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1.  Fasting plasma glucose in non-diabetic participants and the risk for incident cardiovascular events, diabetes and mortality: results from WOSCOPS 15 year follow-up 
European heart journal  2010;31(10):1230-1236.
The evidence base for fasting plasma glucose (FPG) in the non-diabetic range as a risk factor for cardiovascular disease (CVD) is inconclusive. We investigated this question in the West of Scotland Coronary Prevention Study (WOSCOPS).
Methods and Results
In WOSCOPS, we related FPG in 6447 men (mean age 55 years) with hypercholesterolaemia, but no history of CVD or diabetes, to risk of cardiovascular events and mortality over 14.7 years follow-up; 2381 non-fatal/fatal cardiovascular events and 1244 deaths occurred. Participants were divided into fifths of baseline FPG, Q1 (≤4.3mmol/L) to Q5 (>5.1-6.9mmol/L). Q2 was designated the referent based on previous studies which have suggested a J-shaped relationship between FPG and CVD. Compared to Q2 (>4.3-4.6mmol/L), men in Q5 had no elevated risk for cardiovascular events (HR 0.95 [0.83-1.08]), or all cause mortality (HR 0.96 [0.80-1.15]) in fully adjusted analyses despite a significant risk for incident diabetes (HR 22.05 [10.75-45.22]). After further dividing Q5 into fifths, Q5a-e, individuals in Q5e (FPG 5.8-6.9mmol/L) were also not at increased risk of cardiovascular events (HR 1.05 [0.82-1.35]) or other endpoints compared to Q2. All results were similar using Q1 as referent.
Elevations in FPG in the non-diabetic range were not associated with long-term risk of cardiovascular events in middle-aged men in WOSCOPS. These data suggest that the current FPG cutoff for diagnosing diabetes also appropriately identifies western men at risk of CVD.
PMCID: PMC4209362  PMID: 20395260
cardiovascular disease; impaired fasting glycaemia; diabetes mellitus; glucose
3.  Cardio-metabolic risk factors and cortical thickness in a neurologically healthy male population: Results from the psychological, social and biological determinants of ill health (pSoBid) study☆☆☆ 
NeuroImage : Clinical  2013;2:646-657.
Cardio-metabolic risk factors have been associated with poor physical and mental health. Epidemiological studies have shown peripheral risk markers to be associated with poor cognitive functioning in normal healthy population and in disease. The aim of the study was to explore the relationship between cardio-metabolic risk factors and cortical thickness in a neurologically healthy middle aged population-based sample.
T1-weighted MRI was used to create models of the cortex for calculation of regional cortical thickness in 40 adult males (average age = 50.96 years), selected from the pSoBid study. The relationship between cardio-vascular risk markers and cortical thickness across the whole brain, was examined using the general linear model. The relationship with various covariates of interest was explored.
Lipid fractions with greater triglyceride content (TAG, VLDL and LDL) were associated with greater cortical thickness pertaining to a number of regions in the brain. Greater C reactive protein (CRP) and intercellular adhesion molecule (ICAM-1) levels were associated with cortical thinning pertaining to perisylvian regions in the left hemisphere. Smoking status and education status were significant covariates in the model.
This exploratory study adds to a small body of existing literature increasingly showing a relationship between cardio-metabolic risk markers and regional cortical thickness involving a number of regions in the brain in a neurologically normal middle aged sample. A focused investigation of factors determining the inter-individual variations in regional cortical thickness in the adult brain could provide further clarity in our understanding of the relationship between cardio-metabolic factors and cortical structures.
•The relationship between coronary risk factors and cortical thickness is unclear.•We examine this relationship in neurologically healthy middle aged adults.•Greater lipid fractions were associated with greater regional cortical thickness.•Greater CRP and ICAM-1 were associated with regional cortical thinning.
PMCID: PMC3777783  PMID: 24179815
pSoBid, psychological, social and biological determinants of ill health; BMI, body mass index; CIMT, carotid intima-media thickness; SIMD, Scottish Index of Multiple Deprivation; CRP, high sensitivity C-reactive protein; IL-6, interleukin-6; ICAM, intercellular adhesion molecule-1; ELISA, enzyme linked immunosorbent assay; vWF, von Willebrand factor; tPA, tissue plasminogen activator; TAG, triglycerides; LDL, low-density lipoprotein; HDL, high-density lipoprotein; Apo, apolipoprotien; PCA, principal component analysis; Cardiovascular risk; Metabolic risk; Cortical thickness; Inflammation; Cholesterol
4.  Personality, Socio-Economic Status and Inflammation: Cross-Sectional, Population-Based Study 
PLoS ONE  2013;8(3):e58256.
Associations between socio-economic status (SES), personality and inflammation were examined to determine whether low SES subjects scoring high on neuroticism or hostility might suffer relatively higher levels of inflammation than affluent subjects.
In a cross-sectional design, 666 subjects were recruited from areas of high (most deprived – “MD”) and low (least deprived – “LD”) deprivation. IL-6, ICAM-1, CRP and fibrinogen were measured along with demographic and health-behaviour variables, and personality traits of neuroticism, extraversion and psychoticism (hostility). Regression models assessed the prediction of inflammation as a function of personality, deprivation and their interaction.
Levels of CRP and IL-6 were an increasing function of neuroticism and extraversion only in LD subjects opposite trends were seen in MD subjects. The result was ascribed parsimoniously to an inflammatory ceiling effect or, more speculatively, to SES-related health-behaviour differences. Psychoticism was strongly associated with ICAM-1 in both MD and LD subjects.
The association between neuroticism, CRP and IL-6 may be reduced in MD subjects confirming speculation that the association differs across population sub-groups. The association between psychoticism and ICAM-1 supports evidence that hostility has adverse effects upon the endothelium, with consequences for cardiovascular health. Health interventions may be more effective by accounting for personality-related effects upon biological processes.
PMCID: PMC3596406  PMID: 23516457
5.  The envirome and the connectome: exploring the structural noise in the human brain associated with socioeconomic deprivation 
Complex cognitive functions are widely recognized to be the result of a number of brain regions working together as large-scale networks. Recently, complex network analysis has been used to characterize various structural properties of the large-scale network organization of the brain. For example, the human brain has been found to have a modular architecture i.e., regions within the network form communities (modules) with more connections between regions within the community compared to regions outside it. The aim of this study was to examine the modular and overlapping modular architecture of the brain networks using complex network analysis. We also examined the association between neighborhood level deprivation and brain network structure—modularity and gray nodes. We compared network structure derived from anatomical MRI scans of 42 middle-aged neurologically healthy men from the least (LD) and the most deprived (MD) neighborhoods of Glasgow with their corresponding random networks. Cortical morphological covariance networks were constructed from the cortical thickness derived from the MRI scans of the brain. For a given modularity threshold, networks derived from the MD group showed similar number of modules compared to their corresponding random networks, while networks derived from the LD group had more modules compared to their corresponding random networks. The MD group also had fewer gray nodes—a measure of overlapping modular structure. These results suggest that apparent structural difference in brain networks may be driven by differences in cortical thicknesses between groups. This demonstrates a structural organization that is consistent with a system that is less robust and less efficient in information processing. These findings provide some evidence of the relationship between socioeconomic deprivation and brain network topology.
PMCID: PMC3824100  PMID: 24273501
socioeconomic status; neighborhood deprivation; gray nodes; modularity; graph theory; cortical thickness
6.  Soluble ST2 Associates with Diabetes but Not Established Cardiovascular Risk Factors: A New Inflammatory Pathway of Relevance to Diabetes? 
PLoS ONE  2012;7(10):e47830.
Preliminary data mostly from animal models suggest the sST2/IL-33 pathway may have causal relevance for vascular disease and diabetes and thus point to a potential novel inflammatory link to cardiometabolic disease. However, the characterisation of sST2 levels in terms of metabolic or vascular risk in man is completely lacking. We sought to address this gap via a comprehensive analysis of risk factor and vascular correlates of sST2 in a cross-sectional study (pSoBid). We measured sST2 in plasma in 639 subjects and comprehensively related it to cardiovascular and diabetes risk factors and imaged atherosclerosis measures. Circulating sST2 levels increased with age, were lower in women and in highest earners. After adjusting for age and gender, sST2 levels associated strongly with markers of diabetes, including triglycerides [effect estimate (EE) per 1 standard deviation increase in sST2∶1.05 [95%CI 1.01,1.10]), liver function (alanine aminotransaminase [ALT] and γ-glutamyl transferase [GGT]: EE 1.05 [1.01,1.09] and 1.13 [1.07,1.19] respectively), glucose (1.02 [1.00,1.03]) and sICAM-1 (1.05 [1.02,1.07]). However, sST2 levels were not related to smoking, cholesterol, blood pressure, or atheroma (carotid intima media thickness, plaque presence). These results suggest that sST2 levels, in individuals largely without vascular disease, are related principally to markers associated with diabetes and ectopic fat and add support for a role of sST2 in diabetes. Further mechanistic studies determining how sST2 is linked to diabetes pathways may offer new insights into the inflammatory paradigm for type 2 diabetes.
PMCID: PMC3480428  PMID: 23112853
7.  N-terminal pro-B-type natriuretic peptide and the prediction of primary cardiovascular events: results from 15-year follow-up of WOSCOPS 
European Heart Journal  2012;34(6):443-450.
To test whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) was independently associated with, and improved the prediction of, cardiovascular disease (CVD) in a primary prevention cohort.
Methods and results
In the West of Scotland Coronary Prevention Study (WOSCOPS), a cohort of middle-aged men with hypercholesterolaemia at a moderate risk of CVD, we related the baseline NT-proBNP (geometric mean 28 pg/mL) in 4801 men to the risk of CVD over 15 years during which 1690 experienced CVD events. Taking into account the competing risk of non-CVD death, NT-proBNP was associated with an increased risk of all CVD [HR: 1.17 (95% CI: 1.11–1.23) per standard deviation increase in log NT-proBNP] after adjustment for classical and clinical cardiovascular risk factors plus C-reactive protein. N-terminal pro-B-type natriuretic peptide was more strongly related to the risk of fatal [HR: 1.34 (95% CI: 1.19–1.52)] than non-fatal CVD [HR: 1.17 (95% CI: 1.10–1.24)] (P= 0.022). The addition of NT-proBNP to traditional risk factors improved the C-index (+0.013; P < 0.001). The continuous net reclassification index improved with the addition of NT-proBNP by 19.8% (95% CI: 13.6–25.9%) compared with 9.8% (95% CI: 4.2–15.6%) with the addition of C-reactive protein. N-terminal pro-B-type natriuretic peptide correctly reclassified 14.7% of events, whereas C-reactive protein correctly reclassified 3.4% of events. Results were similar in the 4128 men without evidence of angina, nitrate prescription, minor ECG abnormalities, or prior cerebrovascular disease.
N-terminal pro-B-type natriuretic peptide predicts CVD events in men without clinical evidence of CHD, angina, or history of stroke, and appears related more strongly to the risk for fatal events. N-terminal pro-B-type natriuretic peptide also provides moderate risk discrimination, in excess of that provided by the measurement of C-reactive protein.
Clinical trial registration
WOSCOPS was carried out and completed prior to the requirement for clinical trial registration.
PMCID: PMC3566528  PMID: 22942340
NT-proBNP; Natriuretic peptides; Risk factors; Epidemiology
8.  Inheritance of coronary artery disease in men: an analysis of the role of the Y chromosome 
Lancet  2012;379(9819):915-922.
A sexual dimorphism exists in the incidence and prevalence of coronary artery disease—men are more commonly affected than are age-matched women. We explored the role of the Y chromosome in coronary artery disease in the context of this sexual inequity.
We genotyped 11 markers of the male-specific region of the Y chromosome in 3233 biologically unrelated British men from three cohorts: the British Heart Foundation Family Heart Study (BHF-FHS), West of Scotland Coronary Prevention Study (WOSCOPS), and Cardiogenics Study. On the basis of this information, each Y chromosome was tracked back into one of 13 ancient lineages defined as haplogroups. We then examined associations between common Y chromosome haplogroups and the risk of coronary artery disease in cross-sectional BHF-FHS and prospective WOSCOPS. Finally, we undertook functional analysis of Y chromosome effects on monocyte and macrophage transcriptome in British men from the Cardiogenics Study.
Of nine haplogroups identified, two (R1b1b2 and I) accounted for roughly 90% of the Y chromosome variants among British men. Carriers of haplogroup I had about a 50% higher age-adjusted risk of coronary artery disease than did men with other Y chromosome lineages in BHF-FHS (odds ratio 1·75, 95% CI 1·20–2·54, p=0·004), WOSCOPS (1·45, 1·08–1·95, p=0·012), and joint analysis of both populations (1·56, 1·24–1·97, p=0·0002). The association between haplogroup I and increased risk of coronary artery disease was independent of traditional cardiovascular and socioeconomic risk factors. Analysis of macrophage transcriptome in the Cardiogenics Study revealed that 19 molecular pathways showing strong differential expression between men with haplogroup I and other lineages of the Y chromosome were interconnected by common genes related to inflammation and immunity, and that some of them have a strong relevance to atherosclerosis.
The human Y chromosome is associated with risk of coronary artery disease in men of European ancestry, possibly through interactions of immunity and inflammation.
British Heart Foundation; UK National Institute for Health Research; LEW Carty Charitable Fund; National Health and Medical Research Council of Australia; European Union 6th Framework Programme; Wellcome Trust.
PMCID: PMC3314981  PMID: 22325189
9.  Accelerated Telomere Attrition Is Associated with Relative Household Income, Diet and Inflammation in the pSoBid Cohort 
PLoS ONE  2011;6(7):e22521.
It has previously been hypothesized that lower socio-economic status can accelerate biological ageing, and predispose to early onset of disease. This study investigated the association of socio-economic and lifestyle factors, as well as traditional and novel risk factors, with biological-ageing, as measured by telomere length, in a Glasgow based cohort that included individuals with extreme socio-economic differences.
A total of 382 blood samples from the pSoBid study were available for telomere analysis. For each participant, data was available for socio-economic status factors, biochemical parameters and dietary intake. Statistical analyses were undertaken to investigate the association between telomere lengths and these aforementioned parameters.
The rate of age-related telomere attrition was significantly associated with low relative income, housing tenure and poor diet. Notably, telomere length was positively associated with LDL and total cholesterol levels, but inversely correlated to circulating IL-6.
These data suggest lower socio-economic status and poor diet are relevant to accelerated biological ageing. They also suggest potential associations between elevated circulating IL-6, a measure known to predict cardiovascular disease and diabetes with biological ageing. These observations require further study to tease out potential mechanistic links.
PMCID: PMC3144896  PMID: 21818333
10.  Effects of diabetes family history and exercise training on the expression of adiponectin and leptin and their receptors 
Metabolism  2011;60(2):206-214.
Daughters of diabetes patients have lower insulin sensitivity than women with no diabetes family history, but increase insulin sensitivity to a greater extent with exercise training. This study aimed to determine whether differences in circulating concentrations of adiponectin and leptin, and adipose tissue expression of their genes and receptors played a role. Women offspring of patients with type 2 diabetes mellitus (n = 34; age, 35.6 ± 7.0 years; body mass index, 28.1 ± 5.1 kg/m2) and matched controls with no diabetes family history (n = 36; age, 33.6 ± 6.1 years; body mass index, 27.3 ± 4.7 kg/m2) participated. Blood and abdominal subcutaneous adipose tissue samples were obtained at baseline and after a controlled 7-week endurance-type exercise intervention (sessions were performed at 65%-80% of maximum heart rate). At baseline, no significant differences were observed between groups in circulating leptin or adiponectin concentrations, or expression of their genes or receptors. In response to exercise, plasma leptin decreased more in offspring than controls (−32.2% vs −7.3%, P = .005 for interaction); and the long isoform of the leptin receptor messenger RNA (mRNA) increased significantly only in the offspring (+39.4%, P = .026 vs +7.7%, P = .892). Leptin mRNA decreased similarly in both groups (−24.7% vs −25.0%, P < .05 for both). Furthermore, changes in plasma leptin (r = −0.432, P < .001) and leptin mRNA (r = −0.298, P = .019) correlated significantly with changes in insulin sensitivity. Plasma adiponectin decreased similarly in both groups (−12.1% vs −15.2%, P < .01 for both), but no significant changes were observed in adiponectin-related gene expression. This work shows that exercise training has differing effects on leptin-related variables between women with and without a diabetes family history and suggests that these molecular differences may contribute to the differential effects of exercise training on insulin sensitivity between these 2 groups.
PMCID: PMC3032051  PMID: 20153489
11.  Early life socioeconomic adversity is associated in adult life with chronic inflammation, carotid atherosclerosis, poorer lung function and decreased cognitive performance: a cross-sectional, population-based study 
BMC Public Health  2011;11:42.
Socioeconomic gradients in health persist despite public health campaigns and improvements in healthcare. The Psychosocial and Biological Determinants of Ill-health (pSoBid) study was designed to uncover novel biomarkers of chronic disease that may help explain pathways between socioeconomic adversity and poorer physical and mental health.
We examined links between indicators of early life adversity, possible intermediary phenotypes, and markers of ill health in adult subjects (n = 666) recruited from affluent and deprived areas. Classical and novel risk factors for chronic disease (lung function and atherosclerosis) and for cognitive performance were assessed, and associations sought with early life variables including conditions in the parental home, family size and leg length.
Associations were observed between father's occupation, childhood home status (owner-occupier; overcrowding) and biomarkers of chronic inflammation and endothelial activation in adults (C reactive protein, interleukin 6, intercellular adhesion molecule; P < 0.0001) but not number of siblings and leg length. Lung function (forced expiratory volume in 1 second) and cognition (Choice Reaction Time, the Stroop test, Auditory Verbal Learning Test) were likewise related to early life conditions (P < 0.001). In multivariate models inclusion of inflammatory variables reduced the impact and independence of early life conditions on lung function and measures of cognitive ability. Including variables of adult socioeconomic status attenuated the early life associations with disease biomarkers.
Adverse levels of biomarkers of ill health in adults appear to be influenced by father's occupation and childhood home conditions. Chronic inflammation and endothelial activation may in part act as intermediary phenotypes in this complex relationship. Reducing the 'health divide' requires that these life course determinants are taken into account.
PMCID: PMC3032683  PMID: 21241479
12.  Separating the mechanism-based and off-target actions of CETP-inhibitors using CETP gene polymorphisms 
Circulation  2009;121(1):52-62.
Cholesteryl ester transfer protein (CETP) inhibitors raise HDL-cholesterol but torcetrapib, the first-in-class inhibitor tested in a large outcome trial caused 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 hypothesised that common single nucleotide polymorphisms (SNPs) 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 SNPs and torcetrapib treatment on lipid fractions, blood pressure and electrolytes in up to 67,687 individuals from genetic studies and 17,911 from randomised trials. CETP SNPs and torcetrapib treatment reduced CETP activity and had directionally concordant effect on eight lipid and lipoprotein traits (total-, LDL- and HDL-cholesterol, HDL2, HDL3, apolipoproteins A-I, -B, and triglycerides), with the genetic effect on HDL-cholesterol (0.13 mmol/L; 95% CI: 0.11, 0.14) being consistent with that expected of a 10 mg dose of torcetrapib (0.13 mmol/L; 0.10, 0.15). In trials, 60mg torcetrapib elevated systolic and diastolic blood pressure by 4.47mmHg (4.10, 4.84) and 2.08mmHg (1.84, 2.31) respectively. However, the effect of CETP SNPs on systolic 0.16mmHg (−0.28, 0.60) and diastolic blood pressure −0.04mmHg (−0.36, 0.28) was null and significantly different from that expected of 10 mg torcetrapib.
Discordance in the effects of CETP SNPs 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 use in drug development programmes as a new source of randomised evidence for drug target validation in man.
PMCID: PMC2811869  PMID: 20026784
genetics; pharmacology; epidemiology
13.  CCR2 and coronary artery disease: a woscops substudy 
BMC Research Notes  2010;3:31.
Several lines of evidence support a role for CCL2 (monocyte chemotactic protein-1) and its receptor CCR2 in the development of atherosclerosis. The aim of the present study was to determine the association of the CCR2 Val64Ile polymorphism with the development of coronary artery disease in the WOSCOPS study sample set.
A total of 443 cases and 1003 controls from the West of Scotland Coronary Prevention Study (WOSCOPS) were genotyped for the Val64Ile polymorphism in the CCR2 gene. Genotype frequencies were compared between cases and controls. The CCR2 Val64Ile polymorphism was found not to be associated with coronary events in this study population (odds ratio 1.15, 95% CI 0.82-1.61, p = 0.41).
This case-control study does not support an association of the CCR2 Val64Ile polymorphism with coronary artery disease in the WOSCOPS sample set and does not confirm a possible protective role for CCR2 Val64Ile in the development of coronary artery disease.
PMCID: PMC2829582  PMID: 20181074
14.  Leptin Predicts Diabetes but Not Cardiovascular Disease 
Diabetes Care  2009;32(2):308-310.
OBJECTIVE—To clarify the association of circulating levels of leptin with risk for cardiovascular disease (CVD) events and new-onset diabetes in men and women.
RESEARCH DESIGN AND METHODS—We related baseline leptin levels to CVD events (n = 864) and incident diabetes (n = 289) in an elderly population (n = 5,672) over 3.2 years of follow-up.
RESULTS—In treatment-, age-, and country-adjusted models, leptin was not associated with risk of CVD in men (hazard ratio 1.02 [95% CI 0.90–1.16] per unit log-leptin increase) or women (1.05 [0.91–1.20]) but was associated with risk of diabetes in men (2.75 [2.14–3.52]) and women (1.54 [1.22–1.94]). After adjusting for classic risk factors and BMI, C-reactive protein, and glucose, the diabetes association retained significance in men (1.85 [1.30–2.63]) but not in women (0.89 [0.64–1.26]).
CONCLUSIONS—Leptin, similar to other markers of adiposity in general, is more strongly related to risk of diabetes than CVD in the elderly.
PMCID: PMC2628699  PMID: 19001191
15.  Differences in atherosclerosis according to area level socioeconomic deprivation: cross sectional, population based study 
Objectives To examine the relation between area level social deprivation and ultrasound markers of atherosclerosis (common carotid intima-media thickness and plaque score), and to determine whether any differences can be explained by “classic” (currently recognised) or “emerging” (novel) cardiovascular risk factors.
Design Cross sectional, population based study.
Setting NHS Greater Glasgow Health Board area.
Participants 666 participants were selected on the basis of how their area ranked in the Scottish Index of Multiple Deprivation 2004. Approximately equal numbers of participants from the most deprived areas and the least deprived areas were included, as well as equal numbers of men and women and equal numbers of participants from each age group studied (35-44, 45-54, and 55-64 years).
Main outcome measures Carotid intima-media thickness and plaque score, as detected by ultrasound.
Results The mean age and sex adjusted intima-media thickness was significantly higher in participants from the most deprived areas than in those from the least deprived areas (0.70 mm (standard deviation (SD) 0.16 mm) v 0.68 mm (SD 0.12 mm); P=0.015). On subgroup analysis, however, this difference was only apparent in the highest age tertile in men (56.3-66.5 years). The difference in unadjusted mean plaque score between participants from the most deprived and those from the least deprived areas was more striking than the difference in intima-media thickness (least deprived 1.0 (SD 1.5) v most deprived 1.7 (SD 2.0); P<0.0001). In addition, a significant difference in plaque score was apparent in the two highest age tertiles in men (46.8-56.2 years and 56.3-66.5 years; P=0.0073 and P<0.001) and the highest age tertile in women (56.3-66.5 years; P<0.001). The difference in intima-media thickness between most deprived and least deprived males remained significant after adjustment for classic risk factors, emerging risk factors, and individual level markers of socioeconomic status (P=0.010). Adjustment for classic risk factors and emerging cardiovascular risk factors, either alone or in combination, did not abolish the deprivation based difference in plaque presence (as a binary measure; adjusted odds ratio of 1.73, 95% confidence interval 1.07 to 2.82). However, adjustment for classic risk factors and individual level markers of early life socioeconomic status abolished the difference in plaque presence between the most deprived and the least deprived individuals (adjusted odds ratio 0.94, 95% CI 0.54 to 1.65; P=0.84).
Conclusions Deprivation is associated with increased carotid plaque score and intima-media thickness. The association of deprivation with atherosclerosis is multifactorial and not adequately explained by classic or emerging risk factors.
PMCID: PMC2768777  PMID: 19861369
16.  Are Markers of Inflammation More Strongly Associated with Risk for Fatal Than for Nonfatal Vascular Events? 
PLoS Medicine  2009;6(6):e1000099.
In a secondary analysis of a randomized trial comparing pravastatin versus placebo for the prevention of coronary and cerebral events in an elderly at-risk population, Naveed Sattar and colleagues find that inflammatory markers may be more strongly associated with risk of fatal vascular events than nonfatal vascular events.
Circulating inflammatory markers may more strongly relate to risk of fatal versus nonfatal cardiovascular disease (CVD) events, but robust prospective evidence is lacking. We tested whether interleukin (IL)-6, C-reactive protein (CRP), and fibrinogen more strongly associate with fatal compared to nonfatal myocardial infarction (MI) and stroke.
Methods and Findings
In the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), baseline inflammatory markers in up to 5,680 men and women aged 70–82 y were related to risk for endpoints; nonfatal CVD (i.e., nonfatal MI and nonfatal stroke [n = 672]), fatal CVD (n = 190), death from other CV causes (n = 38), and non-CVD mortality (n = 300), over 3.2-y follow-up. Elevations in baseline IL-6 levels were significantly (p = 0.0009; competing risks model analysis) more strongly associated with fatal CVD (hazard ratio [HR] for 1 log unit 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 analyses adjusted for treatment allocation. The findings were consistent in a fully adjusted model. These broad trends were similar for CRP and, to a lesser extent, for fibrinogen. The results were also similar in placebo and statin recipients (i.e., no interaction). The C-statistic for fatal CVD using traditional risk factors was significantly (+0.017; p<0.0001) improved by inclusion of IL-6 but not so for nonfatal CVD events (p = 0.20).
In PROSPER, inflammatory markers, in particular IL-6 and CRP, are more strongly associated with risk of fatal vascular events than nonfatal vascular events. These novel observations may have important implications for better understanding aetiology of CVD mortality, and have potential clinical relevance.
Please see later in the article for Editors' Summary
Editors' Summary
Cardiovascular disease (CVD)—disease that affects the heart and/or the blood vessels—is a common cause of death in developed countries. In the USA, for example, the leading cause of death is coronary heart disease (CHD), a CVD in which narrowing of the heart's blood vessels by “atherosclerotic plaques” (fatty deposits that build up with age) slows the blood supply to the heart and may eventually cause a heart attack (myocardial infarction). Other types of CVD include stroke (in which atherosclerotic plaques interrupt the brain's blood supply) and heart failure (a condition in which the heart cannot pump enough blood to the rest of the body). Smoking, high blood pressure, high blood levels of cholesterol (a type of fat), having diabetes, and being overweight all increase a person's risk of developing CVD. Tools such as the “Framingham risk calculator” take these and other risk factors into account to assess an individual's overall risk of CVD, which can be reduced by taking drugs to reduce blood pressure or cholesterol levels (for example, pravastatin) and by making lifestyle changes.
Why Was This Study Done?
Inflammation (an immune response to injury) in the walls of blood vessels is thought to play a role in the development of atherosclerotic plaques. Consistent with this idea, several epidemiological studies (investigations of the causes and distribution of disease in populations) have shown that people with high circulating levels of markers of inflammation such as interleukin-6 (IL-6), C-reactive protein (CRP), and fibrinogen are more likely to have a stroke or a heart attack (a CVD event) than people with low levels of these markers. Although these studies have generally lumped together fatal and nonfatal CVD events, some evidence suggests that circulating inflammatory markers may be more strongly associated with fatal than with nonfatal CVD events. If this is the case, the mechanisms that lead to fatal and nonfatal CVD events may be subtly different and knowing about these differences could improve both the prevention and treatment of CVD. In this study, the researchers investigate this possibility using data collected in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER; a trial that examined pravastatin's effect on CVD development among 70–82 year olds with pre-existing CVD or an increased risk of CVD because of smoking, high blood pressure, or diabetes).
What Did the Researchers Do and Find?
The researchers used several statistical models to examine the association between baseline levels of IL-6, CRP, and fibrinogen in the trial participants and nonfatal CVD events (nonfatal heart attacks and nonfatal strokes), fatal CVD events, death from other types of CVD, and deaths from other causes during 3.2 years of follow-up. Increased levels of all three inflammatory markers were more strongly associated with fatal CVD than with nonfatal CVD after adjustment for treatment allocation and for other established CVD risk factors but this pattern was strongest for IL-6. Thus, a unit increase in the log of IL-6 levels increased the risk of fatal CVD by half but increased the risk of nonfatal CVD by significantly less. The researchers also investigated whether including these inflammatory markers in tools designed to predict an individual's CVD risk could improve the tool's ability to distinguish between individuals with a high and low risk. The addition of IL-6 to established risk factors, they report, increased this discriminatory ability for fatal CVD but not for nonfatal CVD.
What Do These Findings Mean?
These findings indicate that, at least for the elderly at-risk patients who were included in PROSPER, inflammatory markers are more strongly associated with the risk of a fatal heart attack or stroke than with nonfatal CVD events. These findings need to be confirmed in younger populations and larger studies also need to be done to discover whether the same association holds when fatal heart attacks and fatal strokes are considered separately. Nevertheless, the present findings suggest that inflammation may specifically help to promote the development of serious, potentially fatal CVD and should stimulate improved research into the use of inflammation markers to predict risk of deaths from CVD.
Additional Information
Please access these Web sites via the online version of this summary at
The MedlinePlus Encyclopedia has pages on coronary heart disease, stroke, and atherosclerosis (in English and Spanish)
MedlinePlus provides links to many other sources of information on heart diseases, vascular diseases, and stroke (in English and Spanish)
Information for patients and caregivers is provided by the American Heart Association on all aspects of cardiovascular disease, including information on inflammation and heart disease
Information is available from the British Heart Foundation on heart disease and keeping the heart healthy
More information about PROSPER is available on the Web site of the Vascular Biochemistry Department of the University of Glasgow
PMCID: PMC2694359  PMID: 19554082
17.  Reduced Glomerular Filtration Rate and Its Association with Clinical Outcome in Older Patients at Risk of Vascular Events: Secondary Analysis 
PLoS Medicine  2009;6(1):e1000016.
Reduced glomerular filtration rate (GFR) is associated with increased cardiovascular risk in young and middle aged individuals. Associations with cardiovascular disease and mortality in older people are less clearly established. We aimed to determine the predictive value of the GFR for mortality and morbidity using data from the 5,804 participants randomized in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER).
Methods and Findings
Glomerular filtration rate was estimated (eGFR) using the Modification of Diet in Renal Disease equation and was categorized in the ranges ([20–40], [40–50], [50–60]) ≥ 60 ml/min/1.73 m2. Baseline risk factors were analysed by category of eGFR, with and without adjustment for other risk factors. The associations between baseline eGFR and morbidity and mortality outcomes, accrued after an average of 3.2 y, were investigated using Cox proportional hazard models adjusting for traditional risk factors. We tested for evidence of an interaction between the benefit of statin treatment and baseline eGFR status. Age, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, C-reactive protein (CRP), body mass index, fasting glucose, female sex, histories of hypertension and vascular disease were associated with eGFR (p = 0.001 or less) after adjustment for other risk factors. Low eGFR was independently associated with risk of all cause mortality, vascular mortality, and other noncancer mortality and with fatal and nonfatal coronary and heart failure events (hazard ratios adjusted for CRP and other risk factors (95% confidence intervals [CIs]) for eGFR < 40 ml/min/1.73m2 relative to eGFR ≥ 60 ml/min/1.73m2 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 were no nominally statistically significant interactions (p < 0.05) between randomized treatment allocation and eGFR for clinical outcomes, with the exception of the outcome of coronary heart disease death or nonfatal myocardial infarction (p = 0.021), with the interaction suggesting increased benefit of statin treatment in subjects with impaired GFRs.
We have established that, in an elderly population over the age of 70 y, impaired GFR is associated with female sex, with presence of vascular disease, and with levels of other risk factors that would be associated with increased risk of vascular disease. Further, impaired GFR is independently associated with significant levels of increased risk of all cause mortality and fatal vascular events and with composite fatal and nonfatal coronary and heart failure outcomes. Our analyses of the benefits of statin treatment in relation to baseline GFR suggest that there is no reason to exclude elderly patients with impaired renal function from treatment with a statin.
Using data from the PROSPER trial, Ian Ford and colleagues investigate whether reduced glomerular filtration rate is associated with cardiovascular and mortality risk among elderly people.
Editors' Summary
Cardiovascular disease (CVD)—disease that affects the heart and/or the blood vessels—is a common cause of death in developed countries. In the USA, for example, the single leading cause of death is coronary heart disease, a CVD in which narrowing of the heart's blood vessels slows or stops the blood supply to the heart and eventually causes a heart attack. Other types of CVD include stroke (in which narrowing of the blood vessels interrupts the brain's blood supply) and heart failure (a condition in which the heart can no longer pump enough blood to the rest of the body). Many factors increase the risk of developing CVD, including high blood pressure (hypertension), high blood cholesterol, having diabetes, smoking, and being overweight. Tools such as the “Framingham risk calculator” assess an individual's overall CVD risk by taking these and other risk factors into account. CVD risk can be minimized by taking drugs to reduce blood pressure or cholesterol levels (for example, pravastatin) and by making lifestyle changes.
Why Was This Study Done?
Another potential risk factor for CVD is impaired kidney (renal) function. In healthy people, the kidneys filter waste products and excess fluid out of the blood. A reduced “estimated glomerular filtration rate” (eGFR), which indicates impaired renal function, is associated with increased CVD in young and middle-aged people and increased all-cause and cardiovascular death in people who have vascular disease. But is reduced eGFR also associated with CVD and death in older people? If it is, it would be worth encouraging elderly people with reduced eGFR to avoid other CVD risk factors. In this study, the researchers determine the predictive value of eGFR for all-cause and vascular mortality (deaths caused by CVD) and for incident vascular events (a first heart attack, stroke, or heart failure) using data from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). This clinical trial examined pravastatin's effects on CVD development among 70–82 year olds with pre-existing vascular disease or an increased risk of CVD because of smoking, hypertension, or diabetes.
What Did the Researchers Do and Find?
The trial participants were divided into four groups based on their eGFR at the start of the study. The researchers then investigated the association between baseline CVD risk factors and baseline eGFR and between baseline eGFR and vascular events and deaths that occurred during the 3-year study. Several established CVD risk factors were associated with a reduced eGFR after allowing for other risk factors. In addition, people with a low eGFR (between 20 and 40 units) were twice as likely to die from any cause as people with an eGFR above 60 units (the normal eGFR for a young person is 100 units; eGFR decreases with age) and more than three times as likely to have nonfatal coronary heart disease or heart failure. A low eGFR also increased the risk of vascular mortality, other noncancer deaths, and fatal coronary heart disease and heart failure. Finally, pravastatin treatment reduced coronary heart disease deaths and nonfatal heart attacks most effectively among participants with the greatest degree of eGFR impairment.
What Do These Findings Mean?
These findings suggest that, in elderly people, impaired renal function is associated with levels of established CVD risk factors that increase the risk of vascular disease. They also suggest that impaired kidney function increases the risk of all-cause mortality, fatal vascular events, and fatal and nonfatal coronary heat disease and heart failure. Because the study participants were carefully chosen for inclusion in PROSPER, these findings may not be generalizable to all elderly people with vascular disease or vascular disease risk factors. Nevertheless, increased efforts should probably be made to encourage elderly people with reduced eGFR and other vascular risk factors to make lifestyle changes to reduce their overall CVD risk. Finally, although the effect of statins in elderly patients with renal dysfunction needs to be examined further, these findings suggest that this group of patients should benefit at least as much from statins as elderly patients with healthy kidneys.
Additional Information.
Please access these Web sites via the online version of this summary at
The MedlinePlus Encyclopedia has pages on coronary heart disease, stroke, and heart failure (in English and Spanish)
MedlinePlus provides links to many other sources of information on heart disease, vascular disease, and stroke (in English and Spanish)
The US National Institute of Diabetes and Digestive and Kidney Diseases provides information on how the kidneys work and what can go wrong with them, including a list of links to further information about kidney disease
The American Heart Association provides information on all aspects of cardiovascular disease for patients, caregivers, and professionals (in several languages)
More information about PROSPER is available on the Web site of the Vascular Biochemistry Department of the University of Glasgow
PMCID: PMC2628400  PMID: 19166266
18.  Psychological, social and biological determinants of ill health (pSoBid): Study Protocol of a population-based study 
BMC Public Health  2008;8:126.
Disadvantaged communities suffer higher levels of physical and mental ill health than more advantaged communities. The purpose of the present study was to examine the psychosocial, behavioural and biological determinants of ill health within population groups in Glasgow that differed in socioeconomic status and in their propensity to develop chronic disease especially coronary heart disease and Type 2 diabetes mellitus.
Participants were selected at random from areas known to be at the extremes of the socioeconomic continuum in Glasgow. Within the categories of least deprived and most deprived, recruitment was stratified by sex and age to achieve an overall sample containing approximately equal numbers of males and females and an even distribution across the age categories 35–44, 45–54 and 55–64 years. Individuals were invited by letter to attend for assessment of their medical history, risk factor status, cognitive function and psychological profile, morbidity, and carotid intima-media thickness and plaque count as indices of atherosclerosis. Anonymised data on study subjects were collected from the General Practice Administration System for Scotland to analyse characteristics of participants and non-participants.
700 subjects were recruited. The response (active participants per 100 invitation letters) in the least deprived group was 35.1% and in the most deprived group was 20.3%. Lowest response was seen in young males (least deprived 22.4% and most deprived 14.1%).
This cross-sectional study recruited the planned sample of subjects from least deprived and most deprived areas within Glasgow. As evident in other studies response differed between the most and least deprived areas. This study brought together researchers/academics from diverse disciplines to build a more sophisticated understanding of the determinants of health inequalities than can be achieved through unidisciplinary approaches. Future analyses will enable an understanding of the relationships between the different types of measure, and of the pathways that link poverty, biology, behaviour and psychology and lead to health inequalities.
PMCID: PMC2386810  PMID: 18426568
19.  A Prospective Study of Pravastatin in the Elderly at Risk (PROSPER): Screening Experience and Baseline Characteristics 
PROSPER was designed to investigate the benefits of treatment with pravastatin in elderly patients for whom a typical doctor might consider the prescription of statin therapy to be a realistic option.
The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) is a randomised, double blind, placebo-controlled trial to test the hypothesis that treatment with pravastatin (40 mg/day) will reduce the risk of coronary heart disease death, non-fatal myocardial infarction, and fatal or non-fatal stroke in elderly men and women with pre-existing vascular disease or with significant risk of developing this condition.
In Scotland, Ireland, and the Netherlands, 23,770 individuals were screened, and 5,804 subjects (2,804 men and 3,000 women), aged 70 to 82 years (average 75 years) and with baseline cholesterol 4.0–9.0 mmol/l, were randomised. Randomised subjects had similar distributions with respect to age, blood pressure, and body mass index when compared to the entire group of screenees, but had a higher prevalence of smoking, diabetes, hypertension, and a history of vascular disease. The average total cholesterol level at baseline was 5.4 mmol/l (men) and 6.0 mmol/l (women).
Compared with previous prevention trials of cholesterol-lowering drugs, the PROSPER cohort is significantly older and for the first time includes a majority of women. The study, having achieved its initial goal of recruiting more than 5,500 elderly high-risk men and women, aims to complete all final subject follow-up visits in the first half of 2002 with the main results being available in the fourth quarter of 2002.
PMCID: PMC134480  PMID: 12097148
clinical trial; elderly; pravastatin; baseline characteristics

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