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1.  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
2.  Lower Adiponectin is Associated with Subclinical Cardiovascular Disease among HIV-infected Men 
AIDS (London, England)  2014;28(6):901-909.
To examine if altered levels of adipokines, adipose-derived peptides associated with myocardial infarction in the general population, may contribute to subclinical coronary atherosclerosis in HIV-infected persons.
Nested cohort study.
We studied HIV-infected(HIV+) and HIV-uninfected(HIV−) men in the Multicenter AIDS Cohort Study with noncontrast CT to measure coronary artery calcium and regional adiposity; 75% additionally underwent coronary CT angiography to measure plaque composition and stenosis. Adiponectin and leptin levels were assessed. Multiple regression models were used to assess associations between adipokine levels and HIV disease parameters, regional adiposity, and plaque adjusted for age, race, HIV serostatus and CVD risk factors (RFs).
Significant findings were limited to adiponectin. HIV+ men (n=493) had lower adiponectin levels than HIV− men (n=250) after adjusting for CVD RFs (p<0.0001), which became non-significant after adjustment for abdominal visceral and thigh subcutaneous adipose tissue. Among HIV+ men, lower adiponectin levels were associated with higher CD4+ T cell counts (p= 0.004), longer duration of antiretroviral therapy (p= 0.006) and undetectable HIV RNA levels (p = 0.04) after adjusting for age, race and CVD RFs; only CD4+ cell count remained significant after further adjustment for adipose tissue. In both groups, lower adiponectin levels were associated with increased odds of coronary stenosis > 50% (p <0.007). Lower adiponectin levels were associated with increased extent of plaque in HIV+ and of mixed plaque in HIV− men.
Adiponectin levels were lower in HIV-infected men and related to the severity of subclinical atherosclerosis, independent of traditional CVD risk factors.
PMCID: PMC3967406  PMID: 24401646
Adipokines; adiponectin; leptin; heart; subclinical coronary atherosclerosis; metabolic side effects of HIV infection; coronary CT angiography; cardiac CT
3.  Cardiovascular Risk Factors and Mitral Annular Calcification in Type 2 Diabetes 
Atherosclerosis  2012;226(2):419-424.
Mitral annular calcification (MAC) is a degenerative process of the mitral fibrous annulus associated with cardiac disease and stroke. Although thought to be more prevalent in type 2 diabetes (T2DM), MAC remains poorly characterized in this population, due to confounding by renal and cardiac disease. Our goal was to study the risk factors for MAC in asample of T2DM subjects without renal and cardiac disease.
The Penn Diabetes Heart Study (PDHS) is a cross-sectional study of diabetic individuals without clinical cardiovascular or renal disease. We quantified and analyzed MAC Agatston scores in baseline cardiac CTs from 1753 individuals. Logistic and tobit regression were used to assess MAC’s relationship with risk factors and coronary artery calcification (CAC).
MAC was present in 12.0% of -subjects, with a median Agatston score of 72.3 [Interquartile range (22.2 256.9)]. Older age, diabetes female gender, Caucasian race, and longer duration were independently associated with both the presence and extent MAC even after controlling for the CAC; hypertension, hyperlipidemia, comorbidities however, tobacco use, CRP levels, and other were not associated. CAC was strongly associated with MAC [OR of 4.0, (95% CI 2.4-6.6)] in multivariable models.
Age, AC female gender, Caucasian race, and diabetes duration were associated with the presence and extent of MAC in T2DM subjects, independent of CAC, which was also strongly associated with MAC. These data suggest that additional mechanisms for MAC formation in diabetics may exist which are distinct from those related to generalized atherosclerosis and deserve further investigation.
PMCID: PMC3568504  PMID: 23273961
Diabetes; Mitral Annular Calcification; Coronary Heart Disease; Risk Factors
4.  Coronary Calcium: New Insights, Recent Data, and Clinical Role 
Current cardiology reports  2013;15(1):325.
Calcium artery calcium (CAC) scoring has become an integral part in the era of preventive cardiology, it has been extensively studied and been validated as a powerful tool for cardiovascular risk assessment in conjunction with other traditional well established scoring systems such as Framingham risk score. In addition, CAC testing has found its way into emergency department algorithms assessing low to intermediate risk patients presenting with chest pain, this strategy was recently adopted by the UK NICE guidelines, confidently ruling out cardiac origin of chest pain. Several studies have demonstrated that risk assessment using CAC was motivational to patients leading to better adherence to their preventive practices as well as to medications. Accordingly, this test has several recommendations for use by national and international guidelines.
PMCID: PMC3551450  PMID: 23250661
Coronary artery calcium; Coronary artery disease; Calcium score; Cardiovascular risk
5.  All-cause mortality benefit of coronary revascularization vs. medical therapy in patients without known coronary artery disease undergoing coronary computed tomographic angiography: results from CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter Registry) 
European Heart Journal  2012;33(24):3088-3097.
To date, the therapeutic benefit of revascularization vs. medical therapy for stable individuals undergoing invasive coronary angiography (ICA) based upon coronary computed tomographic angiography (CCTA) findings has not been examined.
Methods and results
We examined 15 223 patients without known coronary artery disease (CAD) undergoing CCTA from eight sites and six countries who were followed for median 2.1 years (interquartile range 1.4–3.3 years) for an endpoint of all-cause mortality. Obstructive CAD by CCTA was defined as a ≥50% luminal diameter stenosis in a major coronary artery. Patients were categorized as having high-risk CAD vs. non-high-risk CAD, with the former including patients with at least obstructive two-vessel CAD with proximal left anterior descending artery involvement, three-vessel CAD, and left main CAD. Death occurred in 185 (1.2%) patients. Patients were categorized into two treatment groups: revascularization (n = 1103; 2.2% mortality) and medical therapy (n = 14 120, 1.1% mortality). To account for non-randomized referral to revascularization, we created a propensity score developed by logistic regression to identify variables that influenced the decision to refer to revascularization. Within this model (C index 0.92, χ2 = 1248, P < 0.0001), obstructive CAD was the most influential factor for referral, followed by an interaction of obstructive CAD with pre-test likelihood of CAD (P = 0.0344). Within CCTA CAD groups, rates of revascularization increased from 3.8% for non-high-risk CAD to 51.2% high-risk CAD. In multivariable models, when compared with medical therapy, revascularization was associated with a survival advantage for patients with high-risk CAD [hazards ratio (HR) 0.38, 95% confidence interval 0.18–0.83], with no difference in survival for patients with non-high-risk CAD (HR 3.24, 95% CI 0.76–13.89) (P-value for interaction = 0.03).
In an intermediate-term follow-up, coronary revascularization is associated with a survival benefit in patients with high-risk CAD by CCTA, with no apparent benefit of revascularization in patients with lesser forms of CAD.
PMCID: PMC3598430  PMID: 23048194
Computed tomography; Coronary revascularization; Medical therapy; Coronary artery disease
6.  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.
PMCID: PMC3820482  PMID: 24278742
7.  Prospective Study of Particulate Air Pollution Exposures, Subclinical Atherosclerosis, and Clinical Cardiovascular Disease 
American Journal of Epidemiology  2012;176(9):825-837.
The Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air) was initiated in 2004 to investigate the relation between individual-level estimates of long-term air pollution exposure and the progression of subclinical atherosclerosis and the incidence of cardiovascular disease (CVD). MESA Air builds on a multicenter, community-based US study of CVD, supplementing that study with additional participants, outcome measurements, and state-of-the-art air pollution exposure assessments of fine particulate matter, oxides of nitrogen, and black carbon. More than 7,000 participants aged 45–84 years are being followed for over 10 years for the identification and characterization of CVD events, including acute myocardial infarction and other coronary artery disease, stroke, peripheral artery disease, and congestive heart failure; cardiac procedures; and mortality. Subcohorts undergo baseline and follow-up measurements of coronary artery calcium using computed tomography and carotid artery intima-medial wall thickness using ultrasonography. This cohort provides vast exposure heterogeneity in ranges currently experienced and permitted in most developed nations, and the air monitoring and modeling methods employed will provide individual estimates of exposure that incorporate residence-specific infiltration characteristics and participant-specific time-activity patterns. The overarching study aim is to understand and reduce uncertainty in health effect estimation regarding long-term exposure to air pollution and CVD.
PMCID: PMC3571256  PMID: 23043127
air pollution; atherosclerosis; cardiovascular diseases; environmental exposure; epidemiologic methods; particulate matter
8.  Genetic Associations with Valvular Calcification and Aortic Stenosis 
The New England journal of medicine  2013;368(6):503-512.
Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease.
We determined genomewide associations with the presence of aorticvalve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis.
One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aorticvalve calcification (odds ratio per allele, 2.05; P = 9.0×10−10), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aorticvalve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P = 1.5×10−8 and P = 1.8×10−8, respectively), but the findings were not replicated consistently.
Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aorticvalve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.)
PMCID: PMC3766627  PMID: 23388002
9.  Differences in Prevalence, Extent, Severity, and Prognosis of Coronary Artery Disease Among Patients With and Without Diabetes Undergoing Coronary Computed Tomography Angiography 
Diabetes Care  2012;35(8):1787-1794.
We examined the prevalence, extent, severity, and prognosis of coronary artery disease (CAD) in individuals with and without diabetes (DM) who are similar in CAD risk factors.
We identified 23,643 consecutive individuals without known CAD undergoing coronary computed tomography angiography. A total of 3,370 DM individuals were propensity matched in a 1-to-2 fashion to 6,740 unique non-DM individuals. CAD was defined as none, nonobstructive (1–49% stenosis), or obstructive (≥50% stenosis). All-cause mortality was assessed by risk-adjusted Cox proportional hazards models.
At a 2.2-year follow-up, 108 (3.2%) and 115 (1.7%) deaths occurred among DM and non-DM individuals, respectively. Compared with non-DM individuals, DM individuals possessed higher rates of obstructive CAD (37 vs. 27%) and lower rates of having normal arteries (28 vs. 36%) (P < 0.0001). CAD extent was higher for DM versus non-DM individuals for obstructive one-vessel disease (19 vs. 14%), two-vessel disease (9 vs. 7%), and three-vessel disease (9 vs. 5%) (P < 0.0001 for comparison), with higher per-segment stenosis in the proximal and mid-segments of every coronary artery (P < 0.001 for all). Compared with non-DM individuals with no CAD, risk of mortality for DM individuals was higher for those with no CAD (hazard ratio 3.63 [95% CI 1.67–7.91]; P = 0.001), nonobstructive CAD (5.25 [2.56–10.8]; P < 0.001), one-vessel disease (6.39 [2.98–13.7]; P < 0.0001), two-vessel disease (12.33 [5.622–27.1]; P < 0.0001), and three-vessel disease (13.25 [6.15–28.6]; P < 0.0001).
Compared with matched non-DM individuals, DM individuals possess higher prevalence, extent, and severity of CAD. At comparable levels of CAD, DM individuals experience higher risk of mortality compared with non-DM individuals.
PMCID: PMC3402246  PMID: 22699296
10.  Associations of Left Ventricular Hypertrophy with Prevalent and Incident Valve Calcification: The Multi-Ethnic Study of Atherosclerosis 
JACC. Cardiovascular imaging  2012;5(8):781-788.
We aim to evaluate the relationship between percent of predicted left ventricular mass (%PredLVM) and valve calcification in the Multi-Ethnic Study of Atherosclerosis (MESA).
Cardiac valve calcification has been associated with left ventricular hypertrophy (LVH), which portends cardiovascular events. However, this relationship and its mediators are poorly understood.
MESA is a longitudinal cohort study of men and women aged 45-84 years without clinical cardiovascular disease in whom serial cardiac magnetic resonance and computed tomography imaging were performed. The relationships between baseline %PredLVM and the prevalence, severity, and incidence of aortic valve (AVC) and mitral annulus calcification (MAC) were determined by regression modeling.
Prevalent AVC was observed in 630 and MAC in 442 of 5,042 subjects (median 55.9 and 71.1 Agatston units, respectively). After adjustment for age, gender, body mass index, ethnicity, socioeconomic status, physical activity, diabetes, cholesterol levels, blood pressure, smoking, kidney function, serum lipids, and antihypertensive and statin medications, %PredLVM was associated with prevalent AVC (OR=1.18 per SD increase in %PredLVM [95%CI 1.08 – 1.30]; p=0.0004) and MAC (OR=1.18 [95%CI 1.06 – 1.32]; p=0.002). Similarly, %PredLVM was associated with increased severity of prevalent AVC (risk difference = 0.26 [95%CI 0.15 – 0.38]; p<0.0001) and MAC (risk difference = 0.20 [95%CI 0.03 – 0.37]; p=0.02). During follow-up (mean 2.4±0.9 years), 153 subjects (4%) developed AVC and 198 (5%) MAC. %PredLVM was associated with incident AVC (OR=1.24 [95%CI 1.04 – 1.47]; p=0.02) and MAC (OR=1.18 [1.01-1.40]; p=0.04). Further adjustment for inflammatory markers and coronary artery calcification did not attenuate these associations. Specifically, concentric LVH most strongly predicted incident valve calcification.
Within the MESA cohort, LVH was associated with prevalence, severity, and incidence of valve calcification independent of hypertension and other identified confounders.
PMCID: PMC3426868  PMID: 22897991
aortic valve; calcification; left ventricular mass; mitral valve annulus
11.  Coronary artery calcium scoring, what is answered and what questions remain 
Coronary artery calcification (CAC) is a widely used imaging modality for cardiovascular risk assessment in moderate risk patients. It has been shown to have a superior role predicting future cardiac events and survival rates when combined with other traditional risk factor scoring systems as Framingham risk score (FRS). Furthermore, it significantly reclassifies moderate risk patients into lower or higher risk categories. Higher risk groups like patients with diabetes, a higher prevalence of CAC has been shown to impart a high short term risk of CV events, while those with zero calcium score had excellent event-free survival, similar to non-diabetic patients. Having a zero calcium score is currently used in United Kingdom practice guidelines (NICE) as a gatekeeper for any further investigations in patients presenting to the emergency department (ED) with chest pain. Unanswered questions include the concept of CAC progression that need to be standardized with respect to technique, interpretation and subsequent management strategies. Studies also demonstrated that risk assessment using CAC was motivational to patients leading to better adherence to their preventive practices as well as medications. However, statin did not consistently prove beneficial in slowing the CAC progression rate, but did reduce CV events significantly in patients with increased CAC. Accordingly, more studies need to be conducted to further help understand the ideal way to utilize this imaging tool and decreasing downstream utilization.
PMCID: PMC3839142  PMID: 24282703
Coronary artery calcium; coronary artery disease; calcium score; cardiovascular risk
12.  Computed Tomography Scans in the Evaluation of Fatty Liver Disease in a Population Based Study: The Multi-Ethnic Study of Atherosclerosis 
Academic Radiology  2012;19(7):811-818.
Rationale and Objectives
Fatty liver disease is a common clinical entity in hepatology practice. This study evaluates the prevalence and reproducibility of computed tomography (CT) measures for diagnosis of fatty liver and compares commonly used CT criteria for the diagnosis of liver fat.
Materials and Methods
The study includes 6,814 asymptomatic participants from a population based sample. The ratio of liver-to-spleen (L/S) Hounsfield units (HU) <1.0 and liver attenuation <40HU were utilized for diagnosing and assessing the severity of liver fat content. Participants with heavy alcohol intake (>7 drinks/week for women and >14 drinks/week for men) were excluded. Final analysis was performed on participants where images of both liver and spleen were available on the scans.
The overall prevalence of fatty liver (4,175 patients) was 17.2% (using L/S ratio <1.0), with 6.3% (with <40HU cutoff) of the population having moderate to severe steatosis (>30% liver fat content). The prevalence was high in participants with dyslipidemia (70.4%), hypertension (56.8%) and obesity (53%). Diabetic patients had 24.1% prevalence of fatty liver. The prevalence provided by L/S ratio <1.0 (17.2%) was comparable to prevalence provided by <51 HU (17.3%), whereas prevalence obtained by <40HU (6.3%) cutoff corresponded to L/S ratio of <0.8 (6.5%). The measurements of liver and spleen HU attenuations were highly reproducible (0.96, 0.99 and 0.99, 0.99 for intra- and inter-reader variability, respectively) in a sample of 100 scans.
Fatty liver can be reliably diagnosed using non-enhanced CT scans.
PMCID: PMC3377794  PMID: 22521729
Computed Tomography; Fatty Liver; MESA
13.  Use of Cardiac CT Angiography Imaging in an Epidemiology Study – the Methodology of the Multicenter AIDS Cohort Study Cardiovascular Disease Substudy 
The methodology for use of cardiac CT angiography (CTA) in low risk populations is not well defined. In order to present a reference for future studies, we present CTA methodology that is being used in an epidemiology study- the Multicenter AIDS Cohort Study (MACS).
The Multicenter AIDS Cohort Study (MACS) is an on-going multicenter prospective, observational cohort study. The MACS Cardiovascular Disease substudy plans to enroll 800 men (n= 575 HIV seropositive and n= 225 HIV seronegative) age 40-75 years for coronary atherosclerosis imaging using cardiac CTA. The protocol includes heart rate (HR) optimization with beta blockers; use of proper field of view; scan length limitation; prospective ECG-gating using the lowest beam voltage possible. All scans are evaluated for presence, extent, and composition of coronary atherosclerosis, left atrial volumes, left ventricular volume and mass and non-coronary cardiac pathology.
The first 498 participants had an average radiation dose of 2.5±1.6 milliSieverts (mSv) for the cardiac CTA study. Overall quality of scans was fair to excellent in 98.6% of studies. There were three significant adverse events- two allergic reactions to contrast and one subcutaneous contrast extravasation.
Cardiac CTA was safe and afforded a low effective radiation exposure to these asymptomatic research participants and provides valuable cardiovascular endpoints for scientific analysis. The cardiac CTA methodology described here may serve as a reference for use in future epidemiology studies aiming to assess coronary atherosclerosis and cardiac anatomy in low risk populations while minimizing radiation exposure.
PMCID: PMC3673004  PMID: 23376648
CT angiography; radiation dose; epidemiological study
14.  Aortic Valve Calcium Independently Predicts Coronary and Cardiovascular Events in a Primary Prevention Population 
Jacc. Cardiovascular Imaging  2012;5(6):619-625.
This study aimed to test whether aortic valve calcium (AVC) is independently associated with coronary and cardiovascular events in a primary-prevention population.
Aortic sclerosis is associated with increased cardiovascular morbidity and mortality among the elderly, but the mechanisms underlying this association remain controversial and it is unknown if this association extends to younger individuals.
We performed a prospective analysis of 6,685 participants in the Multi-Ethnic Study of Atherosclerosis. All subjects, aged 45-84 years and free of clinical cardiovascular disease at baseline, underwent computed tomography for AVC and coronary artery calcium (CAC) scoring. The primary, pre-specified combined endpoint of cardiovascular events included myocardial infarctions, fatal and non-fatal strokes, resuscitated cardiac arrest and cardiovascular death, while a secondary combined endpoint of coronary events excluded strokes. The association between AVC and clinical events was assessed using Cox proportional hazards regression with incremental adjustments for demographics, cardiovascular risk factors, inflammatory biomarkers and subclinical coronary atherosclerosis.
Over a median follow up of 5.8 [IQR 5.6, 5.9] years, adjusting for demographics and cardiovascular risk factors, subjects with AVC (n=894, 13.4%) had higher risks of cardiovascular (HR, 1.50; 95% CI, 1.10-2.03) and coronary (HR, 1.72; 95% CI, 1.19-2.49) events compared to those without AVC. Adjustments for inflammatory biomarkers did not alter these associations, but adjustment for CAC substantially attenuated both cardiovascular (HR, 1.32; 95% CI: 0.98-1.78) and coronary (HR, 1.41; 95% CI, 0.98-2.02) event risk. AVC remained predictive of cardiovascular mortality even after full adjustment (HR, 2.51; 95% CI, 1.22-5.21).
In this multiethnic MESA cohort, free of clinical cardiovascular disease, AVC predicts cardiovascular and coronary event risk independent of traditional risk factors and inflammatory biomarkers, likely due to the strong correlation between AVC and subclinical atherosclerosis. The association of AVC with excess cardiovascular mortality beyond coronary atherosclerosis risk merits further investigation.
PMCID: PMC3376353  PMID: 22698532
15.  The Evolution and Refinement of Traditional Risk Factors for Cardiovascular Disease 
Cardiology in Review  2012;20(3):118-129.
Traditional risk factors for premature cardiovascular disease such as systemic hypertension and hypercholesterolemia, all described more than half a century ago, are relatively few in number. Efforts to expand the epidemiological canon have met with limited success due to the high hurdle of causality. Fortunately, another solution to current deficiencies in risk assessment – in particular, the underestimation of risk both before and after initiation of pharmacotherapy – may exist. Parallel to the investigation of novel biomarkers, such as high-sensitivity C-reactive protein, ongoing research has yielded improved metrics of known causative conditions. This evolution of traditional risk factors, heralded by measures such as ambulatory blood pressure, central hemodynamics, low density lipoprotein particle concentration, genetic testing, and “vascular age,” may better address the detection gap in cardiovascular disease.
PMCID: PMC3310946  PMID: 22183062
prevention; cholesterol; lipoproteins; blood pressure; cardiovascular risk; coronary artery calcium; carotid intima-media thickness
16.  Intra-Thoracic Fat, Cardiometabolic Risk Factors, and Subclinical Cardiovascular Disease in Healthy, Recently Menopausal Women Screened for the Kronos Early Estrogen Prevention Study (KEEPS) 
Atherosclerosis  2011;221(1):198-205.
To examine the correlations between intra-hepatic and intra-thoracic (total, epicardial, and pericardial) fat deposition with cardiovascular disease (CVD) risk factors and subclinical atherosclerosis burden in healthy, recently postmenopausal women.
Women screened for the Kronos Early Estrogen Prevention Study (mean age 52.9 years) who underwent electron beam or multidetector computed tomography (CT) imaging for the quantification of intra-hepatic fat and thoracic adipose tissue, and coronary artery calcification (CAC) were included (n= 650).
Higher levels of intra-hepatic and thoracic fat were each associated with CVD risk markers. After adjustment for BMI, the associations for intra-hepatic fat with hs-CRP and insulin persisted (r= 0.21 and 0.19, respectively; P<0.001), while those between thoracic fat indices and lipids persisted (r for total thoracic fat with HDL, LDL, and triglycerides= −0.16, 0.11, and 0.11, respectively, P<0.05). Total thoracic fat was associated with CAC after initial multivariable adjustment (odds ratio [OR] of 2nd, 3rd, and 4th vs. 1st quartile and [95% confidence intervals]: 0.8 [0.4–1.6], 1.5 [0.8–2.9], and 1.8 [1.0–3.4]; P for linear trend=0.017) and was only slightly attenuated after additional adjustment for BMI. Associations between total thoracic fat and CVD risk markers and CAC appeared due slightly more to associations with epicardial than pericardial fat.
While hepatic fat is related to hs-CRP and insulin, cardiac fat is associated with subclinical atherosclerosis as demonstrated by CAC. Cardiac fat may represent a useful marker for increased CVD risk beyond the standard adiposity measures of BMI and WC.
PMCID: PMC3288598  PMID: 22209479
coronary calcification; ectopic fat; cardiac fat; hepatic fat; risk factors; women
17.  Potential Implications of Coronary Artery Calcium Testing for Guiding Aspirin Use Among Asymptomatic Individuals With Diabetes 
Diabetes Care  2012;35(3):624-626.
It is unclear whether coronary artery calcium (CAC) is effective for risk stratifying patients with diabetes in whom treatment decisions are uncertain.
Of 44,052 asymptomatic individuals referred for CAC testing, we studied 2,384 individuals with diabetes. Subjects were followed for a mean of 5.6 ± 2.6 years for the end point of all-cause mortality.
There were 162 deaths (6.8%) in the population. CAC was a strong predictor of mortality across age-groups (age <50, 50–59, ≥60), sex, and risk factor burden (0 vs. ≥1 additional risk factor). In individuals without a clear indication for aspirin per current guidelines, CAC stratified risk, identifying patients above and below the 10% risk threshold of presumed aspirin benefit.
CAC can help risk stratify individuals with diabetes and may aid in selection of patients who may benefit from therapies such as low-dose aspirin for primary prevention.
PMCID: PMC3322717  PMID: 22228745
18.  Coronary Artery Diameter Related to Calcium Scores and Coronary Risk Factors as Measured with Multidetector Computed Tomography 
Texas Heart Institute Journal  2013;40(3):261-267.
Arterial remodeling, an early change of atherosclerosis, can cause dilated arterial diameter. We measured coronary artery diameter with use of noncontrast 64-slice multidetector computed tomography (MDCT), and studied its association with coronary artery calcium levels and traditional coronary risk factors.
We included 140 patients from the ACCURACY trial whose noncontrast MDCT images showed measurable coronary arteries. Using 3 measurements of left main coronary artery (LMCA) and right coronary artery (RCA) diameters within 3 mm of the ostium, we associated the results with traditional coronary risk factors and calcium scores.
The prevalence of LMCA and RCA calcium was 22% and 51%, respectively. Mean arterial diameters were 5.67 ± 1.18 mm (LMCA) and 4.66 ± 1.08 mm (RCA). Correlations for LMCA and RCA diameters in 50 randomly chosen patients were 0.91 and 0.93 (interobserver) and 0.98 and 0.93 (intraobserver). Adjusted odds ratios for the relationship of LMCA and RCA diameters to calcium in male versus female patients were 5.65 (95% confidence interval [CI], 2.78–11.5) and 4.35 (95% CI, 2.24–8.47), respectively. Adjusted ratios and 95% CIs for the association of larger RCA diameter with age, hypertension, and body mass index were 1.36 (1.00–1.86), 3.13 (1.26–7.78), and 1.60 (1.16–2.22), respectively.
Arterial diameters were larger in women and patients with higher calcium levels, and body mass index and hypertension were predictors of larger RCA diameters. These findings suggest a link between arterial remodeling and the severity of atherosclerosis.
PMCID: PMC3709210  PMID: 23914015
Arteriosclerosis/complications/pathology; calcinosis/complications; coronary artery disease/etiology/pathology; coronary vessels/pathology/physiology; dilatation, pathologic/pathology; disease progression; models, cardiovascular; regression analysis; risk assessment; tomography, x-ray computed/methods
19.  Adipokines and Body Fat Composition in South Asians: Results of the Metabolic syndrome and Atherosclerosis in South Asians Living in America (MASALA) Study 
To investigate whether leptin and adiponectin are associated with body fat composition in a South Asian population independent of metabolic variables.
Cross-sectional study
150 South Asian men and women, between the ages of 45–79 years, in the San Francisco Bay Area without pre-existing clinical cardiovascular disease.
Blood samples were obtained to measure glucose metabolism variables, lipid profiles and adipokines. Total body fat was determined using dual-energy x-ray absorptiometry. Abdominal computed tomography was used to measure subcutaneous, visceral, and hepatic fat.
Average body mass index (BMI) was overweight at 26.1±4.6 kg/m2 and did not differ by sex. However, women had significantly more total body fat (p<0.001) and subcutaneous fat (p<0.001) than men, while men had significantly more visceral fat (p<0.001) and hepatic fat (p=0.04) than women. Women had significantly higher levels of adiponectin (p<0.01) and leptin (p<0.01). In sex-stratified analyses, leptin was strongly associated with all body composition measures in women (p<0.05) as well as in men (p<0.05 except for hepatic fat) while there was an insignificant trend towards an inverse association between adiponectin and body composition in both women and men which was significant in combined bivariate analyses. In multivariate analyses, leptin was strongly associated with all measures of adiposity, including BMI (p<0.001), total body fat (p<0.001), visceral fat (p<0.001), and hepatic fat (p=0.01). However, adiponectin’s inverse association with adiposity was significantly attenuated by high-density lipoprotein (HDL), triglycerides, and insulin resistance. The association between adipokines and diabetes was markedly attenuated after adjusting for body composition.
Despite only modestly elevated BMI, South Asians have elevated levels of total and regional adiposity. Leptin is strongly associated with adiposity while adiponectin’s association with adiposity is attenuated by metabolic variables in South Asians. Adipokines in association with adiposity play an important role in the development of diabetes.
PMCID: PMC3224670  PMID: 21863003
South Asians; body composition; sex differences in adiposity; adiponectin and leptin; hepatic fat
20.  Performance of the Traditional Age, Sex, and Angina Typicality-Based Approach for Estimating Pre-test Probability of Angiographically Significant Coronary Artery Disease in Patients Undergoing Coronary Computed Tomographic Angiography: Results from the Multinational CONFIRM Registry (Coronary CT Angiography Evaluation For Clinical Outcomes: An International Multicenter Registry) 
Circulation  2011;124(22):2423-2432.
Guidelines for the management of patients with suspected coronary artery disease (CAD) rely on the age, sex, and angina typicality-based pre-test probabilities of angiographically significant CAD derived from invasive coronary angiography (“Guideline Probabilities”). Reliability of Guideline Probabilities has not been investigated in patients referred to noninvasive CAD testing.
Methods and Results
We identified 14048 consecutive patients with suspected CAD who underwent coronary computed tomographic angiography (CTA) Angina typicality was recorded using accepted criteria. Pre-test likelihoods of CAD with ≥50% diameter stenosis (CAD50) and ≥70% diameter stenosis (CAD70) were calculated using Guideline Probabilities. CTA images were evaluated by ≥1 expert reader to determine presence of CAD50 and CAD70. Typical angina was associated with the highest prevalence of CAD50 (40% in men, 19% in women) and CAD70 (27% men, 11% women) when compared to other symptom categories (p<0.001 for all). Observed CAD50 and CAD70 prevalence were substantially lower than that predicted by Guideline Probabilities in the overall population (18% vs. 51% for CAD50, 10% vs. 42% for CAD70, p<0.001), driven by pronounced differences in patients with atypical angina (15% vs. 47% for CAD50, 7% vs. 37% for CAD70) and typical angina (29% vs. 86% for CAD50, 19% vs. 71% for CAD70). Marked overestimation of disease prevalence by Guideline Probabilities was found at all participating centers and across all sex and age subgroups.
In this multinational study of patients referred for coronary CTA, determination of pre-test likelihood of angiographically significant CAD by the invasive angiography-based Guideline Probabilities greatly overestimates the actual prevalence of disease.
PMCID: PMC3240578  PMID: 22025600
angina; coronary artery disease; computed tomography angiography; imaging; pre-test probability; stenosis
21.  Myocardial Hypo-enhancement on Resting Computed Tomography Angiography Images Accurately Identifies Myocardial Hypoperfusion 
To test the diagnostic accuracy of myocardial CT perfusion (CTP) imaging using color and gray scale image analysis.
Current myocardial CTP techniques have varying diagnostic accuracy and are prone to artifacts that impair detection. This study evaluated the diagnostic accuracy of color and/or gray-scale CTP and the application of artifact criteria to detect hypoperfusion.
Fifty-nine prospectively-enrolled patients with abnormal single photon emission computed tomography (SPECT) studies were analyzed. True hypoperfusion was defined if SPECT hypoperfusion corresponded to obstructive coronary stenoses on CT angiography (CTA). CTP applied color and gray scale myocardial perfusion maps to resting CTA images. Criteria for identifying artifacts were also applied during interpretation.
Using combined SPECT plus CTA as the diagnostic standard, abnormal myocardial CTP was present in 33 (56%) patients, 19 suggesting infarction and 14 suggesting ischemia. Patient-level color and gray scale myocardial CTP sensitivity to detect infarction was 90%, with specificity 80%, and negative and positive predictive value of 94% and 68%. To detect ischemia or infarction, CTP specificity and positive predictive value were 92% while sensitivity was 70%. Gray scale myocardial CTP had slightly lower specificity but similar sensitivity. Myocardial CTP artifacts were present in 88% of studies and were identified using our criteria.
Color and gray scale myocardial CTP using resting CTA images identified myocardial infarction with high sensitivity as well as infarction or ischemia with high specificity and positive predictive value without additional testing or radiation. Color and gray scale CTP had slightly better specificity than gray scale alone.
PMCID: PMC3246505  PMID: 22146500
Coronary CT Angiography; Myocardial CT perfusion; Cardiac CT; Cardiac CT perfusion
22.  Impact of Subclinical Atherosclerosis on Cardiovascular Disease Events in Individuals With Metabolic Syndrome and Diabetes 
Diabetes Care  2011;34(10):2285-2290.
While metabolic syndrome (MetS) and diabetes confer greater cardiovascular disease (CVD) risk, recent evidence suggests that individuals with these conditions have a wide range of risk. We evaluated whether screening for coronary artery calcium (CAC) and carotid intimal-medial thickness (CIMT) can improve CVD risk stratification over traditional risk factors (RFs) in people with MetS and diabetes.
We assessed CAC and CIMT in 6,603 people aged 45–84 years in the Multi-Ethnic Study of Atherosclerosis (MESA). Cox regression examined the association of CAC and CIMT with coronary heart disease (CHD) and CVD over 6.4 years in MetS and diabetes.
Of the subjects, 1,686 (25%) had MetS but no diabetes and 881 (13%) had diabetes. Annual CHD event rates were 1.0% among MetS and 1.5% for diabetes. Ethnicity and RF-adjusted hazard ratios for CHD for CAC 1–99 to ≥400 vs. 0 in subjects with neither MetS nor diabetes ranged from 2.6 to 9.5; in those with MetS, they ranged from 3.9 to 11.9; and in those with diabetes, they ranged from 2.9 to 6.2 (all P < 0.05 to P < 0.001). Findings were similar for CVD. CAC increased the C-statistic for events (P < 0.001) over RFs and CIMT in each group while CIMT added negligibly to prediction over RFs.
Individuals with MetS or diabetes have low risks for CHD when CAC or CIMT is not increased. Prediction of CHD and CVD events is improved by CAC more than by CIMT. Screening for CAC or CIMT can stratify risk in people with MetS and diabetes and support the latest recommendations regarding CAC screening in those with diabetes.
PMCID: PMC3177707  PMID: 21844289
23.  Relationship of Estimated GFR and Coronary Artery Calcification in the (CRIC) Chronic Renal Insufficiency Cohort Study 
Coronary artery calcification (CAC) is associated with increased mortality risk in the general population. Although individuals with chronic kidney disease (CKD) are at markedly increased mortality risk, the incidence, prevalence, and prognosis of CAC in CKD is not well-understood.
Study Design
Cross-sectional observational study.
Setting and Participants
Analysis of 1,908 participants who underwent coronary calcium scanning as part of the multi-ethnic CRIC (Chronic Renal Insufficiency Cohort) Study.
Estimated glomerular filtration rate (eGFR) computed using the Modification of Diet in Renal Disease (MDRD) Study equation, stratified by race, sex and diabetic status. eGFR was treated as a continous variable and a categorical variable compared to the reference range of >60 ml/min/1.73 m2
CAC detected using CT scans using either an Imatron C-300 electron beam computed tomography scanner or multi-detector CT scanner. CAC was computed using the Agatston score, as a categorical variable. Analyses were performed using ordinal logistic regression.
We found a strong and graded relationship between lower eGFR and increasing CAC. In unadjusted models, ORs increased from 1.68 (95% CI, 1.23–2.31) for eGFR from 50–59 to 2.82 (95% CI, 2.06–3.85) for eGFR of <30. Multivariable adjustment only partially attenuated the results (OR, 1.53; 95% CI, 1.07–2.20) for eGFR<30.
Use of eGFR rather than measured GFR.
We demonstrated a graded relationship between severity of CKD and CAC, independent of traditional risk factors. These findings supports recent guidelines that state that if vascular calcification is present, it should be considered as a complementary component to be included in the decision making required for individualizing treatment of CKD.
PMCID: PMC3183168  PMID: 21783289
24.  The Relationship of Insulin Resistance and Extracoronary Calcification in the Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2011;218(2):507-510.
We hypothesized that insulin resistance, measured by the homeostatic model assessment of insulin resistance (HOMA), is independently associated with prevalent and incident extra-coronary calcification (ECC).
We studied calcium scores of the aortic valve (AVC), mitral valve (MVC), thoracic aorta (TAC) and aortic valve root (AVR) in 6,104 MESA participants not on diabetes medication who had baseline cardiac CT scans; 5,312 had follow-up scans (mean 2.4y). Relative-risk regression modeled prevalent and incident ECC adjusted for baseline demographics (model 1), and additionally for CVD risk factors (model 2).
In model 1, prevalence and incidence risk-ratios for the highest versus lowest quartile of HOMA were 20–30% higher in all ECC locations (p-value for trend ≤0.05 for all but incident-AVC). In model 2, all associations were attenuated, primarily by adjustment for metabolic syndrome components.
HOMA has a positive and graded association with ECC, but not independently of cardiovascular risk factors—particularly metabolic syndrome components.
PMCID: PMC3185155  PMID: 21798541
cardiovascular calcification; insulin resistance; atherosclerosis; metabolic syndrome; computed tomography; valvular calcification; thoracic aortic calcification
25.  Normal Thoracic Aorta Diameter on Cardiac Computed Tomography in Healthy Asymptomatic Adult; Impact of Age and Gender 
Academic radiology  2008;15(7):827-834.
To establish the normal criterion of ascending aortic diameter (AAOD) measured by 64 Multi-Detector Computed Tomography (MDCT) and Electron Beam Computed Tomography (EBT) based on gender and age.
1442 consecutive subjects who were referred for evaluation of possible coronary artery disease underwent coronary CT angiography (CTA) and coronary artery calcium scanning (CACS) (55+11 years, 65% male) without known coronary heart disease, hypertension, chronic pulmonary and renal disease, diabetes and severe aortic calcification. The ascending aortic diameter, descending aortic diameter (DAOD), pulmonary artery (PAD) and chest anterioposterior diameter (CAPD), posterior border of sternal bone to anterior border of spine, were measured at the slice level of mid right pulmonary artery by using end systolic trigger image. The volume of four chambers, ejection fraction of left ventricle, and cardiac output were measured in 56% of the patients. Patients demographic information, age, gender, weight, height and body surface area (BSA), were recorded. The mean value and age specific and gender adjusted upper normal limits (mean + 2 standard deviations) were calculated. The linear correlation analysis was done between AAOD and all parameters. The reproducibility, wall thickness and difference between end systole and diastole were calculated.
AAOD has significant linear association with age, gender, descending aortic diameter and pulmonary artery diameter (P<0.05). There is no significant correlation between AAOD and body surface area, four chamber volume, LVEF, CO and CAPD. The mean Intra-luminal AAOD was 31.1 ± 3.9mm and 33.6 ± 4.1 mm in females and males respectively. The upper normal limits (mean + 2 standard deviations) of Intra-luminal AAOD, mean+ standard deviation, was 35.6, 38.3 and 40 mm for females and 37.8, 40.5 and 42.6 mm for males in age group 20 to 40, 41 to 60, above 60 year respectively. Intra-luminal should parallel echocardiography and invasive angiography. Traditional cross sectional imaging (with computed tomography and magnetic resonance imaging) includes the vessel wall. The mean total AAOD was 33.5mm and 36.0 mm in females and males respectively. The upper normal limits (mean + 2 standard deviations) of Intra-luminal AAOD, mean+ standard deviation, was 38.0, 40.7 and 42.4 mm for females and 40.2, 42.9 and 45.0 mm for males in age group 20 to 40, 41 to 60, above 60 year respectively. The inter and intra observer, scanner and repeated measurement variability was low (R value >0.91, P<0.001, coefficient variation <3.2%). AAOD was 1.7 mm less in end-diastole than end systole(P<0.001).
The ascending aortic diameter increases with age and male gender. Gender specific and age adjusted normals for aortic diameters are necessary to differentiate pathologic atherosclerotic changes in the ascending aorta. Use of intra-luminal or total aortic diameter values depends on the comparison study that may be employed.
PMCID: PMC2577848  PMID: 18572117
Ascending aortic diameter; Electron beam CT; MDCT; Aging aorta

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