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1.  Economic Outcomes with Anatomic versus Functional Diagnostic Testing for Coronary Artery Disease 
Annals of internal medicine  2016;165(2):94-102.
Background
The PROMISE trial found that initial use of ≥64-slice multidetector computed tomographic angiography (CTA) versus functional diagnostic testing strategies did not improve clinical outcomes in stable symptomatic patients with suspected coronary artery disease (CAD) requiring noninvasive testing.
Objective
Economic analysis of PROMISE, a major secondary aim.
Design
Prospective economic study from the US perspective. Comparisons were made by intention-to-treat. Confidence intervals were calculated using bootstrap methods.
Setting
190 U.S. centers
Patients
9649 U.S. patients enrolled in PROMISE. Enrollment began July 2010 and completed September 2013. Median follow-up was 25 months.
Measurements
Technical costs of the initial (outpatient) testing strategy were estimated from Premier Research Database data. Hospital-based costs were estimated using hospital bills and Medicare cost-to-charge ratios. Physician fees were taken from the Medicare Fee Schedule. Costs were expressed in 2014 US dollars discounted at 3% and estimated out to 3 years using inverse probability weighting methods.
Results
The mean initial testing costs were: $174 for exercise ECG; $404 for CTA; $501 to $514 for (exercise, pharmacologic) stress echo; $946 to $1132 for (exercise, pharmacologic) stress nuclear. Mean costs at 90 days for the CTA strategy were $2494 versus $2240 for the functional strategy (mean difference $254, 95% CI −$634 to $906). The difference was associated with more revascularizations and catheterizations (4.25 per 100 patients) with CTA use. After 90 days, the mean cost difference between the arms out to 3 years remained small ($373).
Limitations
Cost weights for test strategies obtained from sources outside PROMISE.
Conclusions
CTA and functional diagnostic testing strategies in patients with suspected CAD have similar costs through three years of follow-up.
doi:10.7326/M15-2639
PMCID: PMC5046832  PMID: 27214597
2.  Coronary Plaque Morphology and the Anti-Inflammatory Impact of Atorvastatin 
Supplemental Digital Content is available in the text.
Background—
Nonobstructive coronary plaques manifesting high-risk morphology (HRM) associate with an increased risk of adverse clinical cardiovascular events. We sought to test the hypothesis that statins have a greater anti-inflammatory effect within coronary plaques containing HRM.
Methods and Results—
In this prospective multicenter study, 55 subjects with or at high risk for atherosclerosis underwent 18F-fluorodeoxyglucose positron emission tomographic/computed tomographic imaging at baseline and after 12 weeks of treatment with atorvastatin. Coronary arterial inflammation (18F-fluorodeoxyglucose uptake, expressed as target-to-background ratio) was assessed in the left main coronary artery (LMCA). While blinded to the PET findings, contrast-enhanced computed tomographic angiography was performed to characterize the presence of HRM (defined as noncalcified or partially calcified plaques) in the LMCA. Arterial inflammation (target-to-background ratio) was higher in LMCA segments with HRM than those without HRM (mean±SEM: 1.95±0.43 versus 1.67±0.32 for LMCA with versus without HRM, respectively; P=0.04). Moreover, atorvastatin treatment for 12 weeks reduced target-to-background ratio more in LMCA segments with HRM than those without HRM (12 week-baseline Δtarget-to-background ratio [95% confidence interval]: −0.18 [−0.35 to −0.004] versus 0.09 [−0.06 to 0.26]; P=0.02). Furthermore, this relationship between coronary plaque morphology and change in LMCA inflammatory activity remained significant after adjusting for baseline low-density lipoprotein and statin dose (β=−0.27; P=0.038).
Conclusions—
In this first study to evaluate the impact of statins on coronary inflammation, we observed that the anti-inflammatory impact of statins is substantially greater within coronary plaques that contain HRM features. These findings suggest an additional mechanism by which statins disproportionately benefit individuals with more advanced atherosclerotic disease.
Clinical Trial Registration—
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00703261.
doi:10.1161/CIRCIMAGING.115.004195
PMCID: PMC5175997  PMID: 27956407
atherosclerosis; carotid artery; coronary artery disease; inflammation; positron emission tomography
3.  Prognostic value of coronary CTA vs. exercise treadmill testing: results from the Partners registry 
Aims
We sought to compare the complementary prognostic value of exercise treadmill testing (ETT) and coronary computed tomographic angiography (CTA) among patients referred for both exams.
Methods and results
We studied 582 patients without known coronary artery disease (CAD) who were clinically referred for ETT and CTA within 6 months. Patients were followed for cardiovascular (CV) death, non-fatal myocardial infarction (MI), or late revascularization (>90 days), stratified by Duke Treadmill Score (DTS) and CAD severity (≥50% stenosis). Mean age was 54 ± 13 years (63% male). In median follow-up of 40 months, there were 3 CV deaths, 7 non-fatal MIs, and 26 late revascularizations. ETT was inconclusive in 23%, positive in 31%, and negative in 46%. CTA demonstrated no CAD in 37%, non-obstructive CAD in 28%, and obstructive CAD in 35%. Among low-risk ETT patients (n = 326), there were 3 MI, 10 late revascularizations, and the frequent presence of non-obstructive (32%, n = 105) and obstructive CAD (27%, n = 88). When present, ETT features (i.e. angina, DTS, ischaemic electrocardiogram changes, and exercise capacity) individually failed to predict CV death/MI after adjustment for Morise score. Conversely, both obstructive CAD [HR 4.9 (1.0–23.3), P = 0.048] and CAD extent by segment involvement score >4 [HR 3.9 (1.0–15.2), P = 0.049] predicted increased risk for CV death or MI.
Conclusion
Patients with a low-risk ETT have an excellent prognosis at 40 months, despite the frequent presence of non-obstructive (32%) and obstructive (27%) CAD. In patients with an intermediate- to high-risk ETT (DTS <5), CTA can provide incremental risk stratification for future CV events.
doi:10.1093/ehjci/jev087
PMCID: PMC4668770  PMID: 25899714
exercise testing; coronary computed tomographic angiography; prognosis; major adverse cardiac events; coronary artery disease
4.  Highly Sensitive Troponin I Followed by Advanced Coronary Artery Disease Assessment Using Computed Tomography Angiography Improves Acute Coronary Syndrome Risk Stratification Accuracy and Work-up in Acute Chest Pain Patients: Results from ROMICAT II Trial 
JACC. Cardiovascular imaging  2015;8(11):1272-1281.
Objectives
We compared diagnostic accuracy of conventional troponin/traditional coronary artery disease (CAD) assessment and highly sensitive troponin (hsTn) I/advanced CAD assessment for acute coronary syndrome (ACS) during the index hospitalization.
Background
HsTn I and advanced assessment of CAD using coronary computed tomography angiography (CTA) are promising candidates to improve the accuracy of emergency department (ED) evaluation of patients with suspected ACS.
Methods
We performed an observational cohort study in patients with suspected ACS enrolled in the ROMICAT II trial and randomized to coronary CTA who also had hsTn I measurement at the time of the ED presentation. We assessed coronary CTA for traditional (no CAD, non-obstructive CAD, ≥50% stenosis) and advanced features of CAD (≥50% stenosis, high-risk plaque features: positive remodeling, low <30 Hounsfield Units plaque, napkin ring sign, spotty calcium).
Results
Of 160 patients (mean age: 53±8 years, 40% women) 10.6% were diagnosed with ACS. The ACS rate in patients with HsTn I below the limit of detection (n=9, 5.6%), intermediate (n=139, 86.9%), and above the 99th percentile (n=12, 7.5%) was 0%, 8.6%, and 58.3%, respectively. Absence of ≥50% stenosis and high-risk plaque ruled out ACS in patients with intermediate hsTn I (n=87, 54.4%; ACS rate 0%), while patients with both ≥50% stenosis and high-risk plaque were at high risk (n=13, 8.1%; ACS rate 69.2%) and patients with either ≥50% stenosis or high-risk plaque were at intermediate risk for ACS (n=39, 24.4%; ACS rate 7.7%). HsTn I/advanced coronary CTA assessment significantly improved the diagnostic accuracy for ACS as compared to conventional troponin/traditional coronary CTA (AUC 0.84, 95%CI 0.80-0.88 vs. 0.74, 95%CI 0.70-0.78; p<0.001).
Conclusions
HsTn I at the time of presentation followed by early advanced coronary CTA assessment improves the risk stratification and diagnostic accuracy for ACS as compared to conventional troponin and traditional coronary CTA assessment. (Multicenter Study to Rule Out Myocardial Infarction/Ischemia by Cardiac Computed Tomography [ROMICAT-II]; NCT01084239)
doi:10.1016/j.jcmg.2015.06.016
PMCID: PMC4644454  PMID: 26476506
highly-sensitive troponin; coronary CT angiography; coronary plaque; acute coronary syndrome; risk stratification; emergency department
5.  Computed Tomography-Based High-Risk Coronary Plaque Score to Predict Acute Coronary Syndrome Among Patients With Acute Chest Pain – Results from the ROMICAT II Trial 
Background
Coronary computed tomography angiography (CTA) can be used to detect and quantitatively assess high-risk plaque features.
Objective
To validate the ROMICAT score, which was derived using semi-automated quantitative measurements of high-risk plaque features, for the prediction of ACS.
Material and methods
We performed quantitative plaque analysis in 260 patients who presented to the emergency department with suspected ACS in the ROMICAT II trial. The readers used a semi-automated software (QAngio, Medis medical imaging systems BV) to measure high-risk plaque features (volume of <60HU plaque, remodeling index, spotty calcium, plaque length) and diameter stenosis in all plaques. We calculated a ROMICAT score, which was derived from the ROMICAT I study and applied to the ROMICAT II trial. The primary outcome of the study was diagnosis of an ACS during the index hospitalization.
Results
Patient characteristics (age 57±8 vs. 56±8 years, cardiovascular risk factors) were not different between those with and without ACS (prevalence of ACS 7.8%). There were more men in the ACS group (84% vs. 59%, p=0.005). When applying the ROMICAT score derived from the ROMICAT I trial to the patient population of the ROMICAT II trial, the ROMICAT score (OR 2.9, 95%CI 1.4–6.0, p=0.003) was a predictor of ACS after adjusting for gender and ≥50% stenosis. The AUC of the model containing ROMICAT score, gender, and ≥50% stenosis was 0.91 (95%CI 0.86–0.96) and was better than with a model that included only gender and ≥50% stenosis (AUC 0.85, 95%CI 0.77–0.92; p=0.002)
Conclusions
The ROMICAT score derived from semi-automated quantitative measurements of high-risk plaque features was an independent predictor of ACS during the index hospitalization and was incremental to gender and presence of ≥50% stenosis.
doi:10.1016/j.jcct.2015.07.003
PMCID: PMC4684738  PMID: 26229036
coronary computed tomography angiography; acute coronary syndrome; coronary atherosclerotic plaque; acute chest pain; risk score
6.  Association Between Visceral and Subcutaneous Adipose Depots and Incident Cardiovascular Disease Risk Factors 
Circulation  2015;132(17):1639-1647.
Background
Visceral and subcutaneous adipose tissue (VAT and SAT) vary in volume and quality. We evaluated whether fat volume or attenuation (indirect measure of quality) predicts metabolic risk factor changes.
Methods and Results
Framingham Heart Study Multi-detector Computed Tomography Substudy participants (n=1730, 45% women) were followed over a mean of 6.2 years. Baseline VAT and SAT volume (in cm3) and attenuation (in Hounsfield units, HU) were assessed. Outcomes included blood pressure, lipids and glucose. We constructed multivariable regression models predicting change from baseline to follow-up. Baseline VAT was associated with metabolic risk factors at follow-up. Per 500 cm3 increment in baseline VAT, glucose was 2.34 mg/dL higher (95% CI 1.71–2.97) and HDL was 1.62 mg/dL lower (95% CI 0.97–2.28) in women (p<0.0001 for both). These findings remained significant after adjustment for BMI. Results for SAT were similar, although less striking. Lower (more negative) fat attenuation was associated with more adverse metabolic profiles at follow-up. For example, per 5 unit decrease in baseline VAT HU, log triglycerides increased by 0.08 mg/dL (95% CI 0.05–0.12,p=0.005), which remained significant after adjustment for baseline VAT. Among men, VAT and SAT HU were associated with changes in CVD risk factors, but were mostly attenuated after baseline volume adjustment.
Conclusions
VAT and SAT volume are associated with incident metabolic risk factors beyond their contributions to overall adiposity. Decrements in fat attenuation are also associated with incident risk factors. These findings suggest that both volume and quality of VAT and SAT contribute to metabolic risk.
doi:10.1161/CIRCULATIONAHA.114.015000
PMCID: PMC4779497  PMID: 26294660
Epidemiology; Population; Prevention; Adipose Depots
7.  Changes in Medical Therapy and Lifestyle After Anatomical or Functional Testing for Coronary Artery Disease 
Background
Diagnostic testing in the care of patients newly presenting with symptoms suggestive of coronary artery disease may influence risk factor management, independent of test type or test results. However, little is known about changes in medications and lifestyle after anatomical or functional testing.
Methods and Results
We examined what factors influenced preventive medical therapy and lifestyle practices at 60 days among 10 003 symptomatic patients (53% women; mean age 61 years) randomly assigned to anatomical testing with coronary computed tomographic angiography or functional testing (NCT01174550). We also assessed the association of preventive changes with major cardiovascular events. There were no differences in medications/lifestyle at baseline. At 60 days, relative to baseline, the computed tomographic angiography strategy was associated with a higher proportion of patients newly initiating aspirin (11.8% versus 7.8%), statins (12.7% versus 6.2%), and β‐blockers (8.1% versus 5.3%), compared to functional testing (P<0.0001 for each). No significant differences between computed tomographic angiography and functional testing strategies were observed for initiation of exercise, quitting smoking, or weight loss in overweight/obese patients, though overall prevalence of healthy eating was higher after computed tomographic angiography (P=0.002) while obese/overweight status was lower (P=0.040). Positive initial test results and revascularization demonstrated stronger associations with preventive medications and lifestyle than test type. Medication initiation was not associated with fewer cardiovascular events.
Conclusions
Positive initial test results and revascularization are primary drivers of changes in preventive medical and lifestyle practices, with test type making secondary contributions. However, substantial opportunities exist to further reduce cardiovascular risk.
Clinical Trial Registration
URL: https://www.clinicaltrials.gov. Unique identifier: NCT01174550.
doi:10.1161/JAHA.116.003807
PMCID: PMC5121482  PMID: 27733347
angina; coronary disease; diagnosis; prevention; Lifestyle; Diagnostic Testing; Coronary Artery Disease
8.  Effect of Late Gadolinium Enhancement on the Recovery of Left Ventricular Systolic Function After Pulmonary Vein Isolation 
Background
The factors that predict recovery of left ventricular (LV) systolic dysfunction among patients with atrial fibrillation (AF) are not completely understood. Late gadolinium enhancement (LGE) of the LV has been reported among patients with AF, and we aimed to test whether the presence LGE was associated with subsequent recovery of LV systolic function among patients with AF and LV dysfunction.
Methods and Results
From a registry of 720 consecutive patients undergoing a cardiac magnetic resonance study prior to pulmonary vein isolation (PVI), patients with LV systolic dysfunction (ejection fraction [EF] <50%) were identified. The primary outcome was recovery of LVEF defined as an EF >50%; a secondary outcome was a combined outcome of subsequent heart failure (HF), admission, and death. Of 720 patients, 172 (24%) had an LVEF of <50% prior to PVI. The mean LVEF pre‐PVI was 41±6% (median 43%, range 20% to 49%). Forty‐three patients (25%) had LGE (25 [58%] ischemic), and the extent of LGE was 7.5±4% (2% to 19%). During follow‐up (mean 42 months), 91 patients (53%) had recovery of LVEF, 68 (40%) had early recurrence of AF, 65 (38%) had late AF, 18 (5%) were admitted for HF, and 23 died (13%). Factors associated with nonrecovery of LVEF were older age, history of myocardial infarction, early AF recurrence, late AF recurrence, and LGE. In a multivariable model, the presence of LGE and any recurrence of AF had the strongest association with persistence of LV dysfunction. Additionally, all patients without recurrence of AF and LGE had normalization of LVEF, and recovery of LVEF was associated with reduced HF admissions and death.
Conclusions
In patients with AF and LV dysfunction undergoing PVI, the absence of LGE and AF recurrence are predictors of LVEF recovery and LVEF recovery in AF with associated reduction in subsequent death and heart failure.
doi:10.1161/JAHA.116.003570
PMCID: PMC5079022  PMID: 27671316
atrial fibrillation; cardiac dysfunction; cardiovascular magnetic resonance imaging; heart failure; late gadolinium enhancement; Atrial Fibrillation; Prognosis; Magnetic Resonance Imaging (MRI); Heart Failure; Cardiomyopathy
9.  The Association between Non-Invasive Hepatic Fibrosis Markers and Cardiometabolic Risk Factors in the Framingham Heart Study 
PLoS ONE  2016;11(6):e0157517.
Background & Aims
Non-alcoholic fatty liver disease (NAFLD) is associated with an increased risk of cardiovascular related death, particularly in those with hepatic fibrosis. We determined the prevalence of predicted fibrosis based on non-invasive fibrosis markers and the association of hepatic fibrosis with cardiovascular risk factors.
Methods
Cross-sectional study of 575 Framingham Heart Study participants with NAFLD based on computed tomography. We determined the prevalence of predicted fibrosis based on the aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio, AST to platelet ratio index (APRI), the Fibrosis-4 score (FIB4), and the NAFLD Fibrosis Score (NFS). Using multivariable logistic regression models, we examined the association between low, indeterminate, or high risk for fibrosis according to the NFS and various cardiometabolic risk factors.
Results
The predicted risk of fibrosis was 12%, 4%, 5%, and 32% for the NFS, FIB4, APRI, and AST/ALT ratio, respectively. In multivariable models, participants with a high risk for advanced fibrosis by the NFS had a wider pulse pressure (adjusted mean difference = 6.87 mm Hg; p = 0.0002) and an increased odds of hypertension (OR 2.92; p = 0.007) compared to those with low risk of fibrosis. There were no statistically significant differences between other cardiovascular risk factors for those with a high versus low risk of fibrosis.
Conclusions
The AST/ALT ratio, APRI, and NFS give widely disparate predictions of liver fibrosis. Participants with a high risk for fibrosis based on NFS had wider pulse pressure and increased odds of hypertension. Whether modifying these risk factors impacts cardiovascular endpoints in NAFLD patients remains unknown.
doi:10.1371/journal.pone.0157517
PMCID: PMC4920364  PMID: 27341207
10.  Statin Effects to Reduce Hepatosteatosis as Measured by Computed Tomography in Patients With Human Immunodeficiency Virus 
Open Forum Infectious Diseases  2016;3(2):ofw062.
Hepatosteatosis is highly prevalent among patients living with human immunodeficiency virus. In a 1-year, randomized, double-blind trial of atorvastatin or placebo, atorvastatin increased liver/spleen ratio among patients with nonalcoholic fatty liver disease, indicating a reduction in hepatosteatosis. This reduction in hepatosteatosis is associated with reduction in low-density lipoprotein cholesterol with statin therapy.
doi:10.1093/ofid/ofw062
PMCID: PMC4943550  PMID: 27419149
hepatosteatosis; human immunodeficiency virus; LDL cholesterol; statin
11.  Relationship of Thoracic Adipose Tissue Depots with Coronary Atherosclerosis and Circulating Inflammatory Biomarkers 
Obesity (Silver Spring, Md.)  2015;23(6):1178-1184.
Objective
Our aim was to determine the relationship of various thoracic fat depots to the presence and extent of coronary artery plaque and circulating biomarkers.
Methods
In 342 patients (52±11 years, 61% male, BMI 29.1±5.9 kg/m2) with coronary CT angiography, we measured the fat volume in four thoracic depots (pericoronary, epicardial, periaortic, extracardiac), assessed coronary plaque and determined the circulating level of C-reactive protein, tumor necrosis factor alpha, plasminogen activator inhibitor-1, monocyte chemoattractant-1, and adiponectin. Extent of coronary plaque was classified into 3 groups: 0, 1–3 and >3 segments.
Results
Patients with plaque (n=169, 49%) had higher volumes of all 4 fat depots as compared to patients without plaque (all p<0.01), despite similar BMI (p=0.18). Extracardiac fat was most strongly correlated with BMI (r=0.45, p<0.001), while pericoronary fat was least (r=0.21, p<0.001). Only pericoronary fat remained associated with coronary plaque in adjusted analyses. Inflammatory biomarkers showed a positive correlation with pericoronary fat (all p<0.0001), whereas adiponectin was not associated to this fat compartment (p=0.60) and showed a negative correlation with all other fat depots (all p<0.001).
Conclusion
Pericoronary fat is independently associated with CAD. Its correlation with inflammatory biomarkers suggests that while systemic inflammation plays a role in the pathogenesis of CAD, there are additional local effects that may exist.
doi:10.1002/oby.21080
PMCID: PMC4446160  PMID: 25960369
pericoronary fat; coronary atherosclerosis; cardiac computed tomography
12.  Hepatic Steatosis is Associated with Lower Levels of Physical Activity Measured via Accelerometry 
Obesity (Silver Spring, Md.)  2015;23(6):1259-1266.
Objective
Prior studies on the association of physical activity (PA) and non-alcoholic fatty liver disease are limited by reliance on subjective measures of PA. We examined the association between objectively measured PA and hepatic steatosis defined by computed tomography (CT).
Methods
We conducted a cross-sectional study of 1060 Framingham Heart Study participants who participated in the Multi-Detector CT 2 substudy and who underwent assessment of PA via accelerometry. Hepatic steatosis was estimated by liver attenuation, as measured by CT. We explored the relationship between liver attenuation and PA using multivariable regression models.
Results
In multivariable-adjusted models, we observed an inverse association between PA and liver attenuation. Each 30 min/day increase in moderate-to-vigorous PA (MVPA) was associated with a reduced odds of hepatic steatosis (OR=0.62, p<0.001). This association was attenuated and no longer statistically significant after adjustment for BMI (OR=0.77, p=0.05) or VAT (OR=0.83, p=0.18). Participants who met the national PA recommendations of engaging in ≥150 minutes/week of MVPA, had the lowest odds of hepatic steatosis, even after adjusting for BMI (OR=0.63, p=0.007) or VAT (OR=0.67, p=0.03).
Conclusions
There is an inverse association between PA and hepatic steatosis. Participants who met the national PA guidelines had the lowest prevalence of hepatic steatosis.
doi:10.1002/oby.21058
PMCID: PMC4446168  PMID: 25959049
13.  Non-alcoholic fatty liver disease and vascular function – a cross-sectional analysis in the Framingham Heart Study 
Objective
Patients with non-alcoholic fatty liver disease (NAFLD) have an increased risk of cardiovascular disease (CVD); however, it is not known if NAFLD contributes to CVD independent of established risk factors. We examined the association between NAFLD and vascular function.
Approach and Results
We conducted a cross-sectional study of 2,284 Framingham Heart Study participants without overt CVD who had liver fat attenuation measured on computed tomography and who had measurements of vascular function and covariates. We evaluated the association between NAFLD and vascular function using multivariable partial correlations adjusting for age, sex, cohort, smoking, diabetes, hyperlipidemia, hypertension, body mass index (BMI) and visceral adipose tissue (VAT). The prevalence of NAFLD in our sample (mean age 52 ± 12 years, 51.4% women) was 15.3%. In age-, sex- and cohort-adjusted analyses, greater liver fat was modestly associated with lower flow-mediated dilation (r = −0.05, P=0.02), lower peripheral arterial tonometry ratio (r = −0.20, P<0.0001), higher carotid-femoral pulse wave velocity (r = 0.13, P<0.0001) and higher mean arterial pressure (r = 0.11, P<0.0001). In multivariable-adjusted models, NAFLD remained associated with higher mean arterial pressure (r=0.06, P=0.005) and lower peripheral arterial tonometry ratio (r= −0.12, P<0.0001). The association between NAFLD and peripheral arterial tonometry ratio persisted after further adjustment for BMI and VAT.
Conclusions
For multiple measures of vascular function, the relation with NAFLD appeared largely determined by shared cardiometabolic risk factors. The persistent relation with reduced peripheral arterial tonometry response beyond established risk factors suggests that NAFLD may contribute to microvascular dysfunction.
doi:10.1161/ATVBAHA.114.305200
PMCID: PMC4520415  PMID: 25745056
vascular endothelial dysfunction; computed tomography; microvascular; obesity; risk factors
14.  Adipose Tissue Depots and Their Cross‐Sectional Associations With Circulating Biomarkers of Metabolic Regulation 
Background
Visceral adipose tissue (VAT) and fatty liver differ in their associations with cardiovascular risk compared with subcutaneous adipose tissue (SAT). Several biomarkers have been linked to metabolic derangements and may contribute to the pathogenicity of fat depots. We examined the association between fat depots on multidetector computed tomography and metabolic regulatory biomarkers.
Methods and Results
Participants from the Framingham Heart Study (n=1583, 47% women) underwent assessment of SAT, VAT, and liver attenuation. We measured circulating biomarkers secreted by adipose tissue or liver (adiponectin, leptin, leptin receptor, fatty acid binding protein 4, fetuin‐A, and retinol binding protein 4). Using multivariable linear regression models, we examined relations of fat depots with biomarkers. Higher levels of fat depots were positively associated with leptin and fatty acid binding protein 4 but negatively associated with adiponectin (all P<0.001). Associations with leptin receptor, fetuin‐A, and retinol binding protein 4 varied according to fat depot type or sex. When comparing the associations of SAT and VAT with biomarkers, VAT was the stronger correlate of adiponectin (β=−0.28 [women]; β=−0.30 [men]; both P<0.001), whereas SAT was the stronger correlate of leptin (β=0.62 [women]; β=0.49 [men]; both P<0.001; P<0.001 for comparing VAT versus SAT). Although fetuin‐A and retinol binding protein 4 are secreted by the liver in addition to adipose tissue, associations of liver attenuation with these biomarkers was not stronger than that of SAT or VAT.
Conclusions
SAT, VAT, and liver attenuation are associated with metabolic regulatory biomarkers with differences in the associations by fat depot type and sex. These findings support the possibility of biological differences between fat depots.
doi:10.1161/JAHA.115.002936
PMCID: PMC4889173  PMID: 27146446
adipokines; adipose tissue; biomarkers; epidemiology; obesity; Obesity; Epidemiology
15.  Cardiac computed tomography in patients with acute chest pain 
European Heart Journal  2015;36(15):906-914.
The efficient and reliable evaluation of patients with acute chest pain is one of the most challenging tasks in the emergency department. Coronary computed tomography (CT) angiography may play a major role, since it permits ruling out coronary artery disease with high accuracy if performed with expertise in properly selected and prepared patients. Several randomized trials have established early cardiac CT as a viable safe and potentially more efficient alternative to functional testing in the evaluation of acute chest pain. Ongoing investigations explore whether advanced anatomic and functional assessments such as high-risk coronary plaque, resting myocardial perfusion, and left ventricular function, or the simulation of the fractional coronary flow reserve will add information to the anatomic assessment for stenosis, which would allow expanding the benefits of cardiac CT from triage to treatment decisions. Especially, the combination of high-sensitive troponins and coronary computed tomography angiography may play a valuable role in future strategies for the management of patients presenting with acute chest pain.
doi:10.1093/eurheartj/ehv034
PMCID: PMC4809998  PMID: 25687351
Computed tomography; Acute chest pain; Acute coronary syndrome; Myocardial infarction; Diagnostic triage; Review
16.  Association Between Interstitial Lung Abnormalities and All-Cause Mortality 
JAMA  2016;315(7):672-681.
IMPORTANCE
Interstitial lung abnormalities have been associated with decreased six-minute walk distance, diffusion capacity for carbon monoxide and total lung capacity; however to our knowledge, an association with mortality has not been previously investigated.
OBJECTIVE
To investigate whether interstitial lung abnormalities are associated with increased mortality.
DESIGN, SETTING, POPULATION
Prospective cohort studies of 2633 participants from the Framingham Heart Study (FHS) (CT scans obtained 9/08–3/11), 5320 from the Age Gene/Environment Susceptibility (AGES)-Reykjavik (recruited 1/02–2/06), 2068 from COPDGene (recruited 11/07–4/10), and 1670 from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) (between 12/05–12/06).
EXPOSURES
Interstitial lung abnormality status as determined by chest CT evaluation.
MAIN OUTCOMES AND MEASURES
All cause mortality over approximately 3 to 9 year median follow up time. Cause-of-death information was also examined in the AGES-Reykjavik cohort.
RESULTS
Interstitial lung abnormalities were present in 177 (7%) of the participants from FHS, 378 (7%) from AGES-Reykjavik, 156 (8%) from COPDGene, and in 157 (9%) from ECLIPSE. Over median follow-up times of ~3–9 years there were more deaths (and a greater absolute rate of mortality) among those with interstitial lung abnormalities compared to those without interstitial lung abnormalities in each cohort; 7% compared to 1% in FHS (6% difference, 95% confidence interval [CI] 2%, 10%), 56% compared to 33% in AGES-Reykjavik (23% difference, 95% CI 18%, 28%), 16% compared to 11% in COPDGene (5% difference, 95% CI −1%, 11%) and 11% compared to 5% in ECLIPSE (6% difference, 95% CI 1%, 11%). After adjustment for covariates, interstitial lung abnormalities were associated with an increase in the risk of death in the FHS (HR=2.7, 95% CI, 1.1–65, P=0.030), AGES-Reykjavik (HR 1.3, 95% CI 1.2–1.4, P<0.001), COPDGene (HR=1.8, 95% CI, 1.1, 2.8, P=0.014), and ECLIPSE (HR=1.4, 95% CI, 1.1–2, P=0.022) cohorts. In the AGES-Reykjavik cohort the higher rate of mortality could be explained by a higher rate of death due to respiratory disease, specifically pulmonary fibrosis.
CONCLUSIONS AND RELEVANCE
In four separate research cohorts, interstitial lung abnormalities were associated with a higher risk of all-cause mortality. The clinical implications of this association require further investigation.
doi:10.1001/jama.2016.0518
PMCID: PMC4828973  PMID: 26881370
Idiopathic pulmonary fibrosis; interstitial lung disease; interstitial lung abnormalities (ILA); undiagnosed; subclinical
17.  Sugar-sweetened beverage, diet soda, and fatty liver disease in the Framingham Heart Study cohorts 
Journal of hepatology  2015;63(2):462-469.
Background & Aims
Non-alcoholic fatty liver disease affects ~30% of US adults, yet the role of sugar-sweetened beverages and diet soda on these diseases remains unknown. We examined the cross-sectional association between intake of sugar-sweetened beverages or diet soda and fatty liver disease in participants of the Framingham Offspring and Third Generation cohorts.
Methods
Fatty liver disease was defined using liver attenuation measurements generated from computed tomography in 2634 participants. Alanine transaminase concentration, a crude marker of fatty liver disease, was measured in 5908 participants. Sugar-sweetened beverage and diet soda intake were estimated using a food frequency questionnaire. Participants were categorized as either non-consumers or consumers (3 categories: 1 serving/month to <1 serving/week, 1 serving/week to <1 serving/-day, and ⩾1 serving/day) of sugar-sweetened beverages or diet soda.
Results
After adjustment for age, sex, smoking status, Framingham cohort, energy intake, alcohol, dietary fiber, fat (% energy), protein (% energy), diet soda intake, and body mass index, the odds ratios of fatty liver disease were 1, 1.16 (0.88, 1.54), 1.32 (0.93, 1.86), and 1.61 (1.04, 2.49) across sugar-sweetened beverage consumption categories (p trend = 0.04). Sugar-sweetened beverage consumption was also positively associated with alanine transaminase levels (p trend = 0.007). We observed no significant association between diet soda intake and measures of fatty liver disease.
Conclusion
In conclusion, we observed that regular sugar-sweetened beverage consumption was associated with greater risk of fatty liver disease, particularly in overweight and obese individuals, whereas diet soda intake was not associated with measures of fatty liver disease.
doi:10.1016/j.jhep.2015.03.032
PMCID: PMC4827616  PMID: 26055949
Sugar-sweetened beverages; Diet soda; Alanine transaminase; Fatty liver disease
18.  Effects of Statin Therapy on Coronary Artery Plaque Volume and High Risk Plaque Morphology in HIV-Infected Patients with Subclinical Atherosclerosis: a Randomized Double-Blind Placebo-Controlled Trial 
The lancet. HIV  2015;2(2):e52-e63.
Background
No studies have yet assessed the ability of statin treatment to reduce arterial inflammation and achieve regression of coronary atherosclerosis in HIV-infected patients, a population with elevated risk of myocardial infarction.
Methods
In a randomized, double-blind, placebo-controlled trial, 40 HIV-infected participants with subclinical coronary atherosclerosis, evidence of arterial inflammation in the aorta by fluorodeoxyglucose positron emission tomography (FDG-PET) and low density lipoprotein(LDL)-cholesterol <3·37mmol/L(130mg/dL) were randomized to one year of treatment with atorvastatin (n=19) or placebo (n=21). Randomization was carried out by the MGH Clinical Research Pharmacy using a permuted-block algorithm, stratified by gender with a fixed block size of four, with 1:1 allocation to atorvastatin or identical matching placebo. Study codes were available only to the MGH Research Pharmacy and not to study investigators or participants. The prespecified primary endpoint was arterial inflammation, as assessed by FDG-PET of the aorta. Additional prespecified endpoints included coronary atherosclerotic plaque as assessed by coronary computed tomography angiography. We quantitatively assessed non-calcified and calcified plaque and high risk plaque features. Analysis was performed using intention-to-treat principle, using all available data, without imputation for missing data.
Findings
Thirty seven out of forty (92·5%) subjects completed the study, with equivalent discontinuation rates in both groups. Baseline parameters were similar between groups. After 12 months, change in FDG-PET uptake of the most diseased segment of the aorta was not different between atorvastatin and placebo, but technically adequate results comparing longitudinal changes in identical regions could only be assessed in a subset of patients (atorvastatin Δ −0·03 [95% CI: −0·17, 0·12] vs. placebo Δ −0·06 [−0·25, 0·13], p=0·77, n=21). Change in plaque could be assessed in all subjects completing the study. Atorvastatin reduced noncalcified coronary plaque volume compared to placebo (−19·4%(IQR: −39·2%, 9·3%) vs. +20·4%(−7·1%, 94·4%), p=0·009, n=37). In addition, the number of high risk plaques was significantly reduced by atorvastatin compared to placebo (change in number of low attenuation plaques −0·2[95% CI: −0·6, 0·2] vs. 0·4[0·0, 0·7], p=0·03, n=37 and change in number of positively remodeled plaques −0·2[95% CI −0·4, 0·1] vs. 0·4[−0·1, 0·8], p=0·04, n=37). Direct LDL-cholesterol (−1·00[95% CI −1·38, 0·61] vs. 0·30[0·04, 0·55] mmol/L, p<0·0001) and lipoprotein-associated phospholipase A2 (−52·2[95% CI −70·4, −34·0] vs. −13·3[−32·8, 6·2] ng/mL, p=0·005, n=37) significantly decreased with atorvastatin compared to placebo. Statin therapy was well-tolerated, with low incidence of clinical adverse events.
Interpretation
Compared to placebo, statin therapy reduces noncalcified plaque volume and high risk plaque features in HIV-infected patients with subclinical coronary atherosclerosis. Significant effects of statin therapy on arterial inflammation of the aorta by FDG-PET were not seen. Further studies should assess whether reduction in high risk coronary artery disease translates into effective prevention of cardiovascular events in this at risk population.
doi:10.1016/S2352-3018(14)00032-0
PMCID: PMC4820828  PMID: 26424461
19.  Sensitive troponin assays in patients with suspected acute coronary syndrome: Results from the multi-center Rule Out Myocardial Infarction Using Computer Assisted Tomography (ROMICAT) II Trial 
American heart journal  2015;169(4):572-578.e1.
Background
Sensitive troponin assays have been developed for the evaluation of patients with suspected acute coronary syndrome (ACS). We sought to compare the performance of a commercially available sensitive troponin I (sTnI) and pre-commercial highly sensitive (hs) TnI method to conventional (c)Tn assays.
Methods
Among patients with acute chest pain but normal cTn in the emergency department of 6 centers, sTnI and hsTnI were measured at baseline, two and four hours following presentation. Diagnostic accuracy of sTnI and hsTnI relative to cTn for diagnosis during index hospitalization, as well as their associations with CAD in patients randomized to coronary computed tomographic angiography (CTA) were assessed.
Results
Overall, 322 patients were enrolled, of whom 161 had a CTA; 28 had ACS (8.7%), including 21 with UAP. Both sTnI and hsTnI values at baseline and second draw had significantly higher sensitivity for ACS and UAP than cTn, and had significantly greater area under the receiver operator characteristic curve than cTn at first and second draws. Compared to cTn, 29% of ACS cases previously categorized as UAP were reclassified to acute MI with sTnI or hsTnI. An hsTnI below limit of detection had 100% negative predictive value for ACS or significant coronary artery stenosis in those randomized to CCTA.
Conclusions
In patients with acute chest discomfort, use of sTnI and hsTnI methods led to significant improvement in the early diagnostic accuracy for ACS, reclassifying one third of UAP to MI. Very low values for hsTnI excluded underlying CAD.
doi:10.1016/j.ahj.2014.12.023
PMCID: PMC4380232  PMID: 25819865
myocardial infarction; troponin; diagnosis; imaging
20.  QCT Volumetric Bone Mineral Density and Vascular and Valvular Calcification: The Framingham Study 
There is increasing evidence that bone and vascular calcification share common pathogenesis. Little is known about potential links between bone and valvular calcification. The purpose of this study was to determine the association between spine bone mineral density (BMD) and vascular and valvular calcification. Participants included 1317 participants (689 women, 628 men) in the Framingham Offspring Study (mean age 60 years). Integral, trabecular, and cortical volumetric bone density (vBMD) and arterial and valvular calcification were measured from computed tomography (CT) scans and categorized by sex-specific quartiles (Q4 = high vBMD). Calcification of the coronary arteries (CAC), abdominal aorta (AAC), aortic valve (AVC), and mitral valve (MVC) were quantified using the Agatston Score (AS). Prevalence of any calcium (AS >0) was 69% for CAC, 81% for AAC, 39% for AVC, and 20% for MVC. In women, CAC increased with decreasing quartile of trabecular vBMD: adjusted mean CAC = 2.1 (Q4), 2.2 (Q3), 2.5 (Q2), 2.6 (Q1); trend p = 0.04. However, there was no inverse trend between CAC and trabecular vBMD in men: CAC = 4.3 (Q4), 4.3 (Q3), 4.2 (Q2), 4.3 (Q1); trend p = 0.92. AAC increased with decreasing quartile of trabecular vBMD in both women (AAC = 4.5 [Q4], 4.8 [Q3], 5.4 [Q2], 5.1 [Q1]; trend p = 0.01) and men (AAC = 5.5 [Q4], 5.8 [Q3], 5.9 [Q2], 6.2 [Q1]; trend p = 0.01). We observed no association between trabecular vBMD and AVC or MVC in women or men. Finally, cortical vBMD was unrelated to vascular calcification and valvular calcification in women and men. Women and men with low spine vBMD have greater severity of vascular calcification, particularly at the abdominal aorta. The inverse relation between AAC and spine vBMD in women and men may be attributable to shared etiology and may be an important link on which to focus treatment efforts that can target individuals at high risk of both fracture and cardiovascular events.
doi:10.1002/jbmr.2530
PMCID: PMC4809363  PMID: 25871790
BONE; AGING; QCT; OSTEOPOROSIS; VASCULAR CALCIFICATION; VALVULAR CALCIFICATION; EPIDEMIOLOGY
21.  Late Gadolinium Enhancement Among Survivors of Sudden Cardiac Arrest 
JACC. Cardiovascular imaging  2015;8(4):414-423.
OBJECTIVES
The aim of this study was to describe the role of contrast-enhanced cardiac magnetic resonance (CMR) in the workup of patients with aborted sudden cardiac arrest (SCA) and in the prediction of long-term outcomes.
BACKGROUND
Myocardial fibrosis is a key substrate for SCA, and late gadolinium enhancement (LGE) on a CMR study is a robust technique for imaging of myocardial fibrosis.
METHODS
We performed a retrospective review of all survivors of SCA who were referred for CMR studies and performed follow-up for the subsequent occurrence of an adverse event (death and appropriate defibrillator therapy).
RESULTS
After a workup that included a clinical history, electrocardiogram, echocardiography, and coronary angiogram, 137 patients underwent CMR for workup of aborted SCA (66% male; mean age 56 ± 11 years; left ventricular ejection fraction 43 ± 12%). The presenting arrhythmias were ventricular fibrillation (n = 105 [77%]) and ventricular tachycardia (n = 32 [23%]). Overall, LGE was found in 98 patients (71%), with an average extent of 9.9 ± 5% of the left ventricular myocardium. CMR imaging provided a diagnosis or an arrhythmic substrate in 104 patients (76%), including the presence of an infarct-pattern LGE in 60 patients (44%), noninfarct LGE in 21 (15%), active myocarditis in 14 (10%), hypertrophic cardiomyopathy in 3 (2%), sarcoidosis in 3, and arrhythmogenic cardiomyopathy in 3. In a median follow-up of 29 months (range 18 to 43 months), there were 63 events. In a multivariable analysis, the strongest predictors of recurrent events were the presence of LGE (adjusted hazard ratio: 6.7; 95% CI: 2.38 to 18.85; p < 0.001) and the extent of LGE (hazard ratio: 1.15; 95% CI: 1.11 to 1.19; p < 0.001).
CONCLUSIONS
Among patients with SCA, CMR with contrast identified LGE in 71% and provided a potential arrhythmic substrate in 76%. In follow-up, both the presence and extent of LGE identified a group at markedly increased risk of future adverse events.
doi:10.1016/j.jcmg.2014.11.017
PMCID: PMC4785883  PMID: 25797123
cardiac magnetic resonance; implantable cardioverter-defibrillator; late gadolinium enhancement
23.  High-Risk Coronary Plaque at Coronary CT Angiography Is Associated with Nonalcoholic Fatty Liver Disease, Independent of Coronary Plaque and Stenosis Burden: Results from the ROMICAT II Trial 
Radiology  2014;274(3):693-701.
The presence of nonalcoholic fatty liver disease is associated with high-risk coronary plaque, independent of cardiovascular risk factors, body mass index, and extent and severity of coronary artery disease.
Purpose
To determine the association between nonalcoholic fatty liver disease (NAFLD) and the presence of high-risk coronary atherosclerotic plaque as assessed with coronary computed tomographic (CT) angiography.
Materials and Methods
This study was approved by the local ethics committees; informed consent was obtained. Patients randomized to the coronary CT angiography arm of the Rule Out Myocardial Infarction using Computer Assisted Tomography, or ROMICAT, II trial who underwent both nonenhanced CT to assess calcium score and contrast material–enhanced coronary CT angiography were included. Readers assessed coronary CT angiography images for the presence of coronary plaque, significant stenosis (≥50%), and high-risk plaque features (positive remodeling, CT attenuation < 30 HU, napkin-ring sign, spotty calcium). NAFLD was defined as hepatic steatosis at nonenhanced CT (liver minus spleen CT attenuation < 1 HU) without evidence of clinical liver disease, liver cirrhosis, or alcohol abuse. To determine the association between high-risk plaque and NAFLD, univariable and multivariable logistic regression analyses were performed, with high-risk plaque as a dependent variable and NAFLD, traditional risk factors, and extent of coronary atherosclerosis as independent variables.
Results
Overall, 182 (40.9%) of 445 patients had CT evidence of NAFLD. High-risk plaque was more frequent in patients with NAFLD than in patients without NAFLD (59.3% vs 19.0%, respectively; P < .001). The association between NAFLD and high-risk plaque (odds ratio, 2.13; 95% confidence interval: 1.18, 3.85) persisted after adjusting for the extent and severity of coronary atherosclerosis and traditional risk factors.
Conclusion
NAFLD is associated with advanced high-risk coronary plaque, independent of traditional cardiovascular risk factors and the extent and severity of coronary artery disease.
© RSNA, 2014
doi:10.1148/radiol.14140933
PMCID: PMC4455680  PMID: 25369449
24.  Utility of Coronary Artery Calcium Scanning Beyond Coronary CT Angiography in the Emergency Department Evaluation for Acute Chest Pain: The ROMICAT II Trial 
Background
Whether a coronary artery calcium (CAC) scan provides added value to coronary CT angiography (CCTA) in emergency department (ED) patients with acute chest pain (ACP) remains unsettled. We sought to determine the value of CAC scan in ACP patients undergoing CCTA.
Methods and Results
In the multicenter ROMICAT II trial, we enrolled low-intermediate risk ED patients with symptoms suggesting acute coronary syndrome (ACS). In this pre-specified sub-analysis of 473 patients (54±8years, 53%male) who underwent both CAC scanning and CCTA, the ACS rate was 8%. Overall, 53% of patients had CAC=0 of whom 2 (0.8%) developed ACS, while 7% had CAC>400 with 49% whom developed ACS. C-statistic of CAC>0 was 0.76, while that using the optimal cutpoint of CAC≥22 was 0.81. Continuous CAC score had lower discriminatory capacity than CCTA (c-statistic 0.86 vs. 0.92, p=0.03). Compared to CCTA alone, there was no benefit combining CAC score with CCTA (c-statistic 0.93, p=0.88) or with selective CCTA strategies after initial CAC>0 or optimal cutpoint CAC≥22 (p≥0.09). Mean radiation dose from CAC acquisition was 1.4±0.7mSv. Higher CAC scores resulted in more non-diagnostic CCTA studies though the majority remained interpretable.
Conclusions
In ED patients with ACP, CAC score does not provide incremental value beyond CCTA for ACS diagnosis. CAC=0 does not exclude ACS, nor a high CAC score preclude interpretation of CCTA in most patients. Thus, CAC results should not influence the decision to proceed with CCTA, and the decision to perform a CAC scan should be balanced with the additional radiation exposure required.
Clinical Trial Registration
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01084239.
doi:10.1161/CIRCIMAGING.114.002225
PMCID: PMC4340089  PMID: 25710925
coronary artery calcium; acute coronary syndrome; coronary computed tomography angiography; emergency department
25.  Cross‐Sectional Associations of Computed Tomography (CT)‐Derived Adipose Tissue Density and Adipokines: The Framingham Heart Study 
Background
Excess accumulation of abdominal subcutaneous (SAT) and visceral adipose tissue (VAT) is associated with adverse levels of adipokines and cardiovascular disease risk. Whether fat quality is associated with adipokines has not been firmly established. This study examined the association between abdominal SAT and VAT density, an indirect measure of fat quality, with a panel of metabolic regulatory biomarkers secreted by adipose tissue or the liver independently of absolute fat volumes.
Methods and Results
We evaluated 1829 Framingham Heart Study participants (44.9% women). Abdominal SAT and VAT density was estimated indirectly by adipose tissue attenuation using computed tomography. Adipokines included adiponectin, leptin receptor, leptin, fatty acid‐binding protein 4 (FABP‐4), retinol‐binding protein 4 (RBP‐4), and fetuin‐A. Fat density was associated with all the biomarkers evaluated, except fetuin‐A. Lower fat density (ie, more‐negative fat attenuation) was associated with lower adiponectin and leptin receptor, but higher leptin and FABP‐4 levels (all P<0.0001). SAT density was inversely associated with RPB‐4 in both sexes, whereas the association between VAT density and RPB‐4 was only observed in men (P<0.0001). In women, after additional adjustment for respective fat volume, SAT density retained the significant associations with adiponectin, leptin, FABP‐4, and RBP‐4; and VAT density with adiponectin only (all P<0.0001). In men, significant associations were maintained upon additional adjustment for respective fat volume (P<0.005).
Conclusions
Lower abdominal fat density was associated with a profile of biomarkers suggestive of greater cardiometabolic risk. These observations support that fat density may be a valid biomarker of cardiometabolic risk.
doi:10.1161/JAHA.115.002545
PMCID: PMC4943240  PMID: 26927600
adipokine; adipose tissue; computed tomography; epidemiology; Epidemiology

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