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1.  Progression of coronary artery atherosclerosis in rheumatoid arthritis: comparison with participants from the Multi-Ethnic Study of Atherosclerosis 
Arthritis Research & Therapy  2013;15(5):R134.
Introduction
In cross-sectional studies, patients with rheumatoid arthritis (RA) have higher coronary artery calcium (CAC) than controls. However, their rate of progression of CAC and the predictors of CAC progression have heretofore remained unknown.
Methods
Incidence and progression of CAC were compared in 155 patients with RA and 835 control participants. The association of demographic characteristics, traditional cardiovascular risk factors, RA disease characteristics and selected inflammatory markers with incidence and progression of CAC were evaluated.
Results
The incidence rate of newly detected CAC was 8.2/100 person-years in RA and 7.3/100 person-years in non-RA control subjects [IRR 1.1 (0.7-1.8)]. RA patients who developed newly detectable CAC were older (59±7 vs. 55±6 years old, p=0.03), had higher triglyceride levels (137±86 vs. 97±60 mg/dL, p=0.03), and higher systolic blood pressure (129±17 vs. 117±15 mm Hg, p=0.01) compared to those who did not develop incident CAC. Differences in blood pressure and triglyceride levels remained significant after adjustment for age (p<=0.05). RA patients with any CAC at baseline had a median rate of yearly progression of 21 (7–62) compared to 21 (5–70) Agatston units in controls. No statistical differences between RA progressors and RA non-progressors were observed for inflammatory markers or for RA disease characteristics.
Conclusions
The incidence and progression of CAC did not differ between RA and non-RA participants. In patients with RA, incident CAC was associated with older age, higher triglyceride levels, and higher blood pressure, but not with inflammatory markers or RA disease characteristics.
doi:10.1186/ar4314
PMCID: PMC3978773  PMID: 24286380
2.  Effect of age on aortic atherosclerosis 
Objective
To examine the association of atherosclerosis burden in the survivors of an asymptomatic elderly cohort study and its relationship to other coronary risk factors (specifically, age) by evaluating aortic atherosclerotic wall burden by magnetic resonance imaging (MRI).
Methods
A total of 312 participants in an ongoing observational cohort study underwent cardiac and descending thoracic aorta imaging by MRI. Maximum wall thickness was measured and the mean wall thickness calculated. Wall/outer wall ratio was used as a normalized wall index (NWI) adjusted for artery size difference among participants. Percent wall volume (PWV) was calculated as NWI × 100.
Results
In this asymptomatic cohort (mean age: 76 years), the mean (SD) aortic wall area and wall thickness were 222 ± 45 mm2 and 2.7 ± 0.4 mm, respectively. Maximum wall thickness was 3.4 ± 0.6 mm, and PWV was 32% ± 4%. Women appeared to have smaller wall area, but after correcting for their smaller artery size, had significantly higher PWV than men (P = 0.03). Older age was associated with larger wall area (P = 0.04 for trend) with similar PWVs. However, there were no statistically significant associations between standard risk factors, Framingham global risk, or metabolic syndrome status, therapy for cholesterol or hypertension, coronary or aortic calcium score, and the aortic wall burden. Aortic calcification was associated with coronary calcification.
Conclusions
Asymptomatic elderly in this cohort had a greater descending thoracic aortic wall volume that correlated with age, and women had a significantly increased PWV compared to men. In these survivors, the atherosclerotic aortic wall burden was not significantly associated with traditional risk factors or with coronary or aortic calcium scores or coronary calcium progression. Results suggest that age, or as yet unidentified risk factor(s), may be responsible for the increase in atherosclerosis.
doi:10.3969/j.issn.1671-5411.2013.02.005
PMCID: PMC3708052  PMID: 23888172
Aging; Aortic atherosclerosis; Magnetic resonance imaging; Atherosclerotic risk factors
3.  Metabolic Syndrome, Diabetes, and Incidence and Progression of Coronary Calcium: The Multiethnic Study of Atherosclerosis (MESA) 
Jacc. Cardiovascular Imaging  2012;5(4):358-366.
Objectives
The purpose of the study was to examine and compare the incidence and progression of coronary artery calcium (CAC) among persons with metabolic syndrome (MetS) and diabetes mellitus (DM), compared to those with neither condition.
Background
MetS and DM are associated with subclinical atherosclerosis as evidenced by coronary artery calcium (CAC).
Methods
The Multiethnic Study of Atherosclerosis included 6,814 African-American, Asian, Caucasian, and Hispanic adults aged 45–84 free of cardiovascular disease at baseline. 5,662 subjects (51% female, mean age 61.0 ± 10.3 years) received baseline and follow-up (mean 2.4 years) cardiac CT scans. We compared the incidence of CAC in 2,927 subjects without CAC at baseline and progression of CAC in 2,735 subjects with CAC at baseline in those with MetS without DM (25.2%), DM without MetS (3.5%), or both DM and MetS (9.0%), compared to neither MetS nor DM (58%). Progression of CAC was also examined in relation to coronary heart disease events over an additional 4.9 years.
Results
Relative to those with neither MetS nor DM, adjusted relative risks (95% confidence intervals) for incident CAC were 1.7 (1.4–2.0), 1.9 (1.4–2.4), and 1.8 (1.4–2.2) (all p<0.01) and absolute differences in mean progression (volume score) were 7.8 (4.0–11.6; p<0.01), 11.6 (2.7–20.5; p<0.05), and 22.6 (17.2–27.9; p<0.01) for those with MetS without DM, DM without MetS, and both DM and MetS, respectively. Similar findings were seen in analysis using Agatston calcium score. In addition, progression predicted CHD events in those with MetS without DM (adjusted hazard ratio 4.1, 95% CI=2.0–8.5, p<0.01) and DM (4.9 [1.3–18.4], p<0.05) among those in highest tertile of CAC increase vs. no increase).
Conclusions
Individuals with MetS and DM have a greater incidence and absolute progression of CAC compared to individuals without these conditions, with progression also predicting CHD events in those with MetS and DM.
doi:10.1016/j.jcmg.2011.12.015
PMCID: PMC3327555  PMID: 22498324
atherosclerosis; diabetes; risk factors; calcification
4.  Abdominal Aortic Diameter and Vascular Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis 
Objectives
To gain insight into early mechanisms of aortic widening, we examined associations between the diameter of the abdominal aorta (AD) and cardiovascular disease (CVD) risk factors and biomarkers, as well as measures of subclinical atherosclerosis, in a multi-ethnic population.
Design
Cross-sectional cohort
Methods
A total of 1926 participants (mean age 62, 50% women) underwent chest and abdomen scanning by computed tomography, ultrasound of the carotid arteries, and CVD risk factor assessment. AD was measured 5 cm above and at the bifurcation.
Results
In a model containing traditional CVD risk factors, biomarkers and ethnicity, only age (standardized β=0.97), male sex (β=1.88), body surface area (standardized β=0.92), current smoking (β=0.42), D-dimer levels (β=0.19) and hypertension (β=0.53) were independently and significantly associated with increasing AD (in mm) at the bifurcation; use of cholesterol-lowering medications predicted smaller AD (β=-0.70) (P<.01 for all). These findings were similar for AD 5 cm above the bifurcation with one exception: compared to Caucasian-Americans, Americans of Chinese, African and Hispanic descent had significantly smaller AD 5 cm above the bifurcation (β's= -0.59, -0.49, and -0.52, respectively, all P<.01), whereas AD at the bifurcation did not differ by ethnicity. Physical activity, alcohol consumption, diabetes and levels of IL-6, CRP and homocysteine were not independently associated with AD. Higher aortic and coronary artery calcium burden, but not common carotid artery intima-media thickness, were independently, but modestly (β=0.11 to 0.19), associated with larger AD.
Conclusions
Incremental widening of the aortic diameter shared some, but not all, risk factors for occlusive vascular disease.
doi:10.1016/j.ejvs.2010.12.015
PMCID: PMC3070051  PMID: 21236707
aorta; aneurysm; atherosclerosis; ethnicity; epidemiology
5.  Fine Particulate Matter Air Pollution, Proximity to Traffic, and Aortic Atherosclerosis 
Epidemiology (Cambridge, Mass.)  2009;20(2):254-264.
Background
The initiation and acceleration of atherosclerosis is hypothesized as a physiologic mechanism underlying associations between air pollution and cardiovascular effects. Despite toxicologic evidence, epidemiologic data are limited.
Methods
In this cross-sectional analysis we investigated exposure to fine particulate matter (PM2.5) and residential proximity to major roads in relation to abdominal aortic calcification a sensitive indicator of systemic atherosclerosis. Aortic calcification was measured by computed tomography among 1147 persons, in 5 U.S. metropolitan areas, enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA). The presence and quantity of aortic calcification were modeled using relative risk regression and linear regression, respectively, with adjustment for potential confounders.
Results
We observed a slightly elevated risk of aortic calcification (RR = 1.06; 95% confidence interval = 0.96–1.16) with a 10-μg/m3 contrast in PM2.5. The PM2.5-associated risk of aortic calcification was stronger among participants with long-term residence near a PM2.5 monitor (RR = 1.11; 1.00–1.24) and among participants not recently employed outside the home (RR = 1.10; 1.00–1.22). PM2.5 was not associated with an increase in the quantity of aortic calcification (Agatston score) and no roadway proximity effects were noted. There was indication of PM2.5 effect modification by lipid-lowering medication use, with greater effects among users, and PM2.5 associations were observed most consistently among Hispanics.
Conclusions
Although we did not find persuasive associations across our full study population, associations were stronger among participants with less exposure misclassification. These findings support the hypothesis of a relationship between particulate air pollution and systemic atherosclerosis.
doi:10.1097/EDE.0b013e31819644cc
PMCID: PMC3292428  PMID: 19129730
6.  The association between non-subcutaneous adiposity and calcified coronary plaque: A substudy of the Multi-Ethnic Study of Atherosclerosis 
Background
Excessive non-subcutaneous fat deposition may impair the functions of surrounding tissues and organs through the release of inflammatory cytokines and free fatty acids.
Objective
We examined the cross-sectional association between non-subcutaneous adiposity and calcified coronary plaque, a non-invasive measure of coronary artery disease burden.
Design
Participants in the Multi-Ethnic Study of Atherosclerosis underwent CT assessment of calcified coronary plaque. We measured multiple fat depots in 398 white and black participants (47% men and 43% black), ages 47–86 years, from Forsyth County, NC during 2002–2005, using cardiac and abdominal CT scans. In addition to examining each depot separately, we also created a non-subcutaneous fat index using the standard scores of non-subcutaneous fat depots.
Results
A total of 219 participants (55%) were found to have calcified coronary plaque. After adjusting for demographics, lifestyle factors and height, calcified coronary plaque was associated with a one standard deviation increment in the non-subcutaneous fat index (OR = 1.41; 95% CI: 1.08, 1.84), pericardial fat (OR = 1.38; 95% CI: 1.04, 1.84), abdominal visceral fat (OR = 1.35; 95% CI: 1.03, 1.76), but not with fat content in the liver, intermuscular fat, or abdominal subcutaneous fat. The relation between non-subcutaneous fat index and calcified coronary plaque remained after further adjustment for abdominal subcutaneous fat (OR = 1.40; 95% CI: 1.00, 1.94). The relation did not differ by gender and ethnicity.
Conclusions
The overall burden of non-subcutaneous fat deposition, but not abdominal subcutaneous fat, may be a correlate of coronary atherosclerosis.
PMCID: PMC3282464  PMID: 18779279
7.  Abdominal Aortic Calcium and Multi-Site Atherosclerosis: The Multiethnic Study of Atherosclerosis 
Atherosclerosis  2011;214(2):436-441.
Background
Abdominal aortic calcification (AAC) is a measure of subclinical cardiovascular disease (CVD). Data are limited regarding its relation to other measures of atherosclerosis.
Methods
Among 1,812 subjects (49% female, 21% black, 14% Chinese, and 25% Hispanic) within the population-based Multiethnic Study of Atherosclerosis, we examined the cross-sectional relation of AAC with coronary artery calcium (CAC), ankle brachial index (ABI), and carotid intimal medial thickness (CIMT), as well as multiple measures of subclinical CVD.
Results
AAC prevalence ranged from 34% in those aged 45–54 to 94% in those aged 75–84 (p<0.0001), was highest in Caucasians (79%) and lowest in blacks (62%) (p<0.0001). CAC prevalence, mean maximum CIMT ≥ 1 mm, and ABI<0.9 was greater in those with vs. without AAC: CAC 60% vs 16%, CIMT 38% vs 7%, and ABI 5% vs 1% for women and CAC 80% vs 37%, CIMT 43% vs 16%, and ABI 4% vs 2% for men (p<0.01 for all except p<0.05 for ABI in men). The presence of multi-site atherosclerosis (≥ 3 of the above) ranged from 20% in women and 30% in men (p<0.001), was highest in Caucasians (28%) and lowest in Chinese (16%) and ranged from 5% in those aged 45–54 to 53% in those aged 75–84 (p<0.01 to p<0.001). Finally, increased AAC was associated with 2 to 3-fold relative risks for the presence of increased CIMT, low ABI, or CAC.
Conclusions
AAC is associated with an increased likelihood of other vascular atherosclerosis. Its additive prognostic value to these other measures is of further interest.
doi:10.1016/j.atherosclerosis.2010.09.011
PMCID: PMC3040451  PMID: 21035803
atherosclerosis; calcification; cardiovascular disease; epidemiology
8.  Subclinical atherosclerosis in northern and southern China: the Chinese paradox 
Background
The incidence of coronary heart disease (CHD) is higher in Northern than that in Southern China, however differences in traditional CHD risk factors do not fully explain this. No study has examined the differences in subclinical atherosclerosis that may help explain the differences in incidence. This study examined these differences in subclinical atherosclerosis using coronary computed tomography (CT) for calcification between the Northern and Southern China.
Methods
We selected a random sample of participants in a large multi-center ongoing epidemiologic study for coronary calcium scanning in one northern city (North) (Beijing, n = 49) and in two southern cities (South) (Shanghai, n = 50, and Guangzhou, n = 50). Participants from the three field centers (mean age 67 years) underwent coronary risk factor evaluation and cardiac CT scanning for coronary calcium measurement using the Multi-Ethnic Study of Atherosclerosis scanning protocol.
Results
Adjusted log-transformed coronary artery calcium score in North China (Beijing) was 3.1 ± 0.4 and in South China (Shanghai and Guangzhou) was 2.2 ± 0.3 (P = 0.04). Mean calcium score for the northern city of Beijing was three times higher than that of the southern city of Guangzhou (P = 0.01) and 2.5 times higher than for the southern city of Shanghai (P = 0.03).
Conclusions
The extent of subclinical atherosclerosis is significantly higher in the northern city of Beijing than that in the two southern cities of Guangzhou and Shanghai, even after adjusting for standard cardiac risk factors. This finding suggests that standard risk factors do not fully explain north south differences in clinical CHD incidence.
doi:10.3724/SP.J.1263.2011.00072
PMCID: PMC3390074  PMID: 22783288
coronary calcium; CT scanning; atherosclerosis; epidemiology; China
9.  Associations of Inflammatory Markers with Coronary Artery Calcification: Results from the Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2009;209(1):226-229.
Objective
Inflammatory markers predict coronary heart disease (CHD). However, associations with coronary artery calcium (CAC), a marker of subclinical CHD, are not established.
Methods
We examined cross-sectional associations of C-reactive protein (CRP), interleukin-6 (IL-6) and fibrinogen with CAC presence (Agatston score > 0 by computed tomography) in 6,783 Multi-Ethnic Study of Atherosclerosis (MESA) participants.
Results
In all participants, those in the highest, compared to lowest, quartile of CRP had a relative risk (RR, 95% confidence interval) of 1.13 (1.06-1.19; p<0.01) for CAC in age, sex and ethnicity adjusted models. For highest versus lowest quartiles, relative risks were 1.22 (1.15-1.30; p<0.01) for IL-6 and 1.18 (1.11-1.24; p<0.01) for fibrinogen. Adjusting for CHD risk factors (smoking, diabetes, blood pressure, obesity and dyslipidemia) attenuated RRs. RRs for CAC were 1.05 (0.99-1.12; p=0.63) for CRP, 1.12 (1.06-1.20; p<0.01) for IL-6 and 1.09 (1.02-1.16; p=0.01) for fibrinogen in multivariable adjusted models. Results were similar for men and women and across ethnic groups.
Conclusion
Inflammatory markers were weakly associated with CAC presence and burden in MESA. Our data support the hypothesis that inflammatory biomarkers and CAC reflect distinct pathophysiology.
doi:10.1016/j.atherosclerosis.2009.08.037
PMCID: PMC2830357  PMID: 19766217
Atherosclerosis; Calcium; Inflammation; Population
10.  Intensive Glucose-Lowering Therapy Reduces Cardiovascular Disease Events in Veterans Affairs Diabetes Trial Participants With Lower Calcified Coronary Atherosclerosis 
Diabetes  2009;58(11):2642-2648.
OBJECTIVE
This study investigated the hypothesis that baseline calcified coronary atherosclerosis may determine cardiovascular disease events in response to intensive glycemic control within the Veterans Affairs Diabetes Trial (VADT).
RESEARCH DESIGN AND METHODS
At baseline, 301 type 2 diabetic participants in the VADT, a randomized trial comparing the effects of intensive versus standard glucose lowering on cardiovascular events, had baseline coronary atherosclerosis assessed by coronary artery calcium (CAC) measured by computed tomography. Participants were followed over the 7.5-year study for development of cardiovascular end points.
RESULTS
During a median follow-up duration of 5.2 years, 89 cardiovascular events occurred. Although intensive glucose-lowering therapy did not significantly reduce cardiovascular events in the substudy cohort as a whole, there was evidence that the response was modified by baseline CAC, as indicated by significant P values for treatment by log(CAC + 1) interaction terms in unadjusted and multivariable-adjusted models (0.01 and 0.03, respectively). Multivariable-adjusted hazard ratios (HRs) for the effect of treatment indicated a progressive diminution of benefit with increasing CAC. Subgroup analyses were also conducted for clinically relevant CAC categories: those above and below an Agatston score of 100. Among those randomized to intensive treatment, for the subgroup with CAC >100, 11 of 62 individuals had events, while only 1 of 52 individuals with CAC ≤100 had an event. The multivariable HR for intensive treatment for those with CAC >100 was 0.74 (95% CI 0.46–1.20; P = 0.21), while for the subgroup with CAC ≤100, the corresponding HR was 0.08 (0.008–0.77; P = 0.03), with event rates of 39 and 4 per 1,000 person-years, respectively.
CONCLUSIONS
These data indicate that intensive glucose lowering reduces cardiovascular events in those with less extensive calcified coronary atherosclerosis.
doi:10.2337/db09-0618
PMCID: PMC2768182  PMID: 19651816
11.  Association of Electrocardiographic Abnormalities with Coronary Artery Calcium and Carotid Artery Intima-Media Thickness in Individuals without Clinical Coronary Heart Disease (From the Multi-Ethnic Study of Atherosclerosis [MESA]) 
The American journal of cardiology  2009;104(8):1086-1091.
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.
doi:10.1016/j.amjcard.2009.05.060
PMCID: PMC2871277  PMID: 19801030
12.  Relationship between Baseline Coronary Calcium Score and Demonstration of Coronary Artery Stenoses During Follow up in the Multi-Ethnic Study of Atherosclerosis (MESA) 
JACC. Cardiovascular imaging  2009;2(10):1175-1183.
Objectives
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.
Background
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.
Methods
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.
Results
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)
Conclusion
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.
doi:10.1016/j.jcmg.2009.06.014
PMCID: PMC2803053  PMID: 19833306
13.  Reproducibility and validity of lung density measures from cardiac CT scans – the Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study 
Academic radiology  2009;16(6):689-699.
Purpose
Cardiac CT scans for the assessment of coronary calcium scores include approximately 70% of the lung volume and may be useful for the quantitative assessment of emphysema. The reproducibility of lung density measures from cardiac CTs and their validity compared to lung density measures from full-lung scans is unknown.
Methods and Methods
The Multi-Ethnic Study of Atherosclerosis (MESA) performed paired cardiac CT scans for 6,814 participants at baseline and at follow-up. The MESA-Lung Study assessed lung density measures in the lung fields of these cardiac scans, counting voxels below -910 HU as moderate-to-severe emphysema-like lung regions. We evaluated: 1) the reproducibility of lung density measures among 120 randomly selected participants, 2) the comparability of measures acquired on electron-beam CT (EBT) and multidetector CT (MDCT) scanners among 10 participants; and 3) the validity of these measures compared to full-lung scans among 42 participants. Limits of agreement were determined using Bland-Altman approaches.
Results
Percent emphysema measures from paired cardiac scans were highly correlated (r=0.92-0.95) with mean difference of -0.05% (95% limits of agreement: -8.3, 8.4%). Measures from EBT and MDCT scanners were comparable (mean difference -0.9%; 95% limits of agreement: -5.1, 3.3%). Percent emphysema measures from MDCT cardiac and MDCT full-lung scans were highly correlated (r=0.93) and demonstrated reasonable agreement (mean difference 2.2%; 95% limits of agreement: -9.2, 13.8%).
Conclusion
While full-lung imaging is preferred for the quantification of emphysema, the lung imaging from paired cardiac CTs provided a reproducible and valid quantitative assessment of emphysema in a population-based sample.
doi:10.1016/j.acra.2008.12.024
PMCID: PMC2943871  PMID: 19427979
14.  Ethnic-Specific Risks for Atherosclerotic Calcification of the Thoracic and Abdominal Aorta (From the Multi-Ethnic Study of Atherosclerosis) 
The American journal of cardiology  2009;104(6):812-817.
The aims of this study were to 1) determine the association between ethnicity and both thoracic and abdominal aortic calcium (TAC and AAC) and 2) investigate associations between cardiovascular disease (CVD) risk factors and both TAC and AAC. Participants were 1,957 men and women enrolled in the Multi-Ethnic Study of Atherosclerosis who had computed tomography scans of both the chest and abdomen. These scans were obtained at the same clinic visit and calcium scores were computed using the Agatston method. Regression analyses were conducted using relative risk regression. The mean age was 65 years and 50% were female. Forty % were White, 26% Hispanic, 21% African American and 13% Chinese. Whites had the highest prevalence of AAC (80%), which was significantly higher than Hispanics (68%, p<0.001), African Americans (63%, p<0.001) and Chinese (74%, p=0.029). Similarly, Whites had the highest prevalence of TAC (42%), which was significantly higher than Hispanics (30%, p < 0.01) and African Americans (27%, p<0.001) but was not significantly different from that in Chinese (38%). Compared to Whites and after adjustment for age, sex, body mass index, hypertension, diabetes, dyslipidemia, smoking and family history of CVD, Hispanics and African Americans, but not Chinese Americans, had a significantly lower risk for the presence of any AAC or any TAC. In these models, diabetes, smoking and dyslipidemia had stronger associations with AAC while hypertension was stronger for TAC. In conclusion, compared to Whites, African-Americans and Hispanics, but not Chinese, have evidence of less atherosclerosis in both the thoracic and abdominal aorta which does not appear to be accounted for by traditional CVD risk factors.
doi:10.1016/j.amjcard.2009.05.004
PMCID: PMC2755558  PMID: 19733716
15.  Subclinical Atherosclerosis is Weakly Associated with Lower Cognitive Function in Healthy Hyperhomocysteinemic Adults without Clinical Cardiovascular Disease 
OBJECTIVE
Atherosclerosis is the most common pathologic process underlying cardiovascular disease (CVD). It is not well known whether subclinical atherosclerosis is an independent risk factor for lower cognitive function among individuals without clinically evident CVD.
METHODS
We examined cross-sectional associations between subclinical atherosclerosis and cognitive function in a community-based sample of otherwise healthy adults with plasma homocysteine ≥8.5 µmol/L enrolled in the BVAIT study (n=504, mean age 61 years). Carotid artery intima-media thickness (CIMT), coronary (CAC) and abdominal aortic calcium (AAC) were used to measure subclinical atherosclerosis. Cognitive function was assessed with a battery of neuropsychological tests. A principal components analysis was used to extract five uncorrelated cognitive factors from scores on individual tests, and a measure of global cognition was derived. Multivariable linear regression was used to examine the association between subclinical atherosclerosis and cognitive function, adjusting for other correlates of cognition.
RESULTS
Increasing thickness of CIMT was associated with significantly lower scores on the verbal learning factor (β = −0.07 per 0.1 mm increase CIMT [SE(β)=0.03], p=0.01). CAC and AAC were not individually associated with any of the cognitive factors.
CONCLUSIONS
This study provides evidence that increasing CIMT is weakly associated with lower verbal learning abilities but not global cognition in a population of otherwise healthy middle-to-older aged adults with elevated plasma homocysteine but without clinically evident CVD. The association between CIMT and poor verbal learning may pertain particularly to men.
doi:10.1002/gps.2134
PMCID: PMC2661006  PMID: 18836986
cognitive function; atherosclerosis; cardiovascular disease; memory; verbal learning
16.  High-Dose B-Vitamin Supplementation and Progression of Subclinical Atherosclerosis: A Randomized Controlled Trial 
Background and Purpose
Although plasma total homocysteine (tHcy) levels are associated with cardiovascular disease (CVD), it remains unclear whether homocysteine is a cause or a marker of atherosclerotic vascular disease. We determined whether reduction of tHcy levels with B-vitamin supplementation reduces subclinical atherosclerosis progression.
Methods
In this double-blind clinical trial, 506 participants 40–89 years of age with an initial tHcy >8.5 μmol/L without diabetes and CVD were randomized to high-dose B-vitamin supplementation (folic acid 5 mg + vitamin B12 0.4 mg + vitamin B6 50 mg) or matching placebo for 3.1 years. Subclinical atherosclerosis progression across 3 vascular beds was assessed using high-resolution B-mode ultrasonography to measure carotid artery intima-media thickness (primary outcome) and multidetector spiral computed tomography to measure aortic and coronary artery calcium (secondary outcome).
Results
Although the overall carotid artery intima-media thickness progression rate was lower with B-vitamin supplementation than with placebo, statistically significant between-group differences were not found (p=0.31). However, among subjects with baseline tHcy≥9.1 μmol/L, those randomized to B-vitamin supplementation had a statistically significant lower average rate of carotid artery intima-media thickness progression compared with placebo (p=0.02); among subjects with a baseline tHcy <9.1 μmol/L there was no significant treatment effect (p-value for treatment interaction=0.02). B-vitamin supplementation had no effect on progression of aortic or coronary artery calcification overall or within subgroups.
Conclusion
High-dose B-vitamin supplementation significantly reduces progression of early stage subclinical atherosclerosis (carotid artery intima-media thickness) in well-nourished healthy B-vitamin “replete” individuals at low-risk for CVD with a fasting tHcy >9.1 μmol/L.
doi:10.1161/STROKEAHA.108.526798
PMCID: PMC2701290  PMID: 19118243
Atherosclerosis; Computed tomography; Folate; Homocysteine; Intima-media thickness; Randomized controlled trials; Vitamin B12
17.  Coronary calcium predicts events better with absolute calcium scores than age-gender-race percentiles – The Multi-Ethnic Study of Atherosclerosis (MESA) 
Background
The presence and extent of coronary artery calcium (CAC) correlates with the overall magnitude of coronary atherosclerotic plaque burden and with the development of subsequent coronary events. In this study we aim to establish whether age-gender specific percentiles of CAC predict cardiovascular outcomes better than the actual (absolute) CAC score.
Methods
MESA is a prospective cohort study of asymptomatic 6814 participants, followed for coronary heart disease (CHD) events including myocardial infarction, angina, resuscitated cardiac arrest, or CHD death. Time to incident CHD was modeled using Cox regression, and we compared models using percentiles based on age, gender and/or race/ethnicity to categories commonly used(0, 1-100, 101-400, 400+ Agatston units).
Results
There were 163(2.4%) incident CHD events (median follow-up 3.75 years). Expressing CAC in terms of age and gender specific percentiles had significantly lower area under the ROC curve(AUC) than using absolute scores (women: AUC 0.73 versus 0.76,p=0.044; men: AUC 0.73 versus 0.77,p<0.001). Akaike’s information criterion (AIC) indicated better model fit using the overall score. Both methods robustly predicted events(>90th percentile associated with a hazard ratio(HR) of 16.4(95% c.i. 9.30,28.9), and score >400 associated with HR of 20.6(95% c.i. 11.8, 36.0). Within groups based on age/gender/race/ethnicity specific percentiles there remains a clear trend of increasing risk across levels of the absolute CAC groups. In contrast, once absolute CAC category is fixed, there is no increasing trend across levels of age/gender/race/ethnicity specific categories. Patients with low absolute scores are low risk, regardless of age-gender-ethnicity percentile rank. Persons with an absolute CAC score of >400 are high risk, regardless of percentile rank.
Conclusion
Using absolute CAC in standard groups performed better than age-gender-ethnicity percentiles in terms of model fit and discrimination. We recommend using cut-points based on the absolute CAC amount and the common CAC cutpoints of 100 and 400 appear to perform well.
doi:10.1016/j.jacc.2008.07.072
PMCID: PMC2652569  PMID: 19161884
prognosis; atherosclerosis; cardiac CT; coronary calcium
18.  Relation of Framingham Risk Score to Subclinical Atherosclerosis Evaluated Across Three Arterial Sites 
The American journal of cardiology  2008;102(7):825-830.
The Framingham risk score (FRS) is widely used in clinical practice to identify subjects at high risk for developing coronary heart disease (CHD). However, FRS may not accurately identify subjects at risk. We measured subclinical atherosclerosis in the coronary arteries and aorta with the presence of calcium (CAC and AC, respectively) and in the common carotid artery by intima-media thickness (CIMT) in 498 healthy subjects. The distribution of these subclinical atherosclerosis measures was evaluated across 3 strata of the FRS. CAC, AC and CIMT were significantly independently associated with FRS. The FRS increased with the number of arterial sites with atherosclerosis. Sixty-nine percent of the subjects categorized in the low risk group (FRS<10%), 95% of the intermediate risk group (FRS 10–20%), and 100% of the high risk group (FRS>20%) had 1 or more vascular imaging studies demonstrating subclinical atherosclerosis. Among the low risk group, subjects with atherosclerosis had a longer history of lifetime smoking compared to those without atherosclerosis. In conclusion, subclinical atherosclerosis is prominent across the spectrum of FRS. Evaluation of subclinical atherosclerosis in different arterial sites in addition to FRS may be useful in targeting subjects for lifestyle and other interventions.
doi:10.1016/j.amjcard.2008.05.039
PMCID: PMC2648859  PMID: 18805105
Subclinical atherosclerosis; Framingham risk score; Carotid IMT; Coronary artery calcium; Aortic calcium
19.  The Effect of Intensive Glycemic Treatment on Coronary Artery Calcification in Type 1 Diabetic Participants of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study 
Diabetes  2006;55(12):3556-3565.
The Epidemiology of Diabetes Interventions and Complications (EDIC) study, an observational follow-up of the Diabetes Control and Complications Trial (DCCT) type 1 diabetes cohort, measured coronary artery calcification (CAC), an index of atherosclerosis, with computed tomography (CT) in 1,205 EDIC patients at ~7–9 years after the end of the DCCT. We examined the influence of the 6.5 years of prior conventional versus intensive diabetes treatment during the DCCT, as well as the effects of cardiovascular disease risk factors, on CAC. The prevalences of CAC >0 and >200 Agatston units were 31.0 and 8.5%, respectively. Compared with the conventional treatment group, the intensive group had significantly lower geometric mean CAC scores and a lower prevalence of CAC >0 in the primary retinopathy prevention cohort, but not in the secondary intervention cohort, and a lower prevalence of CAC >200 in the combined cohorts. Waist-to-hip ratio, smoking, hypertension, and hypercholesterolemia, before or at the time of CT, were significantly associated with CAC in univariate and multivariate analyses. CAC was associated with mean HbA1c (A1C) levels before enrollment, during the DCCT, and during the EDIC study. Prior intensive diabetes treatment during the DCCT was associated with less atherosclerosis, largely because of reduced levels of A1C during the DCCT.
doi:10.2337/db06-0653
PMCID: PMC2701297  PMID: 17130504
20.  Relationships of thoracic aortic wall calcification to cardiovascular risk factors: the Multi-Ethnic Study of Atherosclerosis 
American heart journal  2008;155(4):765-771.
Background
The aim of this paper is to determine the relationships between aortic wall calcification (AWC) including ascending and descending thoracic aortic calcification and gender, race/ethnicity, age, and traditional risk factors. Allison et al and Post et al previously described the relationship of noted risk factors and AWC as detected by computed tomography (CT) in smaller cohorts. We performed a cross-sectional study to determine which of these variables are independently associated with thoracic calcium.
Methods
The Multi-Ethnic Study of Atherosclerosis (MESA) study population included a population based sample of four ethnic groups (12% Chinese, 38% White, 22% Hispanic and 28% black) of 6814 women and men ages 45–84 years old. CT scans were performed for all participants. We quantified AWC, which ranged from the lower edge of the pulmonary artery bifurcation to the cardiac apex. Multivariable logistic regression was used to evaluate relationships between AWC and measured cardiovascular risk factors.
Results
Overall prevalence of AWC was 28.0%. In the ethnic groups, prevalence of AWC was 32.4% Chinese, 32.4% White, 24.9% Hispanic and 22.4% Black. All age categories of females had a higher prevalence of thoracic calcification than males (total age prevalence: 29.1% and 26.8%, respectively). AWC were most strongly associated with hypertension and current smoking. In addition, diabetes, hypercholesterolemia, high LDL, low HDL, family history of heart attack and high CRP were all associated with increased AWC. Overall p-value for difference between genders for prevalence of AWC = 0.037. Overall p-value for difference between race for prevalence of AWC <0.001. The only significant gender differences distributed by race were for Chinese (p=0.035) and Hispanic (p=0.042) participants.
Conclusions
Risk factors for aortic calcification were similar to cardiovascular risk factors in a large population based cohort. Suprisingly, AWC was similar for the Chinese and white populations despite the fact that MESA demonstrated that coronary caclium was more prevalent in the white population. Further studies are needed to investigate whether aortic calcification is a risk factor for coronary disease, independent of coronary calcification.
doi:10.1016/j.ahj.2007.11.019
PMCID: PMC2323597  PMID: 18371491
21.  Coronary arterial calcification in rheumatoid arthritis: comparison with the Multi-Ethnic Study of Atherosclerosis 
Introduction
Although cardiovascular morbidity and mortality are increased in rheumatoid arthritis, little is known about the burden of subclinical coronary atherosclerosis in these patients.
Methods
Using computed tomography, coronary artery calcification was measured in 195 men and women with rheumatoid arthritis aged 45 to 84 years without clinical cardiovascular disease and compared with 1,073 controls without rheumatoid arthritis enrolled in the Baltimore cohort of the Multi-Ethnic Study of Atherosclerosis.
Results
The prevalence of coronary calcification (Agatston score > 0) was significantly higher in men, but not women, with rheumatoid arthritis after adjusting for sociodemographic and cardiovascular risk factors (prevalence ratio = 1.19; P = 0.012). Among participants with prevalent calcification, those with rheumatoid arthritis had adjusted mean Agatston scores 53 units higher than controls (P = 0.002); a difference greater for men than women (P for interaction = 0.017). In all analyses, serum IL-6 attenuated the association between rheumatoid arthritis and coronary calcification, suggesting its role as a potential mediator of enhanced atherosclerosis. Notably, increasing severity of rheumatoid arthritis was associated with a higher prevalence and extent of coronary calcification among both men and women with rheumatoid arthritis, and for all age categories. The largest percentage difference in coronary arterial calcification between rheumatoid arthritis patients and their nonrheumatoid arthritis counterparts was observed in the youngest age category.
Conclusions
Increasing rheumatoid arthritis disease severity was associated with a higher prevalence and greater extent of coronary artery calcification, potentially mediated through an atherogenic effect of chronic systemic inflammation. Gender and age differences in association with coronary calcification suggest that preventive measures should be emphasized in men with rheumatoid arthritis, and considered even in younger rheumatoid arthritis patients with low levels of traditional cardiovascular risk factors.
doi:10.1186/ar2641
PMCID: PMC2688181  PMID: 19284547
22.  Ethnic Differences in the Relationship of Carotid Atherosclerosis to Coronary Calcification: The Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2007;197(1):132-138.
Ethnic differences in non-invasive measures of atherosclerosis are increasingly being reported, but the relationship of these measures to each other has not been widely explored. Carotid ultrasonographic and computed cardiac tomographic findings were compared in 6,814 participants of White, Black, Hispanic, and Chinese ethnicities free of overt cardiovascular disease. Coronary calcium and carotid atherosclerosis were strongly related to each other in all ethnic groups. Associations of coronary calcium prevalence and common carotid intimal-medial thickness (IMT) differed by ethnicity in women, being weakest among Black women (0.07 mm IMT difference between those with and without coronary calcium) compared to the other three groups (0.10–0.12 mm difference, p = 0.007). Estimated percent increments in internal carotid IMT per 10% increment in coronary calcium score were highest in Hispanics (18.5%) and lowest in Blacks (6.1%, p < 0.01).
Coronary calcium may be less strongly associated with carotid atherosclerosis in Blacks, particularly Black women, than in other ethnic groups. These differences should be pursued for relationships to coronary events to determine whether coronary calcium carries the same risk information in other ethnic groups as it does in Whites.
doi:10.1016/j.atherosclerosis.2007.02.030
PMCID: PMC2314669  PMID: 17412347
atherosclerosis; calcium; carotid arteries; epidemiology
23.  Coronary Artery Calcification Compared with Carotid Intima-Media Thickness in Prediction of Cardiovascular Disease Incidence: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Archives of internal medicine  2008;168(12):1333-1339.
Context
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.
Objective
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.
Results
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.
Conclusions
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.
doi:10.1001/archinte.168.12.1333
PMCID: PMC2555989  PMID: 18574091
24.  Coronary Artery Calcification and Myocardial Perfusion in Asymptomatic Adults: The MESA (Multi-Ethnic Study of Atherosclerosis) 
OBJECTIVES
This study assessed the cross-sectional association between coronary artery calcification (CAC) and myocardial perfusion in an asymptomatic population.
BACKGROUND
Clinical studies showed that the prevalence of stress-induced ischemia increased with CAC burden among patients with coronary heart disease (CHD). Whether an association between CAC and myocardial perfusion exists in subjects without a history of CHD remains largely unknown.
METHODS
A total of 222 men and women, ages 45 to 84 years old and free of CHD diagnosis, in the Minnesota field center of the MESA (Multi-Ethnic Study of Atherosclerosis) were studied. Myocardial blood flow (MBF) was measured using magnetic resonance imaging during rest and adenosine-induced hyperemia. Perfusion reserve was calculated as the ratio of hyperemic to resting MBF. Agatston CAC score was determined from chest multidetector computed tomography.
RESULTS
Mean values of hyperemic MBF and perfusion reserve, but not resting MBF, were monotonically lower across increasing CAC levels. After adjusting for age and gender, odds ratios (95% confidence intervals) of reduced perfusion reserve (<2.5) for subjects with CAC scores of 0, 0.1 to 99.9, 100 to 399, and ≥400 were 1.00 (reference), 2.16 (0.96 to 4.84), 2.81 (1.04 to 7.58), and 4.99 (1.73 to 14.4), respectively. Further adjustment for other coronary risk factors did not substantially modify the association. However, the inverse association between perfusion reserve and CAC attenuated with advancing age (p for interaction < 0.05).
CONCLUSIONS
Coronary vasodilatory response was associated inversely with the presence and severity of CAC in asymptomatic adults. Myocardial perfusion could be impaired by or manifest the progression to subclinical coronary atherosclerosis in the absence of clinical CHD.
doi:10.1016/j.jacc.2006.04.089
PMCID: PMC1853335  PMID: 16949496

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