The purpose of this study was to assess coronary arterial remodeling as a marker of subclinical atherosclerosis using coronary wall MRI in an asymptomatic population-based cohort.
In early atherosclerosis, compensatory enlargement of both the outer wall of the vessel as well as the lumen, termed compensatory enlargement or positive remodeling, occurs before luminal narrowing.
179 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) were evaluated using black-blood coronary wall MRI. Coronary cross-sectional area (vessel size), lumen area, and mean wall thickness of the proximal coronary arteries were measured.
Men had a greater vessel size, lumen area, and mean wall thickness than women (38.3±11.3 versus 32.6±9.4 mm2, 6.7±3.2 versus 5.3±2.4 mm2, and 2.0±0.3 versus 1.9±0.3 mm, respectively, p<0.05). No significant coronary artery narrowing was present by magnetic resonance angiography. Overall, coronary vessel size increased 25.9 mm2 per millimeter increase in coronary wall thickness, while lumen area increased only slightly at 3.1 mm2 for every millimeter increase in wall thickness (difference in slopes, p<0.0001). Adjusting for age and gender, participants with Agatston score greater than zero were more likely to have wall thickness greater than 2.0 mm (odds ratio 2.0, 95% CI 1.01–3.84).
Coronary wall MRI detected positive arterial remodeling, in asymptomatic men and women with subclinical atherosclerosis.
subclinical atherosclerosis; magnetic resonance imaging; coronary artery disease; plaque
To test the hypothesis that A1C is associated with subclinical cardiovascular disease (CVD) in a population without evident diabetes, after adjusting for traditional CVD risk factors and BMI.
RESEARCH DESIGN AND METHODS
This was a cross-sectional study of 5,121 participants without clinically evident CVD or diabetes (fasting glucose ≥7.0 mmol/l or use of diabetes medication), aged 47–86 years, enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA). Measurements included carotid intimal-medial wall thickness (CIMT) and coronary artery calcification (CAC). Results were adjusted for age, sex, ethnicity, smoking, systolic blood pressure, LDL cholesterol, HDL cholesterol, antihypertensive medication use, lipid-lowering medication use, and BMI.
Compared with those in the lowest quartile for A1C ([mean ± SD] 5.0 ± 0.2%), participants in the highest quartile (6.0 ± 0.3%) had higher adjusted mean values for common CIMT (0.85 vs. 0.87 mm, P = 0.003) and internal CIMT (1.01 vs. 1.08 mm, P = 0.003). A1C quartile was not associated with prevalence of CAC in the entire cohort (P = 0.27); however, the association was statistically significant in women (adjusted prevalence of CAC in lowest and highest A1C quartiles 37.5 vs. 43.0%, P = 0.01). Among those with some CAC, higher A1C quartile tended to be associated with higher CAC score, but the results were not statistically significant (adjusted P = 0.11).
In this multiethnic cohort, there were small, positive associations between A1C, common CIMT, and internal CIMT in the absence of clinically evident diabetes. An association between higher A1C and CAC prevalence was evident only in women.
Coronary artery wall magnetic resonance imaging (MRI) has been developed to assess coronary lumen diameter and wall thickness. The purpose of this study was to evaluate the physiological parameters that affect the measures of coronary wall thickness using black-blood MRI pulse sequences.
Eighty-seven participants (38 men and 49 women) of the Multi-Ethnic Study of Atherosclerosis were enrolled in the coronary artery wall MRI study. Cine 4-chamber imaging was used to determine the coronary artery rest period. Free-breathing whole-heart magnetic resonance angiography with motion adaptor navigator was performed to localize the coronary arteries in 64 participants. Cross-sectional free-breathing black-blood images were acquired using electrocardiogram-gated, turbo spin echo sequence. Imaging parameters were as follows: repetition time = 2 R-R intervals, time to echo = 33 milliseconds, echo train length = 13, bandwidth = 305 Hz/pixel, matrix = 416 × 416, field of view = 420 × 420 mm, and slice thickness = 4 to 5 mm.
Imaging was completed in 215 (92%) of 234 coronary segments; 9 participants had incomplete scans. Mean age was 62.6 ± 8.4 years (range, 45–81 years). Mean body mass index was 29.2 ± 5.9 kg/m2. A higher proportion of images with quality of “good” was seen in the right coronary artery (40.5%) compared to the left main and left anterior descending coronary arteries (31.9% and 26.4%, respectively). There was a very good agreement between observers in the image quality scores (κ = 0.79, P < 0.001). Lower heart rate, male sex, and longer coronary rest period were associated with higher image quality score (P < 0.05). Signal-to-noise ratio was higher in participants with Agatston calcium score of more than 10 in the right coronary and left main arteries (48.5 vs 69.7, P = 0.001; and 53.4 vs 61.6, P = 0.032, respectively).
Improved depiction of the coronary artery wall with MRI is related to coronary rest period and atherosclerotic plaque burden as measured by calcium score and inversely related to heart rate. Because longer coronary artery rest periods are associated with improved image quality both for angiography with MRI and coronary artery wall imaging, heart rate–lowering methods in association with these techniques appear to be a logical application.
coronary; magnetic resonance imaging; image quality; MRI; cardiac
While metabolic syndrome (MetS) and diabetes confer greater cardiovascular disease (CVD) risk, recent evidence suggests that individuals with these conditions have a wide range of risk. We evaluated whether screening for coronary artery calcium (CAC) and carotid intimal-medial thickness (CIMT) can improve CVD risk stratification over traditional risk factors (RFs) in people with MetS and diabetes.
RESEARCH DESIGN AND METHODS
We assessed CAC and CIMT in 6,603 people aged 45–84 years in the Multi-Ethnic Study of Atherosclerosis (MESA). Cox regression examined the association of CAC and CIMT with coronary heart disease (CHD) and CVD over 6.4 years in MetS and diabetes.
Of the subjects, 1,686 (25%) had MetS but no diabetes and 881 (13%) had diabetes. Annual CHD event rates were 1.0% among MetS and 1.5% for diabetes. Ethnicity and RF-adjusted hazard ratios for CHD for CAC 1–99 to ≥400 vs. 0 in subjects with neither MetS nor diabetes ranged from 2.6 to 9.5; in those with MetS, they ranged from 3.9 to 11.9; and in those with diabetes, they ranged from 2.9 to 6.2 (all P < 0.05 to P < 0.001). Findings were similar for CVD. CAC increased the C-statistic for events (P < 0.001) over RFs and CIMT in each group while CIMT added negligibly to prediction over RFs.
Individuals with MetS or diabetes have low risks for CHD when CAC or CIMT is not increased. Prediction of CHD and CVD events is improved by CAC more than by CIMT. Screening for CAC or CIMT can stratify risk in people with MetS and diabetes and support the latest recommendations regarding CAC screening in those with diabetes.
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
Coronary artery calcium (CAC) and carotid intima-media thickness (IMT) are noninvasive measures of atherosclerosis that consensus panels have recommended as possible additions to risk factor assessment for predicting the probability of cardiovascular disease (CVD) occurrence.
To assess whether maximum carotid IMT or CAC (Agatston Score) is the better predictor of incident CVD.
Design, Setting, Patients
Prospective cohort study of 45–84 year-olds initially free of CVD (n = 6,698) in four ethnic groups, with standardized carotid IMT and CAC measures at baseline, in six field centers of the Multi-Ethnic Study of Atherosclerosis (MESA).
Main Outcome Measure(s)
Incident CVD events (coronary heart disease, stroke, and fatal CVD) over a maximum of 5.3 years of follow-up.
There were 222 CVD events during follow-up. CAC was associated more strongly than carotid IMT with risk of incident CVD. After adjustment for each other and traditional CVD risk factors, the hazard of CVD increased 2.1-fold (95% CI 1.8–2.5) for each standard deviation greater level of log-transformed CAC, versus 1.3-fold (95% CI 1.1–1.4) for each standard deviation greater maximum IMT. For coronary heart disease, the hazard ratios per standard deviation increment were 2.5-fold (95% CI 2.1–3.1) for CAC and 1.2-fold (95% CI 1.0–1.4) for IMT. An ROC analysis also suggested that CAC predicted incident CVD better than IMT did.
Although whether and how to clinically use bio-imaging tests of subclinical atherosclerosis remains a topic of debate, this study found that CAC predicts subsequent CVD events better than does carotid IMT.
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
Modern imaging technology allows us the visualization of coronary artery calcification (CAC), a marker of subclinical coronary atherosclerosis. The prevalence, quantity, and risk factors for CAC were compared between two studies with similar imaging protocols but different source populations: the Multi-Ethnic Study of Atherosclerosis (MESA) and the Heinz Nixdorf Recall Study (HNR).
Methods and results
The measured CAC in 2220 MESA participants were compared with those in 3126 HNR participants with the inclusion criteria such as age 45–75 years, Caucasian race, and free of baseline cardiovascular disease. Despite similar mean levels of CAC of 244.6 among participants in MESA and of 240.3 in HNR (P = 0.91), the prevalence of CAC > 0 was lower in MESA (52.6%) compared with HNR (67.0%) with a prevalence rate ratio of CAC > 0 of 0.78 [95% confidence interval (CI): 0.72–0.85] after adjustment for known risk factors. Consequently, among participants with CAC > 0, the participants in MESA tended to have higher levels of CAC than those in HNR (ratio of CAC levels: 1.39; 95% CI: 1.19–1.63), since many HNR participants have small (near zero) CAC values.
The CAC prevalence was lower in the United States (MESA) cohort than in the German (HNR) cohort, which may be explained by more favourable risk factor levels among the MESA participants. The predictors for increased levels of CAC were, however, similar in both cohorts with the exception that male gender, blood pressure, and body mass index were more strongly associated in the HNR cohort.
Epidemiology; Atherosclerosis; Coronary artery calcium; Risk factors; Screening
Coronary wall cardiovascular magnetic resonance (CMR) is a promising noninvasive approach to assess subclinical atherosclerosis, but data are limited in subjects over 60 years old, who are at increased risk. The purpose of the study was to evaluate coronary wall CMR in an asymptomatic older cohort.
Cross-sectional images of the proximal right coronary artery (RCA) were acquired using spiral black-blood coronary CMR (0.7 mm resolution) in 223 older, community-based patients without a history of cardiovascular disease (age 60-72 years old, 38% female). Coronary measurements (total vessel area, lumen area, wall area, and wall thickness) had small intra- and inter-observer variabilities (r = 0.93~0.99, all p < 0.0001), though one-third of these older subjects had suboptimal image quality. Increased coronary wall thickness correlated with increased coronary vessel area (p < 0.0001), consistent with positive remodeling. On multivariate analysis, type 2 diabetes was the only risk factor associated with increased coronary wall area and thickness (p = 0.03 and p = 0.007, respectively). Coronary wall CMR measures were also associated with coronary calcification (p = 0.01-0.03).
Right coronary wall CMR in asymptomatic older subjects showed increased coronary atherosclerosis in subjects with type 2 diabetes as well as coronary calcification. Coronary wall CMR may contribute to the noninvasive assessment of subclinical coronary atherosclerosis in older, at-risk patient groups.
The purpose of this study was to evaluate the relationship of left ventricular mass and geometry measured with cardiac MRI to incident cardiovascular events in the Multi-Ethnic Study of Atherosclerosis (MESA) study.
MRI is highly accurate for evaluation of heart size and structure and has not previously been used in a large epidemiologic study to predict cardiovascular events.
5098 participants in the MESA study underwent cardiac MRI at the baseline examination and were followed for a median of 4 years. Cox proportional hazard models were constructed to predict the endpoints of coronary heart disease (CHD), stroke and heart failure (HF) after adjustment for cardiovascular risk factors.
216 incident events were observed during the follow-up period. In adjusted models, the endpoints of incident CHD and stroke were positively associated with increased left ventricular mass to volume ratio (coronary heart disease, hazard ratio 2.1 per g/ml, p = 0.02; stroke, hazard ratio 4.2 per g/ml, p =0.005). In contrast, left ventricular mass showed the strongest association with incident HF events (hazard ratio 1.4 per 10% increment, p < 0.0001). HF events occurred primarily in participants with left ventricular hypertrophy, i.e.,≥ 95th percentile of left ventricular mass (hazard ratio 8.6, confidence interval, 3.7 – 19.9, reference group <50th percentile of LV mass).
Left ventricular size was related to incident HF, stroke and CHD in this multi-ethnic cohort. While body-size adjusted left ventricular mass alone predicted incident HF, concentric ventricular remodeling predicted incident stroke and CHD.
Heart failure; stroke; coronary heart disease; epidemiology; magnetic resonance imaging; left ventricular hypertrophy
It has been proposed that coronary artery calcium (CAC) can be used to estimate an arterial age in adults. Supporting this concept is that chronologic age, as used in cardiovascular risk assessment, is a surrogate for atherosclerotic burden. This measure can provide the patient with a more understandable version of their CAC score (e.g. you are 55 years old, but your arteries are more consistent with an arterial age of 65). We describe a method of estimating arterial age by equating estimated coronary heart disease (CHD) risk for observed age and coronary artery calcium (CAC). Arterial age is then the risk-equivalent of coronary artery calcium. We use data from the Multi-Ethnic Study of Atherosclerosis (MESA), a cohort study of 6814 participants free of clinical cardiovascular disease, followed for an average of 4 years. Estimated arterial age is obtained as a simple linear function of log-transformed CAC. In a model for incident CHD risk controlling for both age and arterial age, only arterial age was significant, indicating that observed age does not provide additional information after controlling for arterial age. Framingham risk calculated using this arterial age is more predictive of short-term incident coronary events than Framingham risk based on observed age (area under the ROC curve 0.75 for Framingham risk based on observed age, 0.79 using arterial age, p=0.006). In conclusion, arterial age provides a convenient transformation of CAC from Agatston units to a scale more easily appreciated by both patients and treating physicians.
Elevated coronary artery calcium (CAC) is a marker for increase risk of coronary heart disease (CHD). While the majority of CHD events occur among individuals with advanced CAC, CHD can also occur in individuals with little or no calcified plaque. In this study, we sought to evaluate the characteristics associated with incident CHD events in the setting of minimal (score ≤10) or absent CAC (score of zero).
Asymptomatic participants in the Multi-Ethnic Study of Atherosclerosis (MESA) (N=6,809), were followed for occurrence of all CHD events (including myocardial infarction(MI), angina, resuscitated cardiac arrest, or CHD death) and hard CHD events (MI or CHD death). Time to incident CHD was modeled using age-and gender-adjusted Cox regression.
The final study population consisted of 3,923 MESA asymptomatic participants (mean age: 58±9years,39% males) had with CAC scores of 0-10. Overall no detectable CAC was seen in 3415 individuals, whereas 508 had CAC scores of 1-10. During follow up (median 4.1 years) there were 16 incident hard events, and 28 all CHD events in individuals with absent or minimal CAC. In age, gender, race and CHD risk factors adjusted analysis, minimal CAC (1-10) was associated with an estimated 3-fold greater risk of a hard CHD event (HR: 3.23, 95% CI: 1.17-8.95), or of all CHD event (HR: 3.66, 95% CI 1.71-7.85) compared to those with CAC=0. Former smoking (HR=3.57; 1.08-11.77), current smoking (HR=4.93; 1.20-20.30), and diabetes (HR=3.09; 1.07-8.93) were significant risk factors for events in those with CAC=0.
Asymptomatic persons with absent or minimal CAC are at very low risk of future cardiovascular events. Individuals with minimal CAC (1-10) were significantly increased to three fold increased risk for incident CHD events relative to those with CAC scores of zero.
Computed Tomography; Prognosis; Coronary Artery Calcification; Atherosclerosis; Coronary Calcium Score; Cardiac Events
Isolated minor non-specific ST-segment and T-wave (NSSTA), minor and major electrocardiographic (ECG) abnormalities are established, independent risk markers for incident cardiovascular events. Their association with subclinical atherosclerosis has been postulated but is not clearly defined. The aim of this study is to define the association between ECG abnormalities and measures of subclinical atherosclerosis. We studied participants from MESA, a multi-ethnic sample of men and women aged 45–84 and free of clinical cardiovascular disease at enrollment. Baseline examination included measurement of traditional risk factors, resting 12-lead electrocardiograms, coronary artery calcium (CAC) measurement and common carotid intima-media thickness (CCIMT). Electrocardiograms were coded using Novacode criteria and were defined as having either minor abnormalities (e.g., minor non-specific STTA, first degree atrioventricular block, and QRS axis deviations) or major abnormalities (e.g., pathologic Q waves, major ST-segment and T-wave abnormalities, significant dysrhythmias and conduction system delays). Multivariable logistic and linear regressions were used to determine the cross-sectional associations of ECG abnormalities with CAC and common carotid-IMT. Among 6710 participants, 52.7% were women, with a mean age of 62 years. After multivariable-adjustment, isolated minor STTA, minor and major ECG abnormalities were not associated with the presence of CAC (>0) among men (OR 1.04, 95% CI 0.81–1.33; 1.10, 0.91–1.32; and 1.03, 0.81–1.31, respectively) or women (1.01, 0.82–1.24; 1.04, 0.87–1.23; and 0.94, 0.73–1.22, respectively). Lack of association remained consistent when using both log CAC and CC-IMT as continuous variables. ECG abnormalities are not associated with markers of subclinical atherosclerosis in a large multi-ethnic cohort.
To determine the relationship between aortic wall thickness (WT) and distensibility with traditional cardiovascular risk factors in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort; 1053 participants of the MESA study with cardiac MRI were consecutively selected for measurement of aortic wall thickness and distensibility. Double inversion recovery fast spin echo images of the thoracic aorta were obtained to measure average and maximum WT. Aortic distensibility (AD) was measured at the same level using a gradient echo cine sequence. Both average and maximum WT were positively correlated with increasing age, and AD was inversely related to age (p<0.01). Compared to normotensive participants, those with hypertension had significantly greater mean average WT (2.45 mm vs. 2.23 mm, p<0.01), maximum WT (3.61 mm vs. 3.41 mm, p<0.01) and lower AD (0.15 vs. 0.2 mm Hg−1, p<0.01), respectively. In multiple regression analysis, older age and hypertension were significantly associated with higher mean average WT, while older age, male gender, and higher blood pressure were associated with higher mean maximum WT. AD was inversely related to older age, hypertension, current smoker status, African-American ethnicity and lower HDL-cholesterol (HDL-c) levels. In conclusion, in the MESA cohort, older age and higher blood pressure were associated with higher aortic wall thickness and lower aortic distensibilility. Decreased aortic distensibility was further associated with current smoking, African American ethnicity and higher HDL-c levels.
We compared the ability of separately measured intimal-medial thickness and atherosclerotic plaque to predict incident cardiovascular disease. American Indian men and women from the Strong Heart Study who were free of cardiovascular disease were evaluated with carotid ultrasound and cardiovascular disease risk factor assessment. End-diastolic intimal-medial thickness of the common carotid arteries was measured and averaged. Arterial mass (cross-sectional area) was calculated from intimal-medial thickness and end-diastolic diameter. Atherosclerosis was defined by focal plaque (discrete thickening >50% relative to the adjacent wall) and the number of carotid segments containing plaque (plaque score). 2441 participants (age 63±8 years) were followed for a mean of 7.7±2.8 years during which time 495 experienced incident cardiovascular disease events. Time to event analyses were performed in groups stratified according to diabetes and hypertension status. cardiovascular disease events were predicted by presence and extent of atherosclerosis in all groups; intimal-medial thickness and arterial mass were only associated with outcomes when neither hypertension nor diabetes were present. Unequivocal evidence of atherosclerosis (plaque) and its extent (plaque score) are independently associated with incident cardiovascular disease events in individuals without preexisting cardiovascular disease regardless of diabetes and hypertension status. Hypertension-related increases in IMT and arterial mass appear to limit their use as measures of early or diffuse atherosclerosis and hence association with cardiovascular disease outcomes. These findings support the utility of separate assessment of focal atherosclerosis and intimal-medial thickness in epidemiologic studies, trials, and risk stratification protocols.
carotid arteries; epidemiologic methods; cardiovascular disease prognosis
Circulating adiponectin has been associated with both clinical and subclinical cardiovascular disease (CVD). Variants of the adiponectin gene (ADIPOQ) are associated with clinical CVD, but little is known about associations with subclinical CVD. We studied the association of 11 ADIPOQ SNPs with common and internal carotid intima media thickness (cIMT), presence of coronary artery calcification (CAC), and CAC scores (in those with CAC) in 2847 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Participants were Caucasian (n=712), African-American (n=712), Chinese (n=718), and Hispanic (n=705). All models were adjusted for age, sex, and field site, and stratified by race/ethnic group. African-Americans with genotypes AG/GG of rs2241767 had 36% greater (95% CI (16%, 59%), p=0.0001) CAC prevalence; they also had a larger common cIMT (p=0.0043). Also in African-Americans, genotypes AG/AA of rs1063537 were associated with a 35% (95% CI (14%, 59%), p=0.0005) greater CAC prevalence. Hispanics with the AA genotype of rs11711353 had a 37% (95% CI (14%, 66%), p=0.0011), greater CAC prevalence compared to those with the GG genotype. Additional adjustment for ancestry in African-American and Hispanic participants did not change the results. No single SNP was associated with subclinical CVD phenotypes in Chinese or Caucasian participants. There appears to be an association between ADIPOQ SNPs and subclinical CVD in African-American and Hispanics. Replication as well as assessment of other ADIPOQ SNPs appears warranted.
Coronary artery calcium score (CACS) has been shown to predict future coronary heart disease (CHD) events. However, the extent to which adding CACS to traditional CHD risk factors improves classification of risk is unclear.
To determine whether adding CACS to a prediction model based on traditional risk factors improves classification of risk.
Design, Setting and Participants
CACS was measured by computed tomography on 6,814 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), a population-based cohort without known cardiovascular disease. Recruitment spanned July 2000 to September 2002; follow-up extended through May 2008. Participants with diabetes were excluded for the primary analysis. Five-year risk estimates for incident CHD were categorized as 0-<3%, 3-<10%, and ≥10% using Cox proportional hazards models. Model 1 used age, gender, tobacco use, systolic blood pressure, antihypertensive medication use, total and high-density lipoprotein cholesterol, and race/ethnicity. Model 2 used these risk factors plus CACS. We calculated the net reclassification improvement (NRI) and compared the distribution of risk using Model 2 versus Model 1.
Main Outcome Measures
Incident CHD events
Over 5.8 years median follow-up, 209 CHD events occurred, of which 122 were myocardial infarction, death from CHD, or resuscitated cardiac arrest. Model 2 resulted in significant improvements in risk prediction compared to Model 1 (NRI=0.25, 95% confidence interval 0.16-0.34, P<0.001). With Model 1, 69% of the cohort was classified in the highest or lowest risk categories, compared to 77% with Model 2. An additional 23% of those who experienced events were reclassified to high risk, and an additional 13% without events were reclassified to low risk using Model 2.
In the MESA cohort, addition of CACS to a prediction model based on traditional risk factors significantly improved the classification of risk and placed more individuals in the most extreme risk categories.
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
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
The MESA (Multi-Ethnic Study of Atherosclerosis) is an ongoing study of the prevalence, risk factors, and progression of subclinical cardiovascular disease in a multi-ethnic cohort. It provides a valuable opportunity to examine the development and progression of CAC (coronary artery calcium), which is an important risk factor for the development of coronary heart disease. In MESA, about half of the CAC scores are zero and the rest are continuously distributed. Such data has been referred to as “zero-inflated data” and may be described using two-part models. Existing two-part model studies have limitations in that they usually consider parametric models only, make the assumption of known forms of the covariate effects, and focus only on the estimation property of the models. In this article, we investigate statistical modeling of CAC in MESA. Building on existing studies, we focus on two-part models. We investigate both parametric and semiparametric, and both proportional and nonproportional models. For various models, we study their estimation as well as prediction properties. We show that, to fully describe the relationship between covariates and CAC development, the semiparametric model with nonproportional covariate effects is needed. In contrast, for the purpose of prediction, the parametric model with proportional covariate effects is sufficient. This study provides a statistical basis for describing the behaviors of CAC and insights into its biological mechanisms.
Cardiovascular disease (CVD) is an increasing cause of morbidity and mortality in HIV-infected patients. However, it is controversial whether HIV infection contributes to accelerated atherosclerosis independent of traditional CVD risk factors.
Cross-sectional study of HIV-infected and control subjects without pre-existing CVD from the study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) and the Multi-Ethnic Study of Atherosclerosis (MESA). Pre-clinical atherosclerosis was assessed by carotid intima-medial thickness (IMT) measurements in the internal/bulb and common regions in HIV-infected and control subjects after adjusting for traditional CVD risk factors.
For internal carotid, mean IMT was 1.17±0.50mm for HIV-infected participants and 1.06±0.58mm for controls (p<0.0001). After multivariable adjustment for demographic characteristics, the mean difference of HIV-infected vs. controls was +0.188mm (95%CI 0.113-0.263, p<0.0001). Further adjustment for traditional CVD risk factors modestly attenuated the HIV association (+0.148mm, 95%CI 0.072-0.224, p=0.0001). For the common carotid, HIV infection was independently associated with greater IMT (+0.033mm, 95%CI 0.010, 0.056, p=0.005). The association of HIV infection with IMT was similar to that of smoking which was also associated with greater IMT (internal +0.173mm, common +0.020mm).
Even after adjustment for traditional CVD risk factors, HIV infection was accompanied by more extensive atherosclerosis measured by IMT. The stronger association of HIV infection with IMT in the internal/bulb region compared to the common carotid may explain previous discrepancies in the literature. The association of HIV infection with IMT was similar to that of traditional CVD risk factors, such as smoking.
HIV; carotid IMT; smoking; cholesterol; diabetes; atherosclerosis
Extent of atherosclerosis measured by amount of coronary artery calcium (CAC) in computed tomography (CT) has been traditionally assessed using thresholded scoring methods, such as the Agatston score (AS). These thresholded scores have value in clinical prediction, but important information might exist below the threshold, which would have important advantages for understanding genetic, environmental, and other risk factors in atherosclerosis. We developed a semi-automated threshold-free scoring method, the spatially weighted calcium score (SWCS) for CAC in the Multi-Ethnic Study of Atherosclerosis (MESA).
Chest CT scans were obtained from 6814 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). The SWCS and the AS were calculated for each of the scans. Cox proportional hazards models and linear regression models were used to evaluate the associations of the scores with CHD events and CHD risk factors. CHD risk factors were summarized using a linear predictor.
Among all participants and participants with AS > 0, the SWCS and AS both showed similar strongly significant associations with CHD events (hazard ratios, 1.23 and 1.19 per doubling of SWCS and AS; 95% CI, 1.16 to 1.30 and 1.14 to 1.26) and CHD risk factors (slopes, 0.178 and 0.164; 95% CI, 0.162 to 0.195 and 0.149 to 0.179). Even among participants with AS = 0, an increase in the SWCS was still significantly associated with established CHD risk factors (slope, 0.181; 95% CI, 0.138 to 0.224). The SWCS appeared to be predictive of CHD events even in participants with AS = 0, though those events were rare as expected.
The SWCS provides a valid, continuous measure of CAC suitable for quantifying the extent of atherosclerosis without a threshold, which will be useful for examining novel genetic and environmental risk factors for atherosclerosis.
The Multi-Ethnic Study of Atherosclerosis (MESA) is a population-based study of 6,814 men and women. We sought to analyze the relationship between the extent of coronary calcium (CC) at baseline and the severity of coronary stenoses in clinically indicated coronary angiography studies during follow-up.
CC is an established predictor of major cardiovascular events. Yet, the relationship between CC and the distribution and severity of coronary artery stenoses has not been widely explored.
All MESA participants underwent non-contrast enhanced cardiac CT during enrollment to determine baseline CC. We analyzed 175 consecutive angiography reports from participants who underwent coronary catheterization for clinical indications during a median follow-up period of 18 months. The association between baseline CC and the severity of coronary stenosis detected in coronary angiographies was determined.
Baseline Agatston score was zero in only 7/175 (4%) MESA participants who underwent invasive angiography during follow-up. When coronary arteries were studied separately, 13–18% of coronary arteries with ≥75% stenosis had zero calcium mass scores at baseline. There was close association between baseline calcium mass score and the severity of stenosis in each of the coronary arteries (test for trend, p<0.001). As an example, mean calcium mass scores for <50, 50–74 and ≥75% stenosis in the left anterior descending coronary artery were 105.1 mg, 157.2 mg and 302.2 mg, respectively (p<0.001). Finally, there was a direct relationship between the total Agatston Score at baseline and the number of diseased vessels (test for trend, p<0.001)
The majority of patients with clinically indicated coronary angiography during follow up had detectable coronary calcification at baseline. While there is a significant relationship between the extent of calcification and mean degree of stenosis in individual coronary vessels, 16% of the coronary arteries with significant stenoses had no calcification at baseline.
To assess the importance of the obesity epidemic on cardiovascular disease (CVD) risk, we determined the prevalence of obesity and the relationship of obesity to CVD risk factors and subclinical vascular disease.
The Multi-Ethnic Study of Atherosclerosis is an observational cohort study involving 6814 persons aged 45 to 84 years who were free of clinical CVD at baseline (2000–2002). The study assessed the association between body size and CVD risk factors, medication use, and subclinical vascular disease (coronary artery calcium, carotid artery intimal medial thickness, and left ventricular mass).
A large proportion of white, African American, and Hispanic participants were overweight (60% to 85%) and obese (30% to 50%), while fewer Chinese American participants were overweight (33%) or obese (5%). Hypertension and diabetes were more prevalent in obese participants despite a much higher use of antihy-pertensive and/or antidiabetic medications. Obesity was associated with a greater risk of coronary artery calcium (17%), internal carotid artery intimal medial thickness greater than 80th percentile (32%), common carotid artery intimal medial thickness greater than 80th percentile (45%), and left ventricular mass greater than 80th percentile (2.7-fold greater) compared with normal body size. These associations persisted after adjustment for traditional CVD risk factors.
These data confirm the epidemic of obesity in most but not all racial and ethnic groups. The observed low prevalence of obesity in Chinese American participants indicates that high rates of obesity should not be considered inevitable. These findings may be viewed as indicators of potential future increases in vascular disease burden and health care costs associated with the obesity epidemic.
Coronary artery calcium (CAC), carotid intima-media thickness, and left ventricular (LV) mass and geometry offer the potential to characterize incident cardiovascular disease (CVD) risk in clinically asymptomatic individuals. The objective of the study was to compare these cardiovascular imaging measures for their overall and sex-specific ability to predict CVD.
Methods and Results
The study sample consisted of 4965 Multi-Ethnic Study of Atherosclerosis participants (48% men; mean age, 62±10 years). They were free of CVD at baseline and were followed for a median of 5.8 years. There were 297 CVD events, including 187 coronary heart disease (CHD) events, 65 strokes, and 91 heart failure (HF) events. CAC was most strongly associated with CHD (hazard ratio [HR], 2.3 per 1 SD; 95% CI, 1.9 to 2.8) and all CVD events (HR, 1.7; 95% CI, 1.5 to 1.9). Most strongly associated with stroke were LV mass (HR, 1.3; 95% CI, 1.1 to 1.7) and LV mass/volume ratio (HR, 1.3; 95% CI, 1.1 to 1.6). LV mass showed the strongest association with HF (HR, 1.8; 95% CI, 1.6 to 2.1). There were no significant interactions for imaging measures with sex and ethnicity for any CVD outcome. Compared with traditional risk factors alone, overall risk prediction (C statistic) for future CHD, HF, and all CVD was significantly improved by adding CAC, LV mass, and CAC, respectively (all P<0.05).
There was no evidence that imaging measures differed in association with incident CVD by sex. CAC was most strongly associated with CHD and CVD; LV mass and LV concentric remodeling best predicted stroke; and LV mass best predicted HF.
imaging; cardiovascular diseases; sex