The Course of Skin and Serum Biomarkers of Advanced Glycation Endproducts and Its Association with Oxidative Stress, Inflammation, Disease Severity, and Mortality during ICU Admission in Critically Ill Patients: Results from a Prospective Pilot Study.

BACKGROUND: Advanced glycation end products (AGEs) have been implicated in multiple organ failure, predominantly via their cellular receptor (RAGE) in preclinical studies. Little is known about the time course and prognostic relevance of AGEs in critically ill human patients, including those with severe sepsis. OBJECTIVE: 1) To explore the reliability of Skin Autofluorescence (AF) as an index of tissue AGEs in ICU patients, 2) to compare its levels to healthy controls, 3) to describe the time course of AGEs and influencing factors during ICU admission, and 4) to explore their association with disease severity, outcome, and markers of oxidative stress and inflammation. METHODS: Skin AF, serum N"-(carboxyethyl)lysine (CEL), N"-(carboxymethyl)lysine (CML), and soluble RAGE (sRAGE) were serially measured for a maximum of 7 days in critically ill ICU patients with multiple organ failure and compared to age-matched healthy controls. Correlations with (changes in) clinical parameters of disease severity, LDL dienes, and CRP were studied and survival analysis for in-hospital mortality was performed. RESULTS: Forty-five ICU patients (age: 59±15 years; 60% male), and 37 healthy controls (59±14; 68%) were included. Skin AF measurements in ICU patients were reproducible (CV right-left arm: 13%, day-to-day: 10%), with confounding effects of skin reflectance and plasma bilirubin levels. Skin AF was higher in ICU patients vs healthy controls (2.7±0.7 vs 1.8±0.3 au; p<0.001). Serum CEL (23±10 vs, 16±3 nmol/gr protein; p<0.001), LDL dienes (19 (15-23) vs. 9 (8-11) µmol/mmol cholesterol; <0.001), and sRAGE (1547 (998-2496) vs. 1042 (824-1388) pg/ml; p = 0.003) were significantly higher in ICU patients compared to healthy controls, while CML was not different (27 (20-39) vs 29 (25-33) nmol/gr protein). While CRP and LDL dienes decreased significantly, Skin AF and serum AGEs and sRAGE did not change significantly during the first 7 days of ICU admission. CML and CEL were strongly correlated with SOFA scores and CML above the median at baseline was associated with increased risk for mortality (Hazard ratio 3.3 (1.3-8.3); p = 0.01). All other markers did not correlate with disease severity and did not predict mortality. CONCLUSIONS: This study demonstrates that markers for the AGE-RAGE axis are elevated in critically ill patients compared to healthy controls but remain stable for at least 7 days despite clearly fading inflammation and oxidative stress. Circulating AGEs may be associated with disease severity and outcome. Further research should be conducted to elucidate the role of the AGE-RAGE axis in the exaggerated inflammatory response leading to multiple organ failure and death, and whether or not this may be a target for treatment.

Is lipoprotein (a) protective of dementia?

Lipoprotein(a) [Lp(a)]-an established risk factor for vascular disease, has been suggested to be associated with risk of dementia, however no prospective evidence exists to support this finding. We aimed to assess the association of Lp(a) with dementia risk. Lp(a) concentration was assessed at baseline in a prospective cohort of 2532 men aged 42-61 years. During a median follow-up of 24.9 years, 228 new cases of dementia were recorded. Lp(a) was approximately log-linearly associated with dementia risk. In age-adjusted analysis, the hazard ratio for dementia in a comparison of extreme quartiles of Lp(a) levels was 0.68 (95 % CI: 0.47-0.99), which persisted after adjustment for several physical measures, history of coronary heart disease, smoking status, history of diabetes, serum lipids, alcohol consumption, and socio-economic status 0.68 (0.46-0.99). Lp(a) is protective of future dementia risk in a middle-aged male Caucasian population. Further research is needed replicate these findings.

Lipoprotein(a) and risk of sudden cardiac death in middle-aged Finnish men: A new prospective cohort study.

BACKGROUND: Lipoprotein(a) [Lp(a)] is an established and independent risk factor for cardiovascular outcomes. However, the relationship of Lp(a) with risk of sudden cardiac death (SCD) is unknown. We aimed to assess the association of Lp(a) with risk of SCD in the Kuopio Ischemic Heart Disease prospective cohort study of 1881 men aged 42-61years at recruitment. METHODS AND RESULTS: Plasma Lp(a) concentration was assessed at baseline and repeat measurements made several years apart. After a median follow-up of 24.7years, 141 SCDs were recorded. Hazard ratios (HRs) (95% confidence intervals [CI]) were assessed and were corrected for within-person variability in Lp(a) levels. The regression dilution ratio of loge Lp(a) adjusted for age was 0.84 (95% CI: 0.81-0.88). Lipoprotein(a) levels were log-linearly associated with risk of SCD. In analyses adjusted for established risk factors, the HR (95% CI) for SCD per 1 standard deviation (3.56-fold) higher baseline loge Lp(a) was 1.24 (1.05-1.47; P=0.013). This remained consistent on further adjustment for alcohol consumption, resting heart rate, lipids, and C-reactive protein 1.23 (1.04-1.46; P=0.018). HRs remained unchanged after accounting for incident coronary events and did not vary importantly in several relevant clinical subgroups. Adding Lp(a) to a SCD risk prediction model did not significantly improve risk discrimination beyond established risk factors, but improved the continuous net reclassification 30.2% (1.1 to 59.2%, P=0.042). CONCLUSIONS: Available evidence shows a continuous and independent association between Lp(a) levels and risk of SCD. Further research is needed to replicate these findings.

Olive Oil Polyphenols Decrease LDL Concentrations and LDL Atherogenicity in Men in a Randomized Controlled Trial.

BACKGROUND: Olive oil polyphenols have shown protective effects on cardiovascular risk factors. Their consumption decreased oxidative stress biomarkers and improved some features of the lipid profile. However, their effects on LDL concentrations in plasma and LDL atherogenicity have not yet been elucidated. OBJECTIVE: Our objective was to assess whether the consumption of olive oil polyphenols could decrease LDL concentrations [measured as apolipoprotein B-100 (apo B-100) concentrations and the total number of LDL particles] and atherogenicity (the number of small LDL particles and LDL oxidizability) in humans. METHODS: The study was a randomized, cross-over controlled trial in 25 healthy European men, aged 20-59 y, in the context of the EUROLIVE (Effect of Olive Oil Consumption on Oxidative Damage in European Populations) study. Volunteers ingested 25 mL/d raw low-polyphenol-content olive oil (LPCOO; 366 mg/kg) or high-polyphenol-content olive oil (HPCOO; 2.7 mg/kg) for 3 wk. Interventions were preceded by 2-wk washout periods. Effects of olive oil polyphenols on plasma LDL concentrations and atherogenicity were determined in the sample of 25 men. Effects on lipoprotein lipase (LPL) gene expression were assessed in another sample of 18 men from the EUROLIVE study. RESULTS: Plasma apo B-100 concentrations and the number of total and small LDL particles decreased (mean ± SD: by 5.94% ± 16.6%, 11.9% ± 12.0%, and 15.3% ± 35.1%, respectively) from baseline after the HPCOO intervention. These changes differed significantly from those after the LPCOO intervention, which resulted in significant increases of 6.39% ± 16.6%, 4.73% ± 22.0%, and 13.6% ± 36.4% from baseline (P < 0.03). LDL oxidation lag time increased by 5.0% ± 10.3% from baseline after the HPCOO intervention, which was significantly different only relative to preintervention values (P = 0.038). LPL gene expression tended to increase by 26% from baseline after the HPCOO intervention (P = 0.08) and did not change after the LPCOO intervention. CONCLUSION: The consumption of olive oil polyphenols decreased plasma LDL concentrations and LDL atherogenicity in healthy young men. This trial was registered at www.controlled-trials.com as ISRCTN09220811.

Olive oil polyphenols enhance high-density lipoprotein function in humans: a randomized controlled trial.

OBJECTIVE: Olive oil polyphenols have shown beneficial properties against cardiovascular risk factors. Their consumption has been associated with higher cholesterol content in high-density lipoproteins (HDL). However, data on polyphenol effects on HDL quality are scarce. We, therefore, assessed whether polyphenol-rich olive oil consumption could enhance the HDL main function, its cholesterol efflux capacity, and some of its quality-related properties, such HDL polyphenol content, size, and composition. APPROACH AND RESULTS: A randomized, crossover, controlled trial with 47 healthy European male volunteers was performed. Participants ingested 25 mL/d of polyphenol-poor (2.7 mg/kg) or polyphenol-rich (366 mg/kg) raw olive oil in 3-week intervention periods, preceded by 2-week washout periods. HDL cholesterol efflux capacity significantly improved after polyphenol-rich intervention versus the polyphenol-poor one (+3.05% and -2.34%, respectively; P=0.042). Incorporation of olive oil polyphenol biological metabolites to HDL, as well as large HDL (HDL2) levels, was higher after the polyphenol-rich olive oil intervention, compared with the polyphenol-poor one. Small HDL (HDL3) levels decreased, the HDL core became triglyceride-poor, and HDL fluidity increased after the polyphenol-rich intervention. CONCLUSIONS: Olive oil polyphenols promote the main HDL antiatherogenic function, its cholesterol efflux capacity. These polyphenols increased HDL size, promoted a greater HDL stability reflected as a triglyceride-poor core, and enhanced the HDL oxidative status, through an increase in the olive oil polyphenol metabolites content in the lipoprotein. Our results provide for the first time a first-level evidence of an enhancement in HDL function by polyphenol-rich olive oil.

Prediagnostic circulating markers of inflammation and risk of prostate cancer.

Accruing evidence suggests that inflammation plays a role in prostate carcinogenesis. However, studies evaluating this association using C-reactive protein (CRP) and interleukin-6 as markers of inflammation have reported conflicting results. We investigated the associations of three common markers of inflammation (CRP, fibrinogen and leukocyte count) with the risk of prostate cancer in a prospective cohort of 2,571 men from Finland. During an average follow-up period of 24 years (21-26 years), 203 men from the cohort who developed prostate cancer were identified via linkage to the nationwide Finnish Cancer Registry. We investigated the associations between the markers and the risk of prostate cancer using Cox proportional hazards model, adjusting for potential confounders. Elevated prediagnostic leukocyte count was associated with an increased risk of prostate cancer. In multivariable adjusted model, the relative risk of prostate cancer among men in the highest tertile of leukocyte count compared to men in the lowest tertile was 1.60 (95% confidence interval [CI] = 1.10-2.29, p-trend = 0.01). Circulating CRP and fibrinogen were not associated with increased risk. The corresponding relative risks for elevated CRP and fibrinogen concentrations were 1.08 (95% CI: 0.74-1.60, p-trend = 0.56) and 1.25 (95% CI: 0.87-1.81, p-trend = 0.14), respectively. Men with elevated leukocyte counts had a 2.57-fold (95% CI: 0.99-6.79) increased risk of prostate cancer mortality. The increased risk associated with elevated leukocyte counts warrants confirmation in other studies. Larger studies should consider combining at least two markers or using an inflammation score derived from many inflammatory markers to evaluate prostate cancer risk.

A gene-centric study of common carotid artery remodelling.

BACKGROUND: Expansive remodelling is the process of compensatory arterial enlargement in response to atherosclerotic stimuli. The genetic determinants of this process are poorly characterized. METHODS: Genetic association analyses of inter-adventitial common carotid artery diameter (ICCAD) in the IMPROVE study (n = 3427) using the Illumina 200k Metabochip was performed. Single nucleotide polymorphisms (SNPs) that met array-wide significance were taken forward for analysis in three further studies (n = 5704), and tested for association with Abdominal Aortic Aneurysm (AAA). RESULTS: rs3768445 on Chromosome 1q24.3, in a cluster of protein coding genes (DNM3, PIGC, C1orf105) was associated with larger ICCAD in the IMPROVE study. For each copy of the rare allele carried, ICCAD was on average 0.13 mm greater (95% CI 0.08-0.18 mm, P = 8.2 × 10(-8)). A proxy SNP (rs4916251, R(2) = 0.99) did not, however, show association with ICCAD in three follow-up studies (P for replication = 0.29). There was evidence of interaction between carotid intima-media thickness (CIMT) and rs4916251 on ICCAD in two of the cohorts studies suggesting that it plays a role in the remodelling response to atherosclerosis. In meta-analysis of 5 case-control studies pooling data from 5007 cases and 43,630 controls, rs4916251 was associated with presence of AAA 1.10, 95% CI 1.03-1.17, p = 2.8 × 10(-3), I(2) = 18.8, Q = 0.30). A proxy SNP, rs4916251 was also associated with increased expression of PIGC in aortic tissue, suggesting that this may the mechanism by which this locus affects vascular remodelling. CONCLUSIONS: Common variation at 1q24.3 is associated with expansive vascular remodelling and risk of AAA. These findings support a hypothesis that pathways involved in systemic vascular remodelling play a role in AAA development.

Identification of the BCAR1-CFDP1-TMEM170A locus as a determinant of carotid intima-media thickness and coronary artery disease risk.

BACKGROUND: Carotid intima-media thickness (cIMT) is a widely accepted marker of subclinical atherosclerosis. To date, large-scale investigations of genetic determinants of cIMT are sparse. METHODS AND RESULTS: To identify cIMT-associated genes and genetic variants, a discovery analysis using the Illumina 200K CardioMetabochip was conducted in 3430 subjects with detailed ultrasonographic determinations of cIMT from the IMPROVE (Carotid Intima Media Thickness [IMT] and IMT-Progression as Predictors of Vascular Events in a High Risk European Population) study. Segment-specific IMT measurements of common carotid, bifurcation, and internal carotid arteries, and composite IMT variables considering the whole carotid tree (IMT(mean), IMT(max), and IMT(mean-max)), were analyzed. A replication stage investigating 42 single-nucleotide polymorphisms for association with common carotid IMT was undertaken in 5 independent European cohorts (total n=11,590). A locus on chromosome 16 (lead single-nucleotide polymorphism rs4888378, intronic in CFDP1) was associated with cIMT at significance levels passing multiple testing correction at both stages (array-wide significant discovery P=6.75 × 10(-7) for IMT(max); replication P=7.24×10(-6) for common cIMT; adjustments for sex, age, and population substructure where applicable; minor allele frequency 0.43 and 0.41, respectively). The protective minor allele was associated with lower carotid plaque score in a replication cohort (P=0.04, n=2120) and lower coronary artery disease risk in 2 case-control studies of subjects with European ancestry (odds ratio [95% confidence interval] 0.83 [0.77-0.90], P=6.53 × 10(-6), n=13 591; and 0.95 [0.92-0.98], P=1.83 × 10(-4), n=82 297, respectively). Queries of human biobank data sets revealed associations of rs4888378 with nearby gene expression in vascular tissues (n=126-138). CONCLUSIONS: This study identified rs4888378 in the BCAR1-CFDP1-TMEM170A locus as a novel genetic determinant of cIMT and coronary artery disease risk in individuals of European descent.

Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism.

OBJECTIVES: The purpose of this study is investigate the effects of variants in the apolipoprotein(a) gene (LPA) on vascular diseases with different atherosclerotic and thrombotic components. BACKGROUND: It is unclear whether the LPA variants rs10455872 and rs3798220, which correlate with lipoprotein(a) levels and coronary artery disease (CAD), confer susceptibility predominantly via atherosclerosis or thrombosis. METHODS: The 2 LPA variants were combined and examined as LPA scores for the association with ischemic stroke (and TOAST [Trial of Org 10172 in Acute Stroke Treatment] subtypes) (effective sample size [n(e)] = 9,396); peripheral arterial disease (n(e) = 5,215); abdominal aortic aneurysm (n(e) = 4,572); venous thromboembolism (n(e) = 4,607); intracranial aneurysm (n(e) = 1,328); CAD (n(e) = 12,716), carotid intima-media thickness (n = 3,714), and angiographic CAD severity (n = 5,588). RESULTS: LPA score was associated with ischemic stroke subtype large artery atherosclerosis (odds ratio [OR]: 1.27; p = 6.7 × 10(-4)), peripheral artery disease (OR: 1.47; p = 2.9 × 10(-14)), and abdominal aortic aneurysm (OR: 1.23; p = 6.0 × 10(-5)), but not with the ischemic stroke subtypes cardioembolism (OR: 1.03; p = 0.69) or small vessel disease (OR: 1.06; p = 0.52). Although the LPA variants were not associated with carotid intima-media thickness, they were associated with the number of obstructed coronary vessels (p = 4.8 × 10(-12)). Furthermore, CAD cases carrying LPA risk variants had increased susceptibility to atherosclerotic manifestations outside of the coronary tree (OR: 1.26; p = 0.0010) and had earlier onset of CAD (-1.58 years/allele; p = 8.2 × 10(-8)) than CAD cases not carrying the risk variants. There was no association of LPA score with venous thromboembolism (OR: 0.97; p = 0.63) or intracranial aneurysm (OR: 0.85; p = 0.15). CONCLUSIONS: LPA sequence variants were associated with atherosclerotic burden, but not with primarily thrombotic phenotypes.

Protection of LDL from oxidation by olive oil polyphenols is associated with a downregulation of CD40-ligand expression and its downstream products in vivo in humans.

BACKGROUND: Recently, the European Food Safety Authority approved a claim concerning the benefits of olive oil polyphenols for the protection of LDL from oxidation. Polyphenols could exert health benefits not only by scavenging free radicals but also by modulating gene expression. OBJECTIVE: We assessed whether olive oil polyphenols could modulate the human in vivo expressions of atherosclerosis-related genes in which LDL oxidation is involved. DESIGN: In a randomized, crossover, controlled trial, 18 healthy European volunteers daily received 25 mL olive oil with a low polyphenol content (LPC: 2.7 mg/kg) or a high polyphenol content (HPC: 366 mg/kg) in intervention periods of 3 wk separated by 2-wk washout periods. RESULTS: Systemic LDL oxidation and monocyte chemoattractant protein 1 and the expression of proatherogenic genes in peripheral blood mononuclear cells [ie, CD40 ligand (CD40L), IL-23α subunit p19 (IL23A), adrenergic ß-2 receptor (ADRB2), oxidized LDL (lectin-like) receptor 1 (OLR1), and IL-8 receptor-α (IL8RA)] decreased after the HPC intervention compared with after the LPC intervention. Random-effects linear regression analyses showed 1) a significant decrease in CD40, ADRB2, and IL8RA gene expression with the decrease of LDL oxidation and 2) a significant decrease in intercellular adhesion molecule 1 and OLR1 gene expression with increasing concentrations of tyrosol and hydroxytyrosol in urine. CONCLUSIONS: In addition to reducing LDL oxidation, the intake of polyphenol-rich olive oil reduces CD40L gene expression, its downstream products, and related genes involved in atherogenic and inflammatory processes in vivo in humans. These findings provide evidence that polyphenol-rich olive oil can act through molecular mechanisms to provide cardiovascular health benefits. This trial was registered at www.controlled-trials.com as ISRCTN09220811.

The effect of olive oil polyphenols on antibodies against oxidized LDL. A randomized clinical trial.

BACKGROUND & AIM: Oxidized LDL (oxLDL) is a highly immunogenic particle that plays a key role in the development of atherosclerosis. Some data suggest a protective role of OxLDL autoantibodies (OLAB) in atherosclerosis. Our aim was to assess the effect of olive oil polyphenols on the immunogenicity of oxLDL to autoantibody generation. METHODS: In a crossover, controlled trial, 200 healthy men were randomly assigned to 3-week sequences of 25 mL/day of 3 olive oils with high (366 mg/kg), medium (164 mg/kg), and low (2.7 mg/kg) phenolic content. RESULTS: Plasma OLAB concentration was inversely associated with oxLDL (p < 0.001). Olive oil phenolic content increased OLAB generation, with the effect being stronger at higher concentrations of oxLDL (p = 0.020 for interaction). A direct relationship was observed between OLAB and the total olive oil phenol content in LDL (r = 0.209; p = 0.014). OLAB concentrations, adjusted for oxLDL, increased directly in a dose-dependent manner with the polyphenol content of the olive oil administered (p = 0.023). CONCLUSION: Olive oil polyphenols promote OLAB generation. This effect is stronger at higher concentrations of lipid oxidative damage.

Lycopene, lutein and beta-carotene as determinants of LDL conjugated dienes in serum.

Oxidative modification of low-density lipoprotein (LDL) in the vascular endothelium is considered to be important in the development of early atherosclerosis. The aim of this study was to investigate the main determinants of serum LDL conjugated dienes in women (n=124) and men (n=225). We focused on the influence of fat-soluble vitamins and carotenoids on the concentration of conjugated dienes in LDL. In multivariate linear regression models, including age, body mass index, diastolic blood pressure, symptomatic ischaemic heart disease (IHD) or IHD history, statin medication, leukocytes and serum triglycerides as covariates, plasma lycopene (standardized beta=-0.33; P=0.002) and lutein (standardized beta=-0.22; P=0.027) concentrations were the strongest determinants of serum LDL conjugated dienes in women, whereas plasma beta-carotene (standardized beta=-0.23; P=0.002) was the most important factor in men. Furthermore, statin medication, diastolic blood pressure, age and serum triglycerides were significant determinants of LDL conjugated dienes. The regression model with lycopene contributed to 29% in women and 15% in men with beta-carotene of the variation of serum LDL conjugated dienes. Results of the present study suggest that plasma lycopene, lutein and beta-carotene are the most powerful antioxidants for explaining the content of in vivo oxidatively modified LDL in serum.

Cross-sectional analysis of baseline data to identify the major determinants of carotid intima-media thickness in a European population: the IMPROVE study.

AIMS: The 'IMPROVE study' was designed to investigate whether cross-sectional carotid artery intima-media thickness (IMT) and overall IMT progression are predictors of new vascular events in European individuals at high risk of cardiovascular diseases. This paper reports the results of the baseline analyses aimed at identifying the major determinants of increased carotid IMT (C-IMT). METHODS AND RESULTS: IMPROVE is a prospective, multicentre, longitudinal, observational study. A total of 3711 subjects (age range 54-79 years) with at least three vascular risk factors (VRFs) were recruited in seven centres in Finland, France, Italy, the Netherlands, and Sweden. Collected variables included clinical, biochemical, genetic, socioeconomic, psychological, nutritional, and educational data, personal and family history of diseases, drug intake, and physical activity. By multiple linear regression analysis, C-IMT was positively associated with latitude, age, gender, pulse pressure, pack-years, and hypertension, and inversely with educational level (all P < 0.0001 for IMT(mean-max)). Latitude was the strongest independent determinant of C-IMT (partial r(2) for IMT(mean-max) = 0.109, P < 0.0001) and alone accounted for nearly half of the variation explained by the regression model (partial r(2) for IMT(mean-max) = 0.243, P < 0.0001). The geographical gradient for C-IMT paralleled the well-known north-to-south cardiovascular mortality gradient (r(2) for IMT(mean) = 0.96). CONCLUSION: Latitude is an important determinant of C-IMT, which is not explained by between-country differences in established VRFs. Other unknown contributory mechanisms such as heritable, nutritional, or environmental factors may be important in the genesis of this geographical gradient.

Serum lycopene and the risk of cancer: the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) study.

PURPOSE: Lycopene is thought to decrease the risk of cancers, although previous epidemiologic studies have produced inconsistent results. The aim of the present study was to evaluate the protective effect of lycopene against the risk of cancer. METHODS: The study population consisted of 997 middle-aged Finnish men in the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) cohort. During the mean follow-up time of 12.6 years, a total of 141 cancer cases appeared, of which 55 were prostate cancers. The association between the serum concentrations of lycopene and the risk of cancer was studied using the Cox proportional hazard models. RESULTS: An inverse association was observed between serum lycopene and overall cancer incidence. The adjusted risk ratio (RR) in the highest tertile of serum lycopene was 0.55 (95% confidence interval [CI], 0.34-0.89; p=0.015) compared with the lowest serum lycopene group. No association was observed between the lycopene concentrations and a prostate cancer risk. RR for other cancers was 0.43 (95% CI, 0.23-0.79; p=0.007). CONCLUSIONS: These findings suggest that in middle-aged men, the higher circulating concentrations of lycopene may contribute to the lower risk of cancer, with the exception of prostate cancer.

Hopelessness -- novel facet of the metabolic syndrome in men.

AIMS: Recent studies have shown that lack of hope is linked to cardiovascular morbidity and mortality. Little is known, however, about the relationship of hopelessness and the metabolic syndrome. The aim of this study is to examine the association of hopelessness and the metabolic syndrome. METHODS: This cross-sectional study examines the relationship between hopelessness and the metabolic syndrome as defined by the National Cholesterol Education Program in a population-based cohort of 1743 non-diabetic men aged 42, 48, 54 and 60 years old at baseline (1984-89). Hopelessness was measured by one's expectations about the future and reaching goals. RESULTS: In simple age-adjusted univariate analyses the prevalence of the metabolic syndrome, many of its components and other cardiovascular risk factors were more common in men with higher levels of hopelessness. In a logistic regression model adjusted for age, smoking, alcohol consumption, cardiovascular disease, adult socioeconomic status and physical activity, men in the highest third were 2.1 (95% CI 1.3-3.2) times more likely to have the metabolic syndrome than those in the lowest third. After further adjusting for body mass index and elevated depressive symptoms the respective figures were 1.9 (95% CI 1.2-3.1) and 2.1 (95% CI 1.4-3.4). CONCLUSIONS: Hopelessness was strongly associated with the metabolic syndrome in these middle-aged men, independent of other depressive symptoms and traditional cardiovascular risk factors. These findings suggest that hopelessness is very closely related to the metabolic syndrome. Therefore lifestyle management of the metabolic syndrome should also take into account patients' expectations more thoroughly than hitherto acknowledged.

Changes in LDL fatty acid composition as a response to olive oil treatment are inversely related to lipid oxidative damage: The EUROLIVE study.

OBJECTIVE: The aim of our study was to assess the changes in the fatty acid composition of low density lipoproteins (LDL) after sustained consumption of olive oil at real-life doses (25 mL/day) and their relationship with lipid oxidative damage. METHODS: A multi-center randomized, cross-over, clinical trial with 3 similar types of olive oils, but with differences in the phenolic content, was conducted on 200 healthy European subjects. Intervention periods were of 3 weeks separated by 2-week washout periods. The LDL fatty acid content was measured in samples drawn at baseline and after the last intervention period. RESULTS: After olive oil ingestion oleic acid concentration in LDL increased (1.9%; p < 0.001) and those of linoleic (1.1%; p < 0.002) and arachidonic acid (0.5%; p < 0.001) decreased. Monounsaturated/polyunsaturated fatty acid and oleic/linoleic acid ratios in LDL increased after olive oil consumption. An inverse relationship between the oleic/linoleic acid ratio and biomarkers of oxidative stress was observed. One unit increase in the oleic/linoleic acid ratio was associated with a decrease of 4.2 microg/L in plasma isoprostanes. CONCLUSION: Consumption of olive oil at real-life doses improved the fatty acid profile in LDL, the changes being associated with a reduction of the oxidative damage to lipids.

Simultaneous measurement of retinol, alpha-tocopherol and six carotenoids in human plasma by using an isocratic reversed-phase HPLC method.

A simple and sensitive isocratic reversed-phase high-performance liquid chromatography (HPLC) method for simultaneous determination of retinol, alpha-tocopherol and six carotenoids in human plasma was described. Sample preparation of the earlier published method was further developed by addition of ultrapure water, which enabled aqueous layer to freeze facilitating phase separation without pipetting thus also improving precision of the method. Developed method appeared to be less laborious and time consuming compared to the traditional extraction methods, which require removal of organic layer by pipetting. The recoveries (absolute and relative) were between 80% and 103%. The intra-assay CVs were 1.1-4.0% (normal level) and 3.3-9.0% (low level). Inter-assay CVs were 5.3-8.8%. Reference method for all these analytes was not available, but a comparison with another published method was carried out. The results of the comparison matched satisfactorily. The method is used routinely in our laboratory in a large population-based study.

Dyslipidaemia as a predictor of hypertension in middle-aged men.

AIMS: Dyslipidaemia and hypertension are features of the metabolic syndrome, but the role of dyslipidaemia in the development of hypertension is less clear. We assessed the association of dyslipidaemia with incident hypertension during a 7-year follow-up in a population-based cohort of middle-aged men without hypertension at baseline. METHODS AND RESULTS: In all, 88 of 311 men developed hypertension during the follow-up. A 1-SD increment in triglyceride concentrations was associated with a 1.6-fold [95% CI(confidence interval) 1.2-2.3] increased risk of developing hypertension, independently of features related to the metabolic syndrome. In separate multivariable models, the triglyceride content of high-density lipoprotein (HDL) cholesterol and apolipoprotein B concentrations were also associated with new-onset hypertension. In a stepwise backwards logistic regression model, concentrations of low-density lipoprotein (LDL) cholesterol [odds ratio (OR) 1.3, 95% CI 1.0-1.7 for a 1-SD change] and triglyceride content of HDL cholesterol (OR) 1.5, 95% CI 1.1-1.9) were positively associated with incident hypertension, whereas HDL concentrations (OR 0.7, 95% CI 0.5-0.9) seemed protective. In factor analyses, elevated triglyceride levels and related disturbances in lipid and cholesterol metabolism were associated with new-onset hypertension. CONCLUSION: Dyslipidaemia characteristic of the metabolic syndrome predicts the development of hypertension during a 7-year follow-up of eastern Finnish men, independently of features related to insulin resistance. The recognition of dyslipidaemia and initiation of lifestyle treatment even in the absence of hypertension is likely to reduce the long-term burden of cardiovascular disease.

Apolipoprotein E polymorphism is associated with both carotid and coronary atherosclerosis in patients with coronary artery disease.

BACKGROUND AND AIMS: Apolipoprotein E (apoE) polymorphism plays a significant role in the development of atherosclerosis and cardiovascular disease. Therefore, the aim of the present study was to examine the association between apoE polymorphism and carotid intima-media thickness (IMT), and severity and extent of coronary artery disease (CAD). METHODS AND RESULTS: B-mode ultrasound and quantitative coronary angiography (QCA) were used to assess carotid, and coronary artery atherosclerosis in 91 patients with clinically suspected CAD referred for cardiac catheterization. Two apoE phenotype groups were defined: apoE3 (E3/E3) and apoE4 (including E4/E3, E4/E4 phenotypes). Maximum IMT was higher in the apoE4 group than in the apoE3 group (p=0.022). The global atheroma burden index was similarly higher in the apoE4 group than in the apoE3 group (p=0.033). ApoE4 subjects had higher levels of apolipoprotein B (apoB) (p=0.008), triglycerides (p=0.006), remnant lipoprotein-cholesterol (RLP-C) (p=0.023), and lipoprotein(a) [(Lp(a)] (p=0.041) than apoE3 subjects. The mean LDL particle size was smaller in the apoE4 group than in the apoE3 group (p=0.041). CONCLUSIONS: ApoE polymorphism was associated with both carotid and coronary atherosclerosis. Patients with the apoE4 isoform had an increased carotid IMT and a more severe and extensive CAD than patients with the apoE3 isoform.

Serum matrix metalloproteinase-8 concentrations are associated with cardiovascular outcome in men.

OBJECTIVE: In culture studies matrix metalloproteinase (MMP)-8 thins the protecting fibrous cap of the atherosclerotic plaque thereby increasing its vulnerability. Results on the association of serum MMP-8 concentrations and cardiovascular diseases (CVD) are, however, scarce and contradictory. METHODS AND RESULTS: We analyzed the association between CVD or subclinical atherosclerosis and serum MMP-8 and tissue inhibitor of metalloproteinase-1 (TIMP-1) concentrations of 1018 men with the follow-up time of 10 years. MMP-8 concentrations or MMP-8/TIMP-1 ratios were higher in men with prevalent CVD or subclinical atherosclerosis at baseline than those without. In men free of CVD at baseline, MMP-8 concentrations associated with acute myocardial infarction, death from coronary heart disease (CHD), CVD, or from any cause with relative risks (RR) (95% CI) of 1.138 (1.009 to 1.284), 1.188 (1.034 to 1.365), 1.171 (1.026 to 1.338), and 1.136 (1.018 to 1.269), respectively, and MMP-8/TIMP-1 ratio with CHD death with an RR of 1.206 (1.028 to 1.414) per standard deviation (SD) increase. In men with no prevalent CVD but with subclinical atherosclerosis at baseline, elevated serum MMP-8 concentration predicted CVD death with an RR of 3.03 (1.09 to 8.44). TIMP-1 concentrations alone had no predictive value. CONCLUSIONS: The results indicate that serum MMP-8 concentrations are elevated in prevalent or subclinical atherosclerosis and associate with the worst cardiovascular outcome.