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1.  Design and Rationale of the RE‐DUAL PCI Trial: A Prospective, Randomized, Phase 3b Study Comparing the Safety and Efficacy of Dual Antithrombotic Therapy With Dabigatran Etexilate Versus Warfarin Triple Therapy in Patients With Nonvalvular Atrial Fibrillation Who Have Undergone Percutaneous Coronary Intervention With Stenting 
Clinical Cardiology  2016;39(10):555-564.
Antithrombotic management of patients with atrial fibrillation (AF) undergoing coronary stenting is complicated by the need for anticoagulant therapy for stroke prevention and dual antiplatelet therapy for prevention of stent thrombosis and coronary events. Triple antithrombotic therapy, typically comprising warfarin, aspirin, and clopidogrel, is associated with a high risk of bleeding. A modest‐sized trial of oral anticoagulation with warfarin and clopidogrel without aspirin showed improvements in both bleeding and thrombotic events compared with triple therapy, but large trials are lacking. The RE‐DUAL PCI trial (NCT 02164864) is a phase 3b, a strategy of prospective, randomized, open‐label, blinded‐endpoint trial. The main objective is to evaluate dual antithrombotic therapy with dabigatran etexilate (110 or 150 mg twice daily) and a P2Y12 inhibtor (either clopidogrel or ticagrelor) compared with triple antithrombotic therapy with warfarin, a P2Y12 inhibtor (either clopidogrel or ticagrelor, and low‐dose aspirin (for 1 or 3 months, depending on stent type) in nonvalvular AF patients who have undergone percutaneous coronary intervention with stenting. The primary endpoint is time to first International Society of Thrombosis and Hemostasis major bleeding event or clinically relevant nonmajor bleeding event. Secondary endpoints are the composite of all cause death or thrombotic events (myocardial infarction, or stroke/systemic embolism) and unplanned revascularization; death or thrombotic events; individual outcome events; death, myocardial infarction, or stroke; and unplanned revascularization. A hierarchical procedure for multiple testing will be used. The plan is to randomize ∼ 2500 patients at approximately 550 centers worldwide to try to identify new treatment strategies for this patient population.
PMCID: PMC5108471  PMID: 27565018
Arrhythmia/all; management; Clinical trials; General clinical cardiology; Stroke prevention; Thrombosis/hypercoagulable states; Pharmacology; Anti platelet therapy; Cardiac; catheterization/diagnostic interventional
2.  Association Between Visceral and Subcutaneous Adipose Depots and Incident Cardiovascular Disease Risk Factors 
Circulation  2015;132(17):1639-1647.
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.
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.
PMCID: PMC4779497  PMID: 26294660
Epidemiology; Population; Prevention; Adipose Depots
3.  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.
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.
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.
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.
PMCID: PMC4920364  PMID: 27341207
4.  Renal Artery Stent Outcomes 
Multiple randomized clinical trials comparing renal artery stent placement plus medical therapy with medical therapy alone have not shown any benefit of stent placement. However, debate continues whether patients with extreme pressure gradients, stenosis severity, or baseline blood pressure benefit from stent revascularization.
The study sought to test the hypothesis that pressure gradients, stenosis severity, and/or baseline blood pressure affects outcomes after renal artery stent placement.
Using data from 947 patients with a history of hypertension or chronic kidney disease from the largest randomized trial of renal artery stent placement, the CORAL (Cardiovascular Outcomes in Renal Atherosclerotic Lesions) study, we performed exploratory analyses to determine if subsets of patients experienced better outcomes after stent placement than the overall cohort. We examined baseline stenosis severity, systolic blood pressure, and translesion pressure gradient (peak systolic and mean) and performed interaction tests and Cox proportional hazards analyses for the occurrence of the primary endpoint through all follow-up, to examine the effect of these variables on outcomes by treatment group.
There were no statistically significant differences in outcomes based on the examined variables nor were there any consistent nonsignificant trends.
Based on data from the CORAL randomized trial, there is no evidence of a significant treatment effect of the renal artery stent procedure compared with medical therapy alone based on stenosis severity, level of systolic blood pressure elevation, or according to the magnitude of the transstenotic pressure gradient. (Benefits of Medical Therapy Plus Stenting for Renal Atherosclerotic Lesions [CORAL]; NCT00081731)
PMCID: PMC4819253  PMID: 26653621
chronic kidney disease; hypertension; renal artery; stenosis; stent
5.  Benefits and Risks of Extended Duration Dual Antiplatelet Therapy after PCI in Patients With and Without Acute Myocardial Infarction 
The benefits and risks of prolonged dual antiplatelet therapy may be different for patients with acute myocardial infarction (MI) compared with more stable presentations.
To assess the benefits and risks of 30 versus 12 months of dual antiplatelet therapy among patients undergoing coronary stent implantation following presentation with and without MI.
The DAPT Study was a randomized double-blind, placebo-controlled trial comparing 30 versus 12 months of dual antiplatelet therapy after coronary stenting. The effect of continued thienopyridine on ischemic and bleeding events among patients initially presenting with versus without MI was assessed. The co-primary endpoints were definite or probable stent thrombosis and major adverse cardiovascular and cerebrovascular events (MACCE, a composite of death, myocardial infarction, or stroke). The primary safety endpoint was GUSTO moderate or severe bleeding.
Of 11,648 randomized patients (9961 treated with drug-eluting, 1687 with bare metal stents), 3,576 (30.7%) presented with MI. Between 12 and 30 months, continued thienopyridine reduced stent thrombosis compared with placebo in patients with and without MI at presentation (MI group 0.5% vs. 1.9%, hazard ratio [HR] 0.27, p<0.001; No MI group, 0.4% vs. 1.1%, HR 0.33, p<0.001; interaction p=0.69). The reduction in MACCE for continued thienopyridine was greater for patients with MI (3.9% vs. 6.8%, HR 0.56, p<0.001) compared to those with no MI (4.4% vs. 5.3%, HR 0.83, p=0.08, interaction p=0.03). In both groups, continued thienopyridine reduced MI (2.2% vs. 5.2%, HR 0.42, p<0.001 for MI; 2.1% vs. 3.5%, HR 0.60, p<0.001 for no MI, interaction p=0.15) but increased bleeding (1.9% vs. 0.8%, p=0.005 for MI; 2.6% vs. 1.7%, p=0.007 for no MI; interaction p = 0.21).
Compared with 12 months of therapy, 30 months of dual antiplatelet therapy reduced the risk of stent thrombosis and myocardial infarction in patients with and without MI, and increased bleeding.
PMCID: PMC4678101  PMID: 25787199
Antiplatelet therapy; acute coronary syndromes; myocardial infarction; percutaneous coronary intervention; randomized clinical trial
6.  Lifestyle Factors and Indices of Kidney Function in the Framingham Heart Study 
American journal of nephrology  2015;41(0):267-274.
Background and objectives
Lifestyle characteristics are modifiable factors that could be targeted as part of chronic kidney disease (CKD) prevention. We sought to determine the association of lifestyle characteristics with incident estimated glomerular filtration rate (eGFR)<60mL/min/1.73m2 and rapid eGFR decline in older adults in the United States.
Prospective cohort study of Framingham Offspring participants with baseline eGFR<60mL/min/1.73m2 (n=1802) who attended the seventh (1998–2001; baseline) and eighth (2005–2008; follow-up) examinations (mean age=59years, 54.8% women). Predictors included measures of diet quality, physical activity, alcohol intake, and current smoking status assessed during baseline. Outcomes were based on creatinine-based eGFR at baseline and follow-up and included incident eGFR<60mL/min/1.73m2 (at follow-up) and rapid eGFR decline (annual eGFR decrease≥3mL/min/1.73m2).
Over 6.6 years average follow-up 9.5% (n=171) of participants developed incident eGFR<60. A trend was observed across quartiles of diet quality, with higher levels of diet quality associated with a decreased odds ratio [OR] of incident eGFR<60 (p-trend=0.045). Higher diet quality was associated with decreased odds of rapid eGFR decline (p-trend=0.03) and was attenuated with additional adjustment (p-trend=0.07). In sensitivity analysis for rapid eGFR decline using a secondary definition (annual eGFR decrease≥3 and incident eGFR<60), diet associations remained significant with additional adjustment (p-trend=0.04). No associations were observed with physical activity, smoking status, or alcohol intake with incident eGFR<60 or rapid eGFR decline (all p>0.19).
Higher diet quality may be associated with a decreased risk of incident eGFR<60mL/min/1.73m2, and rapid eGFR decline. Whether adherence to a healthy diet can prevent reduction in kidney function warrants further study.
PMCID: PMC4514559  PMID: 25998023
lifestyle factors; dietary quality; physical activity; smoking; alcohol intake; chronic kidney disease; epidemiology
7.  Hepatic Steatosis is Associated with Lower Levels of Physical Activity Measured via Accelerometry 
Obesity (Silver Spring, Md.)  2015;23(6):1259-1266.
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).
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.
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).
There is an inverse association between PA and hepatic steatosis. Participants who met the national PA guidelines had the lowest prevalence of hepatic steatosis.
PMCID: PMC4446168  PMID: 25959049
8.  Remnant Lipoprotein Cholesterol and Incident Coronary Heart Disease: The Jackson Heart and Framingham Offspring Cohort Studies 
Remnant lipoproteins (RLPs), the triglyceride‐enriched precursors to low‐density lipoprotein, are an emerging risk factor for coronary heart disease (CHD). We sought to determine the association of RLP cholesterol (RLP‐C) levels with incident CHD in 2 diverse, prospective, longitudinal observational US cohorts.
Methods and Results
We analyzed cholesterol levels from serum lipoprotein samples separated via density gradient ultracentrifugation in 4114 US black participants (mean age 53.8 years, 64% women) from the Jackson Heart Study and a random sample of 818 predominantly white participants (mean age 57.3 years, 52% women) from the Framingham Offspring Cohort Study. Multivariable‐adjusted hazard ratios (HRs) for RLP‐C (the sum of very low‐density lipoprotein3 cholesterol and intermediate‐density lipoprotein cholesterol) were derived to estimate associations with incident CHD events consisting of myocardial infarction, CHD death, and revascularizations for each cohort separately and as a combined population. There were 146 CHD events in the combined population. After adjustments for age, sex, body mass index, smoking, blood pressure, diabetes, and lipid‐lowering therapy for the combined population, RLP‐C (HR 1.23 per 1‐SD increase, 95% CI 1.06–1.42, P<0.01) and intermediate‐density lipoprotein cholesterol (HR 1.26 per 1‐SD increase, 95% CI 1.08–1.47, P<0.01) predicted CHD during an 8‐year follow‐up. Associations were attenuated by high‐density lipoprotein cholesterol and ultimately lost significance with inclusion of real low‐density lipoprotein cholesterol, which excludes Lp(a) and IDL cholesterol fractions. Similar associations were seen in multivariable analyses within each cohort.
RLP‐C levels are predictive of incident CHD in this diverse group of primary prevention subjects. Interventions aimed at reducing RLP‐C to prevent CHD warrant further intensive investigation.
Clinical Trial Registration
URL: Unique identifier: NCT00415415.
PMCID: PMC4889167  PMID: 27130348
coronary heart disease; lipids; primary prevention; remnant lipoprotein cholesterol; triglycerides; Risk Factors; Epidemiology; Cardiovascular Disease; Clinical Studies; Lipids and Cholesterol
9.  Adipose Tissue Depots and Their Cross‐Sectional Associations With Circulating Biomarkers of Metabolic Regulation 
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.
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.
PMCID: PMC4889173  PMID: 27146446
adipokines; adipose tissue; biomarkers; epidemiology; obesity; Obesity; Epidemiology
10.  Randomized Controlled Trial of Social Media: Effect of Increased Intensity of the Intervention 
A prior randomized controlled trial of social media exposure at Circulation determined that social media did not increase 30‐day page views. Whether insufficient social media intensity contributed to these results is uncertain.
Methods and Results
Original article manuscripts were randomized to social media exposure compared with no social media exposure (control) at Circulation beginning in January 2015. Social media exposure consisted of Facebook and Twitter posts on the journal's accounts. To increase social media intensity, a larger base of followers was built using advertising and organic growth, and posts were presented in triplicate and boosted on Facebook and retweeted on Twitter. The primary outcome was 30‐day page views. Stopping rules were established at the point that 50% of the manuscripts were randomized and had 30‐day follow‐up to compare groups on 30‐day page views. The trial was stopped for futility on September 26, 2015. Overall, 74 manuscripts were randomized to receive social media exposure, and 78 manuscripts were randomized to the control arm. The intervention and control arms were similar based on article type (P=0.85), geographic location of the corresponding author (P=0.33), and whether the manuscript had an editorial (P=0.80). Median number of 30‐day page views was 499.5 in the social media arm and 450.5 in the control arm; there was no evidence of a treatment effect (P=0.38). There were no statistically significant interactions of treatment by manuscript type (P=0.86), by corresponding author (P=0.35), by trimester of publication date (P=0.34), or by editorial status (P=0.79).
A more intensive social media strategy did not result in increased 30‐day page views of original research.
PMCID: PMC4889182  PMID: 27121850
altmetrics; randomized control trial; social media; Health Services
11.  Digital Connectedness in the Framingham Heart Study 
New avenues of data collection such as eHealth and mobile technology have the potential to revolutionize the way large populations can be assessed and managed outside of standard research and clinical settings.
Methods and Results
A digital connectedness survey was administered within the Framingham Heart Study from 2014 to 2015. The exposure was usage of the Internet, email, cell phones, and smartphones in relation to demographic and cardiovascular disease risk factors; all results were adjusted for age and sex. Among 8096 living study participants, 6503 (80.3%) completed the digital survey. Among survey responders, 5678 (87.4%) reported regular Internet use. Participants reporting regular Internet use were younger (aged 59.1 versus 76.5 years, P<0.0001), were more likely to be employed (70.3% versus 23.7%, P=0.002), and had more favorable cardiovascular disease risk factors than those who did not use the Internet (all P≤0.05). Overall, 5946 (92.1%) responders reported using cell phones. Among cell phone users, 3907 (67.8%) had smartphones. Smartphone users were younger (aged 55.4 versus 68.5 years, P<0.0001), more likely to be employed (81.1% versus 43.9%, P<0.0001) and to have a college education, and less likely to have hypertension (27.9% versus 55.7%, P=0.0002) than those who did not use smartphones.
Digital connectedness varies substantially by age; connected persons tend to be younger and better educated and to have more favorable cardiovascular disease risk factor profiles. Less than two‐thirds of study participants who completed the survey had a smartphone. The generalizability of studies focused on digitally connected persons may have limitations.
PMCID: PMC4859293  PMID: 27076568
cardiovascular risk; eHealth; epidemiology; mHealth; smartphones; technology; Lifestyle; Risk Factors; Primary Prevention
13.  Stenting and Medical Therapy for Atherosclerotic Renal-Artery Stenosis 
Atherosclerotic renal-artery stenosis is a common problem in the elderly. Despite two randomized trials that did not show a benefit of renal-artery stenting with respect to kidney function, the usefulness of stenting for the prevention of major adverse renal and cardiovascular events is uncertain.
We randomly assigned 947 participants who had atherosclerotic renal-artery stenosis and either systolic hypertension while taking two or more antihypertensive drugs or chronic kidney disease to medical therapy plus renal-artery stenting or medical therapy alone. Participants were followed for the occurrence of adverse cardiovascular and renal events (a composite end point of death from cardiovascular or renal causes, myocar-dial infarction, stroke, hospitalization for congestive heart failure, progressive renal insufficiency, or the need for renal-replacement therapy).
Over a median follow-up period of 43 months (interquartile range, 31 to 55), the rate of the primary composite end point did not differ significantly between participants who underwent stenting in addition to receiving medical therapy and those who received medical therapy alone (35.1% and 35.8%, respectively; hazard ratio with stenting, 0.94; 95% confidence interval [CI], 0.76 to 1.17; P = 0.58). There were also no significant differences between the treatment groups in the rates of the individual components of the primary end point or in all-cause mortality. During follow-up, there was a consistent modest difference in systolic blood pressure favoring the stent group (−2.3 mm Hg; 95% CI, −4.4 to −0.2; P = 0.03).
Renal-artery stenting did not confer a significant benefit with respect to the prevention of clinical events when added to comprehensive, multifactorial medical therapy in people with atherosclerotic renal-artery stenosis and hypertension or chronic kidney disease. (Funded by the National Heart, Lung and Blood Institute and others; number, NCT00081731.)
PMCID: PMC4815927  PMID: 24245566
14.  Cross‐Sectional Associations of Computed Tomography (CT)‐Derived Adipose Tissue Density and Adipokines: The Framingham Heart Study 
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).
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.
PMCID: PMC4943240  PMID: 26927600
adipokine; adipose tissue; computed tomography; epidemiology; Epidemiology
15.  Guideline-Based Statin Eligibility, Coronary Artery Calcification, and Cardiovascular Events 
JAMA  2015;314(2):134-141.
The 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for cholesterol management defined new eligibility criteria for statin therapy. However, it is unclear whether this approach improves identification of adults at higher risk of cardiovascular events.
To determine whether the ACC/AHA guidelines improve identification of individuals who develop incident cardiovascular disease (CVD) and/or have coronary artery calcification (CAC) compared with the National Cholesterol Education Program’s 2004 Updated Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III) guidelines.
Longitudinal community-based cohort study, with participants for this investigation drawn from the offspring and third-generation cohorts of the Framingham Heart Study. Participants underwent multidetector computed tomography for CAC between 2002 and 2005 and were followed up for a median of 9.4 years for incident CVD.
Statin eligibility was determined based on Framingham risk factors and low-density lipoprotein thresholds for ATP III, whereas the pooled cohort calculator was used for ACC/AHA.
The primary outcome was incident CVD (myocardial infarction, death due to coronary heart disease [CHD], or ischemic stroke). Secondary outcomes were CHD and CAC (as measured by the Agatston score).
Among 2435 statin-naive participants (mean age, 51.3 [SD, 8.6] years; 56% female), 39% (941/2435) were statin eligible by ACC/AHA compared with 14% (348/2435) by ATP III (P < .001). There were 74 incident CVD events (40 nonfatal myocardial infarctions, 31 nonfatal ischemic strokes, and 3 fatal CHD events). Participants who were statin eligible by ACC/AHA had increased hazard ratios for incident CVD compared with those eligible by ATP III: 6.8 (95% CI, 3.8–11.9) vs 3.1 (95% CI, 1.9–5.0), respectively (P <.001). Similar results were seen for CVD in participants with intermediate Framingham Risk Scores and for CHD. Participants who were newly statin eligible (n = 593 [24%]) had an incident CVD rate of 5.7%, yielding a number needed to treat of 39 to 58. Participants with CAC were more likely to be statin eligible by ACC/AHA than by ATP III: CAC score >0 (n = 1015): 63% vs 23%; CAC score >100 (n = 376): 80% vs 32%; and CAC score >300 (n = 186): 85% vs 34% (all P < .001). A CAC score of 0 identified a low-risk group among ACC/AHA statin-eligible participants (306/941 [33%]) with a CVD rate of 1.6%.
In this community-based primary prevention cohort, the ACC/AHA guidelines for determining statin eligibility, compared with the ATP III, were associated with greater accuracy and efficiency in identifying increased risk of incident CVD and subclinical coronary artery disease, particularly in intermediate-risk participants.
PMCID: PMC4754085  PMID: 26172893
16.  Cardiovascular Event Prediction and Risk Reclassification by Coronary, Aortic, and Valvular Calcification in the Framingham Heart Study 
We determined whether vascular and valvular calcification predicted incident major coronary heart disease, cardiovascular disease (CVD), and all‐cause mortality independent of Framingham risk factors in the community‐based Framingham Heart Study.
Methods and Results
Coronary artery calcium (CAC), thoracic and abdominal aortic calcium, and mitral or aortic valve calcium were measured by cardiac computed tomography in participants free of CVD. Participants were followed for a median of 8 years. Multivariate Cox proportional hazards models were used to determine association of CAC, thoracic and abdominal aortic calcium, and mitral and aortic valve calcium with end points. Improvement in discrimination beyond risk factors was tested via the C‐statistic and net reclassification index. In this cohort of 3486 participants (mean age 50±10 years; 51% female), CAC was most strongly associated with major coronary heart disease, followed by major CVD, and all‐cause mortality independent of Framingham risk factors. Among noncoronary calcifications, mitral valve calcium was associated with major CVD and all‐cause mortality independent of Framingham risk factors and CAC. CAC significantly improved discriminatory value beyond risk factors for coronary heart disease (area under the curve 0.78–0.82; net reclassification index 32%, 95% CI 11–53) but not for CVD. CAC accurately reclassified 85% of the 261 patients who were at intermediate (5–10%) 10‐year risk for coronary heart disease based on Framingham risk factors to either low risk (n=172; no events observed) or high risk (n=53; observed event rate 8%).
CAC improves discrimination and risk reclassification for major coronary heart disease and CVD beyond risk factors in asymptomatic community‐dwelling persons and accurately reclassifies two‐thirds of the intermediate‐risk population.
PMCID: PMC4802453  PMID: 26903006
coronary disease; prognosis; risk factors; Computerized Tomography (CT); Cardiovascular Disease; Prognosis
17.  Association Between Prolactin and Incidence of Cardiovascular Risk Factors in the Framingham Heart Study 
Prolactin is an anterior pituitary hormone that may modulate the adverse effects of obesity. Prolactin has been associated with cardiovascular disease mortality, but less is known about whether prolactin predicts incidence of cardiovascular disease risk factors.
Methods and Results
Our sample (n=3232, mean age 40.4 years, 52.1% women) was drawn from Framingham Heart Study participants who attended 2 examinations an average of 6.1 years apart. After excluding those with elevated prolactin (>30 mg/dL for women, >20 mg/dL for men), multivariable‐adjusted regressions modeled the associations between baseline prolactin and changes in cardiovascular disease risk factors. Models were adjusted for age, sex, baseline value of the risk factor, smoking status, hormone replacement therapy, and menopausal status and additionally for body mass index. Mean prolactin levels were 11.9 mg/dL (SD 5.2) in women and 8.0 mg/dL (SD 2.9) in men. No associations were observed for change in weight, body composition, total cholesterol, triglycerides, or fasting glucose. In women, for example, for each 5‐mg/dL increment in prolactin, odds of incident hypercholesterolemia were 1.06, which was not significant (95% CI 0.91–1.23, P=0.46). Some exceptions were of note. In women, for each 5‐mg/dL increment in prolactin, we observed increased odds of low high‐density lipoprotein cholesterol at follow‐up (odds ratio 1.50, 95% CI 1.18–1.91, P=0.001) that persisted after adjustment for body mass index (P=0.001). In men, a 5‐mg/dL increment in prolactin was associated with increased odds of incident hypertension (odds ratio 1.61, 95% CI 1.18–2.20 P=0.002) and incident diabetes (odds ratio 1.70, 95% CI 1.04–2.78, P=0.03).
Prolactin is not associated with a comprehensive panel of incident cardiovascular disease risk factors. Measurement of circulating prolactin levels in the community likely does not provide substantial insight into cardiometabolic risk.
PMCID: PMC4802489  PMID: 26908403
epidemiology; hormones; obesity; population; Epidemiology; Obesity
18.  Correlation of Patient-reported Symptom Outcomes and Treadmill Test Outcomes after Treatment for Aortoiliac Claudication 
To examine the relationship between objective treadmill test outcomes and subjective symptom outcomes among patients with claudication treated with stent revascularization (ST) compared with supervised exercise (SE).
Materials and Methods
Five scales of the Peripheral Artery Questionnaire and Walking Impairment Questionnaire were correlated with peak walking time and treadmill claudication onset time.
The correlation between change in disease-specific quality of life (QOL) and change in peak walking time differed according to treatment group, with statistically significant correlations for all five scales for the ST group and weaker trends for the SE group, only one of which was statistically significant. In contrast, improvements in disease-specific QOL correlated well with increases in claudication onset time, with no significant interaction with treatment group for any of the five scales.
Disease-specific QOL results at 6 months in the CLEVER (Claudication: Exercise Vs. Endoluminal Revascularization) study show that improved maximal treadmill walking in patients with claudication treated with SE correlated poorly with self-reported symptom relief. Conversely, patients treated with ST showed good correlation between improved maximal treadmill walking and self-reported symptom improvement. The correlation between claudication onset time and self-reported symptom relief was good across treatment groups. This finding indicates that traditional objective treadmill test outcomes may not correlate well with symptom relief in patients with claudication. Future studies should investigate these data and improve understanding of patient relevance of traditional objective treadmill-based treatment outcomes.
PMCID: PMC4724411  PMID: 23906799
19.  Predictors of blood pressure response in the SYMPLICITY HTN-3 trial 
European Heart Journal  2014;36(4):219-227.
The SYMPLICITY HTN-3 randomized, blinded, sham-controlled trial confirmed the safety of renal denervation (RDN), but did not meet its primary efficacy endpoint. Prior RDN studies have demonstrated significant and durable reductions in blood pressure. This analysis investigated factors that may help explain these disparate results.
Methods and results
Patients with resistant hypertension were randomized 2 : 1 to RDN (n = 364) or sham (n = 171). The primary endpoint was the difference in office systolic blood pressure (SBP) change at 6 months. A multivariable analysis identified predictors of SBP change. Additional analyses examined the influence of medication changes, results in selected subgroups and procedural factors. Between randomization and the 6-month endpoint, 39% of patients underwent medication changes. Predictors of office SBP reduction at 6 months were baseline office SBP ≥180 mmHg, aldosterone antagonist use, and non-use of vasodilators; number of ablations was a predictor in the RDN group. Non-African-American patients receiving RDN had a significantly greater change in office SBP than those receiving sham; –15.2 ± 23.5 vs. –8.6 ± 24.8 mmHg, respectively (P = 0.012). Greater reductions in office and ambulatory SBP, and heart rate were observed with a higher number of ablations and energy delivery in a four-quadrant pattern.
Post hoc analyses, although derived from limited patient cohorts, reveal several potential confounding factors that may partially explain the unexpected blood pressure responses in both the sham control and RDN groups. These hypothesis-generating data further inform the design of subsequent research to evaluate the potential role of RDN in the treatment of resistant hypertension.
ClinicalTrials. gov identifier
PMCID: PMC4301597  PMID: 25400162
Renal denervation; Resistant hypertension; SYMPLICITY
20.  Association of high-density lipoprotein subclasses and incident coronary heart disease: The Jackson Heart and Framingham Offspring Cohort Studies 
We aimed to clarify the associations of high-density lipoprotein cholesterol (HDL-C) subclasses with incident coronary heart disease (CHD) in two large primary prevention cohorts.
We measured cholesterol at baseline from the two major HDL subfractions (larger, more buoyant HDL2 and smaller, denser HDL3) separated by density gradient ultracentrifugation in 4114 (mean age 53.8 years; 64% female) African American participants from the Jackson Heart Study and 818 (mean age 57.3 years, 52% female) predominantly Caucasian participants from the Framingham Offspring Cohort Study. Multivariable adjusted hazard ratios (HRs) for HDL-C and its subclasses were derived from Cox proportional hazards regression models to estimate associations with incident CHD events including myocardial infarction, CHD death, and revascularization. Analyses were performed for each cohort separately and as a combined population.
In models adjusted for cardiovascular risk factors for the combined population, HDL3-C (HR 0.76 per SD increase; 95% confidence interval (CI), 0.62–0.94; p = 0.01), rather than HDL2-C (HR 0.88 per SD; 95% CI, 0.72–1.09; p = 0.24) drove the inverse association of HDL-C (HR 0.79 per SD; 95% CI, 0.64–0.98; p = 0.03) with CHD. Similar associations were seen in multivariable analyses within each cohort including after adjusting for apolipoprotein A1 in the Jackson Heart Study.
Smaller, denser HDL3-C levels are primarily responsible for the inverse association between HDL-C and incident CHD in this diverse group of primary prevention subjects. These findings have important implications ranging from considerations of HDL biology to interpretations of clinical trials utilizing HDL-C therapeutics.
PMCID: PMC4312248  PMID: 25062744
High-density lipoprotein cholesterol; coronary heart disease; primary prevention
21.  Cross-Sectional Relations of Arterial Stiffness, Pressure Pulsatility, Wave Reflection and Arterial Calcification 
Arterial hemodynamics and vascular calcification are associated with increased risk for CVD, but their inter-relations remain unclear. We sought to examine the associations of arterial stiffness, pressure pulsatility, and wave reflection with arterial calcification in individuals free of prevalent cardiovascular disease (CVD).
Approach and Results
Framingham Heart Study Third Generation and Offspring Cohort participants free of CVD underwent applanation tonometry to measure arterial stiffness, pressure pulsatility, and wave reflection, including carotid-femoral pulse wave velocity (CFPWV), central pulse pressure (CPP), forward wave amplitude, and augmentation index (AI). Participants in each cohort (n=1905, 45±6 years and n=1015, 65±9 years, respectively) underwent multi-detector computed tomography to assess presence and quantity of thoracic (TAC) and abdominal (AAC) aortic calcification and coronary artery calcification (CAC). In multivariable-adjusted models, both higher CFPWV and CPP were associated with greater TAC and AAC, whereas higher AI was associated with AAC. Among the tonometry measures, CFPWV was the strongest correlate of all calcification measures in multivariable-adjusted models (odds ratio [OR] per SD for TAC 2.69 (95%CI 2.17-3.35), AAC 1.47 (95%CI 1.26-1.73), and CAC 1.48 (95%CI 1.28-1.72), all p<0.001, respectively). We observed stronger relations of CFPWV, CPP, and forward wave amplitude with nearly all continuous calcification measures in the younger Third Generation Cohort as compared with the Offspring Cohort.
In community-dwelling individuals without prevalent CVD, abnormal central arterial hemodynamics were positively associated with vascular calcification, and were observed at younger ages than previously recognized. The mechanisms of these associations may be bidirectional and deserve further study.
PMCID: PMC4199901  PMID: 25169933
Aortic stiffness; pressure pulsatility; wave reflection; hemodynamics; vascular calcification
22.  Metabolic Characterization of Adults with Binge Eating in the General Population: The Framingham Heart Study 
Obesity (Silver Spring, Md.)  2014;22(11):2441-2449.
To describe the metabolic profile of individuals with objective binge eating (OBE) and to evaluate whether associations between OBE and metabolic risk factors are mediated by body mass index (BMI).
Participants from the Framingham Heart Study, Third Generation and Omni 2 cohorts (n = 3551, 53.1% women, mean age 46.4 years) were screened for binge eating. We used multivariable-adjusted regression models to examine the associations of OBE with metabolic risk factors.
The prevalence of OBE was 4.8% in women and 4.9% in men. Compared to non-binge eating, OBE was associated with higher odds of hypertension (OR 1.85, 95% CI 1.32–2.60), hypertriglyceridemia (OR 1.42, 95% CI 1.01–2.01), low HDL (OR 1.70, 95% CI 1.18–2.44), insulin resistance (OR 3.18, 95% CI 2.25–4.50) and metabolic syndrome (OR 2.75, 95% CI 1.94–3.90). Fasting glucose was 7.2 mg/dl higher in those with OBE (p=0.0001). Individuals with OBE had more visceral, subcutaneous and liver fat. Most of these associations were attenuated with adjustment for BMI, with the exception of fasting glucose.
Binge eating is associated with a high burden of metabolic risk factors. Much of the associated risk appears to be mediated by BMI, with the exception of fasting glucose.
PMCID: PMC4224974  PMID: 25136837
Epidemiology; Population; Prevention; Binge Eating; Obesity
23.  Assessing the incremental predictive performance of novel biomarkers over standard predictors 
Statistics in medicine  2014;33(15):2577-2584.
It is unclear to what extent the incremental predictive performance of a novel biomarker is impacted by the method used to control for standard predictors. We investigated whether adding a biomarker to a model with a published risk score overestimates its incremental performance as compared to adding it to a multivariable model with individual predictors (or a composite risk score estimated from the sample of interest), and to a null model. We used 1000 simulated datasets (with a range of risk factor distributions and event rates) to compare these methods, using the continuous Net Reclassification Index (NRI), the Integrated Discrimination Index (IDI), and change in the C-statistic as discrimination metrics. The new biomarker was added to a: null model; model including a published risk score; model including a composite risk score estimated from the sample of interest; and multivariable model with individual predictors. We observed a gradient in the incremental performance of the biomarker, with the null model resulting in the highest predictive performance of the biomarker and the model using individual predictors resulting in the lowest (mean increases in C-statistic between models without and with the biomarker: 0.261, 0.085, 0.030, and 0.031; NRI: 0.767, 0.621, 0.513, and 0.530; IDI: 0.153, 0.093, 0.053 and 0.057, respectively). These findings were supported by Framingham Study data predicting atrial fibrillation using novel biomarkers. We recommend that authors report the effect of a new biomarker after controlling for standard predictors modeled as individual variables.
PMCID: PMC4047140  PMID: 24719270
biomarkers; model discrimination; risk model; risk prediction
24.  Twelve or 30 Months of Dual Antiplatelet Therapy After Drug-eluting Stents 
The New England journal of medicine  2014;371(23):2155-2166.
Dual antiplatelet therapy is recommended after coronary stenting to prevent thrombotic complications, yet the benefits and risks of treatment beyond 1 year are uncertain.
Subjects were enrolled after a drug-eluting coronary stent procedure. After 12 months of thienopyridine (clopidogrel bisulfate [Plavix] or prasugrel [Effient/Efient]) with aspirin, subjects were randomized to continued thienopyridine or placebo for another 18 months; all continued aspirin. The co-primary effectiveness end points were stent thrombosis and major adverse cardiovascular and cerebrovascular events (a composite of death, myocardial infarction, or stroke) at 12 to 30 months. The primary safety end point was moderate or severe bleeding.
Subjects (N=9,961) were randomized to continued thienopyridine or placebo. Continued thienopyridine reduced stent thrombosis (0.4% vs. 1.4%, hazard ratio 0.29, 95% confidence interval [CI] 0.17-0.48, P<0.001) and major adverse cardiovascular and cerebrovascular events (4.3% vs. 5.9%, hazard ratio 0.71, 95% CI 0.59-0.85, P<0.001). Myocardial infarction was reduced (2.1% vs. 4.1%, hazard ratio 0.47, P<0.001). Rates of all-cause mortality in the continued thienopyridine and placebo groups were 2.0 and 1.5%, respectively (hazard ratio 1.36, 95% CI 1.00-1.85, P=0.052). Moderate or severe bleeding was increased with continued thienopyridine (2.5% vs. 1.6%, P=0.001). An elevated hazard for stent thrombosis and myocardial infarction was observed in both groups during the 3 months following thienopyridine discontinuation.
Dual antiplatelet therapy beyond one year after drug-eluting stent placement significantly reduced the risks of stent thrombosis and major adverse cardiovascular and cerebrovascular events compared with aspirin alone, but was associated with increased bleeding.
PMCID: PMC4481318  PMID: 25399658
25.  Antiplatelet Therapy Duration Following Bare Metal or Drug-Eluting Coronary Stents: the Dual Antiplatelet Therapy Randomized Clinical Trial 
JAMA  2015;313(11):1113-1121.
Despite antirestenotic efficacy of coronary drug-eluting stents (DES) compared with bare metal stents (BMS), the relative risk of stent thrombosis and adverse cardiovascular events is unclear. Although dual antiplatelet therapy (DAPT) beyond one year provides ischemic event protection following DES, ischemic event risk is perceived to be less following BMS and the appropriate duration of DAPT following BMS is unknown.
To compare: (1) rates of stent thrombosis and major adverse cardiac and cerebrovascular events (MACCE; composite of death, myocardial infarction, or stroke) after 30 vs. 12 months of thienopyridine in patients treated with BMS taking aspirin; and (2) treatment duration effect within the combined cohorts of randomized DES or BMS-treated patients as prespecified, secondary analyses of the Dual Antiplatelet Therapy Study.
Design, Setting, Participants
International, multicenter, randomized, double-blinded, placebo-controlled trial, comparing extended (30 months) thienopyridine versus placebo in aspirin-treated patients who completed 12 months of DAPT without bleeding or ischemic events post-stenting. Study initiation August 2009 with last follow-up visit May 2014.
Continued thienopyridine or placebo at months 12-30 after stenting, in 11648 randomized patients treated with aspirin, of whom 1687 received BMS and 9961 DES.
Main Outcome and Measures
Stent thrombosis, MACCE, moderate/severe bleeding.
Among 1687 BMS-treated patients randomized to continued thienopyridine vs. placebo, rates of stent thrombosis were 0.5% vs. 1.11%, (N=4 vs. 9, hazard ratio 0.49, 95% CI 0.15-1.64, P=0.24), MACCE 4.04% vs. 4.69%, (N=33 vs. 38, hazard ratio 0.92, 95% CI 0.57-1.47, P=0.72) and moderate/severe bleeding 2.03% vs. 0.90% (N=16 vs. 7, P=0.07), respectively. Among all 11,648 randomized patients (both BMS- and DES-treated), stent thrombosis rates were 0.41% vs. 1.32%, (N=23 vs. 74, hazard ratio 0.31, 95% CI 0.19-0.50, P<0.001), MACCE 4.29% vs. 5.74% (N=244 vs. 323, hazard ratio 0.73, 95% CI 0.62-0.87, P<0.001), and moderate/severe bleeding 2.45% vs. 1.47% (N=135 vs. 80, P<0.001).
Conclusions and Relevance
Among patients undergoing coronary stenting with BMS and who tolerated 12 months of thienopyridine, continuing thienopyridine for an additional 18 months compared with placebo did not result in statistically significant differences in rates of stent thrombosis, MACCE, or moderate/severe bleeding. However, the BMS subset may have been underpowered to identify such differences and further trials are suggested. (DAPT number NCT00977938).
PMCID: PMC4481320  PMID: 25781440

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