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1.  Cross-Sectional Comparison of Coronary Artery Calcium Scores Between Caucasian Men in the United States and Japanese Men in Japan 
American Journal of Epidemiology  2014;180(6):590-598.
The incidence of coronary heart disease in the United States has declined, and prevalences of several coronary disease risk factors have become comparable to those in Japan. Therefore, the burden of coronary atherosclerosis may be closer among younger persons in the 2 countries. We aimed to compare prevalences of coronary atherosclerosis, measured with coronary artery calcium scores, between men in the 2 countries by age group (45–54, 55–64, or 65–74 years). We used community-based samples of Caucasian men in the United States (2000–2002; n = 1,067) and Japanese men in Japan (2006–2008; n = 832) aged 45–74 years, stratifying them into groups with 0, 1, 2, or ≥3 of the following risk factors: current smoking, overweight, diabetes, dyslipidemia, and hypertension. We calculated adjusted odds ratios of US Caucasian men's having Agatston scores of ≥10, ≥100, and ≥400 with reference to Japanese men. Overall, the odds of Caucasian men having each Agatston cutoff point were greater. The ethnic difference, however, became smaller in younger age groups. For example, adjusted odds ratios for Caucasian men's having an Agatston score of ≥100 were 2.05, 2.43, and 3.86 among those aged 45–54, 55–64, and 65–74 years, respectively. Caucasian men in the United States had a higher burden of coronary atherosclerosis than Japanese men, but the ethnic difference was smaller in younger age groups.
doi:10.1093/aje/kwu169
PMCID: PMC4157702  PMID: 25125689
atherosclerosis; coronary artery calcium; ethnic group; men
2.  METHODS AND BASELINE CARDIOVASCULAR DATA FROM THE EARLY VERSUS LATE INTERVENTION TRIAL WITH ESTRADIOL TESTING THE MENOPAUSAL HORMONE TIMING HYPOTHESIS 
Menopause (New York, N.Y.)  2015;22(4):391-401.
Objective
To present methods and baseline data from the Early versus Late Intervention Trial with Estradiol (ELITE), the only clinical trial designed to specifically test the timing hypothesis of postmenopausal hormone therapy (HT). The timing hypothesis posits that HT effects depend on the temporal initiation of HT relative to time-since-menopause.
Methods
ELITE is a randomized, double-blinded, placebo-controlled trial with a 2x2 factorial design. 643 healthy postmenopausal women without cardiovascular disease were randomized to oral estradiol or placebo for up to 6-7 years according to number of years-since-menopause, <6 years or ≥10 years. Carotid artery intima-media thickness (CIMT) and cardiac computed tomography were conducted to determine HT effects on subclinical atherosclerosis across menopause strata.
Results
Participants in the early and late postmenopausal strata were well-separated by mean age, 55.4 versus 65.4 years and median time-since-menopause, 3.5 versus 14.3 years, respectively. The expected risk factors were associated with CIMT at baseline in both strata (age, blood pressure and body mass index). In the early but not in the late postmenopausal group, there were significant associations between CIMT and factors that may play a role in responsiveness of atherosclerosis progression according to timing of HT initiation. These include LDL-C, HDLC, sex hormone binding globulin and serum total estradiol.
Conclusion
The ELITE randomized controlled trial is timely and unique. Baseline data indicate that ELITE is well-positioned to test the HT timing hypothesis in relation to atherosclerosis progression and coronary artery disease. (NCT00114517; www.clinicaltrials.gov)
doi:10.1097/GME.0000000000000343
PMCID: PMC4376597  PMID: 25380275
menopause; postmenopause; women; hormone therapy; estrogen; randomized trials; cardiovascular disease; cognition; timing hypothesis
3.  The Association of Nonalcoholic Fatty Liver Disease, Obesity, and Metabolic Syndrome, with Systemic Inflammation and Subclinical Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Atherosclerosis  2015;239(2):629-633.
Introduction
We characterized the association of 3 metabolic conditions – obesity, metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD) – with increased inflammation and subclinical atherosclerosis.
Methods
We conducted cross-sectional analysis of 3,976 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) with adequate CT imaging to diagnose NAFLD. Obesity was defined as BMI ≥30 kg/m2, metabolic syndrome by AHA/NHLBI criteria, and NAFLD using non-contrast cardiac CT and a liver/spleen attenuation ratio (L/S) <1. Increased inflammation was defined as high sensitivity C-reactive protein (hsCRP) ≥2 mg/L and subclinical atherosclerosis as coronary artery calcium (CAC) >0. We studied the association of a stepwise increase in number of these metabolic conditions (0–3) with increased inflammation and CAC, stratifying results by gender and ethnicity.
Results
Mean age of participants was 63 (±10) years, 45% were male, 37% white, 10% Chinese, 30% African American, and 23% Hispanic. Adjusting for obesity, metabolic syndrome and traditional risk factors, NAFLD was associated with a prevalence odds ratio for hsCRP ≥2 mg/L and CAC >0 of 1.47 (1.20–1.79) and 1.37 (1.11–1.68) respectively. There was a positive interaction between female gender and NAFLD in the association with hsCRP ≥2 mg/L (p= 0.006), with no interaction by race. With increasing number of metabolic conditions, there was a graded increase in prevalence odds ratios of hsCRP ≥2 mg/L and CAC >0.
Conclusion
NAFLD is associated with increased inflammation and CAC independent of traditional risk factors, obesity and metabolic syndrome. There is a graded association between obesity, metabolic syndrome, and NAFLD with inflammation and CAC.
doi:10.1016/j.atherosclerosis.2015.02.011
PMCID: PMC4406399  PMID: 25683387
4.  Prognostic and Therapeutic Implications of Statin and Aspirin Therapy in Individuals With Nonobstructive Coronary Artery Disease 
Objective
We sought to examine the risk of mortality associated with nonobstructive coronary artery disease (CAD) and to determine the impact of baseline statin and aspirin use on mortality.
Approach and Results
Coronary computed tomographic angiography permits direct visualization of nonobstructive CAD. To date, the prognostic implications of nonobstructive CAD and the potential benefit of directing therapy based on nonobstructive CAD have not been carefully examined. A total of 27 125 consecutive patients who underwent computed tomographic angiography (12 enrolling centers and 6 countries) were prospectively entered into the COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter (CONFIRM) registry. Patients, without history of previous CAD or obstructive CAD, for whom baseline statin and aspirin use was available were analyzed. Each coronary segment was classified as normal or nonobstructive CAD (1%–49% stenosis). Patients were followed up for a median of 27.2 months for all-cause mortality. The study comprised 10 418 patients (5712 normal and 4706 with nonobstructive CAD). In multivariable analyses, patients with nonobstructive CAD had a 6% (95% confidence interval, 1%–12%) higher risk of mortality for each additional segment with nonobstructive plaque (P=0.021). Baseline statin use was associated with a reduced risk of mortality (hazard ratio, 0.44; 95% confidence interval, 0.28–0.68; P=0.0003), a benefit that was present for individuals with nonobstructive CAD (hazard ratio, 0.32; 95% confidence interval, 0.19–0.55; P<0.001) but not for those without plaque (hazard ratio, 0.66; 95% confidence interval, 0.30–1.43; P=0.287). When stratified by National Cholesterol Education Program/Adult Treatment Program III, no mortality benefit was observed in individuals without plaque. Aspirin use was not associated with mortality benefit, irrespective of the status of plaque.
Conclusions
The presence and extent of nonobstructive CAD predicted mortality. Baseline statin therapy was associated with a significant reduction in mortality for individuals with nonobstructive CAD but not for individuals without CAD.
Clinical Trial Registration
URL: http://clinicaltrials.gov/. Unique identifier NCT01443637
doi:10.1161/ATVBAHA.114.304351
PMCID: PMC4376658  PMID: 25676000
aspirin; coronary angiography; coronary atherosclerosis; mortality; prognosis; statin
5.  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
6.  The Association of Resistin with Cardiovascular Disease in The Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2014;239(1):101-108.
Objective
To describe the relationship between circulating resistin levels and cardiovascular diseases (CVD) and all-cause death in a multi-ethnic cohort.
Methods and Results
We studied 1,913 participants from the Multi-Ethnic Study of Atherosclerosis with measurements of plasma resistin levels. Absolute proportions experiencing new-onset atrial fibrillation (AF), atherosclerotic CVD (myocardial infarction, angina, resuscitated cardiac arrest, stroke), heart failure (HF), and all-cause death were calculated for each quartile of resistin. We used adjusted Cox proportional regression modeling resistin as a continuous variable per standard deviation of log-transformed resistin and secondarily as a categorical variable using resistin quartiles. Results were stratified by sex and race/ethnicity. The mean age of the population was 64.5 ± 10 years with half being female and a median resistin concentration of 15.1 ng/mL (11.9–19.1). Mean follow-up time was 7.2 ± 1.8 years. There was a graded increase in the occurrence of all outcomes across increasing quartiles of resistin. Modeled as a continuous variable, after adjustment for anthropomorphic measures, traditional risk factors, markers of inflammation, and other adipokines, significant associations were noted for HF (HR 1.4, CI 1.0–2.0), hard and all CVD (HR 1.3, 1.1–1.7 and 1.3, 1.1–1.6, respectively), and CHD (HR 1.31, 1.0–1.6), but not for AF or death. Significant interaction terms were noted between resistin and race, with Hispanic race/ethnicity showing the strongest relationship between resistin and outcomes.
Conclusions
In an ethnically diverse population without known CVD at baseline, there was a strong, independent association between higher resistin levels and incident CVD, CHD and HF.
doi:10.1016/j.atherosclerosis.2014.12.044
PMCID: PMC4331252  PMID: 25585029
atherosclerotic heart disease; risk stratification; resistin; adipokines
7.  Cigarette Smoking and Cardiovascular Events: Role of Inflammation and Subclinical Atherosclerosis 
Objectives
To examine the contemporary impact of smoking in a multi-ethnic sample, and to explore the respective contributions of inflammation and subclinical atherosclerosis to the cardiovascular consequences of smoking.
Approach and Results
We studied 6,814 participants free of cardiovascular disease (CVD) and coronary heart-disease (CHD) from MESA. Smoking status and cumulative exposure were determined by self-report and confirmed by urinary cotinine. Multivariable Cox-regression was used to estimate the association between smoking parameters and; All-cause CVD; All-cause CHD; and Hard CHD events. We further adjusted for high-sensitivity C-reactive protein (hsCRP) and coronary artery calcium (CAC) in hierarchical Cox-models. We identified 3,218 never-smokers, 2,607 former-smokers, and 971 current-smokers. Median follow-up was 10.2 years. Compared to never-smokers, adjusted Hazard-ratios (HRs) in current-smokers were 1.7 (95% CI, 1.3-2.2) for All-cause CVD, 1.6 (1.1-2.1) for All-cause CHD, and 1.7 (1.2-2.4) for Hard CHD. Similarly, among current-smokers, HRs were higher in the 4th vs 1st quartile of pack-years (e.g. All-cause CHD HR=2.7 [1.1-6.6]). Both CAC>100 and hsCRP≥3mg/L identified higher relative-risk among current-smokers (e.g. All-cause CHD HR of 3.0 [1.5-6.0, compared to CAC=0] and 2.6 [1.4-4.8, compared to hsCRP<2mg/L], respectively). However, CAC was a stronger mediator of events and adversely modified the effect of smoking on events (e.g. p-interaction=0.02 for Hard CHD). Compared to never-smokers, former-smokers (median cessation interval=22 years) had similar adjusted hazard for events.
Conclusion
In this multi-ethnic cohort, current smoking and cumulative exposure remain important modifiable determinants of CVD. Both hsCRP≥3mg/L and particularly CAC>100 identified high-risk smokers who may benefit from more intensive smoking-cessation efforts.
doi:10.1161/ATVBAHA.114.304562
PMCID: PMC4404404  PMID: 25573855
Smoking; Inflammation; Coronary Artery Calcium; Cardiovascular Outcomes
8.  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)
9.  Physical Activity, Hormone Replacement Therapy, and the Presence of Coronary Calcium in Midlife Women 
Women & health  2012;52(5):423-436.
Background
Atherosclerotic calcification is a risk factor for cardiovascular events, independent of other traditional risk factors. Studies of the relation of menopausal hormone therapy to cardiovascular events have had inconsistent results, and often have been confounded by lifestyle behaviors and the “healthy user” effect. The authors evaluated the cross-sectional association of hormone therapy use with the presence and severity of atherosclerosis in postmenopausal women, independent of lifestyle factors, including diet and physical activity levels.
Methods
The authors consecutively enrolled postmenopausal asymptomatic women who were referred for coronary artery calcium scanning to measure cardiovascular risk. After consent was obtained, women were interviewed prior to their cardiac scan about cardiac risk factors, hormone therapy use, menopausal status, diet, and physical activity. Coronary artery calcium prevalence was defined as any calcification present (score >0).
Results
Of the 544 enrolled women aged 50–80 years, 252 (46.3%) were hormone therapy users. Hormone therapy users had a significantly lower prevalence of any coronary artery calcium (defined as coronary artery calcium score >0; 37%), than non-users (50%, p = 0.04), as well as significantly lower mean calcium scores (p = 0.02). Multiple logistic regression models demonstrated a significantly reduced odds of coronary artery calcium in hormone therapy users compared to non-users with an adjusted odds ratio of 0.58 (p = 0.04), adjusting for traditional cardiac risk factors and body mass index. Women who reported consuming a vegetarian or a high-protein diet had almost two-fold odds of coronary artery calcium compared with women who reported regular, mixed, or low-fat, low-salt diets (OR = 1.78, p = 0.02). Severity of coronary artery calcium was less with increasing levels of physical activity, and a significant association was observed between physical activity and hormone therapy use (adjusted OR = 4.05, p = 0.03), independent of coronary artery calcium severity.
Conclusion
This cross-sectional study demonstrated a protective association of hormone therapy with the presence and severity of coronary artery calcium. Although a strong relationship was observed between hormone therapy and physical activity, their complex interplay may affect mechanistic biochemical and physiological processes that have yet to be clearly delineated. Thus, physical activity and diet should be taken into account in prospective studies of the relation of hormone therapy use to coronary artery calcium.
doi:10.1080/03630242.2012.682705
PMCID: PMC4281478  PMID: 22747181
hormone therapy; atherosclerosis; coronary calcium; perimenopause; women
10.  A Comparison of Coronary Artery Calcium Presence, Carotid Plaque Presence, and Carotid Intima-Media Thickness for Cardiovascular Disease Prediction in the Multi-Ethnic Study of Atherosclerosis (MESA) 
Background
Presence of coronary artery calcium (CAC), carotid plaque, and increased carotid intima media thickness (IMT) may indicate elevated cardiovascular disease (CVD) risk; however, no large studies have compared them directly. This study compares predictive utilities of CAC presence, carotid artery plaque presence, and high IMT for incident CVD events.
Methods and Results
Participants were from the Multi-Ethnic Study of Atherosclerosis. Predictive values of carotid plaque, IMT and CAC presence were compared using Cox proportional hazards models, c-statistics, and net reclassification indices. The 6,779 participants were mean (standard deviation) 62.2 (10.2) years old; 49.9% had CAC, 46.7% had carotid plaque. The mean left and right IMT were 0.754 (0.210) mm and 0.751 (0.187) mm, respectively. After 9.5 years (mean), 538 CVD events, 388 coronary heart disease (CHD) events, and 196 stroke/transient ischemic attacks (TIA) were observed. CAC presence was a stronger predictor of incident CVD and CHD than carotid ultrasound measures. Mean IMT ≥75th percentile (for age, sex and race) alone did not predict events. Compared to traditional risk factors, c-statistics for CVD (c=0.756) and CHD (c=0.752) increased most by adding of CAC presence (CVD 0.776, CHD, 0.784; p<0.001) followed by carotid plaque presence (CVD c=0.760, CHD 0.757; p<0.05). Compared to risk factors (c=0.782), carotid plaque presence (c=0.787, p=0.045) but not CAC (c=0.785, p=0.438) improved prediction of stroke/TIA.
Conclusions
In adults without CVD, CAC presence improves prediction of CVD and CHD more than carotid plaque presence or high IMT. CAC and carotid ultrasound parameters performed similarly for stroke/TIA event prediction.
doi:10.1161/CIRCIMAGING.114.002262
PMCID: PMC4299916  PMID: 25596139
atherosclerosis; cardiovascular disease; carotid artery; imaging; risk factor
11.  Effects of Cardiac Medications for Patients With Obstructive Coronary Artery Disease by Coronary Computed Tomographic Angiography: Results from the Multicenter CONFIRM Registry 
Atherosclerosis  2014;238(1):119-125.
Objective
This study sought to determine the correlation between baseline cardiac medications and cardiovascular outcomes in patients with obstructive coronary artery disease (CAD) diagnosed by coronary computed tomographic angiography (CCTA).
Methods
1637 patients (mean age 64.8 ± 10.2 years, 69.6% male) with obstructive CAD from the CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter) registry were followed over the course of three years. Obstructive CAD was defined as a >50% stenosis in an epicardial vessel. Medications analyzed included statins, aspirin, beta-blockers, angiotensin converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs). Using Cox proportional-hazards models, we calculated the hazard ratio (HR) with 95% confidence intervals (95% CIs) for incident major adverse cardiovascular events (MACE), defined as death, acute coronary syndrome, or myocardial infarction.
Results
At the time of CCTA, 59%, 54%, 40%, and 46% of patients were using statins, aspirin, beta-blockers, and ACE inhibitors or ARBs, respectively. Statins were associated with a 43% (95% CI = 0.38-0.87, p=0.008) lower adjusted risk of MACE. Following adjustment, aspirin, beta-blockers, ACE inhibitors and ARBs did not attenuate the risk of MACE. When restricted to patients with multivessel obstructive CAD, only statins were associated with lower risk of MACE.
Conclusion
In patients with obstructive CAD by CCTA, the baseline use of statins was associated with improved clinical outcomes. Other cardiac medications—including aspirin, beta-blockers, ACE inhibitors, and ARBs—were not associated with reduced risk of MACE.
doi:10.1016/j.atherosclerosis.2014.11.007
PMCID: PMC4277901  PMID: 25479800
Coronary Artery Disease; Coronary computed tomographic angiography; major adverse cardiac events; medication therapy; statins
12.  Atherosclerotic Plaque Characteristics by CT Angiography Identify Coronary Lesions That Cause Ischemia: a Direct Comparison to Fractional Flow Reserve 
Objective
We evaluated the association between atherosclerotic plaque characteristics (APCs) by coronary CT angiography (CT) and lesion ischemia by fractional flow reserve (FFR).
Background
FFR is the gold standard for determining lesion ischemia. While APCs by CT—including aggregate plaque volume % (%APV), positive remodeling (PR), low attenuation plaque (LAP) and spotty calcification (SC)—are associated with future coronary syndromes, their relationship to lesion ischemia is unclear.
Methods
252 patients (17 centers, 5 countries) [mean age 63 years, 71% males] underwent CT, with FFR performed for 407 coronary lesions. CT was interpreted for < and >50% stenosis, with the latter considered obstructive. APCs by CT were defined as: (1) PR, lesion diameter/reference diameter >1.10; (2) LAP, any voxel <30 HU; and (3) SC, nodular calcified plaque <3 mm. Odds ratios (OR) and net reclassification improvement (NRI) of APCs for lesion ischemia, defined by FFR <0.8, were analyzed.
Results
By FFR, ischemia was present in 151 lesions (37%). %APV was associated with a 10% increased risk of ischemia per 5% additional APV. PR, LAP and SC were associated with ischemia, with a 3-5 times higher prevalence than in non-ischemic lesions. In multivariable analyses, a stepwise increased risk of ischemia was observed for 1 [OR 4.5, p<0.001)] and ≥2 (OR 13.2, p<0.001) APCs. These findings were APC-dependent, with PR (OR 5.4, p<0.001) and LAP (OR 2.2, p=0.028) associated with ischemia, but not SC. When examined by stenosis severity, PR remained a predictor of ischemia for all lesions, while %APV and LAP were associated with ischemia for only >50% but not for <50% stenosis.
Conclusions
%APV and APCs by CT improve identification of coronary lesions that cause ischemia. PR is associated with all ischemia-causing lesions, while %APV and LAP are only associated with ischemia-causing lesions >50%.
doi:10.1016/j.jcmg.2014.11.002
PMCID: PMC4297319  PMID: 25592691
coronary plaque; fractional flow reserve; coronary computed tomography angiography; myocardial ischemia; coronary artery disease
13.  Mediators of Atherosclerosis in South Asians Living in America (MASALA) study: Objectives, Methods, and Cohort Description 
Clinical cardiology  2013;36(12):713-720.
Background
South Asians (individuals from India, Pakistani, Bangladesh, Nepal, and Sri Lanka) have high rates of cardiovascular disease which cannot be explained by traditional risk factors. There are no prospective cohort studies investigating antecedents of cardiovascular disease in South Asians.
Methods
The Mediators of Atherosclerosis in South Asians Living in America (MASALA) study is investigating the prevalence, correlates and outcomes associated with subclinical cardiovascular disease (CVD) in a population-based sample of South Asian men and women between ages 40 – 79 years from two U.S. clinical field centers. This cohort is similar in methods and measures to the Multi-Ethnic Study of Atherosclerosis to allow for efficient cross-ethnic comparisons. Measurements obtained at the baseline examination include sociodemographic information, lifestyle and psychosocial factors, standard CVD risk factors, oral glucose tolerance testing, electrocardiogram, assessment of microalbuminuria, ankle and brachial blood pressures, carotid intima media wall thickness using ultrasonagraphy, coronary artery calcium measurement and abdominal visceral fat using computed tomography. Blood samples will be assayed for biochemical risk factors.
Results
Between October 2010 and March 2013 we enrolled 906 South Asians with mean age of 55±9 years, 46% women, 98% immigrants who have lived 27±11 years in the US.
Conclusions
The sociodemographic characteristics of this cohort are representative of US South Asians. Participants are being followed with annual telephone calls for identification of CVD events including acute myocardial infarction and other coronary heart disease, stroke, peripheral vascular disease, congestive heart failure, therapeutic interventions for CVD, and mortality.
doi:10.1002/clc.22219
PMCID: PMC3947423  PMID: 24194499
14.  The relationship between adiposity-associated inflammation and coronary artery and abdominal aortic calcium differs by strata of central adiposity: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Adipokines regulate metabolic processes linked to coronary artery (CAC) and abdominal aorta calcification (AAC). Because adipokine and other adiposity-associated inflammatory marker (AAIM) secretions differ between visceral and subcutaneous adipose tissue, we hypothesized that central adiposity modifies associations between AAIMs and CAC and AAC. We evaluated 1878 MESA participants with complete measures of AAIMs, anthropometry, CAC, and AAC. Associations of AAIMs with CAC and AAC prevalence and severity were analyzed per standard deviation of predictors (SD) using log binomial and linear regression models. The waist-to-hip ratio (WHR) was dichotomized at median WHR values based on sex/ethnicity. CAC and AAC prevalence were defined as any calcium (Agatston score >0). Severity was defined as ln (Agatston score). Analyses examined interactions with WHR and were adjusted for traditional cardiovascular disease risk factors. Each SD higher interleukin-6 (IL-6), fibrinogen and CRP was associated with 5% higher CAC prevalence; and each SD higher IL-6 and fibrinogen was associated with 4% higher AAC prevalence. Associations of IL-6 and fibrinogen with CAC severity, but not CAC prevalence, were significantly different among WHR strata. Median-and-above WHR: each SD higher IL-6 was associated with 24.8% higher CAC severity. Below-median WHR: no association (pinteraction=0.012). Median-and-above WHR: each SD higher fibrinogen was associated with 19.6% higher CAC severity. Below-median WHR: no association (pinteraction=0.034). Adiponectin, leptin, resistin, and tumor necrosis factor-alpha were not associated with CAC or AAC prevalence or severity. These results support findings that adiposity-associated inflammation is associated with arterial calcification, and further add that central adiposity may modify this association.
doi:10.1177/1358863X14537545
PMCID: PMC4258162  PMID: 24907349
abdominal aorta calcium (AAC); adiposity-associated inflammation; central adiposity; coronary artery calcium (CAC)
15.  Coronary Atherosclerotic Plaque Detected by Computed Tomographic Angiography in Subjects with Diabetes Compared to Those without Diabetes 
PLoS ONE  2015;10(11):e0143187.
Objectives
Little data are available regarding coronary plaque composition and semi-quantitative scores in individuals with diabetes; the extent to which diabetes may affect the presence and extent of Coronary Artery Calcium (CAC) needs more evaluation. Considering that this information may be of great value in formulating preventive interventions in this population, we compared these findings in individuals with diabetes to those without.
Methods
Multi-Detector Computed Tomographic (MDCT) images of 861 consecutive patients with diabetes who were referred to Los Angeles Biomedical Research Institute from January 2000 to September 2012, were evaluated using a 15–coronary segment model. All 861 patients underwent calcium scoring and from these; 389 had coronary CT angiography (CTA). CAC score was compared to 861 age, sex and ethnicity matched controls without diabetes after adjustment for Body Mass Index (BMI), family history of coronary artery disease, hyperlipidemia, hypertension and smoking. Segment Involvement Score (SIS; the total number of segments with any plaque), Segment Stenosis Score (SSS; the sum of maximal stenosis score per segment), Total Plaque Score (TPS; the sum of the plaque amount per segment) and plaque compositionwere compared to 389 age, sex and ethnicity matched controls without diabetes after adjustment for BMI, family history of coronary artery disease, hyperlipidemia, hypertension and smoking.
Results
Diabetes was positively correlated to the presence and extent of CAC (P<0.0001 for both). SIS, SSS and TPS were significantly higher in those with diabetes (P<0.0001). Number of mixed and calcified plaques were significantly higher in those with diabetes (P = 0.018 and P<0.001 respectively) but there was no significant difference in the number of non-calcified plaques between the two groups (P = 0.398).
Conclusions
Patients with diabetes have higher CAC and semi-quantitative coronary plaque scores compared to the age, gender and ethnicity matched controls without diabetes after adjustment for cardiovascular risk factors. Since mixed plaque is associated with worse long-term clinical outcomes, these findings support more aggressive preventive measures in this population.
doi:10.1371/journal.pone.0143187
PMCID: PMC4658152  PMID: 26600086
16.  Screening for Ischemic Heart Disease with Cardiac CT: Current Recommendations 
Scientifica  2012;2012:812046.
Cardiovascular disease remains the leading cause of mortality in the US and worldwide, and no widespread screening for this number one killer has been implemented. Traditional risk factor assessment does not fully account for the coronary risk and underestimates the prediction of risk even in patients with established risk factors for atherosclerosis. Coronary artery calcium (CAC) represents calcified atherosclerosis in the coronary arteries. It has been shown to be the strongest predictor of adverse future cardiovascular events and provides incremental information to the traditional risk factors. CAC consistently outperforms traditional risk factors, including models such as Framingham risk to predict future CV events. It has been incorporated into both the European and American guidelines for risk assessment. CAC is the most robust test today to reclassify individuals based on traditional risk factor assessment and provides the opportunity to better strategize the treatments for these subjects (converting patients from intermediate to high or low risk). CAC progression has also been identified as a risk for future cardiovascular events, with markedly increased events occurring in those patients exhibiting increases in calcifications over time. The exact intervals for rescanning is still being evaluated.
doi:10.6064/2012/812046
PMCID: PMC3820482  PMID: 24278742
17.  Sex-Specific Biatrial Volumetric Measurements Obtained with Use of Multidetector Computed Tomography in Subjects with and without Coronary Artery Disease 
Texas Heart Institute Journal  2014;41(3):286-292.
Atrial volumetric measurement has proven clinical implications. Advances in cardiac imaging, notably the precision enabled by multidetector computed tomography (MDCT), herald the need for new criteria of what constitutes normal volumetric measurements. With use of 64-slice MDCT, we compared the atrial volumes in healthy individuals with those in individuals with coronary artery disease.
By means of manual segmentation, we measured biatrial volume in 686 participants who underwent retrospective electrocardiographic-gated MDCT angiographic evaluation. The study population included a control group of 203 persons with no cardiac abnormalities, and a study group of 483 patients with obstructive coronary artery disease. All variables were compared between men and women and between the groups.
We found a significant difference in left atrial end-systolic and end-diastolic volumes between men and women in the control group (P <0.05); however, right atrial volumes were similar. In comparison with the entire control group, the coronary artery disease group had significantly higher left atrial volume, significantly lower right atrial stroke volume, and significantly lower biatrial ejection fraction, except for left atrial ejection fraction in men. Right atrial volume and left atrial stroke volume were not significantly different. The results imply that a sex-specific reference value is necessary for left atrial volumetric evaluation, and that left atrial volume and biatrial ejection fraction (excluding left atrial ejection fraction in men) might be useful during diagnosis and prognosis in patients who have coronary artery disease.
doi:10.14503/THIJ-12-3061
PMCID: PMC4060347  PMID: 24955043
Atrial function; cardiac volume/physiology; coronary angiography/methods; heart atria/pathology/ultrasonography; image interpretation, computer-assisted/methods; imaging, three-dimensional; predictive value of tests; sensitivity and specificity; tomography, x-ray computed/methods/utilization
18.  Liver steatosis and the risk of albuminuria: the multi-ethnic study of atherosclerosis 
Journal of nephrology  2015;28(5):577-584.
Objective
To measure association between hepatic fat and albuminuria (an early marker of renal injury) in individuals without diabetes or hypertension.
Methods
2,281 individuals in the Multi-Ethnic Study of Atherosclerosis without diabetes or hypertension, renal disease, or excess alcohol consumption underwent computed tomography (CT) for assessment of liver attenuation (marker of hepatic lipid content) and urinalysis (for albuminuria) at initial study visit, with assessment of incident and prevalent albuminuria by logistic regression in follow-up.
Results
After adjustment for age, gender, race, smoking, blood pressure, insulin resistance, and body mass index, individuals with less liver fat (higher liver CT attenuation) had a lower probability of having albuminuria at Exam 1 (OR per 10 unit increase in attenuation 0.77, 95 % CI 0.61–0.97, P = 0.02). At median 9.3 years follow-up, albuminuria was identified in 129 individuals were (5.8 %). In fully adjusted models (with age, smoking, body mass index, blood pressure, diabetes and hypertension as time-dependent covariates), lower liver attenuation (greater liver fat) was associated with higher risk of incident albuminuria (OR 0.79, 95 % CI 0.66–0.94, P = 0.008).
Conclusions
Hepatic attenuation is associated with prevalent and incident albuminuria, an early, potent risk factor for renal risk in a population not clearly at risk for future renal failure.
doi:10.1007/s40620-015-0177-1
PMCID: PMC4549235  PMID: 25712234
Albuminuria; Inflammation; Obesity; Hepatic steatosis
19.  THE TESTOSTERONE TRIALS: THE DESIGN OF SEVEN COORDINATED TRIALS TO DETERMINE IF TESTOSTERONE TREATMENT BENEFITS ELDERLY MEN 
Clinical trials (London, England)  2014;11(3):362-375.
Background
The prevalence of low testosterone levels in men increases with age, as does the prevalence of decreased mobility, sexual function, self-perceived vitality, cognitive abilities, bone mineral density, and glucose tolerance, and of increased anemia and coronary artery disease. Similar changes occur in men who have low serum testosterone concentrations due to known pituitary or testicular disease, and testosterone treatment improves the abnormalities. Prior studies of the effect of testosterone treatment in elderly men, however, have produced equivocal results.
Purpose
To describe a coordinated set of clinical trials designed to avoid the pitfalls of prior studies and determine definitively if testosterone treatment of elderly men with low testosterone is efficacious in improving symptoms and objective measures of age-associated conditions.
Methods
We present the scientific and clinical rationale for the decisions made in the design of this trial.
Results
We designed The Testosterone Trials as a coordinated set of seven trials to determine if testosterone treatment of elderly men with low serum testosterone concentrations and also symptoms and objective evidence of impaired mobility and/or diminished libido and/or reduced vitality would be efficacious in improving mobility (Physical Function Trial), sexual function (Sexual Function Trial), fatigue (Vitality Trial), cognitive function (Cognitive Function Trial), hemoglobin (Anemia Trial), bone density (Bone Trial), and coronary artery plaque volume (Cardiovascular Trial). The scientific advantages of this coordination were common eligibility criteria, treatment and monitoring and the ability to pool safety data. The logistical advantages were a single steering committee, data coordinating center and data safety monitoring board (DSMB), the same clinical trial sites, and the possibility of men participating in multiple trials. The major consideration in subject selection was setting the eligibility criterion for serum testosterone low enough to ensure that the men were unequivocally testosterone deficient, but not so low as to preclude sufficient enrollment or eventual generalizability of the results. The major considerations in choosing primary end points for each trial were identifying those of the highest clinical importance and identifying the minimum clinically important differences between treatment arms for sample size estimation.
Potential Limitations
Setting the serum testosterone concentration sufficiently low to ensure that most men would be unequivocally testosterone deficient, as well as many other entry criteria, resulted in screening approximately 30 men in person to randomize one subject.
Conclusions
The Testosterone Trials were designed to determine definitively if testosterone treatment of elderly men with low testosterone would have any clinical benefit. Designing The Testosterone Trials as a coordinated set of seven trials afforded many important scientific and logistical advantages but required an intensive recruitment and screening effort.
doi:10.1177/1740774514524032
PMCID: PMC4182174  PMID: 24686158
clinical trial; testosterone; hypogonadism; aging; mobility; sexual function; vitality; cognitive function; anemia; CT angiography; volumetric BMD; bone strength
20.  Current trends in patients with chronic total occlusions undergoing coronary CT angiography 
Heart (British Cardiac Society)  2015;101(15):1212-1218.
Objective
Data describing the prevalence, characteristics and management of coronary chronic total occlusions (CTOs) in patients undergoing coronary CT angiography (CCTA) have not been reported. The purpose of this study was to determine the prevalence, characteristics and treatment strategies of CTO identified by CCTA.
Methods
We identified 23 745 patients who underwent CCTA for suspected coronary artery disease (CAD) from the prospective international CCTA registry. Baseline clinical data were collected, and allocation to early coronary revascularisation performed within 90 days of CCTA was determined. Multivariable hierarchical mixed-effects logistic regression reporting OR with 95% CI was performed.
Results
The prevalence of CTO was 1.4% (342/23 745) in all patients and 6.2% in patients with obstructive CAD (≥50% stenosis). The presence of CTO was independently associated with male sex (OR 3.12, 95% CI 2.39 to 4.08, p<0.001), smoking (OR 2.02, 95% CI 1.55 to 2.64, p<0.001), diabetes (OR 1.60, 95% CI 1.22 to 2.11, p=0.001), typical angina (OR 1.51, 95% CI 1.12 to 2.06, p=0.008), hypertension (OR 1.47, 95% CI 1.14 to 1.88, p=0.003), family history of CAD (OR 1.30, 95% CI 1.01 to 1.67, p=0.04) and age (OR 1.06, 95% CI 1.05 to 1.07, p<0.001). Most patients with CTO (61%) were treated medically, while 39% underwent coronary revascularisation. In patients with severe CAD (≥70% stenosis), CTO independently predicted revascularisation by coronary artery bypass grafting (OR 3.41, 95% CI 2.06 to 5.66, p<0.001), but not by percutaneous coronary intervention (p=0.83).
Conclusions
CTOs are not uncommon in a contemporary CCTA population, and are associated with age, gender, angina status and CAD risk factors. Most individuals with CTO undergoing CCTA are managed medically with higher rates of surgical revascularisation in patients with versus without CTO.
Trial registration number
ClinicalTrials.gov identifier NCT01443637.
doi:10.1136/heartjnl-2014-306616
PMCID: PMC4578159  PMID: 26076936
21.  The Role of Carotid Intimal Thickness Testing and Risk Prediction for the Development of Coronary Atherosclerosis 
Carotid Ultrasound is a safe and available non invasive diagnostic tool that provides information about the carotid arteries’ characteristics and may be used for early detection of coronary artery disease as well as cardiovascular and stroke event risk stratifications. We performed a systematic search of the articles discussing carotid ultrasound in English literature, published in PubMed from the year2010 to September 2012. Generally, the studies showed that Internal carotid artery intima media thickness is a more powerful variable than common carotid artery intima media thickness. Moreover, the presence of carotid plaque and plaque volumes are more reliable and accurate estimators of coronary artery disease and risk of a stroke or cardiovascular event than intima media thickness.
doi:10.1007/s11883-012-0306-4
PMCID: PMC3583351  PMID: 23328906
Carotid Ultrasound; Coronary Artery Disease; Risk Prediction; Intima Media Thickness
22.  Impact of coronary artery calcium on coronary heart disease events in individuals at the extremes of traditional risk factor burden: the Multi-Ethnic Study of Atherosclerosis 
European Heart Journal  2013;35(33):2232-2241.
Aims
We sought to evaluate the impact of coronary artery calcium (CAC) in individuals at the extremes of risk factor (RF) burden.
Methods and results
6698 individuals from the Multi-Ethnic Study of Atherosclerosis (MESA) were followed for coronary heart disease (CHD) events over mean 7.1 ± 1 years. Annualized CHD event rates were compared among each RF category (0, 1, 2, or ≥3) after stratification by CAC score (0, 1–100, 101–300, and >300). The following traditional modifiable RFs were considered: cigarette smoking, LDL cholesterol ≥3.4 mmol/L, low HDL cholesterol, hypertension, and diabetes. There were 1067 subjects (16%) with 0 RFs, whereas 1205 (18%) had ≥3 RFs. Among individuals with 0 RFs, 68% had CAC 0, whereas 12 and 5% had CAC >100 and >300, respectively. Among individuals with ≥3 RFs, 35% had CAC 0, whereas 34 and 19% had CAC >100 and >300, respectively. Overall, 339 (5.1%) CHD events occurred. Individuals with 0 RFs and CAC >300 had an event rate 3.5 times higher than individuals with ≥3 RFs and CAC 0 (10.9/1000 vs. 3.1/1000 person-years). Similar results were seen across categories of Framingham risk score.
Conclusion
Among individuals at the extremes of RF burden, the distribution of CAC is heterogeneous. The presence of a high CAC burden, even among individuals without RFs, is associated with an elevated event rate, whereas the absence of CAC, even among those with many RF, is associated with a low event rate. Coronary artery calcium has the potential to further risk stratify asymptomatic individuals at the extremes of RF burden.
doi:10.1093/eurheartj/eht508
PMCID: PMC4150068  PMID: 24366919
Coronary artery calcium; Risk factors; Coronary heart disease
23.  (MESA AC 291) The Association of Endogenous Sex Hormones with Liver Fat - Multi-Ethnic Study of Atherosclerosis (MESA) 
Background
Circulating sex hormone levels are associated with glucose metabolism and adiposity, but their association with ectopic fat deposition in the liver is not well understood.
Methods
We studied the association of the circulating levels of bioavailable testosterone (Bio-T), estradiol (E2), dehydroepiandrosterone (DHEA) and sex hormone binding globulin (SHBG) with fatty liver, defined as attenuation ≤ 40 Hounsfield Units by magnetic resonance imaging in 2835 postmenopausal women and 2899 men in the Multiethnic Study of Atherosclerosis baseline examination.
Results
In women, there was a significantly greater odds ratio of fatty liver prevalence in the highest tertile versus the lowest tertile of Bio-T (1.73, 95% CI 1.05 – 2.87) and E2 (2.42, 95% CI 1.37 – 4.29) adjusting for age, race/ethnicity, body mass index, hypertension, total and high density lipoprotein cholesterol, smoking, insulin sensitivity and hormone replacement therapy use. In men, there was a significantly greater odds ratio of fatty liver prevalence in the highest tertile versus the lowest tertile of E2 (1.96, 95% CI 1.21 – 3.18), but a significantly lower odds ratio for the highest versus lowest tertiles of SHBG (0.50, 95% CI 0.30 – 0.84). Other associations of hormones with fatty liver were not statistically significant.
Conclusions
A more androgenic internal mileu is associated with fatty liver in postmenopausal women. In men, lower levels of SHBG are associated with fatty liver. Higher levels of E2 are associated with fatty liver in both sexes. This pattern is consistent with the sex-specific associations of sex hormones with other cardiometabolic risk factors.
doi:10.1016/j.cgh.2014.12.033
PMCID: PMC4500744  PMID: 25592661
24.  A New Approach in Risk Stratification by Coronary CT Angiography 
Scientifica  2014;2014:278039.
For a decade, coronary computed tomographic angiography (CCTA) has been used as a promising noninvasive modality for the assessment of coronary artery disease (CAD) as well as cardiovascular risks. CCTA can provide more information incorporating the presence, extent, and severity of CAD; coronary plaque burden; and characteristics that highly correlate with those on invasive coronary angiography. Moreover, recent techniques of CCTA allow assessing hemodynamic significance of CAD. CCTA may be potentially used as a substitute for other invasive or noninvasive modalities. This review summarizes risk stratification by anatomical and hemodynamic information of CAD, coronary plaque characteristics, and burden observed on CCTA.
doi:10.1155/2014/278039
PMCID: PMC4165381  PMID: 25254142
25.  An Analysis of Calibration and Discrimination Among Multiple Cardiovascular Risk Scores in a Modern Multiethnic Cohort 
Annals of internal medicine  2015;162(4):266-275.
Background
Accurate risk assessment of atherosclerotic cardiovascular disease (ASCVD) is essential to effectively balance the risks and benefits of therapy for primary prevention.
Objective
To compare the calibration and discrimination of the new American Heart Association (AHA) and American College of Cardiology (ACC) ASCVD risk score with alternative risk scores and to explore preventive therapy as a cause of the reported risk overestimation using the AHA-ACC-ASCVD score.
Design
Prospective epidemiologic study of ASCVD.
Setting
MESA (Multi-Ethnic Study of Atherosclerosis), a community-based, sex-balanced, multiethnic cohort.
Patients
4227 MESA participants aged 50 to 74 years and without diabetes at baseline.
Measurements
Observed and expected events for the AHA-ACC-ASCVD score were compared with 4 commonly used risk scores—and their respective end points—in MESA after a 10.2-year follow-up.
Results
The new AHA-ACC-ASCVD and 3 older Framingham-based risk scores overestimated cardiovascular events by 37% to 154% in men and 8% to 67% in women. Overestimation was noted throughout the continuum of risk. In contrast, the Reynolds Risk Score overestimated risk by 9% in men but underestimated risk by 21% in women. Aspirin, lipid-lowering or antihypertensive therapy, and interim revascularization did not explain the overestimation.
Limitation
Comparability of MESA with target populations for primary prevention and possibility of missed events in MESA.
Conclusion
Of the 5 risk scores, 4, including the new AHA-ACC-ASCVD score, showed overestimation of risk (25% to 115%) in a modern, multiethnic cohort without baseline clinical ASCVD. If validated, overestimation of ASCVD risk may have substantial implications for individual patients and the health care system.
Primary Funding Source
National Heart, Lung, and Blood Institute.
doi:10.7326/M14-1281
PMCID: PMC4414494  PMID: 25686167

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