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Background: Aortic pulse wave velocity is a noninvasive measure of aortic stiffness and arterial aging. Its current value in cardiovascular risk estimation practice is unknown. We aimed to establish whether aortic pulse wave velocity identified individuals with higher risk of incident major adverse cardiovascular events and improved performance of the American Heart Association/American College of Cardiology atherosclerotic cardiovascular disease risk score.Methods: This prospective analysis included 3837 Whitehall II cohort participants screened in 2008 to 2009, and followed for 11.7 years (mean=10.3, SD=1.81), without history of stroke, myocardial infarction, or coronary heart disease.Results: Mean age of the sample was 65.0 years (SD=5.6), 2831 participants (73.8%) were male and mean atherosclerotic cardiovascular disease risk score was 13.8%. At the end of follow-up, 411 individuals (10.7%) had suffered a major cardiovascular event. Those in the highest aortic pulse wave velocity quartile were at high risk (hazard ratio, 2.99 [95% CI, 2.25-3.97]) and reached the threshold for statin medication (7.5% risk) after 5 years whereas others reached it after 10 years (difference P<0.001). The addition of aortic pulse wave velocity to the risk score improved the C statistic (0.68 versus 0.67, P=0.03) and net reclassification index (4.6%, P=0.04 and 11.3%, P=0.02).Conclusions: Our results show that aortic stiffness predicted major adverse cardiovascular events in a cohort of elderly individuals, improving the performance of a widely used cardiovascular disease risk estimator. Aortic pulse wave velocity measurement is scalable, radiation-free, and easy to perform. Further studies on its applicability in cardiovascular disease risk assessment in primary care settings are needed. [ABSTRACT FROM AUTHOR]

Whether poorer pulmonary function accelerates progression of arterial stiffness remains unknown as prior observational studies have not examined longitudinal changes in arterial stiffness in relation to earlier pulmonary function. Data (N=5342, 26% female) were drawn from the Whitehall II cohort study. Participants completed repeated assessments of forced expiratory volume in 1 second (FEV1, L) and carotid-femoral pulse wave velocity (cf-PWV, m/s) over 5 years. The effect of FEV1 on later cf-PWV and its progression was estimated using linear mixed-effects modeling. Possible explanatory mechanisms, such as mediation by low-grade systemic inflammation, common-cause explanation by preexisting cardiometabolic risk factors, and reverse-causation bias, were assessed. Poorer pulmonary function was associated with later higher cf-PWV and its subsequent progression (cf-PWV 5-year change 0.09, 95% CI 0.03-0.17 per SD lower FEV1) after adjustment for age, sex, ethnicity, heart rate, and mean arterial pressure. Decrease in pulmonary function was associated with later higher cf-PWV (0.17, 95% CI 0.04-0.30 in the top compared to bottom quartile of decline in FEV1). There was no evidence to support mediation by circulating CRP (C-reactive protein) or IL (interleukin)-6. Furthermore, arterial stiffness was not associated with later FEV1 after accounting for cardiometabolic status. In conclusion, poorer pulmonary function predicted future arterial stiffness. These findings support pulmonary function as a clinically important risk factor for arterial stiffness and provide justification for future intervention studies for pulmonary function based on its relationship with arterial stiffness. [ABSTRACT FROM AUTHOR]

Background--Adiponectin, a circulating adipocyte-derived protein, has insulin-sensitizing, anti-inflammatory, antiatherogenic, and cardiomyocyte-protective properties in animal models. However, the systemic effects of adiponectin in humans are unknown. Our aims were to define the metabolic profile associated with higher blood adiponectin concentration and investigate whether variation in adiponectin concentration affects the systemic metabolic profile. Methods and Results--We applied multivariable regression in ≤5909 adults and Mendelian randomization (using cis-acting genetic variants in the vicinity of the adiponectin gene as instrumental variables) for analyzing the causal effect of adiponectin in the metabolic profile of ≤37 545 adults. Participants were largely European from 6 longitudinal studies and 1 genome-wide association consortium. In the multivariable regression analyses, higher circulating adiponectin was associated with higher high-density lipoprotein lipids and lower very-low-density lipoprotein lipids, glucose levels, branched-chain amino acids, and inflammatory markers. However, these findings were not supported by Mendelian randomization analyses for most metabolites. Findings were consistent between sexes and after excluding high-risk groups (defined by age and occurrence of previous cardiovascular event) and 1 study with admixed population. Conclusions--Our findings indicate that blood adiponectin concentration is more likely to be an epiphenomenon in the context of metabolic disease than a key determinant. [ABSTRACT FROM AUTHOR]

We sought to determine whether adiposity in later midlife is an independent predictor of accelerated stiffening of the aorta. Whitehall II study participants (3789 men; 1383 women) underwent carotid-femoral applanation tonometry at the mean age of 66 and again 4 years later. General adiposity by body mass index, central adiposity by waist circumference and waist:hip ratio, and fat mass percent by body impedance were assessed 5 years before and at baseline. In linear mixed models adjusted for age, sex, ethnicity, and mean arterial pressure, all adiposity measures were associated with aortic stiffening measured as increase in pulse wave velocity (PWV) between baseline and follow-up. The associations were similar in the metabolically healthy and unhealthy, according to Adult Treatment Panel-III criteria excluding waist circumference. C-reactive protein and interleukin-6 levels accounted for part of the longitudinal association between adiposity and PWV change. Adjusting for chronic disease, antihypertensive medication and risk factors, standardized effects of general and central adiposity and fat mass percent on PWV increase (m/s) were similar (0.14, 95% confidence interval: 0.05-0.24, P=0.003; 0.17, 0.08-0.27, P<0.001; 0.14, 0.05-0.22, P=0.002, respectively). Previous adiposity was associated with aortic stiffening independent of change in adiposity, glycaemia, and lipid levels across PWV assessments. We estimated that the body mass index-linked PWV increase will account for 12% of the projected increase in cardiovascular risk because of high body mass index. General and central adiposity in later midlife were strong independent predictors of aortic stiffening. Our findings suggest that adiposity is an important and potentially modifiable determinant of arterial aging. [ABSTRACT FROM AUTHOR]

Secretory phospholipase A2 (sPLA2) enzymes are considered to play a role in atherosclerosis. sPLA2 activity encompasses several sPLA2 isoenzymes, including sPLA2-V. Although observational studies show a strong association between elevated sPLA2 activity and CHD, no assay to measure sPLA2-V levels exists, and the only evidence linking the sPLA2-V isoform to atherosclerosis progression comes from animal studies. In the absence of an assay that directly quantifies sPLA2-V levels, we used PLA2G5 mRNA levels in a novel, modified Mendelian randomization approach to investigate the hypothesized causal role of sPLA2-V in coronary heart disease (CHD) pathogenesis.Using data from the Advanced Study of Aortic Pathology, we identified the single-nucleotide polymorphism in PLA2G5 showing the strongest association with PLA2G5 mRNA expression levels as a proxy for sPLA2-V levels. We tested the association of this SNP with sPLA2 activity and CHD events in 4 prospective and 14 case-control studies with 27 230 events and 70 500 controls. rs525380C>A showed the strongest association with PLA2G5 mRNA expression (P=5.1×10-6). There was no association of rs525380C>A with plasma sPLA2 activity (difference in geometric mean of sPLA2 activity per rs525380 A-allele 0.4% (95% confidence intervals [-0.9%, 1.6%]; P=0.56). In meta-analyses, the odds ratio for CHD per A-allele was 1.02 (95% confidence intervals [0.99, 1.04]; P=0.20).This novel approach for single-nucleotide polymorphism selection for this modified Mendelian randomization analysis showed no association between rs525380 (the lead single-nucleotide polymorphism for PLA2G5 expression, a surrogate for sPLA2-V levels) and CHD events. The evidence does not support a causal role for sPLA2-V in CHD. [ABSTRACT FROM AUTHOR]

Inflammatory cytokine interleukin-6 (IL-6), a possible risk factor for coronary heart disease, has an estimated heritability of >60%, but to date few genetic variants influencing IL-6 levels are known.We used the ITMAT-Broad-Care (IBC) HumanCVD disease BeadChip in the Whitehall II study (N=4911) and British Women’s Heart and Health Study (N=3445) to identify single-nucleotide polymorphisms associated with circulating IL-6 levels. Twenty-two single-nucleotide polymorphisms from 7 loci (IL6R/TDRD10, HLA-DRB1, BUD13, SEZ6L, IL1RN, TRIB3, and ABO) were associated with IL-6 (P<10-5), although none were associated with the IL6 gene itself. With the exception of TRIB3, all loci have been previously reported in genome-wide association studies for autoimmune and cardiovascular diseases. Fourteen single-nucleotide polymorphisms in the IL6R region in high-linkage disequilibrium (r2>0.9) with a nonsynonymous variant, rs2228145, were also associated with IL-6 and C-reactive protein concentration (P<10-5). An IL-6-specific weighted allele score explained 2% of the variance of log IL-6 levels (P=2.4410-22) in Whitehall II and 1% (P=1.910-8) in British Women’s Heart and Health Studies.Multiple common genetic variants of modest effect influence IL-6 concentration. Several loci contain single-nucleotide polymorphisms, exhibiting overlapping associations with autoimmune and cardiovascular disorders and other circulating biomarkers. Genetic variants associated with IL-6 provide important tools for probing the causal relevance of IL-6 signaling in a range of cardiometabolic diseases. [ABSTRACT FROM AUTHOR]

Carotid intima-media thickness (CIMT), a subclinical measure of atherosclerosis, is associated with risk of coronary heart disease events. Statins reduce progression of CIMT and coronary heart disease risk in proportion to the reduction in low-density lipoprotein cholesterol. However, interventions targeting triglycerides (TGs) or high-density lipoprotein cholesterol (HDL-C) have produced inconsistent effects on CIMT and coronary heart disease risk, making it uncertain whether such agents are ineffective for coronary heart disease prevention or whether CIMT is an inadequate marker of HDL-C or TG-mediated effects. We aimed to determine the causal association among the 3 major blood lipid fractions and common CIMT using mendelian randomization analysis.Genetic scores specific for low-density lipoprotein cholesterol, HDL-C, and TGs were derived based on single nucleotide polymorphisms from a gene-centric array in ≈5000 individuals (Cardiochip scores) and from a genome-wide association meta-analysis in >100 000 individuals (Global Lipids Genetic Consortium scores). These were used as instruments in a mendelian randomization analysis in 2 prospective cohort studies. A genetically predicted 1 mmol/L higher low-density lipoprotein cholesterol concentration was associated with a higher common CIMT by 0.03 mm (95% confidence interval, 0.01-0.04) and 0.04 mm (95% confidence interval, 0.02-0.06) based on the Cardiochip and Global Lipids Genetic Consortium scores, respectively. HDL-C and TGs were not causally associated with CIMT.Our findings confirm a causal relationship between low-density lipoprotein cholesterol and CIMT but not with HDL-C and TGs. At present, the suitability of CIMT as a surrogate marker in trials of cardiovascular therapies targeting HDL-C and TGs is questionable and requires further study. [ABSTRACT FROM AUTHOR]

The article presents a study which identified carotid intima-media thickness (cIMT)-associated genes and genetic variants using the Illumina 200k CardioMetabochip in subjects with ultrasonographic determinations of cIMT. The researchers analyzed segment-specific IMT measurements of common carotid, bifurcation, and internal carotid arteries, and composite IMT variables considering the whole carotid tree. Associations of rs48888378 with nearby gene expression in vascular tissues were revealed.

The article presents a study which evaluated three population-based cohorts genotyped with the Illumina HumanCVD Beadchip and 4 quantitative electrocardiographic traits for single nucleotide polymorphism associations. The researchers modeled the effects of ion channel activity on electrocardiographic parameters. It was found that the association results refine the mapping of previous genome-wide association study findings for electrocardiographic traits.

The article discusses the study that uses data for 2500 men from the Second Northwick Park Heart Study (NPHS-II) to investigate the role of copy number variants (CNVs) in coronary heart disease (CHD) traits, using cnvHap algorithm for CNV detection. The study found the potential of CNV detection algorithms such as cnvHAP to be used for the identification of novel CNVs, of which some have shown to have significant association and replication with coronary heart disease (CHD) risk phenotypes.

The article presents a study which conducted a large-scale gene-centric association analysis of 4 commonly measured indices of electrocardiography left ventricular hypertrophy (ECG-LVH). The researchers found no evidence for association of any of the ECG-LVH variants with echo-LV mass. Findings also revealed that the amount of trait variance by each of the identified loci was low.

Arterial stiffness has been proposed as an indicator of vascular aging. We aimed to examine this concept by analyzing associations of arterial stiffness with age, subjective and objective measures of physical functioning, and self-reported functional limitation. We measured aortic pulse wave velocity by applanation tonometry among 5392 men and women aged 55 to 78 years. Arterial stiffness was strongly associated with age (mean difference [SE] per decade: men, 1.37 m/s [0.06 m/s]; women: 1.39 m/s [0.10 m/s]). This association was robust to individual and combined adjustment for pulse pressure, mean arterial pressure, antihypertensive treatment, and chronic disease. Participants took an 8.00-ft (2.44-m) walking speed test, a spirometry lung function test, and completed health functioning and (instrumental) activities of daily living questionnaires. Associations of stiffness and blood pressure with physical function scores scaled to SD of 10 were compared. One-SD higher stiffness was associated with lower walking speed (coefficient [95% CI]: -0.96 [-1.29 to -0.64] m/s) and physical component summary score (-0.91 [-1.21 to -0.60]) and poorer lung function (-1.23 [-1.53 to -0.92] L) adjusted for age, sex, and ethnic group. Pulse pressure and mean arterial pressure were linked inversely only with lung function. Associations of stiffness with functional limitation were robust to multiple adjustment, including pulse pressure and chronic disease. In conclusion, the concept of vascular aging is reinforced by the observation that arterial stiffness is a robust correlate of physical functioning and functional limitation in early old age. The nature of the link between arterial stiffness and quality of life in older people merits attention. [ABSTRACT FROM AUTHOR]

There is conflicting evidence regarding the association of hypertension with psychological distress, such as anxiety and depressive symptoms. The association may be because of a direct effect of the raised blood pressure, adverse effects of treatment, or the consequences of labeling. In a representative study of 33 105 adults (aged 51.7+/-12.1 years; 45.8% men), we measured levels of psychological distress using the 12-item General Health Questionnaire and collected blood pressure, data on history of hypertension diagnosis, and medication usage. Awareness of hypertension was confirmed through a physician diagnosis or the use of antihypertensive medication, and unaware hypertension was defined by elevated clinic blood pressure (systolic/diastolic > or =140/90 mm Hg) without previous treatment or diagnosis. In comparison with normotensive participants, an elevated risk of distress (General Health Questionnaire score > or =4) was observed in aware hypertensive participants (multivariable adjusted odds ratio: 1.57 [95% CI: 1.41 to 1.74]) but not in unaware hypertensives (odds ratio: 0.91 [95% CI: 0.78 to 1.07]). Antihypertensive medication and comorbidity were also associated with psychological distress, although this did not explain the greater risk of distress in aware hypertensives. We observed a weak curvilinear association between systolic blood pressure and distress, which suggested that distressed participants were more likely to have low or highly elevated blood pressure. These findings suggest that labeling individuals as hypertensive, rather than having elevated blood pressure, per se, may partially explain the greater levels of distress in patients treated for hypertension. [ABSTRACT FROM AUTHOR]

The article presents the findings of the study conducted to determine whether working while ill trigger serious coronary heart disease. The study includes the use of a nested-case control study in an occupational cohort. The result of the study founds no evidence that working while ill acts as a short-term trigger for coronary events.

Background: Various methodologic approaches have been used to estimate the role of risk factors in explaining the social gradient in coronary heart disease (CHD). Our objective was to examine whether there is a discrepancy in results obtained using the relative and absolute approaches.Methods: Data are from the Whitehall II prospective cohort study on 5363 men who were 40- to 62-year-old at the start of the 11-year follow-up period.Results: One or more of the 4 conventional risk factors examined (smoking, hypertension, high cholesterol, and diabetes) were present for 77% of individuals in the low socioeconomic group compared with 68% in the high socioeconomic group. The relative risk for incident CHD in the low socioeconomic group was 1.66 (95% confidence interval = 1.20 to 2.29) compared with the high group. Standardizing the distribution of risk factors in the low and high socioeconomic group to the overall study sample reduced relative risk by 16% and absolute risk by 14%. We also computed the population attributable risk (PAR) to indicate the reduction in CHD if the risk factor were completely removed from the population. The PAR associated with having at least one risk factor was 41% (95% confidence interval = 33% to 57%) in the high and 58% (13% to 91%) in the low socioeconomic group.Conclusions: In situations where the goal is to remove social differences in the distribution of risk factors, conventional risk factors explain a similar proportion of the social gradient in CHD, whether using the relative or absolute approaches to change in risk. This is not comparable to population attributable risk calculations, in which the goal is to completely remove the risk factors from the population. Failure to recognize that these methods address different questions seems to be the reason for discrepancies in previous results. [ABSTRACT FROM AUTHOR]

The aim of the study was to examine associations of social support with early retirement and reported retirement preference. Logistic regression analyses of early retirement (retired before the age of 55) were based on a cohort of 10,489 respondents (5960 female, 4529 male) aged 40-55 years. Analyses of retirement preference (planning of early retirement) were based on a sub-cohort of 7759 full-time employees (4233 female, 3526 male). The measures for social support were the social network size (number of close personal relationships) and social network heterogeneity (number of different roles as sources of social support). Among women, early retirement was associated with small social networks (OR 5.1, 95% CI = 2.8-9.2) and low social network heterogeneity (OR 9.1, 95% CI = 3.2-25.9). Among men, the corresponding associations were somewhat smaller (1.5; 0.9-2.6 and 8.0; 1.8-35.7, respectively). Adjustments for age, occupational training, and spouse at home did not considerably affect these associations. Among men, the association between social network heterogeneity and early retirement was not statistically significant after additional adjustments had been made for marital status and perceived health status. The characteristics of the social network were not associated with a retirement preference among employed men. Among women, the lack of social relations was associated with low retirement preference. Our findings suggested that social support is not independently associated with a retirement preference among men. Socially isolated women prefer retirement less often than other women do. Being retired before the age of 55 years may be predicted by limited social support or it may restrain one's possibilities to establish and maintain social relationships. [ABSTRACT FROM AUTHOR]

Objective: To conduct a comprehensive analysis of circulating metabolites and incident stroke in large prospective population-based settings., Methods: We investigated the association of metabolites with risk of stroke in 7 prospective cohort studies including 1,791 incident stroke events among 38,797 participants in whom circulating metabolites were measured by nuclear magnetic resonance technology. The relationship between metabolites and stroke was assessed with Cox proportional hazards regression models. The analyses were performed considering all incident stroke events and ischemic and hemorrhagic events separately., Results: The analyses revealed 10 significant metabolite associations. Amino acid histidine (hazard ratio [HR] per SD 0.90, 95% confidence interval [CI] 0.85, 0.94; p = 4.45 × 10 -5 ), glycolysis-related metabolite pyruvate (HR per SD 1.09, 95% CI 1.04, 1.14; p = 7.45 × 10 -4 ), acute-phase reaction marker glycoprotein acetyls (HR per SD 1.09, 95% CI 1.03, 1.15; p = 1.27 × 10 -3 ), cholesterol in high-density lipoprotein (HDL) 2, and several other lipoprotein particles were associated with risk of stroke. When focused on incident ischemic stroke, a significant association was observed with phenylalanine (HR per SD 1.12, 95% CI 1.05, 1.19; p = 4.13 × 10 -4 ) and total and free cholesterol in large HDL particles., Conclusions: We found association of amino acids, glycolysis-related metabolites, acute-phase reaction markers, and several lipoprotein subfractions with the risk of stroke. These findings support the potential of metabolomics to provide new insights into the metabolic changes preceding stroke., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: The implications of different adiposity measures on cardiovascular disease etiology remain unclear. In this article, we quantify and contrast causal associations of central adiposity (waist-to-hip ratio adjusted for body mass index [WHRadjBMI]) and general adiposity (body mass index [BMI]) with cardiometabolic disease., Methods: Ninety-seven independent single-nucleotide polymorphisms for BMI and 49 single-nucleotide polymorphisms for WHRadjBMI were used to conduct Mendelian randomization analyses in 14 prospective studies supplemented with coronary heart disease (CHD) data from CARDIoGRAMplusC4D (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics; combined total 66 842 cases), stroke from METASTROKE (12 389 ischemic stroke cases), type 2 diabetes mellitus from DIAGRAM (Diabetes Genetics Replication and Meta-analysis; 34 840 cases), and lipids from GLGC (Global Lipids Genetic Consortium; 213 500 participants) consortia. Primary outcomes were CHD, type 2 diabetes mellitus, and major stroke subtypes; secondary analyses included 18 cardiometabolic traits., Results: Each one standard deviation (SD) higher WHRadjBMI (1 SD≈0.08 U) associated with a 48% excess risk of CHD (odds ratio [OR] for CHD, 1.48; 95% confidence interval [CI], 1.28-1.71), similar to findings for BMI (1 SD≈4.6 kg/m 2 ; OR for CHD, 1.36; 95% CI, 1.22-1.52). Only WHRadjBMI increased risk of ischemic stroke (OR, 1.32; 95% CI, 1.03-1.70). For type 2 diabetes mellitus, both measures had large effects: OR, 1.82 (95% CI, 1.38-2.42) and OR, 1.98 (95% CI, 1.41-2.78) per 1 SD higher WHRadjBMI and BMI, respectively. Both WHRadjBMI and BMI were associated with higher left ventricular hypertrophy, glycemic traits, interleukin 6, and circulating lipids. WHRadjBMI was also associated with higher carotid intima-media thickness (39%; 95% CI, 9%-77% per 1 SD)., Conclusions: Both general and central adiposity have causal effects on CHD and type 2 diabetes mellitus. Central adiposity may have a stronger effect on stroke risk. Future estimates of the burden of adiposity on health should include measures of central and general adiposity., (© 2017 American Heart Association, Inc.)

Background: Smoking is an important cardiovascular disease risk factor, but the mechanisms linking smoking to blood pressure are poorly understood., Methods and Results: Data on 141 317 participants (62 666 never, 40 669 former, 37 982 current smokers) from 23 population-based studies were included in observational and Mendelian randomization meta-analyses of the associations of smoking status and smoking heaviness with systolic and diastolic blood pressure, hypertension, and resting heart rate. For the Mendelian randomization analyses, a genetic variant rs16969968/rs1051730 was used as a proxy for smoking heaviness in current smokers. In observational analyses, current as compared with never smoking was associated with lower systolic blood pressure and diastolic blood pressure and lower hypertension risk, but with higher resting heart rate. In observational analyses among current smokers, 1 cigarette/day higher level of smoking heaviness was associated with higher (0.21 bpm; 95% confidence interval 0.19; 0.24) resting heart rate and slightly higher diastolic blood pressure (0.05 mm Hg; 95% confidence interval 0.02; 0.08) and systolic blood pressure (0.08 mm Hg; 95% confidence interval 0.03; 0.13). However, in Mendelian randomization analyses among current smokers, although each smoking increasing allele of rs16969968/rs1051730 was associated with higher resting heart rate (0.36 bpm/allele; 95% confidence interval 0.18; 0.54), there was no strong association with diastolic blood pressure, systolic blood pressure, or hypertension. This would suggest a 7 bpm higher heart rate in those who smoke 20 cigarettes/day., Conclusions: This Mendelian randomization meta-analysis supports a causal association of smoking heaviness with higher level of resting heart rate, but not with blood pressure. These findings suggest that part of the cardiovascular risk of smoking may operate through increasing resting heart rate., (© 2015 American Heart Association, Inc.)

Background: Secretory phospholipase A2 (sPLA2) enzymes are considered to play a role in atherosclerosis. sPLA2 activity encompasses several sPLA2 isoenzymes, including sPLA2-V. Although observational studies show a strong association between elevated sPLA2 activity and CHD, no assay to measure sPLA2-V levels exists, and the only evidence linking the sPLA2-V isoform to atherosclerosis progression comes from animal studies. In the absence of an assay that directly quantifies sPLA2-V levels, we used PLA2G5 mRNA levels in a novel, modified Mendelian randomization approach to investigate the hypothesized causal role of sPLA2-V in coronary heart disease (CHD) pathogenesis., Methods and Results: Using data from the Advanced Study of Aortic Pathology, we identified the single-nucleotide polymorphism in PLA2G5 showing the strongest association with PLA2G5 mRNA expression levels as a proxy for sPLA2-V levels. We tested the association of this SNP with sPLA2 activity and CHD events in 4 prospective and 14 case-control studies with 27 230 events and 70 500 controls. rs525380C>A showed the strongest association with PLA2G5 mRNA expression (P=5.1×10(-6)). There was no association of rs525380C>A with plasma sPLA2 activity (difference in geometric mean of sPLA2 activity per rs525380 A-allele 0.4% (95% confidence intervals [-0.9%, 1.6%]; P=0.56). In meta-analyses, the odds ratio for CHD per A-allele was 1.02 (95% confidence intervals [0.99, 1.04]; P=0.20)., Conclusions: This novel approach for single-nucleotide polymorphism selection for this modified Mendelian randomization analysis showed no association between rs525380 (the lead single-nucleotide polymorphism for PLA2G5 expression, a surrogate for sPLA2-V levels) and CHD events. The evidence does not support a causal role for sPLA2-V in CHD.

Objective: To investigate the relationship between angiopoietin-like protein 4 (Angptl4) levels, coronary heart disease (CHD) biomarkers, and ANGPTL4 variants., Methods and Results: Plasma Angptl4 was quantified in 666 subjects of the Northwick Park Heart Study II using a validated ELISA. Seven ANGPTL4 single-nucleotide polymorphisms were genotyped, and CHD biomarkers were assessed in the whole cohort (N=2775). Weighted mean±SD plasma Angptl4 levels were 10.0±11.0 ng/mL. Plasma Angptl4 concentration correlated positively with age (r=0.15, P<0.001) and body fat mass (r=0.19, P=0.003) but negatively with plasma high-density lipoprotein cholesterol (r=-0.13, P=0.01). No correlation with triglycerides (TGs) was observed. T266M was independently associated with plasma Angptl4 levels (P<0.001) but was not associated with TGs or CHD risk in the meta-analysis of 5 studies (4061 cases/15 395 controls). E40K showed no independent association with plasma Angptl4 levels. In human embryonic kidney 293 and human hepatoma 7 cells compared with wild type, E40K and T266M showed significantly altered synthesis and secretion, respectively., Conclusions: Circulating Angptl4 levels may not influence TG levels or CHD risk for the following reasons: (1) Angptl4 levels were not correlated with TGs; (2) T266M, although associated with Angptl4 levels, showed no association with plasma TGs; and (3) TG-lowering E40K did not influence Angptl4 levels. These results provide new insights into the role of Angptl4 in TG metabolism.

Background: Higher lipoprotein-associated phospholipase A(2)(Lp-PLA2) activity is associated with increased risk of coronary heart disease (CHD), making Lp-PLA2 a potential therapeutic target. PLA2G7 variants associated with Lp-PLA2 activity could evaluate whether this relationship is causal., Methods and Results: A meta-analysis including a total of 12 studies (5 prospective, 4 case-control, 1 case-only, and 2 cross-sectional studies; n=26 118) was undertaken to examine the association of the following: (1) Lp-PLA2 activity versus cardiovascular biomarkers and risk factors and CHD events (2 prospective studies; n=4884); (2) PLA2G7 single-nucleotide polymorphisms and Lp-PLA2 activity (3 prospective, 2 case-control, 2 cross-sectional studies; up to n=6094); and (3) PLA2G7 single-nucleotide polymorphisms and angiographic coronary artery disease (2 case-control, 1 case-only study; n=4971 cases) and CHD events (5 prospective, 2 case-control studies; n=5523). Lp-PLA2 activity correlated with several CHD risk markers. Hazard ratios for CHD events for the top versus bottom quartile of Lp-PLA2 activity were 1.61 (95% confidence interval, 1.31 to 1.99) and 1.17 (95% confidence interval, 0.91 to 1.51) after adjustment for baseline traits. Of 7 single-nucleotide polymorphisms, rs1051931 (A379V) showed the strongest association with Lp-PLA2 activity, with VV subjects having 7.2% higher activity than AAs. Genotype was not associated with risk markers, angiographic coronary disease (odds ratio, 1.03; 95% confidence interval, 0.80 to 1.32), or CHD events (odds ratio, 0.98; 95% confidence interval, 0.82 to 1.17)., Conclusions: Unlike Lp-PLA2 activity, PLA2G7 variants associated with modest effects on Lp-PLA2 activity were not associated with cardiovascular risk markers, coronary atheroma, or CHD. Larger association studies, identification of single-nucleotide polymorphisms with larger effects, or randomized trials of specific Lp-PLA2 inhibitors are needed to confirm or refute a contributory role for Lp-PLA2 in CHD.

Background: Cholesteryl ester transfer protein (CETP) inhibitors raise high-density lipoprotein (HDL) cholesterol, but torcetrapib, the first-in-class inhibitor tested in a large outcome trial, caused an unexpected blood pressure elevation and increased cardiovascular events. Whether the hypertensive effect resulted from CETP inhibition or an off-target action of torcetrapib has been debated. We hypothesized that common single-nucleotide polymorphisms in the CETP gene could help distinguish mechanism-based from off-target actions of CETP inhibitors to inform on the validity of CETP as a therapeutic target., Methods and Results: We compared the effect of CETP single-nucleotide polymorphisms and torcetrapib treatment on lipid fractions, blood pressure, and electrolytes in up to 67 687 individuals from genetic studies and 17 911 from randomized trials. CETP single-nucleotide polymorphisms and torcetrapib treatment reduced CETP activity and had a directionally concordant effect on 8 lipid and lipoprotein traits (total, low-density lipoprotein, and HDL cholesterol; HDL2; HDL3; apolipoproteins A-I and B; and triglycerides), with the genetic effect on HDL cholesterol (0.13 mmol/L, 95% confidence interval [CI] 0.11 to 0.14 mmol/L) being consistent with that expected of a 10-mg dose of torcetrapib (0.13 mmol/L, 95% CI 0.10 to 0.15). In trials, 60 mg of torcetrapib elevated systolic and diastolic blood pressure by 4.47 mm Hg (95% CI 4.10 to 4.84 mm Hg) and 2.08 mm Hg (95% CI 1.84 to 2.31 mm Hg), respectively. However, the effect of CETP single-nucleotide polymorphisms on systolic blood pressure (0.16 mm Hg, 95% CI -0.28 to 0.60 mm Hg) and diastolic blood pressure (-0.04 mm Hg, 95% CI -0.36 to 0.28 mm Hg) was null and significantly different from that expected of 10 mg of torcetrapib., Conclusions: Discordance in the effects of CETP single-nucleotide polymorphisms and torcetrapib treatment on blood pressure despite the concordant effects on lipids indicates the hypertensive action of torcetrapib is unlikely to be due to CETP inhibition or shared by chemically dissimilar CETP inhibitors. Genetic studies could find a place in drug-development programs as a new source of randomized evidence for drug-target validation in humans.

Objective: The purpose of this study was to examine the relationship between fasting serum lipids and short-term verbal memory in middle-aged adults., Methods and Results: Total cholesterol, high-density lipoprotein cholesterol (HDL-C), triglycerides, and memory were measured twice, at mean ages 55 and 61, in 3673 male and female participants of the Whitehall II study. Short-term verbal memory was assessed using a 20-word list. Logistic regression was used to model associations between ATP-III categories of lipids and memory deficit (recall of < or =4 words) and decline (decrease of > or =2 words). Analyses were adjusted for education, occupational position, coronary heart disease, stroke, hypertension, use of medication, diabetes, smoking, and alcohol consumption. Compared to high HDL-C (> or =60 mg/dL), low HDL-C (<40 mg/dL) was associated with greater odds of memory deficit at the first (OR=1.27; 95% confidence interval [CI]=0.91 to 1.77) and second wave of this study (OR=1.53; 95% CI=1.04 to 2.25) in fully adjusted analysis. Decrease in HDL-C over the 5-year follow-up period was associated with decline in memory in the adjusted analysis (OR=1.61; 95% CI=1.19 to 2.16); no interaction with APOE e4 status was present., Conclusions: HDL-C levels are potentially modifiable, and our results suggest that low HDL-C is associated with poor memory and decline in memory in middle-aged adults.

Objective: The purpose of this study was to test whether psychological factors affect inflammation processes to an extent that increases the risk of coronary heart disease (CHD)., Methods and Results: We used data from 6396 civil servants (4453 men, 1943 women) from the Whitehall II Study, aged 35 to 55 years and free from clinically validated CHD at the start of the follow-up period. Two psychological factors were assessed at phase 1 (1985 to 1988) and phase 2 (1989 to 1990): negative affect and psychological distress. Inflammatory biomarkers (fibrinogen, high-sensitivity C-reactive- protein, interleukin-6) and 12 baseline covariates including biological and behavioral CHD risk factors, sociodemographic variables, and work stress were measured at phase 3 (1991 to 1993). Follow-up for CHD death, first nonfatal myocardial infarction, or definite angina occurring between phase 3 and phase 7 (2003 to 2004) was based on clinical records. Higher levels of inflammatory markers were associated with higher CHD incidence, with hazard ratios (HR) ranging from 1.31 to 2.37 in age-and sex-adjusted models. Higher levels of negative affectivity and psychological distress were not associated with greater concentrations of inflammatory markers. Negative affectivity (relative index of inequality=1.68, 95% confidence interval [CI] 1.20 to 2.36) and higher psychological distress exposure (HR=1.66, 95% CI 1.28 to 2.14) were associated with higher CHD incidence and these associations remained unchanged after adjustment for inflammatory markers., Conclusions: Our findings suggest that psychological factors do not affect inflammation although they predict incident CHD.

Objective: To examine sociodemographic, work-related factors and psychological health as predictors of sustained organizational commitment among temporary hospital employees., Background: The participants were 412 nurses who had a temporary job contract and reported being committed to their organization at baseline., Methods: Organizational commitment was measured again 2 years later., Results: The results of logistic regression analysis showed that age over 35 years, high job control, high participative safety, high perceived justice in decision making, and low psychological distress predicted sustained organizational commitment at follow-up. The change from temporary employment to a permanent job and high job control predicted sustained organizational commitment even after the effect of all the other predictors was taken into account., Conclusion: Organizations that employ temporary workers should pay attention to the job control and career prospects of temporary staff.