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1.  Physical Activity, Hormone Replacement Therapy, and the Presence of Coronary Calcium in Midlife Women 
Women & health  2012;52(5):423-436.
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.
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).
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.
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.
PMCID: PMC4281478  PMID: 22747181
hormone therapy; atherosclerosis; coronary calcium; perimenopause; women
2.  Mediators of Atherosclerosis in South Asians Living in America (MASALA) study: Objectives, Methods, and Cohort Description 
Clinical cardiology  2013;36(12):713-720.
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.
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.
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.
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.
PMCID: PMC3947423  PMID: 24194499
3.  Association of Coronary Artery Calcium Score and Vascular Dysfunction in Long-Term Hemodialysis Patients 
Long-term hemodialysis patients are prone to an exceptionally high burden of cardiovascular disease and mortality. The novel temperature based technology of Digital Thermal Monitoring (DTM) of vascular reactivity appears associated with the severity of coronary artery disease in asymptomatic population. We hypothesized that in hemodialysis patients the DTM and coronary artery calcium (CAC) score have a gradient association that follows that of subjects without kidney disease.
We examined the cross-sectional DTM-CAC associations in a group of long-term hemodialysis patients and their 1:1 matched normal counterparts, Area under the curve for temperature (TMP-AUC), the surrogate of the DTM index of vascular function, was assessed after a 5-minute arm-cuff reactive hyperemia test. Coronary calcium score was measured via EBCT or MDCT scan.
We studied 105 randomly recruited hemodialysis patients (age:58±13 years, 47 % men) and 105 age- and gender-matched controls. In hemodialysis patients vs. controls TMP-AUC was significantly worse (114±72 vs. 143±80. p=0.001) and CAC score was higher (525±425 vs. 240±332, p<0.001). Hemodialysis patients were 14 times more likely to have CAC score >1000 as compared with controls. After adjustment for known confounders, the relative risk for case vs. control for each standard deviation decrease in TMP-AUC was 1.46 (95%CI: 1.12-1.93, p=0.007).
Vascular reactivity measured via the novel DTM technology is incrementally worse across CAC scores in hemodialysis patients, in whom both measures are even worse than their age- and gender matched controls. The DTM technology may offer a convenient and radiation-free approach to risk-stratify hemodialysis patients.
PMCID: PMC4319179  PMID: 22962941
Chronic Kidney Disease; Coronary Calcification; Digital Thermal Monitoring; Hemodialysis; Vascular Disease
4.  Association between inflammatory markers and liver fat: The Multi-Ethnic Study of Atherosclerosis 
Nonalcoholic fatty liver disease (NAFLD) is a common liver disease. Data is emerging that an independent association between markers of subclinical atherosclerosis and NAFLD exists and it may be considered as an independent predictor of cardiovascular (CV) outcomes. We aim to better characterize the relationship between NAFLD and inflammatory markers in a multi-ethnic cohort by assessing fatty liver on computed tomography (CT) scans.
The Multi-Ethnic Study of Atherosclerosis (MESA) is a longitudinal, population-based study from four ethnic groups free of CV disease at baseline. The inflammatory markers studied include: C-reactive protein (CRP) and interleukin 6 (IL-6). On CT scans liver-to-spleen ratio (LSR: Hounsfield Units (HU) of the liver divided by HU of spleen) of <1 and liver attenuation of <40 HU were used as criteria for fatty liver. Unadjusted and adjusted multivariate linear and logistic regression analysis was performed.
4038 participants amongst 6814 MESA population with visible spleen on the CT scan, available CRP and IL-6 levels and no reported liver cirrhosis were included. The average age was 61 +/− 10 years, 37% Caucasians and 45% were males. Mean CRP and IL-6 were 2.36 mg/dl and 1.37 pg/ml respectively. 696 participants (17%) had LSR of <1 and 253 (6%) had liver attenuation of <40 HU. When using LSR <1 as a continuous variable, the correlation (adjusted odds ratio (OR)) with CRP >2.0 was 0.037 (95% CI: 0.02-0.054) and with IL-6 was 0.014 (95% CI: 0.004-0.023). On the other hand when presence and absence of LSR <1 was considered, higher ORs for association with CRP >2: 1.41 (95% CI: 1.16 to 1.73) and IL6:1.18 (95% CI: 1.05 to 1.31) were found. Similarly, the adjusted association of per unit decrease in liver attenuation with CRP>2 was 1.92 (95% CI: 1.20 to 2.63) while for IL-6 was 1.08 (95% CI: 0.69 to 1.47). When considering presence and absence of liver attenuation <40 HU the OR for CRP >2 was 2.27 (95% CI: 1.62 to 3.16) and for IL-6 was 1.33 (95% CI: 1.13 to 1.58).
CRP and IL-6 levels were found to be significantly associated with liver fat assessed on CT scan after adjusting for other risk factors for atherosclerosis.
PMCID: PMC4296580  PMID: 25598995
Inflammation; Non-alcoholic fatty liver disease; computed tomography scan; C reactive protein
5.  Dyslipidemia, Coronary Artery Calcium, and Incident Atherosclerotic Cardiovascular Disease: Implications for Statin Therapy from the Multi-Ethnic Study of Atherosclerosis 
Circulation  2013;129(1):77-86.
Worldwide clinical practice guidelines for dyslipidemia emphasize allocating statin therapy to those at the highest absolute atherosclerotic cardiovascular disease (CVD) risk.
Methods and Results
We examined 5,534 MESA participants who were not on baseline medications for dyslipidemia. Participants were classified by baseline CAC score (>0, ≥100) and the common clinical scheme of counting lipid abnormalities (LA), including LDL-C ≥3.36 mmol/L (130 mg/dL), HDL-C <1.03 mmol/L (40 mg/dL) for men or <1.29 mmol/L (50 mg/dL) for women, and triglycerides ≥1.69 mmol/L (150 mg/dL). Our main outcome measure was incident CVD (myocardial infarction, angina resulting in revascularization, resuscitated cardiac arrest, stroke, cardiovascular death). Over a median follow-up of 7.6 years, more than half of events (55%) occurred in the 21% of participants with CAC≥100. Conversely, 65% of events occurred in participants with zero or one LA. In those with CAC≥100, CVD rates ranged from 22.2 to 29.2 per 1,000 person-years across LA categories. In contrast, with CAC=0, CVD rates ranged from 2.4 to 6.2 per 1,000 person-years across LA categories. Individuals with zero LA and CAC≥100 had a higher event rate compared to individuals with three LA but CAC=0 (22.2 vs 6.2 per 1,000 person-years). Similar results were obtained when classifying LA using dataset-quartiles of TC/HDL-C, LDL-C, non-HDL-C, or LDL particle concentration and guideline-categories of LDL-C or non-HDL-C.
CAC may have the potential to help match statin therapy to absolute CVD risk. Across the spectrum of dyslipidemia, event rates similar to secondary prevention populations were observed for patients with CAC≥100.
PMCID: PMC3919521  PMID: 24141324
Atherosclerosis; Cardiovascular disease risk factors; Cholesterol; Computed tomography
6.  What Have We Learned from CONFIRM? Prognostic Implications from a Prospective Multicenter International Observational Cohort Study of Consecutive Patients Undergoing Coronary Computed Tomographic Angiography 
Coronary computed tomographic angiography (CCTA) employing CT scanners of 64-detector rows or greater represents a novel noninvasive method for detection of coronary artery disease (CAD), providing excellent diagnostic information when compared to invasive angiography. In addition to its high diagnostic performance, prior studies have shown that CCTA can provide important prognostic information, although these prior studies have been generally limited to small cohorts at single centers. The Coronary CT Angiography EvaluatioN For clinical Outcomes: An InterRnational Multicenter Registry, or CONFIRM, is a large, prospective, multinational, dynamic observational cohort study of patients undergoing CCTA. This registry currently represents more than 32,000 consecutive adults suspected of having CAD who underwent ≥ 64–detector row CCTA at 12 centers in 6 countries between 2005 and 2009. Based on its large sample size and adequate statistical power, the data derived from CONFIRM registry has and will continue to provide key answers to many important topics regarding CCTA. Based on its multisite international national design, the results derived from CONFIRM should be considered as more generalizable than prior smaller single-center studies. This article summarizes the current status of several studies from CONFIRM registry.
PMCID: PMC4284147  PMID: 22689072
Prognosis; Coronary artery disease; Coronary CT angiography
7.  Body surface area is a predictor of coronary artery calcium, whereas body mass index is not 
Coronary artery disease  2012;23(2):113-117.
We sought to establish whether elevated BMI and body surface area (BSA), two measures of obesity, are predictors of coronary artery calcium (CAC).
We retrospectively analyzed 3172 consecutive patients who underwent calcium scoring at our center. We applied a multiple logistic regression model to estimate the independent association between BMI of at least 25 kg/m2 and incidence of CAC with adjustment for covariates. We carried out the same analysis to find out if there is an independent association between BSA of at least 1.71m2 (commonly used definition for abnormally elevated BSA) and incidence of CAC. We also performed a sex subanalysis based on BMI and BSA.
There were 2105 patients in the cohort with BMI of at least 25 kg/m2 compared with 1067 patients with BMI of less than 25 kg/m2. After adjustment for covariates, a significant association was not found between increased BMI and incidence of CAC. In addition, no significant findings were found in the sex subanalysis. A total of 2760 patients had a BSA of at least 1.71m2 compared with 412 patients with BSA of less than 1.71m2. After adjustment for covariates, a significant association (odds ratio 2.08, 95% confidence interval 1.16–3.73, P = 0.014) was found between elevated BSA and CAC incidence. There were 89 men with BSA of at least 1.9m2 and 2248 with BSA of at least 1.9m2. After adjustment for covariates, the logistic regression model showed a significant association (odds ratio 2.24, 95% confidence interval 1.19–4.21, P =0.012) between BSA of at least 1.9m2 and incidence of CAC.
Elevated BSA is a predictor of CAC incidence, whereas elevated BMI is not. Moreover, elevated BSA is a predictor of CAC incidence particularly in men.
PMCID: PMC4282517  PMID: 22157358
coronary artery calcium; coronary artery disease; obesity
8.  Prehypertension, Hypertension, and the Risk of Acute Myocardial Infarction in HIV-Infected and -Uninfected Veterans 
We found increased acute myocardial infarction risk among hypertensive and prehypertensive HIV-infected veterans compared to normotensive uninfected veterans, independent of confounding comorbidities.
Background. Compared to uninfected people, human immunodeficiency virus (HIV)–infected individuals may have an increased risk of acute myocardial infarction (AMI). Currently, HIV-infected people are treated to the same blood pressure (BP) goals (<140/90 or <130/80 mm Hg) as their uninfected counterparts. Whether HIV-infected people with elevated BP have excess AMI risk compared to uninfected people is not known. This study examines whether the association between elevated BP and AMI risk differs by HIV status.
Methods. The Veterans Aging Cohort Study Virtual Cohort (VACS VC) consists of HIV-infected and -uninfected veterans matched 1:2 on age, sex, race/ethnicity, and clinical site. For this analysis, we analyzed 81 026 people with available BP data from VACS VC, who were free of cardiovascular disease at baseline. BP was the average of the 3 routine outpatient clinical measurements performed closest to baseline (first clinical visit after April 2003). BP categories used in the analyses were based on criteria of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Analyses were performed using Cox proportional hazards regression.
Results. Over 5.9 years (median), 860 incident AMIs occurred. Low/high prehypertensive and untreated/treated hypertensive HIV-infected individuals had increased AMI risk compared to uninfected, untreated normotensive individuals (hazard ratio [HR], 1.60 [95% confidence interval {CI}, 1.07–2.39]; HR, 1.81 [95% CI, 1.22–2.68]; HR, 2.57 [95% CI, 1.76–3.76]; and HR, 2.76 [95% CI, 1.90–4.02], respectively).
Conclusions. HIV, prehypertensive BP, and hypertensive BP were associated with an increased risk of AMI in a cohort of HIV-infected and -uninfected veterans. Future studies should prospectively investigate whether HIV interacts with BP to further increase AMI risk.
PMCID: PMC3864500  PMID: 24065316
blood pressure; prehypertension; HIV; myocardial infarction
9.  Relation of Thoracic Aortic Distensibility to Left Ventricular Area (From the Multi-ethnic Study of Atherosclerosis [MESA]) 
The American journal of cardiology  2013;113(1):178-182.
Decreased arterial compliance is an early manifestation of adverse structural and functional changes within the vessel wall. Its correlation with left ventricular (LV) area on computed tomography (CT), a marker of LV remodeling, has not been well demonstrated. We tested the hypothesis that decreasing aortic compliance and increasing arterial stiffness is independently associated with increased LV area. The study population consisted of 3,540 (61±10 years, 46% men) from the MESA study who underwent aortic distensibility (AD) assessment on magnetic resonance imaging (MRI) and LV area measurement on CT (adjusted to body surface area). Multivariable logistic regression was performed to assess the association between body surface area (BSA) normalized LV area >75th percentile and AD after adjusting for baseline clinical, historical and imaging covariates. The mean LV area /BSA was 2,153 cm2 and mean AD was 1.84 mm Hg−1 x103. Subjects in the lowest AD quartile were older with higher prevalence of hypertension, diabetes, and hypercholesterolemia (p<0.05 for all comparisons). Using multivariate linear regression adjusting for demographics, traditional risk factors, coronary artery calcium and C-reactive protein, each standard deviation decrease was associated with 18 cm2 increase in the LV area. In addition, decreasing AD quartiles were independently associated with increased BSA LV area defined as >75th percentile. In this multi-ethnic cohort, reduced AD was associated with increased LV area. Longitudinal studies are needed to determine if decreased distensibility precedes and directly influences increased LV area.
PMCID: PMC3912190  PMID: 24210674
Arterial compliance; Left ventricular area; Computed tomography; Aortic Distensibility
10.  Diagnostic Accuracy of Fractional Flow Reserve From Anatomic CT Angiography 
JAMA  2012;308(12):1237-1245.
Coronary computed tomographic (CT) angiography is a noninvasive anatomic test for diagnosis of coronary stenosis that does not determine whether a stenosis causes ischemia. In contrast, fractional flow reserve (FFR) is a physiologic measure of coronary stenosis expressing the amount of coronary flow still attainable despite the presence of a stenosis, but it requires an invasive procedure. Noninvasive FFR computed from CT (FFRCT) is a novel method for determining the physiologic significance of coronary artery disease (CAD), but its ability to identify ischemia has not been adequately examined to date.
To assess the diagnostic performance of FFRCT plus CT for diagnosis of hemodynamically significant coronary stenosis.
Design, Setting, and Patients
Multicenter diagnostic performance study involving 252 stable patients with suspected or known CAD from 17 centers in 5 countries who underwent CT, invasive coronary angiography (ICA), FFR, and FFRCT between October 2010 and October 2011. Computed tomography, ICA, FFR, and FFRCT were interpreted in blinded fashion by independent core laboratories. Accuracy of FFRCT plus CT for diagnosis of ischemia was compared with an invasive FFR reference standard. Ischemia was defined by an FFR or FFRCT of 0.80 or less, while anatomically obstructive CAD was defined by a stenosis of 50% or larger on CT and ICA.
Main Outcome Measures
The primary study outcome assessed whether FFRCT plus CT could improve the per-patient diagnostic accuracy such that the lower boundary of the 1-sided 95% confidence interval of this estimate exceeded 70%.
Among study participants, 137 (54.4%) had an abnormal FFR determined by ICA. On a per-patient basis, diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of FFRCT plus CT were 73% (95% CI, 67%–78%), 90% (95% CI, 84%–95%), 54% (95% CI, 46%–83%), 67% (95% CI, 60%–74%), and 84% (95% CI, 74%–90%), respectively. Compared with obstructive CAD diagnosed by CT alone (area under the receiver operating characteristic curve [AUC], 0.68; 95% CI, 0.62–0.74), FFRCT was associated with improved discrimination (AUC, 0.81; 95% CI, 0.75–0.86; P<.001).
Although the study did not achieve its prespecified primary outcome goal for the level of per-patient diagnostic accuracy, use of noninvasive FFRCT plus CT among stable patients with suspected or known CAD was associated with improved diagnostic accuracy and discrimination vs CT alone for the diagnosis of hemodynamically significant CAD when FFR determined at the time of ICA was the reference standard.
PMCID: PMC4281479  PMID: 22922562
11.  Risk stratification of non-contrast CT beyond the coronary calcium scan 
Coronary artery calcification (CAC) is a well-known marker for coronary artery disease and has important prognostic implications. CAC is able to provide clinicians with a reliable source of information related to cardiovascular atherosclerosis, which carries incremental information beyond Framingham risk. However, non-contrast scans of the heart provide additional information beyond the Agatston score. These studies are also able to measure various sources of fat, including intrathoracic (eg, pericardial or epicardial) and hepatic, both of which are thought to be metabolically active and linked to increased incidence of subclinical atherosclerosis as well as increased prevalence of type 2 diabetes. Testing for CAC is also useful in identifying extracoronary sources of calcification. Specifically, aortic valve calcification, mitral annular calcification, and thoracic aortic calcium (TAC) provide additional risk stratification information for cardiovascular events. Finally, scanning for CAC is able to evaluate myocardial scaring due to myocardial infarcts, which may also add incremental prognostic information. To ensure the benefits outweigh the risks of a scanning for CAC for an appropriately selected asymptomatic patient, the full utility of the scan should be realized. This review describes the current state of the art interpretation of non-contrast cardiac CT, which clinically should go well beyond coronary artery Agatston scoring alone.
PMCID: PMC4277886  PMID: 22981856
CAC; Fat; Myocardial scarring; Tumors; Radiation
12.  Statins use and coronary artery plaque composition: Results from the International Multicenter CONFIRM Registry 
Atherosclerosis  2012;225(1):148-153.
The effect of statins on coronary artery plaque features beyond stenosis severity is not known. Coronary CT angiography (CCTA) is a novel non-invasive method that permits direct visualization of coronary atherosclerotic features, including plaque composition. We evaluated the association of statin use to coronary plaque composition type in patients without known coronary artery disease (CAD) undergoing CCTA.
From consecutive individuals, we identified 6673 individuals (2413 on statin therapy and 4260 not on statin therapy) with no known CAD and available statin use status. We studied the relationship between statin use and the presence and extent of specific plaque composition types, which was graded as non-calcified (NCP), mixed (MP), or calcified (CP) plaque.
The mean age was 59 ± 11 (55% male). Compared to the individuals not taking statins, those taking statins had higher prevalence of risk factors and obstructive CAD. In multivariable analyses, statin use was associated with increased the presence of MP [odds ratio (OR) 1.46, 95% confidence interval (CI) 1.27–1.68), p < 0.001] and CP (OR 1.54, 95% CI 1.36–1.74, p < 0.001), but not NCP (OR 1.11, 95% CI 0.96–1.29, p = 0.1). Further, in multivariable analyses, statin use was associated with increasing numbers of coronary segments possessing MP (OR 1.52, 95% CI 1.34–1.73, p < 0.001) and CP (OR 1.52, 95% CI 1.36–1.70, p < 0.001), but not coronary segments with NCP (OR 1.09, 95% CI 0.94–1.25, p = 0.2).
Statin use is associated with an increased prevalence and extent of coronary plaques possessing calcium. The longitudinal effect of statins on coronary plaque composition warrants further investigation.
PMCID: PMC4277888  PMID: 22981406
Statin; Plaque composition; Coronary CTA; Coronary artery disease; Lipid profile
13.  Identification of Noncalcified Plaque in Young Persons with Diabetes 
Academic radiology  2012;19(7):889-893.
Coronary computed tomographic angiography (CTA) is a valuable tool for assessing coronary artery disease (CAD). Although statin use is widely recommended for persons with diabetes older than age 40, little is known about the presence and severity of CAD in younger patients with diabetes mellitus (DM). We evaluated coronary artery calcium (CAC) and coronary CTA in young persons with both DM1 and DM2 in an attempt to detect the earliest objective evidence of arteriosclerosis eligible for primary prevention.
Methods and Materials
We prospectively enrolled 40 persons with DM (25 type 1 and 15 type 2) between the ages of 19 and 35 presenting with diabetes for 5 years or longer. All patients underwent coronary CTA and CAC scans to evaluate for early atherosclerotic disease. Each plaque in the coronary artery was classified as noncalcified or calcified-mixed. We also evaluated all segments with stenosis, dividing them into mild (<50%), moderate (50–70%), and severe (>70%).
The average age of the DM1 subjects were 26 ± 4 (SD) years and 30 ± 4 years for DM2 patients (P < .01), with duration of diabetes of 8 ± 5 years and average HbA1c% of 8.7 ± 1.6 (norm = 4.6–6.2). Abnormal scans were present in 57.5%, noncalcified in 35% and calcified-mixed plaque in 22.5%. Persons with DM2 had a higher prevalence of positive coronary CTA scans than DM1: 80% versus 44% (P < .03) and more positive CAC scores 53% versus 4%, (P < .01). The total segment score of 2.1 ± 3.4 (P < .01) and total plaque score 1.9 ± 2.8 (P < .01) were highly correlated to each other. Plaque was almost uniformly absent below age 25, and became increasingly common in individuals over the age of 25 years for both groups. The average radiation exposure was 2.5 ± 1.3 mSv.
Our study verifies that early CAD can be diagnosed with coronary CTA and minimal radiation exposure in young adults with DM. A negative CAC score was not sufficient to exclude early CAD as we observed a preponderance of noncalcified plaque in this cohort. Coronary CTA in young DM patients older than age 25 may provide earlier identification of disease than does a CAC because only non-calcified plaque is frequently present. Coronary CTA provides an opportunity to consider initiation of earlier primary CAD prevention rather than waiting for the age of 40 as currently recommended by the American Diabetes Association guidelines.
PMCID: PMC4277701  PMID: 22542200
Atherosclerosis; diabetes mellitus; cardiac computed tomography; coronary calcium
14.  Association of Lipoprotein Subfractions and Coronary Artery Calcium In Patient at Intermediate Cardiovascular Risk 
The American journal of cardiology  2012;111(2):213-218.
More precise estimation of the atherogenic lipid parameters could improve identification of residual risk beyond what is possible using traditional lipid risk factors. The aim of the present study was to explore the association between advanced analysis of lipoprotein subfractions and the prevalence of coronary artery calcium. Consecutive participants at intermediate cardiovascular risk who were undergoing computed tomographic assessment of coronary calcium (calcium score) were included. Using a validated ultracentrifugation method (the vertical autoprofile II test), cholesterol in eluting lipoprotein subfractions [i.e., low- (LDL), very-low-, intermediate-, and high-density lipoprotein subclasses, lipoprotein (a), and predominant LDL distribution] was directly quantified. A total of 410 patients were included (29% women, mean age 57 years), of whom 297 (72.4%) had coronary artery calcium. LDL pattern B (predominance of small dense particles) emerged as an independent predictor of coronary calcium after adjustment for traditional risk factors (odds ratio 4.46, 95% confidence interval 1.19 to 16.7). However, after additional stratification for dyslipidemia, as defined by conventional lipid profiling, a statistically significant prediction was only retained for high-density lipoprotein subfraction 2 (odds ratio 3.45, 95% confidence interval 2.03 to 50.1) and “real” LDL (odds ratio 6.10, 95% confidence interval 1.26 to 23.41) in the normolipidemia group and for lipoprotein (a) (odds ratio 7.81, 95% confidence interval 1.41 to 43.5) in the dyslipidemic group. In conclusion, advanced assessment of the lipoprotein subfractions [i.e., LDL pattern B, high-density lipoprotein subfraction 2, “real” LDL, and lipoprotein (a)] using the vertical autoprofile II test provided additional information to that of conventional risk factors on the prevalence of coronary artery calcium in patients at intermediate cardiovascular risk.
PMCID: PMC4277703  PMID: 23141758
15.  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.
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
16.  Thoracic Aortic Distensibility and Thoracic Aortic Calcium (From the Multi-ethnic Study of Atherosclerosis [MESA]) 
The American journal of cardiology  2010;106(4):575-580.
Decreased arterial distensibility is an early manifestation of adverse structural and functional changes within the vessel wall. Its correlation with thoracic aortic calcium (TAC), a marker of atherosclerosis, has not been well demonstrated. We tested the hypothesis that decreasing aortic compliance and increasing arterial stiffness is independently associated with increased TAC. We included 3,540 (61±10 years, 46% males) subjects from the Multi-ethnic Study of Atherosclerosis (MESA) study who underwent aortic distensibility (AD) assessment on MRI. TAC was calculated using modified Agatston algorithm on non-contrast cardiac CT. Multivariate regression models were calculated for the presence of TAC. Overall, 861 (24%) individuals had detectable TAC. A lower AD was observed among those with vs. without TAC (2.02±1.34 vs. 1.28±0.74, p<0.0001). The prevalence of TAC increased significantly across decreasing quartiles of AD (7%, 17%, 31%, and 42%, p<0.0001). Using multivariate analysis, TAC was independently associated with AD after adjusting for age, gender, ethnicity and other covariates. In conclusion, our analysis demonstrates that increased arterial stiffness is associated with increased TAC independent of ethnicity and other atherosclerotic risk factors.
PMCID: PMC4228943  PMID: 20691319
17.  Null Association between Abdominal Muscle and Calcified Atherosclerosis in Community-Living Persons Without Clinical Cardiovascular Disease: the Multi-Ethnic Study of Atherosclerosis 
Metabolism: clinical and experimental  2013;62(11):10.1016/j.metabol.2013.06.001.
Detrimental effects of lean muscle loss have been hypothesized to explain J-shaped relationships of body mass index (BMI) with cardiovascular disease (CVD), yet associations of muscle mass with CVD are largely unknown. We hypothesized that low abdominal lean muscle area would be associated with greater calcified atherosclerosis, independent of other CVD risk factors.
We investigated 1020 participants from the Multi-Ethnic Study of Atherosclerosis who were free of clinical CVD. Computed tomography (CT) scans at the 4th and 5th lumbar disk space were used to estimate abdominal lean muscle area. Chest and abdominal CT scans were used to assess coronary artery calcification(CAC), thoracic aortic calcification (TAC), and abdominal aortic calcification (AAC).
The mean age was 64±10 years, 48% were female, and mean BMI was 28±5 kg/m2. In models adjusted for demographics, physical activity, caloric intake, and traditional CVD risk factors, there was no inverse association of abdominal muscle mass with CAC(Prevalence Ratio [PR] 1.02 [95% CI 0.95,1.10]), TAC (PR 1.13 [95%CI 0.92, 1.39]) or AAC (PR 0.99 [95%CI 0.94, 1.04]) prevalence. Similarly, there was no significant inverse relationship between abdominal lean muscle area and CAC, TAC, and AAC severity.
In community-living individuals without clinical CVD, greater abdominal lean muscle area is not associated with less calcified atherosclerosis.
PMCID: PMC3740763  PMID: 23916063
Cardiovascular Disease; atherosclerosis; lean muscle
18.  Risk Factors Associated with the Incidence and Progression of Mitral Annulus Calcification: The Multi-Ethnic Study of Atherosclerosis 
American heart journal  2013;166(5):904-912.
Significant cardiovascular morbidity has been associated with mitral annulus calcification (MAC), but limited data exist regarding its progression. The purpose of this study was to examine the natural history of and risk factors for MAC progression.
The Multi-Ethnic Study of Atherosclerosis (MESA) is a longitudinal cohort study of participants aged 45–84 years without clinical cardiovascular disease who underwent serial cardiac computed tomography studies with quantification of MAC. Regression models were used to identify risk factors associated with MAC incidence and progression.
Prevalent MAC was observed in 534 of 5,895 (9%) participants. Over a median 2.3 years, 280 (5%) developed incident MAC. After adjustment, age was the strongest predictor of incident MAC (adjusted OR, 2.25 per 10 yrs; 95% CI, 1.97 to 2.58; P<0.0001). Female gender, white ethnicity, body mass index, diabetes, hypertension, hyperlipidemia, serum cholesterol, smoking, and interleukin-6 were also significant predictors of incident MAC. In participants with prevalent MAC, the median rate of change was 10.1 [IQR, −6.7, 60.7] Agatston units (AU)/year. Baseline MAC severity was the predominant predictor of rate of MAC progression (β-coefficient per 10 AU, 0.88; 95% CI, 0.85 to 0.91; P<0.0001), although ethnicity and smoking status possessed modest influence.
Several cardiovascular risk factors predicted incident MAC, as did female gender. Severity of baseline MAC was the primary predictor of MAC progression, suggesting that, while atherosclerotic processes may initiate MAC, they are only modestly associated with its progression over these time frames.
PMCID: PMC3978772  PMID: 24176447
calcification; mitral valve; progression; risk factors; gender
19.  Risk Factors for Fatty Liver in the Multicenter AIDS Cohort Study 
Human immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) may increase the risk of fatty liver disease. We determined the prevalence of and risk factors for fatty liver by comparing HIV-infected men with HIV-uninfected men who have sex with men in the Multicenter AIDS Cohort Study (MACS).
In 719 MACS participants who consumed less than three alcoholic drinks daily, fatty liver was defined as a liver-to-spleen attenuation ratio < 1 on noncontrast computed tomography (CT). We genotyped single nucleotide polymorphisms in the patatin-like phospholipase domain-containing 3 (PNPLA3) gene and in other genes previously associated with nonalcoholic fatty liver disease. Risk factors for fatty liver were determined using multivariable logistic regression.
Among 254 HIV-uninfected men and 465 HIV-infected men, 56 % were White with median age 53 years and median body mass index 25.8 kg/m 2. The vast majority of HIV-infected men (92 %) were on ART, and 87 % of the HIV-infected men were treated with a nucleoside reverse transcriptase inhibitor for a median duration of 8.5 years. Overall, 15 % of the cohort had fatty liver, which was more common in the HIV-uninfected compared with the HIV-infected men (19 vs. 13 %, P= 0.02). In multivariable analysis, HIV infection was associated with a lower prevalence of fatty liver (odds ratio (OR) = 0.44, P= 0.002), whereas a higher prevalence of fatty liver was seen in participants with PNPLA3 (rs738409) non-CC genotype (OR = 2.06, P= 0.005), more abdominal visceral adipose tissue (OR = 1.08 per 10 cm2, P< 0.001), and homeostatic model assessment of insulin resistance (HOMA-IR) ≥ 4.9 (OR = 2.50, P= 0.001). Among HIV-infected men, PNPLA3 (rs738409) non-CC genotype was associated with a higher prevalence of fatty liver (OR = 3.30, P= 0.001) and cumulative dideoxynucleoside exposure (OR = 1.44 per 5 years, P= 0.02).
CT-defined fatty liver is common among men at risk for HIV infection and is associated with greater visceral adiposity, HOMA-IR, and PNPLA3 (rs738409). Although treated HIV infection was associated with a lower prevalence of fatty liver, prolonged exposure to dideoxynucleo side analogs is associated with higher prevalence.
PMCID: PMC4133993  PMID: 24642579
20.  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.
PMCID: PMC3583351  PMID: 23328906
Carotid Ultrasound; Coronary Artery Disease; Risk Prediction; Intima Media Thickness
21.  Calcium Scoring in Patients with a History of Kawasaki Disease 
JACC. Cardiovascular imaging  2012;5(3):264-272.
To assess coronary artery calcification in patients of age ≥ 10 years with a history of Kawasaki Disease (KD).
Patients with a history of KD and coronary artery aneurysms are at risk for late morbidity from coronary artery events. It is unknown whether KD patients with acutely normal or transiently dilated coronary arteries also have increased risk of late coronary artery complications. Coronary calcium scoring by non-contrast computed tomography (CT) is a well-established tool for risk stratifying patients with atherosclerotic coronary artery disease, but there are limited data on its role in evaluating patients with a history of KD.
We performed coronary artery calcium (CAC) volume scoring using a low radiation dose CT protocol on 70 subjects (median age: 20.0 years) with a remote history of KD (median interval from acute KD to imaging: 14.8 years): 44 (63%) had no history of coronary dilation, 12 (17%) had a history of transient dilation, and 14 (20%) had coronary aneurysms.
All of the subjects with normal coronary artery internal diameter during the acute phase of KD and 11 of 12 subjects with transient dilatation had CAC scores of zero. Coronary calcification was observed in 10 of the 14 subjects with coronary aneurysms, with the degree of calcification ranging from mild to severe and occurring years after the subjects’ acute KD.
Coronary calcification was not observed in subjects with a history of KD and normal coronary arteries during the acute phase. Therefore, CAC scanning may be a useful tool to screen patients with a remote history of KD or suspected KD and unknown coronary artery status. Coronary calcification, which may be severe, occurs late in patients with coronary aneurysms. The pathophysiology and clinical implications of coronary calcification in patients with aneurysms are currently unknown and warrant further study.
PMCID: PMC4188432  PMID: 22421171
Calcium Scoring; Kawasaki Disease; Aneurysm; Computed Tomography
22.  Computed Tomography-Derived Cardiovascular Risk Markers, Incident Cardiovascular Events, and All-Cause Mortality in Non- Diabetics. The Multi-Ethnic Study of Atherosclerosis 
We assess the improvement in discrimination afforded by the addition thoracic aorta calcium (TAC), aortic valve calcification (AVC), mitral annular calcification (MAC), pericardial adipose tissue volume (PAT) and liver attenuation (LA) to Framingham risk score(FRS) + coronary artery calcium (CAC) for incident CHD/CVD in a multi ethnic cohort.
Methods and Results
A total 5745(2710 were intermediate Framingham risk, 210 CVD and 155 CHD events) 251 had adjudicated CHD, 346 had CVD events, 321 died after 9 years of follow-up. Cox proportional hazard, receiver operator curve (ROC) and net reclassification improvement (NRI) analyses.
In the whole cohort and also when the analysis was restricted to only the intermediate risk participants: CAC, TAC, AVC and MAC were all significantly associated with incident CVD/CHD/ mortality; CAC had the strongest association. When added to the FRS, CAC had the highest area under the curve (AUC) for the prediction of incident CHD/CVD; LA had the least. The addition of TAC, AVC, MAC, PAT and LA to FRS + CAC all resulted in a significant reduction in AUC for incident CHD [0.712 vs. 0.646, 0.655, 0.652, 0.648 and 0.569; all p<0.01 respectively] in participants with intermediate FRS. The addition of CAC to FRS resulted in an NRI of 0.547 for incident CHD in the intermediate risk group. The NRI when TAC, AVC, MAC, PAT and LA were added to FRS + CAC were 0.024, 0.026, 0.019, 0.012 and 0.012 respectively, for incident CHD in the intermediate risk group. Similar results were obtained for incident CVD in the intermediate risk group and also when the whole cohort was used instead of the intermediate FRS group.
The addition of CAC to the FRS provides superior discrimination especially in intermediate risk individuals compared with the addition of TAC, AVC, MAC, PAT or LA for incident CHD/CVD. Compared with FRS + CAC, the addition of TAC, AVC, MAC, PAT or LA individually to FRS + CAC worsens the discrimination for incident CHD/CVD. These CT risk markers are unlikely to be useful for improving cardiovascular risk prediction.
PMCID: PMC4150859  PMID: 23689526
cardiac CT derived risk factors; coronary heart disease; cardiovascular events; risk prediction
23.  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.
PMCID: PMC4165381  PMID: 25254142
24.  Progression of Coronary Calcium and Incident Coronary Heart Disease Events: The Multi-Ethnic Study of Atherosclerosis 
Coronary artery calcium (CAC) predicts coronary heart disease (CHD) events and serial measurement of CAC has been proposed to evaluate atherosclerosis progression. We examined whether progression of CAC is a predictor of future CHD events.
Methods and Results
We studied 6,778 persons (52.8% female) aged 45–84 years from the Multi-Ethnic Study of Atherosclerosis. 5,682 persons had baseline and follow-up CAC scans approximately 2.5 ± 0.8 years apart; multiple imputation was used to account for the remainder (n=1,096) missing follow-up scans. Median follow-up duration from the baseline was 7.6 (max=9.0) years. CAC change was assessed by absolute change between baseline and follow-up CAC. Cox proportional hazards regression providing hazard ratios (HR) examined the relation of change in CAC with CHD events, adjusting for age, gender, ethnicity, baseline calcium score, and other risk factors. 343 total and 206 hard CHD events occurred. The annual change in CAC averaged 24.9 ± 65.3 units. Among persons without CAC at baseline (n=3,396), a 5 unit annual change in CAC was associated with an adjusted HR of 1.4 (1.0–1.9) for total and 1.5 (1.1–2.1) for hard CHD. Among those with CAC>0 at baseline HR’s (per 100 unit annual change) were 1.2 (1.1–1.4) and 1.3 (1.1–1.5), respectively. Among participants with baseline CAC, those with annual progression of ≥300 units had adjusted HR’s of 3.8 (1.5–9.6) for total and 6.3 (1.9–21.5) for hard CHD compared to those without progression.
Progression of CAC is associated with an increased risk for future hard and total CHD events.
PMCID: PMC4148074  PMID: 23500326
coronary calcification; atherosclerosis; imaging; coronary heart disease

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