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Background: The extent to which adult height, a biomarker of the interplay of genetic endowment and early-life experiences, is related to risk of chronic diseases in adulthood is uncertain. Methods: We calculated hazard ratios (HRs) for height, assessed in increments of 6.5 cm, using individual-participant data on 174 374 deaths or major non-fatal vascular outcomes recorded among 1 085 949 people in 121 prospective studies. Results: For people born between 1900 and 1960, mean adult height increased 0.5-1 cm with each successive decade of birth. After adjustment for age, sex, smoking and year of birth, HRs per 6.5 cm greater height were 0.97 (95% confidence interval: 0.96-0.99) for death from any cause, 0.94 (0.93-0.96) for death from vascular causes, 1.04 (1.03-1.06) for death from cancer and 0.92 (0.90-0.94) for death from other causes. Height was negatively associated with death from coronary disease, stroke subtypes, heart failure, stomach and oral cancers, chronic obstructive pulmonary disease, mental disorders, liver disease and external causes. In contrast, height was positively associated with death from ruptured aortic aneurysm, pulmonary embolism, melanoma and cancers of the pancreas, endocrine and nervous systems, ovary, breast, prostate, colorectum, blood and lung. HRs per 6.5 cm greater height ranged from 1.26 (1.12-1.42) for risk of melanoma death to 0.84 (0.80-0.89) for risk of death from chronic obstructive pulmonary disease. HRs were not appreciably altered after further adjustment for adiposity, blood pressure, lipids, inflammation biomarkers, diabetes mellitus, alcohol consumption or socio-economic indicators. Conclusion: Adult height has directionally opposing relationships with risk of death from several different major causes of chronic diseases. Published by Oxford University Press on behalf of the International Epidemiological Association © The Author 2012; all rights reserved.

Objective Multiple studies have identified single-nucleotide polymorphisms (SNPs) that are associated with coronary heart disease (CHD). We examined whether SNPs selected based on predefined criteria will improve CHD risk prediction when added to traditional risk factors (TRFs). Methods SNPs were selected from the literature based on association with CHD, lack of association with a known CHD risk factor, and successful replication. A genetic risk score (GRS) was constructed based on these SNPs. Cox proportional hazards model was used to calculate CHD risk based on the Atherosclerosis Risk in Communities (ARIC) and Framingham CHD risk scores with and without the GRS. Results The GRS was associated with risk for CHD (hazard ratio [HR] = 1.10; 95% confidence interval [CI]: 1.07–1.13). Addition of the GRS to the ARIC risk score significantly improved discrimination, reclassification, and calibration beyond that afforded by TRFs alone in non-Hispanic whites in the ARIC study. The area under the receiver operating characteristic curve (AUC) increased from 0.742 to 0.749 ( Δ = 0.007; 95% CI, 0.004–0.013), and the net reclassification index (NRI) was 6.3%. Although the risk estimates for CHD in the Framingham Offspring (HR = 1.12; 95% CI: 1.10–1.14) and Rotterdam (HR = 1.08; 95% CI: 1.02–1.14) Studies were significantly improved by adding the GRS to TRFs, improvements in AUC and NRI were modest. Conclusion Addition of a GRS based on direct associations with CHD to TRFs significantly improved discrimination and reclassification in white participants of the ARIC Study, with no significant improvement in the Rotterdam and Framingham Offspring Studies.

The aim of the study was to evaluate whether knowledge of the circulating concentration of growth differentiation factor 15 (GDF-15) adds predictive information to the Global Registry of Acute Coronary Events (GRACE) score, a validated scoring system for risk assessment in non-ST-elevation acute coronary syndrome (NSTE-ACS). We also evaluated whether GDF-15 adds predictive information to a model containing the GRACE score and N-terminal pro-B-type natriuretic peptide (NT-proBNP), a prognostic biomarker already in clinical use.The GRACE score, GDF-15, and NT-proBNP levels were determined on admission in 1122 contemporary patients with NSTE-ACS. Six-month all-cause mortality or non-fatal myocardial infarction (MI) was the primary endpoint of the study. To obtain GDF-15- and NT-proBNP-adjusted 6-month estimated probabilities of death or non-fatal MI, statistical algorithms were developed in a derivation cohort (n = 754; n = 66 reached the primary endpoint) and applied to a validation cohort (n = 368; n = 33). Adjustment of the GRACE risk estimate by GDF-15 increased the area under the receiver-operating characteristic curve (AUC) from 0.79 to 0.85 (P0.001) in the validation cohort. Discrimination improvement was confirmed by an integrated discrimination improvement (IDI) of 0.055 (P = 0.005). A net 31% of the patients without events were reclassified into lower risk, and a net 27% of the patients with events were reclassified into higher risk, resulting in a total continuous net reclassification improvement [NRI(0)] of 0.58 (P = 0.002). Addition of NT-proBNP to the GRACE score led to a similar improvement in discrimination and reclassification. Addition of GDF-15 to a model containing GRACE and NT-proBNP led to a further improvement in model performance [increase in AUC from 0.84 for GRACE plus NT-proBNP to 0.86 for GRACE plus NT-proBNP plus GDF-15, P = 0.010; IDI = 0.024, P = 0.063; NRI(0) = 0.42, P = 0.022].We show that a single measurement of GDF-15 on admission markedly enhances the predictive value of the GRACE score and provides moderate incremental information to a model including the GRACE score and NT-proBNP. Our study is the first to provide simple algorithms that can be used by the practicing clinician to more precisely estimate risk in individual patients based on the GRACE score and a single biomarker measurement on admission. The rigorous statistical approach taken in the present study may serve as a blueprint for future studies exploring the added value of biomarkers beyond clinical risk scores.

Net reclassification and integrated discrimination improvements have been proposed as alternatives to the increase in the area under the curve for evaluating improvement in the performance of risk assessment algorithms introduced by the addition of new phenotypic or genetic markers. In this paper, we demonstrate that in the setting of linear discriminant analysis, under the assumptions of multivariate normality, all three measures can be presented as functions of the squared Mahalanobis distance. This relationship affords an interpretation of the magnitude of these measures in the familiar language of effect size for uncorrelated variables. Furthermore, it allows us to conclude that net reclassification improvement can be viewed as a universal measure of effect size. Our theoretical developments are illustrated with an example based on the Framingham Heart Study risk assessment model for high-risk men in primary prevention of cardiovascular disease.

Background— Impaired vasodilator function is an early manifestation of coronary artery disease and may precede angiographic stenosis. It is unknown whether noninvasive assessment of coronary vasodilator function in patients with suspected or known coronary artery disease carries incremental prognostic significance. Methods and Results— A total of 2783 consecutive patients referred for rest/stress positron emission tomography were followed up for a median of 1.4 years (interquartile range, 0.7–3.2 years). The extent and severity of perfusion abnormalities were quantified by visual evaluation of myocardial perfusion images. Rest and stress myocardial blood flows were calculated with factor analysis and a 2-compartment kinetic model and were used to compute coronary flow reserve (coronary flow reserve equals stress divided by rest myocardial blood flow). The primary end point was cardiac death. Overall 3-year cardiac mortality was 8.0%. The lowest tertile of coronary flow reserve (P P =0.02) and in a net reclassification improvement of 0.098 (95% confidence interval, 0.025–0.180). Addition of coronary flow reserve resulted in correct reclassification of 34.8% of intermediate-risk patients (net reclassification improvement=0.487; 95% confidence interval, 0.262–0.731). Corresponding improvements in risk assessment for mortality from any cause were also demonstrated. Conclusion— Noninvasive quantitative assessment of coronary vasodilator function with positron emission tomography is a powerful, independent predictor of cardiac mortality in patients with known or suspected coronary artery disease and provides meaningful incremental risk stratification over clinical and gated myocardial perfusion imaging variables.

Background and Purpose— Carotid artery intima-media thickness (IMT) is a marker of cardiovascular disease associated with incident stroke. We studied whether IMT rate of change is associated with stroke. Methods— We studied 5028 participants of the Multi-Ethnic Study of Atherosclerosis (MESA) comprising white, Chinese, Hispanic, and black participants free of cardiovascular disease. In this MESA IMT progression study, IMT rate of change (mm/year) was the difference in right common carotid artery far wall IMT (mm) divided by the interval between 2 ultrasound examinations (median interval, 32 months). Common carotid artery IMT was measured in a region free of plaque. Cardiovascular risk factors and baseline IMT were determined when IMT rate of change was measured. Multivariable Cox proportional hazards models generated hazard risk ratios (HR) with cardiovascular risk factors, ethnicity, and education level/income as predictors. Results— There were 42 first-time strokes seen during a mean follow-up of 3.22 years (median, 3.0 years). Average age was 64.2 years, with 48% males. In multivariable models, age (HR, 1.05 per year), systolic blood pressure (HR, 1.02 per mm Hg), lower high-density lipoprotein cholesterol levels (HR, 0.96 per mg/dL), and IMT rate of change (HR, 1.23 per 0.05 mm/year; 95% confidence limit, 1.02–1.48) were significantly associated with incident stroke. The upper quartile of IMT rate of change had HR of 2.18 (95% confidence limit, 1.07–4.46) compared to the lower 3 quartiles combined. Conclusions— Common carotid artery IMT progression is associated with incident stroke in this cohort free of prevalent cardiovascular disease and atrial fibrillation at baseline.

Background Emergency surgery has become an increasingly rare event after percutaneous coronary intervention (PCI). There have been no randomized trials evaluating whether cardiac surgery services on-site are essential for patient safety and optimal outcomes during and after PCI. Study Design The MASS COMM trial (ClinicalTrials.gov no. NCT01116882 ) is a randomized trial comparing the safety and effectiveness of nonemergency PCI at hospitals without surgery on-site (SOS) (non-SOS hospitals) and hospitals with SOS (SOS hospitals). A total of 3,690 subjects will be randomized in a 3:1 fashion to undergo PCI at non-SOS and SOS hospitals, with follow-up at hospital discharge, 30 days, and 12 months after PCI. The rate of major adverse cardiac events (all-cause mortality, myocardial infarction, repeat revascularization, and stroke) will serve as the primary safety end point at 30 days and the primary effectiveness end point at 12 months. The design is a 1-way randomized trial with a statistical hypothesis of noninferiority of nonemergency PCI at non-SOS hospitals for both safety and effectiveness end points. Conclusions This multicenter, randomized trial will compare the relative safety and effectiveness of nonemergency PCI at sites with and without cardiac SOS.

OBJECTIVE The association between total testosterone and metabolic syndrome has prompted speculation that low testosterone contributes to the pathophysiology of metabolic syndrome in men. We determined whether testosterone or sex hormone–binding globulin (SHBG) is independently associated with the risk of metabolic syndrome. RESEARCH DESIGN AND METHODS Cross-sectional relationships of hormone levels with metabolic syndrome were assessed in a sample of men in generation 2 of the Framingham Heart Study (FHS) who did not receive testosterone or androgen-deprivation therapy (n = 1,625) and confirmed in a validation sample of men in FHS generation 3 (n = 1,912). Hormone levels in generation 2 examination 7 were related prospectively to incident metabolic syndrome 6.6 years later at examination 8. Testosterone was measured using liquid chromatography–tandem mass spectrometry, SHBG was measured by immunofluorometric assay, and free testosterone was calculated. Metabolic syndrome was defined using the National Cholesterol Education Program Adult Treatment Panel III criteria. RESULTS Cross-sectionally, testosterone and SHBG were more strongly associated with metabolic syndrome than free testosterone in the training sample. SHBG, but not testosterone or free testosterone, was significantly associated with metabolic syndrome after adjusting for age, smoking, BMI, and insulin sensitivity (homeostasis model assessment of insulin resistance [HOMA-IR]). These findings were confirmed in a validation sample. Longitudinally, SHBG at examination 7, but not testosterone or free testosterone, was associated with incident metabolic syndrome at examination 8 after adjusting for age, smoking, BMI, and HOMA-IR. Multivariable analyses suggested that age, BMI, and insulin sensitivity independently affect SHBG and testosterone levels and the risk of metabolic syndrome and its components. CONCLUSIONS SHBG, but not testosterone, is independently associated with the risk of metabolic syndrome. These data do not reveal an independent prospective relationship between testosterone and metabolic syndrome in men.

Background— Prior randomized trials have shown reduced bleeding with bivalirudin compared with unfractionated heparin (UFH) in patients undergoing percutaneous coronary intervention (PCI). However, it is not known if this benefit is also present when UFH doses are more tightly controlled (as measured by activated clotting time, ACT). Methods and Results— Patients enrolled in the EVENT (Evaluation of Drug-Eluting Stents and Ischemic Events) registry, were divided into 3 groups, based on the antithrombotic drug used during PCI (UFH monotherapy, UFH+glycoprotein IIb-IIIa receptor inhibitor [GPI], or bivalirudin alone). Propensity score matching was used to adjust for measured covariates (89 variables) and to compare bivalirudin versus UFH monotherapy and bivalirudin versus UFH+GPI groups. The UFH groups were stratified based on ACT achieved (optimal ACT defined as 250–300 for UFH monotherapy and 200–250 when GPI was also used). The primary bleeding outcome was in-hospital composite bleeding, defined as events of access site bleeding, Thrombolysis In Myocardial Infarction major/minor bleeding, or transfusion. Primary (in-hospital death/myocardial infarction) and secondary ischemic outcomes (death/MI/unplanned repeat revascularization at 12 months) were also evaluated. Propensity score matching yielded 3022 patients for the UFH monotherapy versus bivalirudin comparison and 3520 patients for the UFH+GPI versus bivalirudin comparison. Bivalirudin use was associated with numerically lower bleeding rates at all categories of achieved ACT when compared with UFH (low, optimal, high ACT: 2.5% versus 4.7%, 1.9% versus 6.0%, 3.1% versus 4.8%, respectively) or heparin+GPI groups (low, optimal, high ACT: 0.0% versus 2.7%, 2.7% versus 5.2%, 2.4% versus 6.1%, respectively) and was not associated with any statistically significant increase in either primary or secondary ischemic outcomes. Conclusions— Among unselected patients undergoing PCI, bivalirudin use during PCI was associated with a lower risk of bleeding at all comparator ACT levels without an increase in ischemic outcomes.

Background— Creatine kinase-MB (CK-MB) elevation after percutaneous coronary intervention (PCI) has been associated with increased risk for mortality. Although most studies have defined periprocedural myocardial infarction (pMI) as an elevation in CK-MB >3× upper limit of normal (ULN), use of different CK-MB assays and variation in site-specific definitions of the ULN may limit the value of such relative thresholds. Methods and Results— We used data from the multicenter Evaluation of Drug-Eluting Stents and Ischemic Events (EVENT) registry to examine the impact of variations in site-specific thresholds for CK-MB elevation on the incidence of pMI as well as the relationship between absolute peak levels of CK-MB after PCI and 1-year mortality. The study cohort consisted of 6347 patients who underwent nonemergent PCI and had normal CK-MB at baseline. Across the 59 study centers, the ULN for CK-MB ranged from 2.6 to 10.4 ng/mL (median, 5.0 ng/mL), and there was an inverse relationship between the site-specific ULN and the incidence of pMI (defined as CK-MB elevation >3× ULN). Although any postprocedure elevation of CK-MB was associated with an adverse prognosis, in categorical analyses, only CK-MB ≥50 ng/mL was independently associated with increased 1-year mortality (hazard ratio, 4.71; 95% confidence interval, 2.42 to 9.13; P Conclusions— Among unselected patients undergoing PCI, there is a graded relationship between CK-MB elevation after PCI and 1-year mortality that is particularly strong for large CK-MB elevations (>30 to 50 ng/mL). Future studies that include pMI as a clinical end point should consider using a core laboratory to assess CK-MB (to ensure consistency) and raising the threshold for defining pMI above current levels (to enhance clinical relevance).

OBJECTIVE To examine the efficacy of a dose increase of aripiprazole to 5 mg/d in subjects with major depressive disorder (MDD) who did not respond to 4 weeks of treatment with aripiprazole 2 mg/d in a randomized, double-blind, placebo-controlled, parent study. METHOD 221 Subjects with Structured Clinical Interview for DSM-IV Axis I Disorders-Patient Edition-diagnosed DSM-IV-TR MDD (mean ± SD age, 45 ± 11 years; 64% women) with inadequate antidepressant response were recruited from September 2008-July 2009 and randomized to 60 days of double-blind augmentation with either aripiprazole or placebo in two 30-day phases. The study was performed across 8 academic hospital sites and 14 nonacademic (private clinic) sites throughout the United States. Randomization in a 2:3:3 ratio per sequential parallel comparison design was drug/drug (aripiprazole 2 mg/d in phase 1 and 5 mg/d in phase 2), placebo/placebo (placebo in both phases), and placebo/drug (placebo in phase 1 and aripiprazole 2 mg/d in phase 2). In phase 2, we examined efficacy of an aripiprazole dose increase to 5 mg/d in nonresponders to 2 mg/d by assessing response rates (≥ 50% reduction in Montgomery-Asberg Depression Rating Scale [MADRS] score [primary outcome measure]) and score changes in MADRS, Quick Inventory of Depressive Symptomatology-Self-Report, 9-item Patient Health Questionnaire (PHQ-9), the Clinical Global Impressions-Severity of Illness (CGI-S) and -Improvement (CGI-I) scales, and patient-rated versions of the CGI-I and CGI-S scales. RESULTS Response rate for aripiprazole 2 mg/d in phase 1 was 18.5% (n/n = 10/54). Among 39 nonresponders who increased their dose to 5 mg/d, response rate was 12.8% (95% CI, 4.30%-27.43%), with significant overall mean ± SD reductions in MADRS scores (-9.46 ± 7.83 [95% CI, -12.00 to -6.92]; P < .0001), Symptoms Questionnaire Distress scores (19.51 ± 17.73 [95% CI, 13.60 to 25.43]; P < .0001), PHQ-9 scores (-7.92 ± 5.92 [95% CI, -9.89 to -5.94]; P < .0001), and CGI-S scores (-0.86 ± 0.86 [95% CI, -1.15 to -0.58]; P < .0001). Differences in efficacy between drug and placebo groups were nonsignificant, however. Aripiprazole and placebo were well tolerated. CONCLUSIONS Augmentation with aripiprazole 5 mg/d may provide only a modest additional benefit in patients who do not benefit from lower doses. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00683852.

Prediction models are becoming more and more important in medicine and cardiology. Nowadays, specific interest focuses on ways in which models can be improved using new prognostic markers. We aim to describe the similarities and differences between performance measures for prediction models. We analyzed data from 3264 subjects to predict 10-year risk of coronary heart disease according to age, systolic blood pressure, diabetes, and smoking. We specifically study the incremental value of adding high-density lipoprotein cholesterol to this model. We emphasize that we need to separate the evaluation of predictions, where traditional performance measures such as the area under the receiver operating characteristic curve and calibration are useful, from the evaluation of classifications, where various other statistics are now available, including the net reclassification index and net benefit.

Resumen Los modelos de prediccion estan adquiriendo cada vez mayor importancia en medicina y en cardiologia. En la actualidad, hay un interes especifico que se centra en las formas de mejorar los modelos con el empleo de nuevos marcadores pronosticos. Nuestro objetivo es describir las semejanzas y diferencias entre las distintas medidas del rendimiento de los modelos de prediccion. Hemos analizado los datos de 3.264 individuos para predecir el riesgo de enfermedad coronaria a 10 anos, segun la edad, la presion arterial sistolica, la diabetes y el tabaquismo. Estudiamos especificamente el valor incremental de la adicion a este modelo del colesterol unido a lipoproteinas de alta densidad. Resaltamos que es preciso separar la evaluacion de las predicciones —en las que las medidas de rendimiento tradicionales, como el area bajo la curva receiver operating characteristic y la calibracion, resultan utiles— de la evaluacion de las clasificaciones, para las que disponemos actualmente de otros parametros estadisticos, como el net reclassification index y el beneficio neto.

Reference ranges are essential for partitioning testosterone levels into low or normal and making the diagnosis of androgen deficiency. We established reference ranges for total testosterone (TT) and free testosterone (FT) in a community-based sample of men.TT was measured using liquid chromatography tandem mass spectrometry in nonobese healthy men, 19-40 yr old, in the Framingham Heart Study Generation 3; FT was calculated. Values below the 2.5th percentile of reference sample were deemed low. We determined the association of low TT and FT with physical dysfunction, sexual symptoms [European Male Aging Study (EMAS) only], and diabetes mellitus in three cohorts: Framingham Heart Study generations 2 and 3, EMAS, and the Osteoporotic Fractures in Men Study.In a reference sample of 456 men, mean (sd), median (quartile), and 2.5th percentile values were 723.8 (221.1), 698.7 (296.5), and 348.3 ng/dl for TT and 141. 8 (45.0), 134.0 (60.0), and 70.0 pg/ml for FT, respectively. In all three samples, men with low TT and FT were more likely to have slow walking speed, difficulty climbing stairs, or frailty and diabetes than those with normal levels. In EMAS, men with low TT and FT were more likely to report sexual symptoms than men with normal levels. Men with low TT and FT were more likely to have at least one of the following: sexual symptoms (EMAS only), physical dysfunction, or diabetes.Reference ranges generated in a community-based sample of men provide a rational basis for categorizing testosterone levels as low or normal. Men with low TT or FT by these criteria had higher prevalence of physical dysfunction, sexual dysfunction, and diabetes. These reference limits should be validated prospectively in relation to incident outcomes and in randomized trials.

We propose a method that compares Poisson distributed outcomes. Our method uses the exact distribution of the difference between two Poisson variables to calculate the sample size required to detect a given difference with prespecified power. When the true difference between the two Poisson rates is more than 1.2 units, the number of subjects and events needed at the desired power and Type I error rate is 5–10% less than that computed by simulation based on the normal approximation method. The normal approximation method is more comparable to the exact sample size method when the difference between the rates is less than 1.2 units. The proposed method is more intuitive, efficient, and less subjective than the normal approximation method. A simple code is developed in R to estimate the sample size and critical values.

Background New markers may improve prediction of diagnostic and prognostic outcomes. We review various measures to quantify the incremental value of markers over standard, readily available characteristics. Methods Widely used traditional measures include the improvement in model fit or in the area under the receiver operating characteristic (ROC) curve (AUC). New measures include the net reclassification index (NRI) and decision-analytic measures, such as the fraction of true-positive classifications penalized for false-positive classifications [net benefit (NB)]. For illustration, we discuss a case study on the presence of residual tumour vs. benign tissue in 544 patients with testicular cancer. We assessed three tumour markers [Alpha-fetoprotein (AFP), Human chorionic gonadotropin (HCG) and Lactate dehydrogenase (LDH)] for their incremental value over currently standard clinical predictors. Results AUC and R 2 values suggested adding continuous LDH and AFP whereas NB only favoured HCG as a potentially promising marker at a clinically defendable decision threshold of 20% risk. The NRI suggested reclassification potential of all three markers. Conclusions The improvement in standard discrimination measures, which focus on finding variables that might be promising across all decision thresholds, may not detect the most informative markers at a specific threshold of particular clinical relevance. When a marker is intended to support decision-making, calculation of the improvement in a decision-analytic measure, such as NB, is preferable over an overall judgment as obtained from the AUC in ROC analysis.

Background and Purpose— Carotid intima-media thickness (IMT) is a marker of cardiovascular disease derived from ultrasound images of the carotid artery. In most outcome studies, human readers identify and trace the key IMT interfaces. We evaluate an alternate approach using automated edge detection. Methods— We studied a subset of 5640 participants with an average age 61.7 years (48% men) of the Multi-Ethnic Study of Atherosclerosis composed of whites, Chinese, Hispanic, and blacks that are part of the Multi-Ethnic Study of Atherosclerosis IMT progression study. Manual tracing IMT (mt-IMT) and edge-detected IMT (ed-IMT) measurements of the far wall of the common carotid artery served as outcome variables for multivariable linear regression models using Framingham cardiovascular risk factors and ethnicity as independent predictors. Results— Measurements of mt-IMT were obtainable in 99.9% (5633/5640) and measurements of ed-IMT were obtainable in 98.9% (5579/5640) of individuals. Average ed-IMT was 0.19 mm larger than mt-IMT. Inter-reader systematic differences (bias) in IMT measurements were apparent for mt-IMT but not ed-IMT. Based on complete data for 5538 individuals, associations of IMT with risk factors were stronger ( P r 2 , 19.5%) than for ed-IMT (model r 2 , 18.5%). Conclusions— We conclude that this edge-detection process generates IMT values equivalent to manually traced ones because it preserves key associations with cardiovascular risk factors. It also decreases inter-reader bias, potentially making it applicable for use in cardiovascular risk assessment.

Eur J Clin Invest 2011; 41 (9): 1010–1035 Summary Points • The rapid and continuing progress in gene discovery for complex diseases is fuelling interest in the potential application of genetic risk models for clinical and public health practice. • The number of studies assessing the predictive ability is steadily increasing, but they vary widely in completeness of reporting and apparent quality. • Transparent reporting of the strengths and weaknesses of these studies is important to facilitate the accumulation of evidence on genetic risk prediction. • A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by prior reporting guidelines. • These recommendations aim to enhance the transparency, quality and completeness of study reporting and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct or analysis.

Elevated plasma total homocysteine (tHcy) level is an established risk factor for cardiovascular disease. The relationship between tHcy and carotid artery intima-media thickness (IMT) at the internal carotid artery (ICA)/bulb-IMT and common carotid artery (CCA)-IMT had not been systematically studied, however. Because the ICA/bulb segment is more prone to plaque formation than the CCA segment, differential associations with tHcy at these sites might suggest mechanisms of tHcy action. We examined the cross-sectional segment-specific relationships of tHcy to ICA/bulb-IMT and CCA-IMT in 2499 participants from the Framingham Offspring Study who were free of cardiovascular disease. In multivariate linear regression analysis, ICA/bulb-IMT was significantly higher in the fourth tHcy quartile category compared with the other quartile categories, in both the age- and sex-adjusted and the multivariate-adjusted models ( P for trend P =.03) and thus stratified the analyses by median age (58 years). A significant positive trend between tHcy and ICA/bulb-IMT was seen in individuals age ≥58 years ( P for trend P for trend=.24) in multivariate-adjusted models. For CCA-IMT, no significant trends were observed in any of the analyses. The segment-specific association between elevated tHcy level and ICA/bulb-IMT suggests an association between tHcy and plaque formation.

Salt sensitivity, a trait characterized by a pressor blood pressure response to increased dietary salt intake, has been associated with higher rates of cardiovascular target organ damage and cardiovascular disease events. Recent experimental studies have highlighted the potential role of the natriuretic peptides and aldosterone in mediating salt sensitivity.Prospective cohort study.We evaluated 1575 non-hypertensive Framingham Offspring cohort participants (mean age 55 ± 9 years, 58% women) who underwent routine measurements of circulating aldosterone and N-terminal proatrial natriuretic peptide (NT-ANP) and assessment of dietary sodium intake. Participants were categorized as potentially 'salt sensitive' if their serum aldosterone wassex-specific median but plasma NT-ANP was ≤sex-specific median value. Dietary sodium intake was categorized as lower versus higher (dichotomized at the sex-specific median). We used multivariable linear regression to relate presence of salt sensitivity (as defined above) to longitudinal changes (Δ) in systolic and diastolic blood pressure on follow-up (median four years).Participants who were 'salt sensitive' (N = 437) experienced significantly greater increases in blood pressure (Δ systolic, +4.4 and +2.3 mmHg; Δ diastolic, +1.9 and -0.3 mmHg; on a higher versus lower sodium diet, respectively) as compared to the other participants (Δ systolic, +2.8 and +1.0 mmHg; Δ diastolic, +0.5 and -0.2 mmHg; on higher versus lower sodium diet, respectively; P = 0.033 and P = 0.0127 for differences between groups in Δ systolic and Δ diastolic blood pressure, respectively).Our observational data suggest that higher circulating aldosterone and lower NT-ANP concentrations may be markers of salt sensitivity in the community. Additional studies are warranted to confirm these observations.

The aim of the study was to describe the incidence and consequences of minor surgery after drug-eluting stent (DES) implantation.The Evaluation of Drug-Eluting Stents and Ischemic Events (EVENT) Registry prospectively enrolled unselected patients undergoing percutaneous coronary intervention at 47 US centers between July 2004 and December 2007. We examined 8,323 patients who received a DES in EVENT to determine the frequencies of minor surgery and postoperative adverse events.Minor surgery (defined as procedures not requiring a major surgical incision) was performed in 164 (2.0%) of 8,323 patients1 year after stenting, as follows: pacemaker/defibrillator implantation (46%), eye surgery (17%), orthopedic (9%), dermatologic (8%), endovascular (6%), and gastrointestinal procedures (5%). Compared with patients who did not undergo minor surgery, those who did were older, had more comorbidities, had more extensive coronary disease, and were more likely to have received warfarin after stenting. Only 1 (0.6%, 95% CI 0.0%-3.4%) of 164 patients had an event (stent thrombosis causing myocardial infarction) during the first week after minor surgery; this rate was slightly higher than the background rate of ischemic events in the study population (exact mid P = .01). Clopidogrel use at 12 months was similar between patients who did and those who did not undergo minor surgery (65.2% vs 65.5%, P = .95).In the EVENT Registry, minor surgery was performed in 2% of patients in the first year after DES implantation. The risk of stent thrombosis during the first week after surgery was increased slightly compared with background rates, but the absolute event rate was low (0.6%).

In 2013, the American College of Cardiology/American Heart Association published guidelines for atherosclerotic cardiovascular disease (ASCVD) risk assessment.1 They recommended that clinicians calculate ASCVD risk for adult patients and based cholesterol treatment recommendations on these estimates. Persons with severe hypercholesterolemia or those known to have ASCVD were considered to be at high risk for clinical ASCVD, and they fell outside the purview of risk assessment. The remainder, which included most middle-age and older Americans with and without diabetes mellitus, were candidates for ASCVD risk assessment. A reasonable interval has elapsed to evaluate the strategy put forward and to contemplate changes that might improve prevention. Critical issues include how well does the current ASCVD algorithm identify persons who subsequently develop ASCVD events, and can they be improved? Should segments of the US population receive more attention? How can the ASCVD risk estimates be augmented? The 2013 guidelines provided new functions to estimate ASCVD risk in a 10-year time frame, applicable to millions of American adults 40 to 79 years of age, and the committee also suggested considering 30-year and lifetime risk.1 Several American longitudinal population studies served as data sources …

Key Points Question Is the use of statins initiated during late-stage chronic kidney disease and continued after transition to dialysis associated with an improvement in subsequent survival? Findings In this cohort study of 14 298 US veterans transitioning to dialysis, the continuation of statin therapy was associated with a 28% and 18% lower risk of 12-month all-cause mortality and cardiovascular mortality, respectively, compared with the discontinuation of statin therapy. Meaning The continuation of statin therapy after transition to dialysis was associated with reduced all-cause mortality and cardiovascular mortality in veterans., This cohort study compares whether the continuation vs discontinuation of statins from advanced chronic kidney disease into the dialysis therapy period is associated with improved all-cause mortality and cardiovascular mortality in US veterans., Importance De novo statin therapy in patients receiving chronic dialysis has failed to demonstrate cardiovascular (CV) protection in randomized clinical trials and thus is not recommended by current guidelines. However, current guidelines recommend the continuation of statin therapy if initiated before transition to dialysis. Objective To investigate whether the continuation of statins from advanced chronic kidney disease into the dialysis therapy period is associated with improved survival. Design, Setting, and Participants Retrospective cohort study of US veterans transitioning to dialysis between October 1, 2007, and March 30, 2014. Participants were 14 298 US veterans who were receiving statins during the 12-month period before transition to dialysis and survived the first year of dialysis. Data analysis was conducted between August 2, 2017, and June 28, 2018. Exposures Patients were characterized as statin continuers (n = 11 936) if statin therapy was continued for at least 6 months during the first year after dialysis initiation and as statin discontinuers (n = 2362) if therapy with statins was stopped or no statin therapy was received in the year posttransition. Main Outcomes and Measures Associations of statin continuation with 12-month all-cause mortality and CV mortality after 1 year of dialysis initiation were examined using Cox proportional hazards regression models adjusted for demographics and comorbidities. Results The mean (SD) age of the cohort was 71 (10) years; the cohort was 96.7% (n = 13 828) male and 21.3% (n = 3043) African American, and 74.6% (n = 10 627) had diabetes. The 12-month all-cause mortality and CV mortality rates after 1 year of transition to dialysis were lower in statin continuers: deaths per 100 person-years were 21.9 (95% CI, 20.9-22.8) and 8.1 (95% CI, 7.5-8.6) in statin continuers vs 30.3 (95% CI, 27.8-32.8) and 9.8 (95% CI, 8.3-11.2) in statin discontinuers. Moreover, lower all-cause mortality and CV mortality risks with statin continuation persisted in adjusted analyses, with hazard ratios of 0.72 (95% CI, 0.66-0.79) and 0.82 (95% CI, 0.69-0.96), respectively. Associations were similar across subgroups, including age, race, and diabetes status. Conclusions and Relevance In this study, the continuation of statin therapy after transition to dialysis was associated with reduced all-cause mortality and CV mortality. The study findings suggest that future studies are needed to examine potential CV benefits of continuing statin therapy after dialysis initiation.

OBJECTIVE To test if knowledge of type 2 diabetes genetic variants improves disease prediction. RESEARCH DESIGN AND METHODS We tested 40 single nucleotide polymorphisms (SNPs) associated with diabetes in 3,471 Framingham Offspring Study subjects followed over 34 years using pooled logistic regression models stratified by age ( RESULTS In people CONCLUSIONS Knowledge of common genetic variation appropriately reclassifies younger people for type 2 diabetes risk beyond clinical risk factors but not older people.

Objectives This study sought to determine the frequency of noncardiac surgery and adverse post-operative events among patients who recently received a drug-eluting stent (DES) following noncardiac surgery. Background Little is known about frequency of and risks associated with noncardiac surgery after DES implantation. Methods In the EVENT (Evaluation of Drug-Eluting Stents and Ischemic Events) registry, consecutive patients who underwent attempted stent placement at 42 hospitals between July 2004 and September 2005 were enrolled and followed for 1 year. In this study, we analyzed patients who received ≥1 DES to determine the frequency of noncardiac surgery and cardiac death, myocardial infarction, or stent thrombosis in the following week. Results Among 4,637 DES recipients, 206 (4.4%) underwent major noncardiac surgery in the following year (median days to surgery: 179 [interquartile range 112 to 266 days; range 13 to 360 days]). Overall, stent use averaged 1.5 per patient. The most frequent operations were orthopedic (36%), abdominal (31%), and vascular (20%). Compared with patients who did not undergo surgery, those who did were older, more likely to be women, and have had a prior stroke; the frequencies of prior myocardial infarction, prior coronary artery bypass graft, and diabetes were similar, as were left ventricular ejection fraction and indication for percutaneous coronary intervention. In the 7 days after surgery, 4 patients had a cardiac death, myocardial infarction, or stent thrombosis (1.9% [exact 95% confidence interval (CI): 0.5% to 4.9%]). The risk of the composite outcome was increased 27-fold in the week following noncardiac surgery compared with any other week after stent implantation (hazard ratio [HR]: 27.3 [95% CI: 10.0 to 74.2], p Conclusions The frequency of major noncardiac surgery in the year after DES placement is >4%. Although the overall risk of adverse outcomes was less than previously reported when surgery is performed months after DES placement, it is significantly increased in the week after major noncardiac surgery.

Restenosis is associated with acute myocardial infarction (MI) either at presentation or related to complications of target lesion revascularization (TLR). The cumulative late effect of TLR after drug-eluting or bare metal stent placement on cardiac death or MI is uncertain. Of the 1,057 patients with one native coronary lesion randomized to a sirolimus-eluting stent or bare metal stent in the Sirolimus-Eluting Stent in De Novo Native Coronary Lesions (SIRIUS) trial, the 983 who survived free of MI for the first 30 days were evaluated for the primary outcome of cardiac death or MI for 5 years. Patients with events occurring at or after TLR were assigned to TLR group. Cox proportional hazards regression analysis with TLR as a time-dependent variable and adjustment for baseline clinical and demographic covariates was used to assess the independent effect of TLR on the primary outcome. TLR occurred in 160 patients (16.3%) and was an independent predictor of the primary end point (hazard ratio 2.8, 95% confidence interval 1.7 to 4.5). This association was significant for sirolimus-eluting stents and bare metal stents. TLR was also associated with an increased risk of subsequent stent thrombosis and nontarget vessel revascularization. Intracoronary brachytherapy in the TLR group was associated with an increased risk of cardiac death or MI. In conclusion, restenosis requiring TLR was associated with an increased risk of cardiac death or MI occurring at TLR and during the subsequent 5 years.

Experts and regulators have called for methods used in traditional trials to be adapted to “real-world” settings. This article describes 3 promising approaches that meld rigorous methodology with r...

The effect of diet quality on weight change, relative to other body weight determinants, is insufficiently understood. Furthermore, research on long-term weight change in U.S. adults is limited. We evaluated prospectively patterns and predictors of weight change in Framingham Offspring/Spouse (FOS) women and men (n = 1515) aged > or =30 y with BMI > or = 18.5 kg/m2 and without cardiovascular disease, diabetes, and cancer at baseline over a 16-y period. Diet quality was assessed using the validated Framingham Nutritional Risk Score. In women, older age (P < 0.0001) and physical activity (P < 0.05) were associated with lower weight gain. Diet quality interacted with former smoking status (P-interaction = 0.02); former smokers with lower diet quality gained an additional 5.2 kg compared with those with higher diet quality (multivariable-adjusted P-trend = 0.06). Among men, older age (P < 0.0001) and current smoking (P < 0.01) were associated with lower weight gain, and weight fluctuation (P < 0.01) and former smoking status (P < 0.0001) were associated with greater weight gain. Age was the strongest predictor of weight change in both women (partial R(2) = 11%) and men (partial R(2) = 8.6%). Normal- and overweight women gained more than obese women (P < 0.05) and younger adults gained more weight than older adults (P < 0.0001). Patterns and predictors of weight change differ by sex. Age in both sexes and physical activity among women as well as weight fluctuation and smoking status in men were stronger predictors of weight change than diet quality among FOS adults. Women who stopped smoking over follow-up and had poor diet quality gained the most weight. Preventive interventions need to be sex-specific and consider lifestyle factors.

To compare the intensive care unit costs and determine factors influencing these costs in mechanically ventilated patients randomized to dexmedetomidine or midazolam by continuous infusion.Cost minimization analysis of a double-blind, multicenter clinical trial randomizing patients 2:1 to receive dexmedetomidine or midazolam from the institutional perspective.Sixty-eight intensive care units in the United States, Australia, New Zealand, Brazil, and Argentina.A total of 366 intubated intensive care unit patients anticipated to require sedation for24 hrs.Intensive care unit resource use was compared within the two treatment arms, using the U.S. representative costs for these resources. The analyses characterized patient costs from start of study drug until intensive care unit discharge including costs associated with the intensive care unit stay, costs during mechanical ventilation, study drug acquisition cost, and costs of treating adverse drug reactions probably or possibly related to study drugs. Blinded to treatment group, costs were calculated using Medicare reimbursement schedules, average IMS drug costs, expert opinion, and peer-reviewed literature. Censored lengths of intensive care unit stay and mechanical ventilation were imputed, using a nonparametric adjustment algorithm. Crude and multivariate median regressions were performed to relate intensive care unit cost and treatment. Including drug acquisition cost, sedation with dexmedetomidine was associated with a median total intensive care unit cost savings of $9679 (confidence interval, $2314-$17,045) compared with midazolam. The primary cost drivers were reduced costs of intensive care unit stay (median savings, $6584, 95% confidence interval, $727-$12,440) and reduced costs of mechanical ventilation (median savings, $2958, 95% confidence interval, $698-$5219).Continuous sedation with dexmedetomidine results in significantly lower total intensive care unit costs compared with midazolam infusion for intensive care unit sedation, primarily due to decreased intensive care unit stay costs and reduced mechanical ventilation costs.

Cardiovascular risk assessment might be improved with the addition of emerging, new tests derived from atherosclerosis imaging, laboratory tests or functional tests. This article reviews relative risk, odds ratios, receiver-operating curves, posttest risk calculations based on likelihood ratios, the net reclassification improvement and integrated discrimination. This serves to determine whether a new test has an added clinical value on top of conventional risk testing and how this can be verified statistically. Two clinically meaningful examples serve to illustrate novel approaches. This work serves as a review and basic work for the development of new guidelines on cardiovascular risk prediction, taking into account emerging tests, to be proposed by members of the 'Taskforce on Vascular Risk Prediction' under the auspices of the Working Group 'Swiss Atherosclerosis' of the Swiss Society of Cardiology in the future.

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.

The performance of prediction models can be assessed using a variety of methods and metrics. Traditional measures for binary and survival outcomes include the Brier score to indicate overall model performance, the concordance (or c) statistic for discriminative ability (or area under the receiver operating characteristic [ROC] curve), and goodness-of-fit statistics for calibration. Several new measures have recently been proposed that can be seen as refinements of discrimination measures, including variants of the c statistic for survival, reclassification tables, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Moreover, decision-analytic measures have been proposed, including decision curves to plot the net benefit achieved by making decisions based on model predictions. We aimed to define the role of these relatively novel approaches in the evaluation of the performance of prediction models. For illustration, we present a case study of predicting the presence of residual tumor versus benign tissue in patients with testicular cancer (n = 544 for model development, n = 273 for external validation). We suggest that reporting discrimination and calibration will always be important for a prediction model. Decision-analytic measures should be reported if the predictive model is to be used for clinical decisions. Other measures of performance may be warranted in specific applications, such as reclassification metrics to gain insight into the value of adding a novel predictor to an established model.

Objectives Our aim was to examine the prognostic importance of hemorrhagic and ischemic complications after percutaneous coronary intervention (PCI) in unselected patients. Background In randomized trials of PCI, major bleeding and periprocedural myocardial infarction (pMI) have been associated with increased mortality. Whether similar associations exist among un-selected PCI patients is unknown. Methods We used data from the EVENT (Evaluation of Drug Eluting Stents and Ischemic Events) registry—a multicenter registry of unselected patients undergoing PCI—to examine the association between both in-hospital bleeding and pMI and 1-year mortality. Cardiac enzyme levels were assessed in all patients, and pMI was defined as a peak creatine kinase-MB value ≥3× the upper limit of normal. Post-PCI bleeding was classified by Thrombolysis In Myocardial Infarction criteria. Results After excluding patients with elevated pre-PCI creatine kinase-MB values and ST-segment elevation myocardial infarction at presentation (n = 1,626), a total of 5,961 patients were available for evaluation. Rates of post-PCI bleeding and pMI were 3.0% and 7.1%, respectively; 1-year all-cause mortality was 2.8%. After multivariable adjustment, both post-PCI bleeding (adjusted hazard ratio [HR]: 3.83, 95% confidence interval: 2.48 to 5.90, p Conclusions Among unselected PCI patients, both post-PCI bleeding and pMI are independently associated with increased 1-year mortality. Continued efforts to reduce these complications after PCI are warranted.

Objectives The aim of this study was to compare outcomes among unselected patients undergoing percutaneous coronary intervention (PCI) with either sirolimus-eluting (SES) or paclitaxel-eluting stents (PES). Background Although the benefits of both SES and PES are well-established, studies comparing these stents directly have yielded conflicting results. Methods We used data from the EVENT (Evaluation of Drug Eluting Stents and Ischemic Events) registry to compare in-hospital and 1-year outcomes among unselected patients undergoing nonemergent PCI with either SES or PES implantation. Results Between July 2004 and June 2006, 6,035 patients underwent PCI with either SES (n = 3,443) or PES (n = 2,592) at 47 U.S. centers. Baseline clinical and angiographic characteristics were generally similar for the 2 stent types. At 1-year, there were no differences in the primary end point of cardiac death or myocardial infarction (MI) between the SES and PES groups (9.1% vs. 10.0%, p = 0.11) or in any individual end points including cardiac death, nonfatal MI, or stent thrombosis. In unadjusted analyses, target lesion revascularization (TLR) was slightly more common with SES than with PES (4.4% vs. 3.3%, p = 0.048), but this difference was no longer apparent after adjusting for baseline characteristics as well as site-related factors (adjusted hazard ratio: 1.09, 95% confidence interval: 0.78 to 1.50). Conclusions Among unselected patients undergoing PCI, adjusted rates of both ischemic complications as well as clinically important restenosis were similar for SES and PES. The unexpected finding that TLR was influenced by site characteristics suggests that the correlation between TLR and angiographic restenosis might be weaker than previously described and warrants further study.

Background— Information is limited on the longitudinal tracking of left ventricular (LV) mass over the adult life course and the determinants of such change. Methods and Results— We used multilevel modeling to evaluate the correlates of LV mass prospectively over a 16-year period in 4217 Framingham study participants (mean age 45 years, 53% women) using up to 4 serial routine echocardiographic observations on each individual (11 762 observations). Age, sex, body mass index, systolic blood pressure, antihypertensive treatment, smoking, and diabetes mellitus were related to longitudinal measures of LV mass. Women and participants with diabetes mellitus experienced a steeper increase in LV mass with advancing age (compared with men and those without diabetes mellitus; P for interactions P =0.04 for interaction). Participants with optimal values of these risk factors experienced lesser increases in LV mass over time. Analyses evaluating short-term (4-year) changes in LV mass (2605 unique individuals providing 4494 observations) identified the same key determinants that influenced its long-term trajectory (ie, body mass index, sex, systolic blood pressure, antihypertensive treatment, and smoking). Conclusions— Our longitudinal observations on a large community-based sample identified higher blood pressure, excess adiposity, smoking, and diabetes mellitus as fundamental determinants of LV mass tracking over the adult life course. These observations are consistent with the notion that maintenance of optimal levels of these risk factors in midlife will reduce the burden of LV hypertrophy, and possibly heart failure, in older age.

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.

Recent evidence suggests that university students are self-reporting experiencing musculoskeletal discomfort with computer use similar to levels reported by adult workers. The objective of this study was to determine how university students use notebook computers and to determine what ergonomic strategies might be effective in reducing self-reported musculoskeletal discomfort in this population. Two hundred and eighty-nine university students randomly assigned to one of three towers by the university's Office of Housing participated in this study. The results of this investigation showed a significant reduction in self-reported notebook computer-related discomfort from pre- and post-survey in participants who received notebook computer accessories and in those who received accessories and participatory ergonomics training. A significant increase in post-survey rest breaks was seen. There was a significant correlation between self-reported computer usage and the amount measured using computer usage software (odometer). More research is needed however to determine the most effective ergonomics intervention for university students.

The upper interventricular septum may be prominent in elderly individuals, a finding referred to as discrete upper septal thickening (DUST). We examined the prevalence, clinical and echocardiographic correlates, and prognostic significance of DUST in a community-based sample. We evaluated Framingham Study participants who underwent routine echocardiography. In 3562 Framingham Study participants (mean age 58 years, 57% women), DUST was observed in 52 participants. The clinical correlates of DUST were increasing age (odds ratio [OR] per 10 year increment 2.59, 95% confidence intervals [CI] 1.64-4.08) and systolic blood pressure (OR per SD increment 1.55, 95% CI 1.15-2.09). DUST was positively associated with left ventricular (LV) fractional shortening and mitral annular calcification but inversely with LV diastolic dimensions (P0.02 for all). On follow-up (mean 15 years), 732 individuals died (33 with DUST) and 560 experienced a cardiovascular disease (CVD) event (18 with DUST). Adjusting for cardiovascular risk factors, DUST was not associated with CVD or mortality risk (P0.30 for both). The follow-up component of our study suggests that DUST is not independently associated with adverse prognosis.

Objectives This study sought to evaluate ischemic and bleeding outcomes in patients with chronic kidney disease (CKD) undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DES). Background Previous studies have shown that CKD is associated with poor outcomes after PCI. However, these studies were largely conducted before the introduction of DES and aggressive antithrombotic therapy or were performed in the setting of randomized trials. With data from a contemporary registry, we evaluated the influence of CKD on major cardiovascular events and bleeding complications in unselected “real-world” patients undergoing PCI. Methods Data from 4,791 patients enrolled in the EVENT (Evaluation of Drug Eluting Stents and Ischemic Events) Registry between July 2004 and September 2005 were analyzed. Patients were stratified into 4 groups: creatinine clearance (CrCl) >75, 50 to 75, 30 to 49 and Results During the index hospital stay, there was a step-wise increase in bleeding complications with decreasing CrCl (3.3%, 5.0%, 8.8%, and 14.3%; p Conclusions Renal function is an independent and powerful predictor of bleeding and ischemic complications in the era of DES and contemporary antithrombotic therapy in patients undergoing PCI. The low use of guideline-recommended drugs among patients with CKD undergoing PCI might contribute to these adverse outcomes and warrants further evaluation.

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— Although cardiac troponin (cTn) elevation is associated with periprocedural complications during percutaneous coronary intervention (PCI) in the setting of acute coronary syndromes, the prevalence and prognostic significance of preprocedural cTn elevation among patients with stable coronary artery disease undergoing PCI are unknown. Methods and Results— Between July 2004 and September 2006, 7592 consecutive patients who underwent attempted stent placement at 47 hospitals throughout the United States were enrolled in a prospective multicenter registry. We analyzed the frequency of an elevated cTn immediately before PCI and its relationship to in-hospital and 1-year outcomes among patients who underwent PCI for either stable angina or a positive stress test. Among the stable coronary artery disease population (n=2382, 31.4%), 142 (6.0%) had a cTn level above the upper limit of normal before the procedure. Compared with patients who had normal baseline cTn, patients with elevated cTn had a higher rate of in-hospital death or myocardial infarction (13.4% versus 5.6%; P P =0.06). In multivariable analyses adjusted for demographic, clinical, angiographic, and procedural factors, baseline cTn elevation remained independently associated with the composite of death or myocardial infarction at hospital discharge (odds ratio, 2.1; 95% confidence interval, 1.2 to 3.8; P =0.01) and at the 1-year follow-up (odds ratio, 2.0; 95% confidence interval, 1.2 to 3.3; P =0.005). Conclusions— Baseline elevation of cTn is relatively common among patients with stable coronary artery disease undergoing PCI and is an independent prognostic indicator of ischemic complications. If these data are confirmed in future studies, consideration should be given to routine testing of cTn before performance of PCI in this patient population.

Children of parents with hypertension are at increased risk of developing high blood pressure. We hypothesize that circulating concentrations of putative biomarkers (that may play a role in development of high blood pressure) are higher in nonhypertensive offspring of parents with hypertension. We compared concentrations of 4 different biomarkers (urinary albumin:creatinine ratio, circulating C-reactive protein, aldosterone:renin ratio, and plasminogen activator inhibitor-1) in nonhypertensive Framingham offspring study participants with none (n=233), 1 (n=474), or both (n=322) parents with hypertension. Parental hypertension was defined as onset before age 60 years, based on longitudinal observations of the original Framingham cohort. Serum C-reactive protein concentrations were higher in nonhypertensive offspring with 1 (median: 1.7; Q1 to Q3: 0.8 to 3.6 mg/L) or both parents with hypertension (median: 1.8; Q1 to Q3: 0.7 to 3.6 mg/L) compared with offspring without parental hypertension (median: 1.4; Q1 to Q3: 0.7 to 3.2 mg/L). In multivariable analyses, parental hypertension was associated with higher serum C-reactive protein concentration in offspring (15% increase per parent with hypertension; P =0.004). Prospectively, the relation of parental hypertension to longitudinal changes in blood pressure in the nonhypertensive offspring was attenuated on adjustment for C-reactive protein ( P =0.04 for attenuation). The levels of the other biomarkers evaluated did not significantly differ in offspring according to parental hypertension status. In conclusion, serum C-reactive protein concentrations are higher in nonhypertensive offspring of parents with hypertension. These data suggest that inflammation may partly mediate the familial influences on hypertension risk.

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.

Objective: Current guidelines recommend measurement of both BMI and waist circumference (WC) in individuals with BMI between 25.0 and 34.9 kg/m2. We investigated the relative contributions of BMI and WC toward identifying risk of adverse vascular events in a community-based sample. Methods and Procedures: We evaluated Framingham Study participants (n = 4,195 person-examinations, 53% women) using pooled logistic regression to assess the incremental prognostic utility of WC in predicting risk of a first cardiovascular disease (CVD) event in the three BMI categories (normal

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.

Objectives We sought to determine whether impaired fasting glucose (IFG) predicts cardiovascular disease (CVD) events. Background It is unclear which glucose threshold should define prediabetes. We compared the 1997 and 2003 American Diabetes Association (ADA) definitions of IFG to predict CVD. Methods Framingham offspring participants free of CVD, categorized by the 1997 ADA IFG definition (fasting plasma glucose 110 to 125 mg/dl; 6.1 to 6.9 mmol/l) or the 2003 definition (100 to 125 mg/dl; 5.6 to 6.9 mmol/l), were followed from 1983 to 2004. Pooled logistic regression was used to calculate multivariable-adjusted odds ratios (ORs) for incident coronary heart disease (CHD; 291 events) or CVD (423 events). Results Four-year CHD event rates among women were 1.3% (100 to 109 mg/dl), 2.3% (110 to 125 mg/dl), and 2.9% (diabetes); whereas corresponding rates in men were 2.9%, 3.0%, and 8.7%. For the 2003 IFG definition, the OR for CHD among women was 1.7 (95% confidence interval [CI] 1.0 to 3.0, p = 0.048), whereas for the 1997 IFG definition, the OR for CHD in women was 2.2 (95% CI 1.1 to 4.4, p = 0.02), which was almost as high as for women with diabetes (OR 2.5, 95% CI 1.2 to 5.2, p = 0.01). For CVD, only the 1997 IFG definition yielded significantly greater odds of CVD in women (OR 2.1, 95% CI 1.2 to 3.6, p = 0.01). Men were not at increased odds of developing CVD or CHD by either definition. Conclusions In women, both IFG definitions were associated with increased CHD risk, whereas neither IFG definition identified men at increased short-term risk for CHD or CVD. The finding that women with FPG 110 to 125 mg/dl had similar CHD risk compared with women with diabetes suggests that CHD risk in women may be elevated at a lower glucose level than for men.