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3.  Renal Artery Calcium, Cardiovascular Risk Factors and Indices of Renal Function 
The American journal of cardiology  2013;113(1):10.1016/j.amjcard.2013.09.036.
Vascular calcium is well studied in the coronary and peripheral arteries although there is limited data focusing on calcium deposits specific to renal arteries. The associations between renal artery calcium (RAC), cardiovascular disease (CVD) risk factors, and indices of renal function are unknown. We examined 2699 Framingham Heart Study participants who were part of a multidetector computed tomography substudy from 2008–2011. RAC was measured as a calcified plaque of >130 Hounsfield units and an area of >3 contiguous pixels. Detectable RAC was defined as an Agatston score >0. Chronic kidney disease (CKD) was defined as an eGFR <60 mL/min/1.73m2. Microalbuminuria was defined as ACR ≥17 mg/g for men and ≥25 mg/g for women. Multivariable adjusted logistic regression models were used to evaluate the associations between RAC, CVD risk factors, and renal function. The associations were secondarily adjusted for coronary artery calcium (CAC) that was used as a marker of non-renal systemic vascular calcium. The prevalence of RAC was 28.2%; this was similar in women (28.8%) and men (27.5%). Individuals with RAC had a higher odds of microalbuminuria (OR 1.79, 95% CI 1.22–2.61, p=0.003), hypertension (OR 2.11, 95% CI 1.69–2.64, p<0.001) and diabetes (OR 1.60, 95% CI 1.14–2.24, p=0.01) but not CKD (OR 0.87, 95% CI 0.58–1.32). After adjustment for CAC, the association with microalbuminuria and hypertension persisted but the association with diabetes became non-significant. In conclusion, RAC is common and independently associated with microalbuminuria and hypertension after adjustment for non-renal vascular calcium. RAC may be uniquely associated with these markers of renal end-organ damage.
PMCID: PMC3882167  PMID: 24210678
cardiovascular risk factors; microalbuminuria; renal artery calcium
4.  Magnesium Intake Is Inversely Associated With Coronary Artery Calcification 
JACC. Cardiovascular imaging  2013;7(1):59-69.
The aim of this study was to examine whether magnesium intake is associated with coronary artery calcification (CAC) and abdominal aortic calcification (AAC).
Animal and cell studies suggest that magnesium may prevent calcification within atherosclerotic plaques underlying cardiovascular disease. Little is known about the association of magnesium intake and atherosclerotic calcification in humans.
We examined cross-sectional associations of self-reported total (dietary and supplemental) magnesium intake estimated by food frequency questionnaire with CAC and AAC in participants of the Framingham Heart Study who were free of cardiovascular disease and underwent Multi-Detector Computed Tomography (MDCT) of the heart and abdomen (n = 2,695; age: 53 ± 11 years), using multivariate-adjusted Tobit regression. CAC and AAC were quantified using modified Agatston scores (AS). Models were adjusted for age, sex, body mass index, smoking status, systolic blood pressure, fasting insulin, total-to-high-density lipoprotein cholesterol ratio, use of hormone replacement therapy (women only), menopausal status (women only), treatment for hyperlipidemia, hypertension, cardiovascular disease prevention, or diabetes, as well as self-reported intake of calcium, vitamins D and K, saturated fat, fiber, alcohol, and energy. Secondary analyses included logistic regressions of CAC and AAC outcomes as cut-points (AS >0 and AS ≥90th percentile for age and sex), as well as sex-stratified analyses.
In fully adjusted models, a 50-mg/day increment in self-reported total magnesium intake was associated with 22% lower CAC (p < 0.001) and 12% lower AAC (p = 0.07). Consistent with these observations, the odds of having any CAC were 58% lower (p trend: <0.001) and any AAC were 34% lower (p trend: 0.01), in those with the highest compared to those with the lowest magnesium intake. Stronger inverse associations were observed in women than in men.
In community-dwelling participants free of cardiovascular disease, self-reported magnesium intake was inversely associated with arterial calcification, which may play a contributing role in magnesium's protective associations in stroke and fatal coronary heart disease.
PMCID: PMC3957229  PMID: 24290571
abdominal aortic calcification; computed tomography; coronary artery calcification; diet; Framingham Heart Study; magnesium
5.  Coronary CTA using scout-based automated tube potential and current selection algorithm, with breast displacement results in lower radiation exposure in females compared to males 
To evaluate the effect of automatic tube potential selection and automatic exposure control combined with female breast displacement during coronary computed tomography angiography (CCTA) on radiation exposure in women versus men of the same body size.
Materials and methods
Consecutive clinical exams between January 2012 and July 2013 at an academic medical center were retrospectively analyzed. All examinations were performed using ECG-gating, automated tube potential, and tube current selection algorithm (APS-AEC) with breast displacement in females. Cohorts were stratified by sex and standard World Health Organization body mass index (BMI) ranges. CT dose index volume (CTDIvol), dose length product (DLP) median effective dose (ED), and size specific dose estimate (SSDE) were recorded. Univariable and multivariable regression analyses were performed to evaluate the effect of gender on radiation exposure per BMI.
A total of 726 exams were included, 343 (47%) were females; mean BMI was similar by gender (28.6±6.9 kg/m2 females vs. 29.2±6.3 kg/m2 males; P=0.168). Median ED was 2.3 mSv (1.4-5.2) for females and 3.6 (2.5-5.9) for males (P<0.001). Females were exposed to less radiation by a difference in median ED of –1.3 mSv, CTDIvol –4.1 mGy, and SSDE –6.8 mGy (all P<0.001). After adjusting for BMI, patient characteristics, and gating mode, females exposure was lower by a median ED of –0.7 mSv, CTDIvol –2.3 mGy, and SSDE –3.15 mGy, respectively (all P<0.01).
Conclusions: We observed a difference in radiation exposure to patients undergoing CCTA with the combined use of AEC-APS and breast displacement in female patients as compared to their BMI-matched male counterparts, with female patients receiving one third less exposure.
PMCID: PMC4278037  PMID: 25610804
Coronary computed tomography angiography (CCTA); female; breast displacement; radiation exposure
6.  Distribution of Abdominal Aortic Calcium by Computed Tomography: Impact of Analysis Method on Quantitative Calcium Score 
Academic radiology  2013;20(11):10.1016/j.acra.2013.08.008.
Rationale and Objectives
Abdominal aortic calcification (AAC) can be quantified using computed tomography (CT), but imaging planes are prescribed based on bony landmarks, so that individual variation between the landmark and the aortoiliac junction can result in variable aortic coverage. In the Framingham CT substudy, we scanned a 15-cm (Z-direction) abdominal segment cranial to the S1 vertebral body. We sought to determine the range and distribution of length of aorta scanned, the distribution of AAC within the abdominal aorta, and to compare burden of AAC measured from fixed-length segments versus AAC from all slices cranial to the aortoiliac bifurcation.
Materials and Methods
AAC was quantified by modified Agatston score (AS) in 100 Framingham Heart Study participants (60±13 years, 51 men). We compared AS measured from 5-cm and 8-cm segments to ASALL (total visualized aorta).
73/100 participants had AAC > 0. The total length of aorta imaged was ≥ 8 cm in 84% of participants. Qualitatively, 5-cm and 8-cm segments correctly identified 96% and 99%, respectively, of participants as having or not having AAC. Quantitatively, AS8cm was within 20% of ASALL in four-fifths and within 30% of ASALL in nine-tenths of participants. AS5cm more severely underestimated ASALL.
Using S1 as the caudal imaging landmark in a 15-cm slab yields ≥ 8 cm aortic coverage in most adults. Both 5-cm and 8-cm analysis strategies are comparable to analyzing the total visualized abdominal aorta for prevalent AAC, but only 8-cm segment analysis yields quantitatively similar measures of AAC.
PMCID: PMC3842029  PMID: 24119355
abdominal aorta; calcium; population study; segment length; computed tomography
7.  Cost-Effectiveness Analysis of Coronary Artery Disease Screening in HIV-infected Patients 
European journal of preventive cardiology  2013;10.1177/2047487313483607.
HIV-infected patients are at increased risk of coronary artery disease (CAD). We evaluated the cost-effectiveness of cardiac screenings for HIV-positive men at intermediate or greater CAD risk.
We developed a lifetime microsimulation model of CAD incidence and progression in HIV-infected men.
Input parameters were derived from two HIV cohort studies and the literature. We compared no CAD screening with stress testing and coronary computed tomography angiography (CCTA)-based strategies. Patients with test results indicating 3-vessel/left main CAD underwent invasive coronary angiography (ICA) and received coronary artery bypass graft surgery. In the “Stress-testing+Medication”/“CCTA+Medication” strategies, patients with 1-/2-vessel CAD results received lifetime medical treatment without further diagnostics whereas in the “Stress-testing+Intervention”/“CCTA+Intervention” strategies, patients with these results underwent ICA and received percutaneous coronary intervention.
Compared to no screening, the “Stress-testing+Medication”, “Stress-testing+Intervention”, “CCTA+Medication” and “CCTA+Intervention” strategies resulted in 14, 11, 19, and 14 quality-adjusted life days per patient and incremental cost effectiveness ratios of 49,261, 57,817, 34,887 and 56,518 € per quality-adjusted life year (QALY), respectively. Screening only at higher CAD risk thresholds was more cost-effective. Repeated screening was clinically beneficial compared to one-time screening but only “Stress-testing+Medication” every five years remained cost-effective. At a willingness-to-pay threshold of 83,000 €/QALY (~100,000 US$/QALY), implementing any CAD screening was cost-effective with a probability of 75-95%.
Screening HIV-positive men for CAD would be clinically beneficial and comes at a cost-effectiveness ratio comparable to other accepted interventions in HIV care.
PMCID: PMC3841232  PMID: 23539717
HIV; coronary heart disease; prevention; cost-effectiveness; Markov model
8.  Cost and Resource Utilization Associated with Use of Computed Tomography to Evaluate Chest Pain in the Emergency Department: The ROMICAT Study 
Coronary computed tomography angiography (cCTA) allows for rapid non-invasive exclusion of obstructive coronary artery disease (CAD). However, concern exists whether implementation of cCTA in the assessment of patients presenting to the emergency room with acute chest pain will lead to increased downstream testing and costs compared to alternative strategies. Our aim was to compare observed actual costs of usual care (UC) with projected costs of a strategy including early cCTA in the evaluation of patients with acute chest pain in the Rule Out Myocardial Infarction Using Computed Tomography (ROMICAT I) study.
Methods and Results
We compared cost and hospital length of stay of UC observed among 368 patients enrolled in the ROMICAT I trial with projected costs of management based on cCTA. Costs of UC were determined by an electronic cost accounting system. Notably, UC was not influenced by cCTA results, as patients and caregivers were blinded to the cCTA results. Costs after early implementation cCTA were estimated assuming changes in management based on cCTA findings of presence and severity of CAD. Sensitivity analysis was used to test influence of key variables on both outcomes and costs.
We determined that in comparison to UC, cCTA-guided triage whereby patients with no CAD are discharged, could reduce total hospital costs by 23%, p < 0.001. However, when the prevalence of obstructive CAD increases, index hospitalization cost increases such that when the prevalence of ≥50% stenosis is greater than 28–33%, the use of cCTA becomes more costly than UC.
cCTA may be a cost saving tool in acute chest pain populations that have a prevalence of potentially obstructive CAD lower than 30%. However, increased cost would be anticipated in populations with higher prevalence of disease.
PMCID: PMC3888669  PMID: 24021693
coronary CT angiography; chest pain; acute coronary syndrome; economics
9.  Body Fat Distribution, Incident Cardiovascular Disease, Cancer, and All-cause Mortality 
To determine whether ectopic fat depots are prospectively associated with cardiovascular disease, cancer and all-cause mortality.
The morbidity associated with excess body weight varies among individuals of similar body mass index. Ectopic fat depots may underlie this risk differential. However, prospective studies of directly measured fat are limited.
Participants from the Framingham Heart Study (n=3086, 49% women, mean age 50.2 years) underwent assessment of fat depots (visceral adipose tissue, pericardial adipose tissue, and periaortic adipose tissue) using multidetector computed tomography, and were followed longitudinally for a median of 5.0 years. Cox proportional hazards regression models were used to examine the association of each fat depot (per 1 standard deviation increment) with the risk of incident cardiovascular disease, cancer, and all-cause mortality after adjustment for standard risk factors, including body mass index.
Overall, there were 90 cardiovascular events, 141 cancer events, and 71 deaths. After multivariable adjustment, visceral adipose tissue was associated with cardiovascular disease (HR 1.44, 95% CI 1.08–1.92, p=0.01) and cancer (HR 1.43, 95% CI 1.12–1.84, p=0.005). Addition of visceral adipose tissue to a multivariable model that included body mass index modestly improved cardiovascular risk prediction (net reclassification improvement of 16.3%). None of the fat depots were associated with all-cause mortality.
Visceral adiposity is associated with incident cardiovascular disease and cancer after adjustment for clinical risk factors and generalized adiposity. These findings support the growing appreciation of a pathogenic role of ectopic fat.
PMCID: PMC4142485  PMID: 23850922
obesity; visceral fat; body fat distribution; cardiovascular disease; cancer
10.  Aortic Distensibility and its Relationship to Coronary and Thoracic Atherosclerosis Plaque and Morphology by MDCT: Insights from the ROMICAT Trial 
International journal of cardiology  2012;167(4):1616-1621.
Multi-detector cardiac computed tomography (CT) allows for simultaneous assessment of aortic distensibility (AD), coronary atherosclerosis, and thoracic aortic atherosclerosis.
We sought to determine the relationship of AD to the presence and morphological features in coronary and thoracic atherosclerosis.
In 293 patients (53±12 years, 63% male), retrospectively-gated MDCT were performed. We measured intraluminal aortic areas across 10 phases of the cardiac cycle (multiphase reformation 10% increments) at pre-defined locations to calculate the ascending, descending, and local AD (at locations of thoracic plaque). AD was calculated as maximum change in area/(minimum area × pulse pressure). Coronary and thoracic plaques were categorized as calcified, mixed, or non-calcified.
Ascending and descending AD were lower in patients with any coronary plaque, calcified or mixed plaque than those without (all p<0.0001) but not with non-calcified coronary plaque (p≥0.46). Per 1 mmHg−110−3 increase in ascending and descending AD, there was an 18–29% adjusted risk reduction for having any coronary, calcified plaque, or mixed coronary plaque (ascending AD only) (all p≤0.04). AD was not associated with non-calcified coronary plaque or when age was added to the models (all p>0.39). Local AD was lower at locations of calcified and mixed thoracic plaque when compared to non-calcified thoracic atherosclerosis (p<0.04).
A stiffer, less distensible aorta is associated with coronary and thoracic atherosclerosis, particularly in the presence of calcified and mixed plaques, suggesting that the mechanism of atherosclerosis in small and large vessels is similar and influenced by advancing age.
PMCID: PMC3419779  PMID: 22578738
aortic distensibility; coronary atherosclerosis; thoracic atherosclerosis; peripheral vascular disease; computed tomography; cardiovascular aging
11.  Association of Fat Density With Subclinical Atherosclerosis 
Ectopic fat density is associated with cardiovascular disease (CVD) risk factors above and beyond fat volume. Volumetric measures of ectopic fat have been associated with CVD risk factors and subclinical atherosclerosis. The aim of this study was to investigate the association between fat density and subclinical atherosclerosis.
Methods and Results
Participants were drawn from the Multi‐Detector Computed Tomography (MDCT) substudy of the Framingham Heart Study (n=3079; mean age, 50.1 years; 49.2% women). Fat density was indirectly estimated by computed tomography attenuation (Hounsfield Units [HU]) on abdominal scan slices. Visceral fat (VAT), subcutaneous fat (SAT), and pericardial fat HU and volumes were quantified using standard protocols; coronary and abdominal aortic calcium (CAC and AAC, respectively) were measured radiographically. Multivariable‐adjusted logistic regression models were used to evaluate the association between adipose tissue HU and the presence of CAC and AAC. Overall, 17.1% of the participants had elevated CAC (Agatston score [AS]>100), and 23.3% had elevated AAC (AS>age‐/sex‐specific cutoffs). Per 5‐unit decrement in VAT HU, the odds ratio (OR) for elevated CAC was 0.76 (95% confidence interval [CI], 0.65 to 0.89; P=0.0005), even after adjustment for body mass index or VAT volume. Results were similar for SAT HU. With decreasing VAT HU, we also observed an OR of 0.79 (95% CI, 0.67 to 0.92; P=0.004) for elevated AAC after multivariable adjustment. We found no significant associations between SAT HU and AAC. There was no significant association between pericardial fat HU and either CAC or AAC.
Lower VAT and SAT HU, indirect estimates of fat quality, are associated with a lower risk of subclinical atherosclerosis.
PMCID: PMC4310364  PMID: 25169793
atherosclerosis; epidemiology; fat density; obesity
12.  Effect of the 2010 task force criteria on reclassification of cardiovascular magnetic resonance criteria for arrhythmogenic right ventricular cardiomyopathy 
We sought to evaluate the effect of application of the revised 2010 Task Force Criteria (TFC) on the prevalence of major and minor Cardiovascular Magnetic Resonance (CMR) criteria for Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) versus application of the original 1994 TFC. We also assessed the utility of MRI to identify alternative diagnoses for patients referred for ARVC evaluation.
968 consecutive patients referred to our institution for CMR with clinical suspicion of ARVC from 1995 to 2010, were evaluated for the presence of major and minor CMR criteria per the 1994 and 2010 ARVC TFC. CMR criteria included right ventricle (RV) dilatation, reduced RV ejection fraction, RV aneurysm, or regional RV wall motion abnormalities. When quantitative measures of RV size and function were not available, and in whom abnormal size or function was reported, a repeat quantitative analysis by 2 qualified CMR physicians in consensus.
Of 968 patients, 220 (22.7%) fulfilled either a major or a minor 1994 TFC, and 25 (2.6%) fulfilled any of the 2010 TFC criterion. Among patients meeting any 1994 criteria, only 25 (11.4%) met at least one 2010 criterion. All patients who fulfilled a 2010 criteria also satisfied at least one 1994 criterion. Per the 2010 TFC, 21 (2.2%) patients met major criteria and 4 (0.4%) patients fulfilled at least one minor criterion. Eight patients meeting 1994 minor criteria were reclassified as satisfying 2010 major criteria, while 4 patients fulfilling 1994 major criteria were reclassified to only minor or no criteria under the 2010 TFC.
Eighty-nine (9.2%) patients had alternative cardiac diagnoses, including 43 (4.4%) with clinically significant potential ARVC mimics. These included cardiac sarcoidosis, RV volume overload conditions, and other cardiomyopathies.
Application of the 2010 TFC resulted in reduction of total patients meeting any diagnostic CMR criteria for ARVC from 22.7% to 2.6% versus the 1994 TFC. CMR identified alternative cardiac diagnoses in 9.2% of patients, and 4.4% of the diagnoses were potential mimics of ARVC.
PMCID: PMC4105392  PMID: 24996808
Arrhythmogenic right ventricular cardiomyopathy; 2010 task force criteria; Cardiovascular magnetic resonance
13.  Visceral and Subcutaneous Fat Quality is Associated with Cardiometabolic Risk 
JACC. Cardiovascular imaging  2013;6(7):762-771.
The aim of this study was to evaluate whether computed tomography (CT) attenuation, as a measure of fat quality, is associated with cardiometabolic risk factors above and beyond fat quantity.
Visceral (VAT) and subcutaneous adipose tissue (SAT) are pathogenic fat depots associated with cardiometabolic risk. Adipose tissue attenuation in CT images is variable, similar to adipose tissue volume. However, whether the quality of abdominal fat attenuation is associated to cardiometabolic risk independent of the quantity is uncertain.
Participants were drawn from the Framingham Heart Study CT sub-study. VAT and SAT volumes were acquired by semi-quantitative assessment. Fat quality was measured by CT attenuation and recorded as mean Hounsfield Units (HU) within each fat depot. Sex-specific linear and logistic multivariable regression models were used to assess the association between standard deviation (SD) decrease in HU and each risk factor.
Lower CT attenuation of VAT and SAT was correlated with higher BMI levels in both sexes. Risk factors were generally more adverse with decreasing HU values. For example, in women, per 1-SD decrease in VAT HU, the odds ratio (OR) was increased for hypertension (OR 1.80), impaired fasting glucose (OR 2.10), metabolic syndrome (OR 3.65) and insulin resistance (OR 3.36) (all p<0.0001). In models that further adjusted for VAT volume, impaired fasting glucose, metabolic syndrome and insulin resistance remained significant. Trends were similar but less pronounced in SAT and in men. There was evidence of an interaction between HU and fat volume among both women and men.
Lower CT attenuation of VAT and SAT is associated with adverse cardiometabolic risk above and beyond total adipose tissue volume. Qualitative indices of abdominal fat depots may provide insight regarding cardiometabolic risk independent of fat quantity.
PMCID: PMC3745280  PMID: 23664720
Obesity; Epidemiology; CT Imaging; Risk Factors
14.  Sex Differences in the Effectiveness of Early Coronary CT Angiography Compared to Standard Emergency Department Evaluation for Acute Chest Pain: The ROMICAT II Trial 
Circulation  2013;127(25):2494-2502.
We evaluate sex-based differences in the effectiveness of early cardiac computed tomographic angiography (CCTA) versus standard emergency department (ED) evaluation in patients with acute chest pain.
Methods and Results
In the ROMICAT II multicenter controlled trial, we randomized 1000 patients (47% women) 40-74 years old with symptoms suggestive of acute coronary syndrome (ACS) to an early CCTA or standard ED evaluation. In this pre-specified analysis, women in the CCTA arm had greater reduction in length of stay (LOS), lower hospital admission rates, and lesser increased cumulative radiation dose than men when comparing ED strategies (p-interactions≤0.02). While women had lower ACS rates than men (3% vs 12%, p<0.0001), sex differences in LOS persisted after adjustment for baseline differences including ACS rate (p-interaction<0.03). LOS was similar between sexes with normal CCTA findings (p=0.11). There was no missed ACS for either sex. No difference was observed in major adverse cardiac events between sex and ED strategies (p-interaction=0.39). Women had more normal CCTA examinations than men (58% vs 37%, p<0.0001), less obstructive coronary disease by CCTA (5% vs 17%, p=0.0001), but similar normalcy rates for functional testing (p=1.0). Men in the CCTA arm had the highest rate of invasive coronary angiography (18%), while women had comparable low 5% rates irrespective of ED strategies.
This trial provides data supporting an early CCTA strategy as an attractive option in women presenting to the ED with symptoms suggestive of ACS. The findings may be explained by lower CAD prevalence and severity in women than men.
PMCID: PMC3753028  PMID: 23685743
sex; chest pain; acute coronary syndrome; emergency department; cardiac computed tomography
15.  Distribution, Determinants,and Normal Reference Values of Thoracic and Abdominal Aortic Diameters by Computed Tomography (From the Framingham Heart Study) 
The American journal of cardiology  2013;111(10):1510-1516.
Current screening and detection of asymptomatic aortic aneurysms is largely based on uniform cut-point diameters. Our objective was to define normal aortic diameters in asymptomatic men and women in a community-based cohort and to determine the association between aortic diameters and traditional risk factors for cardiovascular disease (CVD).Measurements of the diameter of the ascending aorta(AA), descending thoracic aorta (DTA), infrarenal abdominal (IRA) and lower abdominal aorta (LAA) were acquired from 3,431 Framingham Heart Study participants. Mean diameters were stratified by sex, age, and body surface area (BSA). Univariate associations with risk factor levels were examined and multivariable linear regression analysis was used to assess the significance of covariate-adjusted relations with aortic diameters. For men, the average diameter was 34.1 mm for AA, 25.8 mm for DTA, 19.3 mm for IRA and 18.7 mm for LAA.For women, the average diameter was 31.9 mm for AA, 23.1 mm for DTA, 16.7 mm for IRA, and 16.0 mm for LAA. The mean aorticdiameters were strongly correlated (p<0.0001) with age and BSA in age-adjusted analyses, and these relations remained significant in multivariable regression analyses. Positive associations of diastolic BP with AA and DTA in both sexes and pack years of cigarette smoking with DTA in women and with IRA in men and women were observed. In conclusion, average diameters of the thoracic and abdominal aorta by CT are larger in men compared with women, vary significantly with age and BSA, and are associated with modifiable CVD risk factors including diastolic blood pressure and cigarette smoking.
PMCID: PMC3644324  PMID: 23497775
Aortic diameter; computed tomography; sex; age; body surface area
16.  Classification of Human Coronary Atherosclerotic Plaques Ex-Vivo with T1, T2 and Ultra-short TE MRI 
JACC. Cardiovascular imaging  2013;6(4):466-474.
To determine whether the classification of human coronary atherosclerotic plaques with T1, T2 and ultrashort TE (UTE) MRI would correlate well with atherosclerotic plaque classification by histology.
MRI has been extensively used to classify carotid plaque but its ability to characterize coronary plaque remains unknown. In addition, the detection of plaque calcification by MRI remains challenging. Here we used T1, T2 and UTE MRI to evaluate atherosclerotic plaques in fixed post-mortem human coronary arteries. We hypothesized that the combination of T1, T2 and UTE MRI would allow both calcified and lipid-rich coronary plaques to be accurately detected.
28 plaques from human donor hearts with proven coronary artery disease were imaged at 9.4 Tesla with a T1 weighted 3D FLASH sequence (250 um resolution), a T2 weighted Rare sequence (in plane resolution 0.156mm), and an UTE sequence (300um resolution). Plaques showing selective hypointensity on T2 weighted MRI were classified as lipid-rich. Areas of hypointensity on the T1 weighted images but not the UTE images were classified as calcified. Hyperintensity on the T1 weighted and UTE images was classified as hemorrhage. Following MRI, histological characterization of the plaques was performed with a pentachrome stain and established AHA criteria.
MRI showed high sensitivity and specificity for the detection of calcification (100% and 90%) and lipid-rich necrotic cores (90% and 75%). Only two lipid-rich foci were missed by MRI, both of which were extremely small. Overall, MRI based classification of plaque was in complete agreement with the histological classification in 22/28 cases (weighted κ =0.6945, p<0.0001).
The utilization of UTE MRI allows plaque calcification in the coronary arteries to be robustly detected. High-resolution MRI with T1, T2 and UTE contrast enables accurate classification of human coronary atherosclerotic plaque.
PMCID: PMC3661771  PMID: 23498670
atherosclerosis; coronary artery; MRI; ultra-short TE; plaque classification
17.  Intramuscular Fat and Associations with Metabolic Risk Factors in the Framingham Heart Study 
Intramuscular fat accumulates between muscle fibers or within muscle cells. We investigated the association of intramuscular fat with other ectopic fat deposits and metabolic risk factors.
Approach and Results
Participants (n = 2945; 50.2% women; mean age 50.8 years) from the Framingham Heart Study underwent multidetector computed tomography scanning of the abdomen. Regions of interest were placed on the left and right paraspinous muscle and the muscle attenuation (MA) in Hounsfield units were averaged. We examined the association between MA and metabolic risk factors in multivariable models and additionally adjusted for BMI and visceral fat (VAT) in separate models. MA was associated with dysglycemia, dyslipidemia, and hypertension in both sexes. In women, per standard deviation decrease in MA, there was a 1.34 (95% CI 1.10–1.64) increase in the odds of diabetes, a 1.40 (95% CI 1.22 – 1.61) increase in the odds of high triglycerides, and a 1.29 (95% CI 1.12 – 1.48) increase in the odds of hypertension. However, none of these associations persisted after adjustment for BMI or VAT. In men, we observed similar patterns for most risk factors. The exception was metabolic syndrome, which retained association in women even after adjustment for BMI and VAT, and low HDL and high triglycerides in men, whose associations also persisted after adjustment for BMI and VAT.
MA was associated with metabolic risk factors, but most of these associations were lost after adjustment for BMI or VAT. However, a unique association remained for metabolic syndrome in women and lipids in men.
PMCID: PMC3696991  PMID: 23349188
Metabolism; obesity; intramuscular fat; epidemiology
18.  Pericardial Fat is Associated With Atrial Conduction: The Framingham Heart Study 
Obesity is associated with altered atrial electrophysiology and a prominent risk factor for atrial fibrillation. Body mass index, the most widely used adiposity measure, has been related to atrial electrical remodeling. We tested the hypothesis that pericardial fat is independently associated with electrocardiographic measures of atrial conduction.
Methods and Results
We performed a cross‐sectional analysis of 1946 Framingham Heart Study participants (45% women) to determine the relation between pericardial fat and atrial conduction as measured by P wave indices (PWI): PR interval, P wave duration (P‐duration), P wave amplitude (P‐amplitude), P wave area (P‐area), and P wave terminal force (P‐terminal). We performed sex‐stratified linear regression analyses adjusted for relevant clinical variables and ectopic fat depots. Each 1‐SD increase in pericardial fat was significantly associated with PR interval (β=1.7 ms, P=0.049), P‐duration (β=2.3 ms, P<0.001), and P‐terminal (β=297 μV·ms, P<0.001) among women; and P‐duration (β=1.2 ms, P=0.002), P‐amplitude (β=−2.5 μV, P<0. 001), and P‐terminal (β=160 μV·ms, P=0.002) among men. Among both sexes, pericardial fat was significantly associated with P‐duration in analyses additionally adjusting for visceral fat or intrathoracic fat; a similar but non‐significant trend existed with P‐terminal. Among women, pericardial fat was significantly associated with P wave area after adjustment for visceral and intrathoracic fat.
Pericardial fat is associated with atrial conduction as quantified by PWI, even with adjustment for extracardiac fat depots. Further studies are warranted to identify the mechanisms through which pericardial fat may modify atrial electrophysiology and promote subsequent risk for arrhythmogenesis.
PMCID: PMC4187474  PMID: 24595189
atrium; conduction; electrocardiography; epidemiology; obesity
19.  Depressive symptoms are associated with visceral adiposity in a community-based sample of middle-aged women and men 
Obesity (Silver Spring, Md.)  2013;21(8):1713-1719.
To examine the relation between measures of adiposity and depressive symptoms in a large well characterized community-based sample, we examined the relations of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) to depressive symptoms in 1581 women (mean age 52.2 years) and 1718 men (mean age 49.8 years) in the Framingham Heart Study. Depressive symptoms were measured using the Center for Epidemiologic Studies Depression (CES-D) scale. Regression models were created to examine the association between each fat depot (exposure) and depressive symptoms (outcome). Sex specific models were adjusted for age, body mass index, smoking, alcohol consumption, diabetes, hypertension, total and HDL cholesterol, lipid lowering treatment, CVD, menopause, C-reactive protein, and physical activity. Mean CES-D scores were 6.8 and 5.6 in women and men. High levels of depressive symptoms were present in 22.5% of women and 12.3% of men. In women, one standard deviation increase in VAT was associated with a 1.3 point higher CES-D score after adjusting for age and BMI (p<0.01) and remained significant in the fully adjusted model (p=0.03). The odds ratio of depressive symptoms per 1 standard deviation increase in VAT in women was 1.33 (p=0.015); results were attenuated in fully adjusted models (OR 1.29, p=0.055). In men, the association between VAT and CES-D score and depressive symptoms was not significant. SAT was not associated with CES-D score or depressive symptoms. This study supports an association between VAT and depressive symptoms in women. Further work is needed to uncover the complex biologic mechanisms mediating the association.
PMCID: PMC3748158  PMID: 23666906
21.  Aminotransferase Levels are Associated with Cardiometabolic Risk above and beyond Visceral Fat and Insulin Resistance: The Framingham Heart Study 
We sought to characterize associations between aminotransferase levels and cardiometabolic risk after accounting for visceral adipose tissue (VAT) and insulin resistance.
Methods and Results
Participants (n=2621) from the Framingham Heart Study (mean age 51, 49.8% women) were included. Sex-specific linear and logistic regressions were used to evaluate associations between aminotransferase levels and cardiometabolic risk factors. In multivariable models, increased ALT levels were associated with elevated blood pressure, fasting plasma glucose, and triglycerides and lower HDL levels (all p ≤ 0.007). Further, each 1 standard deviation (SD) increase in ALT corresponded to an increased odds of hypertension, diabetes, the metabolic syndrome, impaired fasting glucose, and insulin resistance estimated by HOMA-IR (OR 1.29–1.85, all p ≤ 0.002). Associations with ALT persisted after additional adjustment for VAT, insulin resistance, and BMI with the exception of HDL cholesterol in both sexes and blood pressure in women. Results were materially unchanged when moderate drinkers were excluded, when the sample was restricted to those with ALT<40 U/L, and when the sample was restricted to those without diabetes. Similar trends were observed for AST levels, but associations were more modest.
Aminotransferase levels are correlated with multiple cardiometabolic risk factors above and beyond VAT and insulin resistance.
PMCID: PMC3593729  PMID: 23162012
liver function tests; obesity; visceral fat; insulin resistance; cardiometabolic risk factors
22.  Thoracic Periaortic and Visceral Adipose Tissue and Their Cross-sectional Associations with Measures of Vascular Function 
Obesity (Silver Spring, Md.)  2013;21(7):1496-1503.
Perivascular fat may have a local adverse effect on the vasculature. We evaluated whether thoracic periaortic adipose tissue (TAT), a type of perivascular fat, and visceral adipose tissue (VAT) are associated with vascular function.
Design and Methods
TAT and VAT were quantified in Framingham Heart Study participants using multidetector computed tomography; vascular function was assessed using brachial artery vasodilator function, peripheral arterial tone and arterial tonometry (n= 2735, 48% women, mean age 50 years, mean BMI 27.7 kg/m2). Using multiple linear regression, we examined relations between TAT, VAT, and vascular measures while adjusting for cardiovascular risk factors.
Mean TAT and VAT volumes were 13.2 and 1763 cm3. TAT and VAT were associated with multiple vascular function measures after multivariable adjustment. After BMI adjustment, TAT and VAT remained negatively associated with peripheral arterial tone and inverse carotid femoral pulse wave velocity (p<0.02); TAT was negatively associated with hyperemic mean flow velocity (p=0.03). Associations of TAT with vascular function were attenuated after VAT adjustment (all p>0.06).
Thoracic periaortic and visceral fat are associated with microvascular function and large artery stiffness after BMI adjustment. These findings support the growing recognition of associations between ectopic fat and vascular function.
PMCID: PMC3742564  PMID: 23754461
obesity; vascular function; arterial stiffness; perivascular adipose tissue; visceral adipose tissue
23.  Relations of Long-Term and Contemporary Lipid Levels and Lipid Genetic Risk Scores with Coronary Artery Calcium in the Framingham Heart Study 
This study evaluated the association of timing of lipid levels and lipid genetic risk score (GRS) with subclinical atherosclerosis.
Atherosclerosis is a slowly progressive disorder influenced by suboptimal lipid levels. Long-term versus contemporary lipid levels may more strongly impact the development of coronary artery calcium (CAC).
Framingham Heart Study (FHS) Offspring Cohort participants (n=1156, 44%M, 63±9 years) underwent serial fasting lipids [low-density lipoprotein (LDL-C), high-density lipoprotein, and triglycerides], Exam 1 (1971–1975) – Exam 7 (1998–2001). FHS Third Generation Cohort participants (n=1954, 55%M, 45±6 years) had fasting lipid profiles assessed, 2002–2005. Computed tomography (2002–2005) measured CAC. Lipid GRSs were computed from significantly associated single nucleotide polymorphisms. The association between early, long-term average, and contemporary lipids, and lipid GRS, with elevated CAC was assessed using logistic regression.
In FHS Offspring, Exam 1 and long-term average versus Exam 7 lipid measurements, including untreated lipid levels, were strongly associated with elevated CAC. In the FHS Third Generation, contemporary lipids were associated with CAC. The LDL-C GRS was associated with CAC (age/sex-adjusted OR 1.14, 95%CI 1.00–1.29, p=0.04). However, addition of the GRS to the lipid models did not result in a significant increase in the OR or C-statistic for any lipid measure.
Early and long-term average lipid levels, as compared with contemporary measures, are more strongly associated with elevated CAC. Lipid GRS was associated with lipid levels but did not predict elevated CAC. Adult early and long-term average lipid levels provide important information when assessing subclinical atherosclerosis and cardiovascular risk.
PMCID: PMC3702262  PMID: 23141485
Lipids; Genetic risk score; Coronary artery calcium
24.  Novel measurements of periaortic adipose tissue in comparison to anthropometric measures of obesity, and abdominal adipose tissue 
Perivascular adipose tissue may be associated with the amount of local atherosclerosis. We developed a novel and reproducible method to standardize volumetric quantification of periaortic adipose tissue by computed tomography (CT) and determined the association with anthropometric measures of obesity, and abdominal adipose tissue.
Measurements of adipose tissue were performed in a random subset of participants from the Framingham Heart Study (n=100) who underwent multidetector CT of the thorax (ECG triggering, 2.5 mm slice thickness) and the abdomen (helical CT acquisition, 2.5 mm slice thickness). Abdominal periaortic adipose tissue (AAT) was defined by a 5 mm cylindrical region of interest around the aortic wall; thoracic periaortic adipose tissue (TAT) was defined by anatomic landmarks. TAT and AAT were defined as any voxel between −195 HU to −45HU and volumes were measured using dedicated semiautomatic software. Measurement reproducibility and association with anthropometric measures of obesity, and abdominal adipose tissue were determined.
The intra- and inter-observer reproducibility for both AAT and TAT was excellent (ICC: 0.97, 0.97; 0.99, and 0.98, respectively). Similarly, the relative intra-and inter-observer difference was small for both AAT (−1.85±1.28% and 7.85±6.08%; respectively) and TAT (3.56±0.83% and −4.56±0.85%, respectively). Both AAT and TAT were highly correlated with visceral abdominal fat (r=0.65 and 0.77, p<0.0001 for both) and moderately correlated with subcutaneous abdominal fat (r=0.39 and 0.42, p<0.0001 and p=0.009), waist circumference (r=0.49 and 0.57, p<0.0001 for both), and body mass index (r=0.47 and 0.58, p<0.0001 for both).
Standardized semiautomatic CT-based volumetric quantification of periaortic adipose tissue is feasible and highly reproducible. Further investigation is warranted regarding associations of periaortic adipose tissue with other body fat deposits, cardiovascular risk factors, and clinical outcomes.
PMCID: PMC3779879  PMID: 19139753
Adipose Tissue; Intra-Abdominal Fat; Tomography; Spiral Computed; Framingham Heart Study; Metabolic Risk Factors
25.  Prevalence and Distribution of Abdominal Aortic Calcium by Sex and Age-Group in a Community-based Cohort (From The Framingham Heart Study) 
The American journal of cardiology  2012;110(6):891-896.
Abdominal aortic calcium (AAC) is associated with incident cardiovascular disease but the age and sex-related distribution of AAC in a community-dwelling population free of standard cardiovascular disease risk factors has not been described. A total of 3285 participants (aged 50.2±9.9 years) in the Framingham Heart Study Offspring and Third Generation cohorts underwent abdominal multidetector computed tomography (MDCT) scanning during 1998-2005. The presence and amount of AAC was quantified (Agatston score) by an experienced reader using standardized criteria. A healthy referent subsample (N=1656, 803 men) free of hypertension, hyperlipidemia, diabetes, obesity and smoking was identified, and participants were stratified by sex and age group (<45, 45-54, 55-64, 65-74, ≥75 years). The prevalence and burden of AAC increased monotonically and supralinearly with age in both sexes but was greater in men than women in each age group. Below age 45 <16% of referent-subsample participants had any quantifiable AAC, while above age 65 nearly 90% of referent participants had >0 AAC. Across the entire study sample, AAC prevalence and burden similarly increased with greater age. Defining the 90th percentile of referent group AAC as “high,” the prevalence of high AAC was 19% for each sex in the overall study sample. AAC also increased across categories of 10-year coronary heart disease risk, as calculated using the Framingham Risk Score, in the entire study sample. We found AAC to be widely prevalent, with the burden of AAC associated with 10-year coronary risk, in a white, free-living adult cohort.
PMCID: PMC3432173  PMID: 22727181
atherosclerosis; aorta; calcification; computed tomography; epidemiology

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