Utilization of absolute monocyte counts to predict cardiovascular events in people living with HIV.

OBJECTIVES: Cardiovascular risk is increased in people living with HIV (PLWH). In HIV-uninfected populations, total absolute monocyte count (AMC) has been shown to be predictive of future cardiovascular events (CVEs). We sought to determine whether AMC predicts CVEs in PLWH independent of established and HIV-related cardiovascular risk factors. METHODS: We identified all PLWH within the Partners HIV Cohort without factors that could confound the monocyte count. CVE was defined as fatal or non-fatal acute myocardial infarction or ischaemic stroke. Baseline-measured AMC was defined as the average of all outpatient AMC counts a year before and after the baseline date. Multivariable Cox proportional hazards models were used to assess the association of baseline AMC with CVEs. RESULTS: Our cohort consisted of 1980 patients, with median follow-up of 10.9 years and 182 CVEs. Mean (± SD) age was 41.9 ± 9.3 years; 73.0% were male. Mean CD4 count was 506.3 ± 307.1 cells/µL, 48% had HIV viral load (VL) < 400 copies/mL, and 87% were on antiretroviral therapy. Mean AMC was 0.38 × 103  ± 0.13 cells/µL. In multivariable modelling adjusted for traditional CV risk factors, CD4 cell count, and HIV VL, AMC quartile 2 (Q2) (HR = 1.01, P = 0.98), Q3 (HR = 1.07, P = 0.76), and Q4 (HR = 0.97, P = 0.89) were not significantly predictive of CVE compared with Q1. DISCUSSION: Baseline AMC was not associated with long-term CVEs in PLWH. AMC obtained in routine clinical encounters does not appear to enhance CV risk stratification in PLWH.

Transfer from paediatric to adult care for young adults with Type 2 diabetes: the SEARCH for Diabetes in Youth Study.

AIM: To describe factors associated with transfer from paediatric to adult care and poor glycaemic control among young adults with Type 2 diabetes, using the SEARCH for Diabetes in Youth study. METHODS: Young adults with Type 2 diabetes were included if they had a baseline SEARCH visit while in paediatric care at < 18 years and ≥ 1 follow-up SEARCH visit thereafter at 18-25 years. At each visit, HbA1c , BMI, self-reported demographic and healthcare provider data were collected. Associations of demographic factors with transfer of care and poor glycaemic control (HbA1c ≥ 75 mmol/mol; 9.0%) were explored with multivariable logistic regression. RESULTS: 182 young adults with Type 2 diabetes (36% male, 75% minority, 87% with obesity) were included. Most (n = 102, 56%) reported transfer to adult care at follow-up; a substantial proportion (n = 28, 15%) reported no care and 29% did not transfer. Duration of diabetes [odds ratio (OR) 1.4, 95% confidence interval (95% CI) 1.1, 1.8] and age at diagnosis (OR 1.8, 95% CI 1.4, 2.4) predicted leaving paediatric care. Transfer to adult or no care was associated with a higher likelihood of poor glycaemic control at follow-up (adult: OR 4.5, 95% CI 1.8, 11.2; none: OR 4.6, 95% CI 1.4, 14.6), independent of sex, age, race/ethnicity or baseline HbA1c level. CONCLUSIONS: Young adults with Type 2 diabetes exhibit worsening glycaemic control and loss to follow-up during the transfer from paediatric to adult care. Our study highlights the need for development of tailored clinical programmes and healthcare system policies to support the growing population of young adults with youth-onset Type 2 diabetes.

A systems analysis of age-related changes in some cardiac aging traits.

Aging process or senescence affects the expression of a wide range of phenotypic traits throughout the life span of organisms. These traits often show modular, synergistic, and even antagonistic relationships, and are also influenced by genomic, developmental, physiological and environmental factors. The cardiovascular system (CVS) in humans represents a major modular system in which the relationships among physiological, anatomical and morphological traits undergo continuous remodeling throughout the life span of an individual. Here we extend the concept of developmental plasticity in order to study the relationships among 14 traits measured on 3,412 individuals from the Framingham Heart Study cohort, relative to age and gender, using exploratory structural equation modeling-a form of systems analysis. Our results reveal differing patterns of association among cardiac traits in younger and older persons in both sexes, indicating that physiological and developmental factors may be channeled differentially in relation to age and gender during the remodeling process. We suggest that systems approaches are necessary in order to understand the coordinated functional relationships among traits of the CVS over the life course of individuals.

Vitamin D in youth with Type 1 diabetes: prevalence of insufficiency and association with insulin resistance in the SEARCH Nutrition Ancillary Study.

AIMS: To determine the prevalence of plasma vitamin D (25-dihydroxyvitamin D) insufficiency in individuals with Type 1 diabetes and to determine the cross-sectional and longitudinal associations of plasma vitamin D with insulin resistance. METHODS: Participants from the SEARCH for Diabetes in Youth Study [n = 1426; mean age 11.2 years (sd 3.9)] had physician-diagnosed Type 1 diabetes [diabetes duration mean 10.2 months (sd 6.5)] with data available at baseline and follow-up (approximately 12 and 24 months after baseline). Insulin resistance was estimated using a validated equation. Cross-sectional and longitudinal multivariate logistic regression models were used to determine the association of plasma vitamin D with insulin resistance, adjusting for potential confounders. RESULTS: Forty-nine per cent of individuals had plasma vitamin D < 50 nmol/l and 26% were insulin resistant. In cross-sectional multivariate analyses, participants who had higher plasma vitamin D (65 nmol/l) had lower odds of prevalent insulin resistance than participants with lower plasma vitamin D (25 nmol/l) (odds ratio 0.70, 95% CI 0.57-0.85). This association was attenuated after additional adjustment for BMI z-score, which could be a confounder or a mediator (odds ratio 0.81, 95% CI 0.64-1.03). In longitudinal multivariate analyses, individuals with higher plasma vitamin D at baseline had lower odds of incident insulin resistance, but this was not significant (odds ratio 0.85, 95% CI 0.63-1.14). CONCLUSIONS: Vitamin D insufficiency is common in individuals with Type 1 diabetes and may increase risk for insulin resistance. Additional prospective studies are needed to determine the association between plasma vitamin D and insulin resistance, and to further examine the role of adiposity on this association.

Adverse outcome analyses of observational data: assessing cardiovascular risk in HIV disease.

Clinical decisions are ideally based on randomized trials but must often rely on observational data analyses, which are less straightforward and more influenced by methodology. The authors, from a series of expert roundtables convened by the Forum for Collaborative HIV Research on the use of observational studies to assess cardiovascular disease risk in human immunodeficiency virus infection, recommend that clinicians who review or interpret epidemiological publications consider 7 key statistical issues: (1) clear explanation of confounding and adjustment; (2) handling and impact of missing data; (3) consistency and clinical relevance of outcome measurements and covariate risk factors; (4) multivariate modeling techniques including time-dependent variables; (5) how multiple testing is addressed; (6) distinction between statistical and clinical significance; and (7) need for confirmation from independent databases. Recommendations to permit better understanding of potential methodological limitations include both responsible public access to de-identified source data, where permitted, and exploration of novel statistical methods.

Diabetic retinopathy in the SEARCH for Diabetes in Youth Cohort: a pilot study.

AIMS: The aim of this pilot study was to generate an initial estimate of the prevalence and correlates of diabetic retinopathy in a racially and ethnically diverse sample of youth with Type 1 and Type 2 diabetes mellitus. METHODS: A pilot study was conducted among 222 individuals with Type 1 diabetes (79% non-Hispanic white, 21% other) and 43 with Type 2 diabetes (28% non-Hispanic white, 72% other), all of > 5 years duration (mean duration 6.8 years) who participated in the SEARCH for Diabetes in Youth study. Diabetic retinopathy was assessed using non-mydriatic retinal photography of both eyes. RESULTS: The prevalence of diabetic retinopathy was 17% for Type 1 diabetes and 42% for Type 2 diabetes (odds ratio 1.50, 95% CI 0.58-3.88; P = 0.40 adjusted for age, duration, gender, race/ethnicity, parental education and HbA(1c). HbA(1c) was significantly higher among those with any diabetic retinopathy (adjusted mean 79 mmol/mol, 9.4%) vs. no diabetic retinopathy (adjusted mean 70 mmol/mol, 8.6%) (P = 0.015). LDL cholesterol was also significantly higher among those with any diabetic retinopathy (adjusted mean 107.2 mg/dl) compared with those without diabetic retinopathy (adjusted mean 97.9 mg/dl) (P = 0.04). CONCLUSIONS: The prevalence of diabetic retinopathy in contemporary young individuals was substantial, particularly among minority youth and those with Type 2 diabetes. Further long-term study of diabetic retinopathy in youth is needed.

Insulin resistance influences the association of adiponectin levels with diabetes incidence in two population-based cohorts: the Cooperative Health Research in the Region of Augsburg (KORA) S4/F4 study and the Framingham Offspring Study.

AIMS/HYPOTHESIS: Lower adiponectin levels are associated with higher risk of incident type 2 diabetes. Most analyses have been adjusted for confounding factors, but few have taken into account insulin resistance per se. We tested the hypothesis that the association of adiponectin levels with incident type 2 diabetes differs between insulin-resistant and insulin-sensitive individuals. METHODS: We studied two prospective cohorts: the Framingham Offspring Study (n = 2,023) and the Cooperative Health Research in the Region of Augsburg (KORA) S4/F4 study (n = 887) cohorts. Insulin resistance was estimated by HOMA-insulin resistance (HOMA-IR). We used logistic regression analysis to test the association between adiponectin and incident type 2 diabetes overall and in insulin-resistant vs insulin-sensitive individuals (defined by ≥ vs <75th percentile of HOMA-IR). RESULTS: At baseline, Framingham's participants were 60 ± 9 years old and 56% were women; KORA's participants were 63 ± 5 years old and 49% were women. Type 2 diabetes incidence was 5.4% over 6.5 years (n = 109) in Framingham and 10.5% over 8 years (n = 93) in KORA. Lower adiponectin levels were associated with type 2 diabetes incidence in both cohorts. In insulin-resistant individuals, lower adiponectin levels were associated with higher risk of type 2 diabetes incidence (OR 1.60 [95% CI 1.10-2.31] per SD decrease in Framingham, p = 0.01; and OR 2.34 [95% CI 1.16-4.73] in KORA, p = 0.02); while this was not observed in insulin-sensitive individuals (OR 1.10 [95% CI 0.73-1.67] in Framingham, p = 0.64; and OR 1.34 [95%CI: 0.88-2.03] in KORA, p = 0.18). CONCLUSIONS/INTERPRETATION: We conclude that lower adiponectin levels are associated with higher risk of type 2 diabetes in insulin-resistant but not in insulin-sensitive individuals. This suggests that some level of insulin resistance is needed to see deleterious effects of low adiponectin.

Development, validation and use of an insulin sensitivity score in youths with diabetes: the SEARCH for Diabetes in Youth study.

AIMS/HYPOTHESIS: The ability to measure insulin sensitivity across the phenotypic spectrum of diabetes may contribute to a more accurate characterisation of diabetes type. Our goal was to develop and validate an insulin sensitivity (IS) score using the euglycaemic-hyperinsulinaemic clamp in a subset (n = 85) of 12- to 19-year-old youths with diabetes participating in the SEARCH study in Colorado, USA. METHODS: Youths with a diagnosis of type 1 (n = 60) or type 2 diabetes (n = 25) underwent a 3 h clamp to measure glucose disposal rate (GDR, mg kg⁻¹ min⁻¹). Demographic (age, sex, race), clinical (BMI, waist, Tanner stage) and metabolic characteristics (HbA1(c), lipids, blood pressure, urine albumin:creatinine) were used to estimate log(e)IS score via stepwise linear regression on a model-development set (n = 53). Estimated IS score was evaluated for reproducibility on two validation sets: youths with diabetes (n = 33) and healthy control youths (n = 22). RESULTS: The best model included waist, triacylglycerol (TG) and HbA1(c) levels (R² = 0.74). Diabetes type did not enter the model and there were no significant interactions between diabetes type and other predictors. Estimated IS score correlated well (r = 0.65, p < 0.0001; r = 0.62, p = 0.002) with GDR on the two validation sets. Based on this analysis, we propose the following formula to estimate insulin sensitivity in youths with diabetes: [Formula: see text]. CONCLUSIONS/INTERPRETATION: Insulin sensitivity can be estimated in adolescents with diabetes using routinely collected measures. This score can be applied to epidemiological studies of youths with diabetes to characterise relationships between dimensions of diabetes type.

Frailty models: Applications to biomedical and genetic studies.

In survival analysis, frailty models are potential choices for modeling unexplained heterogeneity in a population. This tutorial presents an overview and general framework of frailty modeling and estimation for multiplicative hazards models in the context of biomedical and genetic studies. Other topics in frailty models, such as diagnostic methods for model adequacy and inference in frailty models, are also discussed. Examples of analyses using multivariate frailty models in a non-parametric hazards setting on biomedical datasets are provided, and the implications of choosing to use frailty and relevance to genetic applications are discussed.

Prospective association between fasting NEFA and type 2 diabetes: impact of post-load glucose.

AIMS/HYPOTHESIS: Elevated fasting NEFAs are thought to promote type 2 diabetes. Three prospective studies support this concept, showing increased diabetes risk associated with fasting NEFA. However, these prospective associations may be confounded by strong cross-sectional correlations between fasting NEFA and metabolic predictors of diabetes. To examine this assumption, we used cohort data from the Insulin Resistance Atherosclerosis Study (IRAS). METHODS: Within the IRAS cohort (n = 902, 145 incident cases), we examined nine metabolic variables for their confounding effect on the fasting NEFA-diabetes association: 2 h glucose; fasting plasma glucose; body mass index; waist circumference; waist-to-hip ratio; weight; insulin sensitivity (S (I)); fasting insulin; and acute insulin response. We compared odds ratios for fasting NEFA (log( e ) transformed and adjusted for age, sex, ethnicity and clinic) before and after inclusion of each metabolic variable into a logistic regression model. RESULTS: Three variables (2 h glucose, BMI and S (I)) cross-sectionally correlated with fasting NEFA (r > or = 0.1, p < 0.05). Unadjusted for metabolic predictors, fasting NEFA levels were positively associated with diabetes risk: OR 1.37 (95% CI 0.87-2.15) per unit on a log scale. All metabolic variables except AIR showed confounding. Inclusion of 2 h glucose reversed the positive association (OR 0.50 [95% CI 0.30-0.82]), whereas other predictors reduced the association to the null. The final model included the variables correlated with baseline fasting NEFA (2 h glucose, BMI and S (I)) and the demographic variables resulting in OR 0.47 (95% CI 0.27-0.81). CONCLUSIONS/INTERPRETATION: Our results indicate that 2 h glucose strongly confounds the prospective association between fasting NEFA and diabetes; carefully adjusted fasting NEFA levels are inversely associated with diabetes risk.

Extraskeletal Calcifications in Hutchinson-Gilford Progeria Syndrome.

PURPOSE: Children with Hutchinson-Gilford progeria syndrome (HGPS), a rare premature aging disease, exhibit extraskeletal calcifications detected by radiographic analysis and on physical examination. The aim of this study was to describe the natural history and pathophysiology of these abnormal calcifications in HGPS, and to determine whether medications and/or supplements tested in clinical trials alter their development. METHODS: Children from two successive clinical trials administering 1) lonafarnib (n = 26) and 2) lonafarnib + pravastatin + zoledronic acid (n = 37) were studied at baseline (pre-therapy), one year on therapy, and at end-of-therapy (3.3-4.3 years after the baseline visit). Calcium supplementation (oral calcium carbonate) was administered during the first year of the second trial and was subsequently discontinued. Information on calcifications was obtained from physical examinations, radiographs, and serum and urinary biochemical measures. The mineral content of two skin-derived calcifications was determined by x-ray diffraction. RESULTS: Extraskeletal calcifications were detected radiographically in 12/39 (31%) patients at baseline. The odds of exhibiting calcifications increased with age (p = 0.045). The odds were unaffected by receipt of lonafarnib, pravastatin, and zoledronate therapies. However, administration of calcium carbonate supplementation, in conjunction with all three therapeutic agents, significantly increased the odds of developing calcifications (p = 0.009), with the odds plateauing after the supplement's discontinuation. Composition analysis of calcinosis cutis showed hydroxyapatite similar to bone. Although serum calcium, phosphorus, and parathyroid hormone (PTH) were within normal limits at baseline and on-therapy, PTH increased significantly after lonafarnib initiation (p < 0.001). Both the urinary calcium/creatinine ratio and tubular reabsorption of phosphate (TRP) were elevated at baseline in 22/39 (56%) and 31/37 (84%) evaluable patients, respectively, with no significant changes while on-therapy. The mean calcium × phosphorus product (Ca × Pi) was within normal limits, but plasma magnesium decreased over both clinical trials. Fibroblast growth factor 23 (FGF23) was lower compared to age-matched controls (p = 0.03). CONCLUSIONS: Extraskeletal calcifications increased with age in children with HGPS and were composed of hydroxyapatite. The urinary calcium/creatinine ratio and TRP were elevated for age while FGF23 was decreased. Magnesium decreased and PTH increased after lonafarnib therapy which may alter the ability to mobilize calcium. These findings demonstrate that children with HGPS with normal renal function and an unremarkable Ca × Pi develop extraskeletal calcifications by an unidentified mechanism that may involve decreased plasma magnesium and FGF23. Calcium carbonate accelerated their development and is, therefore, not recommended for routine supplementation in these children.

Determinants of adiponectin levels in young people with Type 1 diabetes.

AIMS: To determine whether adiponectin levels are higher in youth with Type 1 diabetes than in non-diabetic controls, and explore potential determinants for this difference. METHODS: Data are from the SEARCH for Diabetes in Youth Case-Control Study. A total of 440 youth with Type 1 diabetes and 191 non-diabetic healthy controls age 10-22 years of non-Hispanic White (NHW), African-American (AA) and Hispanic (H) origin were included in this analysis. Mean adiponectin levels were compared between persons with diabetes and controls within each racial/ethnic group, sequentially adjusting for the following variables: demographic (age, sex, Tanner stage), kidney function (albumin: creatinin ratio: ACR), obesity (body mass index: BMI; waist circumference), behavioral (percent calories from fat, physical activity), and glucose control (hemoglobin A1c: HbA(1c)). RESULTS: Mean adiponectin levels, adjusted for age, sex and Tanner stage, were higher in persons with Type 1 diabetes than in control subjects, among NHW (17.6 vs 13.0 microg/ml, P < 0.001) and H (17.2 vs 13.0, P = 0.01), and slightly higher but not significantly so among AA (14.5 vs 12.6, P = 0.1). The differences persisted after additionally adjusting for differences in ACR, BMI and waist circumference. We found a positive relationship between adiponectin and HbA(1c) in youth with Type 1 diabetes, even after adjustment for age, sex and race/ethnicity. CONCLUSIONS: Adiponectin is higher in an ethnically diverse group of youth with Type 1 diabetes than in control subjects. The relationship between glycemic control and adiponectin in Type 1 diabetes requires further exploration.

Benefits and pitfalls of pooling datasets from comparable observational studies: combining US and Dutch nursing home studies.

Different research groups sometimes carry out comparable studies. Combining the data can make it possible to address additional research questions, particularly for small observational studies such as those frequently seen in palliative care research. We present a systematic approach to pool individual subject data from observational studies that addresses differences in research design, illustrating the approach with two prospective observational studies on treatment and outcomes of lower respiratory tract infection in US and Dutch nursing home residents. Benefits of pooling individual subject data include enhanced statistical power, the ability to compare outcomes and validate models across sites or settings, and opportunities to develop new measures. In our pooled dataset, we were able to evaluate treatments and end-of-life decisions for comparable patients across settings, which suggested opportunities to improve care. In addition, greater variation in participants and treatments in the combined dataset allowed for subgroup analyses and interaction hypotheses, but required more complex analytic methods. Pitfalls included the large amount of time required for equating study procedures and variables and the need for additional funding.

Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis.

CONTEXT: Prediction models to identify healthy individuals at high risk of cardiovascular disease have limited accuracy. A low ankle brachial index (ABI) is an indicator of atherosclerosis and has the potential to improve prediction. OBJECTIVE: To determine if the ABI provides information on the risk of cardiovascular events and mortality independently of the Framingham risk score (FRS) and can improve risk prediction. DATA SOURCES: Relevant studies were identified. A search of MEDLINE (1950 to February 2008) and EMBASE (1980 to February 2008) was conducted using common text words for the term ankle brachial index combined with text words and Medical Subject Headings to capture prospective cohort designs. Review of reference lists and conference proceedings, and correspondence with experts was conducted to identify additional published and unpublished studies. STUDY SELECTION: Studies were included if participants were derived from a general population, ABI was measured at baseline, and individuals were followed up to detect total and cardiovascular mortality. DATA EXTRACTION: Prespecified data on individuals in each selected study were extracted into a combined data set and an individual participant data meta-analysis was conducted on individuals who had no previous history of coronary heart disease. RESULTS: Sixteen population cohort studies fulfilling the inclusion criteria were included. During 480,325 person-years of follow-up of 24,955 men and 23,339 women, the risk of death by ABI had a reverse J-shaped distribution with a normal (low risk) ABI of 1.11 to 1.40. The 10-year cardiovascular mortality in men with a low ABI (< or = 0.90) was 18.7% (95% confidence interval [CI], 13.3%-24.1%) and with normal ABI (1.11-1.40) was 4.4% (95% CI, 3.2%-5.7%) (hazard ratio [HR], 4.2; 95% CI, 3.3-5.4). Corresponding mortalities in women were 12.6% (95% CI, 6.2%-19.0%) and 4.1% (95% CI, 2.2%-6.1%) (HR, 3.5; 95% CI, 2.4-5.1). The HRs remained elevated after adjusting for FRS (2.9 [95% CI, 2.3-3.7] for men vs 3.0 [95% CI, 2.0-4.4] for women). A low ABI (< or = 0.90) was associated with approximately twice the 10-year total mortality, cardiovascular mortality, and major coronary event rate compared with the overall rate in each FRS category. Inclusion of the ABI in cardiovascular risk stratification using the FRS would result in reclassification of the risk category and modification of treatment recommendations in approximately 19% of men and 36% of women. CONCLUSION: Measurement of the ABI may improve the accuracy of cardiovascular risk prediction beyond the FRS.

Pepsin in saliva as a biomarker for oropharyngeal reflux compared with 24-hour esophageal impedance/pH monitoring in pediatric patients.

BACKGROUND: Pepsin in saliva is a proposed biomarker for oropharyngeal reflux. Pepsin may be prevalent in saliva from subjects with gastro-esophageal reflux and may correlate with proximal reflux by intraluminal impedance/pH monitoring (MII/pH). METHODS: Patients (3 days to 17.6 years, n=90) undergoing 24-hour MII/pH monitoring and asymptomatic controls (2 months to 13.7 years, n=43) were included. Salivary pepsin was determined using a pepsin enzyme-linked immunosorbent assay. Eight saliva samples were collected from patients undergoing 24-hr MII/pH: (i) before catheter placement, (ii) before and 30 minutes after each of three meals, and (iii) upon awakening. One sample was collected from each control. KEY RESULTS: In MII/pH subjects, 85.6% (77/90) had at least one pepsin-positive sample compared with 9.3% (4/43) in controls. The range of pepsin observed in individual subjects varied widely over 24 hours. The average pepsin concentration in all samples obtained within 2 hours following the most recent reflux event was 30.7±135 ng/mL, decreasing to 16.5±39.1 ng/mL in samples collected more than 2 hours later. The frequency of pepsin-positive samples correlated significantly with symptom index (rS =0.332, P=.0014), proximal (rS =0.340, P=.0010), and distal (rS =0.272, P=.0095) MII events. CONCLUSIONS & INFERENCES: Concentration of salivary pepsin may not be an accurate measure of severity of reflux because of the wide range observed in individuals over 24 hours. Saliva samples must be obtained soon after a reflux event. Defining a regimen for optimal saliva collection may help to achieve the goal of using salivary pepsin as a biomarker for oropharyngeal reflux. CLINICAL TRIAL REGISTRY: NCT01091805.

Body fat distribution and breast cancer in the Framingham Study.

We examined the relation between central body fat distribution and breast cancer in a prospective cohort of women who participated in the Framingham Study. At the baseline examination in 1948, a total of 2,201 women aged 30-62 years were analyzed. An index of central to peripheral body fat (the central adiposity ratio) was calculated from the sum of the trunkal skinfolds (chest, subscapular, and abdominal) divided by the sum of the extremity skinfolds (triceps and thigh). These skinfolds were measured at the fourth examination in 1954. The cohort was followed for up to 28 years and yielded 106 cases of breast cancer. When divided into quartiles based on the central adiposity ratio, only women in the fourth quartile (those with the highest central to peripheral body fat distribution) demonstrated an increased risk for breast cancer. The age- and adiposity-adjusted relative risk estimate for having an increased central adiposity ratio (fourth quartile) compared to lower central adiposity ratios was 1.8 (95% confidence interval, 1.2-2.6). Adjustment for potential confounders of height, parity, and education did not appreciably alter this estimate (1.7, 1.1-2.5). There was no association between degree of adiposity, as measured by the sum of the five skinfolds or by body mass index (weight in kg divided by height in m2), and subsequent breast cancer. The results of this study suggest that increased central to peripheral body fat distribution predicts breast cancer risk independently of the degree of adiposity and may be a more specific marker of a premalignant hormonal pattern than degree of adiposity.

Plasminogen activator inhibitor and the risk of cardiovascular disease: The Framingham Heart Study.

INTRODUCTION: Although plasminogen activator inhibitor (PAI-1) plays a key regulatory role in fibrinolysis, it has not been clearly shown to independently predict cardiovascular disease (CVD) among individuals without prior CVD. We investigated, in the Framingham Heart Study offspring cohort, whether PAI-1 predicted CVD risk among individuals without prior CVD. METHODS: Plasma PAI-1 antigen and tissue plasminogen activator (TPA) antigen were measured in 3203 subjects without prior CVD between 1991 and 1995; average follow-up of 10 years. PAI-1 was remeasured 4 years after baseline, to determine the effect of serial change on risk. RESULTS: PAI-1 levels (mean ± SD) were 29.1 ng/ml (19.2) versus 22.1 (16.5) for those and without incident CVD; p<0.001, and TPA levels were 12.0 ng/ml (5.7) versus 9.0 (4.7); p<0.001. PAI-1 and TPA antigen levels had a strong unadjusted linear relation with incident CVD (p<0.001). After adjustment for conventional risk factors, the hazard ratios (HRs) for higher quartiles of PAI-1, compared with the lowest, were 1.9, 1.9, 2.6 (linear trend p=0.006), and 1.6, 1.6, 2.9 (p<0.001) for TPA antigen. The adjusted HRs for increasing quartiles of serial change in PAI-1 at 4 years, compared with the lowest, were 0.9, 0.8, 1.3 (p=0.050). C statistic assessment showed that adding PAI-1 or TPA to conventional risk factors resulted in small increases in discrimination and modest reclassification of risk, which was statistically significant for TPA (net reclassification 6.8%, p=0.037) but not PAI-1 (4.8%, p=0.113). CONCLUSION: PAI-1 and TPA antigen levels are predictive of CVD events after accounting for established risk factors. A serial increase in PAI-1 is associated with a further increase in risk. These findings support the importance of fibrinolytic potential in CVD.

Association of fibrinogen with cardiovascular risk factors and cardiovascular disease in the Framingham Offspring Population.

BACKGROUND: Fibrinogen has been identified as an independent risk factor for cardiovascular disease and associated with traditional cardiovascular risk factors. Also, the role of elevated fibrinogen in thrombosis suggests that it may be on the causal pathway for certain risk factors to exert their effect. These associations remain incompletely characterized. Moreover, the optimal fibrinogen assay for risk stratification is uncertain. METHODS AND RESULTS: In 2632 subjects from cycle 5 of the Framingham Offspring Population, fibrinogen levels were determined with a newly developed immunoprecipitation test (American Biogenetic Sciences) and the functional Clauss method. With the immunoprecipitation method, there were significant linear trends across fibrinogen tertiles (P:<0.001) for age, body mass index, smoking, diabetes mellitus, total cholesterol, HDL cholesterol, and triglycerides in men and women. The Clauss method had significant results (P:<0.030), except for triglycerides in men. Fibrinogen levels were higher for those with compared with those without cardiovascular disease. After covariate adjustment, fibrinogen remained significantly higher in those with cardiovascular disease with the use of the immunoprecipitation test (P:=0.035 and P:=0.018 for men and women, respectively) but not with the Clauss method. CONCLUSIONS: Fibrinogen was associated with traditional cardiovascular risk factors. Elevation of fibrinogen may provide a mechanism for risk factors to exert their effect. Also, fibrinogen levels were higher among subjects with cardiovascular disease compared with those without disease. The immunoprecipitation test showed a stronger association with cardiovascular disease than the Clauss method, suggesting that it may be a useful screening tool to identify individuals at increased thrombotic risk.

Platelet glycoprotein IIIa Pl(a) polymorphism, fibrinogen, and platelet aggregability: The Framingham Heart Study.

BACKGROUND: Recent data suggest that the Pl(A2) allele of the platelet glycoprotein IIIa receptor may be a genetic risk factor for cardiovascular disease. We previously reported that the Pl(A2) allele was associated with increased platelet aggregability, as indicated by lower epinephrine threshold concentrations. Paradoxically, however, it has been reported that Pl(A2)-positive platelets have reduced fibrinogen binding. Because fibrinogen mediates platelet aggregability, we hypothesized that plasma fibrinogen levels may interact with Pl(A) genotype in modulating platelet aggregability. Methods and Results-- Glycoprotein IIIa Pl(A) genotype, fibrinogen level, and platelet aggregability were ascertained in 1340 subjects enrolled into the Framingham Offspring Study. Platelet aggregability was evaluated by the Born method. Higher fibrinogen levels were associated with increased epinephrine-induced aggregation (P=0.002) and a trend for ADP-induced aggregation (P=0.07). The fibrinogen effect was genotype specific, however, in that the increase in platelet aggregability with higher fibrinogen was present for the Pl(A1/A1) genotype (P=0.0005 and P=0.03 for epinephrine- and ADP-induced aggregation, respectively) but not for the Pl(A2)-positive genotype (P>0.90). CONCLUSION: Higher fibrinogen levels were associated with increased platelet aggregability. However, the association between fibrinogen and platelet aggregability was genotype specific. This interaction may be responsible for the conflicting findings regarding Pl(A) genotype and platelet aggregability. Further study of this gene-environment interaction may provide insight into cardiovascular disease risk.

Association of blood pressure with fibrinolytic potential in the Framingham offspring population.

BACKGROUND: Hypertension is an established risk factor for acute coronary events. Because fibrinolytic and hemostatic factors are also associated with cardiovascular disease, we examined the relations of systolic and diastolic blood pressures (SBP and DBP) to levels of plasminogen activator inhibitor antigen, tissue plasminogen activator antigen, fibrinogen, factor VII, von Willebrand factor, fibrinogen, and plasma viscosity in subjects of the Framingham Offspring Study. METHODS AND RESULTS: We studied 1193 men and 1459 women after the exclusion of subjects with known cardiovascular disease and those receiving anticoagulant or antihypertensive therapy. Linear regression models were used to evaluate SBP and DBP as predictors of fibrinolytic and hemostatic factor levels in separate sex models, with adjustment for age, body mass index, smoking, diabetes, total cholesterol, HDL, triglycerides, alcohol intake, and estrogen use (in women). In both sexes, levels of plasminogen activator inhibitor and tissue plasminogen activator antigen were positively related to SBP and DBP (P<0.001). Plasma viscosity was positively related to SBP (P=0.008) and DBP (P=0.001) in women only. There was no association between SBP or DBP and fibrinogen, factor VII, or von Willebrand factor in either sex. CONCLUSIONS: These data suggest that impaired fibrinolysis may play an important role in the pathogenesis of cardiovascular disease in hypertensive patients.