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Background: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. Methods: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. Results: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values 105 mL·min –1 ·1.73 m –2 , compared with those with eGFR between 60 and 105 mL·min –1 ·1.73 m –2 . Mendelian randomization analyses for CHD showed an association among participants with eGFR –1 ·1.73 m –2 , with a 14% (95% CI, 3%–27%) higher CHD risk per 5 mL·min –1 ·1.73 m –2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min –1 ·1.73 m –2 . Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. Conclusions: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

Objective: To identify causal pathophysiological mechanisms for atherosclerosis and incident cardiovascular events using protein measurements. Approach and Results: Carotid artery atherosclerosis was assessed by ultrasound, and 86 cardiovascular-related proteins were measured using the Olink CVD-I panel in 7 Swedish prospective studies (11 754 individuals). The proteins were analyzed in relation to intima-media thickness in the common carotid artery (IMT-CCA), plaque occurrence, and incident cardiovascular events (composite end point of myocardial infarction or ischemic stroke) using a discovery/replication approach in different studies. After adjustments for traditional cardiovascular risk factors, 11 proteins remained significantly associated with IMT-CCA in the replication stage, whereas 9 proteins were replicated for plaque occurrence and 17 proteins for incident cardiovascular events. NT-proBNP (N-terminal pro-B-type natriuretic peptide) and MMP (matrix metalloproteinase)-12 were associated with both IMT-CCA and incident events, but the overlap was considerably larger between plaque occurrence and incident events, including MMP-12, TIM-1 (T-cell immunoglobulin and mucin domain 1), GDF (growth/differentiation factor)-15, IL (interleukin)-6, U-PAR (urokinase plasminogen activator surface receptor), LOX-1 (lectin-like oxidized LDL [low-density lipoprotein] receptor 1), and TRAIL-R2 (TNF [tumor necrosis factor]-related apoptosis-inducing ligand receptor 2). Only MMP-12 was associated with IMT-CCA, plaque, and incident events with a positive and concordant direction of effect. However, a 2-sample Mendelian randomization analysis suggested that increased MMP-12 may be protective against ischemic stroke ( P =5.5×10 −7 ), which is in the opposite direction of the observational analyses. Conclusions: The present meta-analysis discovered several proteins related to carotid atherosclerosis that partly differed in their association with IMT-CCA, plaque, and incident atherosclerotic disease. Mendelian randomization analysis for the top finding, MMP-12, suggests that the increased levels of MMP-12 could be a consequence of atherosclerotic burden rather than the opposite chain of events.

Background: It is known that certain cardiovascular diseases (CVD) are associated, like atrial fibrillation and stroke. However, for other CVDs, the links and temporal trends are less studied. In this longitudinal study, we have investigated temporal epidemiological and genetic associations between different CVDs. Methods: The ULSAM (Uppsala Longitudinal Study of Adult Men; 2322 men aged 50 years) has been followed for 40 years regarding 4 major CVDs (incident myocardial infarction, ischemic stroke, heart failure, and atrial fibrillation). For the genetic analyses, publicly available data were used. Results: Using multistate modeling, significant relationships were seen between pairs of all of the 4 investigated CVDs. However, the risk of obtaining one additional CVD differed substantially both between different CVDs and between their temporal order. The relationship between heart failure and atrial fibrillation showed a high risk ratio (risk ratios, 24–26) regardless of the temporal order. A consistent association was seen also for myocardial infarction and atrial fibrillation but with a lower relative risk (risk ratios, 4–5). In contrast, the risk of receiving a diagnosis of heart failure following a myocardial infarction was almost twice as high as for the reverse temporal order (risk ratios, 16 versus 9). Genetic loci linked to traditional risk factors could partly explain the observed associations between the CVDs, but pathway analyses disclosed also other pathophysiological links. Conclusions: During 40 years, all of the 4 investigated CVDs were pairwise associated with each other regardless of the temporal order of occurrence, but the risk magnitude differed between different CVDs and their temporal order. Genetic analyses disclosed new pathophysiological links between CVDs.

Objective: The pathophysiology of hypertension remains incompletely understood. We investigated associations of circulating metabolites with longitudinal blood pressure (BP) changes in the Prospective Investigation of the Vasculature in Uppsala Seniors cohort and validated the findings in the Uppsala Longitudinal Study of Adult Men cohort. Approach and Results: Circulating metabolite levels were assessed with liquid- and gas-chromatography coupled to mass spectrometry among persons without BP-lowering medication at baseline. We studied associations of baseline levels of metabolites with changes in BP levels and the clinical BP stage between baseline and a follow-up examination 5 years later. In the discovery cohort, we investigated 504 individuals that contributed with 757 observations of paired BP measurements. The mean baseline systolic and diastolic BPs were 144 (19.7)/76 (9.7) mm Hg, and change in systolic and diastolic BPs were 3.7 (15.8)/−0.5 (8.6) mm Hg over 5 years. The metabolites associated with diastolic BP change were ceramide, triacylglycerol, total glycerolipids, oleic acid, and cholesterylester. No associations with longitudinal changes in systolic BP or BP stage were observed. Metabolites with similar structures to the 5 top findings in the discovery cohort were investigated in the validation cohort. Diacylglycerol (36:2) and monoacylglycerol (18:0), 2 glycerolipids, were associated with diastolic BP change in the validation cohort. Conclusions: Circulating baseline levels of ceramide, triacylglycerol, total glycerolipids, and oleic acid were positively associated with longitudinal diastolic BP change, whereas cholesterylester levels were inversely associated with longitudinal diastolic BP change. Two glycerolipids were validated in an independent cohort. These metabolites may point towards pathophysiological pathways of hypertension.

Objective— Revealing patterns of associations between circulating protein and lipid levels could improve biological understanding of cardiovascular disease (CVD). In this study, we investigated the associations between proteins related to CVD and triglyceride (TG), total cholesterol, LDL (low-density lipoprotein), and HDL (high-density lipoprotein) cholesterol levels in individuals from the general population. Approach and Results— We measured plasma protein levels using the Olink ProSeek CVD I or II+III arrays and analyzed 57 proteins available in 3 population-based cohorts: EpiHealth (n=2029; 52% women; median age, 61 years), PIVUS (Prospective Study of the Vasculature in Uppsala Seniors; n=790; 51% women; all aged 70 years), and ULSAM (Uppsala Longitudinal Study of Adult Men; n=551; all men aged 77 years). A discovery analysis was performed in EpiHealth in a regression framework (adjusted for sex, age, body mass index, smoking, glucose levels, systolic blood pressure, blood pressure medication, diabetes mellitus medication, and CVD history), and associations with false discovery rate P value of 0.05 was considered a successful replication (validation false discovery rate of 0.1%). We used summary statistics from a genome-wide association study on each protein biomarker (meta-analysis of EpiHealth, PIVUS, ULSAM, and IMPROVE [Carotid Intima–Media Thickness and IMT-Progression as Predictors of Vascular Events in a High-Risk European Population]) and publicly available data from Global Lipids Genetics Consortium to perform Mendelian randomization analyses to address possible causality of protein levels. Of 57 tested proteins, 42 demonstrated an association with at least 1 lipid fraction; 35 were associated with TG, 15 with total cholesterol, 9 with LDL cholesterol, and 24 with HDL cholesterol. Among these associations, we found KIM-1 (kidney injury molecule-1), TNFR (TNF [tumor necrosis factor] receptor) 1 and 2, TRAIL-R2 (TRAIL [TNF-related apoptosis-inducing ligand] receptor 2), and RETN (resistin) to be associated with all 4 lipid fractions. Further, 15 proteins were related to both TG and HDL cholesterol in a consistent and biologically expected manner, that is, higher TG and lower HDL cholesterol or vice versa. Another common pattern of associations was concomitantly higher TG, total cholesterol, and LDL cholesterol, which is associated with higher CVD risk. We did not find evidence of causal links for protein levels. Conclusions— Our comprehensive analysis of plasma proteins and lipid fractions of 3370 individuals from the general population provides new information about lipid metabolism.

Background and Purpose— Emerging technologies have made it possible to simultaneously evaluate a large number of circulating proteins as potential new stroke risk markers. Methods— We explored associations between 85 cardiovascular proteins, assessed by a proteomics chip, and incident ischemic stroke in 2 independent cohorts of elderly (Prospective Investigation of the Vasculature in Uppsala Seniors [PIVUS]: n=977; 50% women, mean age=70.1 years, 71 fatal/nonfatal ischemic stroke events during 10.0 years; and Uppsala Longitudinal Study in Adult Men [ULSAM]: n=720, mean age=77.5 years, 75 ischemic stroke events during 9.5 years). The proteomics chip uses 2 antibodies for each protein and a polymerase chain reaction step to achieve a high-specific binding and the possibility to measure multiple proteins in parallel, but gives no absolute concentrations. Results— In PIVUS, 16 proteins were related to incident ischemic stroke using a false discovery rate of 5%. Of these, N-terminal pro-B-type natriuretic peptide ( P =0.0032), adrenomedullin ( P =0.018), and eosinophil cationic protein ( P =0.0071) were replicated in ULSAM after adjustment for established stroke risk factors. In predefined secondary meta-analyses of individual data, interleukin-27 subunit α, growth/differentiation factor 15, urokinase plasminogen activator surface receptor, tumor necrosis factor receptor superfamily member 6, macrophage colony-stimulating factor 1, and matrix metalloproteinase-7 were also potential risk markers for ischemic stroke after adjustment for multiple comparisons ( P P =0.001). Conclusions— Our data suggest that large-scale proteomics analysis is a promising way of discovering novel biomarkers that could substantially improve the prediction of ischemic stroke.

Background and objectives Although nonesterified fatty acids (NEFAs) are essential as energy substrate for the myocardium, an excess of circulating NEFAs can be harmful. This study aimed to assess plausible relationships between serum NEFA and mortality due to cardiovascular disease (CVD) in individuals with CKD. Design, setting, participants, & measurements This was a prospective cohort study from the third examination cycle of the Uppsala Longitudinal Study of Adult Men, a population-based survey of 1221 elderly men aged 70–71 years residing in Uppsala, Sweden. Data collection took place during 1991–1995. All participants had measures of kidney function; this study investigated 623 (51.7%) of these patients with manifest CKD (defined as either eGFR,60 ml/min per 1.73 m 2 or urine albumin excretion rate $20 mg/min). Follow-up for mortality was donefromexaminationdateuntildeath orDecember 31,2007.After amedianfollow-upof14years(interquartile range, 8–16.8), associations of NEFAs with mortality (related to all causes, CVD, ischemic heart disease [IHD], or acute myocardial infarction) were ascertained. ResultsThemedian serum NEFA was 14.1 mg/dl (interquartile range, 11.3–17.8). No association was found with measures of kidney function. Diabetes and serum triglycerides were the only multivariate correlates of NEFA. During follow-up, 453participants died, of which 209 deaths were due to CVD, including 88 IHD deaths, with 41 attributed to acute myocardial infarction (AMI). In fully adjusted covariates, serum NEFA was an independent riskfactor for all-cause mortality (hazardratio[HR] per log2increase, 1.22;95%confidence interval [95% CI], 1.00 to1.48)andCVD-relateddeath(HR,1.51;95%CI,1.15to1.99),includingbothIHD(HR,1.51;95%CI,1.00to2.32) and AMI mortality (HR, 2.08; 95% CI, 1.09 to 3.98). Conclusions Elevated serum NEFA associated with CVD mortality, and particularly with mortality due to AMI, in a homogeneous population of older men with moderate CKD. Clin J Am Soc Nephrol 10: ccc–ccc, 2015. doi: 10.2215/CJN.08830914

Objectives: Obesity and hypertension are associated, possibly through causal pathways involving insulin resistance and metabolic derangements. We aimed to investigate in a whites sample if overweight or obese persons without insulin resistance are at risk of developing hypertension or blood pressure progression. Methods: In a meta-analysis, using multivariable-adjusted mixed-effects logistic regression models, we investigated the risks of hypertension development and blood pressure progression by combinations of relative weight classes and presence or absence of insulin resistance (defined as highest vs. lower three quartiles using the homeostatic model assessment method) in the Uppsala Longitudinal Study of Adult Men (n ¼2322) and the Prospective Investigation of the Vasculature in Uppsala Seniors studies (n ¼1066). These two samples, consisting mainly of middle-aged and elderly men, provided 1846 observations for the development of hypertension in normotensive individuals and 4223 observations for progressing to a higher blood pressure stage. Results: During a median of 10 years of follow-up, 884 (47.9%) developed hypertension and 1639 (38.8%) progressed to a higher blood pressure stage. Overweight or obese persons without insulin resistance had an increased risk of hypertension development [odds ratio (OR) 1.46, 95% confidence interval 1.14–1.88] and blood pressure progression (OR 1.32, 1.10–1.59) compared with normal-weight persons without insulin resistance. Conclusion: According to this study, being overweight or obese without insulin resistance increases the risk of hypertension and blood pressure progression. This adds to the evidence that overweight and obesity may be harmful per se, and that overweight and obesity without glucometabolic derangements are not benign conditions.

Objective— Current guidelines do not support the use of genetic profiles in risk assessment of coronary heart disease (CHD). However, new single nucleotide polymorphisms associated with CHD and intermediate cardiovascular traits have recently been discovered. We aimed to compare several multilocus genetic risk score (MGRS) in terms of association with CHD and to evaluate clinical use. Approach and Results— We investigated 6 Swedish prospective cohort studies with 10 612 participants free of CHD at baseline. We developed 1 overall MGRS based on 395 single nucleotide polymorphisms reported as being associated with cardiovascular traits, 1 CHD-specific MGRS, including 46 single nucleotide polymorphisms, and 6 trait-specific MGRS for each established CHD risk factors. Both the overall and the CHD-specific MGRS were significantly associated with CHD risk (781 incident events; hazard ratios for fourth versus first quartile, 1.54 and 1.52; P P =0.006 and 0.017). Discrimination improvement was modest (C-index improvement, 0.004). A polygene MGRS performed worse than the CHD-specific MGRS. We estimate that 1 additional CHD event for every 318 people screened at intermediate risk could be saved by measuring the CHD-specific genetic score in addition to the established risk factors. Conclusions— Our results indicate that genetic information could be of some clinical value for prediction of CHD, although further studies are needed to address aspects, such as feasibility, ethics, and cost efficiency of genetic profiling in the primary prevention setting.

Circulating fibroblast growth factor-23 is associated with adverse cardiovascular outcomes in CKD and non-CKD individuals, but the underlying mechanism remains unclear. This study tested whether this association is independent of mineral metabolism and indices of subclinical cardiovascular pathology.The prospective association between fibroblast growth factor-23 and major cardiovascular events (a composite of hospital-treated myocardial infarction, hospital-treated stroke, or all-cause mortality) was investigated in the community-based Prospective Investigation of the Vasculature in Uppsala Seniors (n=973; mean age=70 years, 50% women) using multivariate logistic regression. Subjects were recruited between January of 2001 and June of 2004.During follow-up (median=5.1 years), 112 participants suffered a major cardiovascular event. In logistic regression models adjusted for age, sex, and estimated GFR, higher fibroblast growth factor-23 was associated with increased risk for major cardiovascular events (odds ratio for tertiles 2 and 3 versus tertile 1=1.92, 95% confidence interval=1.19-3.09, P0.01). After additional adjustments in the model, adding established cardiovascular risk factors, confounders of mineral metabolism (calcium, phosphate, parathyroid hormone, and 25(OH)-vitamin D), and indices of subclinical pathology (flow-mediated vasodilation, endothelial-dependent and -independent vasodilation, arterial stiffness, and atherosclerosis and left ventricular mass) attenuated this relationship, but it remained significant (odds ratio for tertiles 2 and 3 versus tertile 1=1.69, 95% confidence interval=1.01-2.82, P0.05).Fibroblast growth factor-23 is an independent predictor of cardiovascular events in the community, even after accounting for mineral metabolism abnormalities and subclinical cardiovascular damage. Circulating fibroblast growth factor-23 may reflect novel and important aspects of cardiovascular risk yet to be unraveled.

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: We used a proteomics array to simultaneously measure 92 proteins that have been suggested to be associated with atherosclerosis and related them to plaque prevalence and echogenicity in carotid arteries in a human population-based study. Methods: In the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS; n=931, 50% women, all aged 70 years), the number of carotid arteries with plaques was recorded by ultrasound and plaque echogenicity was determined. Levels of 92 proteins were assessed in plasma by a proximity extension assay (Proseek Multiplex CVD, Olink Bioscience, Uppsala, Sweden) and related to carotid measures in a regression framework. Results: Following adjustment for multiple testing, six of the proteins were significantly related to the number of carotid arteries affected by plaques in sex-adjusted models (osteoprotegrin, T-cell immunoglobulin and mucin domain-1, renin, growth hormone, matrix metalloprotease-12 and lecitin-like oxidized LDL receptor 1). When these six proteins were included jointly in a model adjusting for traditional cardiovascular risk factors, renin (odds ratio [OR], 1.30; 95% confidence interval [CI], 1.13-1.50 per standard deviation increase) and growth hormone (OR, 1.26; 95% CI, 1.10-1.45) were related to plaque prevalence independently of each other and known risk factors for atherosclerosis. Thirty-one proteins were related to plaque echogenicity after adjustment for known risk factors. Of these, interleukin-27 subunit alpha (beta, 5.20; P=0.00032), vascular endothelial growth factor-delta (beta, 4.73; P=0.0013) and matrix metalloprotease-1 (beta, 3.93; P=0.0034) were associated with plaque echogenicity independently of each other. Conclusion: A novel targeted proteomics approach using the proximity extension technique discovered several new associations of candidate proteins with plaque prevalence and echogenicity in the carotid arteries in a large human sample.

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"

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 …