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Background— The purpose of this study was to investigate associations between combinations of body mass index (BMI) categories and metabolic syndrome (MetS) and the risk of cardiovascular disease and death in middle-aged men. Methods and Results— At age 50 years, cardiovascular risk factors were assessed in 1758 participants without diabetes in the community-based Uppsala Longitudinal Study of Adult Men (ULSAM). According to BMI-MetS status, they were categorized as normal weight (BMI 2 ) without MetS (National Cholesterol Education Program criteria; n=891), normal weight with MetS (n=64), overweight (BMI 25 to 30 kg/m 2 ) without MetS (n=582), overweight with MetS (n=125), obese (BMI >30 kg/m 2 ) without MetS (n=30), or obese with MetS (n=66). During follow-up (median 30 years), 788 participants died, and 681 developed cardiovascular disease (composite of cardiovascular death or hospitalization for myocardial infarction, stroke, or heart failure). In Cox proportional-hazards models that adjusted for age, smoking, and low-density lipoprotein cholesterol, an increased risk for cardiovascular disease was observed in normal-weight participants with MetS (hazard ratio 1.63, 95% confidence interval 1.11 to 2.37), overweight participants without MetS (hazard ratio 1.52, 95% confidence interval 1.28 to 1.80), overweight participants with MetS (hazard ratio 1.74, 95% confidence interval 1.32 to 2.30), obese participants without MetS (hazard ratio 1.95, 95% confidence interval 1.14 to 3.34), and obese participants with MetS (hazard ratio 2.55, 95% confidence interval 1.81 to 3.58) compared with normal-weight individuals without MetS. These BMI-MetS categories significantly predicted total mortality rate in a similar pattern. Conclusions— Middle-aged men with MetS had increased risk for cardiovascular events and total death regardless of BMI status during more than 30 years of follow-up. In contrast to previous reports, overweight and obese individuals without MetS also had an increased risk. The present data refute the notion that overweight and obesity without MetS are benign conditions.

Background— Data are limited with regard to the relations of low-grade albuminuria (below the microalbuminuria threshold) and incidence of cardiovascular disease (CVD) events in nondiabetic, nonhypertensive individuals. Methods and Results— We examined the association of urinary albumin excretion (spot urine albumin indexed to creatinine [UACR]) and the incidence of CVD events and all-cause mortality in 1568 nonhypertensive, nondiabetic Framingham Offspring Study participants (mean age, 55 years; 58% women) free of CVD. On follow-up (median, 6 years), 54 participants (20 women) developed a first CVD event, and 49 (19 women) died. After adjustment for established risk factors, increasing UACR was associated with greater risk of CVD (hazards ratio [HR] per SD increment in log UACR, 1.36; 95% CI, 1.00 to 1.87) and death (HR per SD increment in log UACR, 1.55; 95% CI, 1.10 to 2.20). Participants with UACR greater than or equal to the sex-specific median (≥3.9 μg/mg for men, ≥7.5 μg/mg for women) experienced a nearly 3-fold risk of CVD (adjusted HR, 2.92; 95% CI, 1.57 to 5.44; P P =0.08) compared with those with UACR below the median. The increased CVD risk associated with UACR at or above the median remained robust in analyses restricted to individuals without microalbuminuria (n=1470) and in subgroups with intermediate (n=1469) and low (n=1186) pretest probabilities of CVD. Conclusions— In our community-based sample of middle-aged nonhypertensive, nondiabetic individuals, low levels of urinary albumin excretion well below the current microalbuminuria threshold predicted the development of CVD. Our observations add to the growing body of evidence that challenges the notion that UACR

Introduction: Despite the high risk of cardiovascular disease (CVD) in those with chronic kidney disease (CKD), there are conflicting data as to whether two key kidney measures, estimated glomerular filtration rate (eGFR) and albuminuria, contribute to better CVD prediction, beyond conventional risk factors, warranting a more comprehensive investigation over a broad range of populations. Methods: We studied 127,825 participants without history of CVD from 12 general population, 3 high risk and 1 CKD cohorts with data on eGFR (based on the CKD-EPI creatinine equation) and urinary albumin-creatinine ratio (ACR) and at least 4 years of median follow-up for CVD mortality (4,133 deaths from 15 cohorts), coronary heart disease (CHD) (5,420 events from 9 cohorts), stroke (2,651 events from 9 cohorts), or heart failure (2,507 events from 8 cohorts). To compare eGFR and ACR with conventional predictors independently of the order of modeling, we examined the worsening of 5-year prediction of CVD outcomes by omitting each predictor in turn compared to a full model with all kidney and conventional predictors. Results: C-statistics for full models ranged from 0.759-0.836 in general population and high risk cohorts and 0.712-0.796 in the CKD population (Table). All the conventional and kidney measures contributed to better prediction of CVD outcomes. The contribution of ACR was greater than that of any conventional modifiable risk factors except in predicting CHD in both general/high-risk cohorts and CKD population. Although weaker than ACR, eGFR also contributed significantly to better prediction of CVD mortality (especially in CKD populations) and CHD. Largely similar results were observed for categorical net reclassification index. Conclusion: The two key kidney measures (particularly albuminuria) contribute as much as some or all of the conventional risk factors to CVD prediction, supporting their use for CVD risk classification in certain circumstances.

Background: Adding cystatin C to serum creatinine improves accuracy of estimated glomerular filtration rate (eGFR), but the impact on detection, staging and prognosis of chronic kidney disease (CKD) across diverse populations has not been determined. Methods: Meta-analyses including 11 general population cohorts (N=90,750 participants) and 5 CKD cohorts (N=2,960) with standardized serum creatinine and cystatin C at baseline. We compared associations of baseline GFR estimated by CKD-EPI equations using creatinine (eGFR cr ) vs. cystatin C (eGFR cys ) with mortality (13,202 deaths from 15 cohorts) and incident end-stage renal disease (ESRD) (1,654 cases from 7 cohorts) during mean follow-up of 7.7 years and studied prognostic consequences of reclassification. Results: In the general population cohorts, mean eGFRs were 85 ml/min/1.73m 2 for both equations but prevalence of eGFR2 was higher for eGFR cys vs. eGFR cr (13.7% vs. 9.7% [12,403 vs. 8,833 of 90,750]). Across all eGFR cr categories (≥90, 60-89, 45-59, 30-44, 15-29, and 2 ), upward and downward reclassification by eGFR cys was associated with lower and higher risk, respectively; net reclassification improvement for eGFR cys compared with eGFR cr was 0.23 (0.18-0.28) for mortality and 0.10 (0.00-0.21) for ESRD. Among participants with eGFR cr 45-59 ml/min/1.73m 2 (N=6,358), ~40% were reclassified to higher eGFR cys categories and had lower risks of mortality (adjusted hazard ratio 0.66; 95% CI 0.57-0.77) and ESRD (0.20; 0.08-0.53) compared to those who were not reclassified. Among participants with eGFR cr 60-89 ml/min/1.73m 2 (N=43,630), ~13% were reclassified to lower eGFR cys categories and had higher risk for mortality (1.57; 1.39-1.78) and ESRD (2.66; 1.52-4.67) compared to no reclassification. The results for CKD cohorts were largely similar. Conclusions: Cystatin C strengthens the association of eGFR with risk across diverse populations providing a potentially useful adjunct to eGFR cr for detection and staging of CKD.

Objective: The aim of this study was to investigate how the length of the follow-up period influences the strength of the associations between major cardiovascular risk factors and different cardiovascular outcomes (myocardial infarction [MI], stroke and heart failure). Methods: We examined 1826 men aged 50 regarding cardiovascular risk factors in 1970-74. The follow-up time was 33 years. The hazard ratio (HR) was calculated yearly for each risk factor and outcome. During follow-up, 571 cases of MI, 381 cases of stroke and 384 cases of heart failure occurred. Results: Two major patterns were found regarding influence of the follow-up time on the associations between risk factors and the different cardiovascular outcomes. First, a gradual decline in the HR over time was seen for blood pressure in relation to all three outcomes, with the most rapid decline for heart failure and stroke. This pattern was also seen for BMI in relation to MI and heart failure, and for smoking regarding MI and stroke. Second, we observed a gradual increase in HRs to a maximum at 20-25 years, and thereafter a slight decline. This pattern was seen for the apoB/A1 ratio, HDL, and triglycerides, mainly in relation to MI and heart failure. Conclusion: The length of follow-up influenced the associations between traditional risk factors and cardiovascular outcomes in different ways. The collective influence of the risk factors did however show a substantial decline in discrimination over time for the outcomes stroke and heart failure, but not regarding myocardial infarction.

Background: Endostatin, a biological active fragment of the extracellular matrix protein collagen XVIII, is known to be involved in angiogenesis. We evaluated if circulating lvels of this compound was related to future mortality in two different cohorts of elderly subjects. Methods: In the PIVUS cohort of 931 subjects all aged 70 years at baseline, 90 individuals died during a median follow-up of 7.9 years. In the ULSAM cohort of 748 men aged 77 years at baseline, 261 individuals died during a median follow-up of 8.1 years. Results: Circulating levels of endostatin were related to future all-cause mortality in both samples following adjustment for age, gender, education, exercise habits, smoking BMI, blood pressure, lipids, diabetes and prior cardiovascular disease (HR 1.54 for a 1 SD change, 95%CI 1.26-1.90, p Conclusion: Endostatin was related to future mortality in two elderly Swedish sohorts independently of life-style factors and cardiovascular risk factors. The fact that the HR for cardiovascular mortality was higher than for all-cause mortality indicates a role of endostatin in the pathogenesis of cardiovascular diseases.

Response to Letters Regarding Article, "The Impact of Body Mass Index and the Metabolic Syndrome on the Risk of Cardiovascular Disease and Death in Middle-Aged Men"

Background— Diseases with elevated levels of parathyroid hormone (PTH) such as primary and secondary hyperparathyroidism are associated with increased incidence of cardiovascular disease and death. However, data on the prospective association between circulating PTH levels and cardiovascular mortality in the community are lacking. Methods and Results— The Uppsala Longitudinal Study of Adult Men (ULSAM), a community-based cohort of elderly men (mean age, 71 years; n=958), was used to investigate the association between plasma PTH and cardiovascular mortality. During follow-up (median, 9.7 years), 117 participants died of cardiovascular causes. In Cox proportional-hazards models adjusted for established cardiovascular risk factors (age, systolic blood pressure, diabetes, smoking, body mass index, total cholesterol, high-density lipoprotein cholesterol, antihypertensive treatment, lipid-lowering treatment, and history of cardiovascular disease), higher plasma PTH was associated with higher risk for cardiovascular mortality (hazard ratio for 1-SD increase in PTH, 1.38; 95% confidence interval, 1.18 to 1.60; P 50 mL · min −1 · 1.73 m −2 and without vitamin D deficiency, plasma 25-OH vitamin D >37.5 nmol/L). Interestingly, elevated plasma PTH (>5.27 pmol/L) accounted for 20% (95% confidence interval, 10 to 26) of the population-attributable risk proportion for cardiovascular mortality. Conclusions— Plasma PTH levels predict cardiovascular mortality in the community, even in individuals with PTH within the normal range. Further studies are warranted to evaluate the clinical implications of measuring PTH in cardiovascular risk prediction and to elucidate whether PTH is a modifiable risk factor.

Background— The relations of insulin sensitivity (IS) to hypertension incidence may vary according to baseline age, body mass index (BMI), and blood pressure (BP). Methods and Results— We investigated the relations of IS (insulin sensitivity index, ISI 0,120 ) to 4-year incidence of hypertension and BP progression in 1933 nonhypertensive Framingham Study participants (median age, 51 years; 56% women). Analyses were stratified by age (less than versus greater than or equal to median), BMI (2 [obese]), and BP category (systolic BP≥130 or diastolic BP≥85, “high normal” per the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High BP [JNC-VI] versus BP0,120 quartiles were associated with lower multivariable-adjusted odds for hypertension incidence (0.27; 95% CI, 0.09 to 0.83; P P Conclusions— In our large community-based sample, reduced IS predicted BP tracking principally in younger people with normal BMI and BP

Background— Conjugated linoleic acids (CLAs), a group of fatty acids shown to have beneficial effects in animals, are also used as weight loss supplements. Recently, we reported that the t 10 c 12 CLA-isomer caused insulin resistance in abdominally obese men via unknown mechanisms. The aim of the present study was to examine whether CLA has isomer-specific effects on oxidative stress or inflammatory biomarkers and to investigate the relationship between these factors and induced insulin resistance. Methods and Results— In a double-blind placebo-controlled trial, 60 men with metabolic syndrome were randomized to one of 3 groups receiving t 10 c 12 CLA, a CLA mixture, or placebo for 12 weeks. Insulin sensitivity (euglycemic clamp), serum lipids, in vivo lipid peroxidation (determined as urinary 8-iso-PGF 2α [F2-isoprostanes]), 15-ketodihydro PGF 2α , plasma vitamin E, plasma C-reactive protein, tumor necrosis factor-α, and interleukin-6 were assessed before and after treatment. Supplementation with t 10 c 12 CLA markedly increased 8-iso-PGF 2α (578%) and C-reactive protein (110%) compared with placebo ( P P 2α , but not in C-reactive protein, were significantly and independently related to aggravated insulin resistance. Oxidative stress was related to increased vitamin E levels, suggesting a compensatory mechanism. Conclusions— t 10 c 12 CLA supplementation increases oxidative stress and inflammatory biomarkers in obese men. The oxidative stress seems closely related to induced insulin resistance, suggesting a link between the fatty acid-induced lipid peroxidation seen in the present study and insulin resistance. These unfavorable effects of t 10 c 12 CLA might be of clinical importance with regard to cardiovascular disease, in consideration of the widespread use of dietary supplements containing this fatty acid.

To the Editor: Recently, researchers from the Framingham Heart Study reported in Circulation that in middle-aged, nonhypertensive, nondiabetic subjects, low-grade albuminuria predicted the development of cardiovascular disease.1 Subjects with previous coronary heart disease, diabetes mellitus, proteinuria, and hypertension (≥140/90 mm Hg) were excluded from these analyses. In addition to the strong prognostic value of urine albumin excretion in the lower range, another intriguing finding was reported: Baseline characteristics did not differ between subjects with urinary albumin excretion above or below the median. More specifically, body mass index, systolic and diastolic blood pressures, and smoking status did not differ between these groups. All of these factors have previously been reported to influence microalbuminuria.2 In particular, blood pressure is …