Associations of edge-detected and manual-traced common carotid artery intima-media thickness with incident peripheral artery disease: The Multi-Ethnic Study of Atherosclerosis.

Common carotid artery (CCA) intima-media thickness (IMT) is associated with coronary heart disease and can be measured on ultrasound images either by hand or with an automated edge detector. The association of CCA IMT with incident peripheral artery disease (PAD) is poorly studied. We studied 5467 participants of the Multi-Ethnic Study of Atherosclerosis composed of non-Hispanic white, Chinese, Hispanic, and African American participants with a mean age of 61.9 years (47.8% men). Framingham Risk Factors, manual-traced IMT (mt-IMT), and edge-detected IMT (ed-IMT) were entered into multivariable Cox proportional hazards models with incident PAD as the outcome. There were 87 events during a median follow-up of 12.2 years. In fully adjusted models and expressing the hazard ratios (HR) as an increment in SD values, both mt-IMT and ed-IMT were significantly associated with incident PAD: HR 1.36 (95% CI: 1.15, 1.61) and 1.29 (95% CI: 1.04, 1.60), respectively. We conclude that ed- and mt-CCA IMT measurements are associated with incident PAD. ClinicalTrials.gov Identifier: NCT00063440.

GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

Carotid Intima-Media Thickness Score, Positive Coronary Artery Calcium Score, and Incident Coronary Heart Disease: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Common carotid artery and internal carotid artery intima-media thicknesses (IMT) are associated with coronary heart disease (CHD) and increase with age. Using age, sex, and race/ethnicity IMT percentiles may improve CHD prediction when added to Framingham risk factors and coronary artery calcium score. We study these possibilities in the Multi-Ethnic Study of Atherosclerosis (MESA), a multi-ethnic cohort of whites, Chinese, blacks, and Hispanics. METHODS AND RESULTS: IMT data were acquired in the age range 45 to 84 years. Common carotid artery and internal carotid artery IMT, sex, and race/ethnic specific normative values were calculated for each MESA participant and combined as an IMT score. Multivariable Cox-proportional hazards models and logistic regression models were generated with CHD as outcome adding the IMT score to (1) a base model with Framingham risk factors, sex, race/ethnicity and (2) the base model with coronary artery calcium added. Harrell's C-statistics and area under the curve were estimated. Median follow-up was 10.2 years (interquartile range: 9.7, 10.7 years) with 429 first-time CHD events. Mean age was 62.1 years and 52.6% of participants were women. IMT score increased the base area under the curve from 0.7210 to 0.7396 (P=0.0008) and with positive coronary artery calcium score added to the model, from 0.7627 to 0.7714 (P=0.02). CONCLUSIONS: A carotid IMT score based on normative data incrementally adds to Framingham risk factors and a positive calcium score in predicting first-time CHD in an ethnically diverse cohort.

Carotid Intima-Media Thickness as Surrogate for and Predictor of CVD.

Carotid artery intima-media thickness (IMT) is a noninvasive measurement of the artery wall thickness, inclusive of atherosclerotic plaque, obtained using ultrasound imaging. In the MESA (Multi-Ethnic Study of Atherosclerosis) study, IMT measurements are used as a surrogate for subclinical cardiovascular disease and as a variable predictive of cardiovascular events. IMT measurements of the common carotid artery are available in more than 99% of the MESA population and are predictive of cardiovascular events. More importantly, IMT and plaque thickness measurements made in the internal carotid artery and carotid bulb are also available in more than 98% of the population and are also strongly predictive of cardiovascular events. This article reviews the techniques used to obtain the MESA IMT values, compares them to those made in other epidemiological studies, and summarizes how they have been used in the MESA study as both surrogates for and predictors of cardiovascular disease.

Race/Ethnic Differences in the Associations of the Framingham Risk Factors with Carotid IMT and Cardiovascular Events.

BACKGROUND: Clinical manifestations and outcomes of atherosclerotic disease differ between ethnic groups. In addition, the prevalence of risk factors is substantially different. Primary prevention programs are based on data derived from almost exclusively White people. We investigated how race/ethnic differences modify the associations of established risk factors with atherosclerosis and cardiovascular events. METHODS: We used data from an ongoing individual participant meta-analysis involving 17 population-based cohorts worldwide. We selected 60,211 participants without cardiovascular disease at baseline with available data on ethnicity (White, Black, Asian or Hispanic). We generated a multivariable linear regression model containing risk factors and ethnicity predicting mean common carotid intima-media thickness (CIMT) and a multivariable Cox regression model predicting myocardial infarction or stroke. For each risk factor we assessed how the association with the preclinical and clinical measures of cardiovascular atherosclerotic disease was affected by ethnicity. RESULTS: Ethnicity appeared to significantly modify the associations between risk factors and CIMT and cardiovascular events. The association between age and CIMT was weaker in Blacks and Hispanics. Systolic blood pressure associated more strongly with CIMT in Asians. HDL cholesterol and smoking associated less with CIMT in Blacks. Furthermore, the association of age and total cholesterol levels with the occurrence of cardiovascular events differed between Blacks and Whites. CONCLUSION: The magnitude of associations between risk factors and the presence of atherosclerotic disease differs between race/ethnic groups. These subtle, yet significant differences provide insight in the etiology of cardiovascular disease among race/ethnic groups. These insights aid the race/ethnic-specific implementation of primary prevention.

Edge-detected common carotid artery intima-media thickness and incident coronary heart disease in the multi-ethnic study of atherosclerosis.

BACKGROUND: Common carotid artery intima-media thickness (IMT) can be measured either by hand or with an automated edge detector. We performed a direct comparison of these 2 approaches and studied their respective associations with coronary heart disease outcomes. METHODS AND RESULTS: We studied 5468 participants of the Multi-Ethnic Study of Atherosclerosis, composed of white, Chinese, Hispanic, and black participants with an average age of 61.9 years (47.8% men) and who were free of coronary heart disease at baseline. Manual-traced and edge-detected IMT measurements were made in the same location on ultrasound images of the right common carotid artery far wall in an area free of plaque. Manual-traced and edge-detected common carotid artery IMT measurements were added separately to multivariable Cox proportional hazards models with time to incident coronary heart disease as the outcome and adjusted for traditional coronary heart disease Framingham risk factors, lipid-lowering therapy, blood pressure-lowering therapy, and race or ethnicity. Additional models were generated after adding clinic site and reader. There were 349 events during a median follow-up of 10.2 years. In adjusted models, the hazard ratio was not significant (1.31; 95% CI 0.84 to 2.06) for each millimeter increase in manual-traced IMT but was significant for edge-detected IMT (hazard ratio 1.63; 95% CI 1.12 to 2.37). Edge-detected IMT remained statistically associated with outcomes after additional adjustment for clinic site and reader performing the IMT measurement (hazard ratio 1.59; 95% CI 1.07 to 2.35). CONCLUSIONS: Edge-detected common carotid artery far wall IMT has similar if not stronger associations with coronary heart disease outcomes when compared with manual-traced IMT. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00063440.

Associations of Coronary Heart Disease with Common Carotid Artery Near and Far Wall Intima-Media Thickness: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Intima-media thickness (IMT) measured on ultrasound images of the common carotid artery (CCA) is associated with cardiovascular risk factors and events. Given the physics of ultrasound, CCA far wall IMT measurements are favored over near wall measurements, but this theoretical advantage is not well studied. METHODS: A total of 6,606 members of the Multi-Ethnic Study of Atherosclerosis, a longitudinal cohort study (mean age, 62.1 years; 52.7% women) who had near wall and far wall CCA IMT measurements. Multivariate linear regression models were used to estimate model goodness of fit of Framingham risk factors with near wall IMT, far wall IMT, and combined mean IMT. Multivariate Cox proportional hazards models were used to estimate hazard ratios for incident coronary heart disease events for each IMT variable. Change in Harrell's C statistic was used to compare the incremental value of each IMT variable when added to Framingham risk factors. RESULTS: Mean IMT had the strongest association with risk factors (R(2) = 0.31), followed by near wall (R(2) = 0.26) and far wall (R(2) = 0.22) IMT. Far wall IMT improved the prediction of coronary artery disease events over the Framingham risk factors (change in C statistic, 0.012; 95% CI, 0.006-0.017; P < .001), as did mean IMT (P = .004), but near wall IMT did not. CONCLUSIONS: Far wall CCA IMT showed the strongest association with incident coronary heart disease, whereas mean IMT had the strongest associations with risk factors. This difference might affect the selection of appropriate IMT variables in different studies.

Common carotid intima-media thickness relates to cardiovascular events in adults aged <45 years.

Although atherosclerosis starts in early life, evidence on risk factors and atherosclerosis in individuals aged <45 years is scarce. Therefore, we studied the relationship between risk factors, common carotid intima-media thickness (CIMT), and first-time cardiovascular events in adults aged <45 years. Our study population consisted of 3067 adults aged <45 years free from symptomatic cardiovascular disease at baseline, derived from 6 cohorts that are part of the USE-IMT initiative, an individual participant data meta-analysis of general-population-based cohort studies evaluating CIMT measurements. Information on risk factors, CIMT measurements, and follow-up of the combined end point (first-time myocardial infarction or stroke) was obtained. We assessed the relationship between risk factors and CIMT and the relationship between CIMT and first-time myocardial infarction or stroke using a multivariable linear mixed-effects model and a Cox proportional-hazards model, respectively. During a follow-up of 16.3 years, 55 first-time myocardial infarctions or strokes occurred. Median CIMT was 0.63 mm. Of the risk factors under study, age, sex, diastolic blood pressure, body mass index, total cholesterol, and high-density lipoprotein cholesterol related to CIMT. Furthermore, CIMT related to first-time myocardial infarction or stroke with a hazard ratio of 1.40 per SD increase in CIMT, independent of risk factors (95% confidence interval, 1.11-1.76). CIMT may be a valuable marker for cardiovascular risk in adults aged <45 years who are not yet eligible for standard cardiovascular risk screening. This is especially relevant in those with an increased, unfavorable risk factor burden.

Systemic inflammation and cardiovascular risk factors predict rapid progression of atherosclerosis in rheumatoid arthritis.

OBJECTIVE: To estimate atherosclerosis progression and identify influencing factors in rheumatoid arthritis (RA). METHODS: We used carotid ultrasound to measure intima-media thickness (IMT) in RA patients, and ascertained cardiovascular (CV) risk factors, inflammation markers and medications. A second ultrasound was performed approximately 3 years later. We calculated the progression rate by subtracting the baseline from the follow-up IMT, divided by the time between the two scans. We used logistic regression to identify baseline factors predictive of rapid progression. We tested for interactions of erythrocyte sedimentation rate (ESR) with CV risk factors and medication use. RESULTS: Results were available for 487 RA patients. The mean (SD) common carotid IMT at baseline was 0.571 mm (0.151). After a mean of 2.8 years, the IMT increased by 0.050 mm (0.055), p≤0.001, a progression rate of 0.018 mm/year (95% CI 0.016 to 0.020). Baseline factors associated with rapid progression included the number of CV risk factors (OR 1.27 per risk factor, 95% CI 1.01 to 1.61), and the ESR (OR 1.12 per 10 mm/h, 95% CI 1.02 to 1.23). The ESR×CV risk factor and ESR×medication product terms were significant, suggesting these variables modify the association between the ESR and IMT progression. CONCLUSIONS: Systemic inflammation and CV risk factors were associated with rapid IMT progression. CV risk factors may modify the role of systemic inflammation in determining IMT progression over time. Methotrexate and antitumour necrosis factor agents may influence IMT progression by reducing the effect of the systemic inflammation on the IMT.

What do carotid intima-media thickness and plaque add to the prediction of stroke and cardiovascular disease risk in older adults? The cardiovascular health study.

BACKGROUND: The aim of this study was to evaluate whether the addition of ultrasound carotid intima-media thickness (CIMT) measurements and risk categories of plaque help predict incident stroke and cardiovascular disease (CVD) in older adults. METHODS: Carotid ultrasound studies were recorded in the multicenter Cardiovascular Health Study. CVD was defined as coronary heart disease plus heart failure plus stroke. Ten-year risk prediction Cox proportional-hazards models for stroke and CVD were calculated using Cardiovascular Health Study-specific coefficients for Framingham risk score factors. Categories of CIMT and CIMT plus plaque were added to Framingham risk score prediction models, and categorical net reclassification improvement (NRI) and Harrell's c-statistic were calculated. RESULTS: In 4,384 Cardiovascular Health Study participants (61% women, 14% black; mean baseline age, 72 ± 5 years) without CVD at baseline, higher CIMT category and the presence of plaque were both associated with higher incidence rates for stroke and CVD. The addition of CIMT improved the ability of Framingham risk score-type risk models to discriminate cases from noncases of incident stroke and CVD (NRI = 0.062, P = .015, and NRI = 0.027, P < .001, respectively), with no further improvement by adding plaque. For both outcomes, NRI was driven by down-classifying those without incident disease. Although the addition of plaque to CIMT did not result in a significant NRI for either outcome, it was significant among those without incident disease. CONCLUSIONS: In older adults, the addition of CIMT modestly improves 10-year risk prediction for stroke and CVD beyond a traditional risk factor model, mainly by down-classifying risk in those without stroke or CVD; the addition of plaque to CIMT adds no statistical benefit in the overall cohort, although there is evidence of down-classification in those without events.

Prediction of asymptomatic carotid artery stenosis in the general population: identification of high-risk groups.

BACKGROUND AND PURPOSE: Because of a low prevalence of severe carotid stenosis in the general population, screening for presence of asymptomatic carotid artery stenosis (ACAS) is not warranted. Possibly, for certain subgroups, screening is worthwhile. The present study aims to develop prediction rules for the presence of ACAS (>50% and >70%). METHODS: Individual participant data from 4 population-based cohort studies (Malmö Diet and Cancer Study, Tromsø Study, Carotid Atherosclerosis Progression Study, and Cardiovascular Health Study; totaling 23 706 participants) were pooled. Multivariable logistic regression was performed to determine which variables predict presence of ACAS (>50% and >70%). Calibration and discrimination of the models were assessed, and bootstrapping was used to correct for overfitting. RESULTS: Age, sex, history of vascular disease, systolic and diastolic blood pressure, total cholesterol/high-density lipoprotein ratio, diabetes mellitus, and current smoking were predictors of stenosis (>50% and >70%). The calibration of the model was good confirmed by a nonsignificant Hosmer and Lemeshow test for moderate (P=0.59) and severe stenosis (P=0.07). The models discriminated well between participants with and without stenosis, with an area under the receiver operating characteristic curve corrected for over optimism of 0.82 (95% confidence interval, 0.80-0.84) for moderate stenosis and of 0.87 (95% confidence interval, 0.85-0.90) for severe stenosis. The regression coefficients of the predictors were converted into a score chart to facilitate practical application. CONCLUSIONS: A clinical prediction rule was developed that allows identification of subgroups with high prevalence of moderate (>50%) and severe (>70%) ACAS. When confirmed in comparable cohorts, application of the prediction rule may lead to a reduction in the number needed to screen for ACAS.

Associations of common carotid intima-media thickness with coronary heart disease risk factors and events vary with distance from the carotid bulb.

BACKGROUND: Common carotid artery (CCA) intima-media thickness (IMT) can be measured using ultrasound near to or below the carotid bulb. This might affect associations of IMT with coronary heart disease (CHD) risk factors and events. METHODS: IMT measurements were performed near and below the divergence of the CCA bulb in 279 white individuals aged 45 to 54 years free of CHD at baseline and a subset of the Multi-Ethnic Study of Atherosclerosis, a cohort composed of whites, blacks, Chinese, and Hispanic subjects. Participants were followed for an average of 8.2 years. Far wall mean of the maximum IMT (MMaxIMT) and mean of the mean IMT of the right and left CCAs were averaged. Framingham risk factors were used in multivariate linear regression models. Parsimonious Cox proportional regression models included first-time CHD as outcome. RESULTS: Mean of the mean IMT below the bulb was smaller than near the bulb (0.51 ± 0.078 vs 0.56 ± 0.088 mm, P < .001) and had similar associations with risk factors (model R(2) = 0.215 vs 0.186). MMaxIMT below the bulb was associated with risk factors (model R(2) = 0.211), but MMaxIMT near to the bulb was not (R(2) = 0.025). Mean of the mean IMT and MMaxIMT below the bulb were associated with CHD events (hazard ratios, 1.67 [P = .047] and 1.72 [P = .037], respectively) but not when measured near the bulb. CONCLUSIONS: CCA IMT measurements made below the bulb are smaller but have more consistent associations with CHD risk factors and outcomes compared with IMT measured near the bulb.

Common carotid intima-media thickness measurements do not improve cardiovascular risk prediction in individuals with elevated blood pressure: the USE-IMT collaboration.

Carotid intima-media thickness (CIMT) is a marker of cardiovascular risk. It is unclear whether measurement of mean common CIMT improves 10-year risk prediction of first-time myocardial infarction or stroke in individuals with elevated blood pressure. We performed an analysis among individuals with elevated blood pressure (i.e., a systolic blood pressure ≥140 mm Hg and a diastolic blood pressure ≥ 90 mm Hg) in USE-IMT, a large ongoing individual participant data meta-analysis. We refitted the risk factors of the Framingham Risk Score on asymptomatic individuals (baseline model) and expanded this model with mean common CIMT (CIMT model) measurements. From both models, 10-year risks to develop a myocardial infarction or stroke were estimated. In individuals with elevated blood pressure, we compared discrimination and calibration of the 2 models and calculated the net reclassification improvement (NRI). We included 17 254 individuals with elevated blood pressure from 16 studies. During a median follow-up of 9.9 years, 2014 first-time myocardial infarctions or strokes occurred. The C-statistics of the baseline and CIMT models were similar (0.73). NRI with the addition of mean common CIMT was small and not significant (1.4%; 95% confidence intervals, -1.1 to 3.7). In those at intermediate risk (n=5008, 10-year absolute risk of 10% to 20%), the NRI was 5.6% (95% confidence intervals, 1.6-10.4). There is no added value of measurement of mean common CIMT in individuals with elevated blood pressure for improving cardiovascular risk prediction. For those at intermediate risk, the addition of mean common CIMT to an existing cardiovascular risk score is small but statistically significant.

Incident stroke is associated with common carotid artery diameter and not common carotid artery intima-media thickness.

BACKGROUND AND PURPOSE: The common carotid artery interadventitial diameter is measured on ultrasound images as the distance between the media-adventitia interfaces of the near and far walls. It is associated with common carotid intima-media thickness (IMT) and left ventricular mass and might therefore also have an association with incident stroke. METHODS: We studied 6255 individuals free of coronary heart disease and stroke at baseline with mean age of 62.2 years (47.3% men), members of a multiethnic community-based cohort of whites, blacks, Hispanics, and Chinese. Ischemic stroke events were centrally adjudicated. Common carotid artery interadventitial diameter and IMT were measured. Cases with incident atrial fibrillation (n=385) were excluded. Multivariable Cox proportional hazards models were generated with time to ischemic event as outcome, adjusting for risk factors. RESULTS: There were 115 first-time ischemic strokes at 7.8 years of follow-up. Common carotid artery interadventitial diameter was a significant predictor of ischemic stroke (hazard ratio, 1.86; 95% confidence interval, 1.59-2.17 per millimeter) and remained so after adjustment for risk factors and common carotid IMT with a hazard ratio of 1.52/mm (95% confidence interval, 1.22-1.88). Common carotid IMT was not an independent predictor after adjustment (hazard ratio, 0.14; 95% confidence interval, 0.14-1.19). CONCLUSIONS: Although common carotid IMT is not associated with stroke, interadventitial diameter of the common carotid artery is independently associated with first-time incident ischemic stroke even after adjusting for IMT. Our hypothesis that this is in part attributable to the effects of exposure to blood pressure needs confirmation by other studies. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00063440.

Genetics of coronary artery calcification among African Americans, a meta-analysis.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

The value of carotid artery plaque and intima-media thickness for incident cardiovascular disease: the multi-ethnic study of atherosclerosis.

BACKGROUND: Carotid artery plaques are associated with coronary artery atherosclerotic lesions. We evaluated various ultrasound definitions of carotid artery plaque as predictors of future cardiovascular disease (CVD) and coronary heart disease (CHD) events. METHODS AND RESULTS: We studied the risk factors and ultrasound measurements of the carotid arteries at baseline of 6562 members (mean age 61.1 years; 52.6% women) of the Multi-Ethnic Study of Atherosclerosis (MESA). ICA lesions were defined subjectively as >0% or ≥25% diameter narrowing, as continuous intima-media thickness (IMT) measurements (maximum IMT or the mean of the maximum IMT of 6 images) and using a 1.5-mm IMT cut point. Multivariable Cox proportional hazards models were used to estimate hazard ratios for incident CVD, CHD, and stroke. Harrell's C-statistics, Net Reclassification Improvement, and Integrated Discrimination Improvement were used to evaluate the incremental predictive value of plaque metrics. At 7.8-year mean follow-up, all plaque metrics significantly predicted CVD events (n=515) when added to Framingham risk factors. All except 1 metric improved the prediction of CHD (by C-statistic, Net Reclassification Improvement, and Integrated Discrimination Improvement. Mean of the maximum IMT had the highest NRI (7.0%; P=0.0003) with risk ratio of 1.43/mm; 95% CI 1.26-1.63) followed by maximum IMT with an NRI of 6.8% and risk ratio of 1.27 (95% CI 1.18-1.38). CONCLUSION: Ultrasound-derived plaque metrics independently predict cardiovascular events in our cohort and improve risk prediction for CHD events when added to Framingham risk factors.

Genetic architecture of carotid artery intima-media thickness in Mexican Americans.

BACKGROUND- Intima-media thickness (IMT) of the common and internal carotid arteries is an established surrogate for atherosclerosis and predicts risk of stroke and myocardial infarction. Often IMT is measured as the average of these 2 arteries; yet, they are believed to result from separate biological mechanisms. The aim of this study was to conduct a family-based genome-wide association study (GWAS) for IMT to identify polymorphisms influencing IMT and to determine if distinct carotid artery segments are influenced by different genetic components. METHODS AND RESULTS- IMT for the common and internal carotid arteries was determined through B-mode ultrasound in 772 Mexican Americans from the San Antonio Family Heart Study. A GWAS using 931219 single-nucleotide polymorphisms was undertaken with 6 internal and common carotid artery IMT phenotypes using an additive measured genotype model. The most robust association detected was for 2 single-nucleotide polymorphisms (rs16983261, rs6113474; P=1.60e(-7)) in complete linkage disequilibrium on chromosome 20p11 for the internal carotid artery near wall, next to the gene PAX1. We also replicated previously reported GWAS regions on chromosomes 19q13 and 7q22. We found no overlapping associations between internal and common carotid artery phenotypes at P<5.0e(-6). The genetic correlation between the 2 carotid IMT arterial segments was 0.51. CONCLUSIONS- This study represents the first large-scale GWAS of carotid IMT in a non-European population and identified several novel loci. We do not detect any shared GWAS signals between common and internal carotid arterial segments, but the moderate genetic correlation implies both common and unique genetic components.

Carotid artery plaque and progression of coronary artery calcium: the multi-ethnic study of atherosclerosis.

BACKGROUND: Carotid and coronary atherosclerosis are associated with each other in imaging and autopsy studies. The aim of this study was to evaluate whether carotid artery plaque seen on carotid ultrasound can predict incident coronary artery calcification (CAC). METHODS: Agatston calcium score measurements were repeated in 5,445 participants of the Multi-Ethnic Study of Atherosclerosis (MESA; mean age, 57.9 years; 62.9% women). Internal carotid artery lesions were graded as 0%, 1% to 24%, or >25% diameter narrowing, and intima-media thickness (IMT) was measured. Plaque was present for any stenosis >0%. CAC progression was evaluated with multivariate relative risk regression for CAC scores of 0 at baseline and with multivariate linear regression for CAC score > 0, adjusting for cardiovascular risk factors, body mass index, ethnicity, and common carotid IMT. RESULTS: CAC was positive at baseline in 2,708 of 5,445 participants (49.7%) and became positive in 458 of 2,837 (16.1%) at a mean interval of 2.4 years between repeat examinations. Plaque and internal carotid artery IMT were both strongly associated with the presence of CAC. After statistical adjustment, the presence of carotid artery plaque significantly predicted incident CAC with a relative risk of 1.37 (95% confidence interval, 1.12-1.67). Incident CAC was associated with internal carotid artery IMT, with a relative risk of 1.13 (95% confidence interval, 1.03-1.25) for each 1-mm increase. Progression of CAC was also significantly associated (P < .001) with plaque and internal carotid artery IMT. CONCLUSIONS: In individuals free of cardiovascular disease, subjective and quantitative measures of carotid artery plaques by ultrasound imaging are associated with CAC incidence and progression.

Changes in carotid intima-media thickness during the cardiac cycle: the multi-ethnic study of atherosclerosis.

BACKGROUND: Common carotid artery intima-media thickness (IMT), a measure of subclinical cardiovascular disease, changes during the cardiac cycle. The magnitude of this effect and its implications have not been well studied. METHODS AND RESULTS: Far-wall IMT measurements of the right common carotid artery were measured at end diastole and peak systole in 5633 individuals from the Multi-Ethnic Study of Atherosclerosis (MESA). Multivariable regression models were generated with end-diastolic IMT, peak-systolic IMT, and change in IMT during the cardiac cycle as dependent variables and traditional cardiovascular risk factors as independent variables. The average age of our population was 61.9 (45 to 84) years. Average change in carotid IMT during the cardiac cycle was 0.041 mm (95% confidence interval: 0.039 to 0.042 mm), with a mean IMT of 0.68 mm. End-diastolic IMT and peak-systolic IMT were similarly associated with risk factors. In a fully adjusted model, change in carotid IMT during the cardiac cycle was associated with ethnicity and pulse pressure (P=0.001) and not age, sex, or other risk factors. Chinese and Hispanics had less of a change in IMT than did non-Hispanic whites. With peak-systolic IMT reference values used as normative data, 31.3% more individuals were classified as being in the upper quartile of IMT and at high risk for cardiovascular disease than would be expected when IMT is measured at end diastole. CONCLUSIONS: Measurable differences in IMT are seen during the cardiac cycle. This affects the interpretation of IMT measurements used for cardiovascular risk assessment, given published normative data with IMT measured at peak systole. CLINICAL TRIAL REGISTRATION: URL: www.ClinicalTrials.gov. Unique identifier: NCT00063440. (J Am Heart Assoc. 2012;1:e001420 doi: 10.1161/JAHA.112.001420.).

Prospective study of particulate air pollution exposures, subclinical atherosclerosis, and clinical cardiovascular disease: The Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air).

The Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air) was initiated in 2004 to investigate the relation between individual-level estimates of long-term air pollution exposure and the progression of subclinical atherosclerosis and the incidence of cardiovascular disease (CVD). MESA Air builds on a multicenter, community-based US study of CVD, supplementing that study with additional participants, outcome measurements, and state-of-the-art air pollution exposure assessments of fine particulate matter, oxides of nitrogen, and black carbon. More than 7,000 participants aged 45-84 years are being followed for over 10 years for the identification and characterization of CVD events, including acute myocardial infarction and other coronary artery disease, stroke, peripheral artery disease, and congestive heart failure; cardiac procedures; and mortality. Subcohorts undergo baseline and follow-up measurements of coronary artery calcium using computed tomography and carotid artery intima-medial wall thickness using ultrasonography. This cohort provides vast exposure heterogeneity in ranges currently experienced and permitted in most developed nations, and the air monitoring and modeling methods employed will provide individual estimates of exposure that incorporate residence-specific infiltration characteristics and participant-specific time-activity patterns. The overarching study aim is to understand and reduce uncertainty in health effect estimation regarding long-term exposure to air pollution and CVD.