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1.  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
2.  Competing Cardiovascular Outcomes Associated with Subclinical Atherosclerosis (From the Multi-Ethnic Study of Atherosclerosis) 
The American journal of cardiology  2013;111(11):1541-1546.
Subclinical atherosclerosis measured by coronary artery calcium (CAC) is associated with increased risk for multiple cardiovascular disease (CVD) outcomes and non-CVD death simultaneously, and we sought to determine the competing risks of specific cardiovascular disease (CVD) events and non-CVD death associated with varying burdens of subclinical atherosclerosis. We included 3095 men and 3486 women from the Multi-Ethnic Study of Atherosclerosis, aged 45–84 years, and from 4 ethnic groups. Participants were stratified by CAC scores: 0, 1–99, and ≥ 100. We used competing Cox models to determine competing cumulative incidences and hazards ratios within a group (e.g., among those with CAC ≥ 100) and hazards ratios for specific events between groups (e.g., CAC ≥ 100 vs. CAC = 0). We compared risks for specific CVD events and also compared against non-CVD death. In women, during a mean follow up of 7.1 years, the hazards ratios (HR) for any CVD event compared with a non-CVD death occurring first for CAC = 0 and CAC ≥ 100 were 1.40 (95% CI, 0.97–2.04) and 3.07 (2.02–4.67), respectively. CHD was the most common first CVD event type at all levels of CAC, and CHD rates were 9.5% vs. 1.6% (HR 6.24; 3.99–9.75) for women with CAC ≥100 compared with CAC = 0. We observed similar results in men. In conclusion, at all levels of CAC, CHD was the most common first CVD event and this analysis represents a novel approach to understanding the temporal sequence of cardiovascular events associated with atherosclerosis.
doi:10.1016/j.amjcard.2013.02.003
PMCID: PMC3657323  PMID: 23499272
coronary artery calcium; competing risks
3.  Impact of Subclinical Atherosclerosis on Cardiovascular Disease Events in Individuals With Metabolic Syndrome and Diabetes 
Diabetes Care  2011;34(10):2285-2290.
OBJECTIVE
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.
RESULTS
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.
CONCLUSIONS
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.
doi:10.2337/dc11-0816
PMCID: PMC3177707  PMID: 21844289
4.  Age-Related Macular Degeneration and Incident Cardiovascular Disease: The Multi-Ethnic Study of Atherosclerosis 
Ophthalmology  2011;119(4):765-770.
Objective
To determine whether age-related macular degeneration (AMD) is a risk indicator for coronary heart disease (CHD) and cardiovascular disease (CVD) events independent of other known risk factors in a multi-ethnic cohort.
Design
Population-based prospective cohort study.
Participants
A diverse population sample of 6233 men and women aged 45–84 without known CVD from the Multi-Ethnic Study of Atherosclerosis (MESA).
Methods
Participants in the MESA had retinal photographs taken between 2002 and 2003. Photographs were evaluated for AMD. Incident CHD/CVD events were ascertained during clinical follow-up visits for up to 8 years after the retinal images were taken.
Main Outcome Measures
Incident CHD/CVD events.
Results
Of the 6814 persons at risk of CHD, there were 893 participants with early AMD (13.1%) and 27 (0.5%) at baseline. Over a mean follow-up period of 5.4 years, there was no statistically significant difference in incident CHD or CVD between the AMD and non-AMD groups (5.0%vs. 3.9%, p=0.13 for CHD and 6.6 vs. 5.5%, p=0.19 for CVD, respectively). In Cox regression models adjusting for CVD risk factors, there was no significant relationship between presence of any AMD and any CHD/CVD events (HR=0.99, 95% CI 0.74–1.33, p=0.97). No significant association was found between subgroups of early AMD or late AMD and incident CHD/CVD events.
Conclusions
In persons without a history of cardiovascular disease, AMD was not associated with an increased risk of CHD or CVD.
doi:10.1016/j.ophtha.2011.09.044
PMCID: PMC3314126  PMID: 22197438
5.  Circulating CD34+ Cell Count is Associated with Extent of Subclinical Atherosclerosis in Asymptomatic Amish Men, Independent of 10-Year Framingham Risk 
Background
Bone-marrow derived progenitor cells (PCs) may play a role in maintaining vascular health by actively repairing damaged endothelium. The purpose of this study in asymptomatic Old Order Amish men (n = 90) without hypertension or diabetes was to determine if PC count, as determined by CD34+ cell count in peripheral blood, was associated with 10-year risk of cardiovascular disease (CVD) and measures of subclinical atherosclerosis.
Methods and Results
CD34+ cell count by fluorescence-activated cell sorting, coronary artery calcification (CAC) by electron beam computed tomography, and CVD risk factors were obtained. Carotid intimal-medial thickness (CIMT) also was obtained in a subset of 57 men. After adjusting for 10-year CVD risk, CD34+ cell count was significantly associated with CAC quantity (p = 0.03) and CIMT (p < 0.0001). A 1-unit increase in natural-log transformed CD34+ cell count was associated with an estimated 55.2% decrease (95% CI: −77.8% to −9.3%) in CAC quantity and an estimated 14.3% decrease (95% CI: −20.1% to −8.1%) in CIMT.
Conclusions
Increased CD34+ cell count was associated with a decrease in extent of subclinical atherosclerosis in multiple arterial beds, independent of 10-year CVD risk. Further investigations of associations of CD34+ cell count with subclinical atherosclerosis in asymptomatic individuals could provide mechanistic insights into the atherosclerotic process.
PMCID: PMC2856343  PMID: 20407620
atherosclerosis; carotid arteries; coronary artery calcification; epidemiology; risk factors
6.  Circulating CD34+ Cell Count is Associated with Extent of Subclinical Atherosclerosis in Asymptomatic Amish Men, Independent of 10-Year Framingham Risk 
Background:
Bone-marrow derived progenitor cells (PCs) may play a role in maintaining vascular health by actively repairing damaged endothelium. The purpose of this study in asymptomatic Old Order Amish men (n = 90) without hypertension or diabetes was to determine if PC count, as determined by CD34+ cell count in peripheral blood, was associated with 10-year risk of cardiovascular disease (CVD) and measures of subclinical atherosclerosis.
Methods and Results:
CD34+ cell count by fluorescence-activated cell sorting, coronary artery calcification (CAC) by electron beam computed tomography, and CVD risk factors were obtained. Carotid intimal-medial thickness (CIMT) also was obtained in a subset of 57 men. After adjusting for 10-year CVD risk, CD34+ cell count was significantly associated with CAC quantity (p = 0.03) and CIMT (p < 0.0001). A 1-unit increase in natural-log transformed CD34+ cell count was associated with an estimated 55.2% decrease (95% CI: −77.8% to −9.3%) in CAC quantity and an estimated 14.3% decrease (95% CI: −20.1% to −8.1%) in CIMT.
Conclusions:
Increased CD34+ cell count was associated with a decrease in extent of subclinical atherosclerosis in multiple arterial beds, independent of 10-year CVD risk. Further investigations of associations of CD34+ cell count with subclinical atherosclerosis in asymptomatic individuals could provide mechanistic insights into the atherosclerotic process.
PMCID: PMC2856343  PMID: 20407620
atherosclerosis; carotid arteries; coronary artery calcification; epidemiology; risk factors
7.  Cardiovascular Risk Assessment with Vascular Function, Carotid Atherosclerosis and the UKPDS Risk Engine in Korean Patients with Newly Diagnosed Type 2 Diabetes 
Diabetes & Metabolism Journal  2011;35(6):619-627.
Background
Patients with type 2 diabetes have an increased risk of cardiovascular disease. Few studies have evaluated the cardiovascular disease (CVD) risk simultaneously using the United Kingdom Prospective Diabetes Study (UKPDS) risk engine and non-invasive vascular tests in patients with newly diagnosed type 2 diabetes.
Methods
Participants (n=380; aged 20 to 81 years) with newly diagnosed type 2 diabetes were free of clinical evidence of CVD. The 10-year coronary heart disease (CHD) and stroke risks were calculated for each patient using the UKPDS risk engine. Carotid intima media thickness (CIMT), flow mediated dilation (FMD), pulse wave velocity (PWV) and augmentation index (AI) were measured. The correlations between the UKPDS risk engine and the non-invasive vascular tests were assessed using partial correlation analysis, after adjusting for age, and multiple regression analysis.
Results
The mean 10-year CHD and 10-year stroke risks were 14.92±11.53% and 4.03±3.95%, respectively. The 10-year CHD risk correlated with CIMT (P<0.001), FMD (P=0.017), and PWV (P=0.35) after adjusting for age. The 10-year stroke risk correlated only with the mean CIMT (P<0.001) after adjusting for age. FMD correlated with age (P<0.01) and systolic blood pressure (P=0.09). CIMT correlated with age (P<0.01), HbA1c (P=0.05), and gender (P<0.01).
Conclusion
The CVD risk is increased at the onset of type 2 diabetes. CIMT, FMD, and PWV along with the UKPDS risk engine should be considered to evaluate cardiovascular disease risk in patients with newly diagnosed type 2 diabetes.
doi:10.4093/dmj.2011.35.6.619
PMCID: PMC3253973  PMID: 22247905
Atherosclerosis; Cardiovascular risk; Diabetes mellitus, type 2; United Kingdom Prospective Diabetes Study risk engine; Vascular function
8.  Activated TLR Signaling in Atherosclerosis among Women with Lower Framingham Risk Score: The Multi-Ethnic Study of Atherosclerosis 
PLoS ONE  2011;6(6):e21067.
Background
Atherosclerosis is the leading cause of cardiovascular disease (CVD). Traditional risk factors can be used to identify individuals at high risk for developing CVD and are generally associated with the extent of atherosclerosis; however, substantial numbers of individuals at low or intermediate risk still develop atherosclerosis.
Results
A case-control study was performed using microarray gene expression profiling of peripheral blood from 119 healthy women in the Multi-Ethnic Study of Atherosclerosis cohort aged 50 or above. All participants had low (<10%) to intermediate (10% to 20%) predicted Framingham risk; cases (N = 48) had coronary artery calcium (CAC) score >100 and carotid intima-media thickness (IMT) >1.0 mm, whereas controls (N = 71) had CAC<10 and IMT <0.65 mm. We identified two major expression profiles significantly associated with significant atherosclerosis (odds ratio 4.85; P<0.001); among those with Framingham risk score <10%, the odds ratio was 5.30 (P<0.001). Ontology analysis of the gene signature reveals activation of a major innate immune pathway, toll-like receptors and IL-1R signaling, in individuals with significant atherosclerosis.
Conclusion
Gene expression profiles of peripheral blood may be a useful tool to identify individuals with significant burden of atherosclerosis, even among those with low predicted risk by clinical factors. Furthermore, our data suggest an intimate connection between atherosclerosis and the innate immune system and inflammation via TLR signaling in lower risk individuals.
doi:10.1371/journal.pone.0021067
PMCID: PMC3116882  PMID: 21698167
9.  Associations of SNPs in ADIPOQ and subclinical cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis (MESA) 
Obesity (Silver Spring, Md.)  2010;19(4):840-847.
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.
doi:10.1038/oby.2010.229
PMCID: PMC3510267  PMID: 20930713
10.  Viewpoint: Personalizing Statin Therapy 
Cardiovascular disease (CVD), associated with vascular atherosclerosis, is the major cause of death in Western societies. Current risk estimation tools, such as Framingham Risk Score (FRS), based on evaluation of multiple standard risk factors, are limited in assessment of individual risk. The majority (about 70%) of the general population is classified as low FRS where the individual risk for CVD is often underestimated but, on the other hand, cholesterol lowering with statin is often excessively administered. Adverse effects of statin therapy, such as muscle pain, affect a large proportion of the treated patients and have a significant influence on their quality of life.
Coronary artery calcification (CAC), as assessed by computed tomography, carotid artery intima-media thickness (CIMT), and especially presence of plaques as assessed by B-mode ultrasound are directly correlated with increased risk for cardiovascular events and provide accurate and relevant information for individual risk assessment. Absence of vascular pathology as assessed by these imaging methods has a very high negative predictive value and therefore could be used as a method to reduce significantly the number of subjects who, in our opinion, would not benefit from statins and only suffer from their side-effects.
In summary, we suggest that in very-low-risk subjects, with the exception of subjects with low FRS with a family history of coronary artery disease (CAD) at young age, if vascular imaging shows no CAC or normal CIMT without plaques, statin treatment need not be administered.
doi:10.5041/RMMJ.10108
PMCID: PMC3678834  PMID: 23908858
Framingham Risk Score; cardiovascular disease; coronary artery calcification; carotid artery intima-media thickness; statin; atherosclerosis
11.  Walking speed and subclinical atherosclerosis in healthy older adults: the Whitehall II study 
Heart  2010;96(5):380-384.
Objective
Extended walking speed is a predictor of incident cardiovascular disease (CVD) in older individuals, but the ability of an objective short-distance walking speed test to stratify the severity of preclinical conditions remains unclear. This study examined whether performance in an 8-ft walking speed test is associated with metabolic risk factors and subclinical atherosclerosis.
Design
Cross-sectional.
Setting
Epidemiological cohort.
Participants
530 adults (aged 63±6 years, 50.3% male) from the Whitehall II cohort study with no known history or objective signs of CVD.
Main outcome
Electron beam computed tomography and ultrasound was used to assess the presence and extent of coronary artery calcification (CAC) and carotid intima-media thickness (IMT), respectively.
Results
High levels of CAC (Agatston score >100) were detected in 24% of the sample; the mean IMT was 0.75 mm (SD 0.15). Participants with no detectable CAC completed the walking course 0.16 s (95% CI 0.04 to 0.28) faster than those with CAC ≥400. Objectively assessed, but not self-reported, faster walking speed was associated with a lower risk of high CAC (odds ratio 0.62, 95% CI 0.40 to 0.96) and lower IMT (β=−0.04, 95% CI −0.01 to −0.07 mm) in comparison with the slowest walkers (bottom third), after adjusting for conventional risk factors. Faster walking speed was also associated with lower adiposity, C-reactive protein and low-density lipoprotein cholesterol.
Conclusions
Short-distance walking speed is associated with metabolic risk and subclinical atherosclerosis in older adults without overt CVD. These data suggest that a non-aerobically challenging walking test reflects the presence of underlying vascular disease.
doi:10.1136/hrt.2009.183350
PMCID: PMC2921267  PMID: 19955091
Ageing; atherosclerosis; computed tomography scanning; epidemiology; exercise testing; gait speed; imaging; physical function; risk stratification
12.  Impact of Blood Pressure and Blood Pressure Change during Middle Age on the Remaining Lifetime Risk for Cardiovascular Disease: The Cardiovascular Lifetime Risk Pooling Project 
Circulation  2011;125(1):37-44.
Background
Prior estimates of lifetime risk (LTR) for cardiovascular disease (CVD) examined the impact of blood pressure at the index age and did not account for changes in blood pressure over time. We examined how changes in blood pressure during middle-age affect LTR for CVD, coronary heart disease (CHD) and stroke.
Methods and Results
Data from 7 diverse US cohort studies were pooled. Remaining LTR for CVD, CHD and stroke were estimated for White and Black men and women with death free of CVD as a competing event. LTR for CVD by blood pressure (BP) strata and by changes in BP over an average of 14 years were estimated. Starting at age 55, we followed 61,585 men and women for 700,000 person-years. LTR for CVD was 52.5% (95% CI 51.3–53.7) for men and 39.9% (38.7–41.0) for women. LTR for CVD was higher for Blacks and increased with increasing BP at index age. Individuals who maintained or decreased their BP to normal levels had the lowest remaining LTR for CVD, 22–41%, as compared to individuals who had or developed hypertension by the age of 55, 42–69%; suggesting a dose-response effect for the length of time at high BP levels
Conclusions
Individuals who experience increases or decreases in BP in middle age have associated higher and lower remaining LTR for CVD. Prevention efforts should continue to emphasize the importance of lowering BP and avoiding or delaying the incidence of hypertension in order to reduce the LTR for CVD.
doi:10.1161/CIRCULATIONAHA.110.002774
PMCID: PMC3310202  PMID: 22184621
cardiovascular disease; coronary heart disease; stroke; hypertension; risk factors
13.  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
14.  The Epidemiology of Subclavian Stenosis and its Association with Markers of Subclinical Atherosclerosis: the Multi-Ethnic Study of Atherosclerosis (MESA) 
Atherosclerosis  2010;211(1):266-270.
Background
Recent studies indicate that subclavian stenosis (SS), diagnosed by a large systolic blood pressure difference (SBPD) between the right and left brachial arteries, is associated with cardiovascular disease (CVD) risk factors and outcomes. We sought to describe the epidemiology of SS and determine its association with markers of subclinical CVD in the baseline cohort of the Multi-Ethnic Study of Atherosclerosis.
Methods
We defined SS by an absolute SBPD ≥15 mmHg. Peripheral artery disease (PAD) was defined by an ankle-brachial index ≤0.90. The coronary artery calcium score (CAC) and the common-carotid artery intima-media thickness (CCA-IMT) were measured by computed tomography and B-mode ultrasound, respectively. Odds ratios for the associations of SS with risk factors and subclinical disease were estimated using logistic regression.
Results
Of 6,743 subjects studied, 307 participants (4.6%) had SS, with a higher prevalence in women (5.1%) than men (3.9%), and in African-Americans (7.4%) and non-Hispanic whites (5.1%) than Hispanic (1.9%) or Chinese (1.0%) participants (p<0.01). In a model including age, gender, ethnicity, traditional and novel CVD risk factors, significant associations with SS were observed for C-reactive protein (highest vs. three lower quartiles: OR=1.41; 95%CI: 1.06-1.87) and brachial artery pulse pressure (OR=1.12 /10 mmHg; 95%CI: 1.03-1.21). Adjusted for age, gender, ethnicity, traditional and novel CVD risk factors, SS was significantly associated with PAD (OR=2.35; 1.55-3.56), with CCA-IMT (highest vs. the lower three quartiles: OR=1.32; 1.00-1.75), and high CAC (score >100 vs. score=0; OR=1.43; 1.03-2.01).
Conclusions
The subclavian stenosis is positively associated with other markers of subclinical atherosclerosis.
doi:10.1016/j.atherosclerosis.2010.01.013
PMCID: PMC2925848  PMID: 20138280
subclavian artery; blood pressure; atherosclerosis; epidemiology
15.  Cardiovascular events with absent or minimal coronary calcification: the Multi-Ethnic Study of Atherosclerosis (MESA) 
American heart journal  2009;158(4):554-561.
Background
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).
Methods
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.
Results
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.
Conclusion
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.
doi:10.1016/j.ahj.2009.08.007
PMCID: PMC2766514  PMID: 19781414
Computed Tomography; Prognosis; Coronary Artery Calcification; Atherosclerosis; Coronary Calcium Score; Cardiac Events
16.  Cardiovascular disease incidence and mortality in older men with diabetes and in men with coronary heart disease 
Heart  2004;90(12):1398-1403.
Objective: To examine the relation of diabetes and coronary heart disease (CHD; myocardial infarction (MI) or angina) to the incidence of major CHD and stroke events and total mortality.
Methods: Prospective study of 5934 men aged 52–74 years followed up for 10 years. The men were divided into five groups according to their diabetes and CHD status.
Results: During the follow up there were 662 major CHD events, 305 major stroke events, and 1357 deaths from all causes (637 cardiovascular disease (CVD) deaths, 417 CHD deaths). Men with diabetes had significantly increased cardiovascular and total mortality risk compared with non-diabetic men with no CHD but lower risk than men with prior MI only. The adjusted relative risk for CHD deaths was 2.82 (95% confidence interval (CI) 1.85 to 4.28) in men with diabetes only, 2.12 (95% CI 1.53 to 2.93) in men with angina only, 3.91 (95% CI 3.07 to 4.99) in men with MI, and 8.93 (95% CI 6.13 to 12.99) in men with both diabetes and CHD. Case fatality among men with diabetes only was similar to those with prior MI only. CHD and CVD mortality increased with increasing duration of diabetes with risk eventually approaching that of patients with MI without diabetes.
Conclusion: Men with diabetes only have a CVD risk intermediate between men with angina and men with prior MI. Their absolute risk is high and the prognosis for diabetic patients who develop CHD is extremely poor.
doi:10.1136/hrt.2003.026104
PMCID: PMC1768570  PMID: 15547012
non-insulin dependent diabetes mellitus; myocardial infarction; cardiovascular disease; mortality
17.  Associations between markers of subclinical atherosclerosis and dietary patterns derived by principal components analysis and reduced rank regression in the Multi-Ethnic Study of Atherosclerosis (MESA)1–3 
Background
The association between diet and cardiovascular disease (CVD) may be mediated partly through inflammatory processes and reflected by markers of subclinical atherosclerosis.
Objective
We investigated whether empirically derived dietary patterns are associated with coronary artery calcium (CAC) and common and internal carotid artery intima media thickness (IMT) and whether prior information about inflammatory processes would increase the strength of the associations.
Design
At baseline, dietary patterns were derived with the use of a food-frequency questionnaire, and inflammatory biomarkers, CAC, and IMT were measured in 5089 participants aged 45–84 y, who had no clinical CVD or diabetes, in the Multi-Ethnic Study of Atherosclerosis. Dietary patterns based on variations in C-reactive protein, interleukin-6, homocysteine, and fibrinogen concentrations were created with reduced rank regression (RRR). Dietary patterns based on variations in food group intake were created with principal components analysis (PCA).
Results
The primary RRR(RRR 1) and PCA(PCA factor 1) dietary patterns were high in total and saturated fat and low in fiber and micronutrients. However, the food sources of these nutrients differed between the dietary patterns. RRR 1 was positively associated with CAC [Agatston score >0: OR(95% CI) for quartile 5 compared with quartile 1 = 1.34 (1.05, 1.71); ln(Agatston score = 1): P for trend = 0.023] and with common carotid IMT [≥1.0 mm: OR (95% CI) for quartile 5 compared with quartile 1 = 1.33 (0.99, 1.79); ln(common carotid IMT): P for trend = 0.006]. PCA 1 was not associated with CAC or IMT.
Conclusion
The results suggest that subtle differences in dietary pattern composition, realized by incorporating measures of inflammatory processes, affect associations with markers of subclinical atherosclerosis.
PMCID: PMC2858465  PMID: 17556701
Dietary patterns; principal components analysis; reduced rank regression; carotid artery intima media thickness; coronary artery calcium
18.  Carotid Plaque, Carotid Intima-Media Thickness, and Coronary Calcification Equally Discriminate Prevalent Cardiovascular Disease in Kidney Disease 
American journal of nephrology  2012;36(4):342-347.
Background
Despite the significant morbidity and mortality attributable to cardiovascular disease (CVD), risk stratification remains an important challenge in the chronic kidney disease(CKD) population. We examined the discriminative ability of non-invasive measures of atherosclerosis, including carotid intima-media thickness(cIMT), carotid plaque, coronary artery calcification(CAC) and ascending and descending thoracic aorta calcification(TCAC), and Framingham Risk Score (FRS) to predict self-reported prevalent CVD.
Methods and Results
Participants were enrolled in the cIMT ancillary study of the Chronic Renal Insufficiency Cohort(CRIC) Study and also had all of the above measures within an 18 month period. CVD was present in 21% of study participants. C-statistics were used to ascertain the discriminatory power of each measure of atherosclerosis. The study population (n=220) was 64% male; 51% black and 45% white. The proportion of individuals with estimated glomerular filtration rate ≥60, 45–59, 30–44, and <30ml/min/1.73m2 was 21%, 41%, 28%, and 11%, respectively. In multivariable analyses adjusting for demographic factors, we failed to find a difference between CAC, carotid plaque, and cIMT as predictors of self-reported prevalent CVD (c-statistic 0.70, 95% confidence interval [CI]: 0.62–0.78; c-statistic 0.68, 95% CI: 0.60–0.75, and c-statistic 0.64, CI: 0.56–0.72, respectively). CAC was statistically better than FRS. FRS was the weakest discriminator of self-reported prevalent CVD (c-statistic 0.58).
Conclusions
There was a significant burden of atherosclerosis among individuals with CKD, ascertained by several different imaging modalities. We were unable to find a difference in the ability of CAC, carotid plaque, and cIMT to predict self-reported prevalent CVD.
doi:10.1159/000342794
PMCID: PMC3538165  PMID: 23107930
carotid intima media thickness; coronary artery calcification; kidney; plaque
19.  Low free testosterone in HIV-infected men is not associated with subclinical cardiovascular disease 
HIV medicine  2012;13(6):358-366.
Objectives
Low testosterone (T) is associated with cardiovascular disease (CVD) and increased mortality in the general population; however, the impact of T on subclinical CVD in HIV disease is unknown. This study examined the relationships among free testosterone (FT), subclinical CVD, and HIV disease.
Methods
This was a cross-sectional analysis in 322 HIV-uninfected and 534 HIV-infected men in the Multicenter AIDS Cohort Study. Main outcomes were coronary artery calcification presence, defined as a coronary artery calcium (CAC) score > 10 (CAC score was the geometric mean of the Agatston scores of two computed tomography replicates), and far wall common carotid intima-media thickness (IMT)/carotid lesion presence by B-mode ultrasound.
Results
Compared with the HIV-uninfected men in our sample, HIV-infected men were younger, with lower body mass index (BMI) and more often Black. HIV-infected men had lower FT (age-adjusted FT 88.7 ng/dL vs. 101.7 ng/dL in HIV-uninfected men; P = 0.0004); however, FT was not associated with CAC, log carotid IMT, or the presence of carotid lesions. HIV status was not associated with CAC presence or log carotid IMT, but was associated with carotid lesion presence (adjusted odds ratio 1.69; 95% confidence interval 1.06, 2.71) in HIV-infected men compared with HIV-uninfected men.
Conclusions
Compared with HIV-uninfected men, HIV-infected men had lower FT, as well as more prevalent carotid lesions. In both groups, FT was not associated with CAC presence, log carotid IMT, or carotid lesion presence, suggesting that FT does not influence subclinical CVD in this population of men with and at risk for HIV infection.
doi:10.1111/j.1468-1293.2011.00988.x
PMCID: PMC3505881  PMID: 22296297
cardiovascular disease; HIV; testosterone
20.  Polymorphisms in the Selenoprotein S gene and subclinical cardiovascular disease in the Diabetes Heart Study 
Acta diabetologica  2012;50(3):391-399.
Selenoprotein S (SelS), has previously been associated with a range of inflammatory markers, particularly in the context of cardiovascular disease (CVD). The aim of this study was to examine the role of SELS genetic variants in risk for subclinical CVD and mortality in individuals with type 2 diabetes mellitus (T2DM). The association between 10 polymorphisms tagging SELS and coronary (CAC), carotid (CarCP) and abdominal-aortic calcified plaque (AACP), carotid intima media thickness (IMT) and other known CVD risk factors was examined in 1220 European Americans from the family-based Diabetes Heart Study. The strongest evidence of association for SELS SNPs was observed for CarCP; rs28665122 (5′ region; β=0.329, p=0.044), rs4965814 (intron 5; β=0.329, p=0.036), rs28628459 (3′ region; β=0.331, p=0.039) and rs7178239 (downstream; β=0.375, p=0.016) were all associated. In addition, rs12917258 (intron 5) was associated with CAC (β =−0.230, p=0.032) and rs4965814, rs28628459 and rs9806366 were all associated with self reported history of prior CVD (p=0.020–0.043). These results suggest a potential role for the SELS region in the development subclinical CVD in this sample enriched for T2DM. Further understanding the mechanisms underpinning these relationships may prove important in predicting and managing CVD complications in T2DM.
doi:10.1007/s00592-012-0440-z
PMCID: PMC3597768  PMID: 23161441
genetics; atherosclerosis; calcified plaque; diabetes mellitus
21.  Coronary Artery Calcium Score and Risk Classification for Coronary Heart Disease Prediction: The Multi-Ethnic Study of Atherosclerosis 
Context
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.
Objective
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
Results
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.
Conclusions
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.
doi:10.1001/jama.2010.461
PMCID: PMC3033741  PMID: 20424251
22.  Carotid artery plaque and progression of coronary artery calcium: the Multi-Ethnic Study of Atherosclerosis 
Background
Carotid and coronary atherosclerosis are associated to each other in imaging and autopsy studies. We evaluated whether carotid artery plaque seen on carotid ultrasound can predict incident coronary artery calcification (CAC).
Materials and Methods
We repeated Agatston calcium score measurements in 5445 participants of the Multi-Ethnic Study of Atherosclerosis (MESA) (mean age 57.9 years; 62.9% female). Internal carotid artery lesions were graded as 0%, 1-24%, >25% diameter narrowing and intima-media thickness (IMT) was measured. Plaque was present for any stenosis > 0%. CAC progression was evaluated with multivariable relative risk regression in cases with CAC = 0 at baseline and with multivariable linear regression for CAC > 0 adjusting for cardiovascular risk factors, body mass index, ethnicity, and common carotid IMT.
Results
CAC was positive at baseline in 2708/5445 (49.7%) participants and became positive in 458/2837 (16.1%) at mean interval of 2.4 years between repeat examinations. Plaque and ICA IMT were both strongly associated with presence of CAC. After statistical adjustment, presence of carotid artery plaque significantly predicted incident CAC with a relative risk(RR) of 1.37 (95% Confidence Intervals: 1.12, 1.67). Incident CAC was associated with ICA IMT with an RR of 1.13 (95% Confidence Intervals: 1.03, 1.25) for each mm increase. Progression of CAC was also significantly associated (p < 0.001) with plaque and ICA IMT.
Conclusions
In individuals free of cardiovascular disease, subjective and quantitative measures of carotid artery plaques by ultrasound imaging are associated with CAC incidence and progression.
doi:10.1016/j.echo.2013.02.009
PMCID: PMC4084492  PMID: 23522805
23.  Association of Small Artery Elasticity With Incident Cardiovascular Disease in Older Adults 
American Journal of Epidemiology  2011;174(5):528-536.
Functional biomarkers like large artery elasticity (LAE) and small artery elasticity (SAE) may predict cardiovascular disease (CVD) events beyond blood pressure. The authors examined the prognostic value of LAE and SAE for clinical CVD events among 6,235 Multi-Ethnic Study of Atherosclerosis participants who were initially aged 45–84 years and without symptomatic CVD. LAE and SAE were derived from diastolic pulse contour analysis. During a median 5.8 years of follow-up between 2000 and 2008, 454 adjudicated CVD events occurred, including 256 cases of coronary heart disease (CHD), 93 strokes, and 126 heart failures (multiple diagnoses were possible). After adjustment for age, race/ethnicity, sex, clinic, height, heart rate, body mass index, systolic and diastolic blood pressure, use of antihypertensive and cholesterol-lowering medications, smoking, total cholesterol, high density lipoprotein cholesterol, triglycerides, diabetes, and high-sensitivity C-reactive protein, the hazard ratio for any CVD per standard-deviation increase in SAE was 0.71 (95% confidence interval: 0.61, 0.83; P < 0.0001). The lowest (stiffest) SAE quartile had a hazard ratio of 2.28 (95% confidence interval: 1.55, 3.36) versus the highest (most elastic) quartile. The net reclassification index, conditional on base risk, was 0.11. SAE was significantly associated with future CHD, stroke, and heart failure. After adjustment, LAE was not significantly related to CVD. In asymptomatic participants free of overt CVD, lower SAE added prognostic information for CVD, CHD, stroke, and heart failure events.
doi:10.1093/aje/kwr120
PMCID: PMC3202150  PMID: 21709134
arteries; cardiovascular diseases; elasticity; risk factors
24.  The Relationship of Left Ventricular Mass and Geometry to Incident Cardiovascular Events: The MESA Study 
Objective
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.
Background
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1016/j.jacc.2008.09.014
PMCID: PMC2706368  PMID: 19095132
Heart failure; stroke; coronary heart disease; epidemiology; magnetic resonance imaging; left ventricular hypertrophy
25.  Incidence and risk factors for cardiovascular disease in African Americans with diabetes: the Atherosclerosis Risk in Communities (ARIC) study. 
To determine the incidence rate of cardiovascular disease (CVD) and its association with conventional and less well-established risk factors in African Americans with diabetes, we studied 741 African Americans aged 45 to 64 years with diabetes, in the Atherosclerosis Risk in Communities (ARIC) study. Risk factors were measured from 1987 to 1989, and incident CVD (n = 143 coronary heart disease (CHD) or stroke events) was ascertained through 1998. The crude incidence rate (per 1000 person-years) of CVD was 22.5 (11.9 for CHD and 12.0 for stroke). After multivariate adjustments, total cholesterol, prevalent hypertension and current smoking were significantly and positively associated with incident CVD among these African Americans with diabetes. Among the non-conventional risk factors, serum creatinine, factor VIII, von Willebrand factor, and white blood cell count were positively and serum albumin negatively and independently associated with CVD incidence. Adjusted relative risks for highest versus lowest tertiles of these risk factors ranged from 1.77 to 2.13. This study confirms that the major risk factors (hypercholesterolemia, hypertension and smoking) are important determinants of CVD in African Americans with diabetes. In addition, several blood markers of hemostasis or inflammatory response and elevated serum creatinine also proved to be CVD risk factors in African Americans with diabetes.
PMCID: PMC2568397  PMID: 12510702

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