AAs were evaluated in European Ancestry (EA) CAC data; conversely, the significance of published SNPs for CAC/CHD in EA was queried within our AA meta-analysis.
Heritability of CAC was lower in AA (~30%) than previously reported for EA (~50%). No SNP reached genome wide significance (p < 5E-08). Of 67 SNPs with p < 1E-05 in AA there was no evidence of association in EA CAC data. Four SNPs in regions previously implicated in CAC/CHD (at 9p21 and PHACTR1) in EA reached nominal significance for CAC in AA, with concordant direction. Among AA, rs16905644 (p = 4.08E-05) had the strongest association in the 9p21 region.
While we observed substantial heritability for CAC in AA, we failed to identify loci for CAC at genome-wide significant levels despite having adequate power to detect alleles with moderate to large effects. Although suggestive signals in AA were apparent at 9p21 and additional CAC and CAD EA loci, overall the data suggest that even larger samples and an ethnic specific focus will be required for GWAS discoveries for CAC in AA populations.
Atherosclerosis; Coronary artery calcium; Genetics; Meta-analysis; African-American