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BACKGROUND: Hutchinson-Gilford progeria syndrome (HGPS) is an ultrarare, fatal, premature aging disease caused by a toxic protein called progerin. Circulating progerin has not been previously detected, precluding research using readily available biological samples. This study aimed to develop a plasma progerin assay to evaluate progerin’s quantity, response to progerin-targeted therapy, and relationship to patient survival. METHODS: Biological samples were collected by The Progeria Research Foundation Cell and Tissue Bank from a non-HGPS cohort cross-sectionally and a HGPS cohort longitudinally. HGPS donations occurred at baseline and intermittently while treated with farnesylation inhibitors lonafarnib±pravastatin and zoledronate, within 3 sequential open-label clinical trials at Boston Children’s Hospital totaling >10 years of treatment. An ultrasensitive single-molecule counting progerin immunoassay was developed with prespecified performance parameters. Intra- and interpatient group statistics were descriptive. The relationship between progerin and survival was assessed by using joint modeling with time-dependent slopes parameterization. RESULTS: The assay’s dynamic detection range was 59 to 30 000 pg/mL ( R 2 =0.9987). There was no lamin A cross-reactivity. Mean plasma progerin in non-HGPS participants (n=69; 39 male, 30 female; age, 0.2–71.3 years) was 351±251 pg/mL, and in drug-naive participants with HGPS (n=74; 37 female, 37 male; age, 2.1–17.5 years) was 33 261±12 346 pg/mL, reflecting a 95-fold increase in affected children ( P P =0.99). Lonafarnib treatment resulted in an average per-visit progerin decrease from baseline of between 35% to 62% (all P P CONCLUSIONS: A sensitive, quantitative immunoassay for progerin was developed and used to demonstrate high progerin levels in HGPS plasma that decreased with lonafarnib therapy. The extent of improved survival was associated with both the magnitude of progerin decrease and duration at lower levels. Thus, plasma progerin is a biomarker for HGPS whose reduction enables short- and long-term assessment of progerin-targeted treatment efficacy. REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT00879034 and NCT00916747

Introduction: Fewer than 1/4th of US youth meet physical activity guidelines, leading to physical fitness-related cardiovascular disease disparities tracking into adulthood. Neighborhood opportunity may serve as a critical modifiable factor to reduce youth cardiovascular health-related disparities. The present analysis uses the Child Opportunity Index (COI), a comprehensive measure of children’s neighborhood opportunity, to examine associations between neighborhood context and multiple youth cardiovascular fitness outcomes. Methods: Data were drawn from the NYC FITNESSGRAM (n = 300,000), comprising of fitness data from New York City (NYC) public school youth (grades K-12). Generalized linear mixed models were run to estimate overall and sex-stratified associations between overall COI and individual COI indicators (greenspace, healthy food, walkability, commute time) and youth cardiovascular fitness (body mass index (BMI) percentiles, curl-ups, push-ups, PACER, and sit and reach). Geographically weighted regression (GWR) models explored spatial variation of COI-fitness associations across NYC. Results: Overall COI was associated with improved youth cardiovascular fitness outcomes, with the strongest magnitude of effects across aerobic capacity and muscular strength and endurance measures (PACER: β: 0.15, 95% CI: 0.14, 0.15, curl-ups: β: 0.13, 95% CI: 0.12, 1490.13, and push-ups: β: 0.13, 95% CI: 0.12, 0.13). Greenspace was positively associated with muscular endurance (curl-ups: β: 1.13, 95% CI:0.76, 1.50; push-ups: β: 1.53, 95% CI: 1.21, 1.84), and walkability and commuting time were positively associated with aerobic capacity (PACER: β: 2.11, 95% CI: 1.72, 2.50; β: 2.03, 95% CI: 1.87, 2.19, respectively). Stratified models showed strengthened COI-fitness associations among girls versus boys. GWR models were largely consistent with findings from multilevel models, except for overall COI-BMI associations, which varied in magnitude and direction across regions in NYC. Conclusion: Neighborhood opportunity was associated with multiple measures of youth cardiovascular fitness, though geographic models demonstrate that certain associations vary in magnitude and direction across NYC. Continued research on neighborhood factors and cardiovascular fitness may better inform public health efforts to reduce health disparities modifiable through comprehensive place-based interventions.

Overweight and obesity rates increased dramatically among United States youth from 1999-2016, particularly among adolescents. Promoting physical activity can reduce youth obesity rates, particularly among overweight adolescents, most of whom do not meet guidelines for at least 60 minutes of daily physical activity. Neighborhood public transportation usage is an important environmental factor that has potential to impact adolescent physical activity. We examined the association between neighborhood public transportation usage and adolescent body mass index (BMI) drawing from the Family Life, Activity, Sun, Health, and Eating (FLASHE) study, a cross-sectional national survey conducted in 2014 that assessed cancer preventative behaviors, including physical activity and diet, among adolescents (aged 12-17 years, n=1,737) and their parents. We used linear regression models to test the moderating effects of age, sex, and socioeconomic status and the mediating effect of physical activity on the association between neighborhood public transportation usage and adolescent BMI. The analytic sample included 357 adolescents of middle school (44%) and high school (56%) ages evenly distributed by sex (51% female) with 39% of the sample below 200% of the Federal Poverty Line. On average, adolescents had a BMI percent of the 95 th percentile of 81.77 (17.09) or 22.24 (4.67) BMI and self-reported 71 daily (out-of-school) moderate-to-vigorous activity minutes. While we found no overall association between neighborhood public transportation usage and BMI, we found that low neighborhood public transportation is associated with increased BMI among high school (14% (95% CI 5.72, 21.41)) and male (7.16 (95% CI -13.41, -0.91)) adolescents respectively. We also found that physical activity does not mediate the effect of neighborhood public transportation usage on adolescent BMI. Our findings suggest that our adult reported public transportation measure could be pointing to neighborhood factors, such as poverty or crime, that affect the association between neighborhood public transit and adolescent BMI. Our findings help inform future research on the dynamic relationships between individual and social environmental factors that impact adolescent physical activity.

Supplemental Digital Content is available in the text., Background: To optimize preventive strategies for coronary heart disease (CHD), it is essential to understand and appropriately quantify the contribution of its key risk factors. Our objective was to compare the associations of key modifiable CHD risk factors—specifically lipids, systolic blood pressure (SBP), diabetes mellitus, and smoking—with incident CHD events based on their prognostic performance, attributable risk fractions, and treatment benefits, overall and by age. Methods: Pooled participant-level data from 4 observational cohort studies sponsored by the National Heart, Lung, and Blood Institute were used to create a cohort of 22 626 individuals aged 45 to 84 years who were initially free of cardiovascular disease. Individuals were followed for 10 years from baseline evaluation for incident CHD. Proportional hazards regression was used to estimate metrics of prognostic model performance (likelihood ratio, C index, net reclassification, discrimination slope), hazard ratios, and population attributable fractions for SBP, non–high-density lipoprotein cholesterol (non–HDL-C), diabetes mellitus, and smoking. Expected absolute risk reductions for antihypertensive and lipid-lowering treatment were assessed. Results: Age, sex, and race capture 63% to 80% of the prognostic performance of cardiovascular risk models. In contrast, adding either SBP, non–HDL-C, diabetes mellitus, or smoking to a model with other risk factors increases the C index by only 0.004 to 0.013. However, primordial prevention could have a substantial effect as demonstrated by population attributable fractions of 28% for SBP≥130 mm Hg and 17% for non–HDL-C≥130 mg/dL. Similarly, lowering the SBP of all individuals to

Background: The adult mammalian heart has limited ability to repair itself after injury. Zebrafish, newts, and neonatal mice can regenerate cardiac tissue, largely by cardiac myocyte (CM) proliferation. It is unknown whether hearts of young large mammals can regenerate. Methods: We examined the regenerative capacity of the pig heart in neonatal animals (ages 2, 3, or 14 days postnatal) after myocardial infarction or sham procedure. Myocardial scar and left ventricular function were determined by cardiac magnetic resonance imaging and echocardiography. Bromodeoxyuridine pulse-chase labeling, histology, immunohistochemistry, and Western blotting were performed to study cell proliferation, sarcomere dynamics, and cytokinesis and to quantify myocardial fibrosis. RNA-sequencing was also performed. Results: After myocardial infarction, there was early and sustained recovery of cardiac function and wall thickness in the absence of fibrosis in 2-day-old pigs. In contrast, older animals developed full-thickness myocardial scarring, thinned walls, and did not recover function. Genome-wide analyses of the infarct zone revealed a strong transcriptional signature of fibrosis in 14-day-old animals that was absent in 2-day-old pigs, which instead had enrichment for cytokinesis genes. In regenerating hearts of the younger animals, up to 10% of CMs in the border zone of the myocardial infarction showed evidence of DNA replication that was associated with markers of myocyte division and sarcomere disassembly. Conclusions: Hearts of large mammals have regenerative capacity, likely driven by cardiac myocyte division, but this potential is lost immediately after birth.

Background:Cardiovascular disease (CVD) risk is elevated in HIV-infected individuals, with contributions from both traditional and nontraditional risk factors. The accuracy of established CVD risk prediction functions in HIV is uncertain. We sought to assess the performance of 3 established CVD risk prediction functions in a longitudinal cohort of HIV-infected men.Methods:The FHS (Framingham Heart Study) functions for hard coronary heart disease (FHS CHD) and atherosclerotic CVD (FHS ASCVD) and the American College of Cardiology/American Heart Association ASCVD function were applied to the Partners HIV cohort. Risk scores were calculated between January 1, 2006, and December 31, 2008. Outcomes included CHD (myocardial infarction or coronary death) for the FHS CHD function and ASCVD (myocardial infarction, stroke, or coronary death) for the FHS ASCVD and American College of Cardiology/American Heart Association ASCVD functions. We investigated the accuracy of CVD risk prediction for each function when applied to the HIV cohort using comparison of Cox regression coefficients, discrimination, and calibration.Results:The HIV cohort was comprised of 1272 men followed for a median of 4.4 years. There were 78 (6.1%) ASCVD events; the 5-year incidence rate was 16.4 per 1000 person-years. Discrimination was moderate to poor as indicated by the lowcstatistic (0.68 for FHS CHD, 0.65 for American College of Cardiology/American Heart Association ASCVD, and 0.67 for FHS ASCVD). Observed CVD risk exceeded the predicted risk for each of the functions in most deciles of predicted risk. Calibration, or goodness of fit of the models, was consistently poor, with significant χ2Pvalues for all functions. Recalibration did not significantly improve model fit.Conclusions:Cardiovascular risk prediction functions developed for use in the general population are inaccurate in HIV infection and systematically underestimate risk in a cohort of HIV-infected men. Development of tailored CVD risk prediction functions incorporating traditional CVD risk factors and HIV-specific factors is likely to result in more accurate risk estimation to guide preventative CVD care.

Background: Thienopyridine plus aspirin beyond 1 year after coronary stenting reduces myocardial infarction (MI) risk and increases bleeding risk in comparison with aspirin alone. The hazard associated with late thienopyridine discontinuation and risk factors for MI after discontinuation are poorly defined. Methods: In the DAPT Study (Dual Antiplatelet Therapy), after percutaneous coronary intervention and 12 months of thienopyridine (clopidogrel or prasugrel) plus aspirin, eligible patients remained on aspirin and were randomly assigned to continued thienopyridine versus placebo for 18 months. At 30 months, patients stopped the study drug and were observed for 3 months. Cumulative incidence of MI was assessed over 3 months after randomization (months 12–15) and 3 months after study drug discontinuation (months 30–33). The MI hazard for each of these periods was assessed across randomized treatment arms and by DAPT score values Results: Among the 11 648 randomly assigned patients, the monthly cumulative incidence of MI was lower with continued thienopyridine versus placebo at 12 to 15 months (0.12% versus 0.37%, P P =0.02, in patients not treated with paclitaxel-eluting stents), and higher at 30 to 33 months (0.30% versus 0.15%, P =0.013, in all patients; in patients without paclitaxel-eluting stents, 0.18% versus 0.17%, P =0.91). The majority of MIs in both time periods (74% and 76%) were not related to stent thrombosis. After multivariable adjustment, treatment arm independently predicted MI at months 12 to 15 ( P P =0.011). During months 12 to 15, patients with DAPT scores P P =0.012, for scoresP =0.064). Conclusions: Discontinuing thienopyridine after either 12 or 30 months is associated with an early increase in MI risk, mainly unrelated to stent thrombosis; the magnitude of risk is highest in the earlier time frame, and lower in patients not treated with paclitaxel-eluting stents. Although higher DAPT scores identify patients with greater absolute ischemic benefit (relative to bleeding harm) with continued thienopyridine therapy, discontinuation at 12 months increases MI hazard regardless of DAPT score group. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00977938.

Introduction: Transportation equity ensures that all citizens benefit from a clean, fair, safe and healthy environment. Residential segregation also impacts health, and transportation disadvantage is particularly high in areas with high segregation, where residents typically lack proximity to quality education, jobs, healthy food, safe playgrounds, and medical care. Recent research demonstrates improvements in cardiovascular risk profiles among minority girls after reduced exposure to segregation. There is a need to examine differences in the segregation-youth cardiovascular health association across transportation vulnerability and gender to inform health equity interventions. Hypothesis: It was hypothesized that girls with reduced segregation exposure and low transportation vulnerability would have the most improved cardiovascular health. Methods: Data for these analyses were drawn from the Fit2Play dataset (2010-2018; N=2742). Youth were followed over 4 consecutive years of participation in a year-long afterschool physical activity program. Change in segregation exposure was based on concentration of minorities living in block groups from the participant’s home to program areas using the 2010 Census. Transportation vulnerability was based on percent of households in the participant’s home zip code with vehicle access (0, 1, 2, or ≥3 vehicles) drawn from the American Community Survey (2012-16). Longitudinal mixed models were used to compare the association between change in residential segregation and five cardiovascular health risk measures (body mass index, systolic and diastolic blood pressure, skinfold thickness and 400 meter run tests) stratified by transportation vulnerability and gender. Results: Participants were 54% male, 51% Hispanic, 49% non-Hispanic black, and 52% high poverty (mean age 9.5 years). After accounting for child age, race/ethnicity, poverty, and year, girls with high transportation vulnerability and reduced segregation exposure showed the most reduced cardiovascular health risk profiles, including improvements in body mass index (26%, 95% CI: 23.84, 28.30), skinfold thicknesses (18%, 95% CI: 14.90, 20.46), run time (17%, 95% CI: 14.88, 18.64), systolic blood pressure (15%, 95% CI: 11.96, 17.08), and diastolic blood pressure (12%, 95% CI: 9.09, 14.61). In contrast, no clear patterns emerged for low transportation vulnerable girls, and high or low transportation vulnerable boys. Conclusions: In conclusion, high transportation vulnerable girls exposed to reduced segregation had greater improvements in all cardiovascular health risk outcomes compared with low transportation vulnerable girls, and both high and low transportation vulnerable boys. Transportation equity interventions may provide a means to reduce youth cardiovascular health disparities, particularly for girls living highly segregated areas.

Introduction: Recent research demonstrates that cardiovascular fitness improvements are associated with lower absenteeism, particularly for girls attending schools located in high poverty neighborhoods. Poverty at the student, school, and neighborhood levels may each have unique effects on both cardiovascular fitness and school absenteeism. There is a need to simultaneously explore the effects of poverty measures collected at different levels of observation on the longitudinal fitness-absenteeism relationship and across gender in order to inform policy targeting reduced school absenteeism. Hypothesis: It was hypothesized that poverty measured at the neighborhood level would have the strongest magnitude of effects on the cardiovascular fitness-absenteeism relationship compared with poverty measured at the school and student levels. Methods: Data for this study were drawn from the New York City Fitnessgram dataset. Inclusion criteria were enrollment in a New York City public school for at least 2 consecutive years in grades 6-8 (2006-2013) while attending a school that collected Fitnessgram measurements. Negative binomial longitudinal mixed models with random-intercepts were run to test the association between the exposure, child-specific change in cardiovascular fitness from the year prior, and the outcome, days absent the subsequent year. Separate crude and adjusted models were run stratified by student (individual household), school (percent of students living in poverty or qualifying for free/reduced price school meals) and neighborhood (home- and school-area) poverty measures, and also by gender. Models were adjusted for individual- and group-level confounders (time, grade, race/ethnicity, place of birth, change in obesity status, and school size), and clustering by individual student and school. Results: The sample included 360,743 students (67% black or Hispanic, 51% male, 69% qualifying for free/reduced price school meals). Adjusted estimates showed an inverse-dose response fitness-absenteeism relationship across all poverty measures, with the highest magnitude of effects for youth attending schools in high poverty neighborhoods (IRR= -0.12, 95%CI: -0.20, -0.04 in girls; IRR= -.13, 95%CI: -.29, .03 in boys), and in girls attending schools with a high proportion of students qualifying for free/reduced school meals (IRR= -.11, 95%CI: -.23, -.01). Conclusions: In conclusion, there is an inverse, dose-response trend between cardiovascular fitness and subsequent absenteeism in high poverty youth, regardless of how poverty is measured, and particularly among girls. Future research should examine the potential for distinct youth physical activity interventions tailored to the individual, school and neighborhood levels to reduce school absenteeism associated with poverty.

Background: Hutchinson-Gilford progeria syndrome is an extremely rare, fatal, segmental premature aging syndrome caused by a mutation in LMNA yielding the farnesylated aberrant protein progerin. Without progerin-specific treatment, death occurs at an average age of 14.6 years from an accelerated atherosclerosis. A previous single-arm clinical trial demonstrated that the protein farnesyltransferase inhibitor lonafarnib ameliorates some aspects of cardiovascular and bone disease. This present trial sought to further improve disease by additionally inhibiting progerin prenylation. Methods: Thirty-seven participants with Hutchinson-Gilford progeria syndrome received pravastatin, zoledronic acid, and lonafarnib. This combination therapy was evaluated, in addition to descriptive comparisons with the prior lonafarnib monotherapy trial. Results: No participants withdrew because of side effects. Primary outcome success was predefined by improved per-patient rate of weight gain or carotid artery echodensity; 71.0% of participants succeeded ( P P =0.001) and volumetric ( P P P =0.001) and femoral (0% to 12%; P =0.13) artery plaques and extraskeletal calcifications (34.4% to 65.6%; P =0.006) increased. Other than increased bone mineral density, no improvement rates exceeded those of the prior lonafarnib monotherapy treatment trial. Conclusions: Comparisons with lonafarnib monotherapy treatment reveal additional bone mineral density benefit but likely no added cardiovascular benefit with the addition of pravastatin and zoledronic acid. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifiers: NCT00879034 and NCT00916747.

Introduction: One-fifth to one-third of students in high-poverty, urban school districts do not attend school regularly (missing ≥6 days per year). Health related fitness is shown to be associated with absenteeism, although this relationship may differ across poverty and gender subgroups. Hypothesis: We hypothesized that area poverty would be a stronger effect modifier on the association of fitness (cardiorespiratory, muscular endurance, and muscular strength fitness composite percentile scores) and subsequent absenteeism (one-year lagged days absent) in girls compared with boys. Methods: Six cohorts of New York City public school students were followed from grades 5-8 during 2006/7-2012/13 (n=349,381). Stratified three-level longitudinal generalized linear mixed models were used to test the modification of poverty on the association of fitness changes and one-year lagged child-specific days absent across gender. Results: The fitness-absenteeism association was not significant in boys attending schools in high/very high (p=0.075) or low/mid poverty (p=0.454) areas. In girls attending schools in high/very high poverty areas, greater improvements in fitness the prior year were associated with greater improvements in attendance (p=0.034). Relative to the reference group (>20% decrease in fitness composite percentile scores from the prior year), girls with a large increase in fitness (>20%) demonstrated 10.3% fewer days absent (IRR 95% CI: 0.834, 0.964), followed by those who had a 10-20% increase in fitness (9.2%, IRR 95% CI: 0.835, 0.987), no change (5.4%, IRR 95% CI: 0.887, 1.007) and a 10-20% decrease in fitness (3.8%, IRR 95% CI: 0.885, 1.045). In girls attending schools in low/mid poverty areas, the fitness-attendance relationship was also positive, but no clear trend emerged. Conclusions: Fitness improvements may be more important to attendance improvements in high/very high poverty girls compared with low/mid poverty girls, and both high/very high and low/mid poverty boys. In conclusion, expanding school-based physical activity programs for girls in high-poverty neighborhoods may increase student attendance.

Introduction: Only 18% of high school girls compared with 37% of boys are reported to meet national physical activity guidelines, but much less is known about sex differences in fitness levels during the elementary and middle school years. This study aimed to describe sex differences in longitudinal fitness outcomes after participation in Fit2Play TM , a park-based afterschool health and wellness program targeting high risk youth ages 6-to-14 years old. Hypothesis: It was hypothesized that over time boys would have more improvement in (1) cardiorespiratory fitness via the Progressive Aerobic Cardiovascular Endurance Run (PACER) and 400 meter run test; (2) strength via 1-minute timed push-ups and sit-ups; and (3) flexibility via the sit-and-reach test, versus girls. Methods: Youth who participated in Fit2Play TM for either 1, 2 or 3 school years between 2010-2016 (N=2129, mean age 9.1 years, 52% Hispanic, 48% non-Hispanic black, 54% male) participated in a fitness battery at the beginning and end of the school year(s). Effects of length of Fit2Play TM participation on fitness outcomes were assessed via 3-level repeated measures analysis stratified by sex and adjusted for child sociodemographics, weight category, area poverty, and year. Results: Adjusted models showed significant improvements for both boys and girls in the PACER and 400 meter run tests (pTM . Specifically, from baseline to 1, 2 and 3 years of program participation, girls demonstrated 8% (95% CI: 0.87, 0.97), 14% (95% CI: 0.77, 0.96), and 23% (95% CI: 0.65, 0.92) mean improvement in 400 meter run times versus 9% (95% CI: 0.86, 0.96), 9% (95% CI: 0.82, 1.01), and 17% (95% CI: 0.70, 0.98) for boys, respectively (p Conclusions: Park-based afterschool physical activity programs have the potential to improve fitness performance in all youth, and particularly girls. Future research should further examine sex differences in the effects of park and other community based programs to ultimately reduce sex disparities in youth fitness, particularly in light of the current youth obesity epidemic that continues to challenge our nation.

Background— Many young adults with moderate hyperlipidemia do not meet statin treatment criteria under the new American Heart Association/American College of Cardiology cholesterol guidelines because they focus on 10-year cardiovascular risk. We evaluated the association between years of exposure to hypercholesterolemia in early adulthood and future coronary heart disease (CHD) risk. Methods and Results— We examined Framingham Offspring Cohort data to identify adults without incident cardiovascular disease to 55 years of age (n=1478), and explored the association between duration of moderate hyperlipidemia (non–high-density lipoprotein cholesterol≥160 mg/dL) in early adulthood and subsequent CHD. At median 15-year follow-up, CHD rates were significantly elevated among adults with prolonged hyperlipidemia exposure by 55 years of age: 4.4% for those with no exposure, 8.1% for those with 1 to 10 years of exposure, and 16.5% for those with 11 to 20 years of exposure ( P Conclusions— Cumulative exposure to hyperlipidemia in young adulthood increases the subsequent risk of CHD in a dose-dependent fashion. Adults with prolonged exposure to even moderate elevations in non–high-density lipoprotein cholesterol have elevated risk for future CHD and may benefit from more aggressive primary prevention.

Introduction: Adverse aortic remodeling, such as dilation, is cross-sectionally associated with multiple cardiovascular disease (CVD) risk factors. We sought to determine whether increased, though not necessarily aneurysmal, abdominal aortic diameters augment prediction of incident adverse CVD events above standard CVD risk factors in a community-dwelling cohort. This may be useful since the aorta is often incidentally visualized on computed tomography (CT) body scans performed for indications other than CVD risk stratification. Methods: Participants (N=3318, aged 50±10y, 51% M) from the Framingham Offspring and Third Generation Cohorts who were free of clinical CVD, had complete risk factor profiles (collected at the adjacent cycle exams), and had non-contrast, abdominal multidetector CT scans (MDCT) during 2002-2005 were included in this study. Anteroposterior (AP) and left-right (LR) diameters were measured in the infrarenal (IAA) and lower abdominal (LAA) aorta. The IAA was measured at 5 cm above the aortoiliac bifurcation and the LAA was measured at one slice level (2.5mm) above the bifurcation of the abdominal aorta into the common iliac arteries. For each segment, the greater of AP and LR diameters was used in the analyses. Adverse events comprised CVD death, myocardial infarction, coronary insufficiency, index admission for heart failure, and stroke. For each aortic segment, hazard of an adverse event for enlarged IAA or LAA diameter (enlarged was defined as ≥ upper 90 th percentile diameter for age, sex and BSA) was determined using multivariable (MV) adjusted Cox proportional hazards models. Results: Over a mean 8.8±2.0y of follow-up, there were 149 incident adverse CVD events. In multivariable models adjusted for traditional CVD risk factors, enlarged IAA was associated with greater hazard of an adverse CVD event (HR 1.62; 95% CI 1.07-2.46; p=0.022). However, the association of enlarged LAA with adverse CVD events was borderline (HR 1.56; 95% CI 0.99-2.46; p=0.054). Conclusion: Among community-dwelling adults initially free of clinical CVD, enlarged infrarenal abdominal (IAA) aortic diameter, as determined from noncontrast MDCT scans, augments prediction of incident adverse CVD events above traditional risk factors alone.

Background— Hutchinson-Gilford progeria syndrome is an ultrarare segmental premature aging disease resulting in early death from heart attack or stroke. There is no approved treatment, but starting in 2007, several recent single-arm clinical trials administered inhibitors of protein farnesylation aimed at reducing toxicity of the disease-producing protein progerin. No study assessed whether treatments influence patient survival. The key elements necessary for this analysis are a robust natural history of survival and comparison with a sufficiently large patient population that has been treated for a sufficient time period with disease-targeting medications. Methods and Results— We generated Kaplan–Meier survival analyses for the largest untreated Hutchinson-Gilford progeria syndrome cohort to date. Mean survival was 14.6 years. Comparing survival for treated versus age- and sex-matched untreated cohorts, hazard ratio was 0.13 (95% confidence interval, 0.04–0.37; P Conclusions— This study provides a robust untreated disease survival profile that can be used for comparisons now and in the future to assess changes in survival with treatments for Hutchinson-Gilford progeria syndrome. The current comparisons estimating increased survival with protein farnesylation inhibitors provide the first evidence of treatments influencing survival for this fatal disease. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique Indentifiers: NCT00425607, NCT00879034, and NCT00916747.

Background: Exposure to traffic and ambient air pollution is associated with an increased risk of cardiovascular disease, potentially through atherosclerosis promotion. Few studies have assessed associations of these exposures with thoracic aortic calcium (TAC) or abdominal aortic calcium (AAC), which are correlates of atherosclerosis. Objective: We assessed whether living close to a major road and residential exposure to fine particulate matter (PM 2.5 ) were associated with TAC and AAC in a community-based Northeastern U.S. cohort. Methods: TAC was measured from 2002[[Unable to Display Character: –]]2005 and AAC up to two times (2002[[Unable to Display Character: –]]2005; 2008[[Unable to Display Character: –]]2011) among participants from the Framingham Offspring or Third Generation Cohorts. We first assessed associations of residential distance to a major road and PM 2.5 exposure (2003 annual average from a spatiotemporal model) with detectable aortic calcium. We used logistic regression for TAC and generalized estimating equations (logit link) for AAC. As aortic calcium scores were right-skewed, we next used linear regression models and mixed effects models to assess associations with log-transformed TAC and AAC, respectively, among participants with aortic calcium scores > 0 (95% CIs bootstrapped). We also assessed associations with AAC progression. Models were adjusted for demographic variables, individual and area-level markers of socioeconomic position and time. Results: Among 3518 participants with TAC or AAC measured, 52% had AAC measured twice. Mean age was 55.8 years; 50% female. There were no associations of distance to a major road or PM 2.5 with detectable TAC or AAC, though some estimates were in the opposite direction than expected ( Table ). There were no associations with extent of TAC or AAC ( Table ), or with AAC progression. Conclusions: Proximity to a major road and PM 2.5 were not associated with the presence or extent of aortic calcium, or with AAC progression in this cohort from a region with relatively low PM 2.5 levels. Future work should explore these associations in other populations.

Introduction: Neurotensin is a 13-amino acid peptide whose receptor (SORT1) is strongly linked to cardiovascular disease (CVD) development through several mechanisms, including a role in hepatic low density lipoprotein (LDL) metabolism. We measured concentrations of proneurotensin (PNT; the stable pro-fragment of neurotensin) in subjects from the Framingham Heart Study (FHS) Offspring cohort. Hypothesis: Concentrations of PNT provide incremental information for incident CV events, possibly through interactions with LDL. Methods: Blood samples from 3439 fasting subjects (mean age 59.2 years, 47.1% male) were tested for PNT (Sphingotec, Hennigsdorf, GE). The primary outcome of interest was incident hard CVD (composite of myocardial infarction [MI], stroke, and CV death). Incident hard CHD (MI and CV death) was also examined. Results: Compared to subjects in PNT quartiles 1-3, those in the highest quartile were more likely to be younger and heavier, more likely to smoke (all P Conclusions: Higher concentrations of PNT are associated with a greater risk of incident hard CVD and CHD in the community independent of LDL concentrations and other risk factors.

Cardiovascular diseases (CVD) are the leading cause of mortality and morbidity in Western Countries. Coronary artery disease is the etiology underlying the most prevalent clinical manifestations of CVD. Atherosclerosis is often diagnosed only at late stages, when it manifests in clinically overt forms. Coronary angiography often does not show critical stenoses. We recently showed that the latency of flow mediated dilation (FMD) correlates with the presence of carotid atherosclerosis and the individual cardiovascular risk. Hence, we aimed at evaluating whether the latency of the vasodilator response at the brachial artery could predict the presence of critical coronary stenoses. We evaluated FMD in 74 consecutive patients, before performing coronary angiography for clinical indication at our hospital. Patients were classified in early (ED), late (LD) and no dilators (ND), based on the latency of the vasodilator response. Briefly, ED showed maximal dilation at 60s after ischemic stimulus, and LD over 60s. Very interestingly, lost of early vasodilator response showed a much better diagnostic performance than maximal FMD for the prediction of critical (>70%) coronary stenoses. In fact, classification match of loss of early vasodilator response with coronary angiography was twice as good as with FMD max (72% vs 39%, p=0.002). Using this approach, the number of false negative results was quite low at 4/74 (0.5%), yielding a 89% specificity. Furthermore, ischemia extension - measured by means of the Gensini score - was progressively larger with longer latency (4.5±13.5 in ED, 17.5±27.1 in LD, 39.7±55.0 in ND; p

Background: The Centers for Medicare & Medicaid Services (CMS) recently approved lung cancer screening with CT. It is unclear whether reporting coronary artery calcium (CAC) on lung screening CT could improve identification of adults at risk for cardiovascular events (CVD) and competing risk from lung cancer. Thus we determined the incidence of hard CVD (myocardial infarction, stroke or coronary/cerebrovascular death), lung cancer (diagnosis or death) and CAC in adults eligible and ineligible for lung cancer screening. Methods: This longitudinal community-based cohort study included Framingham Heart Study Offspring Cohort participant-exams age 55-77 and free of prevalent cardiovascular disease and lung cancer from exams 3 (1984 – 1987) and 7 (1998 – 2001). Participants were divided into screening eligible and ineligible groups by CMS criteria (current or recent (≤15 years) former smokers with ≥30 pack-year history). Multivariate-adjusted cox proportional hazards models assessed the effect of screening eligibility on incident hard CVD and incident lung cancer. In participants who had CAC CT at exam 7, cross-sectional association between screening eligibility, high CAC score >300 and incident CVD was assessed. Raw incidence rates are reported; p values are adjusted for age, sex and traditional risk factors aside from smoking. Results: Of 3085 participant-exams 20% were eligible for lung cancer screening. In mean follow up of 9.9 years, there were 281 incident CVD and 69 lung cancer events. In both groups, incident CVD was more frequent than lung cancer (eligible: 13% vs 7%, p=0.002; ineligible: 8% vs 1%, p300 was more common in the screening eligible (33% vs 23%, p=0.007). Conclusion: In a community-based primary prevention cohort, 20% aged 55-77 were eligible for lung cancer screening CT. CMS eligibility criteria identified disease-free persons with substantially more incident hard CVD and CAC; CVD was more common than lung cancer. The results support cardiovascular prevention and reporting of CAC as part of routine lung cancer screening CT.

In this review of cardiovascular risk estimation, we focus on 4 key aspects: (1) The rationale for estimating cardiovascular risk; (2) a comparison of current cardiovascular disease (CVD) risk-estimation systems; (3) an examination of whether there is any evidence that cardiovascular risk estimation improves patient outcomes; and (4) how CVD risk estimation may change in the future. Some of the material presented is derived from a recent general review of cardiovascular risk scores1 that we have used to underpin the present, more focused discussion. The atherosclerosis underlying most CVD is rarely the result of a single risk factor, such as familial hyperlipidemia, but more usually the end result of the combined effect of several risk factors. If one considers single risk factors, even if the evidence for intervention is based on randomized controlled trials, either overtreatment or undertreatment may result. Consider, for example, Table 1, taken from the current Joint European Guidelines on the prevention of CVD in clinical practice.2 Who should receive the statin? The 60-year-old woman with a blood cholesterol level of 8 mmol/L (309 mg/dL) and a 2% 10-year risk of fatal CVD or the man of the same age with a cholesterol level of 5 mmol/L (193 mg/dL) but a 10-fold higher risk because of multiple other risk factors? Current therapeutic trial data do not tell us, but logic would suggest the man, along with, of course, attention to all other factors. View this table: Table 1. Impact of Combinations of Risk Factors on Total CVD Risk These considerations have led the authors of all current guidelines to stress the need to consider the likely impact of all risk factors before making clinical management decisions and, in most cases, to recommend a system of evaluating combined risk factor effects.2–5 To be clinically useful, a CVD …

Background— Cholesteryl ester transfer protein (CETP) inhibitors raise high-density lipoprotein (HDL) cholesterol, but torcetrapib, the first-in-class inhibitor tested in a large outcome trial, caused an unexpected blood pressure elevation and increased cardiovascular events. Whether the hypertensive effect resulted from CETP inhibition or an off-target action of torcetrapib has been debated. We hypothesized that common single-nucleotide polymorphisms in the CETP gene could help distinguish mechanism-based from off-target actions of CETP inhibitors to inform on the validity of CETP as a therapeutic target. Methods and Results— We compared the effect of CETP single-nucleotide polymorphisms and torcetrapib treatment on lipid fractions, blood pressure, and electrolytes in up to 67 687 individuals from genetic studies and 17 911 from randomized trials. CETP single-nucleotide polymorphisms and torcetrapib treatment reduced CETP activity and had a directionally concordant effect on 8 lipid and lipoprotein traits (total, low-density lipoprotein, and HDL cholesterol; HDL2; HDL3; apolipoproteins A-I and B; and triglycerides), with the genetic effect on HDL cholesterol (0.13 mmol/L, 95% confidence interval [CI] 0.11 to 0.14 mmol/L) being consistent with that expected of a 10-mg dose of torcetrapib (0.13 mmol/L, 95% CI 0.10 to 0.15). In trials, 60 mg of torcetrapib elevated systolic and diastolic blood pressure by 4.47 mm Hg (95% CI 4.10 to 4.84 mm Hg) and 2.08 mm Hg (95% CI 1.84 to 2.31 mm Hg), respectively. However, the effect of CETP single-nucleotide polymorphisms on systolic blood pressure (0.16 mm Hg, 95% CI −0.28 to 0.60 mm Hg) and diastolic blood pressure (−0.04 mm Hg, 95% CI −0.36 to 0.28 mm Hg) was null and significantly different from that expected of 10 mg of torcetrapib. Conclusions— Discordance in the effects of CETP single-nucleotide polymorphisms and torcetrapib treatment on blood pressure despite the concordant effects on lipids indicates the hypertensive action of torcetrapib is unlikely to be due to CETP inhibition or shared by chemically dissimilar CETP inhibitors. Genetic studies could find a place in drug-development programs as a new source of randomized evidence for drug-target validation in humans.

Background— We evaluated the progression of the metabolic syndrome (MetS) and its components, the trajectories followed by individuals entering MetS, and the manner in which different trajectories predict cardiovascular disease and mortality. Methods and Results— Using data from 3078 participants from the Framingham Offspring Study (a cohort study) who attended examinations 4 (1987), 5 (1991), and 6 (1995), we evaluated the progression of MetS and its components. MetS was defined according to the Adult Treatment Panel III criteria. Using logistic regression, we evaluated the predictive ability of the presence of each component of the MetS on the subsequent development of MetS. Additionally, we examined the probability of developing cardiovascular disease or mortality (until 2007) by having specific combinations of 3 that diagnose MetS. The prevalence of MetS almost doubled in 10 years of follow-up. Hyperglycemia and central obesity experienced the highest increase. High blood pressure was most frequently present when a diagnosis of MetS occurred (77.3%), and the presence of central obesity conferred the highest risk of developing MetS (odds ratio, 4.75; 95% confidence interval, 3.78 to 5.98). Participants who entered the MetS having a combination of central obesity, high blood pressure, and hyperglycemia had a 2.36-fold (hazard ratio, 2.36; 95% confidence interval, 1.54 to 3.61) increase of incident cardiovascular events and a 3-fold (hazard ratio, 3.09, 95% confidence interval, 1.93 to 4.94) increased risk of mortality. Conclusions— Particular trajectories and combinations of factors on entering the MetS confer higher risks of incident cardiovascular disease and mortality in the general population and among those with MetS. Intense efforts are required to identify populations with these particular combinations and to provide them with adequate treatment at early stages of disease.

Background— Present cardiovascular disease (CVD) risk prediction algorithms were developed for a ≤10-year follow up period. Clustering of risk factors at younger ages and increasing life expectancy suggest the need for longer-term risk prediction tools. Methods and Results— We prospectively followed 4506 participants (2333 women) of the Framingham Offspring cohort aged 20 to 59 years and free of CVD and cancer at baseline examination in 1971–1974 for the development of “hard” CVD events (coronary death, myocardial infarction, stroke). We used a modified Cox model that allows adjustment for competing risk of noncardiovascular death to construct a prediction algorithm for 30-year risk of hard CVD. Cross-validated survival C statistic and calibration χ 2 were used to assess model performance. The 30-year hard CVD event rates adjusted for the competing risk of death were 7.6% for women and 18.3% for men. Standard risk factors (male sex, systolic blood pressure, antihypertensive treatment, total and high-density lipoprotein cholesterol, smoking, and diabetes mellitus), measured at baseline, were significantly related to the incidence of hard CVD and remained significant when updated regularly on follow-up. Body mass index was associated positively with 30-year risk of hard CVD only in models that did not update risk factors. Model performance was excellent as indicated by cross-validated discrimination C=0.803 and calibration χ 2 =4.25 ( P =0.894). In contrast, 30-year risk predictions based on different applications of 10-year functions proved inadequate. Conclusions— Standard risk factors remain strong predictors of hard CVD over extended follow-up. Thirty-year risk prediction functions offer additional risk burden information that complements that of 10-year functions.

Background— Pericardial fat has been implicated in the pathogenesis of obesity-related cardiovascular disease. Whether the associations of pericardial fat and measures of cardiac structure and function are independent of the systemic effects of obesity and visceral adiposity has not been fully explored. Methods and Results— Participants from the Framingham Heart Study (n=997; 54.4% women) underwent chest and abdominal computed tomography and cardiovascular magnetic resonance imaging between 2002 and 2005. Pericardial fat, intrathoracic fat, and visceral adipose tissue quantified from multidetector computed tomography, along with body mass index and waist circumference, were examined in relation to cardiovascular magnetic resonance measures of left ventricular (LV) mass, LV end-diastolic volume, and left atrial dimension. In women, pericardial fat ( r =0.20 to 0.35, P r =0.25 to 0.37, P r =0.24 to 0.45, P r =0.36 to 0.53, P r =0.30 to 0.48, P r =0.19 to 0.37, P r =0.17 to 0.31, P r =0.19 to 0.36, P r =0.32 to 0.44, P r =0.34 to 0.44, P Conclusions— Pericardial fat is correlated with cardiovascular magnetic resonance measures, but the association is not independent of or stronger than other ectopic fat stores or proxy measures of visceral adiposity. An important exception is left atrial dimension in men. These results suggest that the systemic effects of obesity on cardiac structure and function may outweigh the local pathogenic effects of pericardial fat.

Background— Although mortality after myocardial infarction (MI) has declined in the United States in recent decades, there have been few community-based investigations of the long-term trends in the incidence of heart failure after MI, and their results appear to be conflicting. Methods and Results— We evaluated 676 Framingham Heart Study participants between 45 and 85 years of age (mean age 67 years, 34% women) who developed a first MI between 1970 and 1999. We assessed the incidence rates of heart failure and of death without heart failure in each of 3 decades (1970 to 1979, 1980 to 1989, and 1990 to 1999). We estimated the multivariable-adjusted risk of events in the latter 2 decades, with the period 1970 to 1979 serving as the referent. The 30-day incidence of heart failure after MI rose from 10% in 1970 to 1979 to 23.1% in 1990 to 1999 ( P for trend 0.003), whereas 30-day mortality after MI declined from 12.2% (1970 to 1979) to 4.1% (1990 to 1999). The 5-year incidence of heart failure after MI rose from 27.6% in 1970 to 1979 to 31.9% in 1990 to 1999 ( P for trend 0.02), whereas 5-year mortality after MI declined from 41.1% (1970 to 1979) to 17.3% (1990 to 1999). In multivariable analyses, compared with the period 1970 to 1979, we observed higher 30-day (risk ratio 2.05, 95% confidence interval 1.25 to 3.36) and 5-year (risk ratio 1.74, 95% confidence interval 1.07 to 2.84) risks of heart failure in the decade 1990 to 1999. These trends were accompanied by lower 30-day (risk ratio 0.21, 95% confidence interval 0.09 to 0.47) and 5-year (risk ratio 0.31, 95% confidence interval 0.18 to 0.54) mortality rates in 1990 to 1999. Conclusions— In the present community-based sample, we observed an increase in the incidence of heart failure in recent decades that paralleled the decrease in mortality after MI.

Background— Preservation of renal function is an important objective of renal artery stent procedures. Although atheroembolization can cause renal dysfunction during renal stent procedures, whether adjunctive use of embolic protection devices or glycoprotein IIb/IIIa inhibitors improves renal function is unknown. Methods and Results— One hundred patients undergoing renal artery stenting at 7 centers were randomly assigned to an open-label embolic protection device, Angioguard, or double-blind use of a platelet glycoprotein IIb/IIIa inhibitor, abciximab, in a 2×2 factorial design. The main effects of treatments and their interaction were assessed on percentage change in Modification in Diet in Renal Disease–derived glomerular filtration rate from baseline to 1 month using centrally analyzed creatinine. Filter devices were analyzed for the presence of platelet-rich thrombus. With stenting alone, stenting and embolic protection, and stenting with abciximab alone, glomerular filtration rate declined ( P P P P =0.08). An interaction was observed between abciximab and embolic protection ( P P Conclusions— Renal artery stenting alone, stenting with embolic protection, and stenting with abciximab were associated with a decline in glomerular filtration rate. An unanticipated interaction between Angioguard and abciximab was seen, with combination therapy better than no treatment or either treatment alone.

Background— Measurement of carotid intima-media thickness (CIMT) has been validated as a measure of atherosclerosis and as a predictor of future cardiovascular events. Compared with glimepiride, pioglitazone has been shown to slow the progression of atherosclerosis measured by CIMT in patients with type 2 diabetes mellitus. Methods and Results— We evaluated individual cardiovascular risk factors as predictors of the change in CIMT produced by pioglitazone treatment by determining whether their addition to a baseline model resulted in loss of significance for the treatment effect on CIMT. Pioglitazone treatment led to improvement in levels of multiple cardiovascular risk markers, including high-sensitivity C-reactive protein, apolipoprotein B, apolipoprotein A1, high-density lipoprotein (HDL) cholesterol, triglyceride, insulin, and free fatty acid. At 24 weeks, there were significant differences in HDL cholesterol, triglyceride, total cholesterol, low-density lipoprotein cholesterol, insulin, body mass index, hip circumference, and high-sensitivity C-reactive protein between the pioglitazone and glimepiride treatment groups. After adjustment for 24-week on-treatment values of cardiovascular risk factors, only inclusion of the changes in HDL cholesterol and insulin significantly impacted the magnitude and significance of the treatment effect on CIMT. Furthermore, irrespective of treatment assignment, increased HDL cholesterol at 24 weeks was a significant predictor of reduced CIMT progression at 72 weeks. Conclusions— The beneficial effect of pioglitazone on HDL cholesterol at 24 weeks predicted its beneficial effect for reducing CIMT progression at 72 weeks. Changes in HDL cholesterol at 24 weeks, irrespective of treatment, predicted less progression of CIMT at 72 weeks. These results suggest that suppression of atherosclerosis with pioglitazone therapy is linked to its ability to raise HDL cholesterol.

Background— Vitamin D receptors have a broad tissue distribution that includes vascular smooth muscle, endothelium, and cardiomyocytes. A growing body of evidence suggests that vitamin D deficiency may adversely affect the cardiovascular system, but data from longitudinal studies are lacking. Methods and Results— We studied 1739 Framingham Offspring Study participants (mean age 59 years; 55% women; all white) without prior cardiovascular disease. Vitamin D status was assessed by measuring 25-dihydroxyvitamin D (25-OH D) levels. Prespecified thresholds were used to characterize varying degrees of 25-OH D deficiency (P =0.01) for incident cardiovascular events compared with those with 25-OH D ≥15 ng/mL. This effect was evident in participants with hypertension (hazard ratio 2.13, 95% confidence interval 1.30 to 3.48) but not in those without hypertension (hazard ratio 1.04, 95% confidence interval 0.55 to 1.96). There was a graded increase in cardiovascular risk across categories of 25-OH D, with multivariable-adjusted hazard ratios of 1.53 (95% confidence interval 1.00 to 2.36) for levels 10 to P for linear trend=0.01). Further adjustment for C-reactive protein, physical activity, or vitamin use did not affect the findings. Conclusions— Vitamin D deficiency is associated with incident cardiovascular disease. Further clinical and experimental studies may be warranted to determine whether correction of vitamin D deficiency could contribute to the prevention of cardiovascular disease.

Background— The metabolic syndrome (MetS) is associated with increased cardiovascular risk. We evaluated the relative contributions of circulating biomarkers representing distinct biological pathways to the incidence of MetS and to longitudinal changes of its constituent risk factors. Methods and Results— We measured 8 circulating biomarkers reflecting inflammation (C-reactive protein), hemostasis (plasminogen activator inhibitor-1, fibrinogen), neurohormonal activity (aldosterone, renin, B-type natriuretic peptide, N-terminal proatrial natriuretic peptide), and endothelial dysfunction (homocysteine) in 2292 Framingham Offspring Study participants (mean age, 57 years; 56% women). We related the biomarker panel to incidence of MetS on follow-up initially and then related biomarkers associated with incident MetS to longitudinal change in its components. On follow-up (mean, 2.9 years), 282 participants (of 1473 participants without prevalent MetS at baseline) developed MetS. After adjustment for clinical risk factors, the biomarker panel was associated with incident MetS ( P =0.008). On backward elimination, plasminogen activator inhibitor-1 and aldosterone remained associated with incident MetS (multivariable-adjusted odds ratio per 1-SD increment log marker, 1.31 [ P =0.004] and 1.21 [ P =0.015], respectively). In multivariable analyses evaluating longitudinal change in MetS components (analyzed as continuous variables), plasminogen activator inhibitor-1 was significantly and positively associated with changes in fasting glucose, systolic blood pressure, and triglycerides (all P P =0.023) and inversely with change in high-density lipoprotein cholesterol ( P =0.001). Conclusions— Higher circulating plasminogen activator inhibitor-1 and aldosterone levels are associated with the development of MetS and with longitudinal change of its components, suggesting that these biomarkers and related pathways play a key role in mediating metabolic risk.

Background— The burden and prognostic importance of subclinical cardiovascular disease (CVD) in obesity has not been investigated systematically. Methods and Results— We examined prevalence of subclinical disease in 1938 Framingham Study participants (mean age, 57 years; 59% women) by use of 5 tests (electrocardiography, echocardiography, carotid ultrasound, ankle-brachial pressure, and urinary albumin excretion) and stratified by body mass index (BMI) (normal, 2 ) and waist circumference (WC) (increased, ≥88 cm for women or ≥102 cm for men). We investigated risk of overt CVD associated with adiposity according to presence versus absence of subclinical disease on any of the 5 tests. Prevalence of subclinical disease was higher in overweight (40.0%; adjusted odds ratio, 1.68) and obese individuals (49.7%; odds ratio, 2.82) compared with individuals with normal BMI (29.3%) and in individuals with increased WC (44.9%; odds ratio, 1.67) compared with normal WC (31.9%). On follow-up (mean 7.2 years), 139 participants had developed overt CVD. Presence of subclinical disease was associated with >2-fold risk of overt CVD in all BMI and WC strata, with no evidence of an interaction between BMI and subclinical disease. CVD risk was attenuated in participants with obesity or increased WC but without subclinical disease (adjusted hazard ratio for obesity, 1.57; 95% confidence interval, 0.74 to 3.33; adjusted hazard ratio for increased WC, 1.22; 95% confidence interval, 0.69 to 2.15), compared with individuals with normal BMI or WC and no subclinical disease, respectively. Conclusions— In our community-based sample, overweight and obesity were associated with high prevalence of subclinical disease, which partly contributed to the increased risk of overt CVD in these strata.

We thank Dr Hayward for his interest in our article.1 First, we note that our study was not intended to negate a risk-based approach to statin therapy. In fact, some of us have pioneered and led multiple efforts in the development of risk prediction algorithms.2 Our finding that cumulative exposure to elevated non–high-density lipoprotein cholesterol increases coronary heart disease risk highlights that both cardiovascular disease risk and cardiovascular disease risk factor exposures should be considered over >10-year windows. In other words, duration of exposure to a risk factor, in this case hyperlipidemia, is important and should be used in part to identify those who may benefit from statin therapy and those who may be identified by current risk-based algorithms. Dr Hayward notes that our …