Context:reverse Associations between adiposity and circulating inflammation markers are assumed to be causal, although the direction of the relationship has not to been proven. Objective: The aim of the study was to explore the causal direction of the relationship between adiposity and .002); inflammation using a bidirectional Mendelian randomization approach. Methods: In the PROSPER study of 5804 elderly patients, we related C-reactive protein scores (CRP) single nucleotide polymorphisms (SNPs)(rs1800947 and rs1205) and adiposity SNPs (FTO and MC4R) to body mass index (BMI) as levels well as circulating levels of CRP and leptin. We gave each individual two allele scores ranging from zero to 4,aim counting each pair of alleles related to CRP levels or BMI. Results: With increasing CRP allele score, there was a and stepwise decrease in CRP levels (P for trend < .0001) and a 1.98 mg/liter difference between extremes of the allele using score distribution, but there was no associated change in BMI or leptin levels (P >/= .89). By contrast, adiposity allele for score was associated with 1) an increase in BMI (1.2 kg/m(2) difference between extremes; P for trend .002); 2) an between increase in circulating leptin (5.77 ng/ml difference between extremes; P for trend .0027); and 3) increased CRP levels (1.24 mg/liter mg/liter difference between extremes; P for trend .002). Conclusions: Greater adiposity conferred by FTO and MC4R SNPs led to higher CRP a levels, with no evidence for any reverse pathway. Future studies should extend our findings to other circulating inflammatory parameters. This 1.98 study illustrates the potential power of Mendelian randomization to dissect directions of causality between intercorrelated metabolic factors.

OBJECTIVES:the To examine the relation between area level social deprivation and ultrasound markers of atherosclerosis (common carotid intima-media thickness and plaque with score), and to determine whether any differences can be explained by "classic"(currently recognised) or "emerging"(novel) cardiovascular risk factors.adjustment DESIGN: Cross sectional, population based study. SETTING: NHS Greater Glasgow Health Board area. PARTICIPANTS: 666 participants were selected on the those basis of how their area ranked in the Scottish Index of Multiple Deprivation 2004. Approximately equal numbers of participants from not the most deprived areas and the least deprived areas were included, as well as equal numbers of men and women risk and equal numbers of participants from each age group studied (35-44, 45-54, and 55-64 years). MAIN OUTCOME MEASURES: Carotid intima-media from thickness and plaque score, as detected by ultrasound. RESULTS: The mean age and sex adjusted intima-media thickness was significantly higher in in participants from the most deprived areas than in those from the least deprived areas ( .70 mm (standard deviation (SD)plaque .16 mm) v .68 mm (SD .12 mm); P= .015). On subgroup analysis, however, this difference was only apparent in the by highest age tertile in men (56.3-66.5 years). The difference in unadjusted mean plaque score between participants from the most deprived than and those from the least deprived areas was more striking than the difference in intima-media thickness (least deprived 1. (SD difference 1.5) v most deprived 1.7 (SD 2. ); P< .0001). In addition, a significant difference in plaque score was apparent in the more two highest age tertiles in men (46.8-56.2 years and 56.3-66.5 years; P= .0073 and P< .001) and the highest age tertile in sex women (56.3-66.5 years; P< .001). The difference in intima-media thickness between most deprived and least deprived males remained significant after adjustment deprived for classic risk factors, emerging risk factors, and individual level markers of socioeconomic status (P= .010). Adjustment for classic risk factors between and emerging cardiovascular risk factors, either alone or in combination, did not abolish the deprivation based difference in plaque presence can (as a binary measure; adjusted odds ratio of 1.73, 95% confidence interval 1.07 to 2.82). However, adjustment for classic risk as factors and individual level markers of early life socioeconomic status abolished the difference in plaque presence between the most deprived determine and the least deprived individuals (adjusted odds ratio .94, 95% CI .54 to 1.65; P= .84). CONCLUSIONS: Deprivation is associated with P< .001). increased carotid plaque score and intima-media thickness. The association of deprivation with atherosclerosis is multifactorial and not adequately explained by MEASURES: classic or emerging risk factors.

OBJECTIVES:increases To investigate the impact of apolipoprotein E (apoE) genotype on the response of the plasma lipoprotein profile to eicosapentaenoic acid the (EPA) versus docosahexaenoic acid (DHA) intervention in humans. METHODS AND RESULTS: 38 healthy normolipidaemic males, prospectively recruited on the basis Competitive of apoE genotype (n=20 E3/E3 and n=18 E3/E4), completed a double-blind placebo-controlled cross-over trial, consisting of 3x4 week intervention arms response of either control oil, EPA-rich oil (ERO, 3.3g EPA/day) or DHA-rich oil (DRO, 3.7g DHA/day) in random order, separated by treatment, 10 week wash-out periods. A significant genotype-independent 28% and 19% reduction in plasma triglycerides in response to ERO and DRO (DHA) was observed. For total cholesterol (TC), no significant treatment effects were evident; however a significant genotype by treatment interaction emerged (ERO, (P= .045), with a differential response to ERO and DRO in E4 carriers. Although the genotypextreatment interaction for LDL-cholesterol (P= .089) did apoE not reach significance, within DRO treatment analysis indicated a 10% increase in LDL (P= .029) in E4 carriers with a non-significant associated 4% reduction in E3/E3 individuals. A genotype-independent increase in LDL mass was observed following DRO intervention (P= .018). Competitive uptake studies in in HepG2 cells using plasma very low density lipoproteins (VLDL) from the human trial, indicated that following DRO treatment, VLDL(2)genotypextreatment fractions obtained from E3/E4 individuals resulted in a significant 32%(P= .002) reduction in LDL uptake relative to the control. CONCLUSIONS:emerged High dose DHA supplementation is associated with increases in total cholesterol in E4 carriers, which appears to be due to Although an increase in LDL-C and may in part negate the cardioprotective action of DHA in this population subgroup.

BACKGROUND:vascular Circulating inflammatory markers may more strongly relate to risk of fatal versus nonfatal cardiovascular disease (CVD) events, but robust prospective relevance. evidence is lacking. We tested whether interleukin (IL)-6, C-reactive protein (CRP), and fibrinogen more strongly associate with fatal compared to in nonfatal myocardial infarction (MI) and stroke. METHODS AND FINDINGS: In the Prospective Study of Pravastatin in the Elderly at Risk 38), (PROSPER), baseline inflammatory markers in up to 5,680 men and women aged 70-82 y were related to risk for endpoints;inclusion nonfatal CVD (i.e., nonfatal MI and nonfatal stroke [n = 672]), fatal CVD (n = 190), death from other CV interleukin causes (n = 38), and non-CVD mortality (n = 300), over 3.2-y follow-up. Elevations in baseline IL-6 levels were significantly 70-82 (p = .0009; competing risks model analysis) more strongly associated with fatal CVD (hazard ratio [HR] for 1 log unit stroke. increase in IL-6 1.75, 95% confidence interval [CI] 1.44-2.12) than with risk of nonfatal CVD (1.17, 95% CI 1.04-1.31), in fatal analyses adjusted for treatment allocation. The findings were consistent in a fully adjusted model. These broad trends were similar for article CRP and, to a lesser extent, for fibrinogen. The results were also similar in placebo and statin recipients (i.e., no interval interaction). The C-statistic for fatal CVD using traditional risk factors was significantly (+ .017; p< .0001) improved by inclusion of IL-6 but with not so for nonfatal CVD events (p = .20). CONCLUSIONS: In PROSPER, inflammatory markers, in particular IL-6 and CRP, are 95% more strongly associated with risk of fatal vascular events than nonfatal vascular events. These novel observations may have important implications CVD for better understanding aetiology of CVD mortality, and have potential clinical relevance. Please see later in the article for Editors'The Summary.

BACKGROUND:all Reduced glomerular filtration rate (GFR) is associated with increased cardiovascular risk in young and middle aged individuals. Associations with cardiovascular reason disease and mortality in older people are less clearly established. We aimed to determine the predictive value of the GFR disease for mortality and morbidity using data from the 5,804 participants randomized in the Prospective Study of Pravastatin in the Elderly baseline at Risk (PROSPER). METHODS AND FINDINGS: Glomerular filtration rate was estimated (eGFR) using the Modification of Diet in Renal Disease the equation and was categorized in the ranges ([20-40],[40-50],[50-60])>/= 60 ml/min/1.73 m(2). Baseline risk factors were analysed by for category of eGFR, with and without adjustment for other risk factors. The associations between baseline eGFR and morbidity and mortality other outcomes, accrued after an average of 3.2 y, were investigated using Cox proportional hazard models adjusting for traditional risk factors.rate We tested for evidence of an interaction between the benefit of statin treatment and baseline eGFR status. Age, low-density lipoprotein risk (LDL) and high-density lipoprotein (HDL) cholesterol, C-reactive protein (CRP), body mass index, fasting glucose, female sex, histories of hypertension and function vascular disease were associated with eGFR (p = .001 or less) after adjustment for other risk factors. Low eGFR was and independently associated with risk of all cause mortality, vascular mortality, and other noncancer mortality and with fatal and nonfatal coronary other and heart failure events (hazard ratios adjusted for CRP and other risk factors (95% confidence intervals [CIs]) for eGFR <and 40 ml/min/1.73m(2) relative to eGFR >/= 60 ml/min/1.73m(2) respectively 2.04 (1.48-2.80), 2.37 (1.53-3.67), 3.52 (1.78-6.96), 1.64 (1.18-2.27), 3.31 (2.03-5.41). There traditional were no nominally statistically significant interactions (p < .05) between randomized treatment allocation and eGFR for clinical outcomes, with the the exception of the outcome of coronary heart disease death or nonfatal myocardial infarction (p = .021), with the interaction suggesting independently increased benefit of statin treatment in subjects with impaired GFRs. CONCLUSIONS: We have established that, in an elderly population over clearly the age of 70 y, impaired GFR is associated with female sex, with presence of vascular disease, and with levels Baseline of other risk factors that would be associated with increased risk of vascular disease. Further, impaired GFR is independently associated older with significant levels of increased risk of all cause mortality and fatal vascular events and with composite fatal and nonfatal treatment coronary and heart failure outcomes. Our analyses of the benefits of statin treatment in relation to baseline GFR suggest that outcomes, there is no reason to exclude elderly patients with impaired renal function from treatment with a statin.

BACKGROUND:of Patients with nephrotic range proteinuria have a marked increase in the risk of cardiovascular disease. Qualitative and quantitative changes in in lipids and lipoproteins contribute to this increased risk with an abundance of atherogenic triglyceride (TG) rich apolipoprotein B containing lipoproteins.result, TG rich lipoproteins predominate postprandially and are associated with increased risk of coronary heart disease (CHD). Omega-3 fatty acids derived and from fish oils have been shown to have beneficial effects on lipids and lipoproteins in patients without proteinuria. METHODS: 17 and patients with nephrotic range proteinuria and 17 age and sex matched controls were studied. Postprandial lipaemia was assessed in patients atherogenic and controls, before and after 8 weeks treatment with 4g daily of omega-3 fatty acids (Omacor). A standard fat load 17 (90g) was administered and blood sampling was performed in the fasting state and at 2, 4, 6 and 8h after disease the fat load. Chylomicrons and VLDL(1) density fraction was isolated from plasma by density ultracentrifugation. Postprandial chylomicron and VLDL(1) triglyceride an concentrations were measured and quantified using the incremental area under the curve (AUC) method. RESULTS: Baseline postprandial chylomicron TG AUC high was greater in patients compared with controls: median 18.5mmol/lh (interquartile range 8.9-32.6) vs 9.3mmol/lh (4.8-14.4) p= .05. Following treatment patient chylomicron RESULTS: AUC fell [mean reduction 6.8mmol/lh (95% CI .1-13.6) p= .05]. No significant reduction in chylomicron AUC was observed in the controls Postprandial [mean reduction 3.9mmol/lh (95% CI -3.6 to 11.5)]. As a result, following 8 weeks treatment with omega-3 fatty acids, patient (AUC) and control chylomicron AUC were no longer significantly different [patients 13.5mmol/lh (7.4-22.9), controls 7.2mmol/lh (4.6-14.5) both median and IQR, p=nsd].daily VLDL(1) TG AUC did not differ at baseline between patients and controls. Furthermore, there was no significant effect on VLDL(1)CI AUC following treatment in either group. CONCLUSIONS: We have shown that there is an excess of postprandial chylomicron density fraction concentrations in patients with nephrotic range proteinuria, which is reduced by treatment with omega-3 fatty acids. We suggest that this would lipoproteins be an ideal therapy in combination with statins for this high risk group of patients.

Objective:markers To clarify the association of circulating levels of leptin with risk for CVD events and new onset diabetes in men than and women. Research Design and Methods: We related baseline leptin levels to CVD events (n=864) and incident diabetes (n=289) in risk the elderly (n=5672) over 3.2 years follow-up. Results: In treatment, age, and country adjusted models, leptin was not associated with country risk of CVD in men (HR 1.02 [95%CI .90-1.16] per unit log-leptin increase) or women (HR 1.05 [ .91-1.20]), but did retained associate with risk for diabetes in men (HR 2.75 [2.14-3.52]) and women (HR 1.54 [1.22-1.94]). After adjusting for classical risk events factors, BMI, CRP and glucose, the diabetes association in men retained significance (HR 1.85 [1.30-2.63]), but not in women (HR incident .89 [ .64-1.26]). Conclusions: Leptin, like other markers of adiposity in general, is more strongly related to risk of diabetes than Design CVD in the elderly.

PURPOSE New OF REVIEW: To assess recent advances in cardiovascular disease biomarkers, focusing on past failings, current promise, and areas for future risk work. RECENT FINDINGS: Despite intense interest in novel biomarkers, few have yet to show utility in improving cardiovascular disease risk been scores as assessed by predictive statistical models. Indeed, there is current debate as to how to evaluate clinical utility. There metabolic is increasing interest in biomarkers from pathophysiological pathways other than inflammation (cardiac signals, renal function, metabolic measures, novel lipids, nutritional,further etc), as well as interest in combining such markers in panels to increase cardiovascular disease risk discrimination, and in 'omics'future techniques. A challenge to the biomarker concept in cardiovascular disease is the contribution of other factors - for example, socioeconomic as position or family history of premature cardiovascular disease - that present cheaper and more efficient way of gaining discrimination. Some show have been added already to risk score guidelines in some countries. Whether novel plasma biomarkers can add further prediction requires way. study. SUMMARY: The jury is still out on the ability of biomarkers to enhance risk scores in a cost-efficient way.raised New technologies and statistical models may optimize efforts but use of simpler lifestyle and demographic markers in recent risk scores concept revisions have raised the bar.

Inflammation C804A plays a prominent role in the development of atherosclerosis, which is the most important risk factor for vascular events. Lymphotoxin-alpha is (LTA) is a pro-inflammatory cytokine and is found to be expressed in atherosclerotic lesions. We investigated the association between the endpoint C804A polymorphism within the LTA gene and coronary and cerebrovascular events in 5804 participants of the PROspective Study of Pravastatin primary in the Elderly at Risk (PROSPER). The primary endpoint was the combined endpoint of death from coronary heart disease, non-fatal we myocardial infarction, and clinical stroke. Secondary endpoints were the coronary and cerebrovascular components separately. All associations were assessed with a vascular Cox-proportional hazards model adjusted for sex, age, pravastatin use, and country. Our overall analysis showed a significant association between the and C804A polymorphism and the primary endpoint (p= .03). After stratification for gender, this association was found only in males. Furthermore, we be found that the association between the C804A polymorphism and the primary endpoint was mainly attributable to clinical strokes (p= .02). The The C804A polymorphism in the LTA gene associates with clinical stroke, especially in men. But further research is warranted to confirm confirm our results.

BACKGROUND:populations, Clinical use of criteria for metabolic syndrome to simultaneously predict risk of cardiovascular disease and diabetes remains uncertain. We investigated algorithms to what extent metabolic syndrome and its individual components were related to risk for these two diseases in elderly populations.strong METHODS: We related metabolic syndrome (defined on the basis of criteria from the Third Report of the National Cholesterol Education aged Program) and its five individual components to the risk of events of incident cardiovascular disease and type 2 diabetes in cardiovascular 4812 non-diabetic individuals aged 70-82 years from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). We corroborated related these data in a second prospective study (the British Regional Heart Study [BRHS]) of 2737 non-diabetic men aged 60-79 years.individuals FINDINGS: In PROSPER, 772 cases of incident cardiovascular disease and 287 of diabetes occurred over 3.2 years. Metabolic syndrome was from not associated with increased risk of cardiovascular disease in those without baseline disease (hazard ratio 1.07 [95% CI .86-1.32]) but in was associated with increased risk of diabetes (4.41 [3.33-5.84]) as was each of its components, particularly fasting glucose (18.4 [13.9-24.5]).UK Results were similar in participants with existing cardiovascular disease. In BRHS, 440 cases of incident cardiovascular disease and 105 of of diabetes occurred over 7 years. Metabolic syndrome was modestly associated with incident cardiovascular disease (relative risk 1.27 [1.04-1.56]) despite strong disease association with diabetes (7.47 [4.90-11.46]). In both studies, body-mass index or waist circumference, triglyceride, and glucose cutoff points were not increased associated with risk of cardiovascular disease, but all five components were associated with risk of new-onset diabetes. INTERPRETATION: Metabolic syndrome second and its components are associated with type 2 diabetes but have weak or no association with vascular risk in elderly cardiovascular populations, suggesting that attempts to define criteria that simultaneously predict risk for both cardiovascular disease and diabetes are unhelpful. Clinical disease focus should remain on establishing optimum risk algorithms for each disease. FUNDING: Diabetes UK and British Heart Foundation.