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1.  Carotid Intima-Media Thickness Progression and Risk of Vascular Events in People With Diabetes: Results From the PROG-IMT Collaboration 
Diabetes Care  2015;38(10):1921-1929.
OBJECTIVE
Carotid intima-media thickness (CIMT) is a marker of subclinical organ damage and predicts cardiovascular disease (CVD) events in the general population. It has also been associated with vascular risk in people with diabetes. However, the association of CIMT change in repeated examinations with subsequent CVD events is uncertain, and its use as a surrogate end point in clinical trials is controversial. We aimed at determining the relation of CIMT change to CVD events in people with diabetes.
RESEARCH DESIGN AND METHODS
In a comprehensive meta-analysis of individual participant data, we collated data from 3,902 adults (age 33–92 years) with type 2 diabetes from 21 population-based cohorts. We calculated the hazard ratio (HR) per standard deviation (SD) difference in mean common carotid artery intima-media thickness (CCA-IMT) or in CCA-IMT progression, both calculated from two examinations on average 3.6 years apart, for each cohort, and combined the estimates with random-effects meta-analysis.
RESULTS
Average mean CCA-IMT ranged from 0.72 to 0.97 mm across cohorts in people with diabetes. The HR of CVD events was 1.22 (95% CI 1.12–1.33) per SD difference in mean CCA-IMT, after adjustment for age, sex, and cardiometabolic risk factors. Average mean CCA-IMT progression in people with diabetes ranged between −0.09 and 0.04 mm/year. The HR per SD difference in mean CCA-IMT progression was 0.99 (0.91–1.08).
CONCLUSIONS
Despite reproducing the association between CIMT level and vascular risk in subjects with diabetes, we did not find an association between CIMT change and vascular risk. These results do not support the use of CIMT progression as a surrogate end point in clinical trials in people with diabetes.
doi:10.2337/dc14-2732
PMCID: PMC4580609  PMID: 26180107
2.  Associations of coronary heart disease with common carotid artery near and far wall intima-media thickness (IMT): the Multi-Ethnic Study of Atherosclerosis 
Background
Intima-media thickness (IMT) measured on ultrasound images of the common carotid artery (CCA) is associated with cardiovascular risk factors and events. Based on the physics of ultrasound, CCA far wall IMT measurements are favored over near wall measurements but this theoretical advantage is not well studied.
Methods
We studied 6606 members of the Multi-Ethnic Study of Atherosclerosis (MESA), a longitudinal cohort study (mean age 62.1 years; 52.7% female) who had near wall and far wall CCA IMT measurements. Multivariable linear regression models were used to estimate model goodness-of-fit of Framingham risk factors (FRF) with near wall IMT, far wall IMT, and combined mean IMT. Multivariable Cox proportional hazards models were used to estimate hazard ratios for incident coronary heart disease (CHD) events for each IMT variable. Change in Harrell’s C-statistic was used to compare the incremental value of each IMT variable when added to FRF.
Results
Mean IMT had the strongest association with risk factors (R2 = 0.31), followed by the near wall (R2 = 0.26) and far wall IMT (R2 = 0.22). Far wall IMT improved the prediction of coronary artery disease events over the FRF (change in C-statistic of 0.012; 95% confidence intervals: 0.006, 0.017; p < 0.001) as did mean IMT (p = 0.004) but near wall IMT did not.
Conclusions
Far wall CCA IMT showed the strongest association with incident CHD whereas mean IMT had the strongest associations with risk factors. This difference might affect the selection of appropriate IMT variables in different studies.
doi:10.1016/j.echo.2015.04.001
PMCID: PMC4567434  PMID: 25944425
risk factors; common carotid artery; ultrasound; coronary heart disease; intima media thickness; carotid artery bifurcation
3.  ADIPONECTIN IS INDEPENDENTLY ASSOCIATED WITH NT-ProBNP: THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS 
Background and Aims
To investigate the associations between selected adipokines and the N-terminal prohormone of B-type natriuretic peptide (NT-proBNP).
Methods and Results
1489 individuals enrolled in the Multi-Ethnic Study of Atherosclerosis were evaluated at 4 clinic visits about every 2 years. The evaluation included fasting venous blood, which was analyzed for NT-proBNP (at visits 1 and 3) and the adipokines adiponectin and leptin (at visits 2 and 3). The mean age was 64.8 ± 9.6 years and 48% were female. After multivariable adjustment, a 1-SD increment in adiponectin was associated with a 14 pg/ml higher NT-proBNP level (p < 0.01), while, compared to the 1st quartile of adiponectin, the 2nd, 3rd and 4th quartiles had 28, 45 and 67% higher NT-proBNP levels (p < 0.01 for all). For changes in NT-proBNP over the follow-up period, and after multivariable adjustment including baseline NT-proBNP, a 1-SD increment in adiponectin was associated with a 25 pg/ml absolute increase in NT-proBNP (p < 0.01), while those in the 2nd, 3rd and 4th quartiles of adiponectin were associated with increases of 5, 28 and 65 pg/ml (p = 0.74, 0.09 and < 0.01, respectively). There was a significant interaction between adiponectin and sex for visit 3 NT-proBNP (p-interaction < 0.01), with significantly stronger associations in men. Leptin was not associated with NT-proBNP.
Conclusion
Higher adiponectin, but not leptin, is significantly associated with higher levels of NT-proBNP, as well as with greater longitudinal increases in NT-proBNP. The associations were stronger in men.
doi:10.1016/j.numecd.2015.04.005
PMCID: PMC4515181  PMID: 26026204
4.  Associations of Anger, Anxiety and Depressive symptoms with Carotid Arterial Wall Thickness: the Multi-Ethnic Study of Atherosclerosis 
Psychosomatic medicine  2012;74(5):517-525.
Objective
Carotid arterial wall thickness, measured as intima-media thickness (IMT), is an early subclinical indicator of cardiovascular disease. Few studies have investigated the association of psychological factors with IMT across multiple ethnic groups and by gender.
Methods
We included 6,561 men and women (2,541 whites, 1,790 African Americans, 1,436 Hispanics, and 794 Chinese) aged 45 to 84 years who took part in the first examination of the Multi-Ethnic Study of Atherosclerosis. Associations of trait anger, trait anxiety, and depressive symptoms with mean values of common carotid artery (CCA) and internal carotid artery (ICA) IMTs were investigated using multivariable regression and logistic models.
Results
In age, gender, race/ethnicity-adjusted analyses, the trait anger score was positively associated with CCA and ICA IMTs (mean differences per one SD increment of trait anger score were 0.014 (95% CI, 0.003–0.025, p=0.01) and 0.054 (0.017–0.090, p=0.004) for CCA and ICA IMTs respectively). Anger was also associated with the presence of carotid plaque (age, gender, and race/ethnicity-adjusted odds ratio per one SD increase in trait anger: 1.27 (95%CI, 1.06–1.52)). The associations of the trait anger score with thicker IMT was attenuated after adjustment for covariates, but remained statistically significant. Associations were stronger in men than in women and in whites than in other race/ethnic groups but heterogeneity was only marginally statistically significant by race/ethnicity. There was no association of depressive symptoms or trait anxiety with IMT.
Conclusions
Only one of the three measures examined was associated with IMT and the patterns appeared to be heterogeneous across race/ethnic groups.
doi:10.1097/PSY.0b013e31824f6267
PMCID: PMC4966673  PMID: 22511725
Anger; Anxiety; Carotid artery wall thickness; Depressive symptoms; Intima-media thickness; Race/Ethnicity
5.  P-selectin and subclinical and clinical atherosclerosis: the Multi-Ethnic Study of Atherosclerosis (MESA) 
Atherosclerosis  2015;240(1):3-9.
Objective
P-selectin is a cellular adhesion molecule that has been shown to be crucial in development of coronary heart disease (CHD). We sought to determine the role of P-selectin on the risk of atherosclerosis in a large multi-ethnic population.
Methods
Data from the Multi-Ethnic Study of Atherosclerosis (MESA), including 1628 African, 702 Chinese, 2393 non-Hispanic white, and 1302 Hispanic Americans, were used to investigate the association of plasma P-selectin with CHD risk factors, coronary artery calcium (CAC), intima-media thickness, and CHD. Regression models were used to investigate the association between P-selectin and risk factors, Tobit model for CAC, and Cox regression for CHD events.
Results
Mean levels of P-selectin differed by ethnicity and were higher in men (P < 0.001). For all ethnic groups, P-selectin was positively associated with measures of adiposity, blood pressure, current smoking, LDL, and triglycerides and inversely with HDL. A significant ethnic interaction was observed for the association of P-selectin and prevalent diabetes; however, P-selectin was positively associated with HbA1c in all groups. Higher P-selectin levels were associated with greater prevalence of CAC. Over 10.1 years of follow-up, there were 335 incident CHD events. There was a positive linear association between P-selectin levels and rate of incident CHD after adjustment for traditional risk factors. However, association was only significant in non-Hispanic white Americans (HR: 1.81, 95% CI 1.07 to 3.07, P = 0.027).
Conclusion
We observed ethnic heterogeneity in the association of P-selectin and risk of CHD.
doi:10.1016/j.atherosclerosis.2015.02.036
PMCID: PMC4397161  PMID: 25744700
Atherosclerosis; Cardiovascular risk factors; Coronary artery calcium; P-selectin
6.  Carotid Intima‐Media Thickness and Arterial Stiffness and the Risk of Atrial Fibrillation: The Atherosclerosis Risk in Communities (ARIC) Study, Multi‐Ethnic Study of Atherosclerosis (MESA), and the Rotterdam Study 
Background
We evaluated the association of carotid intima‐media thickness (cIMT), carotid plaque, carotid distensibility coefficient (DC), and aortic pulse wave velocity (PWV) with incident atrial fibrillation (AF) and their role in improving AF risk prediction beyond the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE)‐AF risk score.
Methods and Results
We analyzed data from 3 population‐based cohort studies: Atherosclerosis Risk in Communities (ARIC) Study (n=13 907); Multi‐Ethnic Study of Atherosclerosis (MESA; n=6640), and the Rotterdam Study (RS; n=5220). We evaluated the association of arterial indices with incident AF and computed the C‐statistic, category‐based net reclassification improvement (NRI), and relative integrated discrimination improvement (IDI) of incorporating arterial indices into the CHARGE‐AF risk score (age, race, height weight, systolic and diastolic blood pressure, antihypertensive medication use, smoking, diabetes, previous myocardial infarction, and previous heart failure). Higher cIMT (meta‐analyzed hazard ratio [95% CI] per 1‐SD increment, 1.12 [1.08–1.16]) and presence of carotid plaque (1.30 [1.19–1.42]) were associated with higher AF incidence after adjustment for CHARGE‐AF risk‐score variables. Lower DC and higher PWV were associated with higher AF incidence only after adjustment for the CHARGE‐AF risk‐score variables excepting height, weight, and systolic and diastolic blood pressure. Addition of cIMT or carotid plaque marginally improved CHARGE‐AF score prediction as assessed by the relative IDI (estimates, 0.025–0.051), but not when assessed with the C‐statistic and NRI.
Conclusions
Higher cIMT, presence of carotid plaque, and greater arterial stiffness are associated with higher AF incidence, indicating that atherosclerosis and arterial stiffness play a role in AF etiopathogenesis. However, arterial indices only modestly improve AF risk prediction.
doi:10.1161/JAHA.115.002907
PMCID: PMC4889172  PMID: 27207996
arterial stiffness; atherosclerosis; atrial fibrillation; carotid intima‐media thickness; Atrial Fibrillation; Epidemiology
7.  Concentration of Smaller High‐Density Lipoprotein Particle (HDL‐P) Is Inversely Correlated With Carotid Intima Media Thickening After Confounder Adjustment: The Multi Ethnic Study of Atherosclerosis (MESA) 
Background
Recent studies have failed to establish a causal relationship between high‐density lipoprotein cholesterol levels (HDL‐C) and cardiovascular disease (CVD), shifting focus to other HDL measures. We previously reported that smaller/denser HDL levels are protective against cerebrovascular disease. This study sought to determine which of small+medium HDL particle concentration (HDL‐P) or large HDL‐P was more strongly associated with carotid intima‐media thickening (cIMT) in an ethnically diverse cohort.
Methods and Results
In cross‐sectional analyses of participants from the Multi Ethnic Study of Atherosclerosis (MESA), we evaluated the associations of nuclear magnetic resonance spectroscopy–measured small+medium versus large HDL‐P with cIMT measured in the common and internal carotid arteries, through linear regression. After adjustment for CVD confounders, low‐density lipoprotein cholesterol (LDL‐C), HDL‐C, and small+medium HDL‐P remained significantly and inversely associated with common (coefficient=−1.46 μm; P=0.00037; n=6512) and internal cIMT (coefficient=−3.82 μm; P=0.0051; n=6418) after Bonferroni correction for 4 independent tests (threshold for significance=0.0125; α=0.05/4). Large HDL‐P was significantly and inversely associated with both cIMT outcomes before HDL‐C adjustment; however, after adjustment for HDL‐C, the association of large HDL‐P with both common (coefficient=1.55 μm; P=0.30; n=6512) and internal cIMT (coefficient=4.84 μm; P=0.33; n=6418) was attenuated. In a separate sample of 126 men, small/medium HDL‐P was more strongly correlated with paraoxonase 1 activity (r p=0.32; P=0.00023) as compared to both total HDL‐P (r p=0.27; P=0.0024) and large HDL‐P (r p=0.02; P=0.41) measures.
Conclusions
Small+medium HDL‐P is significantly and inversely correlated with cIMT measurements. Correlation of small+medium HDL‐P with cardioprotective paraoxonase 1 activity may reflect a functional aspect of HDL responsible for this finding.
doi:10.1161/JAHA.115.002977
PMCID: PMC4889175  PMID: 27207961
antioxidant; carotid intima media thickening; cerebrovascular disease; high‐density lipoprotein cholesterol; high‐density lipoprotein particle concentration; paraoxonase 1; Cardiovascular Disease; Lipids and Cholesterol; Oxidant Stress; Cerebrovascular Disease/Stroke
8.  Association of Subclinical Atherosclerosis Using Carotid Intima-Media Thickness, Carotid Plaque, and Coronary Calcium Score with Left Ventricular Dyssynchrony: The Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2015;239(2):412-418.
Background
The role of atherosclerosis in the progression of global left ventricular dysfunction and cardiovascular events has been well recognized. Left ventricular (LV) dyssynchrony is a measure of regional myocardial dysfunction. Our objective was to investigate the relationship of subclinical atherosclerosis with mechanical LV dyssynchrony in a population-based asymptomatic multi-ethnic cohort.
Methods and Results
Participants of the Multi-Ethnic Study of Atherosclerosis (MESA) at exam 5 were evaluated using 1.5T cardiac magnetic resonance (CMR) imaging, carotid ultrasound (n=2,062) for common carotid artery (CCA) and internal carotid artery (ICA) intima-media thickness (IMT), and cardiac computed tomography (n=2,039) for coronary artery calcium (CAC) assessment (Agatston method). Dyssynchrony indices were defined as the standard deviation of time to peak systolic circumferential strain (SD-TPS) and the difference between maximum and minimum (max-min) time to peak strain using harmonic phase imaging in 12 segments (3-slices × 4 segments). Multivariable regression analyses were performed to assess associations after adjusting for participant demographics, cardiovascular risk factors, LV mass, and ejection fraction. In multivariable analyses, SD-TPS was significantly related to measures of atherosclerosis, including CCA-IMT (8.7msec/mm change in IMT, p=0.020), ICA-IMT (19.2 msec/mm change in IMT, p<0.001), carotid plaque score (1.2 msec/unit change in score, p<0.001), and log transformed CAC+1 (0.66 msec/unit log-CAC+1, p=0.018). These findings were consistent with other parameter of LV dyssynchrony i.e. max-min.
Conclusion
In the MESA cohort, measures of atherosclerosis are associated with parameters of subclinical LV dyssynchrony in the absence of clinical coronary event and left-bundle-branch block.
doi:10.1016/j.atherosclerosis.2015.01.041
PMCID: PMC4361257  PMID: 25682041
Left Ventricular Dyssynchrony; Carotid IMT; Coronary Calcium Score; Atherosclerosis
9.  The Relationship of Cigarette Smoking with Inflammation and Subclinical Vascular Disease: The Multi-Ethnic Study of Atherosclerosis 
Objectives
We sought to assess the impact of smoking status, cumulative pack-years, and time since cessation (the latter in former-smokers only) on three important domains of cardiovascular disease (CVD): inflammation, vascular dynamics and function, and subclinical atherosclerosis.
Approach and Results
The MESA cohort enrolled 6,814 adults without prior CVD. Smoking variables were determined by self-report and confirmed with urinary cotinine. We examined cross-sectional associations between smoking parameters and; 1) inflammatory biomarkers (high-sensitivity C-reactive protein [hsCRP], interleukin-6 [IL-6], and fibrinogen); 2) vascular dynamics and function (brachial flow-mediated dilation [FMD] and carotid distensibility by ultrasound, as well as aortic distensibility by MRI); and 3) subclinical atherosclerosis (coronary artery calcification [CAC], carotid intima-media thickness [CIMT], and ankle-brachial index [ABI]). We identified 3,218 never-smokers, 2,607 former-smokers, and 971 current-smokers. Mean age was 62 years and 47% were male. There was no consistent association between smoking and vascular distensibility or FMD outcomes. In contrast, compared to never-smokers, the adjusted association between current-smoking and measures of either inflammation or subclinical atherosclerosis was consistently stronger than for former-smoking (e.g. odds-ratio (OR) for hs-CRP > 2mg/L of 1.7 [95%CI, 1.5-2.1] Vs. 1.2 [1.1-1.4], OR for CAC > 0 of 1.8 [1.5-2.1] Vs. 1.4 [1.2-1.6], respectively). Similar associations were seen for IL-6, fibrinogen, CIMT, and ABI. A monotonic relationship was also found between increasing pack-years exposure and elevated inflammatory markers. Further, current smokers with hsCRP > 2mg/L were more likely to have increased CIMT, abnormal ABI, and CAC > 75th percentile for age, sex and race (relative to smokers with hsCRP < 2mg/L, interaction p < 0.05 for all three outcomes). In contrast, time since quitting in former-smokers was independently associated with lower inflammation and atherosclerosis (e.g. OR for hsCRP > 2mg/L of 0.91 [0.88-0.95] and OR for CAC > 0 of 0.94 [0.90-0.97] for every 5-year cessation interval).
Conclusion
These findings expand our understanding of the harmful effects of smoking and help explain the cardiovascular benefits of smoking cessation.
doi:10.1161/ATVBAHA.114.304960
PMCID: PMC4484586  PMID: 25745060
Smoking; Inflammation; Atherosclerosis; Coronary Artery Calcium
10.  Carotid Atherosclerosis and Cerebral Microbleeds: The Framingham Heart Study 
Background
Carotid atherosclerosis is associated with subclinical ischemic cerebrovascular disease, but its role in hemorrhage‐prone small vessel disease—represented by cerebral microbleed (CMB)—is unclear, although vascular risk factors underlie both conditions. We hypothesized that persons with carotid atherosclerosis would have higher risk of CMB, particularly in deep regions.
Methods and Results
We studied 1243 participants in the Framingham Offspring Study (aged 56.9±8.8 years; 53% women) with carotid ultrasound available on 2 occasions (1995–1998 and 2005–2008) prior to brain magnetic resonance imaging. Using multivariable logistic regression, we related baseline carotid stenosis, baseline intima–media thickness, and site‐specific carotid intima–media thickness progression (at internal and common carotid locations) to the prevalence and location (lobar or deep plus mixed) of CMB. In addition, we assessed effect modification by lipid levels and use of statin and antithrombotic medications. Carotid stenosis ≥25% (a marker of cerebrovascular atherosclerosis) was associated with presence of CMB overall (Odds Ratio 2.20, 95% CI 1.10–4.40) and at deep and mixed locations (odds ratio 3.60, 95% CI 1.23–10.5). Baseline carotid intima–media thickness was not associated with CMB. Progression of common carotid artery intima–media thickness among persons on hypertension treatment was associated with lower risk of deep and mixed CMB (odds ratio per SD 0.41, 95% CI 0.18–0.96).
Conclusions
Cumulative vascular risk factor exposure may increase the risk of CMB, especially in deep regions. The apparent paradoxical association of carotid intima–media thickness progression with lower risk of CMB may reflect benefits of intensive vascular risk factor treatment among persons with higher cardiovascular risk and deserves further investigation. If replicated, the results may have potential implications for assessment of preventive and therapeutic interventions for subclinical cerebral hemorrhage.
doi:10.1161/JAHA.115.002377
PMCID: PMC4943235  PMID: 26994127
brain magnetic resonance imaging; carotid atherosclerosis; carotid intima–media thickness; cerebral microbleeds; Epidemiology; Magnetic Resonance Imaging (MRI); Ultrasound; Cerebrovascular Disease/Stroke; Atherosclerosis
11.  Detailed analysis of association between common single nucleotide polymorphisms and subclinical atherosclerosis: The Multi-ethnic Study of Atherosclerosis 
Data in Brief  2016;7:229-242.
Previously identified single nucleotide polymorphisms (SNPs) in genome wide association studies (GWAS) of cardiovascular disease (CVD) in participants of mostly European descent were tested for association with subclinical cardiovascular disease (sCVD), coronary artery calcium score (CAC) and carotid intima media thickness (CIMT) in the Multi-Ethnic Study of Atherosclerosis (MESA). The data in this data in brief article correspond to the article Common Genetic Variants and Subclinical Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis [1]. This article includes the demographic information of the participants analyzed in the article as well as graphical displays and data tables of the association of the selected SNPs with CAC and of the meta-analysis across ethnicities of the association of CIMT-c (common carotid), CIMT-I (internal carotid), CAC-d (CAC as dichotomous variable with CAC>0) and CAC-c (CAC as continuous variable, the log of the raw CAC score plus one) and CVD. The data tables corresponding to the 9p21 fine mapping experiment as well as the power calculations referenced in the article are also included.
doi:10.1016/j.dib.2016.01.048
PMCID: PMC4773483  PMID: 26958643
Single nucleotide polymorphism (SNP); Common genetic variant; Subclincal atherosclerosis; Coronary artery calcium (CAC); Carotid intima-media thickness (CIMT)
12.  Inflammatory markers and extent and progression of early atherosclerosis: Meta-analysis of individual-participant-data from 20 prospective studies of the PROG-IMT collaboration 
Background
Large-scale epidemiological evidence on the role of inflammation in early atherosclerosis, assessed by carotid ultrasound, is lacking. We aimed to quantify cross-sectional and longitudinal associations of inflammatory markers with common-carotid-artery intima-media thickness (CCA-IMT) in the general population.
Methods
Information on high-sensitivity C-reactive protein, fibrinogen, leucocyte count and CCA-IMT was available in 20 prospective cohort studies of the PROG-IMT collaboration involving 49,097 participants free of pre-existing cardiovascular disease. Estimates of associations were calculated within each study and then combined using random-effects meta-analyses.
Results
Mean baseline CCA-IMT amounted to 0.74mm (SD = 0.18) and mean CCA-IMT progression over a mean of 3.9 years to 0.011 mm/year (SD = 0.039). Cross-sectional analyses showed positive linear associations between inflammatory markers and baseline CCA-IMT. After adjustment for traditional cardiovascular risk factors, mean differences in baseline CCA-IMT per one-SD higher inflammatory marker were: 0.0082mm for high-sensitivity C-reactive protein (p < 0.001); 0.0072mm for fibrinogen (p < 0.001); and 0.0025mm for leucocyte count (p = 0.033). ‘Inflammatory load’, defined as the number of elevated inflammatory markers (i.e. in upper two quintiles), showed a positive linear association with baseline CCA-IMT (p < 0.001). Longitudinal associations of baseline inflammatory markers and changes therein with CCA-IMT progression were null or at most weak. Participants with the highest ‘inflammatory load’ had a greater CCA-IMT progression (p = 0.015).
Conclusion
Inflammation was independently associated with CCA-IMT cross-sectionally. The lack of clear associations with CCA-IMT progression may be explained by imprecision in its assessment within a limited time period. Our findings for ‘inflammatory load’ suggest important combined effects of the three inflammatory markers on early atherosclerosis.
doi:10.1177/2047487314560664
PMCID: PMC4544641  PMID: 25416041
Inflammation; atherosclerosis; meta-analysis
13.  Association of exhaled carbon monoxide with subclinical cardiovascular disease and their conjoint impact on the incidence of cardiovascular outcomes 
European Heart Journal  2014;35(42):2980-2987.
Aims
Whereas endogenous carbon monoxide (CO) is cytoprotective at physiologic levels, excess CO concentrations are associated with cardiometabolic risk and may represent an important marker of progression from subclinical to clinical cardiovascular disease (CVD).
Methods and results
In 1926 participants of the Framingham Offspring Study (aged 57 ± 10 years, 46% women), we investigated the relationship of exhaled CO, a surrogate of blood CO concentration, with both prevalent subclinical CVD and incident clinical CVD events. Presence of subclinical CVD was determined using a comprehensive panel of diagnostic tests used to assess cardiac and vascular structure and function. Individuals with the highest (>5 p.p.m.) compared with lowest (≤4 p.p.m.) CO exposure were more likely to have subclinical CVD [odds ratios (OR): 1.67, 95% CI: 1.32–2.12; P < 0.001]. During the follow-up period (mean 5 ± 3 years), 193 individuals developed overt CVD. Individuals with both high CO levels and any baseline subclinical CVD developed overt CVD at an almost four-fold higher rate compared with those with low CO levels and no subclinical disease (22.1 vs. 6.3%). Notably, elevated CO was associated with incident CVD in the presence [hazards ration (HR): 1.83, 95% CI: 1.08–3.11; P = 0.026] but not in the absence (HR: 0.80, 95% CI: 0.42–1.53; P = 0.51) of subclinical CVD (Pinteraction = 0.019). Similarly, subclinical CVD was associated with incident CVD in the presence of high but not low CO exposure.
Conclusion
Our findings in a community-based sample suggest that elevated CO is a marker of greater subclinical CVD burden and, furthermore, a potential key component in the progression from subclinical to clinical CVD.
doi:10.1093/eurheartj/ehu052
PMCID: PMC4271053  PMID: 24574370
Carbon monoxide; Subclinical vascular disease; Cardiovascular outcomes
14.  Healthy Lifestyle Change and Subclinical Atherosclerosis in Young Adults: Coronary Artery Risk Development in Young Adults (CARDIA) Study 
Circulation  2014;130(1):10-17.
Background
The benefits of healthy habits are well-established, but it is unclear whether making health behavior changes as an adult can still alter coronary artery disease risk.
Methods and Results
The Coronary Artery Risk Development in Young Adults (CARDIA) prospective cohort study (n = 3538) assessed 5 healthy lifestyle factors (HLFs) among young adults between ages 18–30 (Year 0 baseline) and 20 years later (Year 20): not overweight/obese, low alcohol intake, healthy diet, physically active, nonsmoker. We tested whether change from Year 0 to 20 in a continuous composite HLF score (HLF change; range: −5 to +5) is associated with subclinical atherosclerosis [coronary artery calcification (CAC) and carotid intima-media thickness (IMT)] at Year 20, after adjustment for demographics, medications, and baseline HLFs. By Year 20, 25·3% of the sample improved (HLF change ≥ +1); 40·4% deteriorated (had fewer HLFs); 34·4% stayed the same; 19·2% had CAC (>0). Each increase in HLFs was associated with reduced odds of detectable CAC (OR = .85, 95% CI: .74 – .98) and lower IMT (carotid bulb β = −.024, p = 0.001), and each decrease in HLFs was predictive to a similar degree of greater odds of CAC (OR = 1.17, 95% CI: 1.02 – 1.33) and greater IMT (β = +.020, p < 0.01).
Conclusions
Healthy lifestyle changes during young adulthood are associated with decreased, and unhealthy lifestyle changes with increased risk for subclinical atherosclerosis in middle age.
doi:10.1161/CIRCULATIONAHA.113.005445
PMCID: PMC4615574  PMID: 24982115
epidemiology; follow-up studies; risk factors; prevention; behavior modification
15.  Individual-Level Concentrations of Fine Particulate Matter Chemical Components and Subclinical Atherosclerosis: A Cross-Sectional Analysis Based on 2 Advanced Exposure Prediction Models in the Multi-Ethnic Study of Atherosclerosis 
American Journal of Epidemiology  2014;180(7):718-728.
Long-term exposure to outdoor particulate matter with an aerodynamic diameter less than or equal to 2.5 µm (PM2.5) has been associated with cardiovascular morbidity and mortality. The chemical composition of PM2.5 that may be most responsible for producing these associations has not been identified. We assessed cross-sectional associations between long-term concentrations of PM2.5 and 4 of its chemical components (sulfur, silicon, elemental carbon, and organic carbon (OC)) and subclinical atherosclerosis, measured as carotid intima-media thickness (CIMT) and coronary artery calcium, between 2000 and 2002 among 5,488 Multi-Ethnic Study of Atherosclerosis participants residing in 6 US metropolitan areas. Long-term concentrations of PM2.5 components at participants' homes were predicted using both city-specific spatiotemporal models and a national spatial model. The estimated differences in CIMT associated with interquartile-range increases in sulfur, silicon, and OC predictions from the spatiotemporal model were 0.022 mm (95% confidence interval (CI): 0.014, 0.031), 0.006 mm (95% CI: 0.000, 0.012), and 0.026 mm (95% CI: 0.019, 0.034), respectively. Findings were generally similar using the national spatial model predictions but were often sensitive to adjustment for city. We did not find strong evidence of associations with coronary artery calcium. Long-term concentrations of sulfur and OC, and possibly silicon, were associated with CIMT using 2 distinct exposure prediction modeling approaches.
doi:10.1093/aje/kwu186
PMCID: PMC4172166  PMID: 25164422
atherosclerosis; cardiovascular diseases; carotid intima-media thickness; cohort studies; particulate matter
16.  Associations of common carotid intima-media thickness (IMT) with coronary heart disease risk factors and events vary with distance from the carotid bulb 
Background
Common carotid artery (CCA) intima-media thickness (IMT) can be measured by ultrasound near to or below the carotid bulb. This might affect associations of IMT with coronary heart disease (CHD) risk factors and events.
Methods
We performed IMT measurements near and below the divergence of the CCA bulb, in 279 white individuals, aged 45–54 years, free of CHD at baseline and a subset of the Multi-Ethnic Study of Atherosclerosis (MESA), a cohort composed of Whites, Blacks, Chinese and Hispanics. Participants were followed for an average of 8.2 years. Far wall mean of the maximum IMT (MMaxIMT) and mean of the mean IMT (MMeanIMT) of the right and left CCA were averaged. Framingham risk factors were used in multivariable linear regression models. Parsimonious Cox proportional regression models included first time CHD as outcome.
Results
MMeanIMT below the bulb was smaller than near the bulb (0.51 mm +/− 0.078 mm versus 0.56 +/− 0.088 mm; p < 0.001) and had similar associations with risk factors (model R2 of 0.215 versus 0.186). MMaxIMT below the bulb was associated with risk factors (model R2: 0.211), MMaxIMT near to the bulb was not (R2: 0.025). MMeanIMT and MMaxIMT below the bulb were associated with CHD events (HR 1.67; p = 0.047 and 1.72; p= 0.037, respectively) but not when measured near the bulb.
Conclusions
CCA IMT measurements made below the bulb are smaller but have more consistent associations with CHD risk factors and outcomes as compared to IMT measured near the bulb.
doi:10.1016/j.echo.2014.04.019
PMCID: PMC4149919  PMID: 24944141
risk factors; common carotid artery; ultrasound; coronary heart disease; intima media thickness; carotid artery bifurcation
17.  What Do Carotid Intima-Media Thickness and Plaque Add to Prediction of Stroke and Cardiovascular Disease Risk in Older Adults? The Cardiovascular Health Study 
Background
We evaluated whether addition of carotid ultrasound intima-media thickness (CIMT) measurements and risk categories of plaque help predict incident stroke and CVD in older adults.
Methods
Carotid ultrasound studies were recorded in the multicenter Cardiovascular Health Study (CHS). Cardiovascular disease (CVD) was defined as coronary heart disease plus heart failure plus stroke. Ten-year risk prediction Cox proportional hazards models for stroke and CVD were calculated using CHS-specific coefficients for Framingham Risk Score (FRS) factors. Categories of CIMT and CIMT plus plaque were added to FRS prediction models and categorical net reclassification improvement (NRI) and Harrell’s c-statistic were calculated.
Results
In 4,384 CHS participants (61% women, 14% black, baseline age 72 ± 5 yrs) without CVD at baseline, higher CIMT category and presence of plaque were both associated with higher incidence rates for stroke and CVD. Addition of CIMT improved ability of FRS-type risk models to discriminate cases from non-cases of incident stroke and CVD (NRI = 0.062, p=0.015 and NRI=0.027, p<0.001 respectively), with no further improvement by adding plaque. For both outcomes, NRI was driven by down-classifying those without incident disease. Although addition of plaque to CIMT did not result in a significant NRI for either outcome, it was significant among those without incident disease.
Conclusion
In older adults, addition of CIMT modestly improves 10-year risk prediction for stroke and CVD beyond a traditional risk factor model, mainly by down-classifying risk in those without stroke or CVD; addition of plaque to CIMT adds no statistical benefit in the overall cohort, although there is evidence of down-classification in those without events.
doi:10.1016/j.echo.2014.06.013
PMCID: PMC4158921  PMID: 25172401
18.  Common Carotid Intima-Media Thickness Measurements Do Not Improve Cardiovascular Risk Prediction in Individuals With Elevated Blood Pressure 
Hypertension  2014;63(6):1173-1181.
Carotid intima-media thickness (CIMT) is a marker of cardiovascular risk. It is unclear whether measurement of mean common CIMT improves 10-year risk prediction of first-time myocardial infarction or stroke in individuals with elevated blood pressure. We performed an analysis among individuals with elevated blood pressure (ie, a systolic blood pressure ≥140 mm Hg and a diastolic blood pressure ≥ 90 mm Hg) in USE-IMT, a large ongoing individual participant data meta-analysis. We refitted the risk factors of the Framingham Risk Score on asymptomatic individuals (baseline model) and expanded this model with mean common CIMT (CIMT model) measurements. From both models, 10-year risks to develop a myocardial infarction or stroke were estimated. In individuals with elevated blood pressure, we compared discrimination and calibration of the 2 models and calculated the net reclassification improvement (NRI). We included 17 254 individuals with elevated blood pressure from 16 studies. During a median follow-up of 9.9 years, 2014 first-time myocardial infarctions or strokes occurred. The C-statistics of the baseline and CIMT models were similar (0.73). NRI with the addition of mean common CIMT was small and not significant (1.4%; 95% confidence intervals, −1.1 to 3.7). In those at intermediate risk (n=5008, 10-year absolute risk of 10% to 20%), the NRI was 5.6% (95% confidence intervals, 1.6–10.4). There is no added value of measurement of mean common CIMT in individuals with elevated blood pressure for improving cardiovascular risk prediction. For those at intermediate risk, the addition of mean common CIMT to an existing cardiovascular risk score is small but statistically significant.
doi:10.1161/HYPERTENSIONAHA.113.02683
PMCID: PMC4523133  PMID: 24614213
atherosclerosis; carotid intima-media thickness; primary prevention; prognosis; risk
19.  Mediation of Cardiovascular Risk Factor Effects Through Subclinical Vascular Disease: The Multi-Ethnic Study of Atherosclerosis 
Objective
It is unclear to what extent subclinical cardiovascular disease (CVD) such as coronary artery calcium (CAC), carotid intima-media thickness (CIMT) and brachial flow mediated dilation (FMD) are mediators of the known associations between traditional cardiovascular risk factors and incident CVD events. We assessed the portion of the effects of risk factors on incident CVD events that are mediated through CAC, CIMT and FMD.
Approach and Results
6355 out of 6814 MESA participants were included. Nonlinear implementation of structural equation modeling (STATA mediation package) were used to assess whether CAC, CIMT or FMD are mediators of the association between traditional risk factors and incident CVD event.
Mean age of 62, with 47% males, 12% diabetics and 13% current smokers. Mean follow up of 7.5 years, 539 CVD events were adjudicated. CAC showed the highest mediation while FMD showed the least. Age had the highest percent of total effect mediated via CAC for CVD outcomes while current cigarette smoking had the least percent of total effect mediated via CAC [percent (95%CI: 80.2(58.8, 126.7) % vs. 10.6(6.1, 38.5) % respectively). BMI showed the highest percent of total effect mediated via CIMT [17.7(11.6, 38.9) %], only a negligible amount of the association between traditional risk factors and CVD was mediated via FMD.
Conclusion
Many of the risk factors for incident CVD (other than age, sex and BMI) showed a modest level of mediation via CAC, CIMT and FMD suggesting that current subclinical CVD markers may not be optimal intermediaries for gauging upstream risk factor modification
doi:10.1161/ATVBAHA.114.303753
PMCID: PMC4329880  PMID: 24876350
20.  Association of Parity with Carotid Diameter and Distensibility: Multi-Ethnic Study of Atherosclerosis 
Hypertension  2014;64(2):253-258.
Pregnancy and childbirth are associated with hemodynamic changes and vascular remodeling. It is not known whether parity is associated with later adverse vascular properties such as larger arterial diameter, wall thickness and lower distensibility.
We used baseline data from 3283 women free of cardiovascular disease aged 45-84 years enrolled in the population based Multi-Ethnic Study of Atherosclerosis. Participants self-reported parity status. Ultrasound derived carotid artery lumen diameters and brachial artery blood pressures were measured at peak-systole and end-diastole. Common carotid intima media thickness (cIMT) was also measured. Regression models to determine the association of carotid distensibility coefficient, lumen diameter, and cIMT with parity were adjusted for age, race, height, weight, diabetes, current smoking, BP medication use, total and high density lipoprotein cholesterol levels.
The prevalence of nulliparity was 18%. In adjusted models, carotid distensibility coefficient was 0.09 × 10−5Pa−1 lower (p = 0.009) in parous vs. nulliparous women. Among parous women, there was a nonlinear association with the greatest carotid DC seen in women with 2 live births, and significantly lower distensibility seen in primiparas (p=0.04) or with higher parity > 2 (p=0.005). No such pattern of association with parity was found for lumen diameter or cIMT.
Parity is associated with lower carotid artery distensibility, suggesting arterial remodeling that lasts beyond childbirth. These long-term effects on the vasculature may explain the association of parity with cardiovascular events later in life.
doi:10.1161/HYPERTENSIONAHA.114.03285
PMCID: PMC4184976  PMID: 24842921
common carotid artery; arterial stiffness; carotid intima-media thickness; women; pregnancy
21.  Race/Ethnic Differences in the Associations of the Framingham Risk Factors with Carotid IMT and Cardiovascular Events 
PLoS ONE  2015;10(7):e0132321.
Background
Clinical manifestations and outcomes of atherosclerotic disease differ between ethnic groups. In addition, the prevalence of risk factors is substantially different. Primary prevention programs are based on data derived from almost exclusively White people. We investigated how race/ethnic differences modify the associations of established risk factors with atherosclerosis and cardiovascular events.
Methods
We used data from an ongoing individual participant meta-analysis involving 17 population-based cohorts worldwide. We selected 60,211 participants without cardiovascular disease at baseline with available data on ethnicity (White, Black, Asian or Hispanic). We generated a multivariable linear regression model containing risk factors and ethnicity predicting mean common carotid intima-media thickness (CIMT) and a multivariable Cox regression model predicting myocardial infarction or stroke. For each risk factor we assessed how the association with the preclinical and clinical measures of cardiovascular atherosclerotic disease was affected by ethnicity.
Results
Ethnicity appeared to significantly modify the associations between risk factors and CIMT and cardiovascular events. The association between age and CIMT was weaker in Blacks and Hispanics. Systolic blood pressure associated more strongly with CIMT in Asians. HDL cholesterol and smoking associated less with CIMT in Blacks. Furthermore, the association of age and total cholesterol levels with the occurrence of cardiovascular events differed between Blacks and Whites.
Conclusion
The magnitude of associations between risk factors and the presence of atherosclerotic disease differs between race/ethnic groups. These subtle, yet significant differences provide insight in the etiology of cardiovascular disease among race/ethnic groups. These insights aid the race/ethnic-specific implementation of primary prevention.
doi:10.1371/journal.pone.0132321
PMCID: PMC4489855  PMID: 26134404
22.  Relationship of Change in Traditional Cardiometabolic Risk Factors to Change in Coronary Artery Calcification Among Individuals with Detectable Subclinical Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis 
Background/Objectives
Data describing relationships between change in risk factors and coronary artery calcification (CAC) are lacking and could inform optimal cardiovascular disease prevention and treatment strategies. This study aimed to examine how change in traditional cardiometabolic risk factors related to change in CAC among individuals with detectable subclinical atherosclerosis.
Methods
Latent growth modeling was used to examine change in cardiometabolic risk factors (waist circumference, body mass index, systolic and diastolic blood pressure, high- and low-density lipoprotein cholesterol, triglycerides, and glucose) related to change in CAC up to an average 4.9-year follow-up in a multi-ethnic cohort of 3,398 asymptomatic individuals (57.8% men) who had detectable CAC (score > 0) at baseline, adjusting for baseline risk factor levels and CAC values, age, gender, race/ethnicity, smoking, family history of CVD, income, and use of antihypertensive, lipid-lowering, and glucose-lowering medications.
Results
Greater declines in blood pressure (systolic and diastolic) and low-density lipoprotein cholesterol at follow-up were each associated with greater CAC progression. The observed inverse associations were attributable to greater CAC progression in participants taking antihypertensive and lipid-lowering drugs who, as expected, had declines in blood pressure and lipid levels, respectively. These inverse associations did not emerge in participants not taking these medications.
Conclusions
Among individuals with subclinical atherosclerosis, the unexpected inverse associations observed between change in blood pressure and lipid levels with CAC progression emphasize the importance of considering medication use, and, when feasible, the severity and duration of disease, in exploring associations between risk factors and CAC change.
doi:10.1016/j.ijcard.2014.03.137
PMCID: PMC4060615  PMID: 24698232
risk factors; coronary artery calcification; atherosclerosis
23.  Plasma and serum L-selectin and clinical and subclinical the Multi-Ethnic Study of Atherosclerosis (MESA)cardiovascular disease 
L-selectin has been suggested to play a role in atherosclerosis. Previous studies on cardiovascular disease (CVD) and serum or plasma L-selectin are inconsistent. The association of serum L-selectin (sL-selectin) with carotid intima-media thickness, coronary artery calcium, ankle-brachial index (subclinical CVD) and incident CVD was assessed within 2403 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Regression analysis and the Tobit model were used to study subclinical disease; Cox Proportional Hazards regression for incident CVD. Mean age was 63 ± 10, 47% were males; mean sL-selectin was significantly different across ethnicities. Within each race/ethnicity, sL-selectin was associated with age and sex; among Caucasians and African Americans, it was associated with smoking status and current alcohol use. sL-selectin levels did not predict subclinical or clinical CVD after correction for multiple comparisons. Conditional logistic regression models were used to study plasma L-selectin and CVD within 154 incident CVD cases, occurred in a median follow up of 8.5 years, and 306 age-, sex-, and ethnicity-matched controls. L-selectin levels in plasma were significantly lower than in serum and the overall concordance was low. Plasma levels were not associated with CVD. In conclusion, this large multi-ethnic population, soluble L-selectin levels did not predict clinical or subclinical CVD.
doi:10.1016/j.trsl.2014.02.001
PMCID: PMC4029851  PMID: 24631064
atherosclerosis; cardiovascular diseases; ethnic groups; L-selectin
24.  Systemic inflammation and cardiovascular risk factors predict rapid progression of atherosclerosis in rheumatoid arthritis 
Annals of the rheumatic diseases  2014;74(6):1118-1123.
Objective
To estimate atherosclerosis progression and identify influencing factors in rheumatoid arthritis (RA).
Methods
We used carotid ultrasound to measure intima-media thickness (IMT) in RA patients, and ascertained cardiovascular (CV) risk factors, inflammation markers and medications. A second ultrasound was performed approximately 3 years later. We calculated the progression rate by subtracting the baseline from the follow-up IMT, divided by the time between the two scans. We used logistic regression to identify baseline factors predictive of rapid progression. We tested for interactions of erythrocyte sedimentation rate (ESR) with CV risk factors and medication use.
Results
Results were available for 487 RA patients. The mean (SD) common carotid IMT at baseline was 0.571 mm (0.151). After a mean of 2.8 years, the IMT increased by 0.050 mm (0.055), p≤0.001, a progression rate of 0.018 mm/year (95% CI 0.016 to 0.020). Baseline factors associated with rapid progression included the number of CV risk factors (OR 1.27 per risk factor, 95% CI 1.01 to 1.61), and the ESR (OR 1.12 per 10 mm/h, 95% CI 1.02 to 1.23). The ESR×CV risk factor and ESR×medication product terms were significant, suggesting these variables modify the association between the ESR and IMT progression.
Conclusions
Systemic inflammation and CV risk factors were associated with rapid IMT progression. CV risk factors may modify the role of systemic inflammation in determining IMT progression over time. Methotrexate and antitumour necrosis factor agents may influence IMT progression by reducing the effect of the systemic inflammation on the IMT.
doi:10.1136/annrheumdis-2013-205058
PMCID: PMC4239202  PMID: 24845391
25.  Edge-Detected Common Carotid Artery Intima–Media Thickness and Incident Coronary Heart Disease in the Multi-Ethnic Study of Atherosclerosis 
Background
Common carotid artery intima–media thickness (IMT) can be measured either by hand or with an automated edge detector. We performed a direct comparison of these 2 approaches and studied their respective associations with coronary heart disease outcomes.
Methods and Results
We studied 5468 participants of the Multi-Ethnic Study of Atherosclerosis, composed of white, Chinese, Hispanic, and black participants with an average age of 61.9 years (47.8% men) and who were free of coronary heart disease at baseline. Manual-traced and edge-detected IMT measurements were made in the same location on ultrasound images of the right common carotid artery far wall in an area free of plaque. Manual-traced and edge-detected common carotid artery IMT measurements were added separately to multivariable Cox proportional hazards models with time to incident coronary heart disease as the outcome and adjusted for traditional coronary heart disease Framingham risk factors, lipid-lowering therapy, blood pressure–lowering therapy, and race or ethnicity. Additional models were generated after adding clinic site and reader. There were 349 events during a median follow-up of 10.2 years. In adjusted models, the hazard ratio was not significant (1.31; 95% CI 0.84 to 2.06) for each millimeter increase in manual-traced IMT but was significant for edge-detected IMT (hazard ratio 1.63; 95% CI 1.12 to 2.37). Edge-detected IMT remained statistically associated with outcomes after additional adjustment for clinic site and reader performing the IMT measurement (hazard ratio 1.59; 95% CI 1.07 to 2.35).
Conclusions
Edge-detected common carotid artery far wall IMT has similar if not stronger associations with coronary heart disease outcomes when compared with manual-traced IMT.
Clinical Trial Registration
URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00063440.
doi:10.1161/JAHA.114.001492
PMCID: PMC4599522  PMID: 26077584
atherosclerosis; carotid arteries; epidemiology; risk factors; ultrasonics

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